Effects of phytoestrogens and environmental estrogens on osteoblastic differentiation in MC3T3-E1 cells.

PubMed

Kanno, Sanae; Hirano, Seishiro; Kayama, Fujio

2004-03-01

Phytoestrogens and environmental estrogens, which have in part some structural similarity to 17beta-estradiol, are reported to act as agonists/antagonists of estrogen in animals and humans. Estrogen is known to play an important role in maintaining bone mass, since the concentration of serum estrogen decreases after menopause and the estrogen deficiency results in bone loss. In this study, we report the effects of phytoestrogens (genistein, daidzein, and coumestrol) and environmental estrogens (bisphenol A (BPA), p-n-nonylphenol (NP) and bis(2-ethylhexyl)phthalate (DEHP)) on osteoblast differentiation using MC3T3-E1 cells, a mouse calvaria osteoblast-like cell line. Coumestrol (10(-10) to 10(-6)M) slightly enhanced cell proliferation, while neither the other phytoestrogens (daidzein, genistein) nor environmental estrogens increased cell proliferation. Alkaline phosphatase (ALP) activity and cellular calcium (Ca) and phosphorus (P) contents were increased by phytoestrogens and BPA; however, neither NP nor DEHP affected those osteoblastic indicators. The effects of estrogenic potency, using the cell proliferation of MCF-7 cells, an estrogen receptor (ER)-positive human breast cancer cell line, indicate that coumestrol has the highest estrogenic potency among those phytoestrogens and environmental estrogens. The estrogenic potency of NP and DEHP were lower than the others. In conclusion, phytoestrogens, such as coumestrol, genistein and daidzein, and BPA increased ALP activity and enhanced bone mineralization in MC3T3-E1 cells, suggesting that not only phytoestrogen but also BPA, an environmental estrogen, is implicated in bone metabolism.

Coexposure to phytoestrogens and bisphenol a mimics estrogenic effects in an additive manner.

PubMed

Katchy, Anne; Pinto, Caroline; Jonsson, Philip; Nguyen-Vu, Trang; Pandelova, Marchela; Riu, Anne; Schramm, Karl-Werner; Samarov, Daniel; Gustafsson, Jan-Åke; Bondesson, Maria; Williams, Cecilia

2014-03-01

Endocrine-disrupting chemicals (EDC) are abundant in our environment. A number of EDCs, including bisphenol A (BPA) can bind to the estrogen receptors (ER), ERα and ERβ, and may contribute to estrogen-linked diseases such as breast cancer. Early exposure is of particular concern; many EDCs cross the placenta and infants have measurable levels of, eg, BPA. In addition, infants are frequently fed soy-based formula (SF) that contains phytoestrogens. Effects of combined exposure to xeno- and phytoestrogens are poorly studied. Here, we extensively compared to what extent BPA, genistein, and an extract of infant SF mimic estrogen-induced gene transcription and cell proliferation. We investigated ligand-specific effects on ER activation in HeLa-ERα and ERβ reporter cells; on proliferation, genome-wide gene regulation and non-ER-mediated effects in MCF7 breast cancer cells; and how coexposure influenced these effects. The biological relevance was explored using enrichment analyses of differentially regulated genes and clustering with clinical breast cancer profiles. We demonstrate that coexposure to BPA and genistein, or SF, results in increased functional and transcriptional estrogenic effects. Using statistical modeling, we determine that BPA and phytoestrogens act in an additive manner. The proliferative and transcriptional effects of the tested compounds mimic those of 17β-estradiol, and are abolished by cotreatment with an ER antagonist. Gene expression profiles induced by each compound clustered with poor prognosis breast cancer, indicating that exposure may adversely affect breast cancer prognosis. This study accentuates that coexposure to BPA and soy-based phytoestrogens results in additive estrogenic effects, and may contribute to estrogen-linked diseases, including breast cancer.

Coexposure to Phytoestrogens and Bisphenol A Mimics Estrogenic Effects in an Additive Manner

PubMed Central

Katchy, Anne; Pinto, Caroline; Williams, Cecilia

2014-01-01

Endocrine-disrupting chemicals (EDC) are abundant in our environment. A number of EDCs, including bisphenol A (BPA) can bind to the estrogen receptors (ER), ERα and ERβ, and may contribute to estrogen-linked diseases such as breast cancer. Early exposure is of particular concern; many EDCs cross the placenta and infants have measurable levels of, eg, BPA. In addition, infants are frequently fed soy-based formula (SF) that contains phytoestrogens. Effects of combined exposure to xeno- and phytoestrogens are poorly studied. Here, we extensively compared to what extent BPA, genistein, and an extract of infant SF mimic estrogen-induced gene transcription and cell proliferation. We investigated ligand-specific effects on ER activation in HeLa-ERα and ERβ reporter cells; on proliferation, genome-wide gene regulation and non-ER–mediated effects in MCF7 breast cancer cells; and how coexposure influenced these effects. The biological relevance was explored using enrichment analyses of differentially regulated genes and clustering with clinical breast cancer profiles. We demonstrate that coexposure to BPA and genistein, or SF, results in increased functional and transcriptional estrogenic effects. Using statistical modeling, we determine that BPA and phytoestrogens act in an additive manner. The proliferative and transcriptional effects of the tested compounds mimic those of 17β-estradiol, and are abolished by cotreatment with an ER antagonist. Gene expression profiles induced by each compound clustered with poor prognosis breast cancer, indicating that exposure may adversely affect breast cancer prognosis. This study accentuates that coexposure to BPA and soy-based phytoestrogens results in additive estrogenic effects, and may contribute to estrogen-linked diseases, including breast cancer. PMID:24284790

Genistein and daidzein: different molecular effects on prostate cancer.

PubMed

Adjakly, Mawussi; Ngollo, Marjolaine; Boiteux, Jean-Paul; Bignon, Yves-Jean; Guy, Laurent; Bernard-Gallon, Dominique

2013-01-01

Diet is believed to play an important role in cancer. It has been revealed by epidemiological studies that Asian populations, who consume phytoestrogens in large amounts, have a lower incidence of prostate cancer in comparison with the Western world, where consumption of soy is lower. Genistein and daidzein, the soy phytoestrogens most widely studied, are believed to be potent anticancer agents and have been shown to possess anticancer properties. It has been shown that these compounds inhibit the growth of cancer cells through the modulation of genes controlling cell-cycle progression. Genistein inhibits the activation of the kappa light polypeptide gene enhancer in B-cells (NF-κB), signaling pathway, which is implicated in the balance between cell survival and programmed cell death (apoptosis). Antioxidant and antiangiogenesis properties of genistein have been also described. Soy isoflavones are also implicated in reversion of epigenetic events observed in prostate cancer. Significant advances have been made for understanding how soy isoflavones are implicated in protection against prostate cancer. However, more studies are needed to better-understand and elucidate all pathways mobilized by genistein and daidzein, in order to fully exploit their anticancer properties.

The differential effect of the phytoestrogen genistein on cardiovascular risk factors in postmenopausal women: relationship with the metabolic status.

PubMed

Villa, Paola; Costantini, Barbara; Suriano, Rosanna; Perri, Concetta; Macrì, Francesca; Ricciardi, Luigi; Panunzi, Simona; Lanzone, Antonio

2009-02-01

The wide family of the phytoestrogens has become an alternative to the classical hormonal therapy in menopause; nevertheless, some findings are still conflicting. To examine the effect of genistein administration on metabolic parameters and vascular reactivity considering the basal endocrine status of the patients. A randomized placebo controlled study was conducted at a university hospital. Fifty postmenopausal women participated. Thirty subjects (group A) were randomized to receive 54 mg/d genistein while 20 subjects (group B) were treated with the placebo for 24 wk. In group A, we distinguish two subgroups: 14 normoinsulinemic and 12 hyperinsulinemic patients. Anthropometric measures, hormonal and lipid assays, oral glucose tolerance test with glycemic, insulin, and C-peptide evaluation, indexes of insulin sensitivity and endothelial function, and euglycemic-hyperinsulinemic clamps were performed. The insulin basal values significantly decreased in group A, whereas the homeostasis model index of insulin sensitivity and the fasting glucose levels significantly improved compared with placebo group. The genistein administration decreased fasting glucose and area under the curve glucose levels in the normoinsulinemic patients after treatment. In the hyperinsulinemic patients, a significant reduction in fasting insulin, fasting C-peptide, and area under the curve insulin levels as well as an increase in fractional hepatic insulin extraction was shown. In these patients, high-density lipoprotein cholesterol levels were significantly improved. The endothelium-dependent and -independent dilatation improved in the treated group. Normoinsulinemic patients showed both a significantly enhanced flow-mediated and nitrate-mediated dilatation, whereas no significant changes were found in the hyperinsulinemic group. The glycoinsulinemic metabolism and the endothelial function were significantly influenced by genistein. In particular, normoinsulinemic patients showed an

Genistein exposure inhibits growth and alters steroidogenesis in adult mouse antral follicles

DOE Office of Scientific and Technical Information (OSTI.GOV)

Patel, Shreya, E-mail: Shreya.patel214@gmail.com; Peretz, Jackye, E-mail: Jackye.peretz@gmail.com; Pan, Yuan-Xiang, E-mail: yxpan@illinois.edu

Genistein is a naturally occurring isoflavone phytoestrogen commonly found in plant products such as soybeans, lentils, and chickpeas. Genistein, like other phytoestrogens, has the potential to mimic, enhance, or impair the estradiol biosynthesis pathway, thereby potentially altering ovarian follicle growth. Previous studies have inconsistently indicated that genistein exposure may alter granulosa cell proliferation and hormone production, but no studies have examined the effects of genistein on intact antral follicles. Thus, this study was designed to test the hypothesis that genistein exposure inhibits follicle growth and steroidogenesis in intact antral follicles. To test this hypothesis, antral follicles isolated from CD-1 micemore » were cultured with vehicle (dimethyl sulfoxide; DMSO) or genistein (6.0 and 36 μM) for 18–96 h. Every 24 h, follicle diameters were measured to assess growth. At the end of each culture period, the media were pooled to measure hormone levels, and the cultured follicles were collected to measure expression of cell cycle regulators and steroidogenic enzymes. The results indicate that genistein (36 μM) inhibits growth of mouse antral follicles. Additionally, genistein (6.0 and 36 μM) increases progesterone, testosterone, and dehydroepiandrosterone (DHEA) levels, but decreases estrone and estradiol levels. The results also indicate that genistein alters the expression of steroidogenic enzymes at 24, 72 and 96 h, and the expression of cell cycle regulators at 18 h. These data indicate that genistein exposure inhibits antral follicle growth by inhibiting the cell cycle, alters sex steroid hormone levels, and dysregulates steroidogenic enzymes in cultured mouse antral follicles. - Highlights: • Genistein exposure inhibits antral follicle growth. • Genistein exposure alters expression of cell cycle regulators. • Genistein exposure alters sex steroid hormones. • Genistein exposure alters expression of steroidogenic enzymes. �

Dietary Supplementation of Genistein Alleviates Liver Inflammation and Fibrosis Mediated by a Methionine-Choline-Deficient Diet in db/db Mice.

PubMed

Yoo, Na-young; Jeon, Sookyoung; Nam, Yerim; Park, Youn-Jin; Won, Sae Bom; Kwon, Young Hye

2015-05-06

Nonalcoholic fatty liver disease is a complex disorder which includes simple steatosis, steatohepatitis, fibrosis and ultimately cirrhosis. Previous studies have reported that genistein, a soy phytoestrogen, attenuates steatohepatitis induced in obese and type 2 diabetic models. Here we investigated the effect of dietary genistein supplementation (0.05%) on nonalcoholic steatohepatitis (NASH) development induced by a methionine-choline-deficient (MCD) diet in db/db mice. MCD-diet-fed mice exhibited a significantly lower body weight and a higher degree of steatohepatitis with increased oxidative stress, steatosis, inflammation, stellate cell activation, and mild fibrosis. Although genistein did not inhibit hepatic steatosis, we observed that oxidative stress, endoplasmic reticulum stress, and AMP-dependent kinase inactivation were alleviated by genistein. Genistein also down-regulated the augmented gene expressions associated with hepatic inflammation and fibrosis. Therefore, these results suggest that genistein may protect MCD-diet-mediated NASH development by suppressing lipid peroxidation, inflammation, and even liver fibrosis in db/db mice.

Genistein effects on stromal cells determines epithelial proliferation in endometrial co-cultures.

PubMed

Sampey, Brante P; Lewis, Terrence D; Barbier, Claire S; Makowski, Liza; Kaufman, David G

2011-06-01

Estrogen is the leading etiologic factor for endometrial cancer. Estrogen-induced proliferation of endometrial epithelial cells normally requires paracrine growth factors produced by stromal cells. Epidemiologic evidence indicates that dietary soy prevents endometrial cancer, and implicates the phytoestrogen genistein in this effect. However, results from previous studies are conflicting regarding the effects of genistein on hormone responsive cancers. The effects of estrogen and genistein on proliferation of Ishikawa (IK) endometrial adenocarcinoma cells were examined in co-cultures of IK cells with endometrial stromal cells, recapitulating the heterotypic cell-to-cell interactions observed in vivo. The roles of estrogen receptor (ER)α and ERβ were evaluated using ERα and ERβ specific agonists. ER activation and cell proliferation in the IK epithelial cells were determined by alkaline phosphatase assay and Coulter counter enumeration, respectively. Both estrogen and genistein increased estrogen receptor-induced gene activity in IK cells over a range of concentrations. Estrogen alone but not genistein increased IK proliferation in co-cultures. When primed by estrogen treatment, increasing concentrations of genistein produced a biphasic effect on IK proliferation: nM concentrations inhibited estrogen-induced proliferation while μM concentrations increased proliferation. Studies with an ERβ-specific agonist produced similar results. Genistein did not influence the effects of estrogen on IK proliferation in monoculture. Our study indicates that nutritionally relevant concentrations (nM) of genistein inhibit the proliferative effects of estrogen on endometrial adenocarcinoma cells presumably through activation of stromal cell ERβ. We believe that sub-micromolar concentrations of genistein may represent a novel adjuvant for endometrial cancer treatment and prevention. Copyright © 2011 Elsevier Inc. All rights reserved.

Improved serotonergic neurotransmission by genistein pretreatment regulates symptoms of obsessive-compulsive disorder in streptozotocin-induced diabetic mice.

PubMed

Phadnis, Pradeep; Dey Sarkar, Purnima; Rajput, Mithun Singh

2018-03-21

Initial evidences have shown that diabetes mellitus occurs concomitantly with obsessive-compulsive disorder (OCD) symptomatology. Serotonergic psychiatric therapy posits that serotonin is a central character in the management of OCD. Hence, it is worth investigating novel chemical entities affecting the serotonergic system for targeting OCD. An isoflavonoid phytoestrogen, genistein, has been recognized as of great pharmacological value especially for protecting neurodegeneration, depression (serotonin regulation), and diabetes. The effectiveness of genistein pretreatment on the symptoms of OCD in streptozotocin-induced diabetic mice is investigated in this study. We also evaluate the probable involvement of the serotonergic system. Groups of diabetic mice were treated with genistein at the dose of 5.0 and 10.0 mg/kg (intraperitoneal, twice daily, 14 days), and symptoms of OCD were assessed by the marble-burying behavior, in comparison with the standard drug fluoxetine. Neurochemical assessment of the serotonergic ratio 5-hydroxyindole-3-methoxyphenylacetic acid/5-hydroxytryptamine (5-HIAA/5-HT) in the cortical region of the brain was performed using HPLC (high-pressure liquid chromatography). Chronic treatment with genistein significantly recovered [F(6, 35)=53.00, p<0.0001, R2=0.9008] the symptoms of OCD as assessed by marble burying behavior in normal and diabetic mice. Locomotor performance was not influenced by the diabetic condition or any associated treatment. The turnover of serotonin neurotransmission (5-HIAA/5-HT) was significantly boosted in the diabetic condition; genistein treatment dragged it [F(6, 35)=35.75, p<0.0001, R2=0.8597] toward the respective control. Genistein supplementation might be a potential therapeutic line for the management and/or prevention of diabetes-associated OCD symptomatology.

Genome-wide DNA methylation modified by soy phytoestrogens: role for epigenetic therapeutics in prostate cancer?

PubMed

Karsli-Ceppioglu, Seher; Ngollo, Marjolaine; Adjakly, Mawussi; Dagdemir, Aslihan; Judes, Gaëlle; Lebert, André; Boiteux, Jean-Paul; Penault-LLorca, Frédérique; Bignon, Yves-Jean; Guy, Laurent; Bernard-Gallon, Dominique

2015-04-01

In prostate cancer, DNA methylation is significantly associated with tumor initiation, progression, and metastasis. Previous studies have suggested that soy phytoestrogens might regulate DNA methylation at individual candidate gene loci and that they play a crucial role as potential therapeutic agents for prostate cancer. The purpose of our study was to examine the modulation effects of phytoestrogens on a genome-wide scale in regards to DNA methylation in prostate cancer. Prostate cancer cell lines DU-145 and LNCaP were treated with 40 μM of genistein and 110 μM of daidzein. DNMT inhibitor 5-azacytidine (2 μM) and the methylating agent budesonide (2 μM) were used to compare their demethylation/methylation effects with phytoestrogens. The regulatory effects of phytoestrogens on DNA methylation were analyzed by using a methyl-DNA immunoprecipitation method coupled with Human DNA Methylation Microarrays (MeDIP-chip). We observed that the methylation profiles of 58 genes were altered by genistein and daidzein treatments in DU-145 and LNCaP prostate cancer cells. In addition, the methylation frequencies of the MAD1L1, TRAF7, KDM4B, and hTERT genes were remarkably modified by genistein treatment. Our results suggest that the modulation effects of phytoestrogens on DNA methylation essentially lead to inhibition of cell growth and induction of apoptosis. Genome-wide methylation profiling reported here suggests that epigenetic regulation mechanisms and, by extension, epigenetics-driven novel therapeutic candidates warrant further consideration in future "omics" studies of prostate cancer.

Dietary genistein stimulates mammary development in gilts

USDA-ARS?s Scientific Manuscript database

The possible role of the phytoestrogen, genistein, on prepubertal development of mammary glands, hormonal status and bone resorption was investigated in gilts. Forty-five gilts were fed a control diet containing soya (CTLS, n = 15), a control diet without soya (CTL0, n = 15) or the CTLS diet supplem...

Liver X receptor alpha mediated genistein induction of human dehydroepiandrosterone sulfotransferase (hSULT2A1) in Hep G2 cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chen, Yue; Zhang, Shunfen; Zhou, Tianyan

2013-04-15

Cytosolic sulfotransferases are one of the major families of phase II drug metabolizing enzymes. Sulfotransferase-catalyzed sulfonation regulates hormone activities, metabolizes drugs, detoxifies xenobiotics, and bioactivates carcinogens. Human dehydroepiandrosterone sulfotransferase (hSULT2A1) plays important biological roles by sulfating endogenous hydroxysteroids and exogenous xenobiotics. Genistein, mainly existing in soy food products, is a naturally occurring phytoestrogen with both chemopreventive and chemotherapeutic potential. Our previous studies have shown that genistein significantly induces hSULT2A1 in Hep G2 and Caco-2 cells. In this study, we investigated the roles of liver X receptor (LXRα) in the genistein induction of hSULT2A1. LXRs have been shown to induce expressionmore » of mouse Sult2a9 and hSULT2A1 gene. Our results demonstrate that LXRα mediates the genistein induction of hSULT2A1, supported by Western blot analysis results, hSULT2A1 promoter driven luciferase reporter gene assay results, and mRNA interference results. Chromatin immunoprecipitation (ChIP) assay results demonstrate that genistein increase the recruitment of hLXRα binding to the hSULT2A1 promoter. These results suggest that hLXRα plays an important role in the hSULT2A1 gene regulation. The biological functions of phytoestrogens may partially relate to their induction activity toward hydroxysteroid SULT. - Highlights: ► Liver X receptor α mediated genistein induction of hSULT2A1 in Hep G2 cells. ► LXRα and RXRα dimerization further activated this induction. ► Western blot results agreed well with luciferase reporter gene assay results. ► LXRs gene silencing significantly decreased hSULT2A1 expression. ► ChIP analysis suggested that genistein enhances hLXRα binding to the hSULT2A1 promoter.« less

Gas chromatographic–mass spectrometric fragmentation study of phytoestrogens as their trimethylsilyl derivatives: Identification in soy milk and wastewater samples

USGS Publications Warehouse

Ferrar, Imma; Barber, Larry B.; Thurman, E. Michael

2009-01-01

An analytical method for the identification of eight plant phytoestrogens (biochanin A, coumestrol, daidzein, equol, formononetin, glycitein, genistein and prunetin) in soy products and wastewater samples was developed using gas chromatography coupled with ion trap mass spectrometry (GC/MS–MS). The phytoestrogens were derivatized as their trimethylsilyl ethers with trimethylchlorosilane (TMCS) and N,O-bis(trimethylsilyl)trifluoroacetamide (BSTFA). The phytoestrogens were isolated from all samples with liquid–liquid extraction using ethyl acetate. Daidzein-d4 and genistein-d4 labeled standards were used as internal standards before extraction and derivatization. The fragmentation patterns of the phytoestrogens were investigated by isolating and fragmenting the precursor ions in the ion-trap and a typical fragmentation involved the loss of a methyl and a carbonyl group. Two characteristic fragment ions for each analyte were chosen for identification and confirmation. The developed methodology was applied to the identification and confirmation of phytoestrogens in soy milk, in wastewater effluent from a soy-milk processing plant, and in wastewater (influent and effluent) from a treatment plant. Detected concentrations of genistein ranged from 50,000 μg/L and 2000 μg/L in soy milk and in wastewater from a soy-plant, respectively, to 20 μg/L and <1 μg/L for influent and effluent from a wastewater treatment plant, respectively.

Phytoestrogens in menopausal supplements induce ER-dependent cell proliferation and overcome breast cancer treatment in an in vitro breast cancer model

DOE Office of Scientific and Technical Information (OSTI.GOV)

Duursen, Majorie B.M. van, E-mail: M.vanDuursen@uu.nl; Smeets, Evelien E.J.W.; Rijk, Jeroen C.W.

Breast cancer treatment by the aromatase inhibitor Letrozole (LET) or Selective Estrogen Receptor Modulator Tamoxifen (TAM) can result in the onset of menopausal symptoms. Women often try to relieve these symptoms by taking menopausal supplements containing high levels of phytoestrogens. However, little is known about the potential interaction between these supplements and breast cancer treatment, especially aromatase inhibitors. In this study, interaction of phytoestrogens with the estrogen receptor alpha and TAM action was determined in an ER-reporter gene assay (BG1Luc4E2 cells) and human breast epithelial tumor cells (MCF-7). Potential interactions with aromatase activity and LET were determined in human adrenocorticocarcinomamore » H295R cells. We also used the previously described H295R/MCF-7 co-culture model to study interactions with steroidogenesis and tumor cell proliferation. In this model, genistein (GEN), 8-prenylnaringenin (8PN) and four commercially available menopausal supplements all induced ER-dependent tumor cell proliferation, which could not be prevented by physiologically relevant LET and 4OH-TAM concentrations. Differences in relative effect potencies between the H295R/MCF-7 co-culture model and ER-activation in BG1Luc4E2 cells, were due to the effects of the phytoestrogens on steroidogenesis. All tested supplements and GEN induced aromatase activity, while 8PN was a strong aromatase inhibitor. Steroidogenic profiles upon GEN and 8PN exposure indicated a strong inhibitory effect on steroidogenesis in H295R cells and H295R/MCF-7 co-cultures. Based on our in vitro data we suggest that menopausal supplement intake during breast cancer treatment should better be avoided, at least until more certainty regarding the safety of supplemental use in breast cancer patients can be provided. - Highlights: • Supplements containing phytoestrogens are commonly used by women with breast cancer. • Phytoestrogens alter steroidogenesis in a co

Genistein inhibits voltage-gated sodium currents in SCG neurons through protein tyrosine kinase-dependent and kinase-independent mechanisms.

PubMed

Jia, Zhanfeng; Jia, Yueqin; Liu, Boyi; Zhao, Zhiying; Jia, Qingzhong; Liang, Huiling; Zhang, Hailin

2008-08-01

Voltage-gated sodium channels play a crucial role in the initiation and propagation of neuronal action potentials. Genistein, an isoflavone phytoestrogen, has long been used as a broad-spectrum inhibitor of protein tyrosine kinases (PTK). In addition, genistein-induced modulation of ion channels has been described previously in the literature. In this study, we investigated the effect of genistein on voltage-gated sodium channels in rat superior cervical ganglia (SCG) neurons. The results show that genistein inhibits Na(+) currents in a concentration-dependent manner, with a concentration of half-maximal effect (IC(50)) at 9.1 +/- 0.9 microM. Genistein positively shifted the voltage dependence of activation but did not affect inactivation of the Na(+) current. The inactive genistein analog daidzein also inhibited Na(+) currents, but was less effective than genistein. The IC(50) for daidzein-induced inhibition was 20.7 +/- 0.1 microM. Vanadate, an inhibitor of protein tyrosine phosphatases, partially but significantly reversed genistein-induced inhibition of Na(+) currents. Other protein tyrosine kinase antagonists such as tyrphostin 23, an erbstatin analog, and PP2 all had small but significant inhibitory effects on Na(+) currents. Among all active and inactive tyrosine kinase inhibitors tested, genistein was the most potent inhibitor of Na(+) currents. These results suggest that genistein inhibits Na(+) currents in rat SCG neurons through two distinct mechanisms: protein tyrosine kinase-independent, and protein tyrosine kinase-dependent mechanisms. Furthermore, the Src kinase family may be involved in the basal phosphorylation of the Na(+) channel.

Genistein treatment increases bone mass in obese, hyperglycemic mice

PubMed Central

Michelin, Richard M; Al-Nakkash, Layla; Broderick, Tom L; Plochocki, Jeffrey H

2016-01-01

Background Obesity and type 2 diabetes mellitus are associated with elevated risk of limb bone fracture. Incidences of these conditions are on the rise worldwide. Genistein, a phytoestrogen, has been shown by several studies to demonstrate bone-protective properties and may improve bone health in obese type 2 diabetics. Methods In this study, we test the effects of genistein treatment on limb bone and growth plate cartilage histomorphometry in obese, hyperglycemic ob/ob mice. Six-week-old ob/ob mice were divided into control and genistein-treated groups. Genistein-treated mice were fed a diet containing 600 mg genistein/kg for a period of 4 weeks. Cross-sectional geometric and histomorphometric analyses were conducted on tibias. Results Genistein-treated mice remained obese and hyperglycemic. However, histomorphometric comparisons show that genistein-treated mice have greater tibial midshaft diameters and ratios of cortical bone to total tissue area than the controls. Genistein-treated mice also exhibit decreased growth plate thickness of the proximal tibia. Conclusion Our results indicate that genistein treatment affects bone of the tibial midshaft in the ob/ob mouse, independent of improvements in the hyperglycemic state and body weight. PMID:27042131

Genistein treatment increases bone mass in obese, hyperglycemic mice.

PubMed

Michelin, Richard M; Al-Nakkash, Layla; Broderick, Tom L; Plochocki, Jeffrey H

2016-01-01

Obesity and type 2 diabetes mellitus are associated with elevated risk of limb bone fracture. Incidences of these conditions are on the rise worldwide. Genistein, a phytoestrogen, has been shown by several studies to demonstrate bone-protective properties and may improve bone health in obese type 2 diabetics. In this study, we test the effects of genistein treatment on limb bone and growth plate cartilage histomorphometry in obese, hyperglycemic ob/ob mice. Six-week-old ob/ob mice were divided into control and genistein-treated groups. Genistein-treated mice were fed a diet containing 600 mg genistein/kg for a period of 4 weeks. Cross-sectional geometric and histomorphometric analyses were conducted on tibias. Genistein-treated mice remained obese and hyperglycemic. However, histomorphometric comparisons show that genistein-treated mice have greater tibial midshaft diameters and ratios of cortical bone to total tissue area than the controls. Genistein-treated mice also exhibit decreased growth plate thickness of the proximal tibia. Our results indicate that genistein treatment affects bone of the tibial midshaft in the ob/ob mouse, independent of improvements in the hyperglycemic state and body weight.

Genistein attenuates brain damage induced by transient cerebral ischemia through up-regulation of ERK activity in ovariectomized mice.

PubMed

Wang, Shiquan; Wei, Haidong; Cai, Min; Lu, Yan; Hou, Wugang; Yang, Qianzi; Dong, Hailong; Xiong, Lize

2014-01-01

Stroke has severe consequences in postmenopausal women. As replacement therapy of estrogen have various adverse effects and the undermined outcomes. Genistein, a natural phytoestrogen, has been suggested to be a potential neuroprotective agent for such stroke patients. However, the role of genistein and its underlying mechanism in ovariectomized mice has not yet been evaluated. In the present study, ovariectomized mice were treated with genistein (10 mg/kg) or vehicle daily for two weeks before developing transient cerebral ischemia (middle cerebral artery occlusion). The neurological manifestation was evaluated, and infarct volumes were demonstrated by 2,3,5-triphenyltetrazolium chloride staining at 24 h after reperfusion. In addition, phosphorylation of extracellular signal-regulated kinase (ERK) was detected by Western blotting and immunofluorescence staining, and cellular apoptosis was evaluated in the ischemic penumbra. We found that treatment with genistein reduced infarct volumes, improved neurological outcomes and attenuated cellular apoptosis at 24 h after reperfusion. ERK1/2 showed increased phosphorylation by genistein treatment after reperfusion, and an ERK1/2 inhibitor U0126 abolished this protective effect of genistein in terms of infarct volumes, neurological scores and cellular apoptosis. Our findings indicate that treatment with genistein can reduce the severity of subsequent stroke episodes, and that this beneficial function is associated with ERK activation.

Suppression of T cell-induced osteoclast formation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Karieb, Sahar; Fox, Simon W., E-mail: Simon.fox@plymouth.ac.uk

2013-07-12

Highlights: •Genistein and coumestrol prevent activated T cell induced osteoclast formation. •Anti-TNF neutralising antibodies prevent the pro-osteoclastic effect of activated T cells. •Phytoestrogens inhibit T cell derived TNF alpha and inflammatory cytokine production. •Phytoestrogens have a broader range of anti-osteoclastic actions than other anti-resorptives. -- Abstract: Inhibition of T cell derived cytokine production could help suppress osteoclast differentiation in inflammatory skeletal disorders. Bisphosphonates are typically prescribed to prevent inflammatory bone loss but are not tolerated by all patients and are associated with an increased risk of osteonecrosis of the jaw. In light of this other anti-resorptives such as phytoestrogens aremore » being considered. However the effect of phytoestrogens on T cell-induced osteoclast formation is unclear. The effect of genistein and coumestrol on activated T cell-induced osteoclastogenesis and cytokine production was therefore examined. Concentrations of genistein and coumestrol (10{sup −7} M) previously shown to directly inhibit osteoclast formation also suppressed the formation of TRAP positive osteoclast induced by con A activated T cells, which was dependent on inhibition of T cell derived TNF-α. While both reduced osteoclast formation their mechanism of action differed. The anti-osteoclastic effect of coumestrol was associated with a dual effect on con A induced T cell proliferation and activation; 10{sup −7} M coumestrol significantly reducing T cell number (0.36) and TNF-α (0.47), IL-1β (0.23) and IL-6 (0.35) expression, whereas genistein (10{sup −7} M) had no effect on T cell number but a more pronounced effect on T cell differentiation reducing expression of TNF-α (0.49), IL-1β (0.52), IL-6 (0.71) and RANKL (0.71). Phytoestrogens therefore prevent the pro-osteoclastic action of T cells suggesting they may have a role in the control of inflammatory bone loss.« less

Effects of genistein in the maternal diet on reproductive development and spatial learning in male rats.

PubMed

Ball, Evan R; Caniglia, Mary Kay; Wilcox, Jenna L; Overton, Karla A; Burr, Marra J; Wolfe, Brady D; Sanders, Brian J; Wisniewski, Amy B; Wrenn, Craige C

2010-03-01

Endocrine disruptors, chemicals that disturb the actions of endogenous hormones, have been implicated in birth defects associated with hormone-dependent development. Phytoestrogens are a class of endocrine disruptors found in plants. In the current study we examined the effects of exposure at various perinatal time periods to genistein, a soy phytoestrogen, on reproductive development and learning in male rats. Dams were fed genistein-containing (5 mg/kg feed) food during both gestation and lactation, during gestation only, during lactation only, or during neither period. Measures of reproductive development and body mass were taken in the male offspring during postnatal development, and learning and memory performance was assessed in adulthood. Genistein exposure via the maternal diet decreased body mass in the male offspring of dams fed genistein during both gestation and lactation, during lactation only, but not during gestation only. Genistein decreased anogenital distance when exposure was during both gestation and lactation, but there was no effect when exposure was limited to one of these time periods. Similarly, spatial learning in the Morris water maze was impaired in male rats exposed to genistein during both gestation and lactation, but not in rats exposed during only one of these time periods. There was no effect of genistein on cued or contextual fear conditioning. In summary, the data indicate that exposure to genistein through the maternal diet significantly impacts growth in male offspring if exposure is during lactation. The effects of genistein on reproductive development and spatial learning required exposure throughout the pre- and postnatal periods. Copyright 2009 Elsevier Inc. All rights reserved.

The effect of zinc and phytoestrogen supplementation on the changes in mineral content of the femur of rats with chemically induced mammary carcinogenesis.

PubMed

Skrajnowska, Dorota; Korczak, Barbara Bobrowska-; Tokarz, Andrzej; Kazimierczuk, Agata; Klepacz, Marta; Makowska, Justyna; Gadzinski, Blazej

2015-10-01

The aim of this study was to assess skeletal effects of zinc or zinc with phytoestrogen (resveratrol or genistein) supplementation in an animal model of rats with DMBA-induced mammary carcinogenesis. The changes in bone parameters such as the length and mass were examined, as well as the changes in concentrations of selected minerals: calcium, magnesium, zinc, iron and phosphorus. Moreover, the investigations focused on finding the differences between the levels of iron and zinc in other tissues: the liver, spleen and serum of the examined rats. Fifty-six female Sprague-Dawley rats, 40 days old, were divided into four groups, regardless of the diets: standard (77mg Zn kg/food), zinc (4.6mg/mL via gavage), zinc (4.6mg/mL) plus resveratrol (0.2mg/kgbw), and zinc (4.6mg/mL) plus genistein (0.2mg/kgbw) for a period from 40 days until 20 weeks of age. The study rats were also treated with 7,12-dimethyl-1,2-benz[a]anthracene (DMBA) to induce mammary carcinogenesis. The applied diet and the advanced mammary cancer did not affect macrometric parameters of the rats' bones, but they strongly affected their mineral content. It was found that mammary cancer, irrespectively of the applied diet, significantly modified the iron level in the femur, liver, spleen and serum of the examined rats. In addition, zinc supplementation significantly lowered the levels of calcium, magnesium and phosphorus in the femur of rats with mammary cancer as compared with respective levels in the control group. So, it was found that additional supplementation with zinc, which is generally considered to be an antioxidant, with the co-existing mammary carcinoma, increased the unfavorable changes as concerns the stability of bone tissue. The appropriate combination of zinc and phytoestrogens (resveratrol or genistein) could help prevent or slow bone loss associated with a range of skeletal disorders in breast cancer. Copyright © 2015 Elsevier GmbH. All rights reserved.

Uterine adenocarcinoma in mice treated neonatally with genistein.

PubMed

Newbold, R R; Banks, E P; Bullock, B; Jefferson, W N

2001-06-01

The developing fetus is uniquely sensitive to perturbation with estrogenic chemicals. The carcinogenic effect of prenatal exposure to diethylstilbestrol (DES) is the classic example. Because phytoestrogen use in nutritional and pharmaceutical applications for infants and children is increasing, we investigated the carcinogenic potential of genistein, a naturally occurring plant estrogen in soy, in an experimental animal model previously reported to result in a high incidence of uterine adenocarcinoma after neonatal DES exposure. Outbred female CD-1 mice were treated on days 1-5 with equivalent estrogenic doses of DES (0.001 mg/kg/day) or genistein (50 mg/kg/day). At 18 months, the incidence of uterine adenocarcinoma was 35% for genistein and 31% for DES. These data suggest that genistein is carcinogenic if exposure occurs during critical periods of differentiation. Thus, the use of soy-based infant formulas in the absence of medical necessity and the marketing of soy products designed to appeal to children should be closely examined.

Antagonistic effects of gestational dietary exposure to low-dose vinclozolin and genistein on rat fetal germ cell development.

PubMed

Lehraiki, Abdelali; Messiaen, Sébastien; Berges, Raymond; Canivenc-Lavier, Marie-Chantal; Auger, Jacques; Habert, René; Levacher, Christine

2011-05-01

Continuous, low-dose exposure to a phytoestrogen (1 mg/kg/day genistein) and/or to an antiandrogenic food contaminant (1 mg/kg/day vinclozolin) has been recently reported to affect male reproductive tract and fertility [1] in adults. We investigated whether alterations of the testis are already present at the end of in utero exposure using the same rat model and doses following exposure from conception to delivery. After vinclozolin exposure, we observed in the neonate a slight but significant alteration of steroidogenesis and gametogenesis with a reduction of testosterone secretion and of the number of gonocytes. In contrast, genistein exposure had no effect. While the vinclozolin-genistein mixture acts in a synergistic manner to induce the most significant alterations in the adult, interestingly, genistein antagonized the deleterious effect of vinclozolin on germ cells in the neonate. This difference emphasizes the importance of studying the effects of endocrine disruptors during various developmental stages to understand their effects. Copyright © 2011 Elsevier Inc. All rights reserved.

Solubilization of Genistein in Poly(Ethylene Glycol) via Eutectic Crystal Melting

NASA Astrophysics Data System (ADS)

Buddhiranon, Sasiwimon; Kyu, Thein

2012-02-01

Genistein (5,7,4'-trihydroxyisoflavone) is a phytoestrogen found in soybean. It possesses various biological/pharmacological functions, e.g., tyrosine kinase inhibitory, anticarcinogenic, antioxidant, anti-inflammatory, and anti-microbial activities. However, genistein has poor water solubility and skin permeability, which have seemingly prohibited the progress to preclinical evaluation. Eutectic melting approach has been performed as a means of solubilizing genistein in poly(ethylene glycol) (PEG). Eutectic phase diagrams of blends containing genistein and PEG having three different molecular weights, i.e., 44k, 7k, and 500 g/mol, were established by means of DSC and compared with the theoretical liquidus and solidus lines, calculated self-consistently by taking into consideration all interactions including amorphous-amorphous, crystal-amorphous, amorphous-crystal, and crystal-crystal interactions. The eutectic temperatures were found to decrease with decreasing molecular weight of PEG. Guided by the phase diagram, it was found that genistein can be dissolved in PEG500 up to ˜7 wt% at room temperature. More importantly, the solubility of genistein in PEG can be improved to meet the end-use criteria of the PEG/genistein mixtures.

Endogenous estrogen status, but not genistein supplementation, modulates 7,12-dimethylbenz[a]anthracene-induced mutation in the liver cII gene of transgenic big blue rats.

PubMed

Chen, Tao; Hutts, Robert C; Mei, Nan; Liu, Xiaoli; Bishop, Michelle E; Shelton, Sharon; Manjanatha, Mugimane G; Aidoo, Anane

2005-06-01

A growing number of studies suggest that isoflavones found in soybeans have estrogenic activity and may safely alleviate the symptoms of menopause. One of these isoflavones, genistein, is commonly used by postmenopausal women as an alternative to hormone replacement therapy. Although sex hormones have been implicated as an important risk factor for the development of hepatocellular carcinoma, there are limited data on the potential effects of the estrogens, including phytoestrogens, on chemical mutagenesis in liver. Because of the association between mutation induction and the carcinogenesis process, we investigated whether endogenous estrogen and supplemental genistein affect 7,12-dimethylbenz[a]anthracene (DMBA)-induced mutagenesis in rat liver. Intact and ovariectomized female Big Blue rats were treated with 80 mg DMBA/kg body weight. Some of the rats also received a supplement of 1,000 ppm genistein. Sixteen weeks after the carcinogen treatment, the rats were sacrificed, their livers were removed, and mutant frequencies (MFs) and types of mutations were determined in the liver cII gene. DMBA significantly increased the MFs in liver for both the intact and ovariectomized rats. While there was no significant difference in MF between the ovariectomized and intact control animals, the mutation induction by DMBA in the ovariectomized groups was significantly higher than that in the intact groups. Dietary genistein did not alter these responses. Molecular analysis of the mutants showed that DMBA induced chemical-specific types of mutations in the liver cII gene. These results suggest that endogenous ovarian hormones have an inhibitory effect on liver mutagenesis by DMBA, whereas dietary genistein does not modulate spontaneous or DMBA-induced mutagenesis in either intact or ovariectomized rats.

The Role of Soy Phytoestrogens on Genetic and Epigenetic Mechanisms of Prostate Cancer.

PubMed

Karsli-Ceppioglu, Seher; Ngollo, Marjolaine; Judes, Gaëlle; Penault-LLorca, Frédérique; Bignon, Yves-Jean; Guy, Laurent; Bernard-Gallon, Dominique

2015-01-01

Soy phytoestrogens are dietary components with considerable effects on reducing the incidence of prostate cancer. Epidemiological studies demonstrated that occurrence of prostate cancer is relatively low in Asia and Southern Europe, a status associated with consuming of soy isoflavones, such as genistein, daidzein, and glycitein. Soy phytoestrogens exert their activity on molecular mechanisms, including cell-cycle control, induction of apoptosis, inhibition of angiogenesis, and metastasis. In addition, they have antioxidant activity and show regulatory effect on the expression of genes involved in DNA damage and repair. Furthermore, the epigenetic regulation of gene expression can be modified by soy phytoestrogens. They show regulatory effects on gene activity by altering DNA methylation and/or histone modification patterns. In this chapter, we discuss the role of soy phytoestrogens on the genetic and epigenetic mechanisms of prostate cancer. We attempt to provide further insight in order to understand the underlying mechanisms of protective effects of soy phytoestrogens in preventing prostate cancer. © 2015 Elsevier Inc. All rights reserved.

Overlapping but distinct effects of genistein and ethinyl estradiol (EE2) in female Sprague-Dawley rats in multigenerational reproductive and chronic toxicity studies

PubMed Central

Delclos, K. Barry; Weis, Constance C.; Bucci, Thomas J.; Olson, Greg; Mellick, Paul; Sadovova, Natalya; Latendresse, John R.; Thorn, Brett; Newbold, Retha R.

2009-01-01

Genistein and ethinyl estradiol (EE2) were examined in multigenerational reproductive and chronic toxicity studies that had different treatment intervals among generations. Sprague-Dawley rats received genistein (0, 5, 100, or 500 ppm) or EE2 (0, 2, 10, or 50 ppb) in a low phytoestrogen diet. Nonneoplastic effects in females are summarized here. Genistein at 500 ppm and EE2 at 50 ppb produced similar effects in continuously exposed rats, including decreased body weights, accelerated vaginal opening, and altered estrous cycles in young animals. At the high dose, anogenital distance was subtly affected by both compounds, and a reduction in litter size was evident in genistein-treated animals. Genistein at 500 ppm induced an early onset of aberrant cycles relative to controls in the chronic studies. EE2 significantly increased the incidence of uterine lesions (atypical focal hyperplasia and squamous metaplasia). These compound-specific effects appeared to be enhanced in the offspring of prior exposed generations. PMID:19159674

Diverse Effects of Phytoestrogens on the Reproductive Performance: Cow as a Model

PubMed Central

Wocławek-Potocka, Izabela; Mannelli, Chiara; Boruszewska, Dorota; Kowalczyk-Zieba, Ilona; Waśniewski, Tomasz; Skarżyński, Dariusz J.

2013-01-01

Phytoestrogens, polyphenolic compounds derived from plants, are more and more common constituents of human and animal diets. In most of the cases, these chemicals are much less potent than endogenous estrogens but exert their biological effects via similar mechanisms of action. The most common source of phytoestrogen exposure to humans as well as ruminants is soybean-derived foods that are rich in the isoflavones genistein and daidzein being metabolized in the digestive tract to even more potent metabolites—para-ethyl-phenol and equol. Phytoestrogens have recently come into considerable interest due to the increasing information on their adverse effects in human and animal reproduction, increasing the number of people substituting animal proteins with plant-derived proteins. Finally, the soybean becomes the main source of protein in animal fodder because of an absolute prohibition of bone meal use for animal feeding in 1995 in Europe. The review describes how exposure of soybean-derived phytoestrogens can have adverse effects on reproductive performance in female adults. PMID:23710176

Influence of long-term dietary administration of procymidone, a fungicide with anti-androgenic effects, or the phytoestrogen genistein to rats on the pituitary-gonadal axis and Leydig cell steroidogenesis.

PubMed

Svechnikov, K; Supornsilchai, V; Strand, M-L; Wahlgren, A; Seidlova-Wuttke, D; Wuttke, W; Söder, O

2005-10-01

Procymidone is a fungicide with anti-androgenic properties, widely used to protect fruits from fungal infection. Thereby it contaminates fruit products prepared for human consumption. Genistein-containing soy products are increasingly used as food additives with health-promoting properties. Therefore we examined the effects of long-term dietary administration (3 months) of the anti-androgen procymidone (26.4 mg/animal per day) or the phytoestrogen genistein (21.1 mg/animal per day) to rats on the pituitary-gonadal axis in vivo, as well as on Leydig cell steroidogenesis and on spermatogenesis ex vivo. The procymidone-containing diet elevated serum levels of LH and testosterone and, furthermore, Leydig cells isolated from procymidone-treated animals displayed an enhanced capacity for producing testosterone in response to stimulation by hCG or dibutyryl cAMP, as well as elevated expression of steroidogenic acute regulatory protein (StAR), cytochrome P450 side-chain cleavage (P450 scc) and cytochrome P450 17alpha (P450c17). In contrast, the rate of DNA synthesis during stages VIII and IX of spermatogenesis in segments of seminiferous tubules isolated from genistein-treated rats was decreased without accompanying changes in the serum level of either LH or testosterone. Nonetheless, genistein did suppress the ex vivo steroidogenic response of Leydig cells to hCG or dibutyryl cAMP by down-regulating their expression of P450 scc. Considered together, our present findings demonstrate that long-term dietary administration of procymidone or genistein to rats exerts different effects on the pituitary-gonadal axis in vivo and on Leydig cell steroidogenesis ex vivo. Possibly as a result of disruption of hormonal feedback control due to its anti-androgenic action, procymidone activates this endocrine axis, thereby causing hyper-gonadotropic activation of testicular steroidogenesis. In contrast, genistein influences spermatogenesis and significantly inhibits Leydig cell

Effect of genistein on endothelial function in postmenopausal women: a randomized, double-blind, controlled study.

PubMed

Squadrito, Francesco; Altavilla, Domenica; Crisafulli, Alessandra; Saitta, Antonino; Cucinotta, Domenico; Morabito, Nunziata; D'Anna, Rosario; Corrado, Francesco; Ruggeri, Pietro; Frisina, Nicola; Squadrito, Giovanni

2003-04-15

Genistein, a phytoestrogen found in soybeans, corrects endothelial dysfunction induced by oophorectomy in animals. Using a double-blind, controlled, randomized design, we evaluated its effects on endothelial function in women. We enrolled 79 healthy postmenopausal women (mean [+/- SD] age, 56 +/- 4 years) and randomly assigned them to receive continuous estrogen/progestin therapy (n = 26; 17beta-estradiol [1 mg/d] combined with norethisterone acetate [0.5 mg/d]), genistein (n = 27; 54 mg/d), or placebo (n = 26). Brachial artery flow-mediated, endothelium-dependent vasodilation and plasma levels of nitrites/nitrates (a marker of nitric oxide metabolism) and endothelin-1 were measured at baseline and after 1 year of therapy. Treatment with genistein increased levels of nitrites/nitrates (mean increase, 21 micromol/L; 95% confidence interval [CI]: 15 to 26 micromol/L; P <0.001 vs. placebo); estrogen/progestin therapy caused similar changes (P <0.001 vs. placebo). Plasma endothelin-1 levels decreased following 12 months of genistein (mean decrease, 7 pg/mL; 95% CI: 3 to 10 pg/mL; P <0.001 vs. placebo) and after 12 months of estrogen/progestin (P <0.001 vs. placebo). When compared with placebo, brachial artery flow-mediated dilation was improved by genistein (mean increase, 5.5%; 95% CI: 3.9% to 7.0%; P <0.001) and by estrogen/progestin (P <0.001). There were no significant differences between estrogen and genistein for any of these parameters (all P >0.4). One year of genistein therapy improves endothelium function in postmenopausal women to a similar extent as does an estrogen/progestin regimen.

Effects of phytoestrogens derived from soy bean on expression of adhesion molecules on HUVEC.

PubMed

Andrade, C M de; Sá, M F Silva de; Toloi, M R Torqueti

2012-04-01

The risks of hormone replacement therapy have led to a search for new alternatives such as phytoestrogens, plant compounds with estrogen-like biological activity. Isoflavones are the phytoestrogens most extensively studied and can be found in soybean, red clover and other plants. Due to this estrogen-like activity, phytoestrogens can have some effect on atherosclerosis. Human umbilical vein endothelial cells (HUVEC) have been extensively used to study the biology and pathobiology of human endothelial cells and most of the knowledge acquired is due to experiments with cultures of these cells. To evaluate the effects of the phytoestrogen extracts from Glycine max soy bean, genistein, formononetin, biochanin A and daidzein, as well as a mixture of these extracts (Mix), on expression of adhesion molecules, VCAM-1, ICAM-1 and E-selectin, by endothelial cell HUVEC, stimulated with lipopolysaccharide. HUVEC were cultured in medium EBM(2), pretreated with isoflavones for 24 and 48 h and then stimulated with lipopolysaccharide; in addition, isoflavones were added, after stimulation by lipopolysaccharide, to HUVEC. We evaluated the production of VCAM-1, ICAM-1 and E-selectin on cell surface, by cell-based enzyme immunoassay, and of sVCAM-1, sICAM-1 and sE-selectin in culture supernatant, by ELISA. Genistein, formononetin, biochanin A and daidzein, as well as the Mix were able to reduce VCAM-1, ICAM-1 and E-selectin on cell surface and in culture supernatant. Conclusion Isoflavones extracted from Glycine max soy bean, in vitro, presented antiatherogenic effects, reducing the expression of adhesion molecules and acting as preventive agents as well as therapeutic agents.

Acute genistein treatment mimics the effects of estradiol by enhancing place learning and impairing response learning in young adult female rats

PubMed Central

Pisani, Samantha L.; Neese, Steven L.; Doerge, Daniel R.; Helferich, William G.; Schantz, Susan L.; Korol, Donna L.

2012-01-01

Endogenous estrogens have bidirectional effects on learning and memory, enhancing or impairing cognition depending on many variables, including the task and the memory systems that are engaged. Moderate increases in estradiol enhance hippocampus-sensitive place learning, yet impair response learning that taps dorsal striatum function. This memory modulation likely occurs via activation of estrogen receptors, resulting in altered neural function. Supplements containing estrogenic compounds from plants are widely consumed despite limited information about their effects on brain function, including learning and memory. Phytoestrogens can enter the brain and signal through estrogen receptors to affect cognition. Enhancements in spatial memory and impairments in executive function have been found following treatment with soy phytoestrogens, but no tests of actions on striatum-sensitive tasks have been made to date. The present study compared the effects of acute exposure to the isoflavone genistein with the effects of estradiol on performance in place and response learning tasks. Long-Evans rats were ovariectomized, treated with 17β-estradiol benzoate, genistein-containing sucrose pellets, or vehicle (oil or plain sucrose pellets) for two days prior to behavioral training. Compared to vehicle controls, estradiol treatment enhanced place learning at a low (4.5 μg/kg) but not high dose (45 μg/kg), indicating an inverted pattern of spatial memory facilitation. Treatment with 4.4 mg of genistein over two days also significantly enhanced place learning over vehicle controls. For the response task, treatment with estradiol impaired learning at both the low and high doses; likewise, genistein treatment impaired response learning compared to rats receiving vehicle. Overall, genistein was found to mimic estradiol-induced shifts in place and response learning, facilitating hippocampus-sensitive learning and slowing striatum-sensitive learning. These results suggest signaling

The phytoestrogen genistein enhances multidrug resistance in breast cancer cell lines by translational regulation of ABC transporters.

PubMed

Rigalli, Juan Pablo; Tocchetti, Guillermo Nicolás; Arana, Maite Rocío; Villanueva, Silvina Stella Maris; Catania, Viviana Alicia; Theile, Dirk; Ruiz, María Laura; Weiss, Johanna

2016-06-28

Breast cancer is the most frequent malignancy in women. Multidrug resistance due to overexpression of ABC drug transporters is a common cause of chemotherapy failure and disease recurrence. Genistein (GNT) is a phytoestrogen present in soybeans and hormone supplements. We investigated the effect of GNT on the expression and function of ABC transporters in MCF-7 and MDA-MB-231 breast cancer cell lines. Results demonstrated an induction at the protein level of ABCC1 and ABCG2 and of ABCC1 in MCF-7 and MDA-MB-231, respectively. MCF-7 cells showed a concomitant increase in doxorubicin and mitoxantrone efflux and resistance, dependent on ABCG2 activity. ABCC1 induction by GNT in MDA-MB-231 cells modified neither drug efflux nor chemoresistance due to simultaneous acute inhibition of the transporter activity by GNT. All inductions took place at the translational level, as no increment in mRNA was observed and protein increase was prevented by cycloheximide. miR-181a, already demonstrated to inhibit ABCG2 translation, was down-regulated by GNT, explaining translational induction. Effects were independent of classical estrogen receptors. Results suggest potential nutrient-drug interactions that could threaten chemotherapy efficacy, especially in ABCG2-expressing tumors treated with substrates of this transporter. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Genistein promotes DNA demethylation of the steroidogenic factor 1 (SF-1) promoter in endometrial stromal cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Matsukura, Hiroshi, E-mail: hmatsukura.epi@mri.tmd.ac.jp; Aisaki, Ken-ichi; Igarashi, Katsuhide

2011-08-26

Highlights: {yields} Genistein (GEN) is a phytoestrogen found in soy products. {yields} GEN demethylated/unsilenced the steroidogenic factor 1 gene in endometrial tissue. {yields} GEN thus altered mRNA expression in uteri of ovariectomized (OVX) mice. {yields} A high-resolution melting assay was used to screen for epigenetic change. {yields} We isolated an endometrial cell clone that was epigenetically modulated by GEN. -- Abstract: It has recently been demonstrated that genistein (GEN), a phytoestrogen in soy products, is an epigenetic modulator in various types of cells; but its effect on endometrium has not yet been determined. We investigated the effects of GEN onmore » mouse uterine cells, in vivo and in vitro. Oral administration of GEN for 1 week induced mild proliferation of the endometrium in ovariectomized (OVX) mice, which was accompanied by the induction of steroidogenic factor 1 (SF-1) gene expression. GEN administration induced demethylation of multiple CpG sites in the SF-1 promoter; these sites are extensively methylated and thus silenced in normal endometrium. The GEN-mediated promoter demethylation occurred predominantly on the luminal side, as opposed to myometrium side, indicating that the epigenetic change was mainly shown in regenerated cells. Primary cultures of endometrial stromal cell colonies were screened for GEN-mediated alterations of DNA methylation by a high-resolution melting (HRM) method. One out of 20 colony-forming cell clones showed GEN-induced demethylation of SF-1. This clone exhibited a high proliferation capacity with continuous colony formation activity through multiple serial clonings. We propose that only a portion of endometrial cells are capable of receiving epigenetic modulation by GEN.« less

Endocrine disruptors and hypospadias: role of genistein and the fungicide vinclozolin.

PubMed

Vilela, Marcelo L B; Willingham, Emily; Buckley, Jill; Liu, Ben Chun; Agras, Koray; Shiroyanagi, Yoshiyuki; Baskin, Laurence S

2007-09-01

The phytoestrogen (plant estrogen) genistein, present in soy products, is of interest because in utero exposure to genistein can cause hypospadias in our mouse model and maternal consumption of soy is prevalent in human populations. Another compound of interest is the fungicide vinclozolin, which also causes hypospadias in the mouse and rat and can occur concurrently with genistein in the diet as a residue on exposed foods. A study in the United Kingdom found no relationship between a maternal organic vegetarian diet and hypospadias frequency, but women who consumed nonorganic vegetarian diets had a greater percentage of sons with hypospadias. Because nonorganic diets can include residues of pesticides such as vinclozolin, we sought to assess the interaction of realistic daily exposures to genistein and vinclozolin and their effects on the incidence of hypospadias. Pregnant mice were fed a soy-free diet and orally gavaged from gestational days 13 to 17 with 0.17 mg/kg/day of genistein, 10 mg/kg/day of vinclozolin, or genistein and vinclozolin together at the same doses, all in 100 microL of corn oil. The controls received the corn oil vehicle. The male fetuses were examined at gestational day 19 for hypospadias, both macroscopically and histologically. We identified no hypospadias in the corn oil group. The incidence of hypospadias was 25% with genistein alone, 42% with vinclozolin alone, and 41% with genistein and vinclozolin together. These findings support the idea that exposure to these compounds during gestation could contribute to the development of hypospadias.

Few effects of multi-generational dietary exposure to genistein or nonylphenol on sodium solution intake in male and female Sprague-Dawley rats.

PubMed

Ferguson, Sherry A; Delclos, K Barry; Newbold, Retha R; Flynn, Katherine M

2009-01-01

Previous work in our laboratory indicated that lifelong dietary exposure to estrogen-like endocrine disrupters increased sodium solution intake in adult male and female rats. Here, we sought to discern the critical periods necessary for this alteration as well as establish the effects of lower dietary concentrations of genistein and nonylphenol. Male and female Sprague-Dawley rats (F0) consumed phytoestrogen-free chow containing 0, 5, 100, or 500 ppm genistein (approximately equal to 0.0, 0.4, 8.0, and 40.0 mg/kg/day) or 0, 25, 200, or 750 ppm nonylphenol (approximately equal to 0.0, 2.0, 16.0, and 60.0 mg/kg/day). Rats were mated within treatment groups and offspring (F1) maintained on the same diets. Mating for the F1, F2, and F3 (genistein only) was within treatment groups. At postnatal day (PND) 21, the F3 generation began to consume unadulterated phytoestrogen-free chow such that genistein exposure occurred only in utero and preweaning. The F4 generation was never directly exposed to genistein. On PNDs 65-68, intake of regular water and a 3.0% sodium chloride solution was measured for F1-F4 generations (genistein portion) or F1-F2 (nonylphenol portion). Although body weights were decreased by the highest dietary concentrations of genistein and nonylphenol, there were only minimal effects of exposure on sodium solution intake. As expected, intake was highest in female rats. With previous data, these results indicate that the dietary concentrations necessary to increase adult sodium solution intake in rats are greater than 500 ppm genistein and 750 ppm nonylphenol and such effects do not appear to increase across generations.

Genistein inhibited ammonia induced astrocyte swelling by inhibiting NF-κB activation-mediated nitric oxide formation.

PubMed

Dai, Hongliang; Jia, Guizhi; Wang, Wei; Liang, Chunguang; Han, Siyu; Chu, Minghui; Mei, Xifan

2017-06-01

Our previous study has indicated the involvement of epidermal growth factor receptor (EGFR) transactivation in ammonia-induced astrocyte swelling, which represents a major pathogenesis of brain edema in hepatic encephalopathy. In this study, we examined the effect of genistein, a naturally occurred broad-spectrum protein tyrosine kinase (PTK) inhibitor, on ammonia-induced cell swelling. We found that genistein pretreatment significantly prevented ammonia-induced astrocyte swelling. Mechanistically, ammonia triggered EGFR/extracellular signal-regulated kinase (ERK) association and subsequent ERK phosphorylation were alleviated by genistein pretreatment. Moreover, ammonia-induced NF-κB nuclear location, iNOS expression, and consequent NO production were all prevented by AG1478 and genistein pretreatment. This study suggested that genistein could alleviate ammonia-induced astrocyte swelling, which may be, at least partly, related to its PTK-inhibiting activity and repression of NF-κB mediated iNOS-derived NO accumulation.

Genistein and daidzein act on a panel of genes implicated in cell cycle and angiogenesis by polymerase chain reaction arrays in human prostate cancer cell lines.

PubMed

Rabiau, Nadège; Kossaï, Myriam; Braud, Martin; Chalabi, Nasséra; Satih, Samir; Bignon, Yves-Jean; Bernard-Gallon, Dominique J

2010-04-01

The prostate cancer most frequently affects men. The ethnic origin and family antecedents of prostate cancer are established as risk factors. The genetic factors associated with environmental factors such as the nutrition also play a role in the development of the cancer. Epidemiological studies showed that the Asian populations exhibited an incidence of prostate cancer markedly subordinate by comparison with the Western populations. This would be explained partially by their important consumption of soy. Both main phytoestrogens of soy, the genistein and the daidzein, present anti-proliferative properties. For that purpose, we used different prostate cancer cell lines (LNCaP, DU 145, PC-3) and, by flow cytometry, we determined the concentration of phytoestrogens inducing a cell cycle arrest and the required time of incubation. Then, the effects of 40microM genistein or 110microM daidzein for 48h were determined and studied on the expression of genes involved in the human cell cycle and angiogenesis and conducted by SYBR green quantitative PCR. We demonstrated modulations of cyclin-dependent kinase-related pathway genes, DNA damage-signaling pathway and a down-regulation of EGF and IGF.

Anti-inflammatory and neuroprotective effect of a phytoestrogen compound on rat microglia.

PubMed

Marotta, F; Mao, G S; Liu, T; Chui, D H; Lorenzetti, A; Xiao, Y; Marandola, P

2006-11-01

Ovariectomized Wistar rats received orally 15 mg/kg of a phytoestrogen compound (genistein, daidzein, glycitein, black cohosh, angelica sin., licorice, vitex agnus) for 2 weeks to test its ability to modulate inflammatory microglia response. Microglial proliferation was tested by trypan blue and by absorbance. Serial supernatant sampling was performed for 24 h to check TNF-alpha, IL-beta, IL-6, and TGF-beta. LPS caused a time course increase of all cytokines, with IL-beta and TNF-alpha peaking at the 12th hour, whereas IL-6 and TGF-beta peaked at the 24 h observation. Rats fed with the phytoestrogen displayed a significantly lower level of proinflammatory cytokines and a higher level of TGF-beta, as shown also by Western blot analysis. This finding may offer promise in the field of nutraceutical intervention.

Genistein suppresses Prevotella intermedia lipopolysaccharide-induced inflammatory response in macrophages and attenuates alveolar bone loss in ligature-induced periodontitis.

PubMed

Choi, Eun-Young; Bae, Seung Han; Ha, Min Hee; Choe, So-Hui; Hyeon, Jin-Yi; Choi, Jeom-Il; Choi, In Soon; Kim, Sung-Jo

2016-02-01

Genistein is a major isoflavone subclass of flavonoids found in soybean and a potent tyrosine kinase inhibitor. The present study aimed to assess the effect of genistein on the production of proinflammatory mediators in murine macrophages stimulated with lipopolysaccharide (LPS) isolated from Prevotella intermedia, a pathogen associated with different forms of periodontal disease, and to evaluate its possible influence on alveolar bone loss in ligature-induced periodontitis using micro-computed tomography (micro-CT) analysis as well. LPS was isolated from P. intermedia ATCC 25611 by using the standard hot phenol-water method. Culture supernatants were analyzed for nitric oxide (NO) and interleukin-6 (IL-6). Inducible NO synthase (iNOS) protein expression was evaluated by immunoblot analysis. Real-time PCR was carried out to measure iNOS and IL-6 mRNA expression. In addition, effect of genistein on alveolar bone loss was evaluated in a rat model of experimental periodontitis using micro-CT analysis. Genistein significantly attenuated P. intermedia LPS-induced production of iNOS-derived NO and IL-6 with attendant decrease in their mRNA expression in RAW264.7 cells. In addition, when genistein was administered to rats, decreases in alveolar bone height and bone volume fraction induced by ligature placement were significantly inhibited. Genistein administration also prevented ligature-induced alterations in the microstructural parameters of trabecular bone, including trabecular thickness, trabecular separation, bone mineral density and structure model index. While additional studies are required, we suggest that genistein could be utilized for the therapy of human periodontitis in the future. Copyright © 2015 Elsevier Ltd. All rights reserved.

Stimulation of Murine Intestinal Secretion by Daily Genistein Injections: Gender-dependent Differences

PubMed Central

Al-Nakkash, Layla; Batia, Lyn; Bhakta, Minoti; Peterson, Amity; Hale, Nathan; Skinner, Ryan; Sears, Steven; Jensen, Jesse

2011-01-01

Background/Aims The effect of daily injections with genistein (naturally occurring phytoestrogen) on intestinal chloride (Cl−) secretion was measured with Ussing chamber short circuit current (Isc, μA/cm2), in C57BL/6J male and female mice, using 600 mg/kg genistein/day (600G), 300 mg/kg genistein/day (300G), 150 mg/kg genistein/day (150G) or genistein-free vehicle control (0G) for 1- or 2-weeks. Methods and Results Injecting with 600G elicited significant increases in basal Isc in females after 1-week (ñ70 μA/cm2, n=15, p < 0.05) and in males after 2-weeks (ñ80 μA/cm2, n=5, p < 0.05) compared to their 0G counterparts. Chloride-free ringer significantly reduced basal Isc by 65% in 600G males and 72% in 600G females, suggesting that Cl− was the major anion comprising the genistein-stimulated secretion. The forskolin-stimulated (10 μM) Isc was significantly inhibited by the CFTR chloride channel inhibitors, glibenclamide (500 μM) and CFTRinh-172 (100 μM) in 600G males and females, suggesting some contribution by genistein-dependent CFTR-mediated Cl− secretion. We found no associated changes in intestinal morphology, nor change in total CFTR protein with 600G. There was a 5% increase in apical/subapical ratio in 600G males compared to controls (no change in females). Conclusion These data suggest that male and female mice both exhibit increased Cl- secretion with 600G, however, the mechanisms mediating this are gender-dependent. PMID:21865731

Protective effect of genistein on radiation-induced intestinal injury in tumor bearing mice

PubMed Central

2013-01-01

Background Radiation therapy is the most widely used treatment for cancer, but it causes the side effect of mucositis due to intestinal damage. We examined the protective effect of genistein in tumor-bearing mice after abdominal irradiation by evaluation of apoptosis and intestinal morphological changes. Methods Mouse colon cancer CT26 cells were subcutaneously injected at the flank of BALB/c mice to generate tumors. The tumor-bearing mice were treated with abdominal radiation at 5 and 10 Gy, and with genistein at 200 mg/kg body weight per day for 1 d before radiation. The changes in intestinal histology were evaluated 12 h and 3.5 d after irradiation. To assess the effect of the combination treatment on the cancer growth, the tumor volume was determined at sacrifice before tumor overgrowth occurred. Results Genistein significantly decreased the number of apoptotic nuclei compared with that in the irradiation group 12 h after 5 Gy irradiation. Evaluation of histological changes showed that genistein ameliorated intestinal morphological changes such as decreased crypt survival, villus shortening, and increased length of the basal lamina 3.5 d after 10 Gy irradiation. Moreover, the genistein-treated group exhibited more Ki-67-positive proliferating cells in the jejunum than the irradiated control group, and crypt depths were greater in the genistein-treated group than in the irradiated control group. The mean weight of the CT26 tumors was reduced in the group treated with genistein and radiation compared with the control group. Conclusion Genistein had a protective effect on intestinal damage induced by irradiation and delayed tumor growth. These results suggest that genistein is a useful candidate for preventing radiotherapy-induced intestinal damage in cancer patients. PMID:23672582

Formononetin prevents ovariectomy-induced bone loss in rats.

PubMed

Ha, Hyekyung; Lee, Ho Young; Lee, Je-Hyun; Jung, Dayoung; Choi, Jiyoon; Song, Kye-Yong; Jung, Hee Jin; Choi, Jae Sue; Chang, Soo-Ik; Kim, Chungsook

2010-04-01

The major risk factor of postmenopausal osteoporosis is estrogen deficiency. Hormone replacement therapy is efficacious against osteoporosis, but it induces several significant adverse effects. In this study, therefore, we compared therapeutic potencies of three phytoestrogens: genistein, daidzein, and formononetin. Our result showed that in Saos-2 cells, formononetin and genistein (5 x 10(-7) M) treatment increased alkaline phosphatase activity by 33.0 +/- 5.8% and 21.1 +/- 4.0%. Genistein inhibited osteoclast formation in a dose-dependent manner. In OVX rats, formononetin-treated groups given 1 and 10 mg/kg/day displayed increased trabecular bone areas (TBAs) within the tibia. Genistein- and daidzein-treated groups also displayed increased tibial TBAs. TBAs of the lumbar vertebrae were higher in all treated groups than in the control group. In conclusion, formononetin as well as other isoflavones, such as daidzein and genistein, inhibited bone loss caused by estrogen-deficiency.

Genistein suppresses leptin-induced proliferation and migration of vascular smooth muscle cells and neointima formation.

PubMed

Tsai, Yung-Chieh; Leu, Sy-Ying; Peng, Yi-Jen; Lee, Yen-Mei; Hsu, Chih-Hsiung; Chou, Shen-Chieh; Yen, Mao-Hsiung; Cheng, Pao-Yun

2017-03-01

Obesity is a strong risk factor for the development of cardiovascular diseases and is associated with a marked increase in circulating leptin concentration. Leptin is a peptide hormone mainly produced by adipose tissue and is regulated by energy level, hormones and various inflammatory mediators. Genistein is an isoflavone that exhibits diverse health-promoting effects. Here, we investigated whether genistein suppressed the atherogenic effect induced by leptin. The A10 cells were treated with leptin and/or genistein, and then the cell proliferation and migration were analysed. The reactive oxygen species (ROS) and proteins levels were also measured, such as p44/42MAPK, cell cycle-related protein (cyclin D1 and p21) and matrix metalloproteinase-2 (MMP-2). Immunohistochemistry and morphometric analysis were used for the neointima formation in a rat carotid artery injury model. Genistein (5 μM) significantly inhibited both the proliferation and migration of leptin (10 ng/ml)-stimulated A10 cells. In accordance with these finding, genistein decreased the leptin-stimulated ROS production and phosphorylation of the p44/42MAPK signal transduction pathway. Meanwhile, genistein reversed the leptin-induced expression of cyclin D1, and cyclin-dependent kinase inhibitor, p21. Genistein attenuated leptin-induced A10 cell migration by inhibiting MMP-2 activity. Furthermore, the leptin (0.25 mg/kg)-augmented neointima formation in a rat carotid artery injury model was attenuated in the genistein (5 mg/kg body weight)-treated group when compared with the balloon injury plus leptin group. Genistein was capable of suppressing the atherogenic effects of leptin in vitro and in vivo, and may be a promising candidate drug in the clinical setting. © 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Genistein protects hematopoietic stem cells against G-CSF-induced DNA damage.

PubMed

Souza, Liliana R; Silva, Erica; Calloway, Elissa; Kucuk, Omer; Rossi, Michael; McLemore, Morgan L

2014-05-01

Granulocyte colony-stimulating factor (G-CSF) has been used to treat neutropenia in various clinical settings. Although clearly beneficial, there are concerns that the chronic use of G-CSF in certain conditions increases the risk of myelodysplastic syndrome (MDS) and/or acute myeloid leukemia (AML). The most striking example is in severe congenital neutropenia (SCN). Patients with SCN develop MDS/AML at a high rate that is directly correlated to the cumulative lifetime dosage of G-CSF. Myelodysplastic syndrome and AML that arise in these settings are commonly associated with chromosomal deletions. We have demonstrated in this study that chronic G-CSF treatment in mice results in expansion of the hematopoietic stem cell (HSC) population. In addition, primitive hematopoietic progenitors from G-CSF-treated mice show evidence of DNA damage as demonstrated by an increase in double-strand breaks and recurrent chromosomal deletions. Concurrent treatment with genistein, a natural soy isoflavone, limits DNA damage in this population. The protective effect of genistein seems to be related to its preferential inhibition of G-CSF-induced proliferation of HSCs. Importantly, genistein does not impair G-CSF-induced proliferation of committed hematopoietic progenitors, nor diminishes neutrophil production. The protective effect of genistein was accomplished with plasma levels that are attainable through dietary supplementation.

Chronic Dietary Exposure to a Low-Dose Mixture of Genistein and Vinclozolin Modifies the Reproductive Axis, Testis Transcriptome, and Fertility

PubMed Central

Eustache, Florence; Mondon, Françoise; Canivenc-Lavier, Marie Chantal; Lesaffre, Corinne; Fulla, Yvonne; Berges, Raymond; Cravedi, Jean Pierre; Vaiman, Daniel; Auger, Jacques

2009-01-01

Background The reproductive consequences and mechanisms of action of chronic exposure to low-dose endocrine disruptors are poorly understood. Objective We assessed the effects of a continuous, low-dose exposure to a phytoestrogen (genistein) and/or an antiandrogenic food contaminant (vinclozolin) on the male reproductive tract and fertility. Methods Male rats were exposed by gavage to genistein and vinclozolin from conception to adulthood, alone or in combination, at low doses (1 mg/kg/day) or higher doses (10 and 30 mg/kg/day). We studied a number of standard reproductive toxicology end points and also assessed testicular mRNA expression profiles using long-oligonucleotide microarrays. Results The low-dose mixture and high-dose vinclozolin produced the most significant alterations in adults: decreased sperm counts, reduced sperm motion parameters, decreased litter sizes, and increased post implantation loss. Testicular mRNA expression profiles for these exposure conditions were strongly correlated. Functional clustering indicated that many of the genes induced belong to the “neuroactive ligand-receptor interactions” family encompassing several hormonally related actors (e.g., follicle-stimulating hormone and its receptor). All exposure conditions decreased the levels of mRNAs involved in ribosome function, indicating probable decreased protein production. Conclusions Our study shows that chronic exposure to a mixture of a dose of a phytoestrogen equivalent to that in the human diet and a low dose—albeit not environmental—of a common anti-androgenic food contaminant may seriously affect the male reproductive tract and fertility. PMID:19672408

Chronic dietary exposure to a low-dose mixture of genistein and vinclozolin modifies the reproductive axis, testis transcriptome, and fertility.

PubMed

Eustache, Florence; Mondon, Françoise; Canivenc-Lavier, Marie Chantal; Lesaffre, Corinne; Fulla, Yvonne; Berges, Raymond; Cravedi, Jean Pierre; Vaiman, Daniel; Auger, Jacques

2009-08-01

The reproductive consequences and mechanisms of action of chronic exposure to low-dose endocrine disruptors are poorly understood. We assessed the effects of a continuous, low-dose exposure to a phytoestrogen (genistein) and/or an antiandrogenic food contaminant (vinclozolin) on the male reproductive tract and fertility. Male rats were exposed by gavage to genistein and vinclozolin from conception to adulthood, alone or in combination, at low doses (1 mg/kg/day) or higher doses (10 and 30 mg/kg/day). We studied a number of standard reproductive toxicology end points and also assessed testicular mRNA expression profiles using long-oligonucleotide microarrays. The low-dose mixture and high-dose vinclozolin produced the most significant alterations in adults: decreased sperm counts, reduced sperm motion parameters, decreased litter sizes, and increased post implantation loss. Testicular mRNA expression profiles for these exposure conditions were strongly correlated. Functional clustering indicated that many of the genes induced belong to the "neuroactive ligand-receptor interactions" family encompassing several hormonally related actors (e.g., follicle-stimulating hormone and its receptor). All exposure conditions decreased the levels of mRNAs involved in ribosome function, indicating probable decreased protein production. Our study shows that chronic exposure to a mixture of a dose of a phytoestrogen equivalent to that in the human diet and a low dose-albeit not environmental-of a common anti-androgenic food contaminant may seriously affect the male reproductive tract and fertility.

Phytoestrogen consumption from foods and supplements and epithelial ovarian cancer risk: a population-based case control study

PubMed Central

2011-01-01

Background While there is extensive literature evaluating the impact of phytoestrogen consumption on breast cancer risk, its role on ovarian cancer has received little attention. Methods We conducted a population-based case-control study to evaluate phytoestrogen intake from foods and supplements and epithelial ovarian cancer risk. Cases were identified in six counties in New Jersey through the New Jersey State Cancer Registry. Controls were identified by random digit dialing, CMS (Centers for Medicare and Medicaid Service) lists, and area sampling. A total of 205 cases and 390 controls were included in analyses. Unconditional logistic regression analyses were conducted to examine associations with total phytoestrogens, as well as isoflavones (daidzein, genistein, formononetin, and glycitein), lignans (matairesinol, lariciresinol, pinoresinol, secoisolariciresinol), and coumestrol. Results No statistically significant associations were found with any of the phytoestrogens under evaluation. However, there was a suggestion of an inverse association with total phytoestrogen consumption (from foods and supplements), with an odds ratio (OR) of 0.62 (95% CI: 0.38-1.00; p for trend: 0.04) for the highest vs. lowest tertile of consumption, after adjusting for reproductive covariates, age, race, education, BMI, and total energy. Further adjustment for smoking and physical activity attenuated risk estimates (OR: 0.66; 95% CI: 0.41-1.08). There was little evidence of an inverse association for isoflavones, lignans, or coumestrol. Conclusions This study provided some suggestion that phytoestrogen consumption may decrease ovarian cancer risk, although results did not reach statistical significance. PMID:21943063

Genistein inhibits cell invasion and motility by inducing cell differentiation in murine osteosarcoma cell line LM8.

PubMed

Nakamura, Atsushi; Aizawa, Junichi; Sakayama, Kenshi; Kidani, Teruki; Takata, Tomoyo; Norimatsu, Yoshiaki; Miura, Hiromasa; Masuno, Hiroshi

2012-09-26

One of the problems associated with osteosarcoma is the frequent formation of micrometastases in the lung prior to diagnosis because the development of metastatic lesions often causes a fatal outcome. Therefore, the prevention of pulmonary metastases during the early stage of tumor development is critical for the improvement of the prognosis of osteosarcoma patients. In Japan, soy is consumed in a wide variety of forms, such as miso soup and soy sauce. The purpose of this study is to investigate the effect of genistein, an isoflavone found in soy, on the invasive and motile potential of osteosarcoma cells. LM8 cells were treated for 3 days with various concentrations of genistein. The effect of genistein on cell proliferation was determined by DNA measurement in the cultures and 5-bromo-2'-deoxyuridine (BrdU) incorporation study. The assays of cell invasion and motility were performed using the cell culture inserts with either matrigel-coated membranes or uncoated membranes in the invasion chambers. The expression and secretion of MMP-2 were determined by immunohistochemistry and gelatin zymography. The subcellular localization and cellular level of β-catenin were determined by immunofluorescence and Western blot. For examining cell morphology, the ethanol-fixed cells were stained with hematoxylin-eosin (H&E). The expression of osteocalcin mRNA was determined by reverse transcription-polymerase chain reaction (RT-PCR). Genistein dose-dependently inhibits cell proliferation. Genistein-treated cells were less invasive and less motile than untreated cells. The expression and secretion of MMP-2 were lower in the genistein-treated cultures than in the untreated cultures. β-Catenin in untreated cells was located in the cytoplasm and/or nucleus, while in genistein-treated cells it was translocated near to the plasma membrane. The level of β-catenin was higher in genistein-treated cells than in untreated cells. Treatment of LM8 cells with genistein induced morphological

Genistein inhibits cell invasion and motility by inducing cell differentiation in murine osteosarcoma cell line LM8

PubMed Central

2012-01-01

genistein induced morphological changes, markedly decreased the formation of multilayer masses of cells, and markedly increased the expression of osteocalcin mRNA. Conclusions Genistein decreased invasive and motile potential by inducing cell differentiation in LM8 cells. Genistein may be useful as an anti-metastatic drug for osteosarcoma through its differentiation-inducing effects. PMID:23013480

Genistein as a potential inducer of the anti-atherogenic enzyme paraoxonase-1: studies in cultured hepatocytes in vitro and in rat liver in vivo

PubMed Central

Schrader, Charlotte; Ernst, Insa M A; Sinnecker, Heike; Soukup, Sebastian T; Kulling, Sabine E; Rimbach, Gerald

2012-01-01

A number of cardioprotective effects, including the reduced oxidation of the low-density lipoprotein (LDL) particles, have been attributed to dietary soy isoflavones. Paraoxonase 1 (PON1), an enzyme mainly synthesized in the liver, may exhibit anti-atherogenic activity by protecting LDL from oxidation. Thus, dietary and pharmacological inducers of PON1 may decrease cardiovascular disease risk. Using a luciferase reporter gene assay we screened different flavonoids for their ability to induce PON1 in Huh7 hepatocytes in culture. Genistein was the most potent flavonoid with regard to its PON1-inducing activity, followed by daidzein, luteolin, isorhamnetin and quercetin. Other flavonoids such as naringenin, cyanidin, malvidin and catechin showed only little or no PON1-inducing activity. Genistein-mediated PON1 transactivation was partly inhibited by the oestrogen-receptor antagonist fulvestrant as well as by the aryl hydrocarbon receptor antagonist 7-ketocholesterol. In contrast to genistein, the conjugated genistein metabolites genistein-7-glucuronide, genistein-7-sulfate and genistein-7,4′-disulfate were only weak inducers of PON1 transactivation. Accordingly, dietary genistein supplementation (2 g/kg diet over three weeks) in growing rats did not increase hepatic PON1 mRNA and protein levels as well as plasma PON1 activity. Thus, genistein may be a PON1 inducer in cultured hepatocytes in vitro, but not in rats in vivo. PMID:22304296

Genistein induces estrogen-like effects in ovariectomized rats but fails to increase cardiac GLUT4 and oxidative stress.

PubMed

Al-Nakkash, Layla; Markus, Brandon; Batia, Lyn; Prozialeck, Walter C; Broderick, Tom L

2010-12-01

This study aimed to determine whether a 2-week genistein treatment induced estrogen-like effects in ovariectomized (OVX) Sprague-Dawley rats, after 2 weeks of subcutaneous genistein injections (250 mg/kg of body weight/day). Uterine weight, uterine-to-body weight ratio, femur weight, and femur-to-body weight ratio were all significantly increased with genistein in OVX rats. Body weight was significantly decreased with genistein in OVX rats. Genistein had no effect on the weights of heart, heart-to-body ratio, and fat pad but significantly decreased heart rate and pulse pressure. Genistein had no effect on cardiac GLUT4 protein, oxidative stress, plasma glucose, nonesterified fatty acids, or low-density lipoprotein levels; however, plasma insulin levels were significantly increased. Our results show that a 2-week genistein treatment produced favorable estrogen-like effects on some physical and physiological characteristics in OVX rats. However, based on our experimental conditions, the effects of genistein were not associated with changes in cardiac GLUT4 or oxidative stress.

Radiolysis study of genistein in methanolic solution

NASA Astrophysics Data System (ADS)

Jung, Hee Jin; Park, Hae Ran; Jung, Uhee; Jo, Sung Kee

2009-06-01

The aim of the present work was to identify products obtained from genistein by ionizing radiation and to enhance the antioxidant properties of genistein through radiation-induced transformation. Genistein dissolved in methanol was irradiated γ-rays at a dose of 100 kGy. NMR and (HR) EI-MS spectroscopy were used to identify radiolysis products (GM1 and GM2). We proposed that rad CH 2OH may be implicated in the formation GM1 and GM2 during radiolysis of genistein in methanol. The genistein in methanol solution showed higher DPPH radical scavenging activity after γ-irradiation. Then, the antioxidant activities of radiolysis products were evaluated and compared to those of genistein.

Transport of steroid hormones, phytoestrogens, and estrogenic activity across a swine lagoon/sprayfield system.

PubMed

Yost, Erin E; Meyer, Michael T; Dietze, Julie E; Williams, C Michael; Worley-Davis, Lynn; Lee, Boknam; Kullman, Seth W

2014-10-07

The inflow, transformation, and attenuation of natural steroid hormones and phytoestrogens and estrogenic activity were assessed across the lagoon/sprayfield system of a prototypical commercial swine sow operation. Free and conjugated steroid hormones (estrogens, androgens, and progesterone) were detected in urine and feces of sows across reproductive stages, with progesterone being the most abundant steroid hormone. Excreta also contained phytoestrogens indicative of a soy-based diet, particularly, daidzein, genistein, and equol. During storage in barn pits and the anaerobic lagoon, conjugated hormones dissipated, and androgens and progesterone were attenuated. Estrone and equol persisted along the waste disposal route. Following application of lagoon slurry to agricultural soils, all analytes exhibited attenuation within 2 days. However, analytes including estrone, androstenedione, progesterone, and equol remained detectable in soil at 2 months postapplication. Estrogenic activity in the yeast estrogen screen and T47D-KBluc in vitro bioassays generally tracked well with analyte concentrations. Estrone was found to be the greatest contributor to estrogenic activity across all sample types. This investigation encompasses the most comprehensive suite of natural hormone and phytoestrogen analytes examined to date across a livestock lagoon/sprayfield and provides global insight into the fate of these analytes in this widely used waste management system.

Transport of Steroid Hormones, Phytoestrogens, and Estrogenic Activity across a Swine Lagoon/Sprayfield System

PubMed Central

Yost, Erin E.; Meyer, Michael T.; Dietze, Julie E.; Williams, C. Michael; Worley-Davis, Lynn; Lee, Boknam; Kullman, Seth W.

2017-01-01

The inflow, transformation, and attenuation of natural steroid hormones, phytoestrogens, and estrogenic activity was assessed across the lagoon/sprayfield system of a prototypical commercial swine sow operation. Free and conjugated steroid hormones (estrogens, androgens, and progesterone) were detected in urine and feces of sows across reproductive stages, with progesterone being the most abundant steroid hormone. Excreta also contained phytoestrogens indicative of a soy-based diet; particularly daidzein, genistein, and equol. During storage in barn pits and the anaerobic lagoon, conjugated hormones dissipated, and androgens and progesterone were attenuated. Estrone and equol persisted along the waste disposal route. Following application of lagoon slurry to agricultural soils, all analytes exhibited attenuation within 2 days. However, analytes including estrone, androstenedione, progesterone, and equol remained detectable in soil at two months post-application. Estrogenic activity in the yeast estrogen screen and T47D-KBluc in vitro bioassays generally tracked well with analyte concentrations. Estrone found to be the greatest contributor to estrogenic activity across all sample types. This investigation encompasses the most comprehensive suite of natural hormone and phytoestrogen analytes examined to date across a lagoon/sprayfield system, and provides global insight into the fate of these analytes in this widely used waste management system. PMID:25148584

Membrane depolarization-induced RhoA/Rho-associated kinase activation and sustained contraction of rat caudal arterial smooth muscle involves genistein-sensitive tyrosine phosphorylation

PubMed Central

Mita, Mitsuo; Tanaka, Hitoshi; Yanagihara, Hayato; Nakagawa, Jun-ichi; Hishinuma, Shigeru; Sutherland, Cindy; Walsh, Michael P.; Shoji, Masaru

2013-01-01

Rho-associated kinase (ROK) activation plays an important role in K+-induced contraction of rat caudal arterial smooth muscle (Mita et al., Biochem J. 2002; 364: 431–40). The present study investigated a potential role for tyrosine kinase activity in K+-induced RhoA activation and contraction. The non-selective tyrosine kinase inhibitor genistein, but not the src family tyrosine kinase inhibitor PP2, inhibited K+-induced sustained contraction (IC50 = 11.3 ± 2.4 µM). Genistein (10 µM) inhibited the K+-induced increase in myosin light chain (LC20) phosphorylation without affecting the Ca2+ transient. The tyrosine phosphatase inhibitor vanadate induced contraction that was reversed by genistein (IC50 = 6.5 ± 2.3 µM) and the ROK inhibitor Y-27632 (IC50 = 0.27 ± 0.04 µM). Vanadate also increased LC20 phosphorylation in a genistein- and Y-27632-dependent manner. K+ stimulation induced translocation of RhoA to the membrane, which was inhibited by genistein. Phosphorylation of MYPT1 (myosin-targeting subunit of myosin light chain phosphatase) was significantly increased at Thr855 and Thr697 by K+ stimulation in a genistein- and Y-27632-sensitive manner. Finally, K+ stimulation induced genistein-sensitive tyrosine phosphorylation of proteins of ∼55, 70 and 113 kDa. We conclude that a genistein-sensitive tyrosine kinase, activated by the membrane depolarization-induced increase in [Ca2+]i, is involved in the RhoA/ROK activation and sustained contraction induced by K+. Ca2+ sensitization, myosin light chain phosphatase, RhoA, Rho-associated kinase, tyrosine kinase PMID:24133693

Inhibition of ultraviolet light-induced oxidative events in the skin and internal organs of hairless mice by isoflavone genistein.

PubMed

Wei, Huachen; Zhang, Xueshu; Wang, Yan; Lebwohl, Mark

2002-11-08

We have previously demonstrated that soybean isoflavone genistein inhibits ultraviolet-B (UVB)-induced skin tumorigenesis in hairless mice. In the present study, we further investigated the possible mechanism(s) of action whereby genistein inhibits photocarcinogenesis with focuses on UVB-induced oxidative events, including hydrogen peroxide (H(2)O(2)) production, lipid peroxidation (as represented by malondialdehyde, MDA), and 8-hydroxy-2'-deoxyguanosine (8-OHdG) formation in vivo. We demonstrated that subacute exposure to UVB substantially increased the level of H(2)O(2), lipid peroxides, and 8-OHdG in skin of hairless mice. In addition, chronic exposure to low-dose UVB (0.9-1.2 kJ/m(2) for 20 weeks) substantially increased the levels of 8-OHdG not only in the epidermis, but also in the internal organs such as liver, brain, and spleen of mice with exception of kidney. However, genistein did not affect the level of UVB-induced pyrimidine dimmers in the same UVB exposed mouse skin, indicating selective inhibition of oxidative DNA damage by genistein. Induction of H(2)O(2) was independent of UVB fluences whereas the levels of MDA and 8-OHdG were induced in an UVB fluence-dependent manner. The results suggest that H(2)O(2) be generated as an acute cutaneous response to UVB irradiation, while MDA and 8-OHdG are accumulated with increasing UVB exposure and more closely related to chronic effects of UVB radiation. Pre-treatment of animals with 10 micromol of genistein 1 h prior to UVB exposure significantly inhibited UVB-induced H(2)O(2) and MDA in skin and 8-OHdG in epidermis as well as internal organs. Suppression of 8-OHdG formation by genistein has been corroborated in purified DNA irradiated with UVA and B. In summary, our results suggest that UVB irradiation elicit a series of oxidative events, which can be substantially inhibited by isoflavonoid genistein through either direct quenching of reactive oxygen species or indirect antiinflammatory effects. Thus, the

Phytoestrogens and avian reproduction: Exploring the evolution and function of phytoestrogens and possible role of plant compounds in the breeding ecology of wild birds.

PubMed

Rochester, Johanna R; Millam, James R

2009-11-01

Phytoestrogens are secondary plant compounds, which can act to mimic estrogen and cause the disruption of estrogenic responses in organisms. Although there is a substantial body of research studying phytoestrogens, including their mechanisms of estrogenic effects, evolution, and detection in biological systems, little is known about their ecological significance. There is evidence, however, that an ecological relationship involving phytoestrogens exists between plants and animals-plants may produce phytoestrogens to reduce fecundity of organisms that eat them. Birds and other vertebrates may also exploit phytoestrogens to regulate their own reproduction-there are well known examples of phytoestrogens inhibiting reproduction in higher vertebrates, including birds. Also, common plant stressors (e.g., high temperature) increase the production of secondary plant compounds, and, as evidence suggests, also induce phytoestrogen biosynthesis. These observations are consistent with the single study ever done on phytoestrogens and reproduction in wild birds [Leopold, A.S., Erwin, M., Oh, J., Browning, B., 1976. Phytoestrogens adverse effects on reproduction in California quail. Science 191, 98-100.], which found that drought stress correlated with increased levels of phytoestrogens in plants, and that increased phytoestrogen levels correlated with decreased young. This review discusses the hypothesis that plants may have an effect on the reproduction of avian species by producing phytoestrogens as a plant defense against herbivory, and that birds may "use" changing levels of phytoestrogens in the vegetation to ensure that food resources will support potential young produced. Evidence from our laboratory and others appear to support this hypothesis.

Genistein abrogates G2 arrest induced by curcumin in p53 deficient T47D cells

PubMed Central

2012-01-01

Background The high cost and low level of cancer survival urge the finding of new drugs having better mechanisms. There is a high trend of patients to be “back to nature” and use natural products as an alternative way to cure cancer. The fact is that some of available anticancer drugs are originated from plants, such as taxane, vincristine, vinblastine, pacitaxel. Curcumin (diferuloylmethane), a dietary pigment present in Curcuma longa rizhome is reported to induce cell cycle arrest in some cell lines. Other study reported that genistein isolated from Glycine max seed inhibited phosphorylation of cdk1, gene involved during G2/M transition and thus could function as G2 checkpoint abrogator. The inhibition of cdk1 phosphorylation is one of alternative strategy which could selectively kill cancer cells and potentially be combined with DNA damaging agent such as curcumin. Methods T47D cell line was treated with different concentrations of curcumin and genistein, alone or in combination; added together or with interval time. Flow Cytometry and MTT assay were used to evaluate cell cycle distribution and viability, respectively. The presence of apoptotic cells was determined using acridine orange-ethidium bromide staining. Results In this study curcumin induced G2 arrest on p53 deficient T47D cells at the concentration of 10 μM. Increasing concentration up to 30 μM increased the number of cell death. Whilst genistein alone at low concentration (≤10 μM) induced cell proliferation, addition of genistein (20 μM) 16 h after curcumin resulted in more cell death (89%), 34% higher than that administered at the same time (56%). The combination treatment resulted in apoptotic cell death. Combining curcumin with high dose of genistein (50 μM) induced necrotic cells. Conclusions Genistein increased the death of curcumin treated T47D cells. Appropriate timing of administration and concentration of genistein determine the outcome of treatment and this method

Comprehensive assessment of hormones, phytoestrogens, and estrogenic activity in an anaerobic swine waste lagoon

USGS Publications Warehouse

Yost, Erin E.; Meyer, Michael T.; Dietze, Julie E.; Meissner, Benjamin M.; Williams, Mike; Worley-Davis, Lynn; Lee, Boknam; Kullman, Seth W.

2013-01-01

In this study, the distribution of steroid hormones, phytoestrogens, and estrogenic activity was thoroughly characterized within the anaerobic waste lagoon of a typical commercial swine sow operation. Three independent rounds of sampling were conducted in June 2009, April 2010, and February 2011. Thirty-seven analytes in lagoon slurry and sludge were assessed using LC/MS-MS, and yeast estrogen screen was used to determine estrogenic activity. Of the hormone analytes, steroidal estrogens were more abundant than androgens or progesterone, with estrone being the predominant estrogen species. Conjugated hormones were detected only at low levels. The isoflavone metabolite equol was by far the predominant phytoestrogen species, with daidzein, genistein, formononetin, and coumestrol present at lower levels. Phytoestrogens were often more abundant than steroidal estrogens, but contributed minimally towards total estrogenic activity. Analytes were significantly elevated in the solid phases of the lagoon; although low observed log KOC values suggest enhanced solubility in the aqueous phase, perhaps due to dissolved or colloidal organic carbon. The association with the solid phase, as well as recalcitrance of analytes to anaerobic degradation, results in a markedly elevated load of analytes and estrogenic activity within lagoon sludge. Overall, findings emphasize the importance of adsorption and transformation processes in governing the fate of these compounds in lagoon waste, which is ultimately used for broadcast application as a fertilizer.

Comprehensive Assessment of Hormones, Phytoestrogens, and Estrogenic Activity in an Anaerobic Swine Waste Lagoon

PubMed Central

2013-01-01

In this study, the distribution of steroid hormones, phytoestrogens, and estrogenic activity was thoroughly characterized within the anaerobic waste lagoon of a typical commercial swine sow operation. Three independent rounds of sampling were conducted in June 2009, April 2010, and February 2011. Thirty-seven analytes in lagoon slurry and sludge were assessed using LC/MS-MS, and yeast estrogen screen was used to determine estrogenic activity. Of the hormone analytes, steroidal estrogens were more abundant than androgens or progesterone, with estrone being the predominant estrogen species. Conjugated hormones were detected only at low levels. The isoflavone metabolite equol was by far the predominant phytoestrogen species, with daidzein, genistein, formononetin, and coumestrol present at lower levels. Phytoestrogens were often more abundant than steroidal estrogens, but contributed minimally toward total estrogenic activity. Analytes were significantly elevated in the solid phases of the lagoon; although low observed log KOC values suggest enhanced solubility in the aqueous phase, perhaps due to dissolved or colloidal organic carbon. The association with the solid phase, as well as recalcitrance of analytes to anaerobic degradation, results in a markedly elevated load of analytes and estrogenic activity within lagoon sludge. Overall, findings emphasize the importance of adsorption and transformation processes in governing the fate of these compounds in lagoon waste, which is ultimately used for broadcast application as a fertilizer. PMID:24144340

SPECT/CT analysis of splenic function in genistein-treated malaria-infected mice.

PubMed

Ha, Young Ran; Kang, Sung-A; Ryu, Jeongeun; Yeom, Eunseop; Kim, Mun Ki; Lee, Sang Joon

2016-11-01

Spleen traps malaria-infected red blood cells, thereby leading to splenomegaly. Splenomegaly induces impairment in splenic function, i.e., rupture. Therefore, splenomegaly inhibition is required to protect the spleen. In our previous study, genistein was found to have an influence on malaria-induced splenomegaly. However, the effect of genistein in malaria-induced splenomegaly, especially on the function of spleen, has not been fully investigated. In this study, hematoxylin and eosin (H&E) staining images show that genistein partially prevents malaria-induced architectural disruption of spleen. In addition, genistein decreases transgenic Plasmodium parasites accumulation in the spleen. Genistein treatment can protect splenic function from impairment caused by malaria infection. To examine the functions of malaria-infected spleen, we employed single-photon emission computed tomography/computed tomography (SPECT/CT) technology. Red blood cells are specifically radiolabeled with Technetium-99m pertechnetate ( 99m TcO 4 - ) and trapped inside the spleen. The standardized uptake values (SUVs) in the spleen of infected mice are higher than those of naive and genistein-treated mice. However, genistein reduces the malaria-induced trapping capacity of spleen for heat-damaged radiolabeled RBCs, while exhibiting a protective effect against malaria. Considering these results, we suggested that genistein could be effectively used in combination therapy for malaria-induced splenic impairment. Copyright © 2016 Elsevier Inc. All rights reserved.

The enhancing effect of genistein on apoptosis induced by trichostatin A in lung cancer cells with wild type p53 genes is associated with upregulation of histone acetyltransferase

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wu, Tzu-Chin; Lin, Yi-Chin; Chen, Hsiao-Ling

Genistein has been shown to enhance the antitumor activity of trichostatin A (TSA) in human lung carcinoma A549 cells. However, whether the combined treatment exerts the same effect in other lung cancer cells is unclear. In the present study we first compared the enhancing effect of genistein on the antitumor effect of TSA in ABC-1, NCI-H460 (H460) and A549 cells. Second, we investigated whether the effects of genistein are associated with increased histone/non-histone protein acetylation. We found that the enhancing effect of genistein on cell-growth-arrest in ABC-1 cells (p53 mutant) was less than in A549 and H460 cells. Genistein enhancedmore » TSA induced apoptosis in A549 and H460 cells rather than in ABC-1 cells. After silencing p53 expression in A549 and H460 cells, the enhancing effect of genistein was diminished. In addition, genistein increased TSA-induced histone H3/H4 acetylation in A549 and H460 cells. Genistein also increased p53 acetylation in H460 cells. The inhibitor of acetyltransferase, anacardic acid, diminished the enhancing effect of genistein on all TSA-induced histone/p53 acetylation and apoptosis. Genistein in combination with TSA increased the expression of p300 protein, an acetyltransferase, in A549 and NCI-H460 cells. Furthermore, we demonstrated that genistein also enhanced the antitumor effect of genistein in A549-tumor-bearing mice. Taken together, these results suggest that the enhancing effects of genistein on TSA-induced apoptosis in lung cancer cells were p53-dependent and were associated with histone/non-histone protein acetylation. - Highlights: • Genistein enhances the antitumor effect of TSA through p53-associated pathways. • Genistein enhances TSA-induced histone acetylation commonly. • An acetyltransferase inhibitor diminishes the antitumor effect of genistein + TSA. • TSA in combination with genistein increases the expression of p300. • Genistein given by i.p. injection increases the antitumor effect of TSA in

Genistein modulates the expression of NF-κB and MAPK (p-38 and ERK1/2), thereby attenuating D-Galactosamine induced fulminant hepatic failure in Wistar rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ganai, Ajaz A., E-mail: ganaikashmir@gmail.com; Khan, Athar A., E-mail: atharbiotech@gmail.com; Malik, Zainul A., E-mail: mzabdin@rediffmail.com

2015-03-01

Genistein is an isoflavanoid abundantly found in soy. It has been found to play an important role in the prevention of various chronic diseases including cancer. In this study, we evaluated potential therapeutic properties of Genistein against D-Galactosamine (D-GalN) induced inflammation and hepatotoxicity in male Wistar rats. Fulminant hepatic failure (FHF) was induced in rats by intraperitoneal injection of D-GalN (700 mg/kgBW). Genistein (5 mg/kgBW/day) was given as pre-treatment for 30 days via intra-gastric route followed by D-GalN (700 mg/kgBW) injection. The hepatoprotective and curative effects of Genistein were evident from a significant decrease in the serum aspartate aminotransferase (AST)more » and alanine aminotransferase (ALT) levels as well as prevention of histological damage by pre-treatment of Genistein. Genistein pre-treatment significantly inhibited the increased protein levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), thereby reducing nitric oxide (NO) and prostaglandin-E2 (PGE) levels, respectively. In addition Genistein significantly suppressed the production of D-GalN-induced proinflammatory cytokines, including tumor necrosis factor-α (TNF-α) and interleukin (IL)-1β. These inhibitory effects were associated with the suppression of nuclear factor-kappa B (NF-ĸB) activation, IKKα/β and Mitogen activated protein kinase (MAPK) phosphorylation by Genistein in D-GalN-treated animals. In conclusion, our results suggest that Genistein may serve as a potential supplement in the prevention of hepatic and inflammatory diseases. Furthermore Genistein is able to maintain the redox potential and strengthens the antioxidant defense system of a cell. - Highlights: • First study to evaluate hepatoprotective effect of Genistein against D-GalN • Genistein prevents oxidative damage induced by D-GalN. • Genistein blunts iNOS, COX-2, NF-ĸB, IKKα/β and MAPK expression. • Genistein prevents D-GalN induced apoptosis

Isoflavone genistein inhibits estrogen-induced chloride and bicarbonate secretory mechanisms in the uterus in rats.

PubMed

Chinigarzadeh, Asma; Karim, Kamarulzaman; Muniandy, Sekaran; Salleh, Naguib

2017-04-01

We hypothesized that genistein could affect the chloride (Cl - ) and bicarbonate (HCO 3 - ) secretory mechanisms in uterus. Ovariectomized female rats were given estradiol or estradiol plus progesterone with 25, 50, or 100 mg/kg/day genistein. Following completion of the treatment, uterine fluid Cl - and HCO 3 - concentrations were determined by in vivo uterine perfusion. Uteri were subjected for molecular biological analysis (Western blot, qPCR, and immunohistochemistry) to detect levels of expression of Cystic Fibrosis transmembrane regulator (CFTR), Cl - /HCO 3 - exchanger (SLC26a6), Na + /HCO 3 - cotransporter (SLC4a4), and estrogen receptor (ER)-α and β. Coadministration of genistein resulted in decrease in Cl - and HCO 3 - concentrations and expression of CFTR, SLC26a6, SLC4a4, and ER-α and ER-β in the uteri of estradiol-treated rats. In estradiol plus progesterone-treated rats, a significant increase in the above parameters were observed following high-dose genistein treatment except for the SLC24a4 level. In conclusion, genistein-induced changes in the uterus could affect the reproductive processes that might result in infertility. © 2016 Wiley Periodicals, Inc.

Bioactivation of Phytoestrogens: Intestinal Bacteria and Health.

PubMed

Landete, J M; Arqués, J; Medina, M; Gaya, P; de Las Rivas, B; Muñoz, R

2016-08-17

Phytoestrogens are polyphenols similar to human estrogens found in plants or derived from plant precursors. Phytoestrogens are found in high concentration in soya, flaxseed and other seeds, fruits, vegetables, cereals, tea, chocolate, etc. They comprise several classes of chemical compounds (stilbenes, coumestans, isoflavones, ellagitannins, and lignans) which are structurally similar to endogenous estrogens but which can have both estrogenic and antiestrogenic effects. Although epidemiological and experimental evidence indicates that intake of phytoestrogens in foods may be protective against certain chronic diseases, discrepancies have been observed between in vivo and in vitro experiments. The microbial transformations have not been reported so far in stilbenes and coumestans. However, isoflavones, ellagitanins, and lignans are metabolized by intestinal bacteria to produce equol, urolithins, and enterolignans, respectively. Equol, urolithin, and enterolignans are more bioavailable, and have more estrogenic/antiestrogenic and antioxidant activity than their precursors. Moreover, equol, urolithins and enterolignans have anti-inflammatory effects and induce antiproliferative and apoptosis-inducing activities. The transformation of isoflavones, ellagitanins, and lignans by intestinal microbiota is essential to be protective against certain chronic diseases, as cancer, cardiovascular disease, osteoporosis, and menopausal symptoms. Bioavailability, bioactivity, and health effects of dietary phytoestrogens are strongly determined by the intestinal bacteria of each individual.

Alterations in the Rat Serum Proteome Induced by Prepubertal Exposure to Bisphenol A and Genistein

PubMed Central

2015-01-01

Humans are exposed to an array of chemicals via the food, drink and air, including a significant number that can mimic endogenous hormones. One such chemical is Bisphenol A (BPA), a synthetic chemical that has been shown to cause developmental alterations and to predispose for mammary cancer in rodent models. In contrast, the phytochemical genistein has been reported to suppress chemically induced mammary cancer in rodents, and Asians ingesting a diet high in soy containing genistein have lower incidence of breast and prostate cancers. In this study, we sought to: (1) identify protein biomarkers of susceptibility from blood sera of rats exposed prepubertally to BPA or genistein using Isobaric Tandem Mass Tags quantitative mass spectrometry (TMT-MS) combined with MudPIT technology and, (2) explore the relevance of these proteins to carcinogenesis. Prepubertal exposures to BPA and genistein resulted in altered expression of 63 and 28 proteins in rat sera at postnatal day (PND) 21, and of 9 and 18 proteins in sera at PND35, respectively. This study demonstrates the value of using quantitative proteomic techniques to explore the effect of chemical exposure on the rat serum proteome and its potential for unraveling cellular targets altered by BPA and genistein involved in carcinogenesis. PMID:24552547

Effects of dietary phytoestrogens on plasma testosterone and triiodothyronine (T3) levels in male goat kids.

PubMed

Gunnarsson, David; Selstam, Gunnar; Ridderstråle, Yvonne; Holm, Lena; Ekstedt, Elisabeth; Madej, Andrzej

2009-12-10

Exposure to xenoestrogens in humans and animals has gained increasing attention due to the effects of these compounds on reproduction. The present study was undertaken to investigate the influence of low-dose dietary phytoestrogen exposure, i.e. a mixture of genistein, daidzein, biochanin A and formononetin, on the establishment of testosterone production during puberty in male goat kids. Goat kids at the age of 3 months received either a standard diet or a diet supplemented with phytoestrogens (3-4 mg/kg/day) for approximately 3 months. Plasma testosterone and total and free triiodothyronine (T3) concentrations were determined weekly. Testicular levels of testosterone and cAMP were measured at the end of the experiment. Repeated measurement analysis of variance using the MIXED procedure on the generated averages, according to the Statistical Analysis System program package (Release 6.12, 1996, SAS Institute Inc., Cary, NC, USA) was carried out. No significant difference in plasma testosterone concentration between the groups was detected during the first 7 weeks. However, at the age of 5 months (i.e. October 1, week 8) phytoestrogen-treated animals showed significantly higher testosterone concentrations than control animals (37.5 nmol/l vs 19.1 nmol/l). This elevation was preceded by a rise in plasma total T3 that occurred on September 17 (week 6). A slightly higher concentration of free T3 was detected in the phytoestrogen group at the same time point, but it was not until October 8 and 15 (week 9 and 10) that a significant difference was found between the groups. At the termination of the experiment, testicular cAMP levels were significantly lower in goats fed a phytoestrogen-supplemented diet. Phytoestrogen-fed animals also had lower plasma and testicular testosterone concentrations, but these differences were not statistically significant. Our findings suggest that phytoestrogens can stimulate testosterone synthesis during puberty in male goats by increasing

Effects of dietary phytoestrogens on plasma testosterone and triiodothyronine (T3) levels in male goat kids

PubMed Central

2009-01-01

Background Exposure to xenoestrogens in humans and animals has gained increasing attention due to the effects of these compounds on reproduction. The present study was undertaken to investigate the influence of low-dose dietary phytoestrogen exposure, i.e. a mixture of genistein, daidzein, biochanin A and formononetin, on the establishment of testosterone production during puberty in male goat kids. Methods Goat kids at the age of 3 months received either a standard diet or a diet supplemented with phytoestrogens (3 - 4 mg/kg/day) for ~3 months. Plasma testosterone and total and free triiodothyronine (T3) concentrations were determined weekly. Testicular levels of testosterone and cAMP were measured at the end of the experiment. Repeated measurement analysis of variance using the MIXED procedure on the generated averages, according to the Statistical Analysis System program package (Release 6.12, 1996, SAS Institute Inc., Cary, NC, USA) was carried out. Results No significant difference in plasma testosterone concentration between the groups was detected during the first 7 weeks. However, at the age of 5 months (i.e. October 1, week 8) phytoestrogen-treated animals showed significantly higher testosterone concentrations than control animals (37.5 nmol/l vs 19.1 nmol/l). This elevation was preceded by a rise in plasma total T3 that occurred on September 17 (week 6). A slightly higher concentration of free T3 was detected in the phytoestrogen group at the same time point, but it was not until October 8 and 15 (week 9 and 10) that a significant difference was found between the groups. At the termination of the experiment, testicular cAMP levels were significantly lower in goats fed a phytoestrogen-supplemented diet. Phytoestrogen-fed animals also had lower plasma and testicular testosterone concentrations, but these differences were not statistically significant. Conclusion Our findings suggest that phytoestrogens can stimulate testosterone synthesis during puberty in

Genistein suppresses adhesion-induced protein tyrosine phosphorylation and invasion of B16-BL6 melanoma cells.

PubMed

Yan, C; Han, R

1998-07-03

Protein tyrosine phosphorylation occurs as one of the earlier events in cancer cell-extracellular matrix (ECM) interaction. With immunoblot analysis and immunofluorescence microscopy, genistein was found to suppress the tyrosine phosphorylation of proteins located at the cell periphery, including a 125 kDa protein, when B16-BL6 melanoma cells attached to and interacted with ECM. When accompanied by the suppression of adhesion-induced protein tyrosine phosphorylation, the invasive potential of B16-BL6 cells through reconstituted basement membrane was decreased significantly. However, neither adhesive capability nor cell growth was significantly affected by genistein. Therefore, the interruption of cancer cell-ECM interaction by suppression of protein tyrosine phosphorylation may contribute to invasion prevention of genistein.

Genistein modifies liver fibrosis and improves liver function by inducing uPA expression and proteolytic activity in CCl4-treated rats.

PubMed

Salas, Alfonso Leija; Montezuma, Tania Díaz; Fariña, German Garrido; Reyes-Esparza, Jorge; Rodríguez-Fragoso, Lourdes

2008-01-01

To evaluate the effect of genistein on the fibrosis and matrix degradation caused by experimentally induced fibrosis in rats. Hepatic fibrosis was brought about by chronic administration of carbon tetrachloride to rats. To evaluate the effect of genistein on liver fibrosis and function, total collagen content and proteolytic activity in the liver were quantified. Urokinase-type plasminogen activator (uPA) expression during experimental fibrosis was localized by immunohistochemistry. Histopathological changes were evaluated using light and electron microscopy. Animals with fibrosis and treated with genistein showed an important reduction (73%) in hepatic collagen content as well as an improvement in liver function (p < 0.001). Genistein increased the capacity of the liver to degrade type I collagen and Matrigel (3.1- and 3.7-fold, respectively; p < 0.001) in animals with liver fibrosis. Genistein increased the number of uPA-immunoreactive cells. The increase in the uPA expression correlated with an increase in proteolytic activity. Histological analysis revealed a reduction in the number of fiber septa in pericentral and perisinusoidal areas. Transmission electron micrographs of livers from animals with fibrosis and treated with genistein showed a reduction in the number of hepatic stellate cells activated and a smaller number of collagen fibers. Genistein is able to improve the liver after injury and fibrosis induced by chronic administration of carbon tetrachloride. This finding suggests that genistein has antifibrogenic potential and could therefore be useful for treating chronic liver disease. (c) 2008 S. Karger AG, Basel.

Genistein induces apoptosis by the inactivation of the IGF-1R/p-Akt signaling pathway in MCF-7 human breast cancer cells.

PubMed

Chen, Jun; Duan, Yuxin; Zhang, Xing; Ye, Yu; Ge, Bo; Chen, Jian

2015-03-01

Genistein is an estrogenic soy-derived compound belonging to the isoflavone class and shows anti-cancer effects. However, the specific cell apoptosis mechanisms of genistein have not been fully understood. In this study, we investigated the specific cell apoptosis mechanisms of genistein and the potential involvement of the IGF1R-Akt-Bcl-2 and Bax-mediated pathways in human breast cancer cells in vitro. MCF-7 human breast cancer cells were treated with various concentrations of genistein, and cell proliferation was evaluated by the MTT assay. Morphological changes in treated cells were examined by Hoechst 33258 staining, and treated cells were examined by flow cytometry. The levels of IGF-1R, p-Akt, Bcl-2, and Bax protein expression and Bcl-2 and Bax mRNA expression were evaluated by western blot and RT-PCR, respectively. Genistein inhibited the proliferation of MCF-7 cells and induced cell apoptosis, as determined by Hoechst staining and flow cytometry analysis. Furthermore, genistein induced the inactivation of IGF-1R and p-Akt and downregulated the Bcl-2/Bax protein ratio. These results suggest that genistein inhibited cell proliferation by inactivating the IGF-1R-PI3 K/Akt pathway and decreasing the Bcl-2/Bax mRNA and protein expressions. Our findings help elucidate the mechanisms by which genistein may contribute to the prevention of breast cancer carcinogenesis.

Effects of genistein on early-stage cutaneous wound healing

DOE Office of Scientific and Technical Information (OSTI.GOV)

Park, Eunkyo; Lee, Seung Min; Jung, In-Kyung

2011-07-08

Highlights: {yields} We examine the effect of genistein on cutaneous wound healing. {yields} Genistein enhanced wound closure during the early stage of wound healing. {yields} These genistein effects on wound closure were induced by reduction of oxidative stress through increasing antioxidant capacity and modulation of pro-inflammatory cytokine expression. -- Abstract: Wound healing occurs in three sequential phases: hemostasis and inflammation, proliferation, and remodeling. Inflammation, the earliest phase, is considered a critical period for wound healing because immune cells remove damaged tissues, foreign debris, and remaining dead tissue. Wound healing would be delayed without inflammation, and this phase is affected bymore » antioxidation capacity. Therefore, we hypothesized that genistein, which has an antioxidant effect, might modulate the wound healing process by altering the inflammatory response. After three days of acclimation, mice were divided into three groups: control, 0.025% genistein, and 0.1% genistein. After two weeks of an experimental diet, skin wounds were induced. Wounded skin areas were imaged, and the healing rate calculated. To measure lipid peroxidation, antioxidant enzyme expression and activity, and pro-inflammatory cytokine expression, skin and liver tissues were harvested at 12, 24, 48, and 72 h. Genistein did not affect body weight. The rate of wound closure in mice fed genistein was significantly faster than in the control group during the early stage of wound healing, especially in first three days. Cu, Zn-SOD and Mn-SOD expression in wound skin tissue in the 0.1% genistein group was lower than in the control group. However, CAT expression did not differ among groups. We also found that genistein modulated NF-{kappa}B and TNF-{alpha} expression during the early stage of wound healing. The genistein group had significantly lower hepatic lipid peroxidation and higher SOD, CAT, and GPx activities than the control group. These

Collagen concentration on the facial skin of postmenopausal women after topical treatment with estradiol and genistein: a randomized double-blind controlled trial.

PubMed

Silva, Lidia Aragão; Ferraz Carbonel, Adriana Aparecida; de Moraes, Andréa Regina Barbosa; Simões, Ricardo S; Sasso, Gisela Rodrigues da Silva; Goes, Lívia; Nunes, Winnie; Simões, Manuel Jesus; Patriarca, Marisa Teresinha

2017-11-01

The objective of this study is to compare the effects of topical estrogen and genistein (a soy isoflavone) on the facial skin collagen of postmenopausal women not undergoing systemic hormonal therapy. This is a prospective, double blind, randomized, controlled clinical trial. Volunteer women (N = 30) 45-55 year old from the Endocrine Gynecology sector of the Gynecology Department of the Federal University of São Paulo (UNIFESP). The Ethical Committee of the Federal University of São Paulo approved the study (report no. 386/2004; registration on ClinicalTrials.gov NCT01553773), were assigned to topical treatment with either estrogen or genistein for 24 weeks. We quantified and compared facial collagen concentration before and after each treatment by performing pre-auricular skin biopsies. Our data showed an increase in the amount of both type I and type III facial collagen by the end of both treatments. However, the outcomes of the estrogen GI (ER) group were superior to the genistein GII (GEN) group, with statistical significance p < 000.1 Conclusion: Treatment with topical estrogen is superior to genistein, but both have positive impacts on facial skin collagen. Nevertheless, it is still unclear whether prolonged use of genistein and other topical phytoestrogens could produce systemic effects and further research is needed to clarify this question.

Phytoestrogens and mycotoxins in Iowa streams: An examination of underinvestigated compounds in agricultural basins

USGS Publications Warehouse

Kolpin, Dana W.; Hoerger, Corinne C.; Meyer, Michael T.; Wettstein, Felix E.; Hubbard, Laura E.; Bucheli, Thomas D.

2010-01-01

This study provides the first broad-scale investigation on the spatial and temporal occurrence of phytoestrogens and mycotoxins in streams in the United States. Fifteen stream sites across Iowa were sampled five times throughout the 2008 growing season to capture a range of climatic and crop-growth conditions. Basin size upstream from sampling sites ranged from 7 km2 to >836,000 km2 Atrazine (herbicide) also was measured in all samples as a frame-of-reference agriculturally derived contaminant. Target compounds were frequently detected in stream samples: atrazine (100%), formononetin (80%), equol (45%), deoxynivalenol (43%), daidzein (32%), biochanin A (23%), zearalenone (13%), and genistein (11%). The nearly ubiquitous detection of formononetin (isoflavone) suggests a widespread agricultural source, as one would expect with the intense row crop and livestock production present across Iowa. Conversely, the less spatially widespread detections of deoxynivalenol (mycotoxin) suggest a more variable source due to the required combination of proper host and proper temperature and moisture conditions necessary to promote Fusarium spp. infections. Although atrazine concentrations commonly exceeded 100 ng L-1 (42/75 measurements), only deoxynivalenol (6/56 measurements) had concentrations that occasionally exceeded this level. Temporal patterns in concentrations varied substantially between atrazine, formononetin, and deoxynivalenol, as one would expect for contaminants with different source inputs and processes of formation and degradation. The greatest phytoestrogen and mycotoxin concentrations were observed during spring snowmelt conditions. Phytoestrogens and mycotoxins were detected at all sampling sites regardless of basin size. The ecotoxicological effects from long-term, low-level exposures to phytoestrogens and mycotoxins or complex chemicals mixtures including these compounds that commonly take place in surface water are poorly understood and have yet to be

Phytoestrogens and mycotoxins in Iowa streams: An examination of underinvestigated compounds in agricultural basins

USGS Publications Warehouse

Kolpin, D.W.; Hoerger, C.C.; Meyer, M.T.; Wettstein, F.E.; Hubbard, L.E.; Bucheli, T.D.

2010-01-01

This study provides the first broad-scale investigation on the spatial and temporal occurrence of phytoestrogens and mycotoxins in streams in the United States. Fifteen stream sites across Iowa were sampled five times throughout the 2008 growing season to capture a range of climatic and crop-growth conditions. Basin size upstream from sampling sites ranged from 7 km2 to >836,000 km2. Atrazine (herbicide) also was measured in all samples as a frame-ofreference agriculturally derived contaminant. Target compounds were frequently detected in stream samples: atrazine (100%), formononetin (80%), equol (45%), deoxynivalenol (43%), daidzein (32%), biochanin A (23%), zearalenone (13%), and genistein (11%). Th e nearly ubiquitous detection of formononetin (isoflavone) suggests a widespread agricultural source, as one would expect with the intense row crop and livestock production present across Iowa. Conversely, the less spatially widespread detections of deoxynivalenol (mycotoxin) suggest a more variable source due to the required combination of proper host and proper temperature and moisture conditions necessary to promote Fusarium spp. infections. Although atrazine concentrations commonly exceeded 100 ng L-1 (42/75 measurements), only deoxynivalenol (6/56 measurements) had concentrations that occasionally exceeded this level. Temporal patterns in concentrations varied substantially between atrazine, formononetin, and deoxynivalenol, as one would expect for contaminants with different source inputs and processes of formation and degradation. The greatest phytoestrogen and mycotoxin concentrations were observed during spring snowmelt conditions. Phytoestrogens and mycotoxins were detected at all sampling sites regardless of basin size. The ecotoxicological effects from long-term, low-level exposures to phytoestrogens and mycotoxins or complex chemicals mixtures including these compounds that commonly take place in surface water are poorly understood and have yet to be

Molecular Mechanism of Action of Genistein and Related Phytoestrogens in Estrogen-Receptor Dependent and Independent Growth of Breast Cancer Cells

DTIC Science & Technology

1999-07-01

quercetin inhibited ER-negative MDA-MB-468 breast cancer cell growth with 1050 values of 8.8 and 18.1 Micronmeter, respectively. The other compounds...were less effective. The mechanism of growth inhibition by genistein and quercetin involved G2/M cell cycle arrest, changes in cyclin B1 levels and...apoptosis. Our results indicate that genistein and quercetin may be useful in the treatment of ER-negative tumors. Results of our studies on MDA-MB-468 cells have been documented and submitted for publication.

Phytoestrogen Concentrations in Human Urine as Biomarkers for Dietary Phytoestrogen Intake in Mexican Women

PubMed Central

Chávez-Suárez, Karina M.; Ortega-Vélez, María I.; Valenzuela-Quintanar, Ana I.; Galván-Portillo, Marcia; López-Carrillo, Lizbeth; Esparza-Romero, Julián; Saucedo-Tamayo, María S.; Robles-Burgueño, María R.; Gutiérrez-Coronado, María L.; Campa-Siqueiros, Melissa M.; Grajeda-Cota, Patricia; Caire-Juvera, Graciela

2017-01-01

There has been substantial interest in phytoestrogens, because of their potential effect in reducing cancer and heart disease risk. Measuring concentrations of phytoestrogens in urine is an alternative method for conducting epidemiological studies. Our objective was to evaluate the urinary excretion of phytoestrogens as biomarkers for dietary phytoestrogen intake in Mexican women. Participants were 100 healthy women from 25 to 80 years of age. A food frequency questionnaire (FFQ) and a 24 h recall were used to estimate habitual and recent intakes of isoflavones, lignans, flavonols, coumestrol, resveratrol, naringenin, and luteolin. Urinary concentrations were measured by liquid chromatography (HPLC) coupled to mass spectrometry (MS) using the electrospray ionization interface (ESI) and diode array detector (DAD) (HPLC-DAD-ESI-MS). Spearman correlation coefficients were used to evaluate associations between dietary intake and urine concentrations. The habitual consumption (FFQ) of total phytoestrogens was 37.56 mg/day. In urine, the higher compounds were naringenin (60.1 µg/L) and enterolactone (41.7 µg/L). Recent intakes (24 h recall) of isoflavones (r = 0.460, p < 0.001), lignans (r = 0.550, p < 0.0001), flavonoids (r = 0.240, p < 0.05), and total phytoestrogens (r = 0.410, p < 0.001) were correlated to their urinary levels. Total phytoestrogen intakes estimated by the FFQ showed higher correlations to urinary levels (r = 0.730, p < 0.0001). Urinary phytoestrogens may be useful as biomarkers of phytoestrogen intake, and as a tool for evaluating the relationship of intake and disease risk in Mexican women. PMID:28961176

Pharmacokinetics interaction between imatinib and genistein in rats.

PubMed

Wang, Zhe; Wang, Li; Xia, Meng-Ming; Sun, Wei; Huang, Cheng-Ke; Cui, Xiao; Hu, Guo-Xin; Lian, Qing-Quan; Wang, Zeng-Shou

2015-01-01

The objective of this work was to investigate the effect of orally administered genistein on the pharmacokinetics of imatinib and N-desmethyl imatinib in rats. Twenty-five healthy male SD (Sprague-Dawley) rats were randomly divided into five groups: A group (control group), B group (multiple dose of 100 mg/kg genistein for consecutive 15 days), C group (multiple dose of 50 mg/kg genistein for consecutive 15 days), D group (a single dose of 100 mg/kg genistein), and E group (a single dose of 50 mg/kg genistein). A single dose of imatinib is administered orally 30 min after administration of genistein (100 mg/kg or 50 mg/kg). The pharmacokinetic parameters of imatinib and N-desmethyl imatinib were calculated by DAS 3.0 software. The multiple dose of 100 mg/kg or 50 mg/kg genistein significantly (P < 0.05) decreased the AUC0-t and C max of imatinib. AUC0-t and the C max of N-desmethyl imatinib were also increased, but without any significant difference. However, the single dose of 100 mg/kg or 50 mg/kg genistein has no effect on the pharmacokinetics of imatinib and N-desmethyl imatinib. Those results indicated that multiple dose of genistein (100 mg/kg or 50 mg/kg) induces the metabolism of imatinib, while single dose of genistein has no effect.

Phytoestrogens and Mycoestrogens Induce Signature Structure Dynamics Changes on Estrogen Receptor α

PubMed Central

Chen, Xueyan; Uzuner, Ugur; Li, Man; Shi, Weibing; Yuan, Joshua S.; Dai, Susie Y.

2016-01-01

Endocrine disrupters include a broad spectrum of chemicals such as industrial chemicals, natural estrogens and androgens, synthetic estrogens and androgens. Phytoestrogens are widely present in diet and food supplements; mycoestrogens are frequently found in grains. As human beings and animals are commonly exposed to phytoestrogens and mycoestrogens in diet and environment, it is important to understand the potential beneficial or hazardous effects of estrogenic compounds. Many bioassays have been established to study the binding of estrogenic compounds with estrogen receptor (ER) and provided rich data in the literature. However, limited assays can offer structure information with regard to the ligand/ER complex. Our current study surveys the global structure dynamics changes for ERα ligand binding domain (LBD) when phytoestrogens and mycoestrogens bind. The assay is based on the structure dynamics information probed by hydrogen deuterium exchange mass spectrometry and offers a unique viewpoint to elucidate the mechanism how phytoestrogens and mycoestrogens interact with estrogen receptor. The cluster analysis based on the hydrogen deuterium exchange (HDX) assay data reveals a unique pattern when phytoestrogens and mycoestrogens bind with ERα LBD compared to that of estradiol and synthetic estrogen modulators. Our study highlights that structure dynamics could play an important role in the structure function relationship when endocrine disrupters interact with estrogen receptors. PMID:27589781

Association between Dietary Share of Ultra-Processed Foods and Urinary Concentrations of Phytoestrogens in the US.

PubMed

Martínez Steele, Eurídice; Monteiro, Carlos A

2017-02-28

The aim of this study was to examine the relationship between dietary contribution of ultra-processed foods and urinary phytoestrogen concentrations in the US. Participants from cross-sectional 2009-2010 National Health and Nutrition Examination Survey aged 6+ years, selected to measure urinary phytoestrogens and with one 24-h dietary recall were evaluated (2692 participants). Food items were classified according to NOVA (a name, not an acronym), a four-group food classification based on the extent and purpose of industrial food processing. Ultra-processed foods are formulations manufactured using several ingredients and a series of processes (hence "ultra-processed"). Most of their ingredients are lower-cost industrial sources of dietary energy and nutrients, with additives used for the purpose of imitating sensorial qualities of minimally processed foods or of culinary preparations of these foods. Studied phytoestrogens included lignans (enterolactone and enterodiol) and isoflavones (genistein, daidzein, O -desmethylangolensin and equol). Gaussian regression was used to compare average urinary phytoestrogen concentrations (normalized by creatinine) across quintiles of energy share of ultra-processed foods. Models incorporated survey sample weights and were adjusted for age, sex, race/ethnicity, family income, and education, among other factors. Adjusted enterodiol geometric means decreased monotonically from 60.6 in the lowest quintile to 35.1 µg/g creatinine in the highest, while adjusted enterolactone geometric means dropped from 281.1 to 200.1 across the same quintiles, respectively. No significant linear trend was observed in the association between these quintiles and isoflavone concentrations. This finding reinforces the existing evidence regarding the negative impact of ultra-processed food consumption on the overall quality of the diet and expands it to include non-nutrients such as lignans.

Phytonutrient genistein is a survival factor for pancreatic β-cells via GPR30-mediated mechanism.

PubMed

Luo, Jing; Wang, Aihua; Zhen, Wei; Wang, Yao; Si, Hongwei; Jia, Zhenquan; Alkhalidy, Hana; Cheng, Zhiyong; Gilbert, Elizabeth; Xu, Bin; Liu, Dongmin

2018-05-12

We previously discovered that phytonutrient genistein rapidly activates cAMP signaling in β-cells and improves islet mass in diabetic mice. However, the mechanism underlying these actions of genistein is still unclear. Here, we show that pharmacological or molecular inhibition of Gαs blocked genistein-stimulated adenylate cyclase activity in plasma membrane and intracellular cAMP production in INS1 cells and islets. Further, genistein stimulation of cAMP generation was abolished in islets exposed to a specific GPR30 inhibitor G15 or islets from GPR30 deficient (GPR30-/-) mice. In vivo, dietary provision of genistein (0.5 g/kg diet) significantly mitigated streptozotocin-induced hyperglycemia in male WT mice, which was associated with improved blood insulin levels and pancreatic islet mass and survival, whereas these effects were absent in Gpr30-/- mice. Genistein treatment promoted survival of INS1 cells and human islets chronically exposed to palmitate and high glucose. At molecular level, genistein activated CREB phosphorylation and subsequently induced Bcl-2 expression, and knockdown of CREB diminished the protective effect of genistein on β-cells induced by lipoglucotoxicity. Finally, deletion of GPR30 in β-cells or islets ablated genistein-induced CREB phosphorylation and its cytoprotective effect. These findings demonstrate that genistein is a survival factor for β-cells via GPR30-initiated, Gαs-mediated activation of CREB. Copyright © 2018 Elsevier Inc. All rights reserved.

Phytoestrogens and risk of prostate cancer: an updated meta-analysis of epidemiologic studies.

PubMed

Zhang, Qiang; Feng, Hongliang; Qluwakemi, Bakare; Wang, Jiaqi; Yao, Songpo; Cheng, Guangdong; Xu, Hui; Qiu, Hongbin; Zhu, Liling; Yuan, Mingxia

2017-02-01

This updated meta-analysis was performed to clarify the relationship between phytoestrogens and prostate cancer risk. Twenty one case-control and two cohort studies were finally selected for this meta-analysis, totaling 11,346 cases and 140,177 controls. Analytical results showed that daidzein (OR = 0.85; 95% CI: 0.75-0.96), genistein (OR = 0.87; 95% CI: 0.78-0.98), and glycitein (OR = 0.89; 95% CI: 0.81-0.98) were associated with a reduction of prostate cancer risk, but total isoflavones (OR = 0.93; 95% CI: 0.84-1.04), equol (OR = 0.86; 95% CI: 0.66-1.14), total lignans (OROgna.05; 95% CI: 0.54-2.04), secoisolariciresinol (OR = 1.02; 95% CI: 0.83-1.24), matairesinol (OR = 0.91; 95% CI: 0.75-1.11), enterolactone (OR = 0.94; 95% CI: 0.73-1.20), and coumestrol (OR = 0.89; 95% CI: 0.76-1.06) were not. Sensitivity and publication bias analyses demonstrated that the pooled estimates were stable and reliable. The results support the notion that some phytoestrogens may have a role in decreasing the risk of prostate cancer. Additional large and well-designed cohort studies are needed to confirm these relationships.

Association between Dietary Share of Ultra-Processed Foods and Urinary Concentrations of Phytoestrogens in the US

PubMed Central

Martínez Steele, Eurídice; Monteiro, Carlos A.

2017-01-01

The aim of this study was to examine the relationship between dietary contribution of ultra-processed foods and urinary phytoestrogen concentrations in the US. Participants from cross-sectional 2009–2010 National Health and Nutrition Examination Survey aged 6+ years, selected to measure urinary phytoestrogens and with one 24-h dietary recall were evaluated (2692 participants). Food items were classified according to NOVA (a name, not an acronym), a four-group food classification based on the extent and purpose of industrial food processing. Ultra-processed foods are formulations manufactured using several ingredients and a series of processes (hence “ultra-processed”). Most of their ingredients are lower-cost industrial sources of dietary energy and nutrients, with additives used for the purpose of imitating sensorial qualities of minimally processed foods or of culinary preparations of these foods. Studied phytoestrogens included lignans (enterolactone and enterodiol) and isoflavones (genistein, daidzein, O-desmethylangolensin and equol). Gaussian regression was used to compare average urinary phytoestrogen concentrations (normalized by creatinine) across quintiles of energy share of ultra-processed foods. Models incorporated survey sample weights and were adjusted for age, sex, race/ethnicity, family income, and education, among other factors. Adjusted enterodiol geometric means decreased monotonically from 60.6 in the lowest quintile to 35.1 µg/g creatinine in the highest, while adjusted enterolactone geometric means dropped from 281.1 to 200.1 across the same quintiles, respectively. No significant linear trend was observed in the association between these quintiles and isoflavone concentrations. This finding reinforces the existing evidence regarding the negative impact of ultra-processed food consumption on the overall quality of the diet and expands it to include non-nutrients such as lignans. PMID:28264475

Attenuation by genistein of sodium-chloride-enhanced gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine in Wistar rats.

PubMed

Tatsuta, M; Iishi, H; Baba, M; Yano, H; Uehara, H; Nakaizumi, A

1999-01-29

The effects of prolonged administration of genistein, a tyrosine-kinase inhibitor, on sodium-chloride-enhanced induction of gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine, and the labeling and apoptotic indices and vessel counts in the gastric mucosa and gastric cancers, were investigated in Wistar rats. After 25 weeks of the carcinogen treatment, rats were fed chow pellets containing 10% sodium chloride and were given s.c. injections of genistein at dosages of 15 mg/kg or 30 mg/kg body weight every other day. In week 52, the incidence of gastric cancers was significantly greater in rats fed sodium chloride than in untreated control rats. Prolonged administration of genistein at a dosage of 30 mg/kg, but not 15 mg/kg, body weight significantly reduced the incidence of gastric cancers, which was increased by oral treatment with sodium chloride. Genistein at the higher dose significantly decreased the labeling index and vessel counts of the antral mucosa and the gastric cancers (which were increased by treatment with sodium chloride) and significantly increased the apoptotic index of the antral mucosa and the cancers (which was lowered by the treatment with sodium chloride). These findings suggest that genistein attenuates gastric carcinogenesis promoted by sodium chloride, by inducing increased apoptosis and lower cell proliferation and angiogenesis of antral mucosa and gastric cancers.

Suppression of adhesion-induced protein tyrosine phosphorylation decreases invasive and metastatic potentials of B16-BL6 melanoma cells by protein tyrosine kinase inhibitor genistein.

PubMed

Yan, C; Han, R

1997-01-01

Protein tyrosine kinase (PTK) appears to be involved in the activation of signaling during cell attachment to and spreading on extracellular matrix (ECM) in the metastatic cascade. To verify the assumption that PTK inhibitors might impair ECM signaling and prevent cancer metastasis, the highly metastatic B16-BL6 mouse melanoma cells were exposed to the PTK inhibitor genistein for 3 days. The ability of the cells to invade through reconstituted basement membrane (Matrigel) and to establish experimental pulmonary metastatic foci in C57BL/6 mice decreased after genistein exposure. The genistein-treated cells were also prevented from attaching to Matrigel and spread extremely poorly on the ECM substratum. Immunoblot analysis showed that tyrosine phosphorylation of a 125-kD protein in response to cell spreading on Matrigel was suppressed in the genistein-treated cells. Adhesion-induced protein tyrosine phosphorylation represents the earlier and specific event in the activation of ECM signaling, so this result implied ECM signaling was impaired in the treated cells. With immunofluorescence microscopy, the adhesion-induced tyrosine phosphorylated proteins were located at the pericytoplasms of well-spread cells, but not at the periphery of poorly spread genistein-treated cells. Therefore, this paper suggests that genistein might impair ECM signaling and subsequently prevent cancer cells from spreading well and invading or establishing metastasis through the suppression of adhesion-induced protein tyrosine phosphorylation. PTKs and adhesion-induced protein tyrosine phosphorylation might play a role in the control of invasion and metastasis.

Ameliorative effect of dietary genistein on diabetes induced hyper-inflammation and oxidative stress during early stage of wound healing in alloxan induced diabetic mice.

PubMed

Eo, Hyeyoon; Lee, Hea-Ji; Lim, Yunsook

2016-09-23

Among the diabetic complications, diabetic foot ulcer due to delayed wound healing is one of the most significant clinical problems. Early inflammatory stage is important for better prognosis during wound healing. Thus, regulation of inflammatory response during early stage of wound healing is main target for complete cutaneous recovery. This study investigated the role of genistein supplementation in inflammation and oxidative stress, which are related to NLRP3 inflammasome, NFκB and Nrf2 activation, during cutaneous wound healing in alloxan-induced diabetic mice. Mice with diabetes with fasting blood glucose (FBG) levels > 250 mg/dl were fed diets with AIN-93G rodent diet containing 0%, 0.025% (LG) or 0.1% (HG) genistein. After 2 weeks of genistein supplementation, excisional wounds were made by biopsy punches (4 mm). Genistein supplementation improved fasting glucose levels and wound closure rate. Moreover, genistein supplementation restored NLRP3 inflammasome (NLRP3, ASC and caspase-1) at the basal level and ameliorated both inflammation (TNFα, iNOS, COX2 and NFκB) and antioxidant defense system (Nrf2, HO-1, GPx, and catalase) during early stage of wound healing in diabetic mice. Taken together, genistein supplementation would be a potential therapeutic nutrient in prevention and treatment of delayed wound healing by modulation of inflammation and oxidative stress during inflammatory stage. Copyright © 2016. Published by Elsevier Inc.

Association between dietary phytoestrogens intakes and prostate cancer risk in Sicily.

PubMed

Russo, Giorgio I; Di Mauro, Marina; Regis, Federica; Reale, Giulio; Campisi, Daniele; Marranzano, Marina; Lo Giudice, Arturo; Solinas, Tatiana; Madonia, Massimo; Cimino, Sebastiano; Morgia, Giuseppe

2018-03-01

In this study we aimed to investigate the association between dietary phytoestrogen consumption and prostate cancer in a sample of southern Italian individuals. A population-based case-control study on the association between prostate cancer and dietary factors was conducted from January 2015 to December 2016 in a single institution of the municipality of Catania, southern Italy (Registration number: 41/2015). A total of 118 histopathological-verified prostate cancer (PCa) cases and a total of 222 controls were collected. Dietary data was collected by using two food frequency questionnaires. Patients with PCa consumed significantly higher levels of phytoestrogens. Multivariate logistic regression showed that lignans (Q[quartile]4 vs. Q1, OR [odds ratio] = 4.72; p < .05) and specifically, lariciresinol (Q4 vs. Q1, OR = 4.60; p < .05), pinoresinol (Q4 vs. Q1, OR = 5.62; p < .05), matairesinol (Q4 vs. Q1, OR = 3.63; p < .05), secoisolariciresinol (Q4 vs. Q1, OR = 4.10; p < .05) were associated with increased risk of PCa. Furthermore, we found that isoflavones (Q3 vs. Q1, OR = 0.28; p < .05) and specifically, genistein (Q4 vs. Q1, OR = 0.40; p < .05) were associated with reduced risk of PCa. We found of an inverse association between dietary isoflavone intake and PCa, while a positive association was found with lignans intake.

Phytochemical genistein in the regulation of vascular function: new insights.

PubMed

Si, Hongwei; Liu, Dongmin

2007-01-01

Genistein, a natural bioactive compound derived from legumes, has drawn wide attention during the last decade because of its potentially beneficial effects on some human degenerative diseases. It has a weak estrogenic effect and is a well-known non-specific tyrosine kinase inhibitor at pharmacological doses. Epidemiological studies show that genistein intake is inversely associated with the risk of cardiovascular diseases. Data from animal and in vitro studies suggest a protective role of genistein in cardiovascular events. However, the mechanisms of the genistein action on vascular protective effects are unclear. Past extensive studies exploring its hypolipidemic effect resulted in contradictory data. Genistein also is a relatively poor antioxidant. However, genistein protects against pro-inflammatory factor-induced vascular endothelial barrier dysfunction and inhibits leukocyte-endothelium interaction, thereby modulating vascular inflammation, a major event in the pathogenesis of atherosclerosis. Recent studies found that genistein exerts a novel non-genomic action by targeting on important signaling molecules in vascular endothelial cells (ECs). Genistein rapidly activates endothelial nitric oxide synthase and production of nitric oxide in ECs. This genistein effect is novel since it is independent of its known effects, but mediated by the cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) cascade. Further studies demonstrated that genistein directly stimulates the plasma membrane-associated adenylate cyclases, leading to activation of the cAMP signaling pathway. In addition, genistein activates peroxisome proliferator-activated receptors, ligand-activated nuclear receptors important to normal vascular function. Furthermore, genistein reduces reactive oxygen species (ROS) by attenuating the expression of ROS-producing enzymes. These new findings reveal the novel roles for genistein in the regulation of vascular function and provide a basis for further

A Commentary on Phytoestrogens and Disease

ERIC Educational Resources Information Center

Hard, Alison; Edelstein, Sari

2015-01-01

On the most basic level, phytoestrogens can be defined as compounds found in plants that exhibit estrogen-like activity in the human body. Phytoestrogens are considered functional foods because of their diverse physiological effects beyond basic nutritional functions. The 2 primary categories of phytoestrogens found in food are lignans and…

Genistein prevents hyperglycemia-induced monocyte adhesion to human aortic endothelial cells through preservation of the cAMP signaling pathway and ameliorates vascular inflammation in obese diabetic mice.

PubMed

Babu, Pon Velayutham Anandh; Si, Hongwei; Fu, Zhuo; Zhen, Wei; Liu, Dongmin

2012-04-01

Hyperglycemia-induced vascular inflammation resulting in the enhanced monocyte-endothelial cell (EC) interaction is the key event in the pathogenesis of atherosclerosis in diabetes. Here, we investigated the effect of isoflavone genistein on hyperglycemia-stimulated vascular inflammation. Human aortic EC (HAEC) were pretreated with genistein before the addition of high glucose (HG; 25 mmol/L) for 48 h. Genistein at a physiological concentration (0.1 μmol/L) significantly inhibited HG-induced adhesion of monocytes to HAEC and suppressed endothelial production of monocyte chemotactic protein-1 (MCP-1) and IL-8. Inhibition of adenylate cyclase or protein kinase A (PKA) significantly attenuated the antiadhesion effect of genistein. Consistently, genistein improved HG-impaired intracellular cAMP production and PKA activity in HAEC. Six-week-old diabetic db/db mice were untreated (db/db) or treated with a diet containing 1 g genistein/kg diet (db/db+G) for 8 wk. Their nondiabetic db/+ mice were used as normal controls. Circulating concentrations of MCP-1/JE and KC were significantly greater, whereas IL-10 concentrations were lower in db/db mice than those in normal mice. Dietary supplementation of genistein did not normalize but significantly suppressed the elevated serum concentrations of MCP-1/JE from 286 ± 30 ng/L to 181 ± 35 ng/L and KC from 321 ± 21 ng/L to 232 ± 20 ng/L while increasing that of IL-10 from 35 ± 4 ng/L to 346 ± 35 ng/L in db/db+G mice. Further, genistein treatment suppressed diabetes-induced adhesion of monocytes to EC by 87% and endothelial secretion of adhesion molecules. We conclude that genistein improves diabetes-caused vascular inflammation, which may be mediated through promoting the cAMP/PKA pathway.

[Research on phytoestrogenic effect of formononetin].

PubMed

Yu, Jie; Zhao, Piwen; Niu, Jianzhao; Wang, Jifeng; Cao, Yuankui; Hao, Qingxiu

2010-11-01

Research on the phytoestrogenic effect and its possible mechanism of formononetin. To evaluate the estrogenic effect and mechanisms of formononetin through the test of its influence on proliferation and ER subtype expression of T47D cells. The proliferation rates of T47D cells treated with 1 x 10(-7) -1 x 10(-6) mol x L(-1) formononetin were not increased. On the influence of ICI182, 780, the proliferation rates of T47D cells treated with 1 x 10(-7) 1 x 10(-6) mol x L(-1) formononetin were decreased. Formonenetin could induce the augment of ERalpha expression significantly of T47D. Formonenetin has phytoestrogenic effect Formonenetin can not accelerate ER(+) T47D cell proliferation. But the expression level of ERalpha subtype in T47D cells change significantly with certain concentrations of formonenetin.

The pros and cons of phytoestrogens

PubMed Central

Patisaul, Heather B.; Jefferson, Wendy

2011-01-01

Phytoestrogens are plant derived compounds found in a wide variety of foods, most notably soy. A litany of health benefits including a lowered risk of osteoporosis, heart disease, breast cancer, and menopausal symptoms, are frequently attributed to phytoestrogens but many are also considered endocrine disruptors, indicating that they have the potential to cause adverse health effects as well. Consequently, the question of whether or not phytoestrogens are beneficial or harmful to human health remains unresolved. The answer is likely complex and may depend on age, health status, and even the presence or absence of specific gut microflora. Clarity on this issue is needed because global consumption is rapidly increasing. Phytoestrogens are present in numerous dietary supplements and widely marketed as a natural alternative to estrogen replacement therapy. Soy infant formula now constitutes up to a third of the US market, and soy protein is now added to many processed foods. As weak estrogen agonists/antagonists with molecular and cellular properties similar to synthetic endocrine disruptors such as Bisphenol A (BPA), the phytoestrogens provide a useful model to comprehensively investigate the biological impact of endocrine disruptors in general. This review weighs the evidence for and against the purported health benefits and adverse effects of phytoestrogens. PMID:20347861

Soy and phytoestrogens: possible side effects.

PubMed

Jargin, Sergei V

2014-01-01

Phytoestrogens are present in certain edible plants being most abundant in soy; they are structurally and functionally analogous to the estrogens. Phytoestrogens have been applied for compensation of hormone deficiency in the menopause. At the same time, soy products are used in infant food and other foodstuffs. Furthermore, soy is applied as animal fodder, so that residual phytoestrogens and their active metabolites such as equol can remain in meat and influence the hormonal balance of the consumers. There have been only singular reports on modified gender-related behavior or feminization in humans in consequence of soy consumption. In animals, the intake of phytoestrogens was reported to impact fertility, sexual development and behavior. Feminizing effects in humans can be subtle and identifiable only statistically in large populations.

Effects of genistein, a soybean-derived isoflavone, on proliferation and differentiation of B16-BL6 mouse melanoma cells.

PubMed

Yan, C H; Chen, X G; Li, Y; Han, R

1999-01-01

Genistein, a soybean-derived isoflavone, may contribute to the lower cancer incidence in South Asian countries. In this study, the effects and molecular mechanisms of genistein on growth and differentiation of B16-BL6 mouse melanoma cells were investigated. Genistein suppressed the growth of these melanoma cells. The IC50 value is 15.5 microM. On the other hand, genistein induced the changes of cell shape and cytoskeletal network. The cytoskeletal filaments were induced to form a bundle along the direction of elongation of the cells. Moreover, tyrosine phosphorylation levels of cytoskeleton-associated proteins decreased after the cells were exposed to 20 or 30 microM of genistein for 3 days. All these morphological and molecular changes were accompanied by appearance of the differentiated phenotypes. Genistein induced the increase of cellular melanin content, enhancement of tyrosinase activity, and decrease of colonization potentials in soft agar in a time-dependent and dose-dependent manner. The effective concentration was no more than 10 microM after 3 days' exposure. The tumorigenic potentials of B16-BL6 cells in C57BL/6 mouse also decreased after exposure to 20 or 30 microM of genistein for 3 days. When expressions of tumor-related genes were investigated in the differentiation-induced cells, the content of P53 dramatically increased while that of c-Myc protein decreased. Therefore, due to its ability to induce cellular and molecular changes, genistein suppressed the growth and induced differentiated phenotypes in B16-BL6 melanoma cells.

Abnormal peripubertal development of the rat mammary gland following exposure in utero and during lactation to a mixture of genistein and the food contaminant vinclozolin.

PubMed

El Sheikh Saad, H; Meduri, G; Phrakonkham, P; Bergès, R; Vacher, S; Djallali, M; Auger, J; Canivenc-Lavier, M C; Perrot-Applanat, M

2011-07-01

The impact of early exposure to endocrine disruptor mixtures on mammary gland development is poorly known. Here, we identify the effects of a conception to weaning exposure of rats to the phytoestrogen genistein (G) and/or the antiandrogen vinclozolin (V) at 1mg/kg-d, alone or in association. Using several approaches, we found that G- and GV-exposed rats displayed significantly greater epithelial branching and proliferation, wider terminal end buds than controls at PND35, as well as ductal hyperplasia and periductal fibrosis. Focal branching defects were present in V-exposed rats. An increased ER and AR expression was observed in G- and GV- as compared to V-exposed rats at PND35. Surprisingly, a significant number of GV- and to a lesser extent, V-exposed animals displayed abnormal hyperplasic alveolar structures at PND50. Thus, gestational and lactational exposure to low doses of genistein plus vinclozolin may seriously affect peripubertal development of the rat mammary gland. Copyright © 2011 Elsevier Inc. All rights reserved.

Genistein Promotes Proliferation of Human Cervical Cancer Cells Through Estrogen Receptor-Mediated PI3K/Akt-NF-κB Pathway

PubMed Central

Chen, Hai-Hong; Chen, Shu-Ping; Zheng, Qiu-Ling; Nie, Shao-Ping; Li, Wen-Juan; Hu, Xiao-Juan; Xie, Ming-Yong

2018-01-01

Phytoestrogens are polyphenol compounds which have similar structure to 17β-estradiol (E2), a kind of main estrogen in women. Thus, phytoestrogens may affect the reproductive and endocrine systems, leading to the development of estrogen-related cancers. The effect of genistein (Gen), one of the most studied phytoestrogens, on human cervical cancer cells (HeLa) was investigated in this study. It was found that Gen at concentrations of 0.001, 0.01, 0.1 and 1 µmol·L-1 promoted the proliferation of HeLa cells in a dose-dependent manner. Gen increased the portion of HeLa cells in S phase and decreased the portion of the cells in G1 phase. Besides, apoptosis rate of the cells was significantly lower when treated with Gen compared with the control group. It was also found that the expression of ERα, Akt or nuclear NF-κB p65 protein was activated by Gen. The correlation between these three proteins may be as following: ERα was the upstream, followed by Akt, and then nuclear NF-κB p65 protein. In addition, the downstream genes of activated nuclear NF-κB p65 were found to be associated with cell cycle and apoptosis of cancer cells. Our results suggested that Gen may stimulate cell proliferation partially through the estrogen receptor-mediated PI3K/Akt-NF-κB pathway and the further activation of the downstream genes of nuclear NF-κB p65. PMID:29344275

Studying the effects of genistein on gene expression of fish embryos as an alternative testing approach for endocrine disruption.

PubMed

Schiller, Viktoria; Wichmann, Arne; Kriehuber, Ralf; Muth-Köhne, Elke; Giesy, John P; Hecker, Markus; Fenske, Martina

2013-01-01

Assessment of endocrine disruption currently relies on testing strategies involving adult vertebrates. In order to minimize the use of animal tests according to the 3Rs principle of replacement, reduction and refinement, we propose a transcriptomics and fish embryo based approach as an alternative to identify and analyze an estrogenic activity of environmental chemicals. For this purpose, the suitability of 48 h and 7 days post-fertilization zebrafish and medaka embryos to test for estrogenic disruption was evaluated. The embryos were exposed to the phytoestrogen genistein and subsequently analyzed by microarrays and quantitative real-time PCR. The functional analysis showed that the genes affected related to multiple metabolic and signaling pathways in the early fish embryo, which reflect the known components of genistein's mode of actions, like apoptosis, estrogenic response, hox gene expression and steroid hormone synthesis. Moreover, the transcriptomic data also suggested a thyroidal mode of action and disruption of the nervous system development. The parallel testing of two fish species provided complementary data on the effects of genistein at gene expression level and facilitated the separation of common from species-dependent effects. Overall, the study demonstrated that combining fish embryo testing with transcriptomics can deliver abundant information about the mechanistic effects of endocrine disrupting chemicals, rendering this strategy a promising alternative approach to test for endocrine disruption in a whole organism in-vitro scale system. Copyright © 2012 Elsevier Inc. All rights reserved.

Cellular DNA breakage by soy isoflavone genistein and its methylated structural analogue biochanin A.

PubMed

Ullah, Mohd Fahad; Shamim, Uzma; Hanif, Sarmad; Azmi, Asfar S; Hadi, Sheikh M

2009-11-01

Epidemiological studies have indicated that populations with high isoflavone intake through soy consumption have lower rates of breast, prostate, and colon cancer. The isoflavone polyphenol genistein in soybean is considered to be a potent chemopreventive agent against cancer. In order to explore the chemical basis of chemopreventive activity of genistein, in this paper we have examined the structure-activity relationship between genistein and its structural analogue biochanin A. We show that both genistein and its methylated derivative biochanin A are able to mobilize nuclear copper in human lymphocyte, leading to degradation of cellular DNA. However, the relative rate of DNA breakage was greater in the case of genistein. Further, the cellular DNA degradation was inhibited by copper chelator (neocuproine/bathocuproine) but not by compounds that specifically bind iron and zinc (desferrioxamine mesylate and histidine, respectively). We also compared the antioxidant activity of the two isoflavones against tert-butylhydroperoxide-induced oxidative breakage in lymphocytes. Again genistein was found to be more effective than biochanin A in providing protection against oxidative stress induced by tert-butylhydroperoxide. It would therefore appear that the structural features of isoflavones that are important for antioxidant properties are also the ones that contribute to their pro-oxidant action through a mechanism that involves redox cycling of chromatin-bound nuclear copper.

Genistein induced anticancer effects on pancreatic cancer cell lines involves mitochondrial apoptosis, G0/G1cell cycle arrest and regulation of STAT3 signalling pathway.

PubMed

Bi, Yi-Liang; Min, Min; Shen, Wei; Liu, Yan

2018-01-15

Genistein is a natural flavonoid that has been reported to exhibit anticancer effects against different types of cancers which include, but are not limited to, breast and oral squamous cell carcinoma. The present study was designed to evaluate the anticancer effects of the natural flavonoid genistein against pancreatic cancer cell lines and to explore the underlying mechanism. Antiproliferative activity was investigated by MTT assay. Apoptosis was detected by DAPI and annexin V/PI staining. DNA damage was assessed by comet assay. Reactive oxygen species (ROS) and reduction of mitochondrial membrane potential (MMP) were determined by flow cytometry. Cell migration was examined by wound healing assay. Protien expressions were determined by western blotting. Antiproliferative assay revealed that genistein reduced the cell viability of pancreatic cancer cells in a dose dependent manner with an IC 50 of 20 and 25 µM against Mia-PaCa2 and PANC-1 cancer cell lines respectively. However, its antiproliferative effects were less pronounced against non-cancerous pancreatic ductal epithelial cell line (H6C7) as evident from the IC 50 of 120 µM. Genistein induced significant morphological changes in pancreatic cancer cells and triggered cell cycle arrest in G 0 /G 1 phase. DAPI staining and flow cytometric analysis revealed that genistein induced apoptosis in a dose dependent manner through generation of substantial amounts of ROS and reduction of MMP. However, treatment of the pancreatic cancer with genistein and ascorbic acid could abrogate the effects of genistein on cell viability. Protien expression analysis revealed that genistein upregulated cytosolic cytochrome c, Bax, cleaved Caspase-3 and cleaved caspase-9 expressions with concomitant downregulation of Bcl-2 expression. Moreover, genistein inhibited the phosphorylation of signal transducer and activator of transcription STAT3 proteins and downregulated the expression of survivin, cyclin D1 and ALDH1A1 in Mia

Preclinical evaluation of the anti-tumor effects of the natural isoflavone genistein in two xenograft mouse models monitored by [18F]FDG, [18F]FLT, and [64Cu]NODAGA-cetuximab small animal PET.

PubMed

Honndorf, Valerie S; Wiehr, Stefan; Rolle, Anna-Maria; Schmitt, Julia; Kreft, Luisa; Quintanilla-Martinez, Letitia; Kohlhofer, Ursula; Reischl, Gerald; Maurer, Andreas; Boldt, Karsten; Schwarz, Michael; Schmidt, Holger; Pichler, Bernd J

2016-05-10

The natural phytoestrogen genistein is known as protein kinase inhibitor and tumor suppressor in various types of cancers. We studied its antitumor effect in two different xenograft models using positron emission tomography (PET) in vivo combined with ex vivo histology and nuclear magnetic resonance (NMR) metabolic fingerprinting. A431 and Colo205 tumor-bearing mice were treated with vehicle or genistein (500 mg/kg/d) over a period of 12 days. Imaging was performed with 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) and 3'-deoxy-3'-[18F]fluorothymidine ([18F] FLT). In a second study A431 tumor-bearing mice were treated with vehicle, genistein (500 mg/kg/d), cetuximab (1 mg/3d) or a combination of the compounds and imaged using [18F]FDG, [18F]FLT and [64Cu]NODAGA-cetuximab. Data were compared to histology and principal components analysis (PCA) of NMR fingerprinting data. Genistein reduced tumor growth significantly in both xenografts. [18F] FLT uptake was consistent in both models and corresponded to histological findings and also PCA whereas [18F]FDG and [64Cu]NODAGA-cetuximab were not suitable for therapy monitoring. As mono-therapy the natural isoflavone genistein has a powerful therapeutic effect in vivo on A431 and Colo205 tumors. [18F]FLT has superior consistency compared to the other tested tracers in therapy monitoring, while the treatment effect could be shown on the molecular level by histology and metabolic fingerprinting.

Genistein Ameliorates Non-alcoholic Fatty Liver Disease by Targeting the Thromboxane A2 Pathway.

PubMed

Wang, Wenzhe; Chen, Junliang; Mao, Jinyan; Li, Hongling; Wang, Mingfu; Zhang, Hao; Li, Haitao; Chen, Wei

2018-06-13

Non-alcoholic fatty liver disease (NAFLD) is now a public health issue worldwide, but no drug has yet received approval. Genistein, an isoflavonoid derived from soybean, ameliorates high-fat-diet-induced NAFLD in mice, but the molecular underpinnings remain largely elusive. Arachidonic acid (AA) is a major ingredient of animal fats, and the AA cascade has been implicated in chronic inflammation. In this study, we investigated whether genistein was against NAFLD by targeting the AA cascade. Using a mouse model, we showed that genistein supplementation improved high-fat-diet-induced NAFLD by normalizing hepatomegaly, liver steatosis, aminotransferase abnormalities, and glucose tolerance. The thromboxane A 2 (TXA 2 ) pathway was aberrantly active in NAFLD, evidenced by an elevation of circulating TXA 2 and hepatic thromboxane A 2 receptor expression. Mechanistically, we found that genistein directly targeted cyclooxygenase-1 activity as well as its downstream TXA 2 biosynthesis, while the TXA 2 pathway might mediate NAFLD progression by impairing insulin sensitivity. Taken together, our study revealed a crucial pathophysiological role of the TXA 2 pathway in NAFLD and provided an explanation as to how genistein was against NAFLD progression.

The potential health effects of dietary phytoestrogens.

PubMed

Rietjens, Ivonne M C M; Louisse, Jochem; Beekmann, Karsten

2017-06-01

Phytoestrogens are plant-derived dietary compounds with structural similarity to 17-β-oestradiol (E2), the primary female sex hormone. This structural similarity to E2 enables phytoestrogens to cause (anti)oestrogenic effects by binding to the oestrogen receptors. The aim of the present review is to present a state-of-the-art overview of the potential health effects of dietary phytoestrogens. Various beneficial health effects have been ascribed to phytoestrogens, such as a lowered risk of menopausal symptoms like hot flushes and osteoporosis, lowered risks of cardiovascular disease, obesity, metabolic syndrome and type 2 diabetes, brain function disorders, breast cancer, prostate cancer, bowel cancer and other cancers. In contrast to these beneficial health claims, the (anti)oestrogenic properties of phytoestrogens have also raised concerns since they might act as endocrine disruptors, indicating a potential to cause adverse health effects. The literature overview presented in this paper illustrates that several potential health benefits of phytoestrogens have been reported but that, given the data on potential adverse health effects, the current evidence on these beneficial health effects is not so obvious that they clearly outweigh the possible health risks. Furthermore, the data currently available are not sufficient to support a more refined (semi) quantitative risk-benefit analysis. This implies that a definite conclusion on possible beneficial health effects of phytoestrogens cannot be made. This article is part of a themed section on Principles of Pharmacological Research of Nutraceuticals. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.11/issuetoc. © 2016 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

Molecular Mechanisms of Anticancer Effects of Phytoestrogens in Breast Cancer.

PubMed

Hsieh, Chia-Jung; Hsu, Ya-Ling; Huang, Ya-Fang; Tsai, Eing-Mei

2018-01-01

Phytoestrogens derived from plants exert estrogenic as well as antiestrogenic effects and multiple actions within breast cancer cells. Chemopreventive properties of phytoestrogens have emerged from epidemiological observations. In recent clinical research studies, phytoestrogens are safe and may even protect against breast cancer. In this brief review, the molecular mechanisms of phytoestrogens on regulation of cell cycle, apoptosis, estrogen receptors, cell signaling pathways, and epigenetic modulations in relation to breast cancer are discussed. Phytoestrogens have a preferential affinity for estrogen receptor (ER)-β, which appears to be associated with antiproliferative and anticarcinogenic effects. Moreover, while phytoestrogens not only inhibit ER-positive but also ER-negative breast cancer cells, the possibility of epigenetic modulation playing an important role is also discussed. In conclusion, as there are multiple targets and actions of phytoestrogens, extensive research is still necessary. However, due to low toxicity, low cost, and easy availability, their potent chemoprevention effects deserve further study. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Estrogenic activity of natural and synthetic estrogens in human breast cancer cells in culture.

PubMed Central

Zava, D T; Blen, M; Duwe, G

1997-01-01

We investigated the estrogenic activity of various environmental pollutants (xenobiotics), in particular the xenoestrogen o,p-DDT, and compared their effects with those of endogenous estrogens, phytoestrogens, and mycoestrogens on estrogen receptor binding capacity, induction of estrogen end products, and activation of cell proliferation in estrogen-sensitive human breast cancer cells in monolayer culture. We also quantified the levels of phytoestrogens in extracts of some common foods, herbs, and spices and in human saliva following consumption of a high phytoestrogen food source (soy milk) to compare phytoestrogen abundance and bioavailability relative to the reported xenoestrogen burden in humans. Results show that natural endogenous estrogens, phytoestrogens, mycoestrogens, and xenoestrogens bind estrogen receptor (ER) in intact cells, but demonstrate marked differences in their ability to induce end products of estrogen action and to regulate cell proliferation. All of the different classes of estrogens stimulated cell proliferation at concentrations that half-saturated ER, but only some classes were able to induce estrogen-regulated end products. Genistein, a common phytoestrogen found in soy foods, differed from the xenoestrogen DDT in its effects on cell proliferation and ability to induce estrogen-regulated end products. Moreover, we found that many of the foods, herbs, and spices commonly consumed by humans contain significant amounts of phytoestrogens, and consumption of soy milk, a phytoestrogen-rich food, markedly increases the levels of phytoestrogens in saliva. In conclusion, our in vitro results predict that a diet high in phytoestrogens would significantly reduce the binding of weak xenoestrogens to ER in target tissues in vivo. PMID:9168008

[Dietary phytoestrogen and its potential benefits in adult human health].

PubMed

Garrido, Argelia; de la Maza, María Pía; Valladares, Luis

2003-11-01

Human diet contains a series of bioactive vegetal compounds that can improve human health. Among these, there has been a special interest for phytoestrogens. This article reviews the evidence about the potential benefits of phytoestrogens for human health. Forty eight manuscripts were selected for their study design and relevance to human health. The cell growth inhibitory effects of phytoestrogens and their implication in breast cancer are reviewed. Also the effects of these compounds on serum lipid levels and the effectiveness of a phytoestrogen derivate, ipriflavone, on the prevention of osteoporosis are analyzed. Although these compounds have a great potential for improving health, there is still not enough evidence to recommend the routine use of phytoestrogens.

Effects of Chronic Genistein Treatment in Mammary Gland, Uterus, and Vagina

PubMed Central

Rimoldi, Guillermo; Christoffel, Julie; Seidlova-Wuttke, Dana; Jarry, Hubertus; Wuttke, Wolfgang

2007-01-01

Background The isoflavone genistein (GEN) is found in soy (Glycine max) and red clover (Trifolium pratense). The estrogenic activity of GEN is known, and it is widely advertised as a phytoestrogen useful in alleviating climacteric complaints and other postmenopausal disorders. Knowledge of effects of long-term administration of GEN in laboratory animals is scarce, and effects in the uterus and mammary gland after long-term administration have not been studied. The uterus and mammary gland are known to be negatively influenced by estrogens used in hormone therapy. Objectives We administered two doses of GEN [mean daily uptake 5.4 (low) or 54 mg/kg (high) body weight (bw)] orally over a period of 3 months to ovariectomized (ovx) rats and compared the effects with a treatment with two doses of 17β-estradiol [E2; 0.17 (low) or 0.7 mg/kg bw (high)]. Mammary glands, vaginae, and uteri were investigated morphologically and immunohistochemically. We quantified the expression of proliferating cell nuclear antigen (PCNA) and progesterone receptor (PR) in the mammary gland. Results In rats treated with either of the E2 doses or the high GEN dose, we found increased uterine weight, and histologic analysis showed estrogen-induced features in the uteri. In vaginae, either E2 dose or GEN high induced hyperplastic epithelium compared with the atrophic controls. In the mammary gland, E2 (either dose) or GEN increased proliferation and PR expression. Serum levels of luteinizing hormone were decreased by E2 (both doses) but not by GEN. Conclusions In summary, E2 and GEN share many effects in the studied organs, particularly in the vagina, uterus, and mammary gland but not in the hypothalamo/pituitary unit. PMID:18174952

Bowman-Birk inhibitor and genistein among soy compounds that synergistically inhibit nitric oxide and prostaglandin E2 pathways in lipopolysaccharide-induced macrophages

USDA-ARS?s Scientific Manuscript database

Inflammation has an important role in the development of chronic diseases. In this study, we evaluated the anti-inflammatory properties of eight soybean bioactive compounds using lipopolysaccharide-induced RAW 264.7 macrophages. Genistein, daidzein, mix isoflavone glucosides, saponin A group glyco...

Changes of growth hormone-releasing hormone and somatostatin neurons in the rat hypothalamus induced by genistein: a stereological study.

PubMed

Trifunović, Svetlana; Manojlović-Stojanoski, Milica; Ristić, Nataša; Nestorović, Nataša; Medigović, Ivana; Živanović, Jasmina; Milošević, Verica

2016-12-01

Genistein is a plant-derived estrogenic isoflavone commonly found in dietary and therapeutic supplements, due to its potential health benefits. Growth hormone-releasing hormone (GHRH) and somatostatin (SS) are neurosecretory peptides synthesized in neurons of the hypothalamus and regulate the growth hormone secretion. Early reports indicate that estrogens have highly involved in the regulation of GHRH and SS secretions. Since little is known about the potential effects of genistein on GHRH and SS neurons, we exposed rats to genistein. Genistein were administered to adult rats in dose of 30 mg/kg, for 3 weeks. The estradiol-dipropionate treatment was used as the adequate controls to genistein. Using applied stereology on histological sections of hypothalamus, we obtained the quantitative information on arcuate (Arc) and periventricular (Pe) nucleus volume and volume density of GHRH neurons and SS neurons. Image analyses were used to obtain GHRH and SS contents in the median eminence (ME). Administration of estradiol-dipropionate caused the increase of Arc and Pe nucleus volume, SS neuron volume density, GHRH and SS staining intensity in the ME, when compared with control. Genistein treatment increased: Arc nucleus volume and the volume density of GHRH neurons (by 26%) and SS neurons (1.5 fold), accompanied by higher GHRH and SS staining intensity in the ME, when compared to the orhidectomized group. These results suggest that genistein has a significant effect on hypothalamic region, involved in the regulation of somatotropic system function, and could contribute to the understanding of genistein as substance that alter the hormonal balance.

Phytoestrogens in the management of the menopause: up-to-date.

PubMed

Ewies, Ayman A A

2002-05-01

Despite the benefits of conventional hormone replacement therapy, some women are not candidates for this treatment and many others choose not to take it. As a result, there is growing interest among patients about natural alternatives. There is some evidence that phytoestrogens may offer protection against a wide range of human conditions, including breast cancer, cardiovascular disease, brain dysfunction, osteoporosis, and menopausal symptoms. The literature on the possible health benefits of phytoestrogens has expanded exponentially since the 1980s, mainly in response to funding initiatives by the U.S. government and soybean industries, and more lately by European and UK Ministries of Food. The physiological effects of phytoestrogens also have created a marketing opportunity that has been used by industry, particularly in soybean-producing countries such as the U.S. and Australia. Nevertheless, clinical applications for phytoestrogens are still in their infancy, and more interventional trials are required to reach definitive conclusions regarding their efficacy and safety, although they appear to represent a promising group of compounds, which may be useful in the future for the treatment of the menopausal syndrome. Also, the lack of clinical data presently available must signal caution in relation to the possible risk of adverse effects. Obstetricians and Gynecologists, Family Physicians. After completion of this article, the reader will be able to identify the various types of phytoestrogens, list the sources of phytoestrogens, and summarize the various effects of phytoestrogens.

Genistein and resveratrol, alone and in combination, suppress prostate cancer in SV-40 tag rats.

PubMed

Harper, Curt E; Cook, Leah M; Patel, Brijesh B; Wang, Jun; Eltoum, Isam A; Arabshahi, Ali; Shirai, Tomoyuki; Lamartiniere, Coral A

2009-11-01

Chemoprevention utilizing dietary agents is an effective means to slow the development of prostate cancer. We evaluated the potential additive and synergistic effects of genistein and resveratrol for suppressing prostate cancer in the Simian Virus-40 T-antigen (SV-40 Tag) targeted probasin promoter rat model, a transgenic model of spontaneously developing prostate cancer. Rats were fed genistein or resveratrol (250 mg/kg AIN-76A diet) alone and in combination, and a low-dose combination (83 mg genistein + 83 mg resveratrol/kg diet). Histopathology and mechanisms of action studies were conducted at 30 and 12 weeks of age, respectively. Genistein, resveratrol, and the high-dose combination treatments suppressed prostate cancer. The low-dose combination did not elicit protection against prostate cancer and was most likely below the effective dose for causing significant histopathological changes. Total genistein and resveratrol concentrations in the blood reached 2,160 and 211 nM, respectively in rats exposed to the single treatments. Polyphenol treatments decreased cell proliferation and insulin-like growth factor-1 (IGF-1) protein expression in the prostate. In addition, genistein as a single agent induced apoptosis and decreased steroid receptor coactivator-3 (SRC-3) in the ventral prostate (VP). Genistein and resveratrol, alone and in combination, suppress prostate cancer development in the SV-40 Tag model. Regulation of SRC-3 and growth factor signaling proteins are consistent with these nutritional polyphenols reducing cell proliferation and increasing apoptosis in the prostate.

Ovario-protective effects of genistein against cyclophosphamide toxicity in rats: Role of anti-müllerian hormone and oestradiol.

PubMed

Saleh, Dalia O; Mansour, Dina F

2016-10-15

Cyclophosphamide (CP), the commonly used chemotherapeutic agent in cancer treatment, is proven to cause ovarian toxicity and infertility in women. In the present study, we investigated the protective effect of genistein (GEN), a phytoestrogen found in the soy protein, against CP-induced ovarian toxicity in rats. Forty female adult rats were allocated into five groups. A normal control group received the vehicle; another group was injected with a single acute intraperitoneal dose of CP (200mg/kg). Three other groups were pretreated with GEN (0.5, 1 or 2mg/kg; s.c.) for 14 days. Sera and ovaries were obtained 48h after CP treatment. Serum levels of anti-müllerian hormone (AMH) and oestradiol (E2) were detected as well as the ovarian level of reduced glutathione (GSH), activity of superoxide dismutase (SOD), level of malondialdehyde (MDA) and interleukin 1β (IL-1β) were evaluated. Histopathological examination and immunohistochemical detection of inducible nitric oxide synthetase (iNOS) were conducted. Results of the present study revealed that CP-induced severe ovarian toxicity via decreasing serum levels of AMH and E2 and elevating oxidative stress and inflammation in ovarian tissues. Histologically, CP caused increase in primordial follicles with less graafian follicles and corpora lutea in ovarian tissues as well as severe induction of iNOS. GEN inhibited the severe decrease in serum AMH and E2 with alleviation of oxidative stress and inflammation significantly compared to CP-treated group. GEN improved ovarian histology and immunostaining of ovarian iNOS disrupted by CP. Finally, it can be concluded that GEN exerted protective effects against CP-induced ovarian toxicity. Copyright © 2016 Elsevier B.V. All rights reserved.

Reduction of post injury neointima formation due to 17β-estradiol and phytoestrogen treatment is not influenced by the pure synthetic estrogen receptor antagonist ICI 182,780 in vitro

PubMed Central

Finking, Gerald; Lenz, Christina; Schochat, Thomas; Hanke, Hartmut

2002-01-01

Background Animal and organ culture experiments have shown beneficial inhibitory estrogen effects on post injury neointima development. The purpose of this study was to investigate whether such estrogen effects are influenced by the estrogen receptor antagonist ICI 182,780. Different concentrations of 17β-estradiol and the phytoestrogens genistein and daidzein were tested. Methods F emale New Zealand White rabbits were benumbed. In situ vascular injury of the thoracic and abdominal aorta was performed by a 3F Fogarty catheter. Segments of 5 mm were randomised and held in culture for 21 days. Three test series were performed: 1) control group – 20 μM ICI – 30 μM ICI – 40 μM ICI. 2) control group – 20 μM ICI – 40 μM 17β-estradiol – 40 μM 17β-estradiol + 20 μM ICI. 3) control group – 20 μM ICI – 40 μM daidzein – 40 μM daidzein + 20 μM ICI – 20 μM genistein – 20 μM genistein + 20 μM ICI. After 21 days the neointima-media-ratio was evaluated. Results 1) Treatment with ICI 182,780 did not reduce neointima formation significantly (p = 0.05). 2) 40 μM 17β-estradiol alone (p < 0.0001) and in combination with 20 μM ICI (p < 0.0001) reduced neointima formation significantly. 3) 20 μM genistein alone (p = 0.0083) and combined with 20 μM ICI (p = 0.0053) reduced neointima formation significantly. 40 μM daidzein did not have a significant (p = 0.0637) effect. Conclusions The estrogen receptor antagonist ICI 182,780 did not modulate the inhibitory estrogen effects on post injury neointima formation. These results do not support the idea that such effects are mediated by vascular estrogen receptors. PMID:12162794

Phytoestrogens and human health effects: weighing up the current evidence.

PubMed

Humfrey, C D

1998-01-01

Phytoestrogens are naturally occurring plant compounds which have oestrogenic and/or anti-oestrogenic activity. They are present in many human foodstuffs including beans, sprouts, cabbage, spinach, soyabean, grains and hops. The main classes are the isoflavones, coumestans and lignans. This review assesses the evidence that these substances may have adverse and/or beneficial impacts on the risk of several hormone-dependent diseases in humans. Evidence from studies of various animal species has demonstrated that ingestion of high levels of phytoestrogens can produce adverse effects on reproductive endpoints including fertility. Studies in laboratory animals have also shown that exposure to high doses of phytoestrogens during development can adversely affect brain differentiation and reproductive development in rodents, but may also have possible beneficial effects. In humans, there is a lack of information concerning the possible effects of high doses of phytoestrogens in infants and this should be addressed as a matter of priority so that any risks (or benefits) can be established. In adults, no current data exist to suggest that consumption of phytoestrogens at the levels normally encountered in the diet is likely to be harmful. Epidemiological studies suggest that foodstuffs containing phytoestrogens may have a beneficial role in protecting against a number of chronic diseases and conditions. For cancer of the prostate, colon, rectum, stomach and lung, the evidence is most consistent for a protective effect resulting from a high intake of grains, legumes, fruits and vegetables; it is not possible to identify particular food types or components that may be responsible. Dietary intervention studies indicate that in women soya and linseed may have beneficial effects on the risk of breast cancer and may help to alleviate postmenopausal symptoms. For osteoporosis, tentative evidence suggests phytoestrogens may have similar effects in maintaining bone density to those

Genistein regulates the IL-1 beta induced activation of MAPKs in human periodontal ligament cells through G protein-coupled receptor 30.

PubMed

Luo, Li-Jun; Liu, Feng; Lin, Zhi-Kai; Xie, Yu-Feng; Xu, Jia-Li; Tong, Qing-Chun; Shu, Rong

2012-06-01

Periodontal ligament (PDL) cells are fibroblasts that play key roles in tissue integrity, periodontal inflammation and tissue regeneration in the periodontium. The periodontal tissue destruction in periodontitis is mediated by host tissue-produced inflammatory cytokines, including interleukin-1β (IL-1β). Here, we report the expression of G protein-coupled receptor 30 (GPR30, also known as G protein-coupled estrogen receptor 1 GPER) in human PDL cells and its regulation by IL-1β. IL-1β-induced GPR30 expression in human PDL cells leads to the activation of multiple signaling pathways, including MAPK, NF-κB and PI3K. In contrast, genistein, an estrogen receptor ligand, postpones the activation of MAPKs induced by IL-1β. Moreover, the inhibition of GPR30 by G15, a GPR30-specific antagonist, eliminates this delay. Thus, genistein plays a role in the regulation of MAPK activation via GPR30, and GPR30 represents a novel target regulated by steroid hormones in PDL cells. Copyright © 2012 Elsevier Inc. All rights reserved.

Breast Cancer Resistance Protein (ABCG2) Determines Distribution of Genistein Phase II Metabolites: Reevaluation of the Roles of ABCG2 in the Disposition of Genistein

PubMed Central

Yang, Zhen; Zhu, Wei; Gao, Song; Yin, Taijun; Jiang, Wen

2012-01-01

It was recently proposed that the improved oral bioavailability of genistein aglycone and conjugates in Bcrp1(−/−) mice is mainly due to increased intestinal absorption of aglycone and subsequent elevated exposure to conjugation enzymes. Here we tested this proposed mechanism and found that intestinal absorption of genistein aglycone did not increase in Bcrp1(−/−) mice compared with wild-type mice using an in situ mouse intestinal perfusion model and that inhibition of breast cancer resistance protein (BCRP) in Caco-2 cells also did not significantly increase permeability or intracellular concentration of aglycone. Separately, we showed that 5- to 10-fold increases in exposures of conjugates and somewhat lower fold increases (<2-fold) in exposures of aglycone were apparent after both oral and intraperitoneal administration in Bcrp1(−/−) mice. In contrast, the intestinal and biliary excretion of genistein conjugates significantly decreased in Bcrp1(−/−) mice without corresponding changes in aglycone excretion. Likewise, inhibition of BCRP functions in Caco-2 cells altered polarized excretion of genistein conjugates by increasing their basolateral excretion. We further found that genistein glucuronides could be hydrolyzed back to genistein, whereas sulfates were stable in blood. Because genistein glucuronidation rates were 110% (liver) and 50% (colon) higher and genistein sulfation rates were 40% (liver) and 42% (colon) lower in Bcrp1(−/−) mice, the changes in genistein exposures are not mainly due to changes in enzyme activities. In conclusion, improved bioavailability of genistein and increased plasma area under the curve of its conjugates in Bcrp1(−/−) mice is due to altered distribution of genistein conjugates to the systemic circulation. PMID:22736306

Phytoestrogens and Their Metabolites in Bulk-Tank Milk: Effects of Farm Management and Season

PubMed Central

Adler, Steffen A.; Purup, Stig; Hansen-Møller, Jens; Thuen, Erling; Steinshamn, Håvard

2015-01-01

Phytoestrogens have structures similar to endogenous steroids and may induce or inhibit the response of hormone receptors. The objectives of the present study were to compare the effects of long-term vs. short-term grassland management in organic and conventional dairy production systems, compare organic and conventional production systems and assess seasonal variation on phytoestrogen concentrations in bulk-tank milk. The concentrations of phytoestrogens were analyzed in bulk-tank milk sampled three times in two subsequent years from 28 dairy farms: Fourteen organic (ORG) dairy farms with either short-term or long-term grassland management were paired with 14 conventional (CON) farms with respect to grassland management. Grassland management varied in terms of time since establishment. Short-term grassland management (SG) was defined as establishment or reseeding every fourth year or more often, and long-term grassland management (LG) was defined as less frequent establishment or reseeding. The proportion of red clover (Trifolium pretense L.) in the herbage was positively correlated with milk concentrations of the mammalian isoflavone equol. Therefore, organically produced bulk-tank milk contained more equol than conventionally produced milk, and milk from ORG-SG farms had more equol than milk from ORG-LG farms. Milk produced during the indoor-feeding periods had more equol than milk produced during the outdoor feeding period, because pastures contained less red clover than fields intended for silage production. Organically produced milk had also higher concentrations of the mammalian lignan enterolactone, but in contrast to equol, concentrations increased in the outdoor-feeding periods compared to the indoor-feeding periods. There were no indications of fertility problems on ORG-SG farms who had the highest red clover proportions in the herbage. This study shows that production system, grassland management, and season affect milk concentrations of phytoestrogens

In Utero Exposure to Di-(2-Ethylhexyl) Phthalate Induces Testicular Effects in Neonatal Rats That Are Antagonized by Genistein Cotreatment1

PubMed Central

Jones, Steven; Boisvert, Annie; Francois, Sade; Zhang, Liandong; Culty, Martine

2015-01-01

Fetal exposure to endocrine disruptors (EDs) is believed to predispose males to reproductive abnormalities. Although males are exposed to combinations of chemicals, few studies have evaluated the effects of ED mixtures at environmentally relevant doses. Our previous work showed that fetal exposure to a mixture of the phytoestrogen genistein (GEN) and the plasticizer di-(2-ethylhexyl) phthalate (DEHP) induced unique alterations in adult testis. In this follow-up study, we examined Postnatal Day 3 (PND3) and PND6 male offspring exposed from Gestational Day 14 to parturition to corn oil, 10mg/kg GEN, DEHP, or their combination, to gain insight into the early molecular events driving long-term alterations. DEHP stimulated the mRNA and protein expression of the steroidogenic enzyme HSD3B, uniquely at PND3. DEHP also increased the mRNA expression of Nestin, a Leydig progenitor/Sertoli cell marker, and markers of Sertoli cell (Wt1), gonocyte (Plzf, Foxo1), and proliferation (Pcna) at PND3, while these genes were unchanged by the mixture. Redox (Nqo1, Sod2, Sod3, Trx, Gst, Cat) and xenobiotic transporter (Abcb1b, Abcg2) gene expression was also increased by DEHP at PND3, while attenuated when combined with GEN, suggesting the involvement of cellular stress in short-term DEHP effects and a protective effect of GEN. The direct effects of GEN and mono-(2-ethylhexyl) phthalate, the principal bioactive metabolite of DEHP, on testis were investigated in PND3 organ cultures, showing a stimulatory effect of 10 μM mono-(2-ethylhexyl) phthalate on basal testosterone production that was normalized by GEN. These effects contrasted with previous reports of androgen suppression and decreased gene expression in perinatal rat testis by high DEHP doses, implying that neonatal effects are not predictive of adult effects. We propose that GEN, through an antioxidant action, normalizes reactive oxygen species-induced neonatal effects of DEHP. The notion that these EDs do not follow classical

Genistein isoflavone glycoconjugates in sour cherry (Prunus cerasus L.) cultivars.

PubMed

Abrankó, László; Nagy, Ádám; Szilvássy, Blanka; Stefanovits-Bányai, Éva; Hegedűs, Attila

2015-01-01

The isoflavone genistein on the contrary to its well-established health-beneficial effects is not a major component of the Western diet, since soy consumption, considered as the main dietary source of genistein, in these populations is low. Genistein compounds in twelve commercial sour cherry (Prunus cerasus L.) cultivars grown in Hungary were studied. High performance liquid chromatography coupled to electrospray ionisation quadrupole/time-of-flight mass spectrometry (HPLC-ESI-qToF-MS) was used for screening and confirmatory analyses. Genistin and genistein were found in 'Pipacs1', 'Kántorjánosi', 'Debreceni bőtermő' and 'Éva', which are native cultivars to Hungary. Genistein content of the latter three were in the range of 0.4-0.6, while in 'Pipacs1' in total 4.4 mg genistein compounds were measured expressed as aglycone equivalents per 100g of fresh fruit flesh. These cultivars may play important role as complementary genistein sources in the Western diet. Especially 'Pipacs 1', may be best utilised in functional food products. Copyright © 2014 Elsevier Ltd. All rights reserved.

Detection of a negative correlation between prescription of Chinese herbal products containing coumestrol, genistein or daidzein and risk of subsequent endometrial cancer among tamoxifen-treated female breast cancer survivors in Taiwan between 1998 and 2008: A population-based study.

PubMed

Hu, Yi-Cheng; Wu, Chien-Tung; Lai, Jung-Nien; Tsai, Yueh-Ting

2015-07-01

Tamoxifen users sometimes seek complementary and alternative medicine advice for treatment of a variety of illness and co-administer with phytoestrogen-containing herbs, resulting in an increasing concern of its influence in subsequent endometrial cancer risk. Our study aims to determine the prevalence of Chinese herbal products containing coumestrol, genistein, or daidzein and their association with subsequent endometrial cancer risk among tamoxifen-treated breast cancer survivors in Taiwan. We selected all patients who were newly diagnosed with invasive breast cancer and received tamoxifen treatment between January 1, 1998, and December 31, 2008, from the National Health Insurance Research Database. Among the 26,656 tamoxifen-treated breast cancer survivors, we evaluated the usage, frequency of service, and prescription of Chinese herbal products containing coumestrol, genistein, or daidzein. The logistic regression method was employed to calculate the odds ratios for utilization of those herbal products. Cox proportional hazard regression was set to calculate the hazard ratios of endometrial cancer associated with such usage. Of the patients surveyed, 36.2% (n=9652) of the tamoxifen-treated breast cancer survivors examined in the study had consumed Chinese herbal products containing coumestrol, genistein, or daidzein during the study period. Exposure to Ge Gen(Puerariae Radix) specifically was the most extensive. For it, the population consumed an average cumulative dose of above 180g. Compared to those who had never used Chinese herbal products, breast cancer survivors who had taken Chinese herbal products containing coumestrol, genistein, or daidzein concurrently with tamoxifen treatment did not have a higher hazard ratio for subsequent development of endometrial cancer. Among those tamoxifen-treated female breast cancer survivors in Taiwan, consumption of Chinese herbal products containing coumestrol, genistein, or daidzein is negatively correlated with

Differential activation of the HCO3− conductance through the cystic fibrosis transmembrane conductance regulator anion channel by genistein and forskolin in murine duodenum

PubMed Central

Tuo, Biguang; Wen, Guorong; Seidler, Ursula

2009-01-01

Background and purpose: Many cystic fibrosis (CF)-associated mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) anion channels affect CFTR-activated HCO3− transport more than Cl− transport. Targeting the CFTR HCO3− conductance, if possible, may therefore be of major therapeutic benefit. In the present study, we examined the effects of genistein and forskolin on duodenal mucosal HCO3− and Cl− secretion. Experimental approach: Murine duodenal mucosal HCO3− and Cl− secretions were examined in vitro in Ussing chambers by the pH stat and short circuit current (Isc) techniques. Key results: Genistein markedly stimulated duodenal HCO3− secretion and Isc in a dose-dependent manner in CFTR wild-type mice, but not in CFTR null mice. CFTRinh-172, a highly specific CFTR inhibitor, inhibited genistein-stimulated duodenal HCO3− secretion and Isc in wild-type mice. Genistein induced 59% net HCO3− increase and 123% net Isc increase over basal value, whereas forskolin, an activator of adenylate cyclase, induced 94% net HCO3− increase and 507% net Isc increase, indicating that, compared with forskolin, genistein induced a relatively high HCO3−/Isc ratio. Further data showed that CFTR HCO3−/Cl− conductance ratio was 1.05 after genistein stimulation, whereas after forskolin stimulation, the CFTR HCO3−/Cl− conductance ratio was 0.27. Conclusions and implications: Genistein stimulates duodenal HCO3− and Cl− secretion through CFTR, and has a relatively high selectivity for the CFTR HCO3− conductance, compared with forskolin. This may indicate the feasibility of selective targeting of the HCO3− conductance of the CFTR channels. PMID:19788494

Acute and Chronic Effects of Oral Genistein Administration in Neonatal Mice1

PubMed Central

Cimafranca, Melissa A.; Davila, Juanmahel; Ekman, Gail C.; Andrews, Rachel N.; Neese, Steven L.; Peretz, Jackye; Woodling, Kellie A.; Helferich, William G.; Sarkar, Jhimly; Flaws, Jodi A.; Schantz, Susan L.; Doerge, Daniel R.; Cooke, Paul S.

2010-01-01

Soy-based infant formulas are widely used in the United States and some other countries. These formulas contain high levels of the estrogenic isoflavone genistein, leading to concern that neonatal genistein exposure could cause acute and/or long-term adverse effects on reproductive and other organs. However, previous work to assess genistein effects in rodent models has not typically replicated the route of delivery and/or serum genistein concentrations reported for soy formula-fed human infants. Our objective was to develop a mouse model that more closely mimics the oral genistein exposure and total serum genistein concentrations observed in soy formula-fed infants. Mouse pups were dosed orally with genistein in a soy formula-corn oil emulsion from Postnatal Day (PND) 1 to PND 5, then effects on reproductive and nonreproductive organs were assessed after dosing and during subsequent development. Neonatal treatment resulted in changes both at the completion of dosing (PND 5) and in adult animals. At PND 5, neonatal genistein treatment caused increased relative uterine weight and down-regulation of progesterone receptor in uterine epithelia. Estrogenic effects of genistein were also seen in the neonatal ovary and thymus, which had an increase in the incidence of multioocyte follicles (MOFs) and a decrease in thymic weight relative to body weight, respectively. The increased incidence of MOFs persisted into adulthood for neonatally treated genistein females, and estrous cycle abnormalities were seen at 6 mo of age despite normal fertility in these mice. The immediate and long-term effects in this neonatal animal model raise concerns that high serum concentrations of genistein are estrogenic and could potentially impact the development of human infants fed soy formula. PMID:20357267

Genistein decreases A549 cell viability via inhibition of the PI3K/AKT/HIF‑1α/VEGF and NF‑κB/COX‑2 signaling pathways.

PubMed

Zhang, Juan; Su, Hongzheng; Li, Qingfeng; Li, Jing; Zhao, Qianfeng

2017-04-01

Genistein is an important chemopreventive agent against atherosclerosis and cancer. However, whether genistein is effective in the treatment of lung cancer, and its underlying mechanism, remains to be determined. The present study demonstrated that genistein treatment of A549 lung cancer cells decreased viability in a dose‑ and time‑dependent manner, and induced apoptosis. Additionally, A549 cells exhibited significantly increased reactive oxygen species formation and cytochrome‑c leakage, and activated caspase‑3, B‑cell lymphoma 2‑associated X protein and apoptosis inducing factor expression levels, which are involved in the mitochondrial apoptosis pathway. Furthermore, the phosphatidylinositol‑4,5‑biphosphate 3‑kinase (PI3K)/protein kinase B (AKT)/hypoxia‑inducible factor‑1α (HIF‑1α) and nuclear factor‑κB (NF‑κB)/cyclooxygenase‑2 (COX‑2) signaling pathways were significantly downregulated by genistein treatment. In conclusion, reduced proliferation and increased apoptosis in A549 lung cancer cells was associated with inhibition of the PI3K/AKT/HIF‑1α/ and NF‑κB/COX‑2 signaling pathways, which implicates genistein as a potential chemotherapeutic agent for the treatment of lung cancer.

Does an apple a day keep the doctor away because a phytoestrogen a day keeps the virus at bay? A review of the anti-viral properties of phytoestrogens.

PubMed

Martin, J H J; Crotty, S; Warren, P; Nelson, P N

2007-02-01

From dengue to herpes and influenza to AIDS, the phytoestrogens that are present in many fruits and vegetables have been shown to exert anti-viral properties. Here we review the various different anti-viral mechanisms employed by phytoestrogens.

Genistein Promotes Endothelial Colony-Forming Cell (ECFC) Bioactivities and Cardiac Regeneration in Myocardial Infarction

PubMed Central

Lee, Sang Hun; Lee, Jun Hee; Asahara, Takayuki; Kim, Yong Sook; Jeong, Hae Chang; Ahn, Youngkeun; Jung, Jin Sup; Kwon, Sang-Mo

2014-01-01

Although stem cell-mediated treatment of ischemic diseases offers significant therapeutic promise, the limitation in the therapeutic efficacy of transplanted stem cells in vivo because of poor engraftment remains a challenge. Several strategies aimed at improving survival and engraftment of stem cells in the ischemic myocardium have been developed, such as cell transplantation in combination with growth factor delivery, genetic modification of stem cells, and/or cell therapy using scaffolds. To improve therapeutic efficacy, we investigated the effects of genistein on the engraftment of transplanted ECFCs in an acute myocardial ischemia model. Results: We found that genistein treatment enhanced ECFCs' migration and proliferation, which was accompanied by increases in the expression of ILK, α-parvin, F-actin, and phospholylation of ERK 1/2 signaling. Transplantation of genistein-stimulates ECFCs (GS-ECFCs) into myocardial ischemic sites in vivo induced cellular proliferation and secretion of angiogenic cytokines at the ischemic sites and thereby enhanced neovascularization and decreased myocardial fibrosis as well as improved cardiac function, as shown by echocardiography. Taken together, these data suggest that pretreatment of ECFCs with genistein prior to transplantation can improve the regenerative potential in ischemic tissues, providing a novel strategy in adult stem cell therapy for ischemic diseases. PMID:24830850

Combination Treatment of Glioblastoma by Low-Dose Radiation and Genistein.

PubMed

Atefeh, Zamanian; Vahid, Changizi; Hasan, Nedaie; Saeed, Amanpour; Mahnaz, Haddadi

2016-01-01

Gioblastoma multiforme as a chemoresistant and radioresistant malignant cell line needs to novel strategies to treatment. Low-dose hyper-radiosensitivity (LDHRS) seems to be an effective phenomenon to irradiation that can save normal brain fibroblasts. Genistein which is a soy isoflavone can be cytotoxic in some tumor cell lines. So we determined to study the effect of combining these two treatment modalities. After 30 hours incubation with Genistein in different concentrations on U87MG cell line, proliferation and clonogenicity were conducted by both clonogenic and MTT assays. A conventional 2Gy radiation dose was compared with 10 doses of 0.2Gy gamma irradiation with 3 minutes and 1 hour intervals. Finally, concurrent effect of these modalities was assessed. Based on acquired cell doubling time (30 hours), one doubling time treatment by Genistein could decrease clonogenicity. U87MG cell line exhibited HRS at low dose irradiations. 2Gy irradiation was more effective than ultra-fractionation methods in comparison with control group. All groups with 50uM concentration of Genistein showed decrease in the survival. This decrease compared with control group, in 10x0.2Gy with 3 minutes intervals plus 50uM Genistein was significant and for groups with the same dose of Genistein but along with continuous 2Gy was more significant. In one day treatment regimen, 10x0.2Gy ultra-fractionation with 3 minutes and 1 hour intervals seems to be less effective than conventional 2Gy irradiation, however adding 50uM Genistein can decrease survival more. Although 2Gy conventional dose plus 50uM Genistein was the most effective regimen. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Role of phytoestrogens in prevention and management of type 2 diabetes

PubMed Central

Talaei, Mohammad; Pan, An

2015-01-01

Type 2 diabetes (T2D) has become a major public health threat across the globe. It has been widely acknowledged that diet plays an important role in the development and management of T2D. Phytoestrogens are polyphenols that are structurally similar to endogenous estrogen and have weak estrogenic properties. Emerging evidence from pre-clinical models has suggested that phytoestrogens may have anti-diabetic function via both estrogen-dependent and estrogen-independent pathways. In the current review, we have summarized the evidence linking two major types of phytoestrogens, isoflavones and lignans, and T2D from epidemiological studies and clinical trials. The cross-sectional and prospective cohort studies have reported inconsistent results, which may due to the large variations in different populations and measurement errors in dietary intakes. Long-term intervention studies using isoflavone supplements have reported potential beneficial effects on glycemic parameters in postmenopausal women, while results from short-term small-size clinical trials are conflicting. Taken together, the current evidence from different study designs is complex and inconsistent. Although the widespread use of phytoestrogens could not be recommended yet, habitual consumption of phytoestrogens, particularly their intact food sources like soy and whole flaxseed, could be considered as a component of overall healthy dietary pattern for prevention and management of T2D. PMID:25789108

Incomplete metabolism of phytoestrogens by gut microbiota from children under the age of three.

PubMed

Gaya, Pilar; Sánchez-Jiménez, Abel; Peirotén, Ángela; Medina, Margarita; Landete, José Maria

2018-05-01

Phytoestrogens are plant-derived polyphenols with structural and functional similarities to mammalian oestrogens. The aim of this work was to study the metabolism of phytoestrogens by children's intestinal microbiota and to compare it with previous results in adults. Faecal samples of 24 healthy children were subjected to phytoestrogen fermentation assay. Only one child produced equol, while O-desmethylangolensin was found in all. Urolithin production was detected in 14 children and enterolactone in 10. Further comparison with the metabolism of phytoestrogens by adult intestinal microbiota reflected that glycitein, dihydrogenistein, urolithins D and E, enterolactone, secoisolariciresinol and arctigenin were the most important metabolites differentiating between adult and child microbial gut metabolism. Although the child intestinal microbiota showed the ability to metabolise isoflavones, ellagitannins and lignans to a certain extent, it generally showed a reduced metabolism of phytoestrogens, with a lack of 5-hydroxy equol and enterodiol, and less urolithins and enterolactone producers.

Genistein improves spatial learning and memory in male rats with elevated glucose level during memory consolidation.

PubMed

Kohara, Yumi; Kawaguchi, Shinichiro; Kuwahara, Rika; Uchida, Yutaro; Oku, Yushi; Yamashita, Kimihiro

2015-03-01

Cognitive dysfunction due to higher blood glucose level has been reported previously. Genistein (GEN) is a phytoestrogen that we hypothesized might lead to improved memory, despite elevated blood glucose levels at the time of memory consolidation. To investigate this hypothesis, we compared the effects of orally administered GEN on the central nervous system in normal versus glucose-loaded adult male rats. A battery of behavioral assessments was carried out. In the MAZE test, which measured spatial learning and memory, the time of normal rats was shortened by GEN treatment compared to the vehicle group, but only in the early stages of testing. In the glucose-loaded group, GEN treatment improved performance as mazes were advanced. In the open-field test, GEN treatment delayed habituation to the new environment in normal rats, and increased the exploratory behaviors of glucose-loaded rats. There were no significant differences observed for emotionality or fear-motivated learning and memory. Together, these results indicate that GEN treatment improved spatial learning and memory only in the early stages of testing in the normal state, but improved spatial learning and memory when glucose levels increased during memory consolidation. Copyright © 2014 Elsevier Inc. All rights reserved.

[The effects of phytoestrogen therapy on the endometrium in postmenopausal women].

PubMed

Caserta, L; Caserta, R; Torella, M; Nappo, C; De Lucia, D; Panariello, S

2005-10-01

The purpose of the present study was to carry out a comparative histological analysis of the endometrium in postmenopausal women who made use of phytoestrogens in order to assess the efficacy and possible side effects of this therapy. This study was carried out by forming 2 groups in order to compare the results. One group was given a dietary supplement of phytoestrogens for 24 months, whereas the other was given a placebo for the same period of time. At the beginning of this study endometrial bioptical samples were taken from those patients who had been previously selected at our University Centre. This study was started only with those postmenopausal patients whose bioptical sample was histologically suitable, and it was neither hyperplastic, nor cancerous and nor secretive. During these 24 months there have been frequent contacts aimed at verifying the standard therapeutic behaviour, symptoms and appearance of side effects. At the end of the study new and final bioptical samples of endometrium were taken from both groups. One-hundred and forty-one patients completed the study. Five patients (3.4%) who were submitted to phytoestrogens therapy showed a weak proliferative endometrium bioptical sample. All the other biopsies at the beginning and at the end of the study showed an atrophic and inactive sample. Hot flushes, night sweats, vaginal dryness and dyspareunia improved at the end of the study for the group treated with phytoestrogens as compared to the one treated with a placebo. Although there have not been very significant differences ias to symptoms and side effects, it was noted that insomnia was the most common symptom in the group treated with non-hormonal therapy based on phytoestrogens. Phytoestrogens did not cause any sensitive and worrisome stimulation of the endometrial mucosa. Insomnia was more frequent in the group treated pharmacologically in the 24 months of the study, whereas hot flushes, night sweats, vaginal dryness and dyspareunia persisted

Tetrahydroisoquinoline alkaloids mimic direct but not receptor-mediated inhibitory effects of estrogens and phytoestrogens on testicular endocrine function. Possible significance for Leydig cell insufficiency in alcohol addiction

DOE Office of Scientific and Technical Information (OSTI.GOV)

Stammel, W.; Thomas, H.; Staib, W.

1991-01-01

Possible effects of various tetrahydroisoquinolines (TIQs) on rat testicular endocrine function were tested in vitro in order to prove whether these compounds may be mediators of the development of Leydig cell insufficiency. TIQ effects on different levels of regulation of testis function were compared in vitro with estrogen effects, since both classes of compounds have structural similarities. Gonadotropin-stimulated testosterone production by testicular Leydig cells was inhibited by tetrahydropapaveroline and isosalsoline, the IC{sub 50} values being comparable to those of estradiol, 2-hydroxyestradiol, and the phytoestrogens, coumestrol and genistein; salsolinol and salsoline were less effective, and salsolidine was ineffective. None of thesemore » TIQs interacted significantly with testicular estrogen receptor as analyzed by estradiol displacement. However, tetrahydropapaveroline, isosalsoline and salsolinol competitively inhibited substrate binding to cytochrome P45OXVII, with similar efficiency as the estrogens did; salsoline and salsolidine were again much less effective.« less

Phytoestrogenic activity of blackcurrant (Ribes nigrum) anthocyanins is mediated through estrogen receptor alpha.

PubMed

Nanashima, Naoki; Horie, Kayo; Tomisawa, Toshiko; Chiba, Mitsuru; Nakano, Manabu; Fujita, Toshifumi; Maeda, Hayato; Kitajima, Maiko; Takamagi, Shizuka; Uchiyama, Daishi; Watanabe, Jun; Nakamura, Toshiya; Kato, Yoji

2015-12-01

Blackcurrants (Ribes nigrum L., Grossulariaceae) contain high amounts of anthocyanin polyphenols, which have antioxidant and anti-carcinogenic health benefits. This study analyzed the potential phytoestrogenic effects of blackcurrant extract (BCE) in breast cancer (MCF-7) and human endometrial cancer (Ishikawa) cell lines that over-express estrogen receptor alpha (ERα), as well as in immature female rats. Microarray analysis and Ingenuity® Pathway Analysis showed that BCE activated the ERα pathway, whereas quantitative-PCR confirmed that BCE and four types of anthocyanins up-regulated genes downstream of ERα. BCE (0.1-1.0 μg/mL) and anthocyanins (0.1-10 μM) induced MCF-7 cell proliferation; however, this effect was blocked by ER antagonist fulvestrant. Flow cytometry showed that anthocyanins reduced and increased the number of MCF-7 cells in the G0/G1 and G2/M phases, respectively. Anthocyanins stimulated ERα transcriptional activity in human ERα reporter assays and induced alkaline phosphatase activity in Ishikawa cells. Competition assays and in silico analysis indicated that anthocyanins bind to ERα. Finally, BCE focally induced stratification of columnar epithelial cells in the rat uterus and increased cytoplasmic mucin levels in these cells. These results suggest that blackcurrant anthocyanins act as phytoestrogens in vitro and in vivo. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

The effects of Cordyceps sinensis phytoestrogen on estrogen deficiency-induced osteoporosis in ovariectomized rats.

PubMed

Zhang, Da-wei; Wang, Zhen-lin; Qi, Wei; Zhao, Guang-yue

2014-12-13

Isoflavones are naturally occurring plant chemicals belonging to the "phytoestrogen" class. The aim of the present study was to examine the effects of isoflavones obtained from Cordyceps sinensis (CSIF) on development of estrogen deficiency-induced osteoporosis in ovariectomized rats. After the rats were treated orally with CSIF, serum alkaline phosphatase (ALP), tartarate resistant acid phosphatase (TRAP), serum osteocalcin (OC), homocysteine (HCY), C-terminal crosslinked telopeptides of collagen type I (CTX), estradiol and interferonγ (IFN-γ) level were examined. At the same time, the urine calcium, plasma calcium, plasma phosphorus and the mass of uterus, thymus and body were also examined. The beneficial effects of CSIF on improvement of osteoporosis in rats were attributable mainly to decrease ALP activity, TRAP activity, CTX level and IFN-γ level. At the same time, CSIF also increase the OC and estradiol level in ovariectomized osteopenic rats. The histological examination clearly showed that dietary CSIF can prevent bone loss caused by estrogen deficiency. The significant estrogenic activity of CSIF demonstrated that CSIF has significant estrogenic effects in OVX rats.

Activation of deltaF508 CFTR in a cystic fibrosis respiratory epithelial cell line by 4-phenylbutyrate, genistein and CPX.

PubMed

Andersson, C; Roomans, G M

2000-05-01

The cellular basis of cystic fibrosis (CF) is a defect in a cyclic adenosine monophosphate (cAMP)-activated chloride channel (CF transmembrane conductance regulator) in epithelial cells that leads to decreased chloride ion transport and impaired water transport across the cell membrane. This study investigated whether it was possible to activate the defective chloride channel in cystic fibrosis respiratory epithelial cells with 4-phenylbutyrate (4PBA), genistein and 8-cyclopentyl-1,3-dipropylxanthine (CPX). The CF bronchial epithelial cell line CFBE41o-, which expresses the deltaF508 mutation, was treated with these agents and loss of Cl-, indicating Cl- efflux, measured by X-ray microanalysis. 8-bromo-cAMP alone did not induce Cl- efflux in CFBE41o- cells, but after incubation with 4PBA a significant efflux of Cl- occurred. Stimulation of cells with a combination of genistein and cAMP also induced Cl- efflux, whereas a combination of pretreatment with 4PBA and a combined stimulation with genistein and cAMP induced an even larger Cl- efflux. Cl- efflux could also be stimulated by CPX, but this effect was not enhanced by 4PBA pretreatment. The deltaF508 mutation leads to impaired processing of the cystic fibrosis transmembrane conductance regulator. The increased efflux of chloride after 4-phenylbutyrate treatment can be explained by the fact that 4-phenylbutyrate allows the deltaF508 cystic fibrosis transmembrane conductance regulator to escape degradation and to be transported to the cell surface. Genistein and 8-cyclopentyl-1,3-dipropylxanthine act by stimulating chloride ion efflux by increasing the probability of the cystic fibrosis transmembrane conductance regulator being open. The combination of 4-phenylbutyrate and genistein may be useful in a potential pharmacological therapy for cystic fibrosis patients with the deltaF508 mutation.

Dietary seaweed modifies estrogen and phytoestrogen metabolism in healthy postmenopausal women.

PubMed

Teas, Jane; Hurley, Thomas G; Hebert, James R; Franke, Adrian A; Sepkovic, Daniel W; Kurzer, Mindy S

2009-05-01

Seaweed and soy foods are consumed daily in Japan, where breast cancer rates for postmenopausal women are significantly lower than in the West. Likely mechanisms include differences in diet, especially soy consumption, and estrogen metabolism. Fifteen healthy postmenopausal women participated in this double-blind trial of seaweed supplementation with soy challenge. Participants were randomized to 7 wk of either 5 g/d seaweed (Alaria) or placebo (maltodextrin). During wk 7, participants also consumed a daily soy protein isolate (2 mg isoflavones/kg body weight). After a 3-wk washout period, participants were crossed over to the alternate supplement schedule. There was an inverse correlation between seaweed dose (mg/kg body weight) and serum estradiol (E2) (seaweed-placebo = y = -2.29 x dose + 172.3; r = -0.70; P = 0.003), [corrected] which was linear across the range of weights. Soy supplementation increased urinary daidzein, glycitein, genistein, and O-desmethylangolensin (P = 0.0001) and decreased matairesinol and enterolactone (P < 0.05). Soy and seaweed plus soy (SeaSoy) increased urinary excretion of 2-hydroxyestrogen (2-OHE) (P = 0.0001) and the ratio of 2-OHE:16alpha-hydroxyestrone (16alphaOHE(1)) (P = 0.01). For the 5 equol excretors, soy increased urinary equol excretion (P = 0.0001); the combination of SeaSoy further increased equol excretion by 58% (P = 0.0001). Equol producers also had a 315% increase in 2:16 ratio (P = 0.001) with SeaSoy. Seaweed favorably alters estrogen and phytoestrogen metabolism and these changes likely include modulation of colonic bacteria.

Determination of Phytoestrogen Content in Fresh-Cut Legume Forage

PubMed Central

Hloucalová, Pavlína; Skládanka, Jiří; Horký, Pavel; Klejdus, Bořivoj; Pelikán, Jan; Knotová, Daniela

2016-01-01

Simple Summary Phytoestrogens comprise a group of substances negatively influencing the development and function of animal reproductive organs. Their appearance in forage crops can reduce feeding values, cause dietary disorders, and lead to animal health damage. This study evaluated the occurrence of individual phytoestrogens in various species of annual and perennial legumes and their levels in dry forage. It appeared that feeding large amounts of red clover presents a potential risk, but red clover can be replaced with the annual Persian clover, in which markedly lower phytoestrogen levels were detected. Abstract The aim of the study was to determine phytoestrogen content in fresh-cut legume forage. This issue has been much discussed in recent years in connection with the health and safety of feedstuffs and thus livestock health. The experiments were carried out on two experimental plots at Troubsko and Vatín, Czech Republic during June and July in 2015. Samples were collected of the four forage legume species perennial red clover (variety “Amos”), alfalfa (variety “Holyně”), and annuals Persian clover and Alexandrian clover. Forage was sampled twice at regular three to four day intervals leading up to harvest and a third time on the day of harvest. Fresh and wilted material was analyzed using liquid chromatography–mass spectrometry (LC-MS). Higher levels (p < 0.05) of isoflavones biochanin A (3.697 mg·g−1 of dry weight) and formononetin (4.315 mg·g−1 of dry weight) were found in red clover than in other species. The highest isoflavone content was detected in red clover, reaching 1.001% of dry matter (p < 0.05), representing a risk for occurrence of reproduction problems and inhibited secretion of animal estrogen. The phytoestrogen content was particularly increased in wilted forage. Significant isoflavone reduction was observed over three to four day intervals leading up to harvest. PMID:27429009

Genistein Enhances or Reduces Glycosaminoglycan Quantity in a Cell Type-Specific Manner.

PubMed

Lan, Ying; Li, Xiulian; Liu, Xuebo; Hao, Cui; Song, Ni; Ren, Sumei; Wang, Wei; Feng, Ningchuan; Zhang, Lijuan

2018-06-27

Genistein is a natural isoflavone enriched in soybeans. It has beneficial effects for patients with mucopolysaccharidose type III through inhibiting glycosaminoglycan biosynthesis. However, other studies indicate that genistein does not always inhibit glycosaminoglycan biosynthesis. To understand the underlying molecular mechanisms, CHOK1, CHO3.1, CHO3.3, and HCT116 cells were treated with genistein and the monosaccharide compositions and quantity of all glycans from the cell lysate were measured after thorough acid hydrolysis followed by HPLC analysis. In addition, the glycosaminoglycan disaccharide compositions were obtained by stable isotope labeling coupled with LC/MS analysis. Genistein treatment reduced the amount of glycans but increased the amount of glycosaminoglycans in HCT116 cells. In contrast, genistein treatment reduced both glycan and glycosaminoglycan quantities in CHOK1, CHO3.1, and CHO3.3 cells in addition to differential changes in glycosaminoglycan disaccharide compositions. Genistein treatment reduced overall glycan quantity but glycosaminoglycan quantities were either increased or decreased in a cell type-dependent manner. © 2018 The Author(s). Published by S. Karger AG, Basel.

In vitro and in vivo evaluation of topical delivery and potential dermal use of soy isoflavones genistein and daidzein.

PubMed

Huang, Zih-Rou; Hung, Chi-Feng; Lin, Yin-Ku; Fang, Jia-You

2008-11-19

Genistein, daidzein, and glycitein are soy isoflavones. These compounds can be used to protect the skin from oxidative stress induced by UVB radiation. To this end, the feasibility of skin absorption of soy isoflavones was evaluated in the present study. As assayed by flow cytometry, UVB-induced H(2)O(2) production in keratinocytes was inhibited by genistein and daidzein, confirming that these two compounds can act as free radical scavengers when keratinocytes are photodamaged. Glycitein showed no protective activity against photodamage. The effects of vehicles on the in vitro topical delivery from saturated solutions such as aqueous buffers and soybean oil were investigated. The isoflavones in a non-ionized form (pH 6) showed higher skin deposition compared to the ionized form (pH 10.8). Soybean oil reduced the isoflavone amount retained in the skin, especially for genistein. Genistein generally exhibited greater skin absorption than did daidzein. However, daidzein permeation was enhanced when an aglycone mixture was used as the active ingredient. An eutectic effect was proposed as the enhancing mechanism. In vivo skin deposition showed a linear correlation with the in vitro results. The safety profiles suggested no or only negligible stratum corneum disruption and skin erythema by topical application of soy isoflavones. It was concluded that topical delivery may serve as a potent route for soy isoflavones against photoaging and photodamage.

Coumestrol and its metabolite in mares' plasma after ingestion of phytoestrogen-rich plants: potent endocrine disruptors inducing infertility.

PubMed

Ferreira-Dias, G; Botelho, M; Zagrajczuk, A; Rebordão, M R; Galvão, A M; Bravo, P Pinto; Piotrowska-Tomala, K; Szóstek, A Z; Wiczkowski, W; Piskula, M; Fradinho, M J; Skarzynski, D J

2013-10-01

Phytoestrogens exist in plants that are present in forages fed to horses. They may compete with 17-β estradiol and influence the estrous cycle. Therefore, the objective was to determine whether coumestrol from clover-mixed pastures is present in mare's plasma after their ingestion (experiment I), and when this phytoestrogen was present in mare's plasma after ingestion (experiment II). The effect of a long-term ingestion of phytoestrogens on estrous cycle disruption was assessed (experiment III; clinical case). Experiment I was carried out in nonpregnant anestrous and cyclic Lusitano mares (n = 14) kept on clover and grass-mixed pastures, and supplemented with concentrate and hay or cereal straw. Blood and feedstuff were obtained from November to March. In experiment II, stabled cyclic Lusitano mares (n = 6) were fed for 14 days with increasing amounts of alfalfa pellets (250 g to 1 kg/day). Sequential blood samples were obtained for 8 hours after feed intake on Day 0 (control) and on Days 13 and 14 (1 kg/day alfalfa pellets). Experiment III mares were fed with a mixture of alfalfa and clover haylage for 5 months (group 1; n = 4) or for 9 months (group 2; n = 12). Estrous cycle was determined on the basis of plasma estradiol (E2), progesterone (P4), and ultrasound (experiment III). Concentrations of phytoestrogen coumestrol and its metabolite methoxycoumestrol were determined by high-performance liquid chromatography coupled with mass spectrometry. Phytoestrogens decreased in pasture from November until March (P < 0.01) (experiment I), but were always detected in mares' plasma. In experiment II, plasma-conjugated forms of coumestrol and methoxycoumestrol were higher on Days 13 and 14 than in control (P < 0.05). The highest concentrations of conjugated form of coumestrol were at 1.5 and 4 hours (P < 0.001), whereas its free forms peaked at 1 and at 3.5 hours after ingestion (P < 0.05). Methoxycoumestrol-conjugated form concentration was the highest at 1.5 and 5

Genetic and Dietary Regulation of Glyburide Efflux by the Human Placental Breast Cancer Resistance Protein Transporter.

PubMed

Bircsak, Kristin M; Gupta, Vivek; Yuen, Poi Yu Sofia; Gorczyca, Ludwik; Weinberger, Barry I; Vetrano, Anna M; Aleksunes, Lauren M

2016-04-01

Glyburide is frequently used to treat gestational diabetes owing to its low fetal accumulation resulting from placental efflux by the breast cancer resistance protein (BCRP)/ABCG2 transporter. Here we sought to determine how exposure to the dietary phytoestrogen genistein and expression of a loss-of-function polymorphism in the ABCG2 gene (C421A) impacted the transport of glyburide by BCRP using stably transfected human embryonic kidney 293 (HEK) cells, human placental choriocarcinoma BeWo cells, and human placental explants. Genistein competitively inhibited the BCRP-mediated transport of (3)H-glyburide in both wild-type (WT) and C421A-BCRP HEK-expressing cells, with greater accumulation of (3)H-glyburide in cells expressing the C421A variant. In BeWo cells, exposure to genistein for 60 minutes increased the accumulation of (3)H-glyburide 30%-70% at concentrations relevant to dietary exposure (IC50 ∼180 nM). Continuous exposure of BeWo cells to genistein for 48 hours reduced the expression of BCRP mRNA and protein by up to 40%, which impaired BCRP transport activity. Pharmacologic antagonism of the estrogen receptor attenuated the genistein-mediated downregulation of BCRP expression, suggesting that phytoestrogens may reduce BCRP levels through this hormone receptor pathway in BeWo cells. Interestingly, genistein treatment for 48 hours did not alter BCRP protein expression in explants dissected from healthy term placentas. These data suggest that whereas genistein can act as a competitive inhibitor of BCRP-mediated transport, its ability to downregulate placental BCRP expression may only occur in choriocarcinoma cells. Overall, this research provides important mechanistic data regarding how the environment (dietary genistein) and a frequent genetic variant (ABCG2, C421A) may alter the maternal-fetal disposition of glyburide. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

Genetic and Dietary Regulation of Glyburide Efflux by the Human Placental Breast Cancer Resistance Protein Transporter

PubMed Central

Bircsak, Kristin M.; Gupta, Vivek; Yuen, Poi Yu Sofia; Gorczyca, Ludwik; Weinberger, Barry I.; Vetrano, Anna M.

2016-01-01

Glyburide is frequently used to treat gestational diabetes owing to its low fetal accumulation resulting from placental efflux by the breast cancer resistance protein (BCRP)/ABCG2 transporter. Here we sought to determine how exposure to the dietary phytoestrogen genistein and expression of a loss-of-function polymorphism in the ABCG2 gene (C421A) impacted the transport of glyburide by BCRP using stably transfected human embryonic kidney 293 (HEK) cells, human placental choriocarcinoma BeWo cells, and human placental explants. Genistein competitively inhibited the BCRP-mediated transport of 3H-glyburide in both wild-type (WT) and C421A-BCRP HEK-expressing cells, with greater accumulation of 3H-glyburide in cells expressing the C421A variant. In BeWo cells, exposure to genistein for 60 minutes increased the accumulation of 3H-glyburide 30%–70% at concentrations relevant to dietary exposure (IC50 ∼180 nM). Continuous exposure of BeWo cells to genistein for 48 hours reduced the expression of BCRP mRNA and protein by up to 40%, which impaired BCRP transport activity. Pharmacologic antagonism of the estrogen receptor attenuated the genistein-mediated downregulation of BCRP expression, suggesting that phytoestrogens may reduce BCRP levels through this hormone receptor pathway in BeWo cells. Interestingly, genistein treatment for 48 hours did not alter BCRP protein expression in explants dissected from healthy term placentas. These data suggest that whereas genistein can act as a competitive inhibitor of BCRP-mediated transport, its ability to downregulate placental BCRP expression may only occur in choriocarcinoma cells. Overall, this research provides important mechanistic data regarding how the environment (dietary genistein) and a frequent genetic variant (ABCG2, C421A) may alter the maternal-fetal disposition of glyburide. PMID:26850786

Effect of genistein added to bull semen after thawing on pronuclear and sperm quality.

PubMed

Silvestre, M A; Vicente-Fiel, S; Raga, E; Salvador, I; Soler, C; Yániz, J L

2015-12-01

The aim of this research was to study the effect of different genistein treatments on bull sperm after thawing on pronuclear formation after in vitro fertilization (IVF) and on different sperm quality variables. Three experiments were performed. In Experiment 1, three treatments (Control, sperm incubation for 1h at 37 °C with or without genistein) and two sperm concentrations during IVF (1 or 3 × 10(6)sperm/mL) were evaluated to study the influence of genistein on pronuclear formation (PNF). Sperm incubation for 1h before IVF reduced PNF regardless of sperm concentration. However, after sperm incubation and with 3 × 10(6)sperm/mL in IVF, the genistein treatment group had greater fertilization rates than the untreated group. In Experiment 2, six treatments plus the control group were performed to study the effect of genistein (presence or not) and incubation conditions (30 min at 37 °C, 1h at 27 °C or at 37 °C) on PNF using 3 × 10(6)sperm/mL for IVF. When incubation time was reduced to 30 min, PNF rate from the genistein treatment group was no different from either the control group or in the group in which incubation occurred for 1h at 27 °C. In Experiment 3, the effect of several genistein treatments (control; genistein treatment for 30 min of incubation at 37 °C; genistein treatment for 1h of incubation at 27 °C) on sperm motility, viability and DNA fragmentation were evaluated. Genistein did not improve sperm motility and, depending on the experimental group or time, it either reduced or had no effect on sperm motility. Genistein treatment did not improve sperm viability after 5h of incubation. However, genistein treatment for 1h at 27 °C decreased sperm DNA fragmentation compared with the control group after 5h of sperm incubation. In conclusion, the treatment of bull sperm with genistein for 1h at 27 °C could decrease sperm DNA fragmentation, although PNF rate after IVF and sperm motility were reduced. Copyright © 2015. Published by Elsevier B.V.

Dietary phytoestrogens maintain contractile responses to carbachol with age in the female rat isolated bladder.

PubMed

Owen, Suzzanne J; Rose'Meyer, Roselyn B; Massa, Helen M

2011-08-15

Development of urinary incontinence, for many women, occurs following menopause. Dietary phytoestrogens consumed over the long term may affect the contractile function and maintenance of the urinary bladder in post menopausal women. This study examined the muscarinic receptor mediated contractile responses in the rat isolated bladder in response to ovariectomy and long term dietary phytoestrogen consumption. Ovariectomised or sham-operated female Wistar rats (8 weeks) were fed either normal rat chow (soy, phytoestrogens) or a non-soy (phytoestrogen free) diet. Bladders were dissected from rats at 12, 24 and 52 weeks of age and placed in 25 ml organ baths filled with McEwans solution. The contractile response to carbachol, in 12 week old female rats did not change as a result of dietary phytoestrogens or ovariectomy (P>0.05). At 24 weeks of age, detrusor muscle strip responses to carbachol from non-soy fed ovariectomised rats were attenuated (P<0.05). At 52 weeks, bladder detrusor strip responses to carbachol were reduced in all treatment groups with the exception of the soy-fed sham operated rats. These results suggest an age-related reduction in the contractile response of the detrusor to the muscarinic receptor agonist carbachol, which may be prevented by long term dietary phytoestrogen intake. Copyright © 2011 Elsevier Inc. All rights reserved.

The regulatory effect of Genistein on granulosa cell in ovary of rat with PCOS through Bcl-2 and Bax signaling pathways.

PubMed

Chi, Xiao-Xing; Zhang, Tao; Chu, Xiao-Li; Zhen, Jing-Long; Zhang, Dong-Jie

2018-06-22

The effect of genistein on Bcl-2 and Bax protein expression in the ovarian tissue of rats with polycystic ovarian syndrome (PCOS) was evaluated. Sixty rats were divided into six groups. Rats in the Dose group received genistein at a concentration of either 5 (L-gen), 10 (M-Gen) or 20 (H-Gen) mg per kg of body weight per day. The expression of Bcl-2 mRNA and Bax mRNA was determined by in situ hybridization. Bcl-2 and Bax protein concentration was quantified by ELISA. The results showed that the expression of Bcl-2 mRNA and Bcl-2 protein was significantly higher in the high genistein Dose group (H-Gen) when compared to the Model group (MG) (P<0.05). Genistein induced higher expression of the Bcl-2 gene at the transcriptional and translational level. Treatment with genistein resulted in an improvement of ovarian function with Bcl-2 expression being enhanced and Bax expression being suppressed. These alterations may be due to the structural and functional modifications that take place in these cells, and could be related to apoptotic changes that occur in rats with PCOS.

Effect of quercetin and genistein on copper- and iron-induced lipid peroxidation in methyl linolenate.

PubMed

Boadi, William Y; Iyere, Peter A; Adunyah, Samuel E

2003-01-01

The single and combined effects of two abundant flavonoids, namely quercetin and genistein, were investigated according to their ability to inhibit the oxidation of methyl linolenate via Fenton's pathway. Antioxidative activity was determined by oxidizing methyl linolenate suspended in a buffer solution with either Fe2+ (50 microM) or Cu2+ (50 microM) and hydrogen peroxide (0.01 mM) without or with a flavonoid sample (10 or 20 microM). Lipid peroxidation products were measured by the thiobarbituric acid (TBA) assay and the amounts of thiobarbituric acid-reactive substances (TBARS) were calculated from a calibration curve using 1,1,3,3-tetraethoxypropane as the standard. Both quercetin and genistein at the 10 or 20 microM level decreased lipid peroxidation significantly compared with their respective controls. Of the two flavonoids tested, quercetin had a more marked effect on inhibiting lipid peroxides. Peroxidation products for the control samples were higher for the Fe2+-treated samples compared with the Cu2+ samples. Combination of both flavonoids at the same dose levels continued to decrease lipid peroxidation, the effect being the same for both metal ions. The data suggest that the combined flavonoids offered better protection than the single treatments and this may be attributed to the better radical scavenging or increased chelating capabilities of the combined over the single treatments. The differences in peroxide levels for the single treatment of quercetin compared with the genistein-treated samples may reflect the structural differences between these compounds in combating oxidative stress. Copyright 2003 John Wiley & Sons, Ltd.

A reporter gene assay for the detection of phytoestrogens in traditional Chinese medicine.

PubMed

Miller-Martini, D M; Chan, R Y; Ip, N Y; Sheu, S J; Wong, Y H

2001-09-01

Bupleurum & Peony Formula (Jia Wei Xiao Yao San) is a herbal formula which possesses a clinical history for the treatment of menopausal syndrome and menstrual irregularity. The present investigation reports the ability to monitor the formula's phytoestrogen content that will allow for the implementation of a standardization protocol that is based on a quantifiable biological response. Utilizing an oestrogen-sensitive chimeric receptor/reporter gene element which has been stably transfected into HeLa cells, the botanical formula was shown to induce the expression of the reporter gene, luciferase, in a dose dependent manner. Pretreatment of the HeLa cells with the botanical formula produced a 5-fold increase in bioluminescence compared with the control. Additionally, our studies showed that the response of the cells, when challenged by the botanical formula, was oestrogen specific. Pretreatment of the cells with tamoxifen effectively blocked the activation of the chimeric oestrogen receptor by the botanical formula. The cell line provides a sensitive assay that can easily detect the presence of phytoestrogens in complex botanical formulas. Copyright 2001 John Wiley & Sons, Ltd.

Phytoestrogen signaling and symbiotic gene activation are disrupted by endocrine-disrupting chemicals.

PubMed Central

Fox, Jennifer E; Starcevic, Marta; Jones, Phillip E; Burow, Matthew E; McLachlan, John A

2004-01-01

Some organochlorine pesticides and other synthetic chemicals mimic hormones in representatives of each vertebrate class, including mammals, reptiles, amphibians, birds, and fish. These compounds are called endocrine-disrupting chemicals (EDCs). Similarly, hormonelike signaling has also been observed when vertebrates are exposed to plant chemicals called phytoestrogens. Previous research has shown the mechanism of action for EDCs and phytoestrogens is as unintended ligands for the estrogen receptor (ER). Although pesticides have been synthesized to deter insects and weeds, plants produce phytoestrogens to deter herbivores, as attractant cues for insects, and as recruitment signals for symbiotic soil bacteria. Our data present the first evidence that some of the same organochlorine pesticides and EDCs known to disrupt endocrine signaling through ERs in exposed wildlife and humans also disrupt the phytoestrogen signaling that leguminous plants use to recruit Sinorhizobium meliloti soil bacteria for symbiotic nitrogen fixation. Here we report that a variety of EDCs and pesticides commonly found in agricultural soils interfere with the symbiotic signaling necessary for nitrogen fixation, suggesting that the principles underlying endocrine disruption may have more widespread biological and ecological importance than had once been thought. PMID:15121509

Genistein, a dietary soy isoflavone, exerts antidepressant-like effects in mice: Involvement of serotonergic system.

PubMed

Hu, Pei; Ma, Li; Wang, Yan-Gui; Ye, Feng; Wang, Chuang; Zhou, Wen-Hua; Zhao, Xin

2017-09-01

Genistein, a principal isoflavone property of soybeans, possesses multiple pharmacological activities such as neuroprotection. Recently, it was reported that genistein exerted antidepressant-like effects in animal models, but the mechanism of action remains ambiguous. The purpose of this study was to investigate the antidepressant-like effect of genistein in mice and explore the underlying mechanism(s), using two mouse models of depression, i.e. forced swim test (FST) and tail suspension test (TST). Chronic, but not acute (single dose), genistein treatment (5, 15 or 45 mg/kg, p.o., once per day for three weeks) exerted dose-dependently antidepressant-like effect in mice, concomitant with escalated levels of brain monoamines and suppressed monoamine oxidase (MAO) activity. Chemical depletion of brain serotonin by PCPA abrogated the antidepressant-like action of genistein, but it was not the case for ablation of NA by DSP-4. Moreover, the anti-depression by genistein was preferentially counteracted by co-administration of 5-HT 1A receptor antagonist WAY-100635, suggesting a pivotal role for 5-HT system coupled with 5-HT 1A receptors in mediating such genistein anti-depression. This point was further validated by the fact that genistein action was potentiated by co-treatment with 8-OH-DPAT, a selective 5-HT 1A receptor agonist. Collectively, these findings confirm that chronic genistein administration to mice engenders antidepressant-like efficacy evidenced by lessened behavioral despair. Serotonergic system that preferentially couples with 5-HT 1A receptors may be critically responsible for the present genistein anti-depression. Copyright © 2017 Elsevier Ltd. All rights reserved.

Relationships between urinary biomarkers of phytoestrogens, phthalates, phenols, and pubertal stages in girls

PubMed Central

Chakraborty, Tandra R; Alicea, Eilliut; Chakraborty, Sanjoy

2012-01-01

Phytoestrogens, phthalates, and phenols are estrogen-disrupting chemicals that have a pronounced effect at puberty. They are exogenous chemicals that are either plant-derived or man-made, and can alter the functions of the endocrine system and cause various health defects by interfering with the synthesis, metabolism, binding, or cellular responses of natural estrogens. Phytoestrogens, phthalates, and phenols are some of the potent estrogens detectable in urine. Phytoestrogens are plant-derived xenestrogens found in a wide variety of food products, like soy-based food, beverages, several fruits, and vegetables. Exposure to phytoestrogens can delay breast development and further lead to precocious puberty. The effect of phytoestrogens is mediated through estrogen receptors α and β or by binding with early immediate genes, such as jun and fos. Phthalates are multifunctional synthetic chemicals used in plastics, polyvinyl chloride products, cosmetics, hair spray, and children’s toys. Phthalates have been shown to cause defeminization, thelarche, precocious puberty, and an increase in breast and pubic hair in pubertal girls. However, reports are also available that show no association of phthalates with precocious puberty in girls. Phthalates can act through a receptor-mediated signaling pathway or affect the production of luteinizing hormone and follicle-stimulating hormone that has a direct effect on estrogen formation. Phenols like bisphenol A are industrial chemicals used mainly in the manufacture of polycarbonates and plastic materials. Bisphenol A has been shown to cause precocious puberty and earlier menarche in pubertal girls. Reports suggest that the neurotoxic effect of bisphenol A can be mediated either by competing with estradiol for binding with estrogen receptors or via the ERK/NK-kappa or ERRγ pathway. This review demonstrates the effects of phytoestrogens, phthalates, and phenols on the development of girls during puberty. PMID:24600283

Genistein supplementation increases bone turnover but does not prevent alcohol-induced bone loss in male mice.

PubMed

Yang, Carrie S; Mercer, Kelly E; Alund, Alexander W; Suva, Larry J; Badger, Thomas M; Ronis, Martin J J

2014-10-01

Chronic alcohol consumption results in bone loss through increased bone resorption and decreased bone formation. These effects can be reversed by estradiol (E2) supplementation. Soy diets are suggested to have protective effects on bone loss in men and women, as a result of the presence of soy protein-associated phytoestrogens such as genistein (GEN). In this study, male mice were pair-fed (PF), a control diet, an ethanol (EtOH) diet, or EtOH diet supplemented with 250 mg/kg of GEN for 8 weeks to test if GEN protects against bone loss associated with chronic drinking. Interestingly, alcohol consumption reduced cortical area and thickness and trabecular bone volume in both EtOH and EtOH/GEN groups when compared to the corresponding PF and PF/GEN controls, P < 0.05. However, in the trabecular bone compartment, we observed a significant increase in overall trabecular bone density in the PF/GEN group compared to the PF controls. Bone loss in the EtOH-treated mice was associated with the inhibition of osteoblastogenesis as indicated by decreased alkaline phosphatase staining in ex vivo bone marrow cultures, P < 0.05. GEN supplementation improved osteoblastogenesis in the EtOH/GEN cultures compared to the EtOH group, P < 0.05. Vertebral expression of bone-formation markers, osteocalcin, and runt-related transcription factor 2 (Runx2) was also significantly up-regulated in the PF/GEN and EtOH/GEN groups compared to the PF and EtOH-treated groups. GEN supplementation also increased the expression of receptor activator of nuclear factor κ-B ligand (RANKL) in the PF/GEN, an increase that persisted in the EtOH/GEN-treated animals (P < 0.05), and increased basal hydrogen peroxide production and RANKL mRNA expression in primary bone marrow cultures in vitro, P < 0.05. These findings suggest that GEN supplementation increases the overall bone remodeling and, in the context of chronic alcohol consumption, does not protect against the oxidative stress

Mechanism of phytoestrogen puerarin-mediated cytoprotection following oxidative injury: Estrogen receptor-dependent up-regulation of PI3K/Akt and HO-1

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hwang, Yong Pil; Jeong, Hye Gwang

2008-12-15

Phytoestrogens are polyphenolic non-steroidal plant compounds with estrogen-like biological activity. The phytoestrogen puerarin, the main isoflavone glycoside found in the root of Pueraria lobata, has been used for various medicinal purposes in traditional Chinese medicines for thousands of years. Recent studies have indicated that the estrogen receptor (ER), through interaction with p85, regulates phosphoinositide 3-kinase (PI3K) activity, revealing a physiologic, non-nuclear function of ER that may be relevant in cytoprotection. In this study, we demonstrate that the phytoestrogen puerarin inhibits tert-butyl hydroperoxide (t-BHP)-induced oxidative injury via an ER-dependent G{beta}1/PI3K/Akt and heme oxygenase-1 (HO-1) pathway. Pretreatment of Hepa1c1c7 and HepG2 cellsmore » with puerarin significantly reduced t-BHP-induced caspase-3 activation and subsequent cell death. Also, puerarin up-regulated HO-1 expression and this expression conferred cytoprotection against oxidative injury induced by t-BHP. Moreover, puerarin induced Nrf2 nuclear translocation, which is upstream of puerarin-induced HO-1 expression, and PI3K activation, a pathway that is involved in induced Nrf2 nuclear translocation, HO-1 expression and cytoprotection. Puerarin-induced up-regulation of HO-1 and cytoprotection against t-BHP were abolished by silencing Nrf2 expression with specific siRNA. Also, puerarin-mediated increases in PI3K activation and HO-1 induction were reversed by co-treatment with ICI 182,780 and pertussis toxin. Taken together, these results suggest that puerarin augments cellular antioxidant defense capacity through ER-dependent HO-1 induction via the G{beta}1/PI3K/Akt-Nrf2 signaling pathway, thereby protecting cells from oxidative stress.« less

Drug combination studies of curcumin and genistein against rhodesain of Trypanosoma brucei rhodesiense.

PubMed

Ettari, Roberta; Previti, Santo; Maiorana, Santina; Allegra, Alessandro; Schirmeister, Tanja; Grasso, Silvana; Zappalà, Maria

2018-06-13

Curcumin and genistein are two natural products obtained from Curcuma longa L. and soybeans, endowed with many biological properties. Within the last years they were shown to possess also a promising antitrypanosomal activity. In the present paper, we investigated the activity of both curcumin and genistein against rhodesain, the main cysteine protease of Trypanosoma brucei rhodesiense; drug combination studies, according to Chou and Talalay method, allowed us to demonstrate a potent synergistic effect for the combination curcumin-genistein. As a matter of fact, with our experiments we observed that the combination index of curcumin-genistein is < 1 for the reduction from 10 to 90% of rhodesain activity.

Regulation of multidrug resistance proteins by genistein in a hepatocarcinoma cell line: impact on sorafenib cytotoxicity.

PubMed

Rigalli, Juan Pablo; Ciriaci, Nadia; Arias, Agostina; Ceballos, María Paula; Villanueva, Silvina Stella Maris; Luquita, Marcelo Gabriel; Mottino, Aldo Domingo; Ghanem, Carolina Inés; Catania, Viviana Alicia; Ruiz, María Laura

2015-01-01

Hepatocellular carcinoma (HCC) is the fifth most frequent cancer worldwide. Sorafenib is the only drug available that improves the overall survival of HCC patients. P-glycoprotein (P-gp), Multidrug resistance-associated proteins 2 and 3 (MRP2 and 3) and Breast cancer resistance protein (BCRP) are efflux pumps that play a key role in cancer chemoresistance. Their modulation by dietary compounds may affect the intracellular accumulation and therapeutic efficacy of drugs that are substrates of these transporters. Genistein (GNT) is a phytoestrogen abundant in soybean that exerts its genomic effects through Estrogen-Receptors and Pregnane-X-Receptor (PXR), which are involved in the regulation of the above-mentioned transporters. We evaluated the effect of GNT on the expression and activity of P-gp, MRP2, MRP3 and BCRP in HCC-derived HepG2 cells. GNT (at 1.0 and 10 μM) increased P-gp and MRP2 protein expression and activity, correlating well with an increased resistance to sorafenib cytotoxicity as detected by the methylthiazole tetrazolium (MTT) assay. GNT induced P-gp and MRP2 mRNA expression at 10 but not at 1.0 μM concentration suggesting a different pattern of regulation depending on the concentration. Induction of both transporters by 1.0 μM GNT was prevented by cycloheximide, suggesting translational regulation. Downregulation of expression of the miR-379 by GNT could be associated with translational regulation of MRP2. Silencing of PXR abolished P-gp induction by GNT (at 1.0 and 10 μM) and MRP2 induction by GNT (only at 10 μM), suggesting partial mediation of GNT effects by PXR. Taken together, the data suggest the possibility of nutrient-drug interactions leading to enhanced chemoresistance in HCC when GNT is ingested with soy rich diets or dietary supplements.

SIX1 Oncoprotein as a Biomarker in a Model of Hormonal Carcinogenesis and in Human Endometrial Cancer.

EPA Science Inventory

The oncofetal protein sine oculis-related homeobox 1 (SIX1) is a developmental transcription factor associated with carcinogenesis in animal models and humans. In a model of hormonal carcinogenesis, mice neonatally exposed to the soy phytoestrogen, genistein (GEN), or the synthet...

Effects of dietary genistein on GH/IGF-I axis of Nile tilapia Oreochromis niloticus

NASA Astrophysics Data System (ADS)

Chen, Dong; Wang, Wei; Ru, Shaoguo

2016-09-01

There is considerable concern that isoflavones, such as genistein in fish feed composed of soybean protein, aff ects somatic growth in fish. Our previous works demonstrated that 30 and 300 μg/g dietary genistein had no significant eff ect on growth performance in Nile tilapia ( Oreochromis niloticus), but the higher level of genistein (3 000 μg/g) significantly depressed growth. This study was conducted to further examine the eff ects of dietary genistein on the endocrine disruption on growth hormone/insulin-like growth factor-I (GH/IGF-I) axis in Nile tilapia ( O. niloticus). Juvenile fish were fed by hand twice daily to satiation with one of four isonitrogenous and isoenergetic diets, each containing either 0, 30, 300 or 3 000 μg/g genistein. Following an 8-week feeding period, plasma GH and IGF-I levels were investigated by radioimmunoassay and gene expression levels of gh, ghrelin, gnrhs, ghr, npy, npyrs, pacap, ghrs, i gf-I, igf-Ir, and igfbp3 were examined by real-time PCR. The results show that no significant change in plasma GH and IGF-I levels in fish fed with diets containing 30 μg/g and 300 μg/g genistein. mRNA expression of genes along the GH/IGF-I axis remained unaff ected, except for igf-Ir, which was stimulated by the 300 μg/g genistein diet. While in fish fed the 3 000 μg/g genistein diet, the plasma GH and IGF-I levels decreased, and mRNA expression of gh, ghr2, npyr1, igf-I, and igf-Ir were also significantly depressed. In contrast, npy and igfbp3 mRNA expression were enhanced. This study provides convincing evidence for growth impediment by genistein by disturbing the GH/IGF-I axis in Nile tilapia O. niloticus.

Genistein and resveratrol: mammary cancer chemoprevention and mechanisms of action in the rat.

PubMed

Whitsett, Timothy G; Lamartiniere, Coral A

2006-12-01

The environment, including diet, plays a critical role in a woman's subsequent risk of breast cancer. Two dietary polyphenols that have received attention from the health and research communities for their ability to protect against breast cancer are: genistein, a component of soy; and resveratrol, a phytoalexin found in red grapes and red wine. We and others have shown that both genistein and resveratrol can protect against mammary cancer in rodents. The timing of exposure to genistein appears critical for its mammary protective effects. It has been reported that genistein early in life causes enhanced mammary gland differentiation, alterations in cell proliferation and apoptosis, and upregulation of tumor-suppressor genes. With resveratrol in the diet, changes in cell proliferation and apoptosis in terminal ductal structures of the mammary gland might help to explain its protective effects. We conclude that genistein and resveratrol can protect against breast cancer by regulating important mammary growth and differentiation pathways.

Effects of the soya isoflavone genistein in early life stages of the Senegalese sole, Solea senegalensis: Thyroid, estrogenic and metabolic biomarkers.

PubMed

Sarasquete, Carmen; Úbeda-Manzanaro, Maria; Ortiz-Delgado, Juan Bosco

2017-09-01

This study examines the effects induced by environmentally relevant concentrations of the isoflavone genistein (3mg/L and 10mg/L) during early life stages of the Senegalese sole. Throughout the hypothalamus-pituitary-thyroid (HPT) axis, several neurohormonal regulatory thyroid signalling patterns (thyroglobulin/Tg, thyroid peroxidase/TPO, transthyretin/TTR, thyroid receptors/TRβ, and iodothrynonine deiodinases, Dio2 and Dio3) were analysed. Furthermore, the expression patterns of estrogen receptor ERβ and haemoprotein Cyp1a were also evaluated. In the control larvae, progressive increases of constitutive hormonal signalling pathways have been evidenced from the pre-metamorphosis phase onwards, reaching the highest expression basal levels at the metamorphosis (Tg, TPO, Dio2) and/or during post-metamorphosis (TTR, TRβ, ERβ). When the early larvae were exposed to both genistein concentrations (3mg/L and 10mg/L), a statistically significant down-regulation of TPO, TTR and Tg mRNA levels was clearly detected at the metamorphic stages. In addition, the Dio2 and Dio3 transcript expression levels were also down and up-regulated when exposed to both genistein concentrations. In the larvae exposed to genistein, no statistically significant responses were recorded for the TRβ expression patterns. Nevertheless, the ERβ and Cyp1a transcript levels were up-regulated at the middle metamorphic stage (S2, at 16 dph) in the larvae exposed to high genistein concentrations and, only the ERβ was down-regulated (S1, at 12dph) at the lower doses. Finally, all these pointed out imbalances were only temporarily disrupted by exposure to genistein, since most of the modulated transcriptional signals (i.e. up or down-regulation) were quickly restored to the baseline levels. Additionally, the control and genistein-exposed Senegalese sole specimens showed characteristic ontogenetic patterns and completely suitable for an optimal development, metamorphosis, and growth. Copyright © 2017

Absorption Study of Genistein Using Solid Lipid Microparticles and Nanoparticles: Control of Oral Bioavailability by Particle Sizes.

PubMed

Kim, Jeong Tae; Barua, Sonia; Kim, Hyeongmin; Hong, Seong-Chul; Yoo, Seung-Yup; Jeon, Hyojin; Cho, Yeongjin; Gil, Sangwon; Oh, Kyungsoo; Lee, Jaehwi

2017-07-01

In this study, the effect of particle size of genistein-loaded solid lipid particulate systems on drug dissolution behavior and oral bioavailability was investigated. Genistein-loaded solid lipid microparticles and nanoparticles were prepared with glyceryl palmitostearate. Except for the particle size, other properties of genistein-loaded solid lipid microparticles and nanoparticles such as particle composition and drug loading efficiency and amount were similarly controlled to mainly evaluate the effect of different particle sizes of the solid lipid particulate systems on drug dissolution behavior and oral bioavailability. The results showed that genistein-loaded solid lipid microparticles and nanoparticles exhibited a considerably increased drug dissolution rate compared to that of genistein bulk powder and suspension. The microparticles gradually released genistein as a function of time while the nanoparticles exhibited a biphasic drug release pattern, showing an initial burst drug release, followed by a sustained release. The oral bioavailability of genistein loaded in solid lipid microparticles and nanoparticles in rats was also significantly enhanced compared to that in bulk powders and the suspension. However, the bioavailability from the microparticles increased more than that from the nanoparticles mainly because the rapid drug dissolution rate and rapid absorption of genistein because of the large surface area of the genistein-solid lipid nanoparticles cleared the drug to a greater extent than the genistein-solid lipid microparticles did. Therefore, the findings of this study suggest that controlling the particle size of solid-lipid particulate systems at a micro-scale would be a promising strategy to increase the oral bioavailability of genistein.

Genistein and cancer: current status, challenges, and future directions.

PubMed

Spagnuolo, Carmela; Russo, Gian Luigi; Orhan, Ilkay Erdogan; Habtemariam, Solomon; Daglia, Maria; Sureda, Antoni; Nabavi, Seyed Fazel; Devi, Kasi Pandima; Loizzo, Monica Rosa; Tundis, Rosa; Nabavi, Seyed Mohammad

2015-07-01

Primary prevention through lifestyle interventions is a cost-effective alternative for preventing a large burden of chronic and degenerative diseases, including cancer, which is one of the leading causes of morbidity and mortality worldwide. In the past decade, epidemiologic and preclinical evidence suggested that polyphenolic phytochemicals present in many plant foods possess chemopreventive properties against several cancer forms. Thus, there has been increasing interest in the potential cancer chemopreventive agents obtained from natural sources, such as polyphenols, that may represent a new, affordable approach to curb the increasing burden of cancer throughout the world. Several epidemiologic studies showed a relation between a soy-rich diet and cancer prevention, which was attributed to the presence of a phenolic compound, genistein, present in soy-based foods. Genistein acts as a chemotherapeutic agent against different types of cancer, mainly by altering apoptosis, the cell cycle, and angiogenesis and inhibiting metastasis. Targeting caspases, B cell lymphoma 2 (Bcl-2)-associated X protein (Bax), Bcl-2, kinesin-like protein 20A (KIF20A), extracellular signal-regulated kinase 1/2 (ERK1/2), nuclear transcription factor κB (NF-κB), mitogen-activated protein kinase (MAPK), inhibitor of NF-κB (IκB), Wingless and integration 1 β-catenin (Wnt/β-catenin), and phosphoinositide 3 kinase/Akt (PI3K/Akt) signaling pathways may act as the molecular mechanisms of the anticancer, therapeutic effects of genistein. Genistein also shows synergistic behavior with well-known anticancer drugs, such as adriamycin, docetaxel, and tamoxifen, suggesting a potential role in combination therapy. This review critically analyzes the available literature on the therapeutic role of genistein on different types of cancer, focusing on its chemical features, plant food sources, bioavailability, and safety. © 2015 American Society for Nutrition.

Novel daidzein analogs enhance osteogenic activity of bone marrow-derived mesenchymal stem cells and adipose-derived stromal/stem cells through estrogen receptor dependent and independent mechanisms

USDA-ARS?s Scientific Manuscript database

Osteoporosis is a disease characterized by low bone mineral density (BMD) and increased risk of fractures. Studies have demonstrated the use of phytoestrogens, or plant-derived estrogens, such as genistein anddaidzein, to effectively increase osteogenic activity of bone marrow-derived mesenchymal s...

Phytoestrogens: a viable option?

PubMed

Russell, Lori; Hicks, G Swink; Low, Annette K; Shepherd, Jinna M; Brown, C Andrew

2002-10-01

Estrogen replacement therapy is one of the most commonly prescribed medicines in the United States by traditional medical professionals. Over the past decade, the market for complementary/ alternative therapies for hormone replacement has dramatically increased. Women are seeking more "natural" alternatives to treat menopausal symptoms. Well-designed randomized clinical trials are often lacking, as is the information on efficacy and safety. This article will review several popular herbal therapies for menopausal symptoms including phytoestrogens, black cohosh (Cimicifuga racemosa), dong quai (Angelica sinensis), chast tree (Vitex agnus-castus), and wild Mexican yam. Their use, mechanism of action, and adverse effects are outlined.

Inhibitory effect of genistein on the invasive potential of human cervical cancer cells via modulation of matrix metalloproteinase-9 and tissue inhibitors of matrix metalloproteinase-1 expression.

PubMed

Hussain, Arif; Harish, Geetganga; Prabhu, Sathyen Alwin; Mohsin, Javeria; Khan, Munawwar Ali; Rizvi, Tahir A; Sharma, Chhavi

2012-12-01

One of the most challenging stumbling blocks for the treatment of cancer is the ability of cancer cells to break the natural barriers and spread from its site of origin to non-adjacent regional and distant sites, accounting for high cancer mortality rates. Gamut experimental and epidemiological data advocate the use of pharmacological or nutritional interventions to inhibit or delay various stage(s) of cancer such as invasion and metastasis. Genistein, a promising chemopreventive agent, has gained considerable attention for its powerful anti-carcinogenic, anti-angiogenic and chemosensitizing activities. In this study, the cytotoxic potential of genistein on HeLa cells by cell viability assay and the mode of cell death induced by genistein were determined by nuclear morphological examination, DNA laddering assay and cell cycle analysis. Moreover, to establish its inhibitory effect on migration of HeLa cells, scratch wound assay was performed and these results were correlated with the expression of genes involved in invasion and migration (MMP-9 and TIMP-1) by RT-PCR. The exposure of HeLa cells to genistein resulted in significant dose- and time-dependent growth inhibition, which was found to be mediated by apoptosis and cell cycle arrest at G(2)/M phase. In addition, it induced migration-inhibition in a time-dependent manner by modulating the expression of MMP-9 and TIMP-1. Our results signify that genistein may be an effective anti-neoplastic agent to prevent cancer cell growth and invasion and metastasis. Therefore therapeutic strategies utilizing genistein could be developed to substantially reduce cancer morbidity and mortality. Copyright © 2012 Elsevier Ltd. All rights reserved.

Estrogen receptor β-selective phytoestrogenic formulation prevents physical and neurological changes in a preclinical model of human menopause.

PubMed

Zhao, Liqin; Mao, Zisu; Schneider, Lon S; Brinton, Roberta D

2011-10-01

As an alternative to estrogen therapy, the efficacy of an estrogen receptor β-selective phytoestrogenic (phyto-β-SERM) formulation to regulate climacteric symptoms and decline in brain responses associated with ovarian hormone loss in menopause was assessed. A phyto-β-SERM formulation-containing diet was compared with a commercial soy extract diet and a phytoestrogen-free base/control diet in an ovariectomized (OVX) mouse model of human menopause. Two treatment studies were conducted: (1) a 2-month study assessed the effects of experimental diets on tail skin temperature as a model of menopausal hot flashes, and (2) a 9-month study assessed the long-term impact of the diets on overall health, hair thinning/loss, spatial working memory, and associated protein expression in the hippocampus. The phyto-β-SERM diet prevented OVX-induced menopause-like changes including the rise in skin temperature, hair thinning/loss, deficit in spatial memory function, and reversed OVX-induced decline in the expression of hippocampal proteins involved in neural plasticity and β-amyloid degradation/clearance. The soy extract diet had no effect or exacerbated OVX-induced changes. Overall, the phyto-β-SERM diet induced physical and neurological responses comparable with ovary-intact mice, suggesting the therapeutic potential of the phyto-β-SERM formulation for the prevention/alleviation of climacteric symptoms and decline in brain responses induced by ovarian hormone loss, which provides the basis for further work in postmenopausal women.

[Response surface method optimize of nano-silica solid dispersion technology assistant enzymatic hydrolysis preparation genistein].

PubMed

Jin, Xin; Zhang, Zhen-Hai; Zhu, Jing; Sun, E; Yu, Dan-Hong; Chen, Xiao-Yun; Liu, Qi-Yuan; Ning, Qing; Jia, Xiao-Bin

2012-04-01

This article reports that nano-silica solid dispersion technology was used to raise genistein efficiency through increasing the enzymatic hydrolysis rate. Firstly, genistin-nano-silica solid dispersion was prepared by solvent method. And differential scanning calorimetry (DSC) and transmission electron microscopy (TEM) were used to verify the formation of solid dispersion, then enzymatic hydrolysis of solid dispersion was done by snailase to get genistein. With the conversion of genistein as criteria, single factor experiments were used to study the different factors affecting enzymatic hydrolysis of genistin and its solid dispersion. And then, response surface method was used to optimize of nano-silica solid dispersion technology assistant enzymatic hydrolysis. The optimum condition to get genistein through enzymatic hydrolysis of genistin-nano-silica solid dispersion was pH 7.1, temperature 52.2 degrees C, enzyme concentration 5.0 mg x mL(-1) and reaction time 7 h. Under this condition, the conversion of genistein was (93.47 +/- 2.40)%. Comparing with that without forming the genistin-nano-silica solid dispersion, the conversion increased 2.62 fold. At the same time, the product of hydrolysis was purified to get pure genistein. The method of enzymatic hydrolysis of genistin-nano-silica solid dispersion by snailase to obtain genistein is simple, efficiency and suitable for the modern scale production.

Exogenous hormonal regulation in breast cancer cells by phytoestrogens and endocrine disruptors.

PubMed

Albini, A; Rosano, C; Angelini, G; Amaro, A; Esposito, A I; Maramotti, S; Noonan, D M; Pfeffer, U

2014-01-01

Observations on the role of ovarian hormones in breast cancer growth, as well as interest in contraception, stimulated research into the biology of estrogens. The identification of the classical receptors ERα and ERβ and the transmembrane receptor GPER and the resolution of the structure of the ligand bound to its receptor established the principal molecular mechanisms of estrogen action. The presence of estrogen-like compounds in many plants used in traditional medicine or ingested as food ingredients, phytoestrogens, as well as the estrogenic activities of many industrial pollutants and pesticides, xenoestrogens, have prompted investigations into their role in human health. Phyto- and xenoestrogens bind to the estrogen receptors with a lower affinity than the endogenous estrogens and can compete or substitute the hormone. Xenoestrogens, which accumulate in the body throughout life, are believed to increase breast cancer risk, especially in cases of prenatal and prepuberal exposure whereas the role of phytoestrogens is still a matter of debate. At present, the application of phytoestrogens appears to be limited to the treatment of post-menopausal symptoms in women where the production of endogenous estrogens has ceased. In this review we discuss chemistry, structure and classification, estrogen signaling and the consequences of the interactions of estrogens, phytoestrogens and xenoestrogens with their receptors, the complex interactions of endogenous and exogenous ligands, the evaluation of the health risks related to xenoestrogens, and the perspectives toward the synthesis of potent third generation selective estrogen receptor modulators (SERMs).

Exogenous Hormonal Regulation in Breast Cancer Cells by Phytoestrogens and Endocrine Disruptors

PubMed Central

Albini, A.; Rosano, C.; Angelini, G.; Amaro, A.; Esposito, A.I.; Maramotti, S.; Noonan, D.M.; Pfeffer, U.

2014-01-01

Observations on the role of ovarian hormones in breast cancer growth, as well as interest in contraception, stimulated research into the biology of estrogens. The identification of the classical receptors ERα and ERβ and the transmembrane receptor GPER and the resolution of the structure of the ligand bound to its receptor established the principal molecular mechanisms of estrogen action. The presence of estrogen-like compounds in many plants used in traditional medicine or ingested as food ingredients, phytoestrogens, as well as the estrogenic activities of many industrial pollutants and pesticides, xenoestrogens, have prompted investigations into their role in human health. Phyto- and xenoestrogens bind to the estrogen receptors with a lower affinity than the endogenous estrogens and can compete or substitute the hormone. Xenoestrogens, which accumulate in the body throughout life, are believed to increase breast cancer risk, especially in cases of prenatal and prepuberal exposure whereas the role of phytoestrogens is still a matter of debate. At present, the application of phytoestrogens appears to be limited to the treatment of post-menopausal symptoms in women where the production of endogenous estrogens has ceased. In this review we discuss chemistry, structure and classification, estrogen signaling and the consequences of the interactions of estrogens, phytoestrogens and xenoestrogens with their receptors, the complex interactions of endogenous and exogenous ligands, the evaluation of the health risks related to xenoestrogens, and the perspectives toward the synthesis of potent third generation selective estrogen receptor modulators (SERMs). PMID:24304271

Phytoestrogens in Postmenopause: The State of the Art from a Chemical, Pharmacological and Regulatory Perspective

PubMed Central

Poluzzi, Elisabetta; Piccinni, Carlo; Raschi, Emanuel; Rampa, Angela; Recanatini, Maurizio; Ponti, Fabrizio De

2014-01-01

Phytoestrogens represent a diverse group of non-steroidal natural products, which seem to have some oestrogenic effects and are often marketed as food supplements. Population exposed to phytoestrogens is potentially increasing, in part because an unfavourable risk-benefit profile of Hormone Replacement Therapy (HRT) for prolonged treatments (e.g., osteoporosis prevention) highlighted by the publication of the Women Health Initiative (WHI) trial in 2002, but also because many post-menopausal women often perceived phytoestrogens in food supplements as a safer alternative than HRT. Despite of increasing preclinical and clinical studies in the past decade, appealing evidence is still lacking to support the overall positive risk-benefit profile of phytoestrogens. Their status as food supplements seems to discourage studies to obtain new evidence, and the chance to buy them by user’s initiative make it difficult to survey their prevalence and pattern of use. The aim of the present review is to: (a) outline the clinical scenario underlying the increased interest on phytoestrogens, by overviewing the evolution of the evidence on HRT and its main therapeutic goals (e.g., menopausal symptoms relief, chemoprevention, osteoporosis prevention); (b) address the chemical and pharmacological features (e.g. chemical structure, botanical sources, mechanism of action) of the main compounds (e.g., isoflavones, lignans, coumestans); (c) describe the clinical evidence on potential therapeutic applications; (d) put available evidence on their riskbenefit profile in a regulatory perspective, in light of the recent regulation on health claims of food supplements. PMID:24164197

Genistein and Cancer: Current Status, Challenges, and Future Directions12

PubMed Central

Spagnuolo, Carmela; Russo, Gian Luigi; Orhan, Ilkay Erdogan; Habtemariam, Solomon; Daglia, Maria; Sureda, Antoni; Nabavi, Seyed Fazel; Devi, Kasi Pandima; Loizzo, Monica Rosa; Tundis, Rosa; Nabavi, Seyed Mohammad

2015-01-01

Primary prevention through lifestyle interventions is a cost-effective alternative for preventing a large burden of chronic and degenerative diseases, including cancer, which is one of the leading causes of morbidity and mortality worldwide. In the past decade, epidemiologic and preclinical evidence suggested that polyphenolic phytochemicals present in many plant foods possess chemopreventive properties against several cancer forms. Thus, there has been increasing interest in the potential cancer chemopreventive agents obtained from natural sources, such as polyphenols, that may represent a new, affordable approach to curb the increasing burden of cancer throughout the world. Several epidemiologic studies showed a relation between a soy-rich diet and cancer prevention, which was attributed to the presence of a phenolic compound, genistein, present in soy-based foods. Genistein acts as a chemotherapeutic agent against different types of cancer, mainly by altering apoptosis, the cell cycle, and angiogenesis and inhibiting metastasis. Targeting caspases, B cell lymphoma 2 (Bcl-2)–associated X protein (Bax), Bcl-2, kinesin-like protein 20A (KIF20A), extracellular signal-regulated kinase 1/2 (ERK1/2), nuclear transcription factor κB (NF-κB), mitogen-activated protein kinase (MAPK), inhibitor of NF-κB (IκB), Wingless and integration 1 β-catenin (Wnt/β-catenin), and phosphoinositide 3 kinase/Akt (PI3K/Akt) signaling pathways may act as the molecular mechanisms of the anticancer, therapeutic effects of genistein. Genistein also shows synergistic behavior with well-known anticancer drugs, such as adriamycin, docetaxel, and tamoxifen, suggesting a potential role in combination therapy. This review critically analyzes the available literature on the therapeutic role of genistein on different types of cancer, focusing on its chemical features, plant food sources, bioavailability, and safety. PMID:26178025

Estrogenicity of the isoflavone genistein pigeon pie seeds (Cajanus cajan L. Mill sp.) on reproductive organs in rat

NASA Astrophysics Data System (ADS)

Novi Primiani, Cicilia; Pujiati; Hardani

2018-05-01

Genistein is a compound with structures and properties similar to 17β estradiol which can be extracted from pigeon pie. The aim of the study was to identify the genistein profiles of pigeon pie in blood, urine, and feces and their effects on uterine and vaginal tissue structures of rats. Nine female white rats of Sprague Dawley, 6-7 months, weighing 150-180 g, were used and given pigeon pie seed solution for 36 days, genistein profiles were analyzed using HPLC, uterine and vaginal tissue structures were analyzed with HE staining. The results showed that the genistein contained in pigeon pie was lower than that in the synthetic genistein; vaginal epithelials and uterine proliferations were indicated. To conclude, pigeon pie was found to contain genistein which is a potential alternative for a natural estrogen source.

Stress (hypothalamic-pituitary-adrenal axis) and pain response in male rats exposed lifelong to high vs. low phytoestrogen diets.

PubMed

Lephart, Edwin D; Galindo, Edwardo; Bu, Li Hong

2003-05-15

Estrogens exhibit complex but beneficial effects on brain structure, function and behavior. Soy-derived dietary phytoestrogens protect against hormone-dependent and age-related diseases, due to their estrogen-like hormonal actions. However, the effects of phytoestrogens on brain and behavior are relatively unknown. This study examined the influence of exposing male Long-Evans rats (lifelong) to either a phytoestrogen-rich (Phyto-600) or a phytoestrogen-free (Phyto-free) diet on body weights, behavioral pain thresholds, the hypothalamic-pituitary-adrenal (HPA) hormonal stress response, hippocampal glucocorticoid receptor and brain neural cell adhesion molecules (NCAM) and synaptophysin levels using standard behavioral and biochemical techniques. Body weights were significantly decreased in Phyto-600 fed animals compared to Phyto-free values. There were no significant changes in behavioral pain thresholds, circulating corticosterone concentrations (after acute immobilization stress) or NCAM and synaptophysin levels in various brain regions by the diet treatments. However, Phyto-600 fed males displayed significantly higher plasma adrenocorticotrophin (ACTH) (post-stress) and hippocampal glucocorticoid receptor levels vs. Phyto-free values. These data suggest that (1) body weights are significantly reduced by soy-derived phytoestrogens, (2) behavioral pain thresholds (via heat stimuli) are not influenced by dietary phytoestrogens, but (3) these estrogenic molecules in the hippocampus enhance glucocorticoid receptor abundance and alter the negative feedback of stress hormones towards a female-like pattern of higher ACTH release after activation of the HPA stress axis. This study is the first to show that lifelong consumption of dietary phytoestrogens alters the HPA stress response in male rats.

A phytoestrogen-rich diet increases energy expenditure and decreases adiposity in mice.

PubMed

Cederroth, Christopher R; Vinciguerra, Manlio; Kühne, Françoise; Madani, Rime; Doerge, Daniel R; Visser, Theo J; Foti, Michelangelo; Rohner-Jeanrenaud, Françoise; Vassalli, Jean-Dominique; Nef, Serge

2007-10-01

Obesity is an increasingly prevalent health problem, and natural effective therapeutic approaches are required to prevent its occurrence. Phytoestrogens are plant-derived compounds with estrogenic activities; they can bind to both estrogen receptors alpha and beta and mimic the action of estrogens on target organs. The purpose of this study was to examine the influence of soy-derived phytoestrogens on energy balance and metabolism. Male outbred mice (CD-1) were allowed ad libitum access to either a high soy-containing diet or a soy-free diet from conception to adulthood. We measured circulating serum isoflavone levels using reverse-phase solid-phase extraction for subsequent liquid chromatography electrospray tandem mass spectrometry analysis. Adult animals were analyzed for body composition by dual-energy X-ray absorptiometry, locomotor activity by running-wheel experiments, respiratory exchange rate by indirect calorimetry, and food intake using metabolic cages. Quantitative reverse transcriptase-polymerase chain reaction was performed to determine the expression of hypothalamic neuropeptide genes. We found that adult mice fed a soy-rich diet had reduced body weight, adiposity, and resistance to cold. This lean phenotype was associated with an increase in lipid oxidation due to a preferential use of lipids as fuel source and an increase in locomotor activity. The modulation of energy balance was associated with a central effect of phytoestrogens on the expression of hypothalamic neuropeptides, including agouti-related protein. The data suggest that dietary soy could have beneficial effects on obesity, but they also emphasize the importance of monitoring the phytoestrogen content of diets as a parameter of variability in animal experiments.

Effect of single neonatal treatment with the soy bean phytosteroid, genistein on the sexual behavior of adult rats.

PubMed

Csaba, G; Karabélyos, Cs

2002-01-01

Hormonal imprinting develops during the perinatal critical period, when the target hormone meets the yet unmatured receptor. As a consequence of imprinting the receptor accomplishes its maturation reaching the binding capacity characteristic to adults. In this period in the presence of foreign molecules similar to the target hormone faulty imprinting may occur with life-long consequences. Soy bean contains phytosteroids which can mimic estrogen effects. In the present experiments single genistein (20 microg) or combined genistein + benzpyrene (20 microg) treatments were done neonatally and the sexual behavior of male and female adult animals was studied. Genistein significantly increased the lordosis quotient of females, which was compensated by neonatal benzpyrene treatment. Genistein also enhanced the sexual activity of males, and this was significantly not reduced by parallel benzpyrene treatment. The results show that neonatal genistein exposure can imprint sexual activity for life and the presence of a second imprinter can modify genistein's behavioral effect.

Genistein Binding to Copper(II)-Solvent Dependence and Effects on Radical Scavenging.

PubMed

Yang, Jing; Xu, Yi; Liu, Hao-Yu; Han, Rui-Min; Zhang, Jian-Ping; Skibsted, Leif H

2017-10-18

Genistein, but not daidzein, binds to copper(II) with a 1:2 stoichiometry in ethanol and with a 1:1 stoichiometry in methanol, indicating chelation by the 5-phenol and the 4-keto group of the isoflavonoid as demonstrated by the Jobs method and UV-visible absorption spectroscopy. In ethanol, the stability constants had the value 1.12 × 10 11 L²∙mol -2 for the 1:2 complex and in methanol 6.0 × 10⁵ L∙mol -1 for the 1:1 complex at 25 °C. Binding was not detected in water, as confirmed by an upper limit for the 1:1 stability constant of K = 5 mol -1 L as calculated from the difference in solvation free energy of copper(II) between methanol and the more polar water. Solvent molecules compete with genistein as demonstrated in methanol where binding stoichiometry changes from 1:2 to 1:1 compared to ethanol and methanol/chloroform (7/3, v / v ). Genistein binding to copper(II) increases the scavenging rate of the stable, neutral 2,2-diphenyl-1-picrylhydrazyl radical by more than a factor of four, while only small effects were seen for the short-lived but more oxidizing β -carotene radical cation using laser flash photolysis. The increased efficiency of coordinated genistein is concluded to depend on kinetic rather than on thermodynamic factors, as confirmed by the small change in reduction potential of -0.016 V detected by cyclic voltammetry upon binding of genistein to copper(II) in methanol/chloroform solutions.

Molecular cloning and characterization of genistein 4'-O-glucoside specific glycosyltransferase from Bacopa monniera.

PubMed

Ruby; Santosh Kumar, R J; Vishwakarma, Rishi K; Singh, Somesh; Khan, Bashir M

2014-07-01

Health related benefits of isoflavones such as genistein are well known. Glycosylation of genistein yields different glycosides like genistein 7-O-glycoside (genistin) and genistein 4'-O-glycoside (sophoricoside). This is the first report on isolation, cloning and functional characterization of a glycosyltransferase specific for genistein 4'-O-glucoside from Bacopa monniera, an important Indian medicinal herb. The glycosyltransferase from B. monniera (UGT74W1) showed 49% identity at amino acid level with the glycosyltransferases from Lycium barbarum. The UGT74W1 sequence contained all the conserved motifs present in plant glycosyltransferases. UGT74W1 was cloned in pET-30b (+) expression vector and transformed into E. coli. The molecular mass of over expressed protein was found to be around 52 kDa. Functional characterization of the enzyme was performed using different substrates. Product analysis was done using LC-MS and HPLC, which confirmed its specificity for genistein 4'-O-glucoside. Immuno-localization studies of the UGT74W1 showed its localization in the vascular bundle. Spatio-temporal expression studies under normal and stressed conditions were also performed. The control B. monniera plant showed maximum expression of UGT74W1 in leaves followed by roots and stem. Salicylic acid treatment causes almost tenfold increase in UGT74W1 expression in roots, while leaves and stem showed decrease in expression. Since salicylic acid is generated at the time of injury or wound caused by pathogens, this increase in UGT74W1 expression under salicylic acid stress might point towards its role in defense mechanism.

Phytoestrogens modulate hepcidin expression by Nrf2: Implications for dietary control of iron absorption.

PubMed

Bayele, Henry K; Balesaria, Sara; Srai, Surjit K S

2015-12-01

Hepcidin is a liver-derived antimicrobial peptide that regulates iron absorption and is also an integral part of the acute phase response. In a previous report, we found evidence that this peptide could also be induced by toxic heavy metals and xenobiotics, thus broadening its teleological role as a defensin. However it remained unclear how its sensing of disparate biotic and abiotic stressors might be integrated at the transcriptional level. We hypothesized that its function in cytoprotection may be regulated by NFE2-related factor 2 (Nrf2), the master transcriptional controller of cellular stress defenses. In this report, we show that hepcidin regulation is inextricably linked to the acute stress response through Nrf2 signaling. Nrf2 regulates hepcidin expression from a prototypical antioxidant response element in its promoter, and by synergizing with other basic leucine-zipper transcription factors. We also show that polyphenolic small molecules or phytoestrogens commonly found in fruits and vegetables including the red wine constituent resveratrol can induce hepcidin expression in vitro and post-prandially, with concomitant reductions in circulating iron levels and transferrin saturation by one such polyphenol quercetin. Furthermore, these molecules derepress hepcidin promoter activity when its transcription by Nrf2 is repressed by Keap1. Taken together, the data show that hepcidin is a prototypical antioxidant response or cytoprotective gene within the Nrf2 transcriptional circuitry. The ability of phytoestrogens to modulate hepcidin expression in vivo suggests a novel mechanism by which diet may impact iron homeostasis. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Effects of Estrogen and Estrus Cycle on Pharmacokinetics, Absorption and Disposition of Genistein in Female Sprague-Dawley Rats

PubMed Central

Kulkarni, Kaustubh H.; Yang, Zhen; Tao, Niu; Hu, Ming

2014-01-01

Genistein is an active soy isoflavone with anticancer activities but it is unknown why it has a higher oral bioavailability in female than in male rats. Our study determined the effects of estrus cycle on genistein’s oral bioavailability. Female rats with various levels of estrogen were orally administered with genistein or used in a four-site rat intestinal perfusion experiment. Rats in “proestrus” group (with elevated estrogen) had significantly reduced (57% decrease, p<0.05) oral bioavailability of total genistein (aglycone+conjugates) than those in “metoestrus” group (with basal level of estrogen). Female ovariectomized rats, due to lack of estrogen, showed oral bioavailability of total genistein similar to the “metoestrus” group but higher (155% increase, p<0.05) than the “proestrus” group. Based on intestinal perfusion studies, the increased bioavailability was partially attributed to the higher (>100% increase, p<0.05) hepatic disposition via glucuronidation and possibly more efficient enterohepatic recycling of genistein in the “metoestrus” group. Furthermore, chronic exogenous supplementation of estradiol in ovariectomized rats significantly reduced (77%, p<0.05) the oral bioavailability of total genistein, mostly via increased sulfation (>10 folds) in liver, to a level comparable to those in the “proestrus” group. In conclusion, the oral bioavailability of total genistein was inversely proportional to elevated estrogen levels in female rats, which is partially mediated through the regulation of hepatic enzymes responsible disposition of genistein. PMID:22757747

Daidzein–Estrogen Interaction in the Rat Uterus and Its Effect on Human Breast Cancer Cell Growth

PubMed Central

Gaete, Leonardo; Bustamante, Rodrigo; Villena, Joan; Lemus, Igor; Gidekel, Manuel; Cabrera, Gustavo; Astorga, Paola

2012-01-01

Abstract Sex hormone replacement therapy provides several advantages in the quality of life for climacteric women. However, estrogen-induced cell proliferation in the uterus and mammary gland increases the risk of cancer development in these organs. The lower incidence of mammary cancer in Asian women as compared with Western women has been attributed to high intake of soy isoflavones, including genistein. We have previously shown that genistein induces an estradiol-like hypertrophy of uterine cells, but does not induce cell proliferation, uterine eosinophilia, or endometrial edema. It also inhibits estradiol-induced mitosis in uterine cells and hormone-induced uterine eosinophilia and endometrial edema. Nevertheless, genistein stimulates growth of human breast cancer cells in culture; therefore, it is not an ideal estrogen for use in hormone replacement therapy (HRD). The present study investigated the effect of another soy isoflavone, daidzein (subcutaneous, 0.066 mg/kg body weight), in the same animal model, and its effect on responses induced by subsequent treatment (1 h later) with estradiol-17β (E2; subcutaneous, 0.33 mg/kg body weight). In addition, we investigated the effects of daidzein (1 μg/mL) or E2 on the growth of human breast cancer cells in culture. Results indicate that daidzein stimulates growth of breast cancer cells and potentiates estrogen-induced cell proliferation in the uterus. We suggest caution for the use of daidzein or formulas containing this compound in HRD. Future research strategies should be addressed in the search for new phytoestrogens that selectively inhibit cell proliferation in the uterus and breast. PMID:23216111

Development and validation of a food frequency questionnaire to estimate the intake of genistein in Malaysia.

PubMed

Fernandez, Anne R; Omar, Siti Zawiah; Husain, Ruby

2013-11-01

To develop and validate a food frequency questionnaire (FFQ) to estimate the genistein intake in a Malaysian population of pregnant women. A single 24-h dietary recall was obtained from 40 male and female volunteers. A FFQ of commonly consumed genistein-rich foods was developed from these recalls, and a database of the genistein content of foods found in Malaysia was set up. The FFQ was validated against 7-d food diary (FD) kept by 46 pregnant women and against non-fasting serum samples obtained from 64 pregnant women. Reproducibility was assessed by comparing the responses on two FFQs administered approximately 1 month apart. The Pearson correlation coefficient between FFQ1 and FD was 0.724 and that between FFQ2 and FD was 0.807. Classification into the same or adjacent quintiles was 78% for FFQ1 versus FD and 88% for FFQ2 versus FD. A significant dose -- response relation was found between FFQ-estimated genistein intake and serum levels. The FFQ developed is a reliable, valid tool for categorising people by level of genistein intake.

Factorial design applied to the optimization of lipid composition of topical antiherpetic nanoemulsions containing isoflavone genistein

PubMed Central

Argenta, Débora Fretes; de Mattos, Cristiane Bastos; Misturini, Fabíola Dallarosa; Koester, Leticia Scherer; Bassani, Valquiria Linck; Simões, Cláudia Maria Oliveira; Teixeira, Helder Ferreira

2014-01-01

The aim of this study was to optimize topical nanoemulsions containing genistein, by means of a 23 full factorial design based on physicochemical properties and skin retention. The experimental arrangement was constructed using oil type (isopropyl myristate or castor oil), phospholipid type (distearoylphosphatidylcholine [DSPC] or dioleylphosphaditylcholine [DOPC]), and ionic cosurfactant type (oleic acid or oleylamine) as independent variables. The analysis of variance showed effect of third order for particle size, polydispersity index, and skin retention of genistein. Nanoemulsions composed of isopropyl myristate/DOPC/oleylamine showed the smallest diameter and highest genistein amount in porcine ear skin whereas the formulation composed of isopropyl myristate/DSPC/oleylamine exhibited the lowest polydispersity index. Thus, these two formulations were selected for further studies. The formulations presented positive ζ potential values (>25 mV) and genistein content close to 100% (at 1 mg/mL). The incorporation of genistein in nanoemulsions significantly increased the retention of this isoflavone in epidermis and dermis, especially when the formulation composed by isopropyl myristate/DOPC/oleylamine was used. These results were supported by confocal images. Such formulations exhibited antiherpetic activity in vitro against herpes simplex virus 1 (strain KOS) and herpes simplex virus 22 (strain 333). Taken together, the results show that the genistein-loaded nanoemulsions developed in this study are promising options in herpes treatment. PMID:25336951

Synthesis and characterization of genistein conjugated with gold nanoparticles and the study of their cytotoxic properties.

PubMed

Stolarczyk, Elżbieta U; Stolarczyk, Krzysztof; Łaszcz, Marta; Kubiszewski, Marek; Maruszak, Wioleta; Olejarz, Wioletta; Bryk, Dorota

2017-01-01

Gold nanoparticles conjugated with drug substances are used in diagnostics and therapies. Apart from the combinations involving gold nanoparticles conjugated with drug substances through linkers, a direct bonding is also known. In our paper the example of such a direct bonding between gold nanoparticles and genistein (AuNPs-GE) is presented. This conjugate was obtained in a one-pot synthesis and the formation of AuNPs-GE was monitored in terms of color change and UV-Vis spectroscopy. It has been shown that genistein reduces Au 3+ ions to spherical Au 0 nanocrystallites and acts as a stabilizing agent. The efficiency of the purification of the conjugate from free genistein was controlled by the capillary electrophoresis. Gold nanoparticles are homogeneously shaped and have a narrow range of size from 14 to 33nm and the size of the nanoparticles modified with genistein is around 64.64±0.41nm, as measured by the TEM and DSL techniques, respectively. The zeta potential of the gold nanoparticles modified with genistein is -19.32±0.82mV and suggests a high stability of the nanoparticles and lower toxicity for the normal cells. The identity of genistein on the gold nanoparticles was proved by the electrochemistry, NMR and Raman spectroscopy. The mechanism of the conjugate forming has been proposed. The coverage of gold nanoparticles with genistein 5.09% (m/m) has been calculated from the TGA analysis. Moreover, it has been proved that the obtained conjugate is characterized by a high cytotoxic activity towards cancer cells, as observed in the cell line test. Copyright © 2016 Elsevier B.V. All rights reserved.

Combined cetuximab and genistein treatment shows additive anti-cancer effect on oral squamous cell carcinoma.

PubMed

Park, Sung-Jin; Kim, Myung-Jin; Kim, Yu-Kyoung; Kim, Soung-Min; Park, Ju-Yong; Myoung, Hoon

2010-06-01

The purpose of this study was to evaluate the potency of EGFR pathway inhibition achieved by combining cetuximab, an anti-EGFR monoclonal antibody, and genistein, a tyrosine kinase inhibitor, which target extracellular and intracellular domains of the receptor, respectively, in oral squamous cell carcinoma (OSCC) in vitro and in vivo. Two OSCC cell lines, HSC3 and KB, were treated with cetuximab (C, 0-400mug/ml), genistein (G, 0-80muM), or a combination of both at a range of concentrations. Downstream protein expression of EGFR, p-EGFR, and p-Akt were evaluated by Western blot. Cell proliferation and apoptosis indices were calculated to assess anti-cancer effects in vitro. The in vivo effects of cetuximab and genistein on tumor cell growth were examined using an OSCC xenografted nude mouse model and immunohistochemical analyses of proliferation (PCNA) and microvessel density (CD31). Treatment of cells with dual anti-EGFR agents reduced the expressions of p-EGFR, and p-Akt in HSC3 cell line, but there was no significant difference in downregulation between cetuximab alone and in combination with genistein in KB cells. Both HSC3 and KB cells showed a dose-dependent decrease in cell proliferation significantly with single agent treatment and combination (p<0.05). In low concentration, combined cetuximab and genistein therapy resulted in additive growth inhibition and more apoptosis compared to that achieved with single-agent exposure in both cell lines. A combination of cetuximab and genistein significantly inhibited tumor growth and caused a substantial growth delay in in vivo models of both cell lines while each single-agent exposure caused no delay of tumor growth. Immunohistochemical staining with PCNA revealed that the group receiving combined cetuximab and genistein exhibited the lowest number of proliferating cells and microvessel density (p<0.05). Combined therapy with genistein and cetuximab can add the potency of EGFR signaling inhibition. Because not all

Perinatal exposure to genistein, a soy phytoestrogen, improves spatial learning and memory but impairs passive avoidance learning and memory in offspring.

PubMed

Kohara, Yumi; Kuwahara, Rika; Kawaguchi, Shinichiro; Jojima, Takeshi; Yamashita, Kimihiro

2014-05-10

This study investigated the effects of perinatal genistein (GEN) exposure on the central nervous system of rat offspring. Pregnant dams orally received GEN (1 or 10 mg/kg/day) or vehicle (1 ml/kg/day) from gestation day 10 to postnatal day 14. In order to assess the effects of GEN on rat offspring, we used a battery of behavioral tests, including the open-field, elevated plus-maze, MAZE and step-through passive avoidance tests. MAZE test is an appetite-motivation test, and we used this mainly for assessing spatial learning and memory. In the MAZE test, GEN groups exhibited shorter latency from start to goal than the vehicle-treated group in both sexes. On the other hand, performances in the step-through passive avoidance test were non-monotonically inhibited by GEN in both sexes, and a significant difference was observed in low dose of the GEN-treated group compared to the vehicle-treated group in female rats. Furthermore, we found that perinatal exposure to GEN did not significantly alter locomotor activity or emotionality as assessed by the open-field and elevated-plus maze tests. These results suggest that perinatal exposure to GEN improved spatial learning and memory of rat offspring, but impaired their passive avoidance learning and memory. Copyright © 2014 Elsevier Inc. All rights reserved.

The effects of phytoestrogen isoflavones on bone density in women: a double-blind, randomized, placebo-controlled trial.

PubMed

Atkinson, Charlotte; Compston, Juliet E; Day, Nicholas E; Dowsett, Mitch; Bingham, Sheila A

2004-02-01

Isoflavone phytoestrogen therapy has been proposed as a natural alternative to hormone replacement therapy (HRT). HRT has a beneficial effect on bone, but few trials in humans have investigated the effects of isoflavones on bone. The objective of the study was to determine the effect on bone density of a red clover-derived isoflavone supplement that provided a daily dose of 26 mg biochanin A, 16 mg formononetin, 1 mg genistein, and 0.5 mg daidzein for 1 y. Effects on biochemical markers of bone turnover and body composition were also studied. Women aged 49-65 y (n = 205) were enrolled in a double-blind, randomized, placebo-controlled trial; 177 completed the trial. Bone density, body composition, bone turnover markers, and diet were measured at baseline and after 12 mo. Loss of lumbar spine bone mineral content and bone mineral density was significantly (P = 0.04 and P = 0.03, respectively) lower in the women taking the isoflavone supplement than in those taking the placebo. There were no significant treatment effects on hip bone mineral content or bone mineral density, markers of bone resorption, or body composition, but bone formation markers were significantly increased (P = 0.04 and P = 0.01 for bone-specific alkaline phosphatase and N-propeptide of collagen type I, respectively) in the intervention group compared with placebo in postmenopausal women. Interactions between treatment group and menopausal status with respect to changes in other outcomes were not significant. These data suggest that, through attenuation of bone loss, isoflavones have a potentially protective effect on the lumbar spine in women.

Solid-state characterization and solubility of a genistein-caffeine cocrystal

NASA Astrophysics Data System (ADS)

Sowa, Michał; Ślepokura, Katarzyna; Matczak-Jon, Ewa

2014-11-01

Combination of genistein and caffeine leads to a 1:1 cocrystalline phase, which was identified by means of a solvent-drop grinding experiment and isolated afterwards in a solution-evaporation approach. Obtained cocrystal was characterized by X-ray single-crystal and powder diffraction as well as investigated in terms of thermal stability and Hirshfeld surfaces. A scale-up procedure was provided by slurry technique, enabling solubility determination. Neutral forms of both compounds cocrystallize in a common P21/c space group of the monoclinic crystal system. Analysis of packing and interactions in the crystal lattice reveals formation of molecular layers, formed by O-H⋯O, O-H⋯N and C-H⋯O-type contacts between genistein and caffeine molecules, whereas stabilization of the three-dimensional crystal lattice is provided by π⋯π interactions. Dissolution studies in a 50:50 v/v ethanol-water medium revealed that the maximum solubility of the cocrystalline phase reached 0.861 mg/mL after 8 h, revealing some degree of enhancement as compared to parent genistein, maximum solubility of which was also reached after 8 h and equalled 0.588 mg/mL.

The influence of genistein on free radicals in normal dermal fibroblasts and keloid fibroblasts examined by EPR spectroscopy.

PubMed

Jurzak, Magdalena; Ramos, Paweł; Pilawa, Barbara

2017-01-01

Normal and keloid fibroblasts were examined using X-band (9.3 GHz) electron paramagnetic resonance spectroscopy. The effect of genistein on the concentration of free radicals in both normal dermal and keloid fibroblasts after ultraviolet irradiation was investigated. The highest concentration of free radicals was seen in keloid fibroblasts, with normal fibroblasts containing a lower concentration. The concentration of free radicals in both normal and keloid fibroblasts was altered in a concentration-dependent manner by the presence of genistein. The change in intra-cellular free radical concentration after the ultraviolet irradiation of both normal and keloid fibroblasts is also discussed. The antioxidant properties of genistein, using its 1,1-Diphenyl-2-picrylhydrazyl (DPPH) free radical-scavenging activity as a model, were tested, and the effect of ultraviolet irradiation on its interaction with free radicals was examined. The electron paramagnetic resonance spectra of DPPH showed quenching by genistein. The interaction of genistein with DPPH free radicals in the absence of ultraviolet irradiation was shown to be slow, but this interaction was much faster under ultraviolet irradiation. Ultraviolet irradiation enhanced the free radical-scavenging activity of genistein.

Adsorption and recognition characteristics of surface molecularly imprinted polymethacrylic acid/silica toward genistein.

PubMed

Zhang, Yanyan; Gao, Baojiao; An, Fuqiang; Xu, Zeqing; Zhang, Tingting

2014-09-12

In this paper, on the basis of surface-initiated graft polymerization, a new surface molecular imprinting technique is established by molecular design. And molecularly imprinted polymer MIP-PMAA/SiO2 is successfully prepared with genistein as template. The adsorption and recognition characteristics of MIP-PMAA/SiO2 for genistein are studied in depth by using static method, dynamic method and competitive adsorption experiment. The experimental results show that MIP-PMAA/SiO2 possesses very strong adsorption affinity and specific recognition for genistein. The saturated adsorption capacity could reach to 0.36mmolg(-1). The selectivity coefficients relative to quercetin and rutin are 5.4 and 11.8, respectively. Besides, MIP-PMAA/SiO2 is regenerated easily and exhibits excellent reusability. Copyright © 2014 Elsevier B.V. All rights reserved.

In planta assays involving epigenetically silenced genes reveal inhibition of cytosine methylation by genistein

PubMed Central

2012-01-01

Background Cytosine methylation is involved in epigenetic control of gene expression in a wide range of organisms. An increasing number of examples indicate that changing the frequency of cytosine methylation in the genome is a feasible tool to engineer novel traits in plants. Although demethylating effects of compounds have been analyzed in human cultured cells in terms of suppressing cancer, their effect in plant cells has not been analyzed extensively. Here, we developed in planta assay systems to detect inhibition of cytosine methylation using plants that contain a transgene transcriptionally silenced by an epigenetic mechanism. Results Seeds of two transgenic plants were used: a petunia line that has been identified as a revertant of the co-suppression of the chalcone synthase-A (CHS-A) gene and contains CHS-A transgenes whose transcription is repressed; Nicotiana benthamiana plants that contain the green fluorescent protein (GFP) reporter gene whose transcription is repressed through virus-induced transcriptional gene silencing. Seeds of these plants were sown on a medium that contained a demethylating agent, either 5-azacytidine or trichostatin A, and the restoration of the transcriptionally active state of the transgene was detected in seedlings. Using these systems, we found that genistein, a major isoflavonoid compound, inhibits cytosine methylation, thus restoring transgene transcription. Genistein also restored the transcription of an epigenetically silenced endogenous gene in Arabidopsis plants. Conclusions Our assay systems allowed us to assess the inhibition of cytosine methylation, in particular of maintenance of methylation, by compounds in plant cells. These results suggest a novel role of flavonoids in plant cells and that genistein is useful for modifying the epigenetic state of plant genomes. PMID:22424588

Preliminary enrichment and separation of genistein and apigenin from extracts of pigeon pea roots by macroporous resins.

PubMed

Liu, Wei; Zhang, Su; Zu, Yuan-Gang; Fu, Yu-Jie; Ma, Wei; Zhang, Dong-Yang; Kong, Yu; Li, Xiao-Juan

2010-06-01

Enrichment and separation of genistein and apigenin from extracts of pigeon pea roots were studied using eleven macroporous resins with different physical and chemical properties. ADS-5 resin showed the maximum effectiveness among the tested resins. The solute affinity towards ADS-5 resin at different temperatures was described in terms of Langmuir and Freundlich isotherms, and the equilibrium experimental data were well-fitted to the two isotherms. In order to optimize the operating parameters for separating genistein and apigenin, dynamic adsorption and desorption tests were carried out. After one run treatment with ADS-5 resin, the contents of genistein and apigenin in the product were 9.36-fold and 11.09-fold increased with recovery yields of 89.78% and 93.41%, respectively. The process achieved easy and effective enrichment and separation of genistein and apigenin by using ADS-5 resin, and it is a promising basis for large-scale preparation of genistein and apigenin from pigeon pea or other plants extracts. (c) 2010 Elsevier Ltd. All rights reserved.

Altered sexually dimorphic nucleus of the preoptic area (SDN-POA) volume in adult Long-Evans rats by dietary soy phytoestrogens.

PubMed

Lund, T D; Rhees, R W; Setchell, K D; Lephart, E D

2001-09-28

Naturally occurring estrogen-like molecules in plants (phytoestrogens), present via soy, in animal diets can alter morphology and physiology in rodents. Phytoestrogens have the ability to bind estrogen receptors and exert many of the biological responses evoked by physiological estrogens. This study characterized the effects of dietary phytoestrogens on the expression of body and prostate weight, circulating testosterone and estradiol levels, puberty onset, vaginal cyclicity, and volume of the sexually dimorphic nucleus of the preoptic area (SDN-POA) in Long-Evans rats. Using different experimental protocols, animals were fed either a phytoestrogen-rich (Phyto-600) or a phytoestrogen-free (Phyto-free) diet. Animals fed the Phyto-600 diet displayed significantly decreased body weights (in males and females), prostate weights and delayed puberty in females compared to that of animals fed the Phyto-free diet. Circulating testosterone or estradiol levels in males or estrous cyclicity were not altered by the diets. The volume of the SDN-POA was significantly altered by a change in diet at 80 days of age where one-half of the males or females fed the Phyto-600 diet (from birth) were switched to the Phyto-free diet until 120 days of age. Males initially fed a Phyto-600 diet but changed to a Phyto-free diet had significantly smaller SDN-POA volumes compared to males fed the Phyto-600 diet (long-term). These data suggest that consumption of phytoestrogens via a soy diet, significantly: (1) decreases body and prostate weight, (2) delays puberty onset, and (3) alters SDN-POA volumes during adulthood.

Prescription profile of Chinese herbal products containing coumestrol, genestein, and/or daidzein among female users: an analysis of national health insurance data in Taiwan between 1997 and 2007.

PubMed

Wu, Chien-Tung; Tzeng, Jeng-Nan; Lai, Jung-Nien; Tsan, Shun-Hua; Wang, Jung-Der

2012-10-16

Some Chinese herbs contain several kinds of phytoestrogens, and these herbs are commonly prescribed in Taiwan. Phytoestrogens may influence the effects of estrogen in females, although their activities are weak. This study aims to identify the risk and analyze the prescription profile of commonly used phytoestrogenic herbs in Taiwan. The study analyzed women who had been prescribed phytoestrogenic herbs including coumestrol, genistein and/or daidzein between 1997 and 2007 in a fixed cohort taken from all female beneficiaries from the National Health Insurance Research Database of Taiwan. The prescription frequencies, cumulated dosages, and primary indications were listed. A total of 462,861 women were included in the study, of whom ~47.0% had used phytoestrogenic herbs at least once during the study period. A total of 6,270,813 prescriptions were recorded, and more than 20% of these contained phytoestrogens. The most commonly prescribed herb and formula were Puerariae Radix and Ge gen tang (Pueraria Decoction), respectively. Most of the prescriptions were issued for diseases of the respiratory system, followed by symptoms, signs, and ill-defined conditions and diseases of the musculoskeletal system and connective tissue. This study shows that women who sought medical treatment from Chinese medicine doctors for relief of respiratory discomfort had a high possibility of exposure to phytoestrogenic herbs. Safety issues related to the female endocrine system should be a priority for future research.

Genistein and tyrphostin AG556 decrease ultra-rapidly activating delayed rectifier K+ current of human atria by inhibiting EGF receptor tyrosine kinase.

PubMed

Xiao, Guo-Sheng; Zhang, Yan-Hui; Wu, Wei; Sun, Hai-Ying; Wang, Yan; Li, Gui-Rong

2017-03-01

The ultra-rapidly activating delayed rectifier K + current I Kur (encoded by K v 1.5 or KCNA5) plays an important role in human atrial repolarization. The present study investigates the regulation of this current by protein tyrosine kinases (PTKs). Whole-cell patch voltage clamp technique and immunoprecipitation and Western blotting analysis were used to investigate whether the PTK inhibitors genistein, tyrphostin AG556 (AG556) and PP2 regulate human atrial I Kur and hKv1.5 channels stably expressed in HEK 293 cells. Human atrial I Kur was decreased by genistein (a broad-spectrum PTK inhibitor) and AG556 (a highly selective EGFR TK inhibitor) in a concentration-dependent manner. Inhibition of I Kur induced by 30 μM genistein or 10 μM AG556 was significantly reversed by 1 mM orthovanadate (a protein tyrosine phosphatase inhibitor). Similar results were observed in HEK 293 cells stably expressing hK v 1.5 channels. On the other hand, the Src family kinase inhibitor PP2 (1 μM) slightly enhanced I Kur and hK v 1.5 current, and the current increase was also reversed by orthovanadate. Immunoprecipitation and Western blotting analysis showed that genistein, AG556, and PP2 decreased tyrosine phosphorylation of hK v 1.5 channels and that the decrease was countered by orthovanadate. The PTK inhibitors genistein and AG556 decrease human atrial I Kur and cloned hK v 1.5 channels by inhibiting EGFR TK, whereas the Src kinase inhibitor PP2 increases I Kur and hK v 1.5 current. These results imply that EGFR TK and the soluble Src kinases may have opposite effects on human atrial I Kur . © 2017 The British Pharmacological Society.

Genistein versus ICI 182, 780: an ally or enemy in metastatic progression of prostate cancer.

PubMed

Nakamura, Hisae; Wang, Yuwei; Xue, Hui; Romanish, Mark T; Mager, Dixie L; Helgason, Cheryl D; Wang, Yuzhuo

2013-12-01

Androgen signalling through the androgen receptor (AR) plays a critical role in prostate cancer (PCa) initiation and progression. Estrogen in synergy with androgen is essential for cell growth of the normal and malignant prostate. However, the exact role that estrogen and the estrogen receptor play in prostate carcinogenesis remains unclear. We have previously demonstrated the metastasis-promoting effect of an estrogen receptor beta (ERβ) agonist (genistein) in a patient-derived PCa xenograft model mimicking localized and metastatic disease. To test the hypothesis that the tumor-promoting activity of genistein was due to its estrogenic properties, we treated the xenograft-bearing mice with genistein and an anti-estrogen compound (ICI 182, 780) and compared the differential gene expression using microarrays. Using a second xenograft model which was derived from another patient, we showed that genistein promoted disease progression in vivo and ICI 182, 780 inhibited metastatic spread. The microarray analysis revealed that the metallothionein (MT) gene family was differentially expressed in tumors treated by these compounds. Using qRT-PCR, the differences in expression levels were validated in the metastatic and non-metastatic LTL313 PCa xenograft tumor lines, both of which were originally derived from the same PCa patient. Together our data provide evidence that genistein stimulates and ICI 182, 780 inhibits metastatic progression, suggesting that these effects may be mediated by ERβ signalling. © 2013 Wiley Periodicals, Inc.

Effect of dietary genistein on growth performance, digestive enzyme activity, and body composition of Nile tilapia Oreochromis niloticus

NASA Astrophysics Data System (ADS)

Chen, Dong; Wang, Wei; Ru, Shaoguo

2015-01-01

An 8-week feeding experiment was performed to evaluate the effect of dietary genistein on growth performance, body composition, and digestive enzymes activity of juvenile Nile tilapia ( Oreochromis niloticus). Four isonitrogenous and isoenergetic diets were formulated containing four graded supplements of genistein: 0, 30, 300, and 3 000 μg/g. Each diet was randomly assigned in triplicate to tanks stocked with 15 juvenile tilapia (10.47±1.24 g). The results show that 30 and 300 μg/g dietary genistein had no significant effect on growth performance of Nile tilapia, but the higher level of genistein (3 000 μg/g) significantly depressed the final body weight and specific growth rate. There was no significant difference in survival rate, feed intake, feed efficiency ratio or whole body composition among all dietary treatments. An assay of digestive enzymes showed that the diet containing 3 000 μg/ggenistein decreased stomach and hepatopancreas protease activity, and amylase activity in the liver and intestine, while a dietary level of 300 μg/g genistein depressed stomach protease and intestine amylase activities. However, no significant difference in stomach amylase activity was found among dietary treatments. Overall, the results of the present study indicate that a high level of dietary genistein (3 000 μg/g, or above) would significantly reduce the growth of Nile tilapia, partly because of its inhibitory effect on the activity of major digestive enzymes. Accordingly, the detrimental effects of genistein, as found in soybean products, should not be ignored when applied as an alternative ingredient source in aquaculture.

Mixed Inhibition of cPEPCK by Genistein, Using an Extended Binding Site Located Adjacent to Its Catalytic Cleft

PubMed Central

Dhanjal, Jaspreet Kaur; Sundar, Durai

2015-01-01

Cytosolic phosphoenolpyruvate carboxykinase (cPEPCK) is a critical enzyme involved in gluconeogenesis, glyceroneogenesis and cataplerosis. cPEPCK converts oxaloacetic acid (OAA) into phosphoenol pyruvate (PEP) in the presence of GTP. cPEPCK is known to be associated with type 2 diabetes. Genistein is an isoflavone compound that shows anti-diabetic and anti-obesitic properties. Experimental studies have shown a decrease in the blood glucose level in the presence of genistein by lowering the functional activity of cPEPCK, an enzyme of gluconeogenesis. Using computational techniques such as molecular modeling, molecular docking, molecular dynamics simulation and binding free energy calculations, we identified cPEPCK as a direct target of genistein. We studied the molecular interactions of genistein with three possible conformations of cPEPCK—unbound cPEPCK (u_cPEPCK), GTP bound cPEPCK (GTP_cPEPCK) and GDP bound cPEPCK (GDP_cPEPCK). Binding of genistein was also compared with an already known cPEPCK inhibitor. We analyzed the interactions of genistein with cPEPCK enzyme and compared them with its natural substrate (OAA), product (PEP) and known inhibitor (3-MPA). Our results demonstrate that genistein uses the mechanism of mixed inhibition to block the functional activity of cPEPCK and thus can serve as a potential anti-diabetic and anti-obesity drug candidate. We also identified an extended binding site in the catalytic cleft of cPEPCK which is used by 3-MPA to inhibit cPEPCK non-competitively. We demonstrate that extended binding site of cPEPCK can further be exploited for designing new drugs against cPEPCK. PMID:26528723

Dietary phytoestrogens and plasma lipids in Dutch postmenopausal women; a cross-sectional study.

PubMed

Kreijkamp-Kaspers, Sanne; Kok, Linda; Bots, Michiel L; Grobbee, Diederick E; van der Schouw, Yvonne T

2005-01-01

Isoflavone supplementation in high doses is associated with plasma lipid, glucose and insulin levels. Little is known about the effects of intake within the range of western diets on these endpoints. We conducted a population-based cross-sectional study in 301 women aged 60-75 years. Dietary isoflavone and lignan intake was assessed with a food frequency questionnaire covering habitual diet during the year preceding enrollment. The outcome measures were total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides, Lp(a), fasting glucose and insulin levels. Data were analysed using linear regression and logistic regression models. In the analyses we adjusted for a wide range of potential confounders. High intake of isoflavones was associated with lower Lp(a) levels (tertile three versus tertile one: odds ratio 0.36, 95% CI 0.16; 0.80). No relation was found between blood levels and the other plasma lipids, glucose or insulin was found. The results of this study suggest that an effect of dietary phytoestrogen intake at low levels on plasma lipid levels is of limited magnitude. It is premature to advise postmenopausal women with low phytoestrogen intake to change their diet towards a phytoestrogen rich diet with the sole aim to prevent cardiovascular disease.

Suramin, Genistein and Collagen Matrix (DuraGen) for Delayed Adjustment after Strabismus Surgery: Which One is Best?

PubMed

Oktem, Caglar; Oto, Sibel; Toru, Serap; Bakar, Coskun; Ozdemir, Handan; Akova, Yonca Aydin

2016-01-01

To evaluate the efficacy and safety of suramin, genistein and collagen matrix for the prevention of inflammation, the reduction of fibrosis and the delay in adjustment after strabismus surgery on a rabbit model. By using an adjustable suture technique, a recession of the superior rectus muscle (SRM) was made in 36 eyes of 18 rabbits. Three study groups were created using genistein, suramin and collagen matrix (n = 6 per group). Two control groups utilized dimethyl sulphoxide (DMSO) (n = 6) and balanced salt solution (n = 12). The adjustments and measurements were made on days 2, 7, 14. After enucleation was done on day 21, the degree of inflammation was evaluated quantitatively in histopathological sections and immunohistochemical investigations were performed for tissue expression of cytoplasmic vascular endothelial growth factor (VEGF), MAC 387, TGF-β and bFGF. The adhesions between conjunctiva and SRM were significantly less in the collagen matrix and suramin groups (p = 0.002) and adhesions between the sclera and SRM were considerably reduced in the genistein and DMSO groups (p = 0.006) on day 7. Force exerted for adjustment was significantly less in the collagen matrix and suramin groups on day 14 (p = 0.006). Expression of b-FGF was significantly lower in the conjunctival epithelium in the suramin and genistein groups (p = 0.0001 for both). TGF-β was significantly lower (p = 0.001) in the suramin group and VEGF expression was totally absent. MAC 387 expression was lower in the genistein and suramin groups (p = 0.0001). Suramin, genistein and collagen matrix successfully reduce adhesions, and facilitate adjustment following recession surgery. Both suramin and genistein effectively suppress growth factor expression, while collagen matrix offers the longest time interval for adjustability after strabismus surgery.

Genistein inhibition of OGD-induced brain neuron death correlates with its modulation of apoptosis, voltage-gated potassium and sodium currents and glutamate signal pathway.

PubMed

Ma, Xue-Ling; Zhang, Feng; Wang, Yu-Xiang; He, Cong-Cong; Tian, Kun; Wang, Hong-Gang; An, Di; Heng, Bin; Liu, Yan-Qiang

2016-07-25

In the present study, we established an in vitro model of hypoxic-ischemia via exposing primary neurons of newborn rats to oxygen-glucose deprivation (OGD) and observing the effects of genistein, a soybean isoflavone, on hypoxic-ischemic neuron viability, apoptosis, voltage-activated potassium (Kv) and sodium (Nav) currents, and glutamate receptor subunits. The results indicated that OGD exposure reduced the viability and increased the apoptosis of brain neurons. Meanwhile, OGD exposure caused changes in the current-voltage curves and current amplitude values of voltage-activated potassium and sodium currents; OGD exposure also decreased GluR2 expression and increased NR2 expression. However, genistein at least partially reversed the effects caused by OGD. The results suggest that hypoxic-ischemia-caused neuronal apoptosis/death is related to an increase in K(+) efflux, a decrease in Na(+) influx, a down-regulation of GluR2, and an up-regulation of NR2. Genistein may exert some neuroprotective effects via the modulation of Kv and Nav currents and the glutamate signal pathway, mediated by GluR2 and NR2. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Binding sites of resveratrol, genistein, and curcumin with milk α- and β-caseins.

PubMed

Bourassa, P; Bariyanga, J; Tajmir-Riahi, H A

2013-02-07

The binding sites of antioxidant polyphenols resveratrol, genistein, and curcumin are located with milk α- and β-caseins in aqueous solution. FTIR, CD, and fluorescence spectroscopic methods and molecular modeling were used to analyze polyphenol binding sites, the binding constant, and the effects of complexation on casein stability and conformation. Structural analysis showed that polyphenols bind casein via hydrophilic and hydrophobic interactions with the number of bound polyphenol molecules (n) 1.20 for resveratrol, 1.42 for genistein, and 1.43 for curcumin with α-casein and 1.14 for resveratrol, 1.27 for genistein, and 1.27 for curcumin with β-casein. The overall binding constants of the complexes formed are K(res-α-casein) = 1.9 (±0.6) × 10(4) M(-1), K(gen-α-casein) = 1.8 (±0.4) × 10(4) M(-1), and K(cur-α-casein) = 2.8 (±0.8) × 10(4) M(-1) with α-casein and K(res-β-casein) = 2.3 (±0.3) × 10(4) M(-1), K(gen-β-casein) = 3.0 (±0.5) × 10(4) M(-1), and K(cur-β-casein) = 3.1 (±0.5) × 10(4) M(-1) for β-casein. Molecular modeling showed the participation of several amino acids in polyphenol-protein complexes, which were stabilized by the hydrogen bonding network with the free binding energy of -11.56 (resveratrol-α-casein), -12.35 (resveratrol-β-casein), -9.68 (genistein-α-casein), -9.97 (genistein-β-casein), -8.89 (curcumin-α-casein), and -10.70 kcal/mol (curcumin-β-casein). The binding sites of polyphenols are different with α- and β-caseins. Polyphenol binding altered casein conformation with reduction of α-helix, indicating a partial protein destabilization. Caseins might act as carriers to transport polyphenol in vitro.

Biotransformation and recovery of the isoflavones genistein and daidzein from industrial antibiotic fermentations

PubMed Central

Weber, J. Mark; Reeves, Andrew R.; Seshadri, Ramya; Cernota, William H.; Gonzalez, Melissa C.; Gray, Danielle L.; Wesley, Roy K.

2013-01-01

The objective of this study was to follow the metabolic fate of isoflavone glucosides from the soybean meal in a model industrial fermentation to determine if commercially useful isoflavones could be harvested as coproducts from the spent broth at the end of the fermentation. The isoflavone aglycones, genistein and daidzein, together make up 0.1 - 0.2% of the soybean meal by weight but serve no known function in the manufacturing process. After feeding genistein to washed cells of the erythromycin-producing organism, Saccharopolyspora erythraea, the first biotransformation product (Gbp1) was determined by x-ray crystallography to be genistein-7-O-α-rhamnoside (rhamnosylgenistein). Subsequent feeding of rhamnosylgenistein to growing cells of S. erythraea led to the production of a second biotransformation product, Gbp2. Chromatographic evidence suggested that Gbp2 accumulated in the spent broth of the erythromycin fermentation. When the spent broth was hydrolyzed with acid or industrial enzyme preparations the isoflavone biotransformation products were returned back to their parental forms, genistein and daidzein, which were then recovered as coproducts. Desirable features of this method are that it does not require modification of the erythromycin manufacturing process or genetic engineering of the producing organism to be put into practice. A preliminary investigation of five additional antibiotic fermentations of industrial importance were also found to have isoflavone coproduct potential. PMID:23604533

Effects of phytoestrogens on protein turnover in rainbow trout primary myocytes

USDA-ARS?s Scientific Manuscript database

Soybean-derived ingredients used in aquaculture feeds may contain phytoestrogens, but it is unknown if these compounds can mimic the catabolic effects of estradiol in fish muscle. Six day-old rainbow trout primary myocytes were exposed to increasing concentrations (10 nM – 100 µM) of either geniste...

Sensitization of Cervical Cancer Cells to Cisplatin by Genistein: The Role of NFκB and Akt/mTOR Signaling Pathways.

PubMed

Sahin, K; Tuzcu, M; Basak, N; Caglayan, B; Kilic, U; Sahin, F; Kucuk, O

2012-01-01

Cervical cancer is among the top causes of death from cancer in women. Cisplatin-based chemotherapy has been shown to improve survival; however, cisplatin treatment is associated with toxicity to healthy cells. Genistein has been used as an adjunct to chemotherapy to enhance the activity of chemotherapeutic agents without causing increased toxicity. The present study was designed to investigate the effect of genistein (25 μM) on antitumor activity of cisplatin (250 nM) on HeLa cervical cancer cells. We have examined the alterations in expression of NF-κB, p-mTOR, p-p70S6K1, p-4E-BP1, and p-Akt protein levels in response to treatment. The combination of 25 μM genistein with 250 nM cisplatin resulted in significantly greater growth inhibition (P < 0.01). Genistein enhanced the antitumor activity of cisplatin and reduced the expression of NF-κB, p-mTOR, p-p70S6K1, p-4E-BP1, and p-Akt. The results in the present study suggest that genistein could enhance the activity of cisplatin via inhibition of NF-κB and Akt/mTOR pathways. Genistein is a promising nontoxic nutritional agent that may enhance treatment outcome in cervical cancer patients when given concomitantly with cisplatin. Clinical trials of genistein and cisplatin combination are warranted to test this hypothesis.

Evaluation of genistein ability to modulate CTGF mRNA/protein expression, genes expression of TGFβ isoforms and expression of selected genes regulating cell cycle in keloid fibroblasts in vitro.

PubMed

Jurzak, Magdalena; Adamczyk, Katarzyna; Antończak, Paweł; Garncarczyk, Agnieszka; Kuśmierz, Dariusz; Latocha, Małgorzata

2014-01-01

Keloids are characterized by overgrowth of connective tissue in the skin that arises as a consequence of abnormal wound healing. Normal wound healing is regulated by a complex set of interactions within a network of profibrotic and antifibrotic cytokines that regulate new extracellular matrix (ECM) synthesis and remodeling. These proteins include transforming growth factor β (TGFβ) isoforms and connective tissue growth factor (CTGF). TGFβ1 stimulates fibroblasts to synthesize and contract ECM and acts as a central mediator of profibrotic response. CTGF is induced by TGFβ1 and is considered a downstream mediator of TGFβ1action in fibroblasts. CTGF plays a crucial role in keloid pathogenesis by promoting prolonged collagen synthesis and deposition and as a consequence sustained fibrotic response. During keloids formation, besides imbalanced ECM synthesis and degradation, fibroblast proliferation and it's resistance to apoptosis is observed. Key genes that may play a role in keloid formation and growth involve: suppressor gene p53.,cyclin-depend- ent kinase inhibitor CDKN1A (p21) and BCL2 family genes: antiapoptotic BCL-2 and proapoptotic BAX. Genistein (4',5,7-trihydroxyisoflavone) exhibits multidirectional biological action. The concentration of genistein is relatively high in soybean. Genistein has been shown as effective antioxidant and chemopreventive agent. Genistein can bind to estrogen receptors (ERs) and modulate estrogen action due to its structure similarity to human estrogens. Genistein also inhibits transcription factors NFκB. Akt and AP-l signaling pathways, that are important for cytokines expression and cell proliferation, differentiation, survival and apoptosis. The aim of the study was to investigate genistein as a potential inhibitor of CTGF and TGFβ1, β2 and β3 isoforms expression and a potential regulator of p53. CDKN1A(p21), BAX and BCL-2 expression in normal fibroblasts and fibroblasts derived from keloids cultured in vitro. Real time

Increased NO bioavailability in aging male rats by genistein and exercise training: using 4, 5-diaminofluorescein diacetate.

PubMed

Eksakulkla, Sukanya; Suksom, Daroonwan; Siriviriyakul, Prasong; Patumraj, Suthiluk

2009-09-07

Several kinds of anti-oxidants have drawn a lot of intention for their benefits on vascular protection. In addition, it has been demonstrated that exercise training could improve endothelial function by up-regulating endothelial nitric oxide synthase (eNOS) protein. Therefore, the present study aims to investigate the effects of genistein, a potent phyto-antioxidant, and exercise training on age-induced endothelial dysfunction in relation to NO bioavailability using in situ NO-sensitive fluorescent dye detection. Male Wistar rats (20-22-month old) were divided into four groups: aged rats treated with corn oil, (Aged+Veh, n = 5), aged rats treated with genistein (Aged+Gen, n = 5, (0.25 mg/kg BW/day, s.c.)), aged rats with and without exercise training (Aged+Ex, n = 5, swimming 40 min/day, 5 days/week for 8 weeks) (Aged+Without-Ex, n = 5). Cremaster arterioles (15-35 micrometer) were visualized by fluorescein isothiocyanate labeled dextran (5 microgram/ml). The vascular response to acetylcholine (Ach; 10(-5)M, 5 ml/5 min) was accessed after 1-min norepinephrine preconstriction (10 micro molar). To determine NO bioavailability, the Krebs-Ringer buffer with 4, 5-diaminofluorescein-diacetate (3 micro molar DAF-2DA), and 10 micro- molar Ach saturated with 95%N2 and 5%CO2 were used. Changes of DAF-2T-intensities along the cremaster arterioles were analyzed by the Image Pro-Plus Software (Media Cybernatics, Inc, USA). Liver malondialdehyde (MDA) level was measured by thiobarbituric acid reaction and used as an indicator for oxidative stress. The results showed that means arterial blood pressure for both Aged+Gen and Aged+Ex groups were significantly reduced when compared to the Aged groups, Aged+Veh and Aged+Without-Ex (P < 0.05). Among the treated groups, Ach-induced vasodilatation were significantly increased (P < 0.05) and was associated with increased NO-associated fluorescent intensities (P < 0.05). On the other hand, MDA levels were significantly reduced (P < 0

A combination of genistein and magnesium enhances the vasodilatory effect via an eNOS pathway and BK(Ca) current amplification.

PubMed

Sun, Lina; Hou, Yunlong; Zhao, Tingting; Zhou, Shanshan; Wang, Xiaoran; Zhang, Liming; Yu, Guichun

2015-04-01

The phytoestrogen genistein (GST) and magnesium have been independently shown to regulate vascular tone; however, their individual vasodilatory effects are limited. The aim of this study was to examine the combined effects of GST plus magnesium on vascular tone in mesenteric arteries. The effects of pretreatment with GST (0-200 μmol/L), MgCl2 (0-4.8 mmol/L) and GST plus MgCl2 on 10 μmol/L phenylephrine (PE) precontracted mesenteric arteries in rats were assessed by measuring isometric force. BK(Ca) currents were detected by the patch clamp method. GST caused concentration- and partial endothelium-dependent relaxation. Magnesium resulted in dual adjustment of vascular tone. Magnesium-free solution eliminated the vasodilatation of GST in both endothelium-intact and denuded rings. GST (50 μmol/L) plus magnesium (4.8 mmol/L) caused stronger relaxation in both endothelium-intact and denuded rings. Pretreatment with the nitric oxide synthase (NOS) inhibitor L-N-nitroarginine methyl ester (L-NAME, 100 μmol/L) significantly inhibited the effects of GST, high magnesium, and the combination of GST and magnesium. BK(Ca) currents were amplified to a greater extent when GST (50 μmol/L) was combined with 4.8 versus 1.2 mmol/L Mg(2+). Our data suggest that GST plus magnesium provides enhanced vasodilatory effects in rat mesenteric arteries compared with that observed when either is used separately, which was related to an eNOS pathway and BK(Ca) current amplification.

Prescription profile of Chinese herbal products containing coumestrol, genestein, and/or daidzein among female users: an analysis of national health insurance data in Taiwan between 1997 and 2007

PubMed Central

2012-01-01

Background Some Chinese herbs contain several kinds of phytoestrogens, and these herbs are commonly prescribed in Taiwan. Phytoestrogens may influence the effects of estrogen in females, although their activities are weak. This study aims to identify the risk and analyze the prescription profile of commonly used phytoestrogenic herbs in Taiwan. Methods The study analyzed women who had been prescribed phytoestrogenic herbs including coumestrol, genistein and/or daidzein between 1997 and 2007 in a fixed cohort taken from all female beneficiaries from the National Health Insurance Research Database of Taiwan. The prescription frequencies, cumulated dosages, and primary indications were listed. Results A total of 462,861 women were included in the study, of whom ~47.0% had used phytoestrogenic herbs at least once during the study period. A total of 6,270,813 prescriptions were recorded, and more than 20% of these contained phytoestrogens. The most commonly prescribed herb and formula were Puerariae Radix and Ge gen tang (Pueraria Decoction), respectively. Most of the prescriptions were issued for diseases of the respiratory system, followed by symptoms, signs, and ill-defined conditions and diseases of the musculoskeletal system and connective tissue. Conclusion This study shows that women who sought medical treatment from Chinese medicine doctors for relief of respiratory discomfort had a high possibility of exposure to phytoestrogenic herbs. Safety issues related to the female endocrine system should be a priority for future research. PMID:23072740

Dose- and Time-Dependent Transcriptional Response of Ishikawa Cells Exposed to Genistein

PubMed Central

Naciff, Jorge M.; Khambatta, Zubin S.; Carr, Gregory J.; Tiesman, Jay P.; Singleton, David W.; Khan, Sohaib A.; Daston, George P.

2016-01-01

To further define the utility of the Ishikawa cells as a reliable in vitro model to determine the potential estrogenic activity of chemicals of interest, transcriptional changes induced by genistein (GES) in Ishikawa cells at various doses (10 pM, 1 nM, 100 nM, and 10 μM) and time points (8, 24, and 48 h) were identified using a comprehensive microarray approach. Trend analysis indicated that the expression of 5342 unique genes was modified by GES in a dose- and time-dependent manner (P ≤ 0.0001). However, the majority of gene expression changes induced in Ishikawa cells were elicited by the highest dose of GES evaluated (10 μM). The GES’ estrogenic activity was identified by comparing the Ishikawa cells’ response to GES versus 17 α-ethynyl estradiol (EE, at equipotent doses, ie, 10 μM vs 1 μM, respectively) and was defined by changes in the expression of 284 unique genes elicited by GES and EE in the same direction, although the magnitude of the change for some genes was different. Further, comparing the response of the Ishikawa cells exposed to high doses of GES and EE versus the response of the juvenile rat uterus exposed to EE, we identified 66 unique genes which were up- or down regulated in a similar manner in vivo as well as in vitro. Genistein elicits changes in multiple molecular pathways affecting various biological processes particularly associated with cell organization and biogenesis, regulation of translation, cell proliferation, and intracellular transport; processes also affected by estrogen exposure in the uterus of the rat. These results indicate that Ishikawa cells are capable of generating a biologically relevant estrogenic response and offer an in vitro model to assess this mode of action. PMID:26865667

Biophysical characterization of genistein-membrane interaction and its correlation with biological effect on cells - The case of EYPC liposomes and human erythrocyte membranes.

PubMed

Pawlikowska-Pawlęga, Bożena; Misiak, Lucjan E; Jarosz-Wilkołazka, Anna; Zarzyka, Barbara; Paduch, Roman; Gawron, Antoni; Gruszecki, Wieslaw I

2014-08-01

With application of EPR and (1)H NMR techniques genistein interaction with liposomes formed with egg yolk lecithin and with erythrocyte membranes was assessed. The present study addressed the problem of genistein localization and its effects on lipid membrane fluidity and protein conformation. The range of microscopic techniques was employed to study genistein effects on HeLa cells and human erythrocytes. Moreover, DPPH bioassay, superoxide anion radical test and enzymatic measurements were performed in HeLa cells subjected to genistein. The gathered results from both EPR and NMR techniques indicated strong ordering effect of genistein on the motional freedom of lipids in the head group region and the adjacent hydrophobic zone in liposomal as well as in red blood cell membranes. EPR study of human ghost showed also the changes in the erythrocyte membrane protein conformation. The membrane effects of genistein were correlated with the changes in internal membranes arrangement of HeLa cells as it was noticed using transmission electron microscopic and fluorescent techniques. Scanning electron and light microscopy methods showed that one of the aftermaths of genistein incorporation into membranes was creation of echinocytic form of the red blood cells with reduced diameter. Genistein improved redox status of HeLa cells treated with H2O2 by lowering radicals' level. In conclusion, the capacity of genistein to incorporate, to affect membrane organization and to change its biophysical properties is correlated with the changes inside the cells. Copyright © 2014 Elsevier B.V. All rights reserved.

Glycation of β-lactoglobulin and antiglycation by genistein in different reactive carbonyl model systems.

PubMed

Kong, Yanghui; Li, Xiaoming; Zheng, Tiesong; Lv, Lishuang

2015-09-15

Advanced glycation end products (AGEs), which are formed in β-lactoglobulin (β-lg) glycation systems via the Maillard reaction, have been implicated in diabetes-related long-term complications. In the present study, we found that reaction conditions, including temperature, time, pH, reactant type and molar ratio of beta-lg to a sugar/MGO/GO, can significantly affect the formation of AGEs. Using SDS-PAGE, we further demonstrated that genistein, a natural isoflavone found in a number of plants including soybeans and kudzu, can efficiently inhibit cross-links of the glycated β-lg, and suppress the formation AGEs in a dose-dependent manner by trapping reactive dicarbonyl compounds. The products formed from genistein and methylglyoxal (MGO) in the β-lg-MGO assay were analyzed using LC/MS. Both mono-MGO and di-MGO adducts of genistein were detected with this method. Copyright © 2015 Elsevier Ltd. All rights reserved.

Dose-response characteristics of neonatal exposure to genistein on pituitary responsiveness to gonadotropin releasing hormone and volume of the sexually dimorphic nucleus of the preoptic area (SDN-POA) in postpubertal castrated female rats.

PubMed

Faber, K A; Hughes, C L

1993-01-01

Estrogen exposure during critical periods of development promotes androgenization of the brain, which is reflected in altered morphology, behavior, and cyclic hormone secretion in females. Previous work in our laboratory demonstrated that neonatal female rats injected with pharmaceutical or naturally occurring estrogens had decreased GnRH-induced LH secretion and increased volume of the SDN-POA as 42 day castrates. The current experiment defines the dose-response characteristics of neonatal exposure to the isoflavonoid phytoestrogen genistein (G) on pituitary sensitivity to GnRH and SDN-POA volume. Litters of rat pups received subcutaneous injections of either corn oil, 1, 10, 100, 200, 400, 500, or 1000 micrograms of G on days 1 to 10 of life. The litters were ovariectomized and weaned on day 21. On day 42 blood was drawn from right atrial catheters immediately prior to, 5, 10, 15, and 30 min following a single injection of 50 ng/kg of GnRH. Only the 10 micrograms dose of G was associated with increased pituitary response to GnRH, while progressive increases in exposure levels of G were associated with decreasing LH secretion. The SDN-POA volume was increased in only the 500 micrograms and 1000 micrograms exposure groups compared to controls. The results confirm that low doses of G have nonandrogenizing, pituitary-sensitizing effects, while higher doses of G mimic the more typical effects of estrogens. The use of both morphologic and physiologic end points more completely defines the reproductive consequences of environmental estrogen exposure during critical periods of CNS development.

Encapsulation of micronutrients resveratrol, genistein, and curcumin by folic acid-PAMAM nanoparticles.

PubMed

Chanphai, P; Tajmir-Riahi, H A

2018-05-21

It has been shown that encapsulation of dietary polyphenols leads to increased solubility and bioavailability of these micronutrients. The encapsulation of dietary polyphenols resveratrol, genistein, and curcumin by folic acid-PAMAM-G3 and folic acid-PAMAM-G4 nanoparticles was studied in aqueous solution at physiological conditions, using multiple spectroscopic methods, TEM images, and docking studies. The polyphenol bindings are via hydrophilic, hydrophobic, and H-bonding contacts with resveratrol forming more stable conjugates. As folic acid-PAMAM nanoparticle size increased, the loading efficacy and the stability of polyphenol-polymer conjugates were increased. Polyphenol encapsulation induced major alterations of dendrimer morphology. Folic acid-PAMAM nanoconjugates are capable of delivery of polyphenols in vitro.

Mitigation of radiation-induced lung injury with EUK-207 and genistein: effects in adolescent rats.

PubMed

Mahmood, J; Jelveh, S; Zaidi, A; Doctrow, S R; Hill, R P

2013-02-01

Exposure of civilian populations to radiation due to accident, war or terrorist act is an increasing concern. The lung is one of the more radiosensitive organs that may be affected in people receiving partial-body irradiation and radiation injury in lung is thought to be associated with the development of a prolonged inflammatory response. Here we examined how effectively damage to the lung can be mitigated by administration of drugs initiated at different times after radiation exposure and examined response in adolescent animals for comparison with the young adult animals that we had studied previously. We studied the mitigation efficacy of the isoflavone genistein (50 mg/kg) and the salen-Mn superoxide dismutase-catalase mimetic EUK-207 (8 mg/kg), both of which have been reported to scavenge reactive oxygen species and reduce activity of the NFkB pathway. The drugs were given by subcutaneous injection to 6- to 7-week-old Fisher rats daily starting either immediately or 2 weeks after irradiation with 12 Gy to the whole thorax. The treatment was stopped at 28 weeks post irradiation and the animals were assessed for levels of inflammatory cytokines, activated macrophages, oxidative damage and fibrosis at 48 weeks post irradiation. We demonstrated that both genistein and EUK-207 delayed and suppressed the increased breathing rate associated with pneumonitis. These agents also reduced levels of oxidative damage (50-100%), levels of TGF-β1 expression (75-100%), activated macrophages (20-60%) and fibrosis (60-80%). The adolescent rats developed pneumonitis earlier following irradiation of the lung than did the adult rats leading to greater severe morbidity requiring euthanasia (∼37% in adolescents vs. ∼10% in young adults) but the extent of the mitigation of the damage was similar or slightly greater.

In vitro metabolism of genistein and tangeretin by human and murine cytochrome P450s.

PubMed

Breinholt, Vibeke M; Rasmussen, Salka E; Brøsen, Kim; Friedberg, Thomas H

2003-07-01

Recombinant cytochrome P450 (CYP) 1A2, 3A4, 2C9 or 2D6 enzymes obtained from Escherichia coli and human liver microsomes samples were used to investigate the ability of human CYP enzymes to metabolize the two dietary flavonoids, genistein and tangeretin. Analysis of the metabolic profile from incubations with genistein and human liver microsomes revealed the production of five different metabolites, of which three were obtained in sufficient amounts to allow a more detailed elucidation of the structure. One of these metabolites was identified as orobol, the 3'-hydroxylated metabolite of genistein. The remaining two metabolites were also hydroxylated metabolites as evidenced by LC/MS. Orobol was the only metabolite formed after incubation with CYP1A2. The two major product peaks after incubation of tangeretin with human microsomes were identical with 4'-hydroxy-5,6,7,8-tetramethoxyflavone and 5,6-dihydroxy-4',7,8-trimethoxyflavone, previously identified in rat urine in our laboratory. By comparison with UV spectra and LC/MS fragmentation patterns of previously obtained standards, the remaining metabolites eluting after 14, 17 and 20 min. were found to be demethylated at the 4',7-, 4',6-positions or hydroxylated at the 3'- and demethylated at the 4'-positions, respectively. Metabolism of tangeretin by recombinant CYP1A2, 3A4, 2D6 and 2C9 resulted in metabolic profiles that qualitatively were identical to those observed in the human microsomes. Inclusion of the CYP1A2 inhibitor fluvoxamine in the incubation mixture with human liver microsomes resulted in potent inhibition of tangeretin and genistein metabolism. Other isozymes-selective CYP inhibitors had only minor effects on tangeretin or genistein metabolism. Overall the presented observations suggest major involvement of CYP1A2 in the hepatic metabolism of these two flavonoids.

[Phytoestrogens in the treatment of menopause].

PubMed

Remport, Júlia; Blázovics, Anna

2017-08-01

In previous centuries many women did not even live until their menopause years due to poor economic conditions, deficiencies of medicine, epidemics and wars. Nowadays in the developed countries, people live until they are 75-80 years old, and with the expansion of average age, the number of people affected by menopause and the years spent in that state increase. Nowadays women spend one third of their lives in the menopausal stage. The only effective way to treat unpleasant symptoms for centuries was with the use of herbs, and the knowledge about them spread through oral tradition. In the 20th century, this therapeutic form was pushed into the background by the development of synthetic drug production and the introduction of hormone replacement therapy. Thanks to the influence of media in the 20th century, women began to have the social need for preserving their beauty and youth for as long as they could. Hormone replacement therapy enjoyed great popularity because women were temporarily relieved of their life quality-impairing menopausal symptoms, but years later it turned out that hormone replacement therapy could pose serious risks. A distinct advantage of herbal therapy is the more advantageous side-effect-profile opposite the used synthetics in hormone replacement therapy. Women are therefore happy to turn to valuable and well-tried natural therapies, which have been used for thousands of years. There is growing interest in herbal remedies. Studying the effects of phytoestrogens has now become an active area for research. However, the results of studies in animals and humans are controversial, some sources suggest that phytoestrogens are effective and safe, other authors claim that they are ineffective in menopause or they have particularly dangerous properties, and cannot be recommended to everyone. It is important to address this issue for the sake of health, mental health and safety of women, and so it is necessary to assess the benefits and the risks

Preparation of a 1:1 cocrystal of genistein with 4,4‧-bipyridine

NASA Astrophysics Data System (ADS)

Zhang, Yu-Nan; Yin, He-Mei; Zhang, Yu; Zhang, Da-Jun; Su, Xin; Kuang, Hai-Xue

2017-01-01

Based on analysing the relationship between the possible number of intermolecular O-H···N hydrogen bonds and the stoichiometric ratio, a 1:1 C15H10O5·C10H8N2 (genistein-4,4‧-bipyridine) cocrystal has been prepared by solution evaporation and characterized. This work successfully demonstrates that the stoichiometric ratio could be inferred by analysing the possible number of intermolecular hydrogen bonds between flavonoids and amines. The strategy provides a facile route for rational designing cocrystal of flavonoids with amines. Additionally, the title cocrystal shows advantages in terms of solubility and antibacterial properties in comparison to pure genistein.

The soy-associated phytoestrogen, genistein, does not protect against alcohol induced osteoporosis in male mice

USDA-ARS?s Scientific Manuscript database

Alcohol abuse acts as a risk factor for osteoporosis by increasing osteoclast activity and decreasing osteoblast activity in bone. These effects can be reversed by estradiol. Soy diets are also suggested to have protective effects on bone loss in men and women, as a result of the presence of soy pro...

Glyphosate induces human breast cancer cells growth via estrogen receptors.

PubMed

Thongprakaisang, Siriporn; Thiantanawat, Apinya; Rangkadilok, Nuchanart; Suriyo, Tawit; Satayavivad, Jutamaad

2013-09-01

Glyphosate is an active ingredient of the most widely used herbicide and it is believed to be less toxic than other pesticides. However, several recent studies showed its potential adverse health effects to humans as it may be an endocrine disruptor. This study focuses on the effects of pure glyphosate on estrogen receptors (ERs) mediated transcriptional activity and their expressions. Glyphosate exerted proliferative effects only in human hormone-dependent breast cancer, T47D cells, but not in hormone-independent breast cancer, MDA-MB231 cells, at 10⁻¹² to 10⁻⁶M in estrogen withdrawal condition. The proliferative concentrations of glyphosate that induced the activation of estrogen response element (ERE) transcription activity were 5-13 fold of control in T47D-KBluc cells and this activation was inhibited by an estrogen antagonist, ICI 182780, indicating that the estrogenic activity of glyphosate was mediated via ERs. Furthermore, glyphosate also altered both ERα and β expression. These results indicated that low and environmentally relevant concentrations of glyphosate possessed estrogenic activity. Glyphosate-based herbicides are widely used for soybean cultivation, and our results also found that there was an additive estrogenic effect between glyphosate and genistein, a phytoestrogen in soybeans. However, these additive effects of glyphosate contamination in soybeans need further animal study. Copyright © 2013 Elsevier Ltd. All rights reserved.

Dose- and Time-Dependent Transcriptional Response of Ishikawa Cells Exposed to Genistein.

PubMed

Naciff, Jorge M; Khambatta, Zubin S; Carr, Gregory J; Tiesman, Jay P; Singleton, David W; Khan, Sohaib A; Daston, George P

2016-05-01

To further define the utility of the Ishikawa cells as a reliable in vitro model to determine the potential estrogenic activity of chemicals of interest, transcriptional changes induced by genistein (GES) in Ishikawa cells at various doses (10 pM, 1 nM, 100 nM, and 10 μM) and time points (8, 24, and 48 h) were identified using a comprehensive microarray approach. Trend analysis indicated that the expression of 5342 unique genes was modified by GES in a dose- and time-dependent manner (P ≤ 0.0001). However, the majority of gene expression changes induced in Ishikawa cells were elicited by the highest dose of GES evaluated (10 μM). The GES' estrogenic activity was identified by comparing the Ishikawa cells' response to GES versus 17 α-ethynyl estradiol (EE, at equipotent doses, ie, 10 μM vs 1 μM, respectively) and was defined by changes in the expression of 284 unique genes elicited by GES and EE in the same direction, although the magnitude of the change for some genes was different. Further, comparing the response of the Ishikawa cells exposed to high doses of GES and EE versus the response of the juvenile rat uterus exposed to EE, we identified 66 unique genes which were up- or down regulated in a similar manner in vivo as well as in vitro Genistein elicits changes in multiple molecular pathways affecting various biological processes particularly associated with cell organization and biogenesis, regulation of translation, cell proliferation, and intracellular transport; processes also affected by estrogen exposure in the uterus of the rat. These results indicate that Ishikawa cells are capable of generating a biologically relevant estrogenic response and offer an in vitro model to assess this mode of action. © The Author 2016. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

The association between dietary lignans, phytoestrogen-rich foods, and fiber intake and postmenopausal breast cancer risk: a German case-control study.

PubMed

Zaineddin, Aida Karina; Buck, Katharina; Vrieling, Alina; Heinz, Judith; Flesch-Janys, Dieter; Linseisen, Jakob; Chang-Claude, Jenny

2012-01-01

Phytoestrogens are structurally similar to estrogens and may affect breast cancer risk by mimicking estrogenic/antiestrogenic properties. In Western societies, whole grains and possibly soy foods are rich sources of phytoestrogens. A population-based case-control study in German postmenopausal women was used to evaluate the association of phytoestrogen-rich foods and dietary lignans with breast cancer risk. Dietary data were collected from 2,884 cases and 5,509 controls using a validated food-frequency questionnaire, which included additional questions phytoestrogen-rich foods. Associations were assessed using conditional logistic regression. All analyses were adjusted for relevant risk and confounding factors. Polytomous logistic regression analysis was performed to evaluate the associations by estrogen receptor (ER) status. High and low consumption of soybeans as well as of sunflower and pumpkin seeds were associated with significantly reduced breast cancer risk compared to no consumption (OR = 0.83, 95% CI = 0.70-0.97; and OR = 0.66, 95% CI = 0.77-0.97, respectively). The observed associations were not differential by ER status. No statistically significant associations were found for dietary intake of plant lignans, fiber, or the calculated enterolignans. Our results provide evidence for a reduced postmenopausal breast cancer risk associated with increased consumption of sunflower and pumpkin seeds and soybeans.

A comparative survey of leguminous plants as sources of the isoflavones, genistein and daidzein: implications for human nutrition and health.

PubMed

Kaufman, P B; Duke, J A; Brielmann, H; Boik, J; Hoyt, J E

1997-01-01

Over 80 taxa of mostly agriculturally important legumes were surveyed as sources of the metabolites, genistein and daidzein. Remarkably high concentrations (over 2 g.kg-1 dry weight) of the anticancer metabolite, genistein, were found in the leaves of Psoralea corylifolia (Indian bread root). All other legumes, with the exception of fermented soybean miso, had genistein levels < 400 mg.kg-1 dry weight. Concentrations of over 1 g.kg-1 dry weight and 0.95 g.kg-1 dry weight of the anticancer metabolite, daidzein, were found in the stems of the fava bean (Vicia faba) and roots of kudzu vine (Pueraria lobata), respectively. From this survey, our results indicate that the legumes, lupine (Lupinus spp.), fava bean, (Vicia faba), soybeans (Glycine max), kudzu (Pueraria lobata), and psoralea (Psoralea corylifolia), are excellent food sources for both genistein and daidzein. Miso, a fermented soybean product, is also a rich source of both isoflavones.

Bradyrhizobium japonicum mutants with enhanced sensitivity to genistein resulting in altered nod gene regulation.

PubMed

Ip, H; D'Aoust, F; Begum, A A; Zhang, H; Smith, D L; Driscoll, B T; Charles, T C

2001-12-01

Bradyrhizobium japonicum mutants with altered nod gene induction characteristics were isolated by screening mutants for genistein-independent nod gene expression. Plasmid pZB32, carrying a nodY::lacZ transcriptional gene fusion, was introduced into B. japonicum cells that had been subjected to UV mutagenesis. Ten independent transformants producing a blue color on plates containing 5bromo-4chloro-3indolyl-beta-D-galactopyranoside but lacking genistein, indicative of constitutive expression of the nodY::lacZ reporter gene, were isolated. Beta-galactosidase activity assays revealed that while all of the 10 strains were sensitive to low concentrations of genistein, none exhibited truly constitutive nodY::lacZ expression in liquid culture. Soybean plants inoculated with three of the mutants were chlorotic and stunted, with shoot dry weights close to those of the uninoculated plants, indicating the absence of nitrogen fixation. Differences in the kinetics of nodY::lacZ expression and lipochitin oligosaccharide Nod signal production suggested that the strains carried different mutations. Some of these strains may be useful in mitigating the low root zone temperature-associated delay in soybean nodulation at the northern extent of soybean cultivation.

Effects of phytoestrogens on indices of protein turnover in rainbow trout (Oncorhynchus mykiss) primary myocytes

USDA-ARS?s Scientific Manuscript database

Soybeans and other legumes investigated as alternative ingredients in aquafeeds contain phytoestrogens that act as endocrine disruptors, capable of binding to and activating estrogen receptors, although at a much lower level of estrogenicity compared to estradiol. Estradiol has catabolic effects on...

Regulation of HMG-CoA reductase in MCF-7 cells by genistein, EPA, and DHA, alone and in combination with mevastatin.

PubMed

Duncan, Robin E; El-Sohemy, Ahmed; Archer, Michael C

2005-06-28

We investigated the regulation of HMG-CoA reductase in MCF-7 human breast cancer cells by genistein, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). All three compounds down-regulated reductase activity, primarily through post-transcriptional effects. In mevastatin-treated cells, only genistein and DHA abrogated the induction of reductase activity caused by this competitive inhibitor. Diets rich in soy isoflavones and fish oils, therefore, may exert anti-cancer effects through the inhibition of mevalonate synthesis in the breast. Genistein and DHA, in particular, may augment the efficacy of statins, increasing the potential for use of these drugs in adjuvant therapy for breast cancer.

Effects of phytoestrogen extracts isolated from rye, green and yellow pea seeds on hormone production and proliferation of trophoblast tumor cells Jeg3.

PubMed

Matscheski, A; Richter, D-U; Hartmann, A-M; Effmert, U; Jeschke, U; Kupka, M S; Abarzua, S; Briese, V; Ruth, W; Kragl, U; Piechulla, B

2006-01-01

Phytoestrogens are a diverse group of non-steroidal plant compounds. Because they have chemical structures similar to estrogens they are able to bind on estrogen receptors in humans. In this study, we tested the effects of crude phytoestrogen extracts from rye (Secale cereale), green pea (Pisum sativum) and yellow pea seeds (Pisum sativum cv.) on cell proliferation and the production of progesterone in trophoblast tumor cells of the cell line Jeg3. Isoflavone extracts from green and yellow pea seeds and lignan extracts from rye seeds were obtained, using different extraction methods. Isolated extracts were incubated in different concentrations with trophoblast tumor cells. Untreated cells were used as controls. At designated times, aliquots were removed and tested for estradiol and progesterone production. In addition, we tested the effects of the phytoestrogen extracts on cell proliferation. Cell proliferation is significantly inhibited by potential phytoestrogens isolated from rye, green and yellow pea seeds in trophoblast tumor cells of the cell line Jeg3. We found a correlation between the effects of proliferation and production of estradiol in isoflavone extracts from green and yellow pea seeds in Jeg3 cells. In addition, higher concentrations of isoflavones isolated from green pea seeds and lignans from rye showed also a inhibition of progesterone production whereas higher concentrations of rye lignans elevated estradiol production in Jeg3 cells. A useful indicator test system for potential phytoestrogens could be established. Based on the obtained results it is proposed that green and yellow pea seeds contain measurable concentrations of isoflavones and rye seeds contain lignans which can be isolated and used for special human diet programs. Copyright 2006 S. Karger AG, Basel.

ADULT EXPOSURE TO PHYTOESTROGEN APIGENIN RESULTS IN CHANGES IN ENDOCRINE PARAMETERS BUT FAILS TO ALTER FECUNDITY

EPA Science Inventory

Plant-derived estrogens offer the opportunity to investigate the potential for weakly estrogenic compounds to influence endocrine function and reproduction. The presence of these phytoestrogens in foods, and agricultural and industrial runoff has the potential to increase the tot...

Genistein modulates oxidative stress in breast cancer cell lines according to ERα/ERβ ratio: effects on mitochondrial functionality, sirtuins, uncoupling protein 2 and antioxidant enzymes.

PubMed

Nadal-Serrano, Mercedes; Pons, Daniel Gabriel; Sastre-Serra, Jorge; Blanquer-Rosselló, M del Mar; Roca, Pilar; Oliver, Jordi

2013-09-01

Genistein is a biologically active isoflavone with estrogenic activity and can be found in a variety of soy products. This natural compound displays a wide array of biological activities, but it is best known for its ability to inhibit cancer progression, especially for hormone-related ones such as breast cancer. Genistein has been shown to bind both the estrogen receptor alpha (ERα) and the estrogen receptor beta (ERβ), although it has a higher affinity for the ERβ. The ERα/ERβ ratio is a prognostic marker for breast tumors, and ERβ expression could indicate the presence of tumors more benign in state, whereas ERα indicates malignant tumors. The objective of the present study was to investigate the effects of genistein on oxidative stress and mitochondrial functionality through its interaction with the estrogen receptor in breast cancer cell lines with different ERα/ERβ ratios. The lower ERα/ERβ ratio T47D cell line showed lower oxidative stress and greater mitochondrial functionality, along with an up-regulation of uncoupling protein 2 and sirtuins. On the other hand, genistein-treated MCF-7 cell line, with the highest ERα/ERβ ratio, reported no changes for the control situation. On the whole, our results show different genistein effects depending on ERα/ERβ ratio for oxidative stress regulation, mitochondrial functionality, and modulation of UCPs, antioxidant enzymes and sirtuins in breast cancer cell lines. Effects of genistein on oxidative stress and mitochondria could be due at least in part, to a higher ERβ presence, but could also be due to up-regulation of ERβ caused by the genistein treatment. Copyright © 2013 Elsevier Ltd. All rights reserved.

Association of dietary soy genistein intake with lung function and asthma control: a post-hoc analysis of patients enrolled in a prospective multicentre clinical trial

PubMed Central

Bime, Christian; Wei, Christine Y; Holbrook, Janet; Smith, Lewis J; Wise, Robert A

2013-01-01

Background Broad dietary patterns have been linked to asthma but the relative contribution of specific nutrients is unclear. Soy genistein has important anti-inflammatory and other biological effects that might be beneficial in asthma. A positive association was previously reported between soy genistein intake and lung function but not with asthma exacerbations. Aims To conduct a post-hoc analysis of patients with inadequately controlled asthma enrolled in a prospective multicentre clinical trial to replicate this association. Methods A total of 300 study participants were included in the analysis. Dietary soy genistein intake was measured using the Block Soy Foods Screener. The level of soy genistein intake (little or no intake, moderate intake, or high intake) was compared with baseline lung function (pre-bronchodilator forced expiratory volume in 1 second (FEV1)) and asthma control (proportion of participants with an episode of poor asthma control (EPAC) and annualised rates of EPACs over a 6-month follow-up period. Results Participants with little or no genistein intake had a lower baseline FEV1 than those with a moderate or high intake (2.26L vs. 2.53L and 2.47L, respectively; p=0.01). EPACs were more common among those with no genistein intake than in those with a moderate or high intake (54% vs. 35% vs. 40%, respectively; p<0.001). These findings remained significant after adjustment for patient demographics and body mass index. Conclusions In patients with asthma, consumption of a diet with moderate to high amounts of soy genistein is associated with better lung function and better asthma control. PMID:22885561

Effects of phytoestrogen supplementation in postmenopausal women with dry eye syndrome: a randomized clinical trial.

PubMed

Scuderi, Gianluca; Contestabile, Maria Teresa; Gagliano, Caterina; Iacovello, Daniela; Scuderi, Luca; Avitabile, Teresio

2012-12-01

To evaluate the correlation between tear osmolarity and blood levels of 17-β estradiol, estrone, and testosterone in postmenopausal women with dry eye syndrome, and to assess the efficacy and safety of oral supplementation with phytoestrogens, lipoic acid, and eicosapentaenoic acid in this population. Cross-sectional study including 66 postmenopausal women with dry eye syndrome. Sixty-six postmenopausal women with dry eye syndrome were enrolled in a randomized, double-blind, placebo-controlled, crossover study. Patients were divided into 2 groups (groups A and B) and treated, respectively, with phytoestrogen (Bioos, Montegiorgio, Italy) tablets or placebo tablets for 30 days. The 2 treatment periods were separated by a 30-day washout. Patients were examined on days 0 and 30 of each period. Assessments included blood levels of sex hormones, the Schirmer test for tear production, and measurement of tear osmolarity and tear film break-up time. At baseline, all patients had low sex hormone levels, which were correlated with high tear film osmolarity values (r = -0.59,-0.61,-0.58, respectively). After 30 days of therapy, the group treated with Lacrisek® (Bioos) had significantly decreased tear osmolarity (P<0.005) and significantly increased tear production evaluated with the Schirmer test and tear film break-up time values (P<0.001) compared with the placebo-treated group. Our study confirms that steroid hormones play an important role in ocular surface equilibrium and functions. Consequently, reduced blood levels of these hormones can produce changes at the ocular surface. Phytoestrogen supplementation can significantly improve the signs and symptoms of dry eye syndrome in postmenopausal women. Copyright © 2012 Canadian Ophthalmological Society. Published by Elsevier Inc. All rights reserved.

Consumption of indigenous medicines by pregnant women in North India for selecting sex of the foetus: what can it lead to?

PubMed

Neogi, Sutapa Bandyopadhyay; Negandhi, Preeti H; Ganguli, Abhijit; Chopra, Sapna; Sandhu, Navraj; Gupta, Ravi Kant; Zodpey, Sanjay; Singh, Amarjeet; Singh, Arun; Gupta, Rakesh

2015-09-04

Sex ratio is an important indicator of development. Despite all the measures undertaken for improvement, it remains an issue of concern in India, with Haryana having a very low sex ratio in the country. Studies have been conducted indicating that consumption of indigenous drugs used for sex selection (SSD) could be strongly associated with adverse effects on the foetal development, including congenital malformations. Some samples of SSDs were collected from parts of North India and analysed in a standard laboratory for its components. Thirty SSDs used by the local community were procured from various sources in north India through a rigorous process of collection. These were subjected to laboratory tests to investigate the presence of phytoestrogen and testosterone. Following sample extraction, thin layer chromatography and high performance liquid chromatography were carried out for analysing phytoestrogen content. SSDs were available in various forms such as powder, tablets, mostly from faith healers. Around 87% of the samples collected from sources like doctors, quacks and faith healers were to be taken by the pregnant women after conception; 63% drugs were strongly positive for phytoestrogens (genistein, daidzein, formononetin) and 20% drugs were positive for testosterone. The average dose of the components as calculated after analyses was as follows: daidzein--14.1 mg/g sample, genistein--8.6 mg/g sample, formononetin--5 mg/g sample. These SSDs could be potentially detrimental to the growth and development of the foetus. This is likely to have implications on the health of the community. In view of the results obtained in our study, we strongly attest the importance in curbing this harmful practice by banning the supply of the drugs as well as by advocating behavioural changes in the community.

Chemopreventive activity of GEN-27, a genistein derivative, in colitis-associated cancer is mediated by p65-CDX2-β-catenin axis

PubMed Central

Wang, Hong; Fan, Huimin; Li, Yan; Wang, Jianing; Zhang, Xu; Lu, Jinrong; Ji, Hui; Hu, Rong

2016-01-01

Nonresolving inflammation in the intestine predisposes individuals to colitis-associated colorectal cancer (CAC), which leads to high morbidity and mortality. Here we show that genistein-27 (GEN-27), a derivative of genistein, inhibited proliferation of human colorectal cancer cells through inhibiting β-catenin activity. Our results showed that GEN-27 increased expressions of adenomatous polyposis coli (APC) and axis inhibition protein 2 (AXIN2), and reduced β-catenin nuclear localization, which resulted from the inhibition of NF-κB/p65 nuclear localization and up-regulation of caudal-related homeobox transcription factor 2 (CDX2). Furthermore, GEN-27 decreased binding of p65 to the silencer region of CDX2 and increased binding of CDX2 to the promoter regions of APC and AXIN2, thus inhibiting the activation of β-catenin induced by TNF-α. Importantly, GEN-27 protected mice from azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colon carcinogenesis, with reduced mortality, tumor number and tumor volume. Histopathology, immunohistochemistry and flow cytometry revealed that dietary GEN-27 significantly decreased secretion of proinflammatory cytokines and macrophage infiltration. Moreover, GEN-27 inhibited AOM/DSS-induced p65 and β-catenin nuclear translocation, while promoted the expression of CDX2, APC, and AXIN2. Taken together, our findings demonstrate that the anti-proliferation effect of GEN-27 in vitro and the prevention of CAC in vivo is mediated by p65-CDX2-β-catenin axis via inhibiting β-catenin target genes. Our results imply that GEN-27 could be a promising candidate for the chemoprevention of CAC. PMID:26910375

The natural dietary genistein boosts bacteriophage-mediated cancer cell killing by improving phage-targeted tumor cell transduction.

PubMed

Tsafa, Effrosyni; Al-Bahrani, Mariam; Bentayebi, Kaoutar; Przystal, Justyna; Suwan, Keittisak; Hajitou, Amin

2016-08-09

Gene therapy has long been regarded as a promising treatment for cancer. However, cancer gene therapy is still facing the challenge of targeting gene delivery vectors specifically to tumors when administered via clinically acceptable non-invasive systemic routes (i.e. intravenous). The bacteria virus, bacteriophage (phage), represents a new generation of promising vectors in systemic gene delivery since their targeting can be achieved through phage capsid display ligands, which enable them to home to specific tumor receptors without the need to ablate any native eukaryotic tropism. We have previously reported a tumor specific bacteriophage vector named adeno-associated virus/phage, or AAVP, in which gene expression is under a recombinant human rAAV2 virus genome targeted to tumors via a ligand-directed phage capsid. However, cancer gene therapy with this tumor-targeted vector achieved variable outcomes ranging from tumor regression to no effect in both experimental and natural preclinical models. Herein, we hypothesized that combining the natural dietary genistein, with proven anticancer activity, would improve bacteriophage anticancer safe therapy. We show that combination treatment with genistein and AAVP increased targeted cancer cell killing by AAVP carrying the gene for Herpes simplex virus thymidine kinase (HSVtk) in 2D tissue cultures and 3D tumor spheroids. We found this increased tumor cell killing was associated with enhanced AAVP-mediated gene expression. Next, we established that genistein protects AAVP against proteasome degradation and enhances vector genome accumulation in the nucleus. Combination of genistein and phage-guided virotherapy is a safe and promising strategy that should be considered in anticancer therapy with AAVP.

The natural dietary genistein boosts bacteriophage-mediated cancer cell killing by improving phage-targeted tumor cell transduction

PubMed Central

Tsafa, Effrosyni; Al-Bahrani, Mariam; Bentayebi, Kaoutar; Przystal, Justyna; Suwan, Keittisak; Hajitou, Amin

2016-01-01

Gene therapy has long been regarded as a promising treatment for cancer. However, cancer gene therapy is still facing the challenge of targeting gene delivery vectors specifically to tumors when administered via clinically acceptable non-invasive systemic routes (i.e. intravenous). The bacteria virus, bacteriophage (phage), represents a new generation of promising vectors in systemic gene delivery since their targeting can be achieved through phage capsid display ligands, which enable them to home to specific tumor receptors without the need to ablate any native eukaryotic tropism. We have previously reported a tumor specific bacteriophage vector named adeno-associated virus/phage, or AAVP, in which gene expression is under a recombinant human rAAV2 virus genome targeted to tumors via a ligand-directed phage capsid. However, cancer gene therapy with this tumor-targeted vector achieved variable outcomes ranging from tumor regression to no effect in both experimental and natural preclinical models. Herein, we hypothesized that combining the natural dietary genistein, with proven anticancer activity, would improve bacteriophage anticancer safe therapy. We show that combination treatment with genistein and AAVP increased targeted cancer cell killing by AAVP carrying the gene for Herpes simplex virus thymidine kinase (HSVtk) in 2D tissue cultures and 3D tumor spheroids. We found this increased tumor cell killing was associated with enhanced AAVP-mediated gene expression. Next, we established that genistein protects AAVP against proteasome degradation and enhances vector genome accumulation in the nucleus. Combination of genistein and phage-guided virotherapy is a safe and promising strategy that should be considered in anticancer therapy with AAVP. PMID:27437775

Creation and study of triterpenoid nanoparticles and radioprotective substance genistein.

PubMed

Nguyen, H Q; Chupin, V V; Prokhorov, D I; Chikunov, I E; Kovtun, V Yu; Tarumov, R A; Grebenyuk, A N; Shvets, V I

2015-01-01

This work is devoted to the study and obtaining of new radioprotective agents based on natural flavonoid genistein and spherical amorphous nanoparticles (SANPs) produced from a mixture of birch bark triterpenoids. The physicochemical characteristics of the nanoparticles were studied by electron microscopy, dynamic light scattering, and UV-VIS spectroscopy. The radioprotective efficacy of the nanodrug in vivo and the possibility of its use as a radioprotective agent was shown.

Phytoestrogenic isoflavonoids in epidemiologic and clinical research

PubMed Central

Franke, Adrian A.; Halm, Brunhild M.; Kakazu, Kerry; Li, Xingnan; Custer, Laurie J.

2015-01-01

Isoflavones (IFLs) are natural products to which humans have been traditionally exposed predominantly through soy foods; more recently humans are also exposed to them through soy protein addition to processed foods or through supplements. They are structurally similar to steroidal estrogens and can exert estrogenic or antiestrogenic effects depending on their concentrations and on the tissue considered. These properties qualify IFLs to be classified as phytoestrogens and are believed to account for many of the biological effects observed for soy and/or IFL exposure including benefits for bone and heart health or prevention of menopausal symptoms and certain types of cancer. In order to evaluate the function of IFLs, alone or when exposure happens through soy intake, pharmacokinetics and bioavailability are critical issues to be considered in epidemiologic and clinical research. For this purpose precise, accurate, robust, fast, and affordable techniques for IFL analyses are required. PMID:20355154

Genistein in 1:1 Inclusion Complexes with Ramified Cyclodextrins: Theoretical, Physicochemical and Biological Evaluation

PubMed Central

Danciu, Corina; Soica, Codruta; Oltean, Mircea; Avram, Stefana; Borcan, Florin; Csanyi, Erzsebet; Ambrus, Rita; Zupko, Istvan; Muntean, Delia; Dehelean, Cristina A.; Craina, Marius; Popovici, Ramona A.

2014-01-01

Genistein is one of the most studied phytocompound in the class of isoflavones, presenting a notable estrogenic activity and in vitro and/or in vivo benefits in different types of cancer such as those of the bladder, kidney, lung, pancreatic, skin and endometrial cancer. A big inconvenience for drug development is low water solubility, which can be solved by using hydrophilic cyclodextrins. The aim of this study is to theoretically analyze, based on the interaction energy, the possibility of a complex formation between genistein (Gen) and three different ramified cyclodextrins (CD), using a 1:1 molar ratio Gen:CD. Theoretical data were correlated with a screening of both in vitro and in vivo activity. Proliferation of different human cancer cell lines, antimicrobial activity and angiogenesis behavior was analyzed in order to see if complexation has a beneficial effect for any of the above mentioned activities and if so, which of the three CDs is the most suitable for the incorporation of genistein, and which may lead to future improved pharmaceutical formulations. Results showed antiproliferative activity with different IC50 values for all tested cell lines, remarkable antimicrobial activity on Bacillus subtilis and antiangiogenic activity as revealed by CAM assay. Differences regarding the intensity of the activity for pure and the three Gen complexes were noticed as explained in the text. The data represent a proof that the three CDs can be used for furtherer research towards practical use in the pharmaceutical and medical field. PMID:24473144

Prostate cancer: The main risk and protective factors-Epigenetic modifications.

PubMed

Adjakly, Mawussi; Ngollo, Marjolaine; Dagdemir, Aslihan; Judes, Gaëlle; Pajon, Amaury; Karsli-Ceppioglu, Seher; Penault-Llorca, Frédérique; Boiteux, Jean-Paul; Bignon, Yves-Jean; Guy, Laurent; Bernard-Gallon, Dominique

2015-02-01

With 13 million new cases worldwide every year, prostate cancer is as a very real public health concern. Prostate cancer is common in over-50s men and the sixth-leading cause of cancer-related death in men worldwide. Like all cancers, prostate cancer is multifactorial - there are non-modifiable risk factors like heredity, ethnicity and geographic location, but also modifiable risk factors such as diet. Diet-cancer linkages have risen to prominence in the last few years, with accruing epidemiological data pointing to between-population incidence differentials in numerous cancers. Indeed, there are correlations between fat-rich diet and risk of hormone-dependent cancers like prostate cancer and breast cancer. Diet is a risk factor for prostate cancer, but certain micronutrients in specific diets are considered protective factors against prostate cancer. Examples include tomato lycopene, green tea epigallocatechin gallate, and soy phytoestrogens. These micronutrients are thought to exert cancer-protective effects via anti-oxidant pathways and inhibition of cell proliferation. Here, we focus in on the effects of phytoestrogens, and chiefly genistein and daidzein, which are the best-researched to date. Soy phytoestrogens are nonsteroid molecules whose structural similarity lends them the ability to mimic the effects of 17ß-estradiol. On top of anti-oxidant effects, there is evidence that soy phytoestrogens can modulate the epigenetic modifications found in prostate cancer. We also studied the impact of phytoestrogens on epigenetic modifications in prostate cancer, with special focus on DNA methylation, miRNA-mediated regulation and histone modifications. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

In vitro and in vivo effects of phytoestrogens on protein turnover in rainbow trout (Oncorhynchus mykiss) white muscle

USDA-ARS?s Scientific Manuscript database

Soybeans and other legumes investigated as fishmeal replacements in aquafeeds contain phytoestrogens capable of binding to and activating estrogen receptors. Estradiol has catabolic effects in salmonid white muscle, partially through increases in protein turnover. The current study determines whet...

ME-143 Is Superior to Genistein in Suppression of WNT Signaling in Colon Cancer Cells.

PubMed

Pintova, Sofya; Planutis, Kestutis; Planutiene, Marina; Holcombe, Randall F

2017-04-01

This study tested the effect of the soy isoflavones genistein and ME-143, and two chemotherapeutic agents, 5-fluorouracil (5FU) and oxaliplatin, on WNT signaling. Colon cancer cell lines RKO (hereditary nonpolyposis colorectal cancer type) and DLD1 (most common colorectal cancer type driven by a mutation in WNT pathway) were utilized. WNT throughput was measured using a β-catenin-responsive SuperTopFlash luciferase assay. A stabilized β-catenin construct was employed to test β-catenin involvement in the mechanism of drug activity. ME-143 was a more than 10-fold potent inhibitor of DLD1 proliferation than genistein at 3.125 μM. Genistein alone did not inhibit WNT signaling in either cell line. In RKO cells, oxaliplatin and its combination with 5FU significantly inhibited WNT throughput. Neither 5FU, oxaliplatin nor their combination inhibited WNT signaling in DLD1 cells. In both the RKO and DLD1 cell lines, ME-143 significantly reduced WNT throughput by 65-75%. The introduction of stabilized β-catenin attenuated the ME-143-dependent inhibition of the WNT/β-catenin pathway. ME-143 alone and in combination with 5FU and oxaliplatin effectively inhibits the WNT/β-catenin pathway in colorectal cancer cells of diverse genetic background. β-Catenin is directly involved in the mechanism of inhibition, and clinical studies are warranted. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

17beta-estradiol, genistein, and 4-hydroxytamoxifen induce the proliferation of thyroid cancer cells through the g protein-coupled receptor GPR30.

PubMed

Vivacqua, Adele; Bonofiglio, Daniela; Albanito, Lidia; Madeo, Antonio; Rago, Vittoria; Carpino, Amalia; Musti, Anna Maria; Picard, Didier; Andò, Sebastiano; Maggiolini, Marcello

2006-10-01

The higher incidence of thyroid carcinoma (TC) in women during reproductive years compared with men and the increased risk associated with the therapeutic use of estrogens have suggested a pathogenetic role exerted by these steroids in the development of TC. In the present study, we evaluated the potential of 17beta-estradiol (E2), genistein (G), and 4-hydroxyta-moxifen (OHT) to regulate the expression of diverse estrogen target genes and the proliferation of human WRO, FRO, and ARO thyroid carcinoma cells, which were used as a model system. We have ascertained that ARO cells are devoid of estrogen receptors (ERs), whereas both WRO and FRO cells express a single variant of ERalpha that was neither transactivated, modulated, nor translocated into the nucleus upon treatment with ligands. However, E2, G, and OHT were able either to induce the transcriptional activity of c-fos promoter constructs, including those lacking the estrogen-responsive elements, or to increase c-fos, cyclin A, and D1 expression. It is noteworthy that we have demonstrated that the G protein-coupled receptor 30 (GPR30) and the mitogen-activated protein kinase (MAPK) pathway mediate both the up-regulation of c-fos and the growth response to E2, G, and OHT in TC cells studied, because these stimulatory effects were prevented by silencing GPR30 and using the MEK inhibitor 2'-amino-3'-methoxyflavone (PD 98059). Our findings provide new insight into the molecular mechanisms through which estrogens may induce the progression of TC.

Multiclass analytical method for the determination of natural/synthetic steroid hormones, phytoestrogens, and mycoestrogens in milk and yogurt.

PubMed

Socas-Rodríguez, Bárbara; Lanková, Darina; Urbancová, Kateřina; Krtková, Veronika; Hernández-Borges, Javier; Rodríguez-Delgado, Miguel Ángel; Pulkrabová, Jana; Hajšlová, Jana

2017-07-01

Within this study, a new method enabling monitoring of various estrogenic substances potentially occurring in milk and dairy products was proposed. Groups of compounds fairly differing in physico-chemical properties and biological activity were analyzed: four natural estrogens, four synthetic estrogens, five mycoestrogens, and nine phytoestrogens. Since they may pass into milk mainly in glucuronated and sulfated forms, an enzymatic hydrolysis was involved prior to the extraction based on the QuEChERS methodology. For the purification of the organic extract, a dispersive solid-phase extraction (d-SPE) with sorbent C18 was applied. The final analysis was performed by ultra-high-performance liquid chromatography (UHPLC) coupled with triple quadrupole tandem mass spectrometry (MS/MS). Method recovery ranged from 70 to 120% with a relative standard deviation (RSD) value lower than 20% and limits of quantification (LOQs) in the range of 0.02-0.60 μg/L (0.2-6.0 μg/kg dry weight) and 0.02-0.90 μg/kg (0.2-6.0 μg/kg dry weight) for milk and yogurt, respectively. The new procedure was applied for the investigation of estrogenic compounds in 11 milk samples and 13 yogurt samples from a Czech retail market. Mainly phytoestrogens were found in the studied samples. The most abundant compounds were equol and enterolactone representing 40-90% of all estrogens. The total content of phytoestrogens (free and bound) was in the range of 149-3870 μg/kg dry weight. This amount is approximately 20 times higher compared to non-bound estrogens.

Genistein enhances the effect of epidermal growth factor receptor tyrosine kinase inhibitors and inhibits nuclear factor kappa B in nonsmall cell lung cancer cell lines.

PubMed

Gadgeel, Shirish M; Ali, Shadan; Philip, Philip A; Wozniak, Antoinette; Sarkar, Fazlul H

2009-05-15

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have shown modest clinical benefit in patients with relapsed nonsmall cell lung cancer (NSCLC). Down-regulation of Akt appears to correlate with the antitumor activity of EGFR-TKIs. Akt activates nuclear factor kappa B (NF-kappaB), which transcribes genes important for cell survival, invasion, and metastasis. The authors hypothesized that genistein, through the inhibition of NF-kappaB, could enhance the activity of EGFR-TKIs in NSCLCs. Three NSCLC cell lines with various EGFR mutation status and sensitivities to EGFR-TKIs were selected: H3255 (L858R), H1650 (del E746-A750), and H1781 (wild-type EGFR). Cells were treated with erlotinib, gefitinib, genistein, or the combination of each of the EGFR-TKIs with genistein. Cell survival and apoptosis were assessed, and expression levels of EGFR, pAkt, cyclooxygenase-2 (COX-2), E-cadherin, prostaglandin E(2) (PGE(2)), and NF-kappaB were measured. Both EGFR-TKIs demonstrated growth inhibition and apoptosis in each of the cell lines, but H1650 and H1781 were much less sensitive. Genistein demonstrated some antitumor activity in all cell lines, but enhanced growth inhibition and apoptosis when combined with the EGFR-TKIs in each of the cell lines. Both combinations down-regulated NF-kappaB significantly more than either agent alone in H3255. In addition, the combinations reduced the expression of EGFR, pAkt, COX-2, and PGE(2,) consistent with inactivation of NF-kappaB. The authors concluded that genistein enhances the antitumor effects of EGFR-TKIs in 3 separate NSCLC cell lines. This enhanced activity is in part because of greater reduction in the DNA-binding activity of NF-kappaB when EGFR-TKIs were combined with genistein.

Isoflavonoid-based bone-sparing treatments exert a low activity on reproductive organs and on hepatic metabolism of estradiol in ovariectomized rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Phrakonkham, Pascal; Chevalier, Joelle; Desmetz, Catherine

2007-10-15

The use of soy isoflavones is a potential alternative to hormone replacement therapy in post-menopausal bone-loss prevention. Nevertheless, phytoestrogens can target other organs and may disrupt cell proliferation, or could modify endogenous steroid hormone metabolism. These mechanisms could be linked to an increased risk of developing cancer. We therefore studied the possible side effects of such treatments in an experimental model of menopause. Forty adult female Wistar rats were ovariectomized and fed with a genistein-, daidzein- or equol-supplemented diet at bone-sparing levels (10 mg/kg BW/day) for 3 months. The estrogenic effects were assessed by histological and molecular analyses on reproductivemore » organs. The impact on the oxidative metabolism of estradiol and on associated cytochrome P450 (CYP) activities was evaluated in liver microsomes. The relative wet weights of both the uterus and the vagina were increased in the equol group, but no significant changes in proliferating cell nuclear antigen or hormone receptor mRNA expression were noticed. In contrast, genistein and daidzein did not induce uterotrophy but caused an overexpression of estrogen receptor {alpha} mRNA which could correspond to a long-lasting effect of physiological concentrations of estrogens. The hepatic metabolism of estradiol was influenced by daidzein which increased the synthesis of putative mutagenic derivatives. At the same time, genistein favored estrogen 2-hydroxylation, and equol decreased 4-hydroxyestrogen production. Surprisingly, no significant alteration in hepatic CYP activities was detected. Taken together, these results demonstrate that isoflavonoid-based bone-sparing treatments are able to cause side effects on other estrogen-sensitive target organs when given in the long-term.« less

Signaling from soybean roots to rhizobium: An ATP-binding cassette-type transporter mediates genistein secretion.

PubMed

Sugiyama, Akifumi; Shitan, Nobukazu; Yazaki, Kazufumi

2008-01-01

Legume plants have a unique ability to fix atmospheric nitrogen via symbiosis with rhizobia. For the establishment of symbiosis, legume plants secrete signaling molecules such as flavonoids from root tissues, leading to the attraction of rhizobia and the induction of rhizobial nod genes. Genistein and daidzein are found in soybean root exudates and function as signal molecules in soybean-Bradyrhizobium japonicum chemical communication. Although it is more than 20 years since these signal flavonoids were identified, almost nothing has been characterized concerning the membrane transport process of these molecules from soybean roots. To elucidate the transport mechanism we performed membrane transport assays with plasma membrane-enriched vesicles and various inhibitors. As a result, we concluded that an ATP-binding cassette-type transporter is involved in the secretion of genistein from soybean roots. The possible involvement of a pleiotropic drug resistance-type ABC transporter in this secretion is also discussed.

Soy and other legumes: 'Bean' around a long time but are they the 'superfoods' of the millennium and what are the safety issues for their constituent phytoestrogens?

PubMed

Setchell, K D; Radd, S

2000-09-01

The recognition that legumes and, in particular, soybeans provide not only an excellent source of vegetable protein but also contain appreciable amounts of a number of phytoprotectants has increased general awareness of their potential nutritional and health properties. Since the discovery that soybeans are one of the richest dietary sources of bioavailable phytoestrogens, this legume has been elevated to the forefront of clinical nutritional research. These natural 'selective oestrogen receptor modulators' have been shown to be bioactive. The recent approval by the Food and Drug Administration in the United States for a health claim for soy protein reducing risk for heart disease by its effects on lowering cholesterol levels has led to the increased awareness of the health benefits of soy protein. However, the presence of high levels of phytoestrogens in soybeans has also led to concerns over the potential safety of soy foods. This review will focus on the cardioprotective benefits of legumes and discuss the hypothetical concerns regarding the constituent phytoestrogens.

The effect of dietary zinc - and polyphenols intake on DMBA-induced mammary tumorigenesis in rats

PubMed Central

2012-01-01

Background The aim of the study was to investigate the effect of dietary supplementation with zinc and polyphenol compounds, i.e. resveratrol and genistein, on the effectiveness of chemically induced mammary cancer and the changes in the content of selected elements (Zn, Cu, Mg, Fe, Ca) in tumors as compared with normal tissue of the mammary gland. Methods Female Sprague-Dawley rats were divided into study groups which, apart from the standard diet and DMBA (7,12-dimethyl-1,2- benz[a]anthracene), were treated with zinc ions (Zn) or zinc ions + resveratrol (Zn + resveratrol) or zinc ions + genistein (Zn + genistein) via gavage for a period from 40 days until 20 weeks of age. The ICP-OES (inductively coupled plasma optical emission spectrometry) technique was used to analyze the following elements: magnesium, iron, zinc and calcium. Copper content in samples was estimated in an atomic absorption spectrophotometer. Results Regardless of the diet (standard; Zn; Zn + resveratrol; Zn + genistein), DMBA-induced breast carcinogenesis was not inhibited. On the contrary, in the Zn + resveratrol supplemented group, tumorigenesis developed at a considerably faster rate. On the basis of quantitative analysis of selected elements we found - irrespectively of the diet applied - great accumulation of copper and iron, which are strongly prooxidative, with a simultaneous considerable decrease of the magnesium content in DMBA-induced mammary tumors. The combination of zinc supplementation with resveratrol resulted in particularly large differences in the amount of the investigated elements in tumors as compared with their content in normal tissue. Conclusions Diet supplementation with zinc and polyphenol compounds, i.e. resveratrol and genistein had no effect on the decreased copper level in tumor tissue and inhibited mammary carcinogenesis in the rat. Irrespectively of the applied diet, the development of the neoplastic process in rats resulted in changes of the iron and magnesium

Effects of isoflavone supplements vs. soy foods on blood concentrations of genistein and daidzein in adults

PubMed Central

Gardner, Christopher D.; Chatterjee, Lorraine M.; Franke, Adrian A.

2012-01-01

The objective of this investigation was to examine the pharmacokinetics of isoflavone concentrations over a 24-hour period among healthy adults consuming either soy foods or soy isoflavone tablets at different doses. This randomized, cross-over trial was conducted with twelve generally healthy adults. The three phases of the intervention included: isoflavone tablets at 1) 144 mg/day or 2) 288 mg/day, and 3) soy foods designed to provide a calculated 96 mg isoflavones/day (doses in aglycone equivalents). Doses were spread out over three meals/day. After 6 days on each study phase, plasma isoflavone concentrations were determined on the seventh day at 0, 4, 8, 10, 12 and 24 hours. Average levels of total isoflavone concentrations at 8, 10 and 12 hours were >4 μmol/L for the soy food phase and for the higher dose tablet phase. Genistein concentrations were higher overall in the soy food vs. both the lower and the higher dose supplement phases of the study (p≤0.05). When comparing plasma concentrations for the two doses of tablets, saturation appeared more evident for genistein than daidzein at the higher dose level. In conclusion, we observed important differences in the pharmacokinetics of genistein and daidzein contrasting the sources and doses of isoflavones when administered three times daily, including a possible advantage for increasing serum concentrations of isoflavones from consuming soy foods relative to isoflavone supplements. PMID:18602820

Effects of isoflavone supplements vs. soy foods on blood concentrations of genistein and daidzein in adults.

PubMed

Gardner, Christopher D; Chatterjee, Lorraine M; Franke, Adrian A

2009-03-01

The objective of this investigation was to examine the pharmacokinetics of isoflavone concentrations over a 24-h period among healthy adults consuming either soy foods or soy isoflavone tablets at different doses. This randomized, cross-over trial was conducted with 12 generally healthy adults. The three phases of the intervention included isoflavone tablets at (1) 144 mg/day or (2) 288 mg/day and (3) soy foods designed to provide a calculated 96 mg isoflavones/day (doses in aglycone equivalents). Doses were spread out over three meals per day. After 6 days on each study phase, plasma isoflavone concentrations were determined on the seventh day at 0, 4, 8, 10, 12 and 24 h. Average levels of total isoflavone concentrations at 8, 10 and 12 h were >4 micromol/L for the soy food phase and for the higher dose tablet phase. Genistein concentrations were higher overall in the soy food vs. both the lower and the higher dose supplement phases of the study (P<.05). When comparing plasma concentrations for the two doses of tablets, saturation appeared more evident for genistein than for daidzein at the higher dose level. In conclusion, we observed important differences in the pharmacokinetics of genistein and daidzein contrasting the sources and doses of isoflavones when administered three times daily, including a possible advantage for increasing serum concentrations of isoflavones from consuming soy foods relative to isoflavone supplements.

Role of pp60(c-src) and p(44/42) MAPK in ANG II-induced contraction of rat tonic gastrointestinal smooth muscles.

PubMed

Puri, Rajinder N; Fan, Ya-Ping; Rattan, Satish

2002-08-01

We examined the role of mitogen-activated protein kinase (p(44/42) MAPK) in ANG II-induced contraction of lower esophageal sphincter (LES) and internal anal sphincter (IAS) smooth muscles. Studies were performed in the isolated smooth muscles and cells (SMC). ANG II-induced changes in the levels of phosphorylation of different signal transduction and effector proteins were determined before and after selective inhibitors. ANG II-induced contraction of the rat LES and IAS SMC was inhibited by genistein, PD-98059 [a specific inhibitor of MAPK kinases (MEK 1/2)], herbimycin A (a pp60(c-src) inhibitor), and antibodies to pp60(c-src) and p(120) ras GTPase-activating protein (p(120) rasGAP). ANG II-induced contraction of the tonic smooth muscles was accompanied by an increase in tyrosine phosphorylation of p(120) rasGAP. These were attenuated by genistein but not by PD-98059. ANG II-induced increase in phosphorylations of p(44/42) MAPKs and caldesmon was attenuated by both genistein and PD-98059. We conclude that pp60(c-src) and p(44/42) MAPKs play an important role in ANG II-induced contraction of LES and IAS smooth muscles.

Estradiol, progesterone and genistein differentially regulate levels of aquaporin (AQP)-1, 2, 5 and 7 expression in the uteri of ovariectomized, sex-steroid deficient rats.

PubMed

Chinigarzadeh, Asma; Muniandy, Sekaran; Salleh, Naguib

2016-11-01

In this study, effects of estradiol, progesterone and genistein on uterine aquaporin (AQP)-1, 2, 5 and 7 expression were investigated in sex-steroid deficient state which could help to elucidate the mechanisms underlying uterine fluid volume changes that were reported under these hormone and hormone-like compound influences. Uteri from ovariectomized, female Sprague-Dawley rats receiving seven days estradiol, progesterone or genistein (25, 50 and 100mg/kg/day) were harvested and levels of AQP-1, 2, 5 and 7 proteins and mRNAs were determined by Western blotting and Real-time PCR (qPCR) respectively. Distribution of these proteins in uterus was observed by immunohistochemistry. Genistein caused a dose-dependent increase in uterine AQP-1, 2, 5 and 7 protein and mRNA expression, however at the levels lower than following estradiol or progesterone stimulations. Effects of genistein were antagonized by estradiol receptor blocker, ICI 182780. Estradiol caused the highest AQP-2 protein and mRNA expression while progesterone caused the highest AQP-1, 5 and 7 protein and mRNA expression in uterus. AQP-1, 2, 5 and 7 protein were found to be distributed in the myometrium as well as in uterine luminal and glandular epithelia and endometrial blood vessels. In conclusion, the observed effects of estradiol, progesterone and genistein on uterine AQP-1, 2, 5 and 7 expression could help to explain the differences in the amount of fluid accumulated in the uterus under these different conditions. Copyright © 2016 Elsevier Inc. All rights reserved.

Influence of partial replacement of soya bean meal by faba beans or peas in heavy pigs diet on meat quality, residual anti-nutritional factors and phytoestrogen content.

PubMed

Gatta, Domenico; Russo, Claudia; Giuliotti, Lorella; Mannari, Claudio; Picciarelli, Piero; Lombardi, Lara; Giovannini, Luca; Ceccarelli, Nello; Mariotti, Lorenzo

2013-06-01

The study evaluated the partial substitution of soybean meal by faba beans (18%) or peas (20%) as additional protein sources in diets destined for typical Italian heavy pig production. It compared animal performances, meat quality, the presence of residual anti-nutritional factors (ANF) and phytoestrogens in plasma and meat and the possible effects on pig health, by evaluating oxidative, inflammatory and pro-atherogenic markers. The results showed that the productive performances, expressed as body weight and feed conversion ratio, of pigs fed with faba bean and pea diets were similar to those of pigs fed only the soybean meal. Meat quality of pigs fed with the three diets was similar in colour, water-holding capacity, tenderness and chemical composition. Despite the higher levels of phytoestrogen in the plasma of pigs fed only the soybean meal, phytoestrogen concentration in the muscle was equivalent to that of animals fed diets with faba beans, whereas pigs fed a diet with peas showed a lower concentration. Inflammation and pro-atherogenic parameters did not show significant differences among the three diets. Overall, the partial substitution of soybean meal by faba beans appears more interesting than with peas, particularly in relation to the higher amount of polyphenols in the diet and the highest concentration of phytoestrogens found in the plasma and muscle of animals, while the pyrimidine anti-nutritional compounds present in the diet did not appear to accumulate and had no effect on the growth performance of animals.

Effects of Fennel Essential Oil on Cisplatin-induced Nephrotoxicity in Ovariectomized Rats

PubMed Central

Mazaheri, Safoora; Nematbakhsh, Mehdi; Bahadorani, Mehrnoosh; Pezeshki, Zahra; Talebi, Ardeshir; Ghannadi, Ali-Reza; Ashrafi, Farzaneh

2013-01-01

Background: Cisplatin (cis-diamminedichloroplatinum II (CDDP)) is an effective drug in cancer therapy to treat solid tumors. However, the drug is accompanied by nephrotoxicity. Previous reports indicated that estrogen has no protective role against CDDP-induced nephrotoxicity, but the role of phytoestrogen as an estrogenic agent in plants is not determined yet. The major composition of fennel essential oil (FEO) is trans-anethole that has estrogenic activity; so, we used FEO as a phytoestrogen source against CDDP-induced nephrotoxicity. Materials and Methods: Fifty-four ovariectomized Wistar rats were divided into seven groups. Groups 1-3 received different doses of FEO (250, 500, and 1000 mg/kg/day, respectively) for 10 days. Group 4 received saline for 10 days plus single dose of CDDP (7 mg/kg, intraperitoneally (ip)) at day 3. Groups 5-7 received FEO similar to groups 1-3, respectively; plus a single dose of CDDP (7 mg/kg, ip) on day 3. On day 10, the animals were sacrificed for histopathological studies. Results: The serum levels of blood urea nitrogen (BUN) and creatinine (Cr), kidney tissue damage score (KTDS), and kidney weight (KW) and body weight changes in CDDP-treated groups increased significantly (P < 0.05). FEO did not reduce the levels of BUN and Cr, KTDS, and KW and body weight changes. Also, the serum and tissue levels of nitrite were not altered significantly by FEO. Conclusion: FEO, as a source of phytoestrogen, did not induce kidney damage. In addition, FEO similar to estrogen was not a nephroprotectant agent against CDDP-induced nephrotoxicity. PMID:24082507

The kinetic basis for age-associated changes in quercetin and genistein glucuronidation by rat liver microsomes

USDA-ARS?s Scientific Manuscript database

The dietary bioavailability of the isoflavone genistein is decreased in older rats compared to young adults. Since flavonoids are metabolized extensively by the UDP-glucuronosyltransferases (UGTs), we hypothesized that UGT flavonoid conjugating activity changes with age. The effect of age on flavono...

Epigenetic regulation of multiple tumor-related genes leads to suppression of breast tumorigenesis by dietary genistein.

PubMed

Li, Yuanyuan; Chen, Huaping; Hardy, Tabitha M; Tollefsbol, Trygve O

2013-01-01

Breast cancer is one of the most lethal diseases in women; however, the precise etiological factors are still not clear. Genistein (GE), a natural isoflavone found in soybean products, is believed to be a potent chemopreventive agent for breast cancer. One of the most important mechanisms for GE inhibition of breast cancer may involve its potential in impacting epigenetic processes allowing reversal of aberrant epigenetic events during breast tumorigenesis. To investigate epigenetic regulation for GE impedance of breast tumorigenesis, we monitored epigenetic alterations of several key tumor-related genes in an established breast cancer transformation system. Our results show that GE significantly inhibited cell growth in a dose-dependent manner in precancerous breast cells and breast cancer cells, whereas it exhibited little effect on normal human mammary epithelial cells. Furthermore, GE treatment increased expression of two crucial tumor suppressor genes, p21(WAF1) (p21) and p16(INK4a) (p16), although it decreased expression of two tumor promoting genes, BMI1 and c-MYC. GE treatment led to alterations of histone modifications in the promoters of p21 and p16 as well as the binding ability of the c-MYC-BMI1 complex to the p16 promoter contributing to GE-induced epigenetic activation of these tumor suppressor genes. In addition, an orally-fed GE diet prevented breast tumorigenesis and inhibited breast cancer development in breast cancer mice xenografts. Our results suggest that genistein may repress early breast tumorigenesis by epigenetic regulation of p21 and p16 by impacting histone modifications as well as the BMI1-c-MYC complex recruitment to the regulatory region in the promoters of these genes. These studies will facilitate more effective use of soybean product in breast cancer prevention and also help elucidate the mechanisms during the process of early breast tumorigenesis.

In utero and lactational exposure to low-dose genistein-vinclozolin mixture affects the development and growth factor mRNA expression of the submandibular salivary gland in immature female rats.

PubMed

Kouidhi, Wided; Desmetz, Catherine; Nahdi, Afef; Bergès, Raymond; Cravedi, Jean-Pierre; Auger, Jacques; El May, Michèle; Canivenc-Lavier, Marie Chantal

2012-06-01

It has been suggested that hormonally controlled submandibular salivary gland (SSG) development and secretions may be affected by endocrine disruptor compounds. We investigated the effects of oral gestation-lactation exposure to 1 mg/kg body weight daily dose of the estrogenic soy-isoflavone genistein and/or the anti-androgenic food contaminant vinclozolin in female rats. The SSGs of female offspring were collected at postnatal day 35 to study gland morphogenesis and mRNA expression of sex-hormone receptors and endocrine growth factors as sex-dependent biomarkers. Because of high expression in neonatal SSG, mRNA expression of transforming growth factor α was also studied. Exposure to genistein, vinclozolin, or a genistein+vinclozolin mixture resulted in significantly lower numbers of striated ducts linked to an increase in their area and lower acinar proliferation (Ki-67-positive nuclei). Exposure to the mixture had the highest significant effects, which were particularly associated with repression of epidermal growth factor, nerve growth factor, and transforming growth factor α expression. In conclusion, early exposure to low doses of genistein and vinclozolin can affect glandular structure and endocrine gene mRNA expression in prepubertal SSG in female rats, and the effects are potentialized by the genistein+vinclozolin mixture. Our study provides the first evidence that SSG are targeted by both estrogenic and anti-androgenic disrupting compounds and are more sensitive to mixtures.

Effects of genistein and swimming exercise on spatial memory and expression of microRNA 132, BDNF, and IGF-1 genes in the hippocampus of ovariectomized rats.

PubMed

Habibi, Parisa; Babri, Shirin; Ahmadiasl, Nasser; Yousefi, Hadi

2017-08-01

The aim of the present study was to investigate the effects of genistein and exercise on the spatial memory and expression of microRNA-132, BDNF, and IGF-1 in the hippocampus of ovariectomized rats. Sixty animals were divided into six groups of control, sham, ovariectomy (OVX), ovariectomized with 8 weeks of genistein administration (OVX.G), with 8 weeks of swimming training (OVX.E), and with 8 weeks of both of them (OVX.G.E). The effect of genistein and/or exercise was evaluated by measuring microRNA-132, BDNF, and IGF-1 expression levels in the hippocampus tissue. Grafts were analyzed using Real-time polymerase chain reaction for microRNA-132, BDNF, IGF-1, and spatial memory via a Morris water maze (MWM). Our findings showed that ovariectomy decreased the expression of microRNA-132, BDNF, and IGF-1 in the hippocampus ( P <0.05) in comparison with the sham group as well as performance in the water maze ( P <0.05). Also according to results ovariectomized groups that were treated with genistein/exercise or both of them showed significant difference in expression of microRNA-132, BDNF, and IGF-1 in the hippocampus ( P <0.05) and decreased latency in MWM ( P <0.05) compared with the OVX group but combination treatment was more effective in the OVX.G.E group in comparison with OVX.E and OVX.G groups. Overall our results emphasized that combination treatment with genistein and exercise could improve microRNA-132, BDNF, and IGF-1 expression in the hippocampus as well as the spatial memory of ovariectomized rats. These effects may have beneficial impacts on the menopausal period.

Assessment of the potential activity of major dietary compounds as selective estrogen receptor modulators in two distinct cell models for proliferation and differentiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lecomte, Sylvain; Lelong, Marie; Bourgine, Gaëlle

Estrogen receptors (ERs) α and β are distributed in most tissues of women and men. ERs are bound by estradiol (E2), a natural hormone, and mediate the pleiotropic and tissue-specific effects of E2, such as proliferation of breast epithelial cells or protection and differentiation of neuronal cells. Numerous environmental molecules, called endocrine disrupting compounds, also interact with ERs. Phytoestrogens belong to this large family and are considered potent therapeutic molecules that act through their selective estrogen receptor modulator (SERM) activity. Using breast cancer cell lines as a model of estrogen-dependent proliferation and a stably ER-expressing PC12 cell line as amore » model of neuronal differentiating cells, we studied the SERM activity of major dietary compounds, such as apigenin, liquiritigenin, daidzein, genistein, coumestrol, resveratrol and zearalenone. The ability of these compounds to induce ER-transactivation and breast cancer cell proliferation and enhance Nerve Growth Factor (NGF) -induced neuritogenesis was assessed. Surprisingly, although all compounds were able to activate the ER through an estrogen responsive element reporter gene, they showed differential activity toward proliferation or differentiation. Apigenin and resveratrol showed a partial or no proliferative effect on breast cancer cells but fully contributed to the neuritogenesis effect of NGF. However, daidzein and zearalenone showed full effects on cellular proliferation but did not induce cellular differentiation. In summary, our results suggest that the therapeutic potential of phytoestrogens can diverge depending on the molecule and the phenotype considered. Hence, apigenin and resveratrol might be used in the development of therapeutics for breast cancer and brain diseases. - Highlights: • SERM activity of dietary compounds on proliferation and differentiation is studied. • All the dietary compounds tested transactivate estrogen receptors. • Apigenin and

Design, characterization, and in vitro cellular inhibition and uptake of optimized genistein-loaded NLC for the prevention of posterior capsular opacification using response surface methodology.

PubMed

Zhang, Wenji; Li, Xuedong; Ye, Tiantian; Chen, Fen; Sun, Xiao; Kong, Jun; Yang, Xinggang; Pan, Weisan; Li, Sanming

2013-09-15

This study was to design an innovative nanostructured lipid carrier (NLC) for drug delivery of genistein applied after cataract surgery for the prevention of posterior capsular opacification. NLC loaded with genistein (GEN-NLC) was produced with Compritol 888 ATO, Gelucire 44/14 and Miglyol 812N, stabilized by Solutol(®) HS15 by melt emulsification method. A 2(4) central composite design of 4 independent variables was performed for optimization. Effects of drug concentration, Gelucire 44/14 concentration in total solid lipid, liquid lipid concentration, and surfactant concentration on the mean particle size, polydispersity index, zeta potential and encapsulation efficiency were investigated. Analysis of variance (ANOVA) statistical test was used to assess the optimization. The optimized GEN-NLC showed a homogeneous particle size of 90.16 nm (with PI=0.33) of negatively charged surface (-25.08 mv) and high encapsulation efficiency (91.14%). Particle morphology assessed by TEM revealed a spherical shape. DSC analyses confirmed that GEN was mostly entrapped in amorphous state. In vitro release experiments indicated a prolonged and controlled genistein release for 72 h. In vitro growth inhibition assay showed an effective growth inhibition of GEN-NLCs on human lens epithelial cells (HLECs). Preliminary cellular uptake test proved a enhanced penetration of genistein into HLECs when delivered in NLC. Copyright © 2013 Elsevier B.V. All rights reserved.

Genistein-mediated inhibition of mammary stromal adipocyte differentiation limits expansion of mammary stem/progenitor cells by paracrine signaling

USDA-ARS?s Scientific Manuscript database

Mammary adiposity may contribute to breast cancer development and progression by releasing cytokines and other inflammatory mediators that promote mammary epithelial proliferation. We evaluated the effects of soy isoflavone genistein (GEN) on the adipogenic differentiation of a SV40-immortalized mou...

In vitro effects of diethylstilbestrol, genistein, 4-tert-butylphenol, and 4-tert-octylphenol on steroidogenic activity of isolated immature rat ovarian follicles

DOE Office of Scientific and Technical Information (OSTI.GOV)

Myllymaeki, Sari; Haavisto, Tapio; Vainio, Minna

2005-04-01

Isolated rat ovarian follicles grow and produce steroid hormones in vitro and so provide a good model for studying the effects of hormonally active compounds on follicular steroidogenesis. We have evaluated the effects of diethylstilbestrol (DES), genistein (GEN) and two alkylphenols, 4-tert-butylphenol (BP) and 4-tert-octylphenol (OP) on the growth, survival, and steroid hormone and cAMP production by isolated 14-day-old rat (Sprague-Dawley) ovarian follicles. During a 5-day culture, FSH was obligatory for follicle growth and increased estradiol and testosterone secretion in a dose-dependent manner. DES (10{sup -6} M) caused the strongest decline in estradiol and testosterone levels but did not havemore » detectable effects on either cAMP production or aromatase enzyme activity. GEN caused a prominent decrease in cAMP and testosterone levels without significant changes in secreted estradiol. The latter, apparently, was due to a dose-dependent stimulation of aromatase enzyme activity in the presence of genistein. Both BP and OP decreased estradiol and testosterone secretion in a dose-dependent manner while no effect on aromatase activity was observed. OP, unlike BP, decreased forskolin-induced cAMP levels. Xenoestrogens at the used concentrations did not interfere with the growth and survival of the follicles. The results indicate that isolated ovarian follicles representing intact morphological and functional units offer a sensitive model system for elucidating the female-specific reproductive effects of environmental chemicals.« less

Regulation of estrogen receptor beta mRNA in the brain: opposite effects of 17beta-estradiol and the phytoestrogen, coumestrol.

PubMed

Patisaul, H B; Whitten, P L; Young, L J

1999-04-06

Estrogen receptor alpha (ERalpha) and estrogen receptor beta (ERbeta) are differentially distributed in the brain and likely mediate different estrogen-dependent processes. ERbeta is abundant in the bed nucleus of the stria terminalis, medial preoptic nucleus, paraventricular nucleus of the hypothalamus and the amygdala of the rat. In the paraventricular nucleus, which is devoid of ERalpha, ERbeta is colocalized with the neuropeptides, oxytocin and vasopressin, suggesting a potential functional role for ERbeta in the regulation of these peptides. We examined the regulation of ERbeta mRNA expression in the rat brain by 17beta-estradiol and the phytoestrogen, coumestrol. 17beta-Estradiol treatment decreased ERbeta mRNA in situ hybridization signal by 44.5% in the paraventricular nucleus of the hypothalamus (PVN), but had no effect in the bed nucleus of the stria terminalis (BnST) or the medial preoptic nucleus (MPA). In contrast, dietary exposure to coumestrol increased ERbeta mRNA signal by 47.5% in the PVN but had no effect in the BnST or the MPA. These data demonstrate that like ERalpha, ERbeta is down regulated by estrogen in a region specific manner in the rat brain. Furthermore, exposure to coumestrol may modulate ERbeta-dependent processes by acting as an anti-estrogen at ERbeta. This data contradicts results from cell transfection assays which suggest an estrogenic activity of coumestrol on ERbeta, indicating that the mode of action may be tissue specific, or that metabolism of dietary coumestrol may alter its effects. Because the highest concentrations of phytoestrogens are found in legumes, vegetables and grains, they are most prevalent in vegetarian and traditional Asian diets. Understanding the neuroendocrine effects of phytoestrogens is particularly important now that they are being marketed as a natural alternative to estrogen replacement therapy and sold in highly concentrated pills and powders. Copyright 1999 Elsevier Science B.V.

Tyrosine kinase inhibitors suppress prostaglandin F2alpha-induced phosphoinositide hydrolysis, Ca2+ elevation and contraction in iris sphincter smooth muscle.

PubMed

Yousufzai, S Y; Abdel-Latif, A A

1998-11-06

We investigated the effects of the protein tyrosine kinase inhibitors, genistein, tyrphostin 47, and herbimycin on prostaglandin F2alpha- and carbachol-induced inositol-1,4,5-trisphosphate (IP3) production, [Ca2+]i mobilization and contraction in cat iris sphincter smooth muscle. Prostaglandin F2alpha and carbachol induced contraction in a concentration-dependent manner with EC50 values of 0.92 x 10(-9) and 1.75 x 10(-8) M, respectively. The protein tyrosine kinase inhibitors blocked the stimulatory effects of prostaglandin F2alpha, but not those evoked by carbachol, on IP3 accumulation, [Ca2+]i mobilization and contraction, suggesting involvement of protein tyrosine kinase activity in the physiological actions of the prostaglandin. Daidzein and tyrphostin A, inactive negative control compounds for genistein and tyrphostin 47, respectively, were without effect. Latanoprost, a prostaglandin F2alpha analog used as an antiglaucoma drug, induced contraction and this effect was blocked by genistein. Genistein (10 microM) markedly reduced (by 67%) prostaglandin F2alpha-stimulated increase in [Ca2+]i but had little effect on that of carbachol in cat iris sphincter smooth muscle cells. Vanadate, a potent inhibitor of protein tyrosine phosphatase, induced a slow gradual muscle contraction in a concentration-dependent manner with an EC50 of 82 microM and increased IP3 generation in a concentration-dependent manner with an EC50 of 90 microM. The effects of vanadate were abolished by genistein (10 microM). Wortmannin, a myosin light chain kinase inhibitor, reduced prostaglandin F2alpha- and carbachol-induced contraction, suggesting that the involvement of protein tyrosine kinase activity may lie upstream of the increases in [Ca2+]i evoked by prostaglandin F2alpha. Further studies aimed at elucidating the role of protein tyrosine kinase activity in the coupling mechanism between prostaglandin F2alpha receptor activation and increases in intracellular Ca2+ mobilization and

Do soy isoflavones lower cholesterol, inhibit atherosclerosis, and play a role in cancer prevention?

PubMed

Arliss, Rebecca M; Biermann, Carol A

2002-10-01

This article is designed to help nursing professionals advise patients about the role of soy in the prevention and treatment of heart disease, breast cancer, and prostate cancer. Soy protein lowers total cholesterol, low-density lipoprotein cholesterol, and triglycerides in humans and inhibits atherosclerosis in animals. In cell culture studies and animal research, the soy isoflavone genistein offers protection from breast cancer and prostate cancer because it prevents cancer initiation, slows promotion, and impedes cancer progression. This article synthesizes the current research concerning soy phytoestrogens and the prevention and treatment of heart disease, breast cancer, and prostate cancer. Nursing professionals may use this information when counseling patients.

Soy promotes juvenile granulosa cell tumor development in mice and in the human granulosa cell tumor-derived COV434 cell line.

PubMed

Mansouri-Attia, Nadéra; James, Rebecca; Ligon, Alysse; Li, Xiaohui; Pangas, Stephanie A

2014-10-01

Soy attracts attention for its health benefits, such as lowering cholesterol or preventing breast and colon cancer. Soybeans contain isoflavones, which act as phytoestrogens. Even though isoflavones have beneficial health effects, a role for isoflavones in the initiation and progression of diseases including cancer is becoming increasingly recognized. While data from rodent studies suggest that neonatal exposure to genistein (the predominant isoflavone in soy) disrupts normal reproductive function, its role in ovarian cancers, particularly granulosa cell tumors (GCT), is largely unknown. Our study aimed to define the contribution of a soy diet in GCT development using a genetically modified mouse model for juvenile GCTs (JGCT; Smad1 Smad5 conditional double knockout mice) as well as a human JGCT cell line (COV434). While dietary soy cannot initiate JGCT development in mice, we show that it has dramatic effects on GCT growth and tumor progression compared to a soy-free diet. Loss of Smad1 and Smad5 alters estrogen receptor alpha (Esr1) expression in granulosa cells, perhaps sensitizing the cells to the effects of genistein. In addition, we found that genistein modulates estrogen receptor expression in the human JGCT cell line and positively promotes cell growth in part by suppressing caspase-dependent apoptosis. Combined, our work suggests that dietary soy consumption has deleterious effects on GCT development. © 2014 by the Society for the Study of Reproduction, Inc.

Soy Promotes Juvenile Granulosa Cell Tumor Development in Mice and in the Human Granulosa Cell Tumor-Derived COV434 Cell Line1

PubMed Central

Mansouri-Attia, Nadéra; James, Rebecca; Ligon, Alysse; Li, Xiaohui; Pangas, Stephanie A.

2014-01-01

ABSTRACT Soy attracts attention for its health benefits, such as lowering cholesterol or preventing breast and colon cancer. Soybeans contain isoflavones, which act as phytoestrogens. Even though isoflavones have beneficial health effects, a role for isoflavones in the initiation and progression of diseases including cancer is becoming increasingly recognized. While data from rodent studies suggest that neonatal exposure to genistein (the predominant isoflavone in soy) disrupts normal reproductive function, its role in ovarian cancers, particularly granulosa cell tumors (GCT), is largely unknown. Our study aimed to define the contribution of a soy diet in GCT development using a genetically modified mouse model for juvenile GCTs (JGCT; Smad1 Smad5 conditional double knockout mice) as well as a human JGCT cell line (COV434). While dietary soy cannot initiate JGCT development in mice, we show that it has dramatic effects on GCT growth and tumor progression compared to a soy-free diet. Loss of Smad1 and Smad5 alters estrogen receptor alpha (Esr1) expression in granulosa cells, perhaps sensitizing the cells to the effects of genistein. In addition, we found that genistein modulates estrogen receptor expression in the human JGCT cell line and positively promotes cell growth in part by suppressing caspase-dependent apoptosis. Combined, our work suggests that dietary soy consumption has deleterious effects on GCT development. PMID:25165122

Suppression of dendritic cells' maturation and functions by daidzein, a phytoestrogen

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yum, Min Kyu; Jung, Mi Young; Cho, Daeho

2011-12-15

Isoflavones are ubiquitous compounds in foods and in the environment in general. Daidzein and genistein, the best known of isoflavones, are structurally similar to 17{beta}-estradiol and known to exert estrogenic effects. They also evidence a broad variety of biological properties, including antioxidant, anti-carcinogenic, anti-atherogenic and anti-osteoporotic activities. Previously, daidzein was reported to increase the phagocytic activity of peritoneal macrophages and splenocyte proliferation, and to inhibit nitric oxide (NO) production in macrophages. However, its potential impacts on immune response in dendritic cells (DCs), antigen-presenting cells that link innate and adaptive immunity, have yet to be clearly elucidated. In this study, wemore » evaluated the effects of isoflavones on the maturation and activation of DCs. Isoflavones (formononetin, daidzein, equol, biochanin A, genistein) were found to differentially affect the expression of CD86, a costimulatory molecule, on lipopolysaccharide (LPS)-stimulated DCs. In particular, daidzein significantly and dose-dependently inhibited the expression levels of maturation-associated cell surface markers including CD40, costimulatory molecules (CD80, CD86), and major histocompatibility complex class II (I-A{sup b}) molecule on LPS-stimulated DCs. Daidzein also suppressed pro-inflammatory cytokine production such as IL-12p40, IL-6 and TNF-{alpha}, whereas it didn't affect IL-10 and IL-1{beta} expression. Furthermore, daidzein enhanced endocytosis and inhibited the allo-stimulatory ability of LPS-stimulated DCs on T cells, indicating that daidzein treatment can inhibit the functional maturation of DCs. These results demonstrate that daidzein may exhibit immunosuppressive activity by inhibiting the maturation and activation of DCs. -- Highlights: Black-Right-Pointing-Pointer Daidzein inhibited expression of maturation-associated cell surface markers in DCs. Black-Right-Pointing-Pointer Daidzein suppressed

Rotenone-induced death of RGC-5 cells is caspase independent, involves the JNK and p38 pathways and is attenuated by specific green tea flavonoids.

PubMed

Kamalden, T A; Ji, D; Osborne, N N

2012-05-01

The aim of the present studies was to characterise cell death following inhibition of mitochondrial complex I with rotenone in a transformed cell line (RGC-5 cells) and to examine the neuroprotective properties of the flavonoids genistein, epigallocatechin gallate (EGCG), epicatechin (EC) and baicalin. Rotenone-induced cell death of RGC-5 cells results in a generation of reactive oxygen species, a breakdown of DNA, the translocation of membrane phosphatidylserine, an up-regulation of haemoxygenase-1 and is unaffected by necrostatin-1 (inhibitor of necroptosis), z-VAD-fmk (pan caspase inhibitor) or NU1025 (PARP inhibitor) but attenuated with SP600125 (JNK inhibitor). Rotenone-induced toxicity of RGC-5 cells also caused an activation of mitogen-activated kinases indicated by an up-regulation and translocation into mitochondria of p-c-Jun, pJNK and pp38. Exposure of RGC-5 cells to rotenone does not affect apoptosis inducing factor or significantly stimulate caspase-3 activity. EGCG and EC both significantly blunt rotenone toxicity of RGC-5 cells at concentrations of 50 μM while genistein and baicalin were without effect. Significantly, genistein is approximately 20 times less efficacious than EGCG (IC(50) 2.5 μM) and EC (IC(50) 1.5 μM) at inhibiting sodium nitroprusside-induced lipid peroxidation. These studies show that rotenone toxicity of RGC-5 cells is neither necroptosis nor caspase-dependent apoptosis but involves the activation of mitogen-activated kinases and is inhibited by a JNK inhibitor, EGCG and EC. Genistein attenuates lipid peroxidation less efficaciously than EC and EGCG and does not affect rotenone toxicity of RGC-5 cells.

[Isoflavone genistein-8-c-glycoside prevents the oxidative damages in structure and function of rat liver microsomal membranes].

PubMed

Zavodnik, L B

2003-01-01

Bioflavonoids (polyhydroxyphenols) are ubiquitous components of plants, fruits and vegetables; these compounds are efficient scavengers of free oxygen radicals and peroxides. The aim of this study was to investigate the antioxidant and radioprotective effects of genistein-8-C-glicoside (G8CG), an isoflavone, isolated from the flowers of Lipinus luteusl L. G8CG prevents dose-dependently the destruction of the cytochrome P-450 and its conversion to an inactive form cytochrome P-420, inhibits membrane lipid peroxidation and membrane SH-group oxidation in isolated rat liver microsomal membranes under tert-butylhydroperoxide-induced oxidative stress. Single whole-body gamma-irradiation (1 Gy) of rats results in blood plasma and liver microsomal membrane lipid peroxidation, impairments of microsomal membrane structure and function. Rat treatment with G8CG (75 mg/kg) developed the clear protective effect, stabilized membrane structure and improved the parameters of the monooxygenase function. We can conclude that G8CG can be used as antioxidant and radioprotective agent.

Comparison of cystic fibrosis transmembrane conductance regulator (CFTR) and ciliary beat frequency activation by the CFTR Modulators Genistein, VRT-532, and UCCF-152 in primary sinonasal epithelial cultures.

PubMed

Conger, Bryant T; Zhang, Shaoyan; Skinner, Daniel; Hicks, Stephen B; Sorscher, Eric J; Rowe, Steven M; Woodworth, Bradford A

2013-08-01

Pharmacologic activation of mucociliary clearance (MCC) represents an emerging therapeutic strategy for patients with chronic rhinosinusitis, even in the absence of congenital mutations of the CFTR gene. Drug discovery efforts have identified small molecules that activate the cystic fibrosis transmembrane conductance regulator (CFTR), including potentiators under development for treatment of cystic fibrosis. To evaluate the properties of CFTR modulators and their effects on ciliary beat frequency (CBF) in human sinonasal epithelium (HSNE). Primary HSNE cultures (wild type and F508del/F508del) were used to compare stimulation of CFTR-mediated Cl- conductance and CBF by the CFTR modulators genistein, VRT-532, and UCCF-152. Increase in CFTR-dependent anion transport and CBF. HSNE cultures were analyzed using pharmacologic manipulation of ion transport (change in short-circuit current [∆ISC]) and high-speed digital imaging (CBF). Activation of CFTR-dependent anion transport was significantly different among agonists (P < .001), with genistein exerting the greatest effect (mean [SD] ∆ISC, genistein, 23.1 [1.8] μA/cm2² > VRT-532, 8.1 [1.0] μA/cm² > UCCF-152, 3.4 [1.4] μA/cm² > control, 0.7 [0.2] μA/cm²; Tukey-Kramer P < .05) in the absence of forskolin. Genistein and UCCF-152 augmented CBF (under submerged conditions) significantly better (Tukey-Kramer P < .05) than cells treated with VRT-532 or dimethyl sulfoxide vehicle control (mean [SD] fold change over baseline, genistein, 1.63 [0.06]; UCCF-152, 1.56 [0.06]; VRT-532, 1.38 [0.08]; control, 1.27 [0.02]). Activation of CBF was blunted in F508del/F508del HSNE cultures. The degree of CBF stimulation was not dependent on the magnitude of Cl- secretion, suggesting that different mechanisms of action may underlie MCC activation by these small molecule potentiators. Agents that activate both CFTR-dependent ISC and CBF are particularly attractive as therapeutics because they may address 2

Biochanin-A antagonizes the interleukin-1β-induced catabolic inflammation through the modulation of NFκB cellular signaling in primary rat chondrocytes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Oh, Ji-Su; Cho, In-A; Kang, Kyeong-Rok

Biochanin-A, a phytoestrogen derived from herbal plants, protected from the IL-1β-induced loss of proteoglycans through the suppression of matrix degrading enzymes such as matrix metalloproteinase (MMP)-13, MMP-3, MMP-1, and ADAMTS-5 in primary rat chondrocytes and the knee articular cartilage. It also suppressed the expression of IL-1β-induced catabolic factors such as nitric oxide synthase 2, cyclooxygenase-2, prostaglandin E{sub 2}, and inflammatory cytokines. Furthermore, biochanin-A suppressed the IL-1β-induced phosphorylation of NFκB, and inhibited its nuclear translocation in primary rat chondrocytes. These results indicate that biochanin-A antagonizes the IL-1β-induced catabolic effects through its anti-inflammatory activity that involves the modulation of NFκB signaling. -more » Highlights: • Biochanin-A is a phytoestrogen derived from medicinal plants. • It suppressed the IL-1β-induced matrix degrading enzymes and catabolic factors. • It inhibited IL-1β-induced proteoglycan loss in chondrocytes and cartilage tissues. • Its anti-catabolic effects were mediated by modulation of NFκB signaling. • It may be used as a potential anti-catabolic biomaterial for osteoarthritis.« less

Plasma isoflavones in Malaysian men according to vegetarianism and by age.

PubMed

Hod, Rafidah; Kouidhi, Wided; Ali Mohd, Mustafa; Husain, Ruby

2016-01-01

Epidemiological studies indicate lower prevalences of breast and prostate cancers and cardiovascular disease in Southeast Asia where vegetarianism is popular and diets are traditionally high in phytoestrogens. This study assessed plasma isoflavones in vegetarian and non-vegetarian Malaysian men according to age. Daidzein, genistein, equol (a daidzein metabolite), formononetin, biochanin A, estrone, estradiol and testosterone were measured by validated liquid chromatography tandem mass spectrometry (LCMSMS). Plasma isoflavone and sex hormone concentrations were measured in 225 subjects according to age (18-34, 35-44 and 45-67 years old). In all age groups, vegetarians had a higher concentration of circulating isoflavones compared with non-vegetarians especially in the 45-67 year age group where all isoflavones except equol, were significantly higher in vegetarians compared with omnivores. By contrast, the 18-34 year group had a significantly higher concentration of daidzein in vegetarians and significantly higher testosterone and estrone concentrations compared with non-vegetarians. In this age group there were weak correlations between estrone, estradiol and testosterone with some of the isoflavones. This human study provides the first Malaysian data for the phytoestrogen status of vegetarian and nonvegetarian men.

Ginsenoside Rb1 protects against 6-hydroxydopamine-induced oxidative stress by increasing heme oxygenase-1 expression through an estrogen receptor-related PI3K/Akt/Nrf2-dependent pathway in human dopaminergic cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hwang, Yong Pil; College of Pharmacy, Chosun University, Gwangju; Jeong, Hye Gwang, E-mail: hgjeong@cnu.ac.k

Phytoestrogens are polyphenolic non-steroidal plant compounds with estrogen-like biological activity. Ginseng, the root of Panax ginseng C.A. Meyer (Araliaceae), is a popular traditional herbal medicine. Ginsenoside Rb1 (Rb1), an active component commonly found in ginseng root, is a phytoestrogen that exerts estrogen-like activity. In this study, we demonstrate that the phytoestrogen Rb1 inhibits 6-hydroxydopamine (6-OHDA)-induced oxidative injury via an ER-dependent Gbeta1/PI3K/Akt and heme oxygenase-1 (HO-1) pathway. Pretreatment of SH-SY5Y cells with Rb1 significantly reduced 6-OHDA-induced caspase-3 activation and subsequent cell death. Rb1 also up-regulated HO-1 expression, which conferred cytoprotection against 6-OHDA-induced oxidative injury. Moreover, Rb1 induced both Nrf2 nuclear translocation,more » which is upstream of HO-1 expression and PI3K activation, a pathway that is involved in induced Nrf2 nuclear translocation, HO-1 expression and cytoprotection. Also, Rb1-mediated increases in PI3K activation and HO-1 induction were reversed by co-treatment with ICI 182,780 and pertussis toxin. Taken together, these results suggest that Rb1 augments the cellular antioxidant defenses through ER-dependent HO-1 induction via the Gbeta1/PI3K/Akt-Nrf2 signaling pathway, thereby protecting cells from oxidative stress. Thus our study indicates that Rb1 has a partial cytoprotective role in dopaminergic cell culture systems.« less

Data set on the characterization of the phytoestrogenic extract and isolated compounds of the roots of Inula racemosa Hook F (Asteraceae).

PubMed

Kalachaveedu, Mangathayaru; Raghavan, Divya; Telapolu, Srivani; Kuruvilla, Sarah; Kedike, Balakrishna

2018-04-01

The data presented in this article are related to the research article entitled ' Phyto estrogenic effect of Inula racemosa Hook. f - A cardio protective root drug in traditional medicine, (Mangathayaru K, Divya R, Srivani T et al., 2018) [1]. It describes the characterization details of the root extract and the compounds isolated from them that were shown to be phytoestrogenic in vivo and in vitro respectively.

Short-term effects of genistein on gamete quality, steroidogenesis and histological changes in gonads in gibel carp, Carassius auratus gibelio

USDA-ARS?s Scientific Manuscript database

The objective of the present investigation was to determine effects of genistein or 17ß-estradiol (E2) on reproductive physiology in gibel carp, Carassius auratus gibelio, during prespawning phase. Maturing gibel carp of both sexes received intraperitoneal injections of E2 (10 µg/g body weight), one...

[Effects of genistein on contractility of isolated right ventricular muscles in guinea pig].

PubMed

Wu, Jin-xia; Li, Hong-fang; Liu, Chong-bin; Tian, Zhi-feng

2008-11-01

To study the effect of genistein (GEN) on contractility of isolated right ventricular muscles in guinea pig and its mechanisms. Isolated guinea pig ventricular muscles were suspended in organ baths containing K-H solution.After an equilibration period, the effect of GEN on contraction of myocardium was observed. GEN and isoprenaline hydrochloride had the positive inotropic effects on contractity of myocardium. Meanwhile, the effect of GEN (1-100 micromol x L(-1)) was in dose-dependent manner. Propranolol (1 micromol x L(-1)) and verapamil hydrochloride (0.5 micromol x L(-1)) attenuated the positive inotropic effect of isoprenaline hydrochloride (1 micromol x L(-1)), but did not change the effect of GEN (50 micromol x L(-1)). Further more, the enhancement of the contraction induced by elevation of extracellular Ca2+ concentration in ventricular muscles had no change after pretreatment with GEN (1.10 micromol x L(-1)). In addition,the positive inotropic effect of GEN was inhibited partially by tamoxifen (1 micromol x L(-1)) and SQ22536 (1 micromol x L(-1)), also, could be attenuated by bpV (1 micromol x L(-1)). GEN has the positive inotropic effect on guinea pig ventricular muscles, which is not related to the activation of beta adrenoceptor, Ca2+ channel on cell membrane,but may involve in cAMP of intracellular signal transduction and tyrosine kinase pathway.

A precisely substituted benzopyran targets androgen refractory prostate cancer cells through selective modulation of estrogen receptors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kumar, Rajeev; Verma, Vikas; Sharma, Vikas

Dietary consumption of phytoestrogens like genistein has been linked with lower incidence of prostate cancer. The estradiol-like benzopyran core of genistein confers estrogen receptor-β (ER-β) selectivity that imparts weak anti-proliferative activity against prostate cancer cells. DL-2-[4-(2-piperidinoethoxy)phenyl]-3-phenyl-2H-1-benzopyran (BP), a SERM designed with benzopyran core, targeted androgen independent prostate cancer (PC-3) cells 14-times more potently than genistein, ~ 25% more efficiently than tamoxifen and 6.5-times more actively than ICI-182780, without forfeiting significant specificity in comparison to genistein. BP increased apoptosis (annexin-V and TUNEL labeling), arrested cell cycle, and significantly increased caspase-3 activity along with mRNA expressions of estrogen receptor (ER)-β and FasLmore » (qPCR) in PC-3 cells. In classical ERE-luc reporter assay BP behaved as a potent ER-α antagonist and ER-β agonist. Accordingly, it decreased expression of ER-α target PS2 (P < 0.01) and increased expression of ER-β target TNF-α (P < 0.05) genes in PC-3. ER-β deficient PC-3 (siRNA-transfected) was resistant to apoptotic and anti-proliferative actions of SERMs, including stimulation of FasL expression by BP. BP significantly inhibited phosphorylation of Akt and ERK-1/2, JNK and p38 in PC-3 (immunoblotting), and thus adopted a multi-pathway mechanism to exert a more potent anti-proliferative activity against prostate cancer cells than natural and synthetic SERMs. Its precise ER-subtype specific activity presents a unique lead structure for further optimization. - Highlights: • BP with benzopyran core of genistein was identified for ER-β selective action. • BP was 14-times more potent than genistien in targeting prostate cancer cells. • It behaved as a potent ER-β agonist and ER-α antagonist in gene reporter assays. • BP's anti-proliferative action was inhibited significantly in ER-β deficient cells. • BP — a unique lead

Compounds from Cynomorium songaricum with Estrogenic and Androgenic Activities Suppress the Oestrogen/Androgen-Induced BPH Process.

PubMed

Wang, Xueni; Tao, Rui; Yang, Jing; Miao, Lin; Wang, Yu; Munyangaju, Jose Edouard; Wichai, Nuttapong; Wang, Hong; Zhu, Yan; Liu, Erwei; Chang, Yanxu; Gao, Xiumei

2017-01-01

To investigate the phytoestrogenic and phytoandrogenic activities of compounds isolated from CS and uncover the role of CS in prevention of oestrogen/androgen-induced BPH. Cells were treated with CS compounds, and immunofluorescence assay was performed to detect the nuclear translocation of ER α or AR in MCF-7 or LNCaP cells; luciferase reporter assay was performed to detect ERs or AR transcriptional activity in HeLa or AD293 cells; MTT assay was performed to detect the cell proliferation of MCF-7 or LNCaP cells. Oestrogen/androgen-induced BPH model was established in rat and the anti-BPH, anti-estrogenic, and anti-androgenic activities of CS in vivo were further investigated. The nuclear translocation of ER α was stimulated by nine CS compounds, three of which also stimulated AR translocation. The transcriptional activities of ER α and ER β were induced by five compounds, within which only ECG induced AR transcriptional activity as well. Besides, ECG stimulated the proliferation of both MCF-7 cells and LNCaP cells. CS extract suppressed oestrogen/androgen-induced BPH progress in vivo by downregulation of E2 and T level in serum and alteration of the expressions of ER α , ER β , and AR in the prostate. Our data demonstrates that compounds from CS exhibit phytoestrogenic and phytoandrogenic activities, which may contribute to inhibiting the oestrogen/androgen-induced BPH development.

Metabolic Engineering of Isoflavonoid Biosynthesis in Alfalfa1[w

PubMed Central

Deavours, Bettina E.; Dixon, Richard A.

2005-01-01

The potential health benefits of dietary isoflavones have generated considerable interest in engineering the synthesis of these phytoestrogens into plants. Genistein glucoside production (up to 50 nmol g−1 fresh weight) was engineered in alfalfa (Medicago sativa) leaves by constitutive expression of isoflavone synthase from Medicago truncatula (MtIFS1). Glucosides of biochanin A (4′-O-methylgenistein) and pratensein (3′-hydroxybiochanin A) also accumulated. Although MtIFS1 was highly expressed in all organs examined, genistein accumulation was limited to leaves. MtIFS1-expressing lines accumulated several additional isoflavones, including formononetin and daidzein, in response to UV-B or Phoma medicaginis, whereas the chalcone and flavanone precursors of these compounds accumulated in control lines. Enhanced accumulation of the phytoalexin medicarpin was observed in P. medicaginis-infected leaves of MtIFS1-expressing plants. Microarray profiling indicated that MtIFS1 expression does not significantly alter global gene expression in the leaves. Our results highlight some of the challenges associated with metabolic engineering of plant natural products, including tissue-specific accumulation, potential for further modification by endogenous enzyme activities (hydroxylation, methylation, and glycosylation), and the differential response of engineered plants to environmental factors. PMID:16006598

Comparison of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) and Ciliary Beat Frequency Activation by the CFTR Modulators Genistein, VRT-532, and UCCF-152 in Primary Sinonasal Epithelial Cultures

PubMed Central

Conger, Bryant T.; Zhang, Shaoyan; Skinner, Daniel; Hicks, Stephen B.; Sorscher, Eric J.; Rowe, Steven M.; Woodworth, Bradford A.

2014-01-01

IMPORTANCE Pharmacologic activation of mucociliary clearance (MCC) represents an emerging therapeutic strategy for patients with chronic rhinosinusitis, even in the absence of congenital mutations of the CFTR gene. Drug discovery efforts have identified small molecules that activate the cystic fibrosis transmembrane conductance regulator (CFTR), including potentiators under development for treatment of cystic fibrosis. OBJECTIVE To evaluate the properties of CFTR modulators and their effects on ciliary beat frequency (CBF) in human sinonasal epithelium (HSNE). DESIGN Primary HSNE cultures (wild type and F508del/F508del) were used to compare stimulation of CFTR-mediated Cl− conductance and CBF by the CFTR modulators genistein, VRT-532, and UCCF-152. MAIN OUTCOMES AND MEASURES Increase in CFTR-dependent anion transport and CBF. RESULTS HSNE cultures were analyzed using pharmacologic manipulation of ion transport (change in short-circuit current [ΔISC]) and high-speed digital imaging (CBF). Activation of CFTR-dependent anion transport was significantly different among agonists (P < .001), with genistein exerting the greatest effect (mean [SD] ΔISC, genistein, 23.1 [1.8] µA/cm2 > VRT-532, 8.1 [1.0] µA/cm2 > UCCF-152, 3.4 [1.4] µA/cm2 > control, 0.7 [0.2] µA/cm2; Tukey-Kramer P < .05) in the absence of forskolin. Genistein and UCCF-152 augmented CBF (under submerged conditions) significantly better (Tukey-Kramer P < .05) than cells treated with VRT-532 or dimethyl sulfoxide vehicle control (mean [SD] fold change over baseline, genistein, 1.63 [0.06]; UCCF-152, 1.56 [0.06]; VRT-532, 1.38 [0.08]; control, 1.27 [0.02]). Activation of CBF was blunted in F508del/F508del HSNE cultures. CONCLUSIONS AND RELEVANCE The degree of CBF stimulation was not dependent on the magnitude of Cl− secretion, suggesting that different mechanisms of action may underlie MCC activation by these small molecule potentiators. Agents that activate both CFTR-dependent ISC and CBF are

Phytoestrogenic effect of Inula racemosa Hook f - A cardioprotective root drug in traditional medicine.

PubMed

Kalachaveedu, Mangathayaru; Raghavan, Divya; Telapolu, Srivani; Kuruvilla, Sarah; Kedike, Balakrishna

2018-01-10

.05) in sub G0-G1 cells by SG at 200 and 400µM in cell cycle analysis and there has been an induction of pS2 by IALT and SG in the ER regulated MCF-7 cells. Demonstration of classical morphological changes induced by estrogen stimulation mediated by IrA in vivo at both the tested doses, isolation of the antioxidant SG from IrA and its dose dependent growth inhibitory effect on estrogen sensitive MCF-7 cells through apoptotic induction and an up regulation of pS2 are suggestive of an anti-estrogenic effect through estrogen receptor binding affinity, typical of phytoestrogens that bind to ER but do not elicit a full estrogenic response. The observed estrogenic effect of IrA suggests a multi mechanistic molecular action involving antioxidant as well as redox signalling pathways acting in consonance with their anti-estrogenic effects owing to the weak estrogen like competitive receptor binding of SG. Copyright © 2017 Elsevier B.V. All rights reserved.

A new class of hybrid anticancer agents inspired by the synergistic effects of curcumin and genistein: Design, synthesis, and anti-proliferative evaluation.

PubMed

Chen, Qiao-Hong; Yu, Kevin; Zhang, Xiaojie; Chen, Guanglin; Hoover, Andrew; Leon, Francisco; Wang, Rubing; Subrahmanyam, Nithya; Addo Mekuria, Ermias; Harinantenaina Rakotondraibe, Liva

2015-10-15

Inspired by the synergistic effects of dietary natural products with different scaffolds on the inhibition of cancer cell proliferation, incorporation of central (1E,4E)-1,4-penta-dien-3-one linker (an optimal substitute for the central metabolically unstable diketone linker of curcumin), 1-alkyl-1H-imidazol-2-yl (a promising bioisostere of terminal aryl group in curcumin), and chromone (the common pharmacophore in genistein and quercetin) into one chemical entity resulted in ten new hybrid molecules, 3-((1E,4E)-5-(1-alkyl-1H-imidazol-2-yl)-3-oxopenta-1,4-dien-1-yl)-4H-chromen-4-ones. They were synthesized through a three-step transformation using acid-catalyzed aldol condensation as key step. The WST-1 cell proliferation assay showed that they have greater anti-proliferative potency than curcumin, quercetin, and genistein on both androgen-dependent and androgen-independent human prostate cancer cells. Published by Elsevier Ltd.

NTP-CERHR monograph on Soy Infant Formula.

PubMed

2010-09-01

Soy infant formula contains soy protein isolates and is fed to infants as a supplement to or replacement for human milk or cow milk. Soy protein isolates contains estrogenic isoflavones ("phytoestrogens") that occur naturally in some legumes, especially soybeans. Phytoestrogens are non-steroidal, estrogenic compounds. In plants, nearly all phytoestrogens are bound to sugar molecules and these phytoestrogen-sugar complexes are not generally considered hormonally active. Phytoestrogens are found in many food products in addition to soy infant formula, especially soy-based foods such as tofu, soy milk, and in some over-the-counter dietary supplements. Soy infant formula was selected for evaluation by the National Toxicology Program (NTP) because of the: (1)availability of large number of developmental toxicity studies in laboratory animals exposed to the isoflavones found in soy infant formula (namely, genistein) or other soy products, as well as a number of studies on human infants fed soy infant formula, (2)the availability of information on exposures in infants fed soy infant formula, and (3)public concern for effects on infant or child development. The NTP evaluation was conducted through its Center for the Evaluation of Risks to Human Reproduction (CERHR) and completed in September 2010. The results of this soy infant formula evaluation are published in an NTP Monograph. This document contains the NTP Brief on Soy Infant Formula, which presents NTP's opinion on the potential for exposure to soy infant formula to cause adverse developmental effects in humans. The NTP Monograph also contains an expert panel report prepared to assist the NTP in reaching conclusions on soy infant formula. The NTP concluded there is minimal concern for adverse effects on development in infants who consume soy infant formula. This level of concern represents a "2" on the five-level scale of concern used by the NTP that ranges from negligible concern ("1") to serious concern ("5"). This

Genistein aglycone effect on bone loss is not enhanced by supplemental calcium and vitamin D3: a dose ranging experimental study.

PubMed

Bitto, A; Marini, H; Burnett, B P; Polito, F; Levy, R M; Irrera, N; Minutoli, L; Adamo, E B; Squadrito, F; Altavilla, D

2011-07-15

Genistein aglycone (GEN) has a favorable effect on bone loss. We investigated the effects of GEN alone or in combination with supplemental calcium and vitamin D(3) in an animal model of bone loss to evaluate if there was additional benefit. Ovariectomized (OVX) and SHAM-OVX rats were used. OVX were divided into 12 groups and randomized to receive: GEN at 27, 54, 200, 500 or 1000 mg (human equivalent dose (HED)/day/ip injection alone or with calcium carbonate (Ca) (360 mg/kg/day/gavages) and vitamin D(3) (D(3)) (50 IU/kg/day/gavages) or Ca/D(3) without GEN or untreated for 6 weeks. SHAM-OVX were randomized into 7 groups and treated with: Ca and D(3) alone or in combination with GEN (same doses as OVX), or left untreated. Bone mineral density (BMD), bone-alkaline phosphatase (b-ALP), collagen C-telopeptides (CTX), osteoprotegerin (OPG) and soluble receptor activator of NFκB ligand (sRANKL) were assessed. Femurs were excised and tested for breaking strength and histology. Uterine weight was analyzed to assess GEN's estrogenic effects on the SHAM-OVX. The most effective dose of GEN, independent of Ca/D(3) supplementation, was 54 mg/day. Higher doses yielded no further improvement in bone biomarkers, histology or strength. Only 1000 mg/day HED of genistein produced statistically significant changes in uterine weight of the SHAM-OVX. This study suggests that 54 mg/day of GEN is the threshold dose for efficacy. In addition, supplemental calcium and vitamin D(3), beyond normal dietary intake do not enhance the effects of genistein on improving measures of bone loss. This observation has implications regarding the use of calcium and vitamin D(3) supplementation. Copyright © 2011 Elsevier GmbH. All rights reserved.

Distribution of six anticancer drugs and a variety of other pharmaceuticals, and their sorption onto sediments, in an urban Japanese river.

PubMed

Azuma, Takashi; Arima, Natsumi; Tsukada, Ai; Hirami, Satoru; Matsuoka, Rie; Moriwake, Ryogo; Ishiuchi, Hirotaka; Inoyama, Tomomi; Teranishi, Yusuke; Yamaoka, Misato; Ishida, Mao; Hisamatsu, Kanae; Yunoki, Ayami; Mino, Yoshiki

2017-08-01

The distributions of 31 pharmaceuticals grouped into nine therapeutic classes, including six anticancer drugs, were investigated in the waters and sediments of an urban river in Japan. The coefficients of sorption (logK d ) to the river sediments were also determined from the results of a field survey and laboratory-scale experiment. Three anticancer drugs-bicalutamide, doxifluridine, and tamoxifen-were detected in the river sediments at maximum concentrations of 391, 392, and 250 ng/kg, respectively. In addition, the transformation products of psychotropic carbamazepine (2-hydroxy carbamazepine, acridine, and acridone) were detected in the range of 108 ng/kg (2-hydroxy carbamazepine) to 2365 ng/kg (acridine), and the phytoestrogen glycitein was detected in the range of N.D. to 821 ng/kg. The logK d values of the targeted pharmaceuticals in river sediments in the field survey ranged from 0.5 (theophylline) to 3.3 (azithromycin). These results were in accord with those of the laboratory-scale sorption experiment. To the best of our knowledge, this is the first report of the detection of the anticancer drugs bicalutamide and tamoxifen, the transformation products of carbamazepine (2-hydroxy carbamazepine, acridine, and acridone), and the phytoestrogen genistein in river sediments.

In utero and lactational exposure to vinclozolin and genistein induces genomic changes in the rat mammary gland.

PubMed

El Sheikh Saad, H; Toullec, A; Vacher, S; Pocard, M; Bieche, I; Perrot-Applanat, M

2013-02-01

Exposure to low doses of environmental estrogens such as bisphenol A and genistein (G) alters mammary gland development. The effects of environmental anti-androgens, such as the fungicide vinclozolin (V), on mammary gland morphogenesis are unknown. We previously reported that perinatal exposure to G, V, and the GV combination causes histological changes in the mammary gland during the peripubertal period, suggesting alterations to the peripubertal hormone response. We now investigate whether perinatal exposure to these compounds alters the gene expression profiles of the developing glands to identify the dysregulated signaling pathways and the underlying mechanisms. G, V, or GV (1 mg/kg body weight per day) was added to diet of Wistar rats, from conception to weaning; female offspring mammary glands were collected at postnatal days (PNDs) 35 and 50. Genes displaying differential expression and belonging to different functional categories were validated by quantitative PCR and immunocytochemistry. At PND35, G had little effect; the slight changes noted were in genes related to morphogenesis. The changes following exposure to V concerned the functional categories associated with development (Cldn1, Krt17, and Sprr1a), carbohydrate metabolism, and steroidogenesis. The GV mixture upregulated genes (Krt17, Pvalb, and Tnni2) involved in muscle development, indicating effects on myoepithelial cells during mammary gland morphogenesis. Importantly, at PND50, cycling females exposed to GV showed an increase in the expression of genes (Csn2, Wap, and Elf5) related to differentiation, consistent with the previously reported abnormal lobuloalveolar development previously described. Thus, perinatal exposure to GV alters the mammary gland hormone response differently at PND35 (puberty) and in animals with established cycles.

Anticancer effect of genistein on BG-1 ovarian cancer growth induced by 17 β-estradiol or bisphenol A via the suppression of the crosstalk between estrogen receptor alpha and insulin-like growth factor-1 receptor signaling pathways

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hwang, Kyung-A; Park, Min-Ah; Kang, Nam-Hee

The interaction between estrogen receptor (ER) and insulin-like growth factor-1 receptor (IGF-1R) signaling pathway plays an important role in proliferation of and resistance to endocrine therapy to estrogen dependent cancers. Estrogen (E2) upregulates the expression of components of IGF-1 system and induces the downstream of mitogenic signaling cascades via phosphorylation of insulin receptor substrate-1 (IRS-1). In the present study, we evaluated the xenoestrogenic effect of bisphenol A (BPA) and antiproliferative activity of genistein (GEN) in accordance with the influence on this crosstalk. BPA was determined to affect this crosstalk by upregulating mRNA expressions of ERα and IGF-1R and inducing phosphorylationmore » of IRS-1 and Akt in protein level in BG-1 ovarian cancer cells as E2 did. In the mouse model xenografted with BG-1 cells, BPA significantly increased a tumor burden of mice and expressions of ERα, pIRS-1, and cyclin D1 in tumor mass compared to vehicle, indicating that BPA induces ovarian cancer growth by promoting the crosstalk between ER and IGF-1R signals. On the other hand, GEN effectively reversed estrogenicity of BPA by reversing mRNA and protein expressions of ERα, IGF-1R, pIRS-1, and pAkt induced by BPA in cellular model and also significantly decreased tumor growth and in vivo expressions of ERα, pIRS-1, and pAkt in xenografted mouse model. Also, GEN was confirmed to have an antiproliferative effect by inducing apoptotic signaling cascades. Taken together, these results suggest that GEN effectively reversed the increased proliferation of BG-1 ovarian cancer by suppressing the crosstalk between ERα and IGF-1R signaling pathways upregulated by BPA or E2.« less

Preventive effects of phytoestrogens against postmenopausal osteoporosis as compared to the available therapeutic choices: An overview

PubMed Central

Al-Anazi, Abdullah Foraih; Qureshi, Viquar Fatima; Javaid, Khalida; Qureshi, Shoeb

2011-01-01

Estrogen deficiency is a major risk factor for osteoporosis in postmenopausal women. Although hormone replacement therapy (HRT) has been rampantly used to recompense for the bone loss, but the procedure is coupled with severe adverse effects. Hence, there is a boost in the production of newer synthetic products to ward off the effects of menopause-related osteoporosis. As of today, there are several prescription products available for the treatment of postmenopause osteoporosis; most of these are estrogenic agents and combination products. Nevertheless, in view of the lack of effect and/or toxicity of these products, majority of the postmenopausal women are now fascinated by highly publicized natural products. This is an offshoot of the generalized consensus that these products are more effective and free from any adverse effects. Recently, certain plant-derived natural products, mostly phytoestrogens (isoflavones, lignans, coumestanes, stilbenes, flavonoids) and many more novel estrogen-like compounds in plants have been immensely used to prevent menopause-related depletion in bone mineral density (BMD). Although, a number of papers are published on menopause-related general symptoms, sexual dysfunction, cardiovascular diseases, Alzheimer's disease, diabetes, colon, and breast cancers, there is paucity of literature on the accompanying osteoporosis and its treatment. In view of the controversies on synthetic hormones and drugs and drift of a major population of patients toward natural drugs, it was found worthwhile to investigate if these drugs are suitable to be used in the treatment of postmenopausal osteoporosis. Preparation of this paper is an attempt to review the (a) epidemiology of postmenopausal osteoporosis, (b) treatment modalities of postmenopausal osteoporosis by hormones and synthetic drugs and the associated drawbacks and adverse effects, and (c) prevention and treatment of postmenopausal osteoporosis by phytoestrogens, their drawbacks and toxicity

Formononetin, an isoflavone, relaxes rat isolated aorta through endothelium-dependent and endothelium-independent pathways.

PubMed

Wu, Jian-Hong; Li, Qing; Wu, Min-Yi; Guo, De-Jian; Chen, Huan-Le; Chen, Shi-Lin; Seto, Sai-Wang; Au, Alice L S; Poon, Christina C W; Leung, George P H; Lee, Simon M Y; Kwan, Yiu-Wa; Chan, Shun-Wan

2010-07-01

We evaluated the vasorelaxation effects of formononetin, an isoflavone/phytoestrogen found abundantly in Astragalus mongholicus Bunge, on rat isolated aorta and the underlying mechanisms involved. Cumulative administration of formononetin, genistein, daidzein and biochanin A relaxed phenylephrine-preconstricted aorta. Formononetin and biochanin A caused a similar magnitude of relaxation whereas daidzein was least potent. Mechanical removal of endothelium, L-NAME (100 microM) and methylene blue (10 microM) suppressed formononetin-induced relaxation. Formononetin increased endothelial nitric oxide (NO) synthase (eNOS), but not inducible NO synthase, activity with an up-regulation of eNOS mRNA and p-eNOS(Ser1177) protein expression. In endothelium-denuded preparations, formononetin-induced vasorelaxation was significantly reduced by glibenclamide (3 microM) and iberiotoxin (100 nM), and a combination of glibenclamide (3 microM) plus iberiotoxin (100 nM) abolished the relaxation. In contrast, formononetin-elicited endothelium-independent relaxation was not altered by ICI 182,780 (10 microM, an estrogen receptor (ER alpha/ER beta) antagonist) or mifepristone (10 microM, a progesterone receptor antagonist). In single aortic smooth muscle cells, formononetin caused opening of iberiotoxin-sensitive Ca(2+)-activated K(+) (BK(Ca)) channels and glibenclamide-sensitive adenosine triphosphate (ATP)-dependent K(+) (K(ATP)) channels. Thus, our results suggest that formononetin caused vascular relaxation via endothelium/NO-dependent mechanism and endothelium-independent mechanism which involves the activation of BK(Ca) and K(ATP) channels. (c) 2010 Elsevier Inc. All rights reserved.

Neonatal estrogenic exposure suppresses PTEN-related endometrial carcinogenesis in recombinant mice.

PubMed

Begum, Monjura; Tashiro, Hironori; Katabuchi, Hidetaka; Suzuki, Akira; Kurman, Robert J; Okamura, Hitoshi

2006-03-01

Human endometrial carcinomas, as well as complex atypical hyperplasias (CAH), are estrogen related and frequently have mutations in the PTEN gene. However, the mutual contribution of estrogen and PTEN mutations to endometrial carcinogenesis in vivo is unknown. To address this issue, we investigated whether neonatal estrogenic treatments augment the incidence of CAH and carcinomas in murine PTEN (mPTEN) heterozygous (+/-) mutant mice, an animal model for endometrial carcinoma. Low doses of diethylstilbestrol (1 ng/g/day), genistein (50 microg/g/day) in phytoestrogens, estriol (E(3)) (4 microg/g/day), and vehicle (ethanol and corn oil) were administered subcutaneously daily to neonatal pups from the 1st to 5th day after birth. At 52 weeks of age, the morphological changes in the endometrium, and uterine expression of Hoxa 10 and Hoxa 11, were evaluated. These Hoxa genes are abdominal B-type homeobox genes, which normally regulate differentiation of the Müllerian duct. The incidence of CAH and adenocarcinomas of the endometrium was significantly decreased by the neonatal estrogenic treatments in the mPTEN+/- mice. Coincidentally, all treatments significantly decreased the stromal cell density, and CAH and adenocarcinomas rarely developed in the epithelium adjacent to the affected endometrial stroma. Moreover, the uterine expression of Hoxa 10 in mice with neonatal genistein and E(3) treatments, and that of Hoxa 11 in mice with all treatments, was significantly lower when compared with vehicle alone. Taken together, neonatal estrogenic exposure induced stromal atrophy and/or hyalinization accompanied by repressed expression of Hoxa 10 and Hoxa 11, and exerted an inhibitory effect on PTEN-related tumorigenesis. These findings provide new insight into the interaction between endometrial epithelium and stroma in endometrial carcinogenesis in vivo.

Experimentally induced mastitis and metritis modulate soy bean derived isoflavone biotransformation in diary cows.

PubMed

Kowalczyk-Zieba, I; Woclawek-Potocka, I; Piskula, M K; Piotrowska-Tomala, K K; Boruszewska, D; Bah, M M; Siemieniuch, M J; Skarzynski, D J

2011-12-01

The present study compared the changes in isoflavone (daidzein and genistein) and their metabolite (equol and para-ethyl-phenol) concentrations in the blood plasma of cows with induced mastitis and metritis after feeding with soy bean. Sixteen cows were divided into four groups: control for mastitis group, cows with induced mastitis group, control for metritis group, and cows with induced metritis group. All cows were fed a single dose of 2.5 kg of soy bean and then blood samples were taken from the jugular vein for 8 h at predetermined intervals. The concentrations of soy bean-derived isoflavones and their active metabolites were measured in the blood plasma on HPLC system. β-Glucuronidase activity in the blood plasma of cows was measured by fluorometric method. In the blood plasma of cows with induced mastitis and metritis, we found considerably higher concentrations and time-dependent increase in isoflavone metabolites (equol and para-ethyl-phenol) with reference to cyclic cows (P < 0.05). Moreover, we noticed significant decrease of genistein in the blood plasma of the cows with induced metritis compared with control cows (P < 0.05). In addition, in the blood plasma of the cows with induced metritis, we found an increase in β-glucuronidase activity compared with control cows (P < 0.05). In conclusion, health status of the females influenced the concentrations of isoflavone metabolites in the blood plasma of the cows. Experimentally induced mastitis and metritis increased isoflavone absorption, biotransformation and metabolism. Therefore, we suggest that cows with induced mastitis and metritis are more exposed to active isoflavone metabolite actions than healthy cows. Copyright © 2011. Published by Elsevier Inc.

Lifetime genistein intake increases the response of mammary tumors to tamoxifen in rats

PubMed Central

Zhang, Xiyuan; Cook, Katherine L; Warri, Anni; Cruz, Idalia M; Rosim, Mariana; Riskin, Jeffrey; Helferich, William; Doerge, Daniel; Clarke, Robert; Hilakivi-Clarke, Leena

2016-01-01

Purpose Whether it is safe for estrogen receptor positive (ER+) breast cancer patients to consume soy isoflavone genistein (GEN) remains controversial. We compared the effects of GEN intake mimicking either Asian (lifetime) or Caucasian (adulthood) intake patterns to that of starting its intake during tamoxifen (TAM) therapy using a preclinical model. Experimental Design Female Sprague-Dawley rats were fed an AIN93G diet supplemented with 0 (control diet) or 500 ppm GEN from postnatal day 15 onwards (lifetime GEN). Mammary tumors were induced with 7,12-dimethylbenz(a)anthracene (DMBA), after which a group of control diet fed rats were switched to GEN diet (adult GEN). When the first tumor in a rat reached 1.4 cm in diameter, TAM was added to the diet, and a subset of previously only control diet fed rats also started GEN intake (post-diagnosis GEN). Results Lifetime GEN intake reduced de novo resistance to TAM, compared with post-diagnosis GEN groups. Risk of recurrence was lower both in the lifetime and adult GEN groups than in the post-diagnosis GEN group. We observed downregulation of unfolded protein response (UPR) and autophagy related genes (GRP78, IRE1α, ATF4 and Beclin-1), and genes linked to immunosuppression (TGFβ and Foxp3), and upregulation of cytotoxic T cell marker CD8a in the tumors of the lifetime GEN group, compared with controls, post-diagnosis, and/or adult GEN groups. Conclusions GEN intake mimicking Asian consumption patterns improved response of mammary tumors to TAM therapy, and this effect was linked to reduced activity of UPR and pro-survival autophagy signaling, and increased anti-tumor immunity. PMID:28148690

Attenuation of Aβ{sub 25–35}-induced parallel autophagic and apoptotic cell death by gypenoside XVII through the estrogen receptor-dependent activation of Nrf2/ARE pathways

DOE Office of Scientific and Technical Information (OSTI.GOV)

Meng, Xiangbao; Wang, Min; Sun, Guibo, E-mail: sunguibo@126.com

Amyloid-beta (Aβ) has a pivotal function in the pathogenesis of Alzheimer's disease. To investigate Aβ neurotoxicity, we used an in vitro model that involves Aβ{sub 25–35}-induced cell death in the nerve growth factor-induced differentiation of PC12 cells. Aβ{sub 25–35} (20 μM) treatment for 24 h caused apoptotic cell death, as evidenced by significant cell viability reduction, LDH release, phosphatidylserine externalization, mitochondrial membrane potential disruption, cytochrome c release, caspase-3 activation, PARP cleavage, and DNA fragmentation in PC12 cells. Aβ{sub 25–35} treatment led to autophagic cell death, as evidenced by augmented GFP-LC3 puncta, conversion of LC3-I to LC3-II, and increased LC3-II/LC3-I ratio.more » Aβ{sub 25–35} treatment induced oxidative stress, as evidenced by intracellular ROS accumulation and increased production of mitochondrial superoxide, malondialdehyde, protein carbonyl, and 8-OHdG. Phytoestrogens have been proved to be protective against Aβ-induced neurotoxicity and regarded as relatively safe targets for AD drug development. Gypenoside XVII (GP-17) is a novel phytoestrogen isolated from Gynostemma pentaphyllum or Panax notoginseng. Pretreatment with GP-17 (10 μM) for 12 h increased estrogen response element reporter activity, activated PI3K/Akt pathways, inhibited GSK-3β, induced Nrf2 nuclear translocation, augmented antioxidant responsive element enhancer activity, upregulated heme oxygenase 1 (HO-1) expression and activity, and provided protective effects against Aβ{sub 25–35}-induced neurotoxicity, including oxidative stress, apoptosis, and autophagic cell death. In conclusion, GP-17 conferred protection against Aβ{sub 25–35}-induced neurotoxicity through estrogen receptor-dependent activation of PI3K/Akt pathways, inactivation of GSK-3β and activation of Nrf2/ARE/HO-1 pathways. This finding might provide novel insights into understanding the mechanism for neuroprotective effects of

Dietary intake of phytoestrogen is associated with increased circulating endothelial progenitor cells in patients with cardiovascular disease.

PubMed

Chan, Yap-Hang; Lam, Tai-Hing; Lau, Kui-Kai; Yiu, Kai-Hang; Siu, Chung-Wah; Li, Sheung-Wai; Chan, Hiu-Ting; Tam, Sidney; Lau, Chu-Pak; Tse, Hung-Fat

2011-06-01

Endogenous estrogen is known to positively influence the level and functionality of endothelial progenitor cells (EPC). However, the effect of phytoestrogen on EPC is unknown. Isoflavone is a major component of phytoestrogen. This study aims to investigate if the intake of isoflavone has any impact on the circulating level of EPC. We studied 102 consecutive patients (mean age: 66.5 ± 9.5 years, 78% male, all female post-menopausal) with cardiovascular disease (atherothrombotic stroke 62%, coronary artery disease 38%). Circulating levels of CD133(+) EPC were determined by flow cytometry. Non-invasive pulse wave velocity (PWV) was measured. Long-term intake of isoflavone was determined by a validated food frequency questionnaire. Isoflavone intake was positively associated with circulating CD133(+) EPC (r = 0.31, p = 0.001). Patients with circulating CD133(+) EPC <10th percentile had significantly lower isoflavone intake than patients with CD133(+)EPC ≥10th percentile (4.6 ± 3.7 mg/day versus 19.3 ± 30.2 mg/day, p < 0.001). A significant overall linear trend of circulating EPC across increasing tertiles of isoflavone intake was observed (p = 0.004). Adjusted for potential confounders, increased isoflavone intake from the 1st to the 3rd tertile independently predicted increased circulating CD133(+) EPC level by 221 cells/µl (95%CI: 71.4 to 369.8, relative increase 160%, p = 0.004). Gender was not a significant factor (p > 0.05). Furthermore, circulating CD133(+) EPC <10th percentile was independently predictive of increased PWV by 261.7 cm/s (95% CI: 37.1 to 486.2, p = 0.024). The study demonstrated that circulating EPC increased by more than one fold in patients with cardiovascular disease who had higher intake of isoflavone, suggesting that isoflavone may confer vascular protection through enhanced endothelial repair.

Exposure to endocrine disrupting chemicals among residents of a rural vegetarian/vegan community.

PubMed

Tordjman, Karen; Grinshpan, Laura; Novack, Lena; Göen, Thomas; Segev, Dar; Beacher, Lisa; Stern, Naftali; Berman, Tamar

2016-12-01

Endocrine-disrupting chemicals (EDCs) are increasingly thought to be involved in the rising prevalence of disorders such as obesity, diabetes, and some hormone-dependent cancers. Several lines of evidence have indicated that vegetarian and vegan diets may offer some protection from such diseases. We hypothesized that exposure to selected EDCs among residents of the unique vegetarian/vegan community of Amirim would be lower than what has recently been reported for the omnivorous population in the first Israel Biomonitoring Study (IBMS). We studied 42 Amirim residents (29 vegetarians/13 vegans; 24 women/18men, aged 50.7±13.7y). Subjects answered detailed lifestyle, and multipass, memory-based 24-hr dietary recall questionnaires. Concentrations of bisphenol A (BPA), 11 phthalate metabolites, and the isoflavone phytoestrogens (genistein and daidzein) were determined by GC or LC tandem mass-spectrometry on a spot urine sample. The results were compared to those obtained following the same methodology in the Jewish subgroup of the IBMS (n=184). While a vegetarian/vegan nutritional pattern had no effect on exposure to BPA, it seemed to confer a modest protection (~21%) from exposure to high molecular weight phthalates. Furthermore, the summed metabolites of the high molecular weight phthalate DiNP were 36% lower in vegans compared to vegetarians (P<0.05). In contrast, Amirim residents exhibited a level of exposure to isoflavone phytoestrogens about an order of magnitude higher than in the IBMS (P<0.001). In Israel, a country whose inhabitants demonstrate exposure to EDCs comparable to that of the US and Canada, a voluntary lifestyle of vegetarianism and preference for organic food has a modest, but possibly valuable, impact on exposure to phthalates, while it is associated with a very steep increase in the exposure to phytoestrogens. Major reduction in exposure to EDCs will require regulatory actions. Copyright © 2016 Elsevier Ltd. All rights reserved.

NORMAL MAMMARY GLAND MORPHOLOGY IN PUBERTAL FEMALE MICE FOLLOWING IN UTERO AND LACTATIONAL EXPOSURE TO GENISTEIN AT LEVELS COMPARABLE TO HUMAN DIETARY EXPOSURE. (R827402)

EPA Science Inventory

The objective of the study was to determine the effect of in utero and lactational exposure to genistein (0, 0.1, 0.5, 2.5 and 10 mg/kg/day) on mammary gland morphology in female B6D2F1 mice at levels comparable to or greater than human exposures. The effect of diethylstilbest...

Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner

PubMed Central

Gertz, Jason; Reddy, Timothy E.; Varley, Katherine E.; Garabedian, Michael J.; Myers, Richard M.

2012-01-01

Endogenous estrogens that are synthesized in the body impact gene regulation by activating estrogen receptors in diverse cell types. Exogenous compounds that have estrogenic properties can also be found circulating in the blood in both children and adults. The genome-wide impact of these environmental estrogens on gene regulation is unclear. To obtain an integrated view of gene regulation in response to environmental and endogenous estrogens on a genome-wide scale, we performed ChIP-seq to identify estrogen receptor 1 (ESR1; previously estrogen receptor α) binding sites, and RNA-seq in endometrial cancer cells exposed to bisphenol A (BPA; found in plastics), genistein (GEN; found in soybean), or 17β-estradiol (E2; an endogenous estrogen). GEN and BPA treatment induces thousands of ESR1 binding sites and >50 gene expression changes, representing a subset of E2-induced gene regulation changes. Genes affected by E2 were highly enriched for ribosome-associated proteins; however, GEN and BPA failed to regulate most ribosome-associated proteins and instead enriched for transporters of carboxylic acids. Treatment-dependent changes in gene expression were associated with treatment-dependent ESR1 binding sites, with the exception that many genes up-regulated by E2 harbored a BPA-induced ESR1 binding site but failed to show any expression change after BPA treatment. GEN and BPA exhibited a similar relationship to E2 in the breast cancer line T-47D, where cell type specificity played a much larger role than treatment specificity. Overall, both environmental estrogens clearly regulate gene expression through ESR1 on a genome-wide scale, although with lower potency resulting in less ESR1 binding sites and less gene expression changes compared to the endogenous estrogen, E2. PMID:23019147

Development and In Vitro Evaluation of Vitamin E-Enriched Nanoemulsion Vehicles Loaded with Genistein for Chemoprevention Against UVB-Induced Skin Damage.

PubMed

Brownlow, Bill; Nagaraj, Vinay J; Nayel, Amy; Joshi, Megha; Elbayoumi, Tamer

2015-10-01

There is a great need for effective protection against cutaneous pathologies arising from chronic exposure to harmful solar UVB radiations. A promising pharmaceutical strategy to improve the efficacy of chemotherapeutic/preventative natural compounds (e.g., soy isoflavone Genistein, Gen) is to enhance their dermal delivery using nanoemulsion (NE) formulations. This report investigates the development of nanoemulsified tocotrienol(T3)-rich fraction of red palm oil (Tocomin®), to yield an optimal NE delivery system for dermal photoprotection (z-average size <150 nm, ζ-potential ≈ -30 mV, polydispersity index < 0.25). Physicochemical characterization and photostability studies indicate NE formulations utilizing surfactant mixture (Smix) of Solutol® HS-15 (SHS15) blended with vitamin E TPGS (TPGS) as cosurfactant was significantly superior to formulations that utilized Lutrol® F68 (LF68) as the cosurfactant. A ratio of 60:40 of SHS15-TPGS-NE was further identified as lead Tocomin® NE topical platform using in vitro pharmaceutical skin reactivity studies that assess cutaneous irritancy and cytotoxicity. Prototype Tocomin® NE loaded with the antiphotocarcinogenic molecule Gen (Gen-Tocomin® NE) showed slow-release profile in both liquid and cream forms. Gen-Tocomin® NE also showed excellent biocompatibility, and provided substantial UVB protection to cultured subcutaneous L929 fibroblasts, indicating the great potential of our Tocomin® NE warranting further prototype development as topical pharmaceutical platform for skin photoprotection applications. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

Genistein, a general kinase inhibitor, as a potential antiviral for arenaviral hemorrhagic fever as described in the Pirital virus-Syrian golden hamster model.

PubMed

Vela, Eric M; Knostman, Katherine A; Mott, Jason M; Warren, Richard L; Garver, Jennifer N; Vela, Lela Johnson; Stammen, Rachelle L

2010-09-01

Arenaviruses are rodent-borne negative strand RNA viruses and infection of these viruses in humans may result in disease and hemorrhagic fever. To date, supportive care, ribavirin, and in some cases immune plasma remain the foremost treatment options for arenaviral hemorrhagic fever. Research with the hemorrhagic fever causing-arenaviruses usually requires a Biosafety level (BSL)-4 environment; however, surrogate animal model systems have been developed to preliminarily study and screen various vaccines and antivirals. The Syrian golden hamster-Pirital virus (PIRV) surrogate model of hemorrhagic fever provides an opportunity to test new antivirals in an ABSL-3 setting. Thus, we challenged hamsters, implanted with telemetry, with PIRV and observed viremia and tissue viral titers, and changes in core body temperature, hematology, clinical chemistry, and coagulation parameters. Physical signs of disease of the PIRV-infected hamsters included weight loss, lethargy, petechial rashes, epistaxis, ocular orbital and rectal hemorrhage, and visible signs of neurologic disorders. However, treating animals with genistein, a plant derived isoflavone and general kinase inhibitor, resulted in increased survival rates and led to an improved clinical profile. In all, the results from this study demonstrate the potential of a general kinase inhibitor genistein as an antiviral against arenaviral hemorrhagic fever. 2010 Elsevier B.V. All rights reserved.

Comparison of the estrogenic potencies of standardized soy extracts by immature rat uterotrophic bioassay.

PubMed

de Lima Toccafondo Vieira, Manuela; Duarte, Rodrigo Ferreira; Campos, Ligia Maria Moreira; Nunan, Elzíria de Aguiar

2008-01-01

Soy phytoestrogens, isoflavones, are a primary class of plant-based estrogen alternatives being sold over the counter nowadays. Genistein, daidzein and glycitein are the major isoflavones found in soybeans, as aglycones and glycosides. Each isoflavone shows distinctive estrogenic activity and pharmacokinetics. Soy dry extracts, employed as pharmaceutical raw material for manufacturing isoflavone supplements, are standardized to contain 40% of total isoflavones, but the amount of each isoflavone is highly diverse. The influence of these compositional differences on the estrogenic potency of soy extracts was evaluated by uterotrophic bioassay. Five commercial samples of standardized soy dry extract, homogeneously suspended in arachis oil, were administered per os in serial doses (125-4150 mg/kg bw/day) to immature female rats for 3 days. Soy extract samples with considerable diversity in isoflavone composition revealed different estrogenic potencies. Our results indicate a need of standardization of the individual isoflavone content in soy extracts.

Genistein and daidzein stimulate hyaluronic acid production in transformed human keratinocyte culture and hairless mouse skin.

PubMed

Miyazaki, Kouji; Hanamizu, Tomoko; Iizuka, Ryoko; Chiba, Katsuyoshi

2002-01-01

We examined the effects of the soy isoflavones genistein (Gen) and daidzein (Dai) on the production of hyaluronic acid (HA) in a transformed human keratinocyte culture and in hairless mouse skin following topical application for 2 weeks. Gen and Dai, but not the glycosides thereof, significantly enhanced the production of HA in vitro and in vivo. Histochemistry using an HA-binding protein revealed that topical Gen and estradiol raised both the density and intensity of HA staining, which was abundant in the murine dermis. It is suggested that Gen and Dai are not released from their respective glycosides in culture or murine skin. Moreover, topical Gen and Dai may prevent and improve the cutaneous alterations caused by the loss of HA in skin. Copyright 2002 S. Karger AG, Basel

Topical application of Bifidobacterium-fermented soy milk extract containing genistein and daidzein improves rheological and physiological properties of skin.

PubMed

Miyazaki, Kouji; Hanamizu, Tomoko; Sone, Toshiro; Chiba, Katsuyoshi; Kinoshita, Takashi; Yoshikawa, Satoshi

2004-01-01

The authors examined the effects of Bifidobacterium-fermented soy milk extract (BE) containing genistein and daidzein on the hyaluronic acid (HA) content and rheological and physiological properties of hairless mouse and/or human skin. Topical application of BE for six weeks significantly restored changes in the elasticity and viscoelasticity of mouse skin, increased the HA content, and hydrated and thickened mouse skin. Also, topical application of a gel formula containing 10% BE to the human forearm for three months significantly lessened the decrease in skin elasticity. Therefore, BE is expected to become a new cosmetic ingredient to prevent the loss of skin elasticity through enhancement of HA production.

Effects of Trifolium alexandrinum phytoestrogens on oestrous behaviour, ovarian activity and reproductive performance of ewes during the non-breeding season.

PubMed

Hashem, N M; El-Azrak, K M; Nour El-Din, A N M; Sallam, S M; Taha, T A; Salem, M H

2018-03-08

Phytoestrogens are classified as naturally occurring endocrine disrupting chemicals that may affect reproductive performance of farm animals. To investigate the effects of Berseem clover phytoestrogens on reproductive performance of seasonal anoestrus ewes, twenty four late pregnant Rahmani ewes were fed either Berseem clover or maize silage (n = 12/treatment). Treatment started 2 months prepartum and continued until oestrous induction (week 8 postpartum), using the CIDR-eCG based protocol, and early pregnancy. Throughout the 2-8 weeks postpartum, oestrous rate and ovarian activity were not affected by treatment. After oestrous induction, ewes in both groups expressed comparable oestrous rates; however feeding Berseem clover extended (P < 0.05) interval to oestrus (57.00 compared with 42.54 h) and shortened (P < 0.05) oestrous duration (20.0 compared with 34.90 h). Feeding Berseem clover did not affect follicular activity except the number of medium follicles, which was less (P < 0.05) on day of oestrus (Day 0). Feeding maize silage increased (P < 0.05) the total number of follicles and number of small and medium follicles the day before oestrus (Day -1). On Day 0, the greater total number of follicles was due to the greater (P < 0.05) number of medium follicles that was associated with less number of small follicles. Although, the number and diameter of corpora lutea (CLs) were not affected by treatment, serum P 4 concentration was greater (P < 0.05) for ewes fed maize silage than for those fed Berseem clover. Fecundity and litter size tended to be greater (about 35%; P = 0.132 and 0.085, respectively) in the maize silage fed ewes. In conclusion, feeding Berseem clover throughout seasonal anoestrus disrupted aspects of behavioural oestrus and there was less luteal P 4 synthesis and fecundity of ewes. Copyright © 2018 Elsevier B.V. All rights reserved.

Efficient topical delivery of chlorogenic acid by an oil-in-water microemulsion to protect skin against UV-induced damage.

PubMed

Kitagawa, Shuji; Yoshii, Kenta; Morita, Shin-ya; Teraoka, Reiko

2011-01-01

We examined the intradermal delivery of a hydrophilic polyphenol chlorogenic acid by in vitro study using excised guinea pig dorsal skin and Yucatan micropig skin. Skin accumulation as well as the solubility of chlorogenic acid in aqueous vehicles was much greater than for other polyphenols such as quercetin and genistein. However, since enhancement of skin delivery seemed to be necessary to exhibit its protective effects against oxidative damage of skin, we examined the effects of microemulsions as vehicles. Using microemulsions consisting of 150 mM NaCl solution, isopropyl myristate, polyoxyethylene sorbitan monooleate (Tween 80) and ethanol, skin accumulation as well as solubility of chlorogenic acid further increased. Enhancement effect of an oil-in-water (o/w-type) microemulsion was greater than that of a water-in-oil (w/o-type) microemulsion possibly due to the greater increase in solubility. This finding was quite different from previous findings on relatively hydrophobic polyphenols such as quercetin and genistein. Pretreatment of guinea pig dorsal skin with chlorogenic acid containing microemulsion gel prevented erythema formation induced by UV irradiation. These findings indicate the potential use of hydrophilic chlorogenic acid with o/w-type microemulsion as a vehicle to protect skin against UV-induced oxidative damage.

Gender disparity in LDL-induced cardiovascular damage and the protective role of estrogens against electronegative LDL

PubMed Central

2014-01-01

Background Increased levels of the most electronegative type of LDL, L5, have been observed in the plasma of patients with metabolic syndrome (MetS) and ST-segment elevation myocardial infarction and can induce endothelial dysfunction. Because men have a higher predisposition to developing coronary artery disease than do premenopausal women, we hypothesized that LDL electronegativity is increased in men and promotes endothelial damage. Methods L5 levels were compared between middle-aged men and age-matched, premenopausal women with or without MetS. We further studied the effects of gender-influenced LDL electronegativity on aortic cellular senescence and DNA damage in leptin receptor–deficient (db/db) mice by using senescence-associated–β-galactosidase and γH2AX staining, respectively. We also studied the protective effects of 17β-estradiol and genistein against electronegative LDL–induced senescence in cultured bovine aortic endothelial cells (BAECs). Results L5 levels were higher in MetS patients than in healthy subjects (P < 0.001), particularly in men (P = 0.001). LDL isolated from male db/db mice was more electronegative than that from male or female wild-type mice. In addition, LDL from male db/db mice contained abundantly more apolipoprotein CIII and induced more BAEC senescence than did female db/db or wild-type LDL. In the aortas of db/db mice but not wild-type mice, we observed cellular senescence and DNA damage, and the effect was more significant in male than in female db/db mice. Pretreatment with 17β-estradiol or genistein inhibited BAEC senescence induced by male or female db/db LDL and downregulated the expression of lectin-like oxidized LDL receptor-1 and tumor necrosis factor-alpha protein. Conclusion The gender dichotomy of LDL-induced cardiovascular damage may underlie the increased propensity to coronary artery disease in men. PMID:24666525

Phytosteroids Beyond Estrogens: Regulators of Reproductive and Endocrine Function in Natural Products

PubMed Central

Dean, Matthew; Murphy, Brian T.; Burdette, Joanna E.

2016-01-01

Foods and botanical supplements can interfere with the endocrine system through the presence of phytosteroids – chemicals that interact with steroids receptors. Phytoestrogens are well studied, but compounds such as kaempferol, apigenin, genistein, ginsenoside Rf, and glycyrrhetinic acid have been shown to interact with non-estrogen nuclear receptors. These compounds can have agonist, antagonist, or mixed agonist/antagonist activity depending on compound, receptor, cell line or tissue, and concentration. Some phytosteroids have also been shown to inhibit steroid metabolizing enzymes, resulting in biological effects through altered endogenous steroid concentrations. An interesting example, compound A (4-[1-chloro-2-(methylamino)ethyl]phenyl acetate hydrochloride (1:1)) is a promising selective glucocorticoid receptor modulator (SGRM) based on a phytosteroid isolated from Salsola tuberculatiformis Botschantzev. Given that $6.9 billion of herbal supplements are sold each year, is clear that further identification and characterization of phytosteroids is needed to ensure the safe and effective use of botanical supplements. PMID:27986590

The anti-metastatic effects of the phytoestrogen arctigenin on human breast cancer cell lines regardless of the status of ER expression.

PubMed

Maxwell, Thressi; Chun, So-Young; Lee, Kyu-Shik; Kim, Soyoung; Nam, Kyung-Soo

2017-02-01

Arctigenin is a plant lignan extracted from Arctium lappa that has been shown to have estrogenic properties. In spite of the health benefits of phytoestrogens reducing the risk of osteoporosis, heart disease, and menopausal symptoms, its benefits against the risk of breast cancer have not been fully elucidated. Thus, we investigated the effects of arctigenin on metastasis of breast cancer using both estrogen receptor (ER)-positive MCF-7 and ER-negative MDA-MB-231 human breast cancer cell lines to see if the effects are dependent on the status of ER expression. In ER-positive MCF-7 cells, arctigenin efficiently inhibited 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced cell migration and invasion. The activity of crucial metastatic protease matrix metalloprotease (MMP)-9 in gelatin zymography was also efficiently decreased by arctigenin, as well as its mRNA expression. Notably, arctigenin exhibited similar anti-metastatic effects even in ER-negative MDA-MB-231 cells, suggesting that the anti-metastatic effects of arctigenin were not exerted via the ER. The upstream signaling pathways involved in the regulation of MMP-9 and urokinase plasminogen activator (uPA) were analyzed using western blotting. The activation of Akt, NF-κB and MAPK (ERK 1/2 and JNK 1/2) was found to be inhibited. Taken together, these data suggest that arctigenin confers anti-metastatic effects by inhibiting MMP-9 and uPA via the Akt, NF-κB and MAPK signaling pathways on breast cancer, regardless of ER expression. Therefore, we propose that the intake of arctigenin could be an effective supplement for breast cancer patients.

Impact of three endocrine disruptors, Bisphenol A, Genistein and Vinclozolin on female rat enamel.

PubMed

Jedeon, K; Berdal, A; Babajko, A

2016-06-28

Concerns about the potential adverse effectsof endocrine disruptors (EDs) have been increasingover the last three decades. BisphenolA (BPA), genistein (G) and vinclozolin (V) arethree widely used EDs sharing similar effects.Since populations are exposed to many diverseEDs simultaneously, we demonstratedrecently their impact alone or combined onmale rat tooth enamel. The purpose of thisstudy was therefore to assess their effects onfemale rat tooth enamel in order to understandwhy they are differentially sensitive. Ratswere exposed daily in utero and after birth tolow doses of EDs during the critical fetal andsuckling periods when amelogenesis takesplace. Enamel of rats exposed to EDs presentedopaque areas of hypomineralization. Theproportion of affected rats was the highestin the groups of rats treated with BPA aloneand higher in males than in females (in all thegroups). Comparison of enamel key gene expressionlevels showed modulations of Klk4and Enamelin in males but no significant variationsin females. These findings show thatfemale rats are less affected than males bythe three EDs chosen in this study and suggestthat enamel hypomineralization may differbetween males and females.

Formononetin induces apoptosis of human osteosarcoma cell line U2OS by regulating the expression of Bcl-2, Bax and MiR-375 in vitro and in vivo.

PubMed

Hu, Wei; Xiao, ZengMing

2015-01-01

Phytoestrogens are known to prevent tumor progression by inhibiting proliferation and inducing apoptosis in cancer cells. Formononetin is one of the main components of red clover plants, and is considered as a typical phytoestrogen. This study investigates formononetin induction of apoptosis of human osteosarcoma cell line U2OS by regulating Bcl-2 and Bax expression in vitro and in vivo. U2OS cells were treated with different concentrations of formononetin and the proliferation of the cells was measured using an MTT assay. Cell apoptosis was examined by flow cytometry. The levels of miR-375, Bax and Bcl-2 protein expression in treated cells were determined by Western blot and RT-PCR. The antitumor activity of formononetin was also evaluated in vivo in nude mice bearing orthotopic tumor implants. High concentrations of formononetin significantly suppress the proliferation of U2OS cells and induce cell apoptosis. Moreover, compared to control group the expression of Bcl-2 and miR-375 decreases with formononetin in the U2OS cells, while Bax increases. Formononetin has inhibitory effects on the proliferation of U2SO cells, both in vitro and in vivo. This antitumor effect is directly correlated with formononetin concentration. © 2015 The Author(s) Published by S. Karger AG, Basel.

Soybean seed extracts preferentially express genomic loci of Bradyrhizobium japonicum in the initial interaction with soybean, Glycine max (L.) Merr.

PubMed

Wei, Min; Yokoyama, Tadashi; Minamisawa, Kiwamu; Mitsui, Hisayuki; Itakura, Manabu; Kaneko, Takakazu; Tabata, Satoshi; Saeki, Kazuhiko; Omori, Hirofumi; Tajima, Shigeyuki; Uchiumi, Toshiki; Abe, Mikiko; Ohwada, Takuji

2008-08-01

Initial interaction between rhizobia and legumes actually starts via encounters of both partners in the rhizosphere. In this study, the global expression profiles of Bradyrhizobium japonicum USDA 110 in response to soybean (Glycine max) seed extracts (SSE) and genistein, a major soybean-released isoflavone for nod genes induction of B. japonicum, were compared. SSE induced many genomic loci as compared with genistein (5.0 microM), nevertheless SSE-supplemented medium contained 4.7 microM genistein. SSE markedly induced four predominant genomic regions within a large symbiosis island (681 kb), which include tts genes (type III secretion system) and various nod genes. In addition, SSE-treated cells expressed many genomic loci containing genes for polygalacturonase (cell-wall degradation), exopolysaccharide synthesis, 1-aminocyclopropane-1-carboxylate deaminase, ribosome proteins family and energy metabolism even outside symbiosis island. On the other hand, genistein-treated cells exclusively showed one expression cluster including common nod gene operon within symbiosis island and six expression loci including multidrug resistance, which were shared with SSE-treated cells. Twelve putatively regulated genes were indeed validated by quantitative RT-PCR. Several SSE-induced genomic loci likely participate in the initial interaction with legumes. Thus, these results can provide a basic knowledge for screening novel genes relevant to the B. japonicum- soybean symbiosis.

Soy isoflavones exert beneficial effects on letrozole-induced rat polycystic ovary syndrome (PCOS) model through anti-androgenic mechanism.

PubMed

Rajan, Ravi Kumar; M, Siva Selva Kumar; Balaji, Bhaskar

2017-12-01

Soy is the main source of phytoestrogens, which has long been used as traditional food. One major subtype of phytoestrogens includes isoflavones and they are scientifically validated for their beneficial actions on many hormone-dependent conditions. The present study examines the effect of soy isoflavones on letrozole-induced polycystic ovary syndrome (PCOS) rat model. PCOS was induced in Sprague-Dawley rats with of 1 mg/kg letrozole, p.o. once daily for 21 consecutive days. Soy isoflavones (50 and 100 mg/kg) was administered for 14 days after PCOS induction. Physical parameters (body weight, oestrous cycle determination, ovary and uterus weight) metabolic parameters (oral glucose tolerance test, total cholesterol), steroidal hormone profile (testosterone and 17β-oestradiol), steroidogenic enzymes (3β-hydroxy steroid dehydrogenase (HSD) and 17β-HSD), oxidative stress and histopathology of ovary were studied. Soy isoflavones (100 mg/kg) treatment significantly altered the letrozole-induced PCOS symptoms as observed by decreased body weight gain (p < 0.05), percentage diestrous phase (p < 0.001), testosterone (p < 0.001), 3β-HSD (p < 0.01) and 17β-HSD (p < 0.001) enzyme activity and oxidative stress. Histological results reveal that soy isoflavones treatment in PCOS rats resulted in well-developed antral follicles and normal granulosa cell layer in rat ovary. Treatment with soy isoflavones exerts beneficial effects in PCOS rats (with decreased aromatase activity) which might be due to their ability to decrease testosterone concentration in the peripheral blood. Analysis of physical, biochemical and histological evidences shows that soy isoflavones may be beneficial in PCOS.

Dietary estrogens--a probable cause of infertility and liver disease in captive cheetahs.

PubMed

Setchell, K D; Gosselin, S J; Welsh, M B; Johnston, J O; Balistreri, W F; Kramer, L W; Dresser, B L; Tarr, M J

1987-08-01

The cheetah in the wild is "racing towards extinction" mostly due to habitat destruction. Its survival will probably depend on accelerated captive breeding. At this time, however, reproductive failure and liver disease threaten the future of the captive cheetah population. Histopathological evaluation of more than 100 cheetah livers identified venocclusive disease as the main hepatic lesion responsible for liver disease in this species. Analysis of the commercial feline diet by high-performance liquid chromatography and gas-liquid chromatography-mass spectrometry revealed large amounts of two phytoestrogens identified as daidzein and genistein. These compounds were found to be derived from a soybean product that was a component of the cheetah diet, and their concentrations both ranged from 18 to 35 micrograms/g diet. The adult cheetah consequently consumes approximately 50 mg/day of these weak estrogens. When extracts of the diet were tested for estrogenicity using a bioassay, a dose-related increase in uterine weight was observed. In 4 cheetahs studied, withdrawal of this feline diet by substitution with a chicken diet resulted in an improvement in conventional liver function tests and a normalization in the appearance of hepatic mitochondria. We conclude that the relatively high concentrations of phytoestrogens from soybean protein present in the commercial diet fed to captive cheetahs in North American zoos may be one of the major factors in the decline of fertility and in the etiology of liver disease in this species. The survival of the captive cheetah population could depend upon a simple change of diet by excluding exogenous estrogen.

Interdependence of Platelet-Derived Growth Factor and Estrogen-Signaling Pathways in Inducing Neonatal Rat Testicular Gonocytes Proliferation1

PubMed Central

Thuillier, Raphael; Mazer, Monty; Manku, Gurpreet; Boisvert, Annie; Wang, Yan; Culty, Martine

2010-01-01

We previously found that platelet-derived growth factor (PDGF) and 17beta-estradiol stimulate gonocyte proliferation in a dose-dependent, nonadditive manner. In the present study, we report that gonocytes express RAF1, MAP2K1, and MAPK1/3. Inhibition of RAF1 and MAP2K1/2, but not phosphoinositide-3-kinase, blocked PDGF-induced proliferation. AG-370, an inhibitor of PDGF receptor kinase activity, suppressed not only PDGF-induced proliferation but also that induced by 17beta-estradiol. In addition, RAF1 and MAP2K1/2 inhibitors blocked 17beta-estradiol-activated proliferation. The estrogen receptor antagonist ICI 182780 inhibited both the effects of 17beta-estradiol and PDGF. PDGF lost its stimulatory effect when steroid-depleted serum or no serum was used. Similarly, 17beta-estradiol did not induce gonocyte proliferation in the absence of PDGF. The xenoestrogens genistein, bisphenol A, and DES, but not coumestrol, stimulated gonocyte proliferation in a dose-dependent and PDGF-dependent manner similarly to 17beta-estradiol. Their effects were blocked by ICI 182780, suggesting that they act via the estrogen receptor. AG-370 blocked genistein and bisphenol A effects, demonstrating their requirement of PDGF receptor activation in a manner similar to 17beta-estradiol. These results demonstrate the interdependence of PDGF and estrogen pathways in stimulating in vitro gonocyte proliferation, suggesting that this critical step in gonocyte development might be regulated in vivo by the coordinated action of PDGF and estrogen. Thus, the inappropriate exposure of gonocytes to xenoestrogens might disrupt the crosstalk between the two pathways and potentially interfere with gonocyte development. PMID:20089883

Effects of Vehicles and Enhancers on the Skin Permeation of Phytoestrogenic Diarylheptanoids from Curcuma comosa.

PubMed

Tuntiyasawasdikul, Sarunya; Limpongsa, Ekapol; Jaipakdee, Napaphak; Sripanidkulchai, Bungorn

2017-04-01

Curcuma comosa (C. comosa) is widely used in traditional medicine as a dietary supplement for health promotion in postmenopausal women in Thailand. It contains several diarylheptanoids, which are considered to be a novel class of phytoestrogens. However, the diarylheptanoids isolated from the plant rhizome are shown to have low oral bioavailability and faster elimination characteristics. The aim of this study was to investigate the permeation behavior of the active compounds of diarylheptanoids. The effects of binary vehicle systems and permeation enhancers on diarylheptanoids permeation and accumulation within the skin were studied using side-by-side diffusion cells through the porcine ear skin. Among the tested binary vehicle systems, the ethanol/water vehicle appeared to be the most effective system for diarylheptanoids permeation with the highest flux and shortest lag time. The presence of transcutol in the vehicle system significantly increased diarylheptanoid's permeation and accumulation within the skin in a concentration-dependent manner. Although the presence of terpenes in formulation decreased the flux of diarylheptanoids, it raised the amount of diarylheptanoids retained within the skin substantially. Based on the feasibility of diarylheptanoid permeation, C. comosa extract should be further developed into an effective transdermal product for health benefits and hormone replacement therapy.

Soy Formula and Epigenetic Modifications: Analysis of Vaginal Epithelial Cells from Infant Girls in the IFED Study

PubMed Central

Harlid, Sophia; Adgent, Margaret; Jefferson, Wendy N.; Panduri, Vijayalakshmi; Umbach, David M.; Xu, Zongli; Stallings, Virginia A.; Williams, Carmen J.; Rogan, Walter J.; Taylor, Jack A.

2016-01-01

Background: Early-life exposure to estrogenic compounds affects the development of the reproductive system in rodent models and humans. Soy products, which contain phytoestrogens such as genistein, are one source of exposure in infants fed soy formula, and they result in high serum concentrations. Objectives: Our goal was to determine whether soy exposure is associated with differential DNA methylation in vaginal cells from soy-fed infant girls. Methods: Using the Illumina HumanMethylation450 BeadChip, we evaluated epigenome-wide DNA methylation in vaginal cells from four soy formula–fed and six cow formula–fed girls from the Infant Feeding and Early Development (IFED) study. Using pyrosequencing we followed up the two most differentially methylated sites in 214 vaginal cell samples serially collected between birth and 9 months of age from 50 girls (28 soy formula–fed and 22 cow formula–fed). With a mouse model, we examined the effect of neonatal exposure to genistein on gene specific mRNA levels in vaginal tissue. Results: The epigenome-wide scan suggested differences in methylation between soy formula–fed and cow formula–fed infants at three CpGs in the gene proline rich 5 like (PRR5L) (p < 104). Pyrosequencing of the two feeding groups found that methylation levels progressively diverged with age, with pointwise differences becoming statistically significant after 126 days. Genistein-exposed mice showed a 50% decrease in vaginal Prr5l mRNA levels compared to controls. Conclusions: Girls fed soy formula have altered DNA methylation in vaginal cell DNA which may be associated with decreased expression of an estrogen-responsive gene. Citation: Harlid S, Adgent M, Jefferson WN, Panduri V, Umbach DM, Xu Z, Stallings VA, Williams CJ, Rogan WJ, Taylor JA. 2017. Soy formula and epigenetic modifications: analysis of vaginal epithelial cells from infant girls in the IFED study. Environ Health Perspect 125:447–452; http://dx.doi.org/10.1289/EHP428 PMID

Soy Formula and Epigenetic Modifications: Analysis of Vaginal Epithelial Cells from Infant Girls in the IFED Study.

PubMed

Harlid, Sophia; Adgent, Margaret; Jefferson, Wendy N; Panduri, Vijayalakshmi; Umbach, David M; Xu, Zongli; Stallings, Virginia A; Williams, Carmen J; Rogan, Walter J; Taylor, Jack A

2017-03-01

Early-life exposure to estrogenic compounds affects the development of the reproductive system in rodent models and humans. Soy products, which contain phytoestrogens such as genistein, are one source of exposure in infants fed soy formula, and they result in high serum concentrations. Our goal was to determine whether soy exposure is associated with differential DNA methylation in vaginal cells from soy-fed infant girls. Using the Illumina HumanMethylation450 BeadChip, we evaluated epigenome-wide DNA methylation in vaginal cells from four soy formula-fed and six cow formula-fed girls from the Infant Feeding and Early Development (IFED) study. Using pyrosequencing we followed up the two most differentially methylated sites in 214 vaginal cell samples serially collected between birth and 9 months of age from 50 girls (28 soy formula-fed and 22 cow formula-fed). With a mouse model, we examined the effect of neonatal exposure to genistein on gene specific mRNA levels in vaginal tissue. The epigenome-wide scan suggested differences in methylation between soy formula-fed and cow formula-fed infants at three CpGs in the gene proline rich 5 like ( PRR5L ) ( p < 10 4 ). Pyrosequencing of the two feeding groups found that methylation levels progressively diverged with age, with pointwise differences becoming statistically significant after 126 days. Genistein-exposed mice showed a 50% decrease in vaginal Prr5l mRNA levels compared to controls. Girls fed soy formula have altered DNA methylation in vaginal cell DNA which may be associated with decreased expression of an estrogen-responsive gene. Citation: Harlid S, Adgent M, Jefferson WN, Panduri V, Umbach DM, Xu Z, Stallings VA, Williams CJ, Rogan WJ, Taylor JA. 2017. Soy formula and epigenetic modifications: analysis of vaginal epithelial cells from infant girls in the IFED study. Environ Health Perspect 125:447-452; http://dx.doi.org/10.1289/EHP428.

Synergistic Phytochemicals Fail to Protect Against Ovariectomy Induced Bone Loss in Rats.

PubMed

Ambati, Suresh; Miller, Colette N; Bass, Erica F; Hohos, Natalie M; Hartzell, Diane L; Kelso, Emily W; Trunnell, Emily R; Yang, Jeong-Yeh; Della-Fera, Mary Anne; Baile, Clifton A; Rayalam, Srujana

2018-05-24

Menopause induces a loss of bone as a result of estrogen deficiency. Despite pharmaceutical options for the treatment of osteopenia and osteoporosis, many aging women use dietary supplements with estrogenic activity to prevent bone loss and other menopausal-related symptoms. Such supplements are yet to be tested for efficacy against a Food and Drug Administration (FDA) approved medication for menopausal bone loss such as zoledronic acid (ZA). The postmenopausal rat model was used to investigate the efficacy of various synergistic phytochemical blends mixed into the diet for 16 weeks. Retired-breeder, Fischer 344 rats were randomly assigned to sham or ovariectomy surgery and 4 treatment groups: ZA; genistein supplementation; and a low dose and high dose blend of genistein, resveratrol, and quercetin. Ovariectomy resulted in a loss of both trabecular and cortical bone which was prevented with ZA. The phytochemical blends tested were unable to reverse these losses. Despite the lack of effectiveness in preventing bone loss, a significant dose-response trend was observed in the phytochemical-rich diets in bone adipocyte number compared to ovariectomized control rats. Data from this study indicate that estrogenic phytochemicals are not as efficacious as ZA in preventing menopausal-related bone loss but may have beneficial effects on bone marrow adiposity in rats.

Isoliquiritigenin, a strong nod gene- and glyceollin resistance-inducing flavonoid from soybean root exudate.

PubMed

Kape, R; Parniske, M; Brandt, S; Werner, D

1992-05-01

Isoflavonoid signal molecules from soybean (Glycine max (L.) Merr.) seed and root exudate induce the transcription of nodulation (nod) genes in Bradyrhizobium japonicum. In this study, a new compound with symbiotic activity was isolated from soybean root exudate. The isolated 2',4',4-trihydroxychalcone (isoliquiritigenin) is characterized by its strong inducing activity for the nod genes of B. japonicum. These genes are already induced at concentrations 1 order of magnitude below those required of the previously described isoflavonoid inducers genistein and daidzein. Isoliquiritigenin is also a potent inducer of glyceollin resistance in B. japonicum, which renders this bacterium insensitive to potentially bactericidal concentrations of glyceollin, the phytoalexin of G. max. No chemotactic effect of isoliquiritigenin was observed. The highly efficient induction of nod genes and glyceollin resistance by isoliquiritigenin suggests the ecological significance of this compound, although it is not a major flavonoid constituent of the soybean root exudate in quantitative terms.

Characteristics of the isomeric flavonoids apigenin and genistein binding to hemoglobin by spectroscopic methods

NASA Astrophysics Data System (ADS)

Yuan, Jiang-Lan; Liu, Hui; Kang, Xu; Lv, Zhong; Zou, Guo-Lin

2008-11-01

Apigenin (Ap) and genistein (Ge), a couple of isomeric flavonoids with extensive bioactivities, are the most common dietary ingredients. They have been widely investigated due to their potential therapeutic actions for some diseases. In our work, binding characteristics of Ap and Ge to hemoglobin (Hb) were analyzed with fluorescence spectroscopy, circular dichroism (CD) and UV-vis absorption spectroscopy. The results indicated that Ap and Ge caused strong fluorescence quenching of Hb by static quenching mechanism, but their quenching efficiency and mechanisms were different. The binding site n suggested that there was a single binding site in Hb for Ap and Ge. The results of synchronous fluorescence showed that the microenvironment around Tyr residues of Hb had a slight trend of polarity decreasing, but the polarity around Trp residues increased by adding Ap. Results of CD indicated that the Ap and Ge did not changed the secondary structure of Hb. According to the theory of Förster resonance energy transfer, the binding distance r between Trp 37 and Ap/Ge was predicted to be 3.4 nm and 3.32 nm, respectively. The affinity of Ge toward Hb was higher than that of Ap.

Lactofen induces isoflavone accumulation and glyceollin elicitation competency in soybean.

PubMed

Landini, Serena; Graham, Madge Y; Graham, Terrence L

2003-03-01

Lactofen, the active ingredient of the soybean disease resistance-inducing herbicide, Cobra, induces large accumulations of isoflavone conjugates and aglycones in soybean tissues. The predominant isoflavones induced in cotyledon tissues are daidzein (and its conjugates) and formononetin and glycitein aglycones. The latter two isoflavones are usually present only at very low levels in soybean seedling tissues. In leaves, the predominant lactofen-induced isoflavones are daidzein and formononetin aglycones and the malonyl-glucosyl conjugate of genistein. Isoflavone induction also occurs in cells distal to the point of treatment, but is only weakly systemic. Lactofen also induces elicitation competency, the capacity of soybean cells to accumulate the pterocarpan phytoalexin glyceollin in response to glucan elicitors from the cell wall of the pathogen Phytophthora sojae. Comparison of the activity of a series of diphenyl ether herbicides demonstrated that while all diphenyl ethers tested induced some degree of elicitation competency, only certain ones induced isoflavone accumulation in the absence of glucan elicitor. As a group the diphenyl ethers are thought to inhibit protoporhyrinogen oxidase, eventually leading to singlet oxygen generation. Another singlet oxygen generator, rose bengal, also induced elicitation competency, but little isoflavone accumulation. It is hypothesized that diphenyl ether-induced activated oxygen species mimic some aspects of hypersensitive cell death, which leads to elicitation competency in infected tissues.

Exploring the Therapeutic Mechanism of Desmodium styracifolium on Oxalate Crystal-Induced Kidney Injuries Using Comprehensive Approaches Based on Proteomics and Network Pharmacology.

PubMed

Hou, Jiebin; Chen, Wei; Lu, Hongtao; Zhao, Hongxia; Gao, Songyan; Liu, Wenrui; Dong, Xin; Guo, Zhiyong

2018-01-01

Purpose: As a Chinese medicinal herb, Desmodium styracifolium (Osb.) Merr (DS) has been applied clinically to alleviate crystal-induced kidney injuries, but its effective components and their specific mechanisms still need further exploration. This research first combined the methods of network pharmacology and proteomics to explore the therapeutic protein targets of DS on oxalate crystal-induced kidney injuries to provide a reference for relevant clinical use. Methods: Oxalate-induced kidney injury mouse, rat, and HK-2 cell models were established. Proteins differentially expressed between the oxalate and control groups were respectively screened using iTRAQ combined with MALDI-TOF-MS. The common differential proteins of the three models were further analyzed by molecular docking with DS compounds to acquire differential targets. The inverse docking targets of DS were predicted through the platform of PharmMapper. The protein-protein interaction (PPI) relationship between the inverse docking targets and the differential proteins was established by STRING. Potential targets were further validated by western blot based on a mouse model with DS treatment. The effects of constituent compounds, including luteolin, apigenin, and genistein, were investigated based on an oxalate-stimulated HK-2 cell model. Results: Thirty-six common differentially expressed proteins were identified by proteomic analysis. According to previous research, the 3D structures of 15 major constituents of DS were acquired. Nineteen differential targets, including cathepsin D (CTSD), were found using molecular docking, and the component-differential target network was established. Inverse-docking targets including p38 MAPK and CDK-2 were found, and the network of component-reverse docking target was established. Through PPI analysis, 17 inverse-docking targets were linked to differential proteins. The combined network of component-inverse docking target-differential proteins was then constructed

Corn silk induces nitric oxide synthase in murine macrophages.

PubMed

Kim, Kyung A; Choi, Sang Kyu; Choi, Hye Seon

2004-12-31

Corn silk has been purified as an anticoagulant previously and the active component is a polysaccharide with a molecular mass of 135 kDa. It activates murine macrophages to induce nitric oxide synthase (NOS) and generate substantial amounts of NO in time and dose-dependent manners. It was detectable first at 15 h after stimulation by corn silk, peaked at 24 h, and undetectable by 48 h. Induction of NOS is inhibited by pyrolidine dithiocarbamate (PDTC) and genistein, an inhibitor of nuclear factor kappa B (NF-kappaB) and tyrosine kinase, respectively, indicating that iNOS stimulated by corn silk is associated with tyrosine kinase and NF-kappaB signaling pathways. IkappaB-alpha degradation was detectible at 10 min, and the level was restored at 120 min after treatment of corn silk. Corn silk induced nuclear translocation of NF-kappaB by phosphorylation and degradation of IkappaB-alpha.

Effects of estradiol, estrogen receptor subtype-selective agonists and genistein on glucose metabolism in leptin resistant female Zucker diabetic fatty (ZDF) rats.

PubMed

Weigt, Carmen; Hertrampf, Torsten; Flenker, Ulrich; Hülsemann, Frank; Kurnaz, Pinar; Fritzemeier, Karl Heinrich; Diel, Patrick

2015-11-01

The leptin resistant Zucker diabetic fatty (ZDF) rats are hyperphagic and become obese, but whereas the males develop type 2 diabetes mellitus (T2DM), the females remain euglycaemic. As estrogen deficiency is known to increase the risk of developing T2DM, we evaluated the role of ER subtypes alpha and beta in the development of glucose tolerance in leptin resistant ovariectomized (OVX) ZDF rats. At least six rats per group were treated with either vehicle (OVX), 17β-estradiol (E2), ER subtype-selective agonists (Alpha and Beta), or genistein (Gen) for 17 weeks. At the end of the treatment period a glucose tolerance assay was performed and the metabolic flux of (13)C-glucose for the E2 group was investigated. OVX ZDF rats treated with E2, Alpha, Beta, and Gen tolerated the glucose significantly better than untreated controls. E2 treatment increased absorbance/flux of (13)C-glucose to metabolic relevant tissues such liver, adipose tissue, gastrocnemius, and soleus muscle. Moreover, whereas Alpha treatment markedly increased mRNA expression of GLUT4 in gastrocnemius muscle, Beta treatment resulted in the largest fiber sizes of the soleus muscle. Treatment with Gen increased both the mRNA expression of GLUT 4 and the fiber sizes in the skeletal muscle. In addition, E2 and Alpha treatment decreased food intake and body weight gain. In summary, estrogen-improved glucose absorption is mediated via different molecular mechanisms: while activation of ER alpha seems to stimulate muscular GLUT4 functionality, activation of ER beta results in a hypertrophy of muscle fibers. In addition, selective activation of ER alpha decreased food intake and body weight gain. Our data further indicate that ER subtype-selective agonists and genistein improve systemic glucose tolerance also in the absence of a functional leptin signaling pathway. Copyright © 2015 Elsevier Ltd. All rights reserved.

FOXO3a-mediated suppression of the self-renewal capacity of sphere-forming cells derived from the ovarian cancer SKOV3 cell line by 7-difluoromethoxyl-5,4'-di-n-octyl genistein.

PubMed

Ning, Yingxia; Luo, Chaoyuan; Ren, Kaiqun; Quan, Meifang; Cao, Jianguo

2014-05-01

Carcinogenesis is predominantly dependent on the cancer stem cells (CSCs) residing or populating within the cancer. We previously demonstrated that the novel synthetic genistein analogue, 7-difluoromethoxyl-5,4'-di-n-octylgenistein (DFOG), induced apoptotic cell death of ovarian and gastric cancer cells. The present study demonstrated that sphere‑forming cells (SFCs) derived from the ovarian cancer cell-line SKOV3 possessed ovarian cancer stem-like cell (OCSLC) properties, including self-renewal and high tumorigenicity. DFOG may be effective in inhibiting the self‑renewal capacity of SFCs derived from the SKOV3 cell line. DFOG decreased the level of phosphorylated FOXO3a protein in SKOV3 cell‑derived SFCs. The inhibition of FOXO3a expression by siRNA significantly attenuated the ability of DFOG to inhibit the self-renewal capacity of SKOV3-derived SFCs. Our results suggested that DFOG has been demonstrated to significantly inhibit the self-renewal capacity of ovarian cancer stem cells (OCSCs) through a mechanism partly dependent on the activation of FOXO3a.

Environmental Estrogens Differentially Engage the Histone Methyltransferase EZH2 to Increase Risk of Uterine Tumorigenesis

PubMed Central

Greathouse, K. Leigh; Bredfeldt, Tiffany; Everitt, Jeffrey I.; Lin, Kevin; Berry, Tia; Kannan, Kurunthachalam; Mittelstadt, Megan L.; Ho, Shuk-mei; Walker, Cheryl L.

2013-01-01

Environmental exposures during sensitive windows of development can reprogram normal physiological responses and alter disease susceptibility later in life in a process known as developmental reprogramming. For example, exposure to the xenoestrogen diethylstilbestrol (DES) during reproductive tract development can reprogram estrogen-responsive gene expression in the myometrium, resulting in hyper-responsiveness to hormone in the adult uterus and promotion of hormone-dependent uterine leiomyoma. We show here that the environmental estrogens genistein (GEN), a soy phytoestrogen, and the plasticizer bisphenol A (BPA), differ in their pattern of developmental reprogramming and promotion of tumorigenesis (leiomyomas) in the uterus. While both GEN and BPA induce genomic estrogen receptor (ER) signaling in the developing uterus, only GEN induced PI3K/AKT non-genomic ER signaling to the histone methyltransferase Enhancer of Zeste homolog 2 (EZH2). As a result, this “pre-genomic” signaling phosphorylates and represses EZH2, and reduces levels of H3K27 repressive mark in chromatin. Furthermore, only GEN caused estrogen-responsive genes in the adult myometrium to become hyper-responsive to hormone; estrogen-responsive genes were repressed in BPA exposed uteri. Importantly, this pattern of EZH2 engagement to decrease versus increase H3K27 methylation correlated with the effect of these xenoestrogens on tumorigenesis. Developmental reprogramming by GEN promoted development of uterine leiomyomas, increasing tumor incidence and multiplicity, while BPA did not. These data demonstrate that environmental estrogens have distinct non-genomic effects in the developing uterus that determines their ability to engage the epigenetic regulator EZH2, decrease levels of the repressive epigenetic histone H3K27 methyl mark in chromatin during developmental reprogramming, and promote uterine tumorigenesis. PMID:22504913

Anxiogenic Effects of Developmental Bisphenol A Exposure Are Associated with Gene Expression Changes in the Juvenile Rat Amygdala and Mitigated by Soy

PubMed Central

Patisaul, Heather B.; Sullivan, Alana W.; Radford, Meghan E.; Walker, Deena M.; Adewale, Heather B.; Winnik, Bozena; Coughlin, Janis L.; Buckley, Brian; Gore, Andrea C.

2012-01-01

Early life exposure to Bisphenol A (BPA), a component of polycarbonate plastics and epoxy resins, alters sociosexual behavior in numerous species including humans. The present study focused on the ontogeny of these behavioral effects beginning in adolescence and assessed the underlying molecular changes in the amygdala. We also explored the mitigating potential of a soy-rich diet on these endpoints. Wistar rats were exposed to BPA via drinking water (1 mg/L) from gestation through puberty, and reared on a soy-based or soy-free diet. A group exposed to ethinyl estradiol (50 µg/L) and a soy-free diet was used as a positive estrogenic control. Animals were tested as juveniles or adults for anxiety-like and exploratory behavior. Assessment of serum BPA and genistein (GEN), a soy phytoestrogen, confirmed that internal dose was within a human-relevant range. BPA induced anxiogenic behavior in juveniles and loss of sexual dimorphisms in adult exploratory behavior, but only in the animals reared on the soy-free diet. Expression analysis revealed a suite of genes, including a subset known to mediate sociosexual behavior, associated with BPA-induced juvenile anxiety. Notably, expression of estrogen receptor beta (Esr2) and two melanocortin receptors (Mc3r, Mc4r) were downregulated. Collectively, these results show that behavioral impacts of BPA can manifest during adolescence, but wane in adulthood, and may be mitigated by diet. These data also reveal that, because ERβ and melanocortin receptors are crucial to their function, oxytocin/vasopressin signaling pathways, which have previously been linked to human affective disorders, may underlie these behavioral outcomes. PMID:22957036

Folate Receptor-targeted Bioflavonoid Genistein-loaded Chitosan Nanoparticles for Enhanced Anticancer Effect in Cervical Cancers

NASA Astrophysics Data System (ADS)

Cai, Limei; Yu, Rufen; Hao, Xi; Ding, Xiangcui

2017-08-01

In this study, novel folic acid-conjugated chitosan nanoparticle was formulated for specific delivery of bioflavonoid, Genistein (GEN), to the cervical cancer cells. The prepared GEN-loaded chitosan nanoparticles (GCN) and folic acid-conjugated GCN (FGCN) showed smaller size with a controlled drug release profile. FGCN exhibited enhanced internalization potential in HeLa cells than that of GCN. The specific internalization of FGCN was mainly due to the affinity of folic acid (FA) with FRs-α which is present in large numbers in HeLa cells. The results revealed that FGCN has a specific affinity towards HeLa cells that will contribute to the better treatment. Folic acid-tagged nanoformulations exhibited a superior cytotoxic effect compared to that of non-targeted formulations. Consistently, IC50 value of GEN decreased from 33.8 to 14.6 μg/ml when treated with FGCN after 24 h incubation. The apoptosis studies indicated that the FGCN nanoparticles were then either GCN or free GEN in terms of anticancer activity. Overall, results revealed that folate conjugation to the delivery system might have great effect on the survival of cervical cancers that will be beneficial for overall cancer treatment.

In vitro antioxidant/prooxidant effects of combined use of flavonoids.

PubMed

Eren-Guzelgun, B; Ince, E; Gurer-Orhan, H

2018-06-01

The present study was undertaken to investigate the individual and combined antioxidant or prooxidant effects of genistein, daidzein and quercetin in human erythrocytes and rat microsomes in vitro. Their reducing potential against oxidation of a redox sensitive fluorescent probe, their protective effect against H 2 O 2 -induced membrane lipid peroxidation and their inhibitory effect on AAPH-induced hemolysis were evaluated. Genistein and daidzein were prooxidant in erythrocytes but antioxidant in microsomes where their metabolites might have been formed which suggests the importance of metabolic capacity in in vitro models to predict the physiological situation. Quercetin showed antioxidant effects in all models and conditions. Prooxidant effect of 'genistein-daidzein mixture', at their concentrations reflecting the real life, was suppressed by addition of quercetin to the mixture. Our study shows that flavonoids can exert prooxidant effects depending on the conditions, but the mixture effect should be considered while assessing their effects and safety in humans.

A Hypothesis Regarding the Molecular Mechanism Underlying Dietary Soy-Induced Effects on Seizure Propensity

PubMed Central

Westmark, Cara Jean

2014-01-01

Numerous neurological disorders including fragile X syndrome, Down syndrome, autism, and Alzheimer’s disease are co-morbid with epilepsy. We have observed elevated seizure propensity in mouse models of these disorders dependent on diet. Specifically, soy-based diets exacerbate audiogenic-induced seizures in juvenile mice. We have also found potential associations between the consumption of soy-based infant formula and seizure incidence, epilepsy comorbidity, and autism diagnostic scores in autistic children by retrospective analyses of medical record data. In total, these data suggest that consumption of high levels of soy protein during postnatal development may affect neuronal excitability. Herein, we present our theory regarding the molecular mechanism underlying soy-induced effects on seizure propensity. We hypothesize that soy phytoestrogens interfere with metabotropic glutamate receptor signaling through an estrogen receptor-dependent mechanism, which results in elevated production of key synaptic proteins and decreased seizure threshold. PMID:25232349

13C CP MAS NMR and GIAO-CHF/DFT calculations of flavonoids: Morin, kaempferol, tricin, genistein, formononetin and 3,7-dihydroxyflavone

NASA Astrophysics Data System (ADS)

Zielińska, Agnieszka; Paradowska, Katarzyna; Jakowski, Jacek; Wawer, Iwona

2008-02-01

13C CP MAS NMR spectra of the flavonoids: morin, kaempferol, 3,7-dihydroxyflavone, tricin and isoflavones: genistein and formononetin were recorded to characterize solid-state conformations. Intramolecular hydrogen bonds forming five-, six- and seven-membered rings are present in the two morin molecules in the crystals - their 13C resonances have been assigned with the aid of the calculated shielding constants. Linear relationships between the calculated shielding constants σDFT (ppm) and chemical shifts ( δCPMAS, ppm) were obtained for all studied compounds. Higher correlation coefficients suggest that the conformation with "clockwise" orientation of both OH groups is more probable in the solid 3,7-dihydroxyflavone, whereas in the solid formononetin the OH and OCH 3 substituents are directed "anticlockwise". The barrier to the rotation of phenyl ring B decreases in the order: morin (2'-OH, 3-OH) > kaempferol (3-OH) > tricin.

Stretch-induced ERK2 phosphorylation requires PLA2 activity in skeletal myotubes.

PubMed

Burkholder, Thomas J

2009-08-14

Mechanical stretch rapidly activates multiple signaling cascades, including phospholipases and kinases, to stimulate protein synthesis and growth. The purpose of this study was to determine whether PLA2 activation contributes to stretch-induced phosphorylation of ERK2 in skeletal muscle myotubes. Myotubes derived from neonatal C57 mice were cultured on silicone membranes and subjected to brief cyclic stretch. Inhibition of PLA2 prevented ERK2 phosphorylation, while inhibition of prostaglandin or leukotriene synthesis did not. ERK2 phosphorylation was also blocked by genistein and PD98059, implicating the canonical raf-MEK-ERK cassette. It appears that PLA2, but not further metabolism of arachidonic acid, is required for stretch-induced activation of ERK2. Exposure to exogenous arachidonic acid had no effect on ERK2 phosphorylation, but exposure to lysophosphatidylcholine, the other metabolite of PLA2, caused a dose-dependent increase in ERK2 phosphorylation. These results suggest that stretch-induced activation of ERK2 may result from an interaction between PLA2 derived lysophosphatidylcholine and membrane receptors.

Stretch-induced ERK2 phosphorylation requires PLA2 activity in skeletal myotubes

PubMed Central

Burkholder, Thomas J.

2009-01-01

Mechanical stretch rapidly activates multiple signaling cascades, including phospholipases and kinases, to stimulate protein synthesis and growth. The purpose of this study was to determine whether PLA2 activation contributes to stretch-induced phosphorylation of ERK2 in skeletal muscle myotubes. Myotubes derived from neonatal C57 mice were cultured on silicone membranes and subjected to brief cyclic stretch. Inhibition of PLA2 prevented ERK2 phosphorylation, while inhibition of prostaglandin or leukotriene synthesis did not. ERK2 phosphorylation was also blocked by genistein and PD98059, implicating the canonical raf-MEK-ERK cassette. It appears that PLA2, but not further metabolism of arachidonic acid, is required for stretch-induced activation of ERK2. Exposure to exogenous arachidonic acid had no effect on ERK2 phosphorylation, but exposure to lysophosphatidylcholine, the other metabolite of PLA2, caused a dose-dependent increase in ERK2 phosphorylation. These results suggest that stretch-induced activation of ERK2 may result from an interaction between PLA2 derived lysophosphatidylcholine and membrane receptors. PMID:19524551

[Evaluation on a fast weight reduction model in vitro].

PubMed

Li, Songtao; Li, Ying; Wen, Ying; Sun, Changhao

2010-03-01

To establish a fast and effective model in vitro for screening weight-reducing drugs and taking preliminary evaluation of the model. Mature adipocytes of SD rat induced by oleic acid were used to establish a obesity model in vitro. Isoprel, genistein, caffeine were selected as positive agents and curcumine as negative agent to evaluate the obesity model. Lipolysis of adipocytes was stimulated significantly by isoprel, genistein and caffeine rather than curcumine. This model could be used efficiently for screening weight-losing drugs.

Estimated intakes of isoflavones and coumestrol in Korean population.

PubMed

Surh, Jeonghee; Kim, Min-Jeong; Koh, Eunmi; Kim, Young-Kyung L; Kwon, Hoonjeong

2006-01-01

The dietary intakes and sources of isoflavones and coumestrol were estimated for each age group of Koreans based on data from the Korean Nutrition Survey conducted in 1998. For quantitative data on the levels of isoflavones and coumestrol, our previous study monitoring phytoestrogens in 220 Korean leguminous foodstuffs was employed and the median value for each food was adopted. The total isoflavones and coumestrol intake per capita was estimated as 23.3 mg/day, which constituted 14.2 mg daidzein, 6.7 mg genistein, 0.9 mg glycitein, 1.0 mg formononetin, 0.2 mg biochanin A, and 0.3 mg coumestrol. The top five foods arrowroot, soybean paste, tofu, soybean, and soybean sprout contributed to 88.2% of isoflavone intake, with the corresponding intake from each food being 8.3 mg/day, 4.9 mg/day, 2.6 mg/day, 2.5 mg/day, and 2.0 mg/day, respectively. Starting at age 3-6, the contributions of fermented soy products to the isoflavones intakes were around 30%. Soybean sprout was a major source of coumestrol intake in Koreans. Slight differences in the preference of these foods were observed among the various age groups. As regards the total isoflavone intakes, the highest value was 33.6 mg/day for people age 30-49, followed by age 50-64 (26.4 mg/day), 20-29 (21.0 mg/day), >or=65 (18.8 mg/day), 1-2 (14.5 mg/day), 7-12 (12.4 mg/day), 13-19 (10.1 mg/day), and 3-6 (8.9 mg/day). The intake levels are likely to be exceeded in groups who have preferably consumed high phytoestrogen-containing foods such as soy-protein-based infant formula and arrowroot.

Soy foods, isoflavones, and the health of postmenopausal women.

PubMed

Messina, Mark

2014-07-01

Over the past 2 decades, soy foods have been the subject of a vast amount of research, primarily because they are uniquely rich sources of isoflavones. Isoflavones are classified as both phytoestrogens and selective estrogen receptor modulators. The phytoestrogenic effects of isoflavones have led some to view soy foods and isoflavone supplements as alternatives to conventional hormone therapy. However, clinical research shows that isoflavones and estrogen exert differing effects on a variety of health outcomes. Nevertheless, there is substantial evidence that soy foods have the potential to address several conditions and diseases associated with the menopausal transition. For example, data suggest that soy foods can potentially reduce ischemic heart disease through multiple mechanisms. Soy protein directly lowers blood low-density lipoprotein-cholesterol concentrations, and the soybean is low in saturated fat and a source of both essential fatty acids, the omega-6 fatty acid linoleic acid and the omega-3 fatty acid alpha-linolenic acid. In addition, soflavones improve endothelial function and possibly slow the progression of subclinical atherosclerosis. Isoflavone supplements also consistently alleviate menopausal hot flashes provided they contain sufficient amounts of the predominant soybean isoflavone genistein. In contrast, the evidence that isoflavones reduce bone loss in postmenopausal women is unimpressive. Whether adult soy food intake reduces breast cancer risk is unclear. Considerable evidence suggests that for soy to reduce risk, consumption during childhood and/or adolescence is required. Although concerns have been raised that soy food consumption may be harmful to breast cancer patients, an analysis in 9514 breast cancer survivors who were followed for 7.4 y found that higher postdiagnosis soy intake was associated with a significant 25% reduction in tumor recurrence. In summary, the clinical and epidemiologic data indicate that adding soy foods to the

The effects of estrogen receptors α- and β-specific agonists and antagonists on cell proliferation and energy metabolism in human bone cell line.

PubMed

Somjen, D; Katzburg, S; Sharon, O; Grafi-Cohen, M; Knoll, E; Stern, N

2011-02-01

In cultured human osteoblasts estradiol-17β (E2) modulated DNA synthesis, the specific activity of creatine kinase BB (CK), 12 and 15 lipoxygenase (LO) mRNA expression and formation of 12- and 15-hydroxyeicosatetraenoic acid (HETE). We now investigate the response of human bone cell line (SaOS2) to phytoestrogens and estrogen receptors (ER)-specific agonists and antagonists. Treatment of SaSO2 with E2, 2,3-bis (4-hydroxyphenyl)-propionitrile (DPN; ERβ-specific agonist), 4,4',4″-[4-propyl-(1H)-pyrazol-1,3,5-triyl] tris-phenol (PPT; ERα-specific agonist), biochainin A (BA), daidzein (D), genistein (G) and raloxifene (Ral) showed increased DNA synthesis and CK. Ral inhibited completely all stimulations except DPN and to some extent D. The ERα-specific antagonist methyl-piperidino-pyrazole (MPP) and the ERβ-specific antagonist 4-[2-phenyl-5,7-bis (tri-fluoro-methyl) pyrazolo [1,5-a]pyrimidin-3-yl] phenol (PTHPP) inhibited DNA synthesis, CK and reactive oxygen species (ROS) formation induced by estrogens according to their receptors affinity. The LO inhibitor baicaleine inhibited only E2, DPN and G's effects. E2 and Ral unlike all other compounds had no effect on ERα mRNA expression, while ERβ mRNA expression was stimulated by all compounds. All compounds modulated the expression of 12LO and 15LO mRNA, except E2, PPT and Ral for 12LO, and 12- and 15-HETE productions and stimulated ROS formation which was inhibited by NADPH oxidase inhibitors diphenyleneiodonium chloride (DPI) and N-acetyl cysteine and the estrogen inhibitor ICI. DPI did not affect hormonal-induced DNA and CK. In conclusion, we provide evidence for the separation of mediation via ERα and ERβ pathways in the effects of estrogenic compounds on osteoblasts, but the role of LO/HETE/ROS is unclear. Copyright © 2010 Wiley-Liss, Inc.

Stimulating the GPR30 estrogen receptor with a novel tamoxifen analogue activates SF-1 and promotes endometrial cell proliferation.

PubMed

Lin, Benjamin C; Suzawa, Miyuki; Blind, Raymond D; Tobias, Sandra C; Bulun, Serdar E; Scanlan, Thomas S; Ingraham, Holly A

2009-07-01

Estrogens and selective estrogen receptor (ER) modulators such as tamoxifen are known to increase uterine cell proliferation. Mounting evidence suggests that estrogen signaling is mediated not only by ERalpha and ERbeta nuclear receptors, but also by GPR30 (GPER), a seven transmembrane (7TM) receptor. Here, we report that primary human endometriotic H-38 cells express high levels of GPR30 with no detectable ERalpha or ERbeta. Using a novel tamoxifen analogue, STX, which activates GPR30 but not ERs, significant stimulation of the phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways was observed in H-38 cells and in Ishikawa endometrial cancer cells expressing GPR30; a similar effect was observed in JEG3 choriocarcinoma cells. STX treatment also increased cellular pools of phosphatidylinositol (3,4,5) triphosphate, a proposed ligand for the nuclear hormone receptor SF-1 (NR5A1). Consistent with these findings, STX, tamoxifen, and the phytoestrogen genistein were able to increase SF-1 transcription, promote Ishikawa cell proliferation, and induce the SF-1 target gene aromatase in a GPR30-dependent manner. Our findings suggest a novel signaling paradigm that is initiated by estrogen activation of the 7TM receptor GPR30, with signal transduction cascades (PI3K and MAPK) converging on nuclear hormone receptors (SF-1/LRH-1) to modulate their transcriptional output. We propose that this novel GPR30/SF-1 pathway increases local concentrations of estrogen, and together with classic ER signaling, mediate the proliferative effects of synthetic estrogens such as tamoxifen, in promoting endometriosis and endometrial cancers.

Soy but not bisphenol A (BPA) or the phytoestrogen genistin alters developmental weight gain and food intake in pregnant rats and their offspring

PubMed Central

Cao, Jinyan; Echelberger, Roger; Liu, Min; Sluzas, Emily; McCaffrey, Katherine; Buckley, Brian; Patisaul, Heather B.

2015-01-01

Endocrine disrupting compounds (EDCs) are hypothesized to promote obesity and early puberty but their interactive effects with hormonally active diets are poorly understood. Here we assessed individual and combinatorial effects of soy diet or the isoflavone genistein (GEN; administered as the aglycone genistin GIN) with bisphenol A (BPA) on body weight, ingestive behavior and female puberal onset in Wistar rats. Soy-fed dams gained less weight during pregnancy and, although they consumed more than dams on a soy-free diet during lactation, did not become heavier. Their offspring (both sexes), however, became significantly heavier (more pronounced in males) pre-weaning. Soy also enhanced food intake and accelerated female pubertal onset in the offspring. Notably, pubertal onset was also advanced in females placed on soy diet at weaning. Males exposed to BPA plus soy diet, but not BPA alone, had lighter testes. BPA had no independent effects. PMID:26216788

Gene expression profiling in Ishikawa cells: A fingerprint for estrogen active compounds

DOE Office of Scientific and Technical Information (OSTI.GOV)

Boehme, Kathleen; Simon, Stephanie; Mueller, Stefan O.

2009-04-01

Several anthropogenous and naturally occurring substances, referred to as estrogen active compounds (EACs), are able to interfere with hormone and in particular estrogen receptor signaling. EACs can either cause adverse health effects in humans and wildlife populations or have beneficial effects on estrogen-dependent diseases. The aim of this study was to examine global gene expression profiles in estrogen receptor (ER)-proficient Ishikawa plus and ER-deficient Ishikawa minus endometrial cancer cells treated with selected well-known EACs (Diethylstilbestrol, Genistein, Zearalenone, Resveratrol, Bisphenol A and o,p'-DDT). We also investigated the effect of the pure antiestrogen ICI 182,780 (ICI) on the expression patterns caused bymore » these compounds. Transcript levels were quantified 24 h after compound treatment using Illumina BeadChip Arrays. We identified 87 genes with similar expression changes in response to all EAC treatments in Ishikawa plus. ICI lowered the magnitude or reversed the expression of these genes, indicating ER dependent regulation. Apart from estrogenic gene regulation, Bisphenol A, o,p'-DDT, Zearalenone, Genistein and Resveratrol displayed similarities to ICI in their expression patterns, suggesting mixed estrogenic/antiestrogenic properties. In particular, the predominant antiestrogenic expression response of Resveratrol could be clearly distinguished from the other test compounds, indicating a distinct mechanism of action. Divergent gene expression patterns of the phytoestrogens, as well as weaker estrogenic gene expression regulation determined for the anthropogenous chemicals Bisphenol A and o,p'-DDT, warrants a careful assessment of potential detrimental and/or beneficial effects of EACs. The characteristic expression fingerprints and the identified subset of putative marker genes can be used for screening chemicals with an unknown mode of action and for predicting their potential to exert endocrine disrupting effects.« less

Dietary genistein supplementation in laying broiler breeder hens alters the development and metabolism of offspring embryos as revealed by hepatic transcriptome analysis.

PubMed

Lv, Zengpeng; Fan, Hao; Zhang, Beibei; Ning, Chao; Xing, Kun; Guo, Yuming

2018-03-08

Genistein (GEN) is a type of isoflavone mainly derived from soy products. In this experiment, we added 40 and 400 mg/kg GEN to the diet of laying broiler breeder hens to clarify the maternal effects of GEN on the development and metabolism of chick embryos. GEN treatment at 40 mg/kg increased embryonic length, weight, and liver index, as well as the width of the proliferative zone in the tibial growth plate of chick embryos. Gene ontology (GO) cluster analysis of the hepatic transcriptome showed that GEN treatment promoted embryonic development and cell proliferation. Low-dose GEN treatment increased insulin growth factor-binding protein (IGFBP)3 mRNA expression in the embryonic liver, whereas high-dose GEN treatment increased IGFBP5 expression and activated the apoptosis and protein tyrosine kinase signaling pathways. Furthermore, adding supplemental GEN to the diet of hens promoted the glycolysis process in the embryonic liver through the insulin-signaling pathway, upregulated target genes (phosphoglucomutase-2, hexokinase 1, dihydroxyacetone phosphate by aldolase, phosphofructokinase, platelet, and enolase 2), and enhanced the transport of carboxylic acids and cholesterol and the synthesis of unsaturated fatty acid (arachidonic acid) in the embryonic liver through upregulation of liver X receptor, sterol regulatory element-binding protein 1, and patatin-like phospholipase A. Additionally, GEN treatment increased fatty acid β-oxidation and Na + /K + -ATPase activity in the embryonic liver through activation of peroxisome proliferator-activated receptors (PPARs; PPARα and PPARδ) and the AMPK signaling pathway, which could provide energy for embryonic development. In addition, GEN treatment in hens increased superoxide dismutase activity and metallothionein expression in the chick embryonic liver and promoted lymphocyte proliferation through upregulation of mRNA expression of CDKN1A, IL12RB1, Sox11, PRKAR1A, PRKCQ, and TCF3. The improved immunity and antioxidant

Effects of a phytoestrogen-containing soy extract on the growth-inhibitory activity of ICI 182 780 in an experimental model of estrogen-dependent breast cancer.

PubMed

Gallo, Daniela; Mantuano, Elisabetta; Fabrizi, Manuela; Ferlini, Cristiano; Mozzetti, Simona; De Stefano, Ilaria; Scambia, Giovanni

2007-06-01

The study reported here was designed to determine whether a phytoestrogen-containing soy extract (SSE) could negate/overwhelm the inhibitory effects of ICI 182 780 on the growth of estrogen-sustained human breast cancer xenografts (MCF-7), in ovariectomized athymic mice. As expected, estradiol-supplemented tumors did not grow over the study period in ICI 182 780-treated females; concomitant administration of 50 mg/kg per day SSE slightly potentiated the inhibitory activity of the drug, while at 100 mg/kg per day, SSE partially negated ICI 182 780 activity. In keeping with these in vivo outcomes, we observed that the level of cyclin D1 (and progesterone receptor) in MCF-7 xenografts was considerably reduced by ICI 182 780, an effect enhanced by concomitant treatment with 50 SSE, but reduced by the higher dosage (i.e. 100 mg/kg per day). Thrombospondin-1 (TSP-1) and kallikrein 6 (KLK6) levels were also reduced following ICI 182 780, although to a lesser degree; again, combined anti-estrogen and SSE produced a dose-dependent regulation in TSP-1 and KLK6 tumor level, with a further reduction in the mRNA gene expression at 50 SSE (compared with ICI 182 780) and a partial reversion of the drug-induced down-regulation at 100 mg/kg per day. No modulation was detected in the serum concentration of IGF-1 (a potent mitogen for estrogen receptor-positive breast cancer cell lines) either upon treatment with ICI 182 780 or concomitant administration of the anti-estrogen with SSE. In conclusion, results from this study raise concerns about the consumption of isoflavone supplements in conjunction with ICI 182 780 therapy, in postmenopausal women with estrogen-dependent breast cancer.

Inhibition of acetylcholinesterase by two genistein derivatives: kinetic analysis, molecular docking and molecular dynamics simulation.

PubMed

Fang, Jiansong; Wu, Ping; Yang, Ranyao; Gao, Li; Li, Chao; Wang, Dongmei; Wu, Song; Liu, Ai-Lin; Du, Guan-Hua

2014-12-01

In this study two genistein derivatives (G1 and G2) are reported as inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), and differences in the inhibition of AChE are described. Although they differ in structure by a single methyl group, the inhibitory effect of G1 (IC50=264 nmol/L) on AChE was 80 times stronger than that of G2 (IC50=21,210 nmol/L). Enzyme-kinetic analysis, molecular docking and molecular dynamics (MD) simulations were conducted to better understand the molecular basis for this difference. The results obtained by kinetic analysis demonstrated that G1 can interact with both the catalytic active site and peripheral anionic site of AChE. The predicted binding free energies of two complexes calculated by the molecular mechanics/generalized born surface area (MM/GBSA) method were consistent with the experimental data. The analysis of the individual energy terms suggested that a difference between the net electrostatic contributions (ΔE ele+ΔG GB) was responsible for the binding affinities of these two inhibitors. Additionally, analysis of the molecular mechanics and MM/GBSA free energy decomposition revealed that the difference between G1 and G2 originated from interactions with Tyr124, Glu292, Val294 and Phe338 of AChE. In conclusion, the results reveal significant differences at the molecular level in the mechanism of inhibition of AChE by these structurally related compounds.

Investigation of relationships between urinary biomarkers of phytoestrogens, phthalates, and phenols and pubertal stages in girls.

PubMed

Wolff, Mary S; Teitelbaum, Susan L; Pinney, Susan M; Windham, Gayle; Liao, Laura; Biro, Frank; Kushi, Lawrence H; Erdmann, Chris; Hiatt, Robert A; Rybak, Michael E; Calafat, Antonia M

2010-07-01

Hormonally active environmental agents may alter the course of pubertal development in girls, which is controlled by steroids and gonadotropins. We investigated associations of concurrent exposures from three chemical classes (phenols, phthalates, and phytoestrogens) with pubertal stages in a multiethnic longitudinal study of 1,151 girls from New York City, New York, greater Cincinnati, Ohio, and northern California who were 6-8 years of age at enrollment (2004-2007). We measured urinary exposure biomarkers at visit 1 and examined associations with breast and pubic hair development (present or absent, assessed 1 year later) using multivariate adjusted prevalence ratios (PR) and 95% confidence intervals (CIs). Modification of biomarker associations by age-specific body mass index percentile (BMI%) was investigated, because adipose tissue is a source of peripubertal hormones. Breast development was present in 30% of girls, and 22% had pubic hair. High-molecular-weight phthalate (high MWP) metabolites were weakly associated with pubic hair development [adjusted PR, 0.94 (95% CI, 0.88-1.00), fifth vs. first quintile]. Small inverse associations were seen for daidzein with breast stage and for triclosan and high MWP with pubic hair stage; a positive trend was observed for low-molecular-weight phthalate biomarkers with breast and pubic hair development. Enterolactone attenuated BMI associations with breast development. In the first enterolactone quintile, for the association of high BMI with any development, the PR was 1.34 (95% CI, 1.23-1.45 vs. low BMI). There was no BMI association in the fifth, highest quintile of enterolactone. Weak hormonally active xenobiotic agents investigated in this study had small associations with pubertal development, mainly among those agents detected at highest concentrations.

Secoisolariciresinol Diglucoside (SDG) Isolated from Flaxseed, an Alternative to ACE Inhibitors in the Treatment of Hypertension

PubMed Central

Prasad, Kailash

2013-01-01

Secoisolariciresionol diglucoside (SDG) is a plant lignan isolated from flaxseed and is phytoestrogen. SDG is a potent and long-acting hypotensive agent. Plant phytoestrogens have inhibitory effects on angiotensin-converting enzyme (ACE). The hypotensive effects of SDG, a phytoestrogen, may be mediated through inhibition of ACE. The objective of this study was to investigate if SDG-induced hypotension is mediated through inhibition of ACE. The Sprague Dawley male rats were anesthetized and trachea was cannulated. The right jugular vein was cannulated to administer the drug and the carotid artery was cannulated to record arterial pressures using PIOEZ-1 miniature model transducer (Becton, Dickinson and Company, Franklin Lakes, NJ) and Beckman dynograph (Beckman Instruments, Inc., Schiller Park, IL). The effects of angiotensin I (0.2 µg/kg, intravenously [IV]) in the absence and presence of SDG (10 mg/kg, IV), and SDG alone on systolic, diastolic, and mean arterial pressures were measured before and after 15, 30, and 60 minutes of drug administration. SDG decreased the systolic, diastolic, and mean arterial pressure by 37, 47, and 43%, respectively, at 15 minutes and 18.8, 21.2, and 20.3%, respectively, at 60 minutes. Angiotensin I increased the arterial pressure. SDG decreased angiotensin I-induced rise in the systolic, diastolic, and mean arterial pressures by 60, 58, and 51%, respectively, at 15 minutes and 48, 46, and 30%, respectively, at 60 minutes. The data suggest that SDG reduced the angiotensin I-induced rise in the arterial pressures and hence SDG is a potent ACE inhibitor. PMID:24436618

Secoisolariciresinol Diglucoside (SDG) Isolated from Flaxseed, an Alternative to ACE Inhibitors in the Treatment of Hypertension.

PubMed

Prasad, Kailash

2013-12-01

Secoisolariciresionol diglucoside (SDG) is a plant lignan isolated from flaxseed and is phytoestrogen. SDG is a potent and long-acting hypotensive agent. Plant phytoestrogens have inhibitory effects on angiotensin-converting enzyme (ACE). The hypotensive effects of SDG, a phytoestrogen, may be mediated through inhibition of ACE. The objective of this study was to investigate if SDG-induced hypotension is mediated through inhibition of ACE. The Sprague Dawley male rats were anesthetized and trachea was cannulated. The right jugular vein was cannulated to administer the drug and the carotid artery was cannulated to record arterial pressures using PIOEZ-1 miniature model transducer (Becton, Dickinson and Company, Franklin Lakes, NJ) and Beckman dynograph (Beckman Instruments, Inc., Schiller Park, IL). The effects of angiotensin I (0.2 µg/kg, intravenously [IV]) in the absence and presence of SDG (10 mg/kg, IV), and SDG alone on systolic, diastolic, and mean arterial pressures were measured before and after 15, 30, and 60 minutes of drug administration. SDG decreased the systolic, diastolic, and mean arterial pressure by 37, 47, and 43%, respectively, at 15 minutes and 18.8, 21.2, and 20.3%, respectively, at 60 minutes. Angiotensin I increased the arterial pressure. SDG decreased angiotensin I-induced rise in the systolic, diastolic, and mean arterial pressures by 60, 58, and 51%, respectively, at 15 minutes and 48, 46, and 30%, respectively, at 60 minutes. The data suggest that SDG reduced the angiotensin I-induced rise in the arterial pressures and hence SDG is a potent ACE inhibitor.

Soy but not bisphenol A (BPA) induces hallmarks of polycystic ovary syndrome (PCOS) and related metabolic co-morbidities in rats.

PubMed

Patisaul, Heather B; Mabrey, Natalie; Adewale, Heather B; Sullivan, Alana W

2014-11-01

Polycystic ovarian syndrome (PCOS) is the most common female endocrine disorder with a prevalence as high as 8-15% depending on ethnicity and the diagnostic criteria employed. The basic pathophysiology and mode of inheritance remain unclear, but environmental factors such as diet, stress and chemical exposures are thought to be contributory. Developmental exposure to endocrine disrupting compounds (EDCs) have been hypothesized to exacerbate risk, in part because PCOS hallmarks and associated metabolic co-morbidities can be reliably induced in animal models by perinatal androgen exposure. Here we show that lifetime exposure to a soy diet, containing endocrine active phytoestrogens, but not developmental exposure (gestational day 6-lactational day 40) to the endocrine disrupting monomer bisphenol A (BPA), can induce key features of PCOS in the rat; results which support the hypothesis that hormonally active diets may contribute to risk when consumed throughout gestation and post-natal life. Copyright © 2014 Elsevier Inc. All rights reserved.

Inhibition of 3alpha-hydroxysteroid dehydrogenase (3alpha-HSD) activity of human lung microsomes by genistein, daidzein, coumestrol and C(18)-, C(19)- and C(21)-hydroxysteroids and ketosteroids.

PubMed

Blomquist, Charles H; Lima, Paul H; Hotchkiss, John R

2005-07-01

Epidemiologic data suggest a relationship between dietary intake of phytochemicals and a lower incidence of some cancers. Modulation of steroid hormone metabolism has been proposed as a basis for this effect. It has been shown that aromatase, 3beta-hydroxysteroid dehydrogenase and 17beta-hydroxysteroid dehydrogenase (17beta-HSD) are inhibited by the isoflavones, genistein and daidzein, and by coumestrol. In general, the extent of inhibition has been expressed in terms of IC50-values, which do not give information as to the pattern of inhibition, i.e., competitive, non-competitive, or mixed. Less is known of the effects of these compounds on 3alpha-HSD. The human lung is known to have a high level of 17beta-HSD and 3alpha-HSD activity. During the course of studies to characterize both activities in normal and inflamed lung and lung tumors we noted that 3alpha-HSD activity with 5alpha-DHT of microsomes from normal, adult lung was particularly susceptible to inhibition by coumestrol. To clarify the pattern of inhibition, the inhibition constants Ki and K'i were evaluated from plots of 1/v versus [I] and [S]/v versus [I]. Genistein, daidzein and coumestrol gave mixed inhibition patterns versus both 5alpha-DHT and NADH. In contrast, 5alpha-androstane-3,17-dione and 5alpha-pregnane-3,20-dione were competitive with 5alpha-DHT. NAD inhibited competitively with NADH. Our findings demonstrate that phytochemicals have the potential to inhibit 5alpha-DHT metabolism and thereby affect the androgen status of the human lung. The observation of a mixed inhibition pattern suggests these compounds bind to more than one form of the enzyme within the catalytic pathway.

Soy isoflavones and immunity.

PubMed

Sakai, Tohru; Kogiso, Mari

2008-08-01

The amount of soy products consumed in Japan is much greater than that in Western countries. Recent evidence indicates that soy isoflavones play a beneficial role in obesity, cancer, osteoporosis, and cardiovascular disease. The soybean isoflavone genistein is present at high levels in soy products. Genistein is structurally similar to 17beta-estradiol (E2), and genistein has been suggested to be act as E2 or an antagonist against E2. Genistein suppresses antigen-specific immune response in vivo and lymphocyte proliferation response in vitro. However, genistein enhances the cytotoxic response mediated by NK and cytotoxic T cells and the cytokine production from T cells. Thus, the effect of genistein on immunity is immune cell-dependent. Due to its unique effect on immune function, genistein has been used for the treatment of the diseases in animal models and it has been found that genistein inhibits allergic inflammatory responses. In this review, we summarize current studies related to the effect of isoflavone genistein on the immune system.

Lespedeza bicolor ameliorates endothelial dysfunction induced by methylglyoxal glucotoxicity.

PubMed

Do, Moon Ho; Lee, Jae Hyuk; Wahedi, Hussain Mustatab; Pak, Chaeho; Lee, Choong Hwan; Yeo, Eui-Ju; Lim, Yunsook; Ha, Sang Keun; Choi, Inwook; Kim, Sun Yeou

2017-12-01

Lespedeza species have been used as a traditional medicine to treat nephritis, azotemia, inflammation, energy depletion, diabetes, and diuresis. The purpose of this study is to screen the most potent Lespedeza species against methylglyoxal (MGO)-induced glucotoxicity, and to elucidate the mechanisms of action. Also, we will attempt to identify small chemical metabolites that might be responsible for such anti-glucotoxicity effects. Firstly, the protective effect of 26 different Lespedeza species against MGO-induced toxicity in human umbilical vein endothelial cells was investigated. The chemical metabolites of the most potent species (Lespedeza bicolor 1 (LB1) were identified by high pressure liquid chromatography quadrupole time-of-flight tandem mass spectrometry (HPLC-Q-TOF-MS/MS), then quantified by HPLC. The effects of LB1 on MGO-induced apoptosis were measured by annexin V-FITC staining and western blot. Inhibitory effects of LB1 on MGO-induced ROS generation, and effect of LB1 on advanced glycation end products (AGEs) inhibitor or a glycated cross-link breaker are also measured. Among different Lespedeza species, LB1 extract was shown to reduce intracellular reactive oxidative species, exhibit anti-apoptotic effects, strongly inhibit all the mitogen-activated protein kinase signals, inhibit MGO-induced AGEs formation, and break down preformed AGEs. We tentatively identified 17 chemical constituents of LB1 by HPLC-Q-TOF-MS/MS. Among those, some components, such as genistein and quercetin, significantly reduced the AGEs formation and increased the AGEs-breaking activity, resulting in the reduction of glucotoxicity. LB1 extract has shown to be effective in preventing or treating MGO-induced endothelial dysfunction. Copyright © 2017 Elsevier GmbH. All rights reserved.

Isoflavones isolated from red clover (Trifolium pratense) inhibit smooth muscle contraction of the isolated rat prostate gland.

PubMed

Brandli, A; Simpson, J S; Ventura, S

2010-09-01

This study investigated whether red clover contains any bioactive constituents which may affect contractility of rat prostatic smooth muscle in an attempt to determine whether its medicinal use in the treatment of benign prostatic hyperplasia is supported by pharmacological effects. A commercially available red clover extract was chemically fractionated and various isoflavones (genistein, formononetin and biochanin A) were isolated from these fractions and their effects on contractility were examined on preparations of the isolated rat prostate gland. Contractile effects of the isolated fractions were compared with commercially available isoflavones (genistein, formononetin and biochanin A). Pharmacological tools were used to investigate the mechanism of action modifying smooth muscle contraction. Crude red clover extract (Trinovin) inhibited electrical field stimulation induced contractions of the rat prostate across a range of frequencies with an IC(50) of approximately 68 microg/ml. Contractions of the rat prostate elicited by exogenous administration of acetylcholine, noradrenaline or adenosine 5'-triphosphate (ATP) were also inhibited. Chromatographic separation, and final purification by high performance liquid chromatography (HPLC) permitted the isolation of the isoflavones: daidzein, calycosin, formononetin, prunetin, pratensin, biochanin A and genistein. Genistein, formononetin and biochanin A (100 microM) from either commercial sources or isolated from red clover extract inhibited electrical field stimulation induced contractions of the isolated rat prostate. It is concluded that isoflavones contained in red clover are able to inhibit prostatic smooth muscle contractions in addition to their antiproliferative effects. However, the high concentrations required to observe these smooth muscle relaxant effects mean that a therapeutic benefit from this mechanism is unlikely at doses used clinically. Crown Copyright 2010. Published by Elsevier GmbH. All rights

Resveratrol protects rats from Aβ-induced neurotoxicity by the reduction of iNOS expression and lipid peroxidation.

PubMed

Huang, Tai-Chun; Lu, Kwok-Tung; Wo, Yu-Yuan Peter; Wu, Yao-Ju; Yang, Yi-Ling

2011-01-01

Alzheimer disease (AD) is an age-dependent neurodegenerative disease characterized by the formation of β-amyloid (Aβ)-containing senile plaque. The disease could be induced by the administration of Aβ peptide, which was also known to upregulate inducible nitric oxide synthase (iNOS) and stimulate neuronal apoptosis. The present study is aimed to elucidate the cellular effect of resveratrol, a natural phytoestrogen with neuroprotective activities, on Aβ-induced hippocampal neuron loss and memory impairment. On adult Sprague-Dawley rats, we found the injection of Aβ could result in a significant impairment in spatial memory, a marked increase in the cellular level of iNOS and lipid peroxidation, and an apparent decrease in the expression of heme oxygenase-1 (HO-1). By combining the treatment with Aβ, resveratrol was able to confer a significant improvement in spatial memory, and protect animals from Aβ-induced neurotoxicity. These neurological protection effects of resveratrol were associated with a reduction in the cellular levels of iNOS and lipid peroxidation and an increase in the production of HO-1. Moreover, the similar neurological and cellular response were also observed when Aβ treatment was combined with the administration of a NOS inhibitor, N(G)-nitro-L-arginine methyl ester hydrochloride (L-NAME). These findings strongly implicate that iNOS is involved in the Aβ-induced lipid peroxidation and HO-1 downregulation, and resveratrol protects animals from Aβ-induced neurotoxicity by suppressing iNOS production.

Resveratrol Protects Rats from Aβ-induced Neurotoxicity by the Reduction of iNOS Expression and Lipid Peroxidation

PubMed Central

Wo, Yu-Yuan Peter; Wu, Yao-Ju; Yang, Yi-Ling

2011-01-01

Alzheimer disease (AD) is an age-dependent neurodegenerative disease characterized by the formation of β–amyloid (Aβ)-containing senile plaque. The disease could be induced by the administration of Aβ peptide, which was also known to upregulate inducible nitric oxide synthase (iNOS) and stimulate neuronal apoptosis. The present study is aimed to elucidate the cellular effect of resveratrol, a natural phytoestrogen with neuroprotective activities, on Aβ-induced hippocampal neuron loss and memory impairment. On adult Sprague-Dawley rats, we found the injection of Aβ could result in a significant impairment in spatial memory, a marked increase in the cellular level of iNOS and lipid peroxidation, and an apparent decrease in the expression of heme oxygenase-1 (HO-1). By combining the treatment with Aβ, resveratrol was able to confer a significant improvement in spatial memory, and protect animals from Aβ-induced neurotoxicity. These neurological protection effects of resveratrol were associated with a reduction in the cellular levels of iNOS and lipid peroxidation and an increase in the production of HO-1. Moreover, the similar neurological and cellular response were also observed when Aβ treatment was combined with the administration of a NOS inhibitor, N(G)-nitro-L-arginine methyl ester hydrochloride (L-NAME). These findings strongly implicate that iNOS is involved in the Aβ-induced lipid peroxidation and HO-1 downregulation, and resveratrol protects animals from Aβ-induced neurotoxicity by suppressing iNOS production. PMID:22220203

The estrogenic effects of apigenin, phloretin and myricetin based on uterotrophic assay in immature Wistar albino rats.

PubMed

Barlas, Nurhayat; Özer, Saadet; Karabulut, Gözde

2014-04-07

Chemicals that occur in vegetal food and known as phytoestrogens, because of their structures similarity to estrogen, have benefits on chronic diseases. Despite this, when they are taken at high amounts, they can cause harmful effects on endocrine system of human and animals. In this study, it has been intended to determine the estrogenic potencies of phytoestrogens apigenin, phloretin and myricetin whose affinities for estrogen receptors in vitro. The female rats divided into 17 groups, each containing six rats. There was a negative control group and there were positive control dose groups which contains ethinyl estradiol, ethinyl estradiol+tamoxifen and genistein. The other dose groups which were tested for estrogenic activity contains apigenin, myricetin and phloretin All chemicals have been given to Wistar immature female rats with oral gavage for 3 consecutive days. By using uterotrophic analysis, uterus wet and blotted weights, vaginal opening, uterus length of female rats has been recorded at the end of the experiment. For detect of cell response, luminal epithelium height, gland number and lactoferrin intensity in luminal epithelium of uterus were evaluated. Biochemical analysises in blood were performed. Relative uterus weights of rats in 100 mg/kg/day dose group of myricetin were statistically increased according to vehicle control and positive control groups. In dose groups of apigenin and phloretin it was found that there were cell responses in uterus. All treatment groups had a significant difference in the high intensity of lactoferrin and uterine gland count compared to oil control group. There was no difference between phloretin and apigenin treatment groups in uterine weight statictically. Uterine heights were increased in positive control groups and 100 mg/kg/day dose group of myricetin. Epithelial cell heights were increased in treatment groups except apigenin and phloretin dose groups. There was no difference between all treatment groups in

Phytoestrogens/insoluble fibers and colonic estrogen receptor β: Randomized, double-blind, placebo-controlled study

PubMed Central

Principi, Mariabeatrice; Di Leo, Alfredo; Pricci, Maria; Scavo, Maria Principia; Guido, Raffaella; Tanzi, Sabina; Piscitelli, Domenico; Pisani, Antonio; Ierardi, Enzo; Comelli, Maria Cristina; Barone, Michele

2013-01-01

AIM: To assess the safety and effect of the supplementation of a patented blend of dietary phytoestrogens and insoluble fibers on estrogen receptor (ER)-β and biological parameters in sporadic colonic adenomas. METHODS: A randomized, double-blind placebo-controlled trial was performed. Patients scheduled to undergo surveillance colonoscopy for previous sporadic colonic adenomas were identified, and 60 eligible patients were randomized to placebo or active dietary intervention (ADI) twice a day, for 60 d before surveillance colonoscopy. ADI was a mixture of 175 mg milk thistle extract, 20 mg secoisolariciresinol and 750 mg oat fiber extract. ER-β and ER-α expression, apoptosis and proliferation (Ki-67 LI) were assessed in colon samples. RESULTS: No adverse event related to ADI was recorded. ADI administration showed a significant increases in ER-β protein (0.822 ± 0.08 vs 0.768 ± 0.10, P = 0.04) and a general trend to an increase in ER-β LI (39.222 ± 2.69 vs 37.708 ± 5.31, P = 0.06), ER-β/ER-α LI ratio (6.564 ± 10.04 vs 2.437 ± 1.53, P = 0.06), terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (35.592 ± 14.97 vs 31.541 ± 11.54, P = 0.07) and Ki-67 (53.923 ± 20.91 vs 44.833 ± 10.38, P = 0.07) approximating statistical significance. A significant increase of ER-β protein (0.805 ± 0.13 vs 0.773 ± 0.13, P = 0.04), mRNA (2.278 ± 1.19 vs 1.105 ± 1.07, P < 0.02) and LI (47.533 ± 15.47 vs 34.875 ± 16.67, P < 0.05) and a decrease of ER-α protein (0.423 ± 0.06 vs 0.532 ± 0.11, P < 0.02) as well as a trend to increase of ER-β/ER-α protein in ADI vs placebo group were observed in patients without polyps (1.734 ± 0.20 vs 1.571 ± 0.42, P = 0.07). CONCLUSION: The role of ER-β on the control of apoptosis, and its amenability to dietary intervention, are supported in our study. PMID:23885143

Impact of soy isoflavones on the epigenome in cancer prevention.

PubMed

Pudenz, Maria; Roth, Kevin; Gerhauser, Clarissa

2014-10-15

Isoflavones (IF) such as genistein are cancer preventive phytochemicals found in soy and other legumes. Epidemiological studies point to a reduced risk for hormone‑dependent cancers in populations following a typical Asian diet rich in soy products. IF act as phytoestrogens and prevent tumorigenesis in rodent models by a broad spectrum of bioactivities. During the past 10 years, IF were shown to target all major epigenetic mechanisms regulating gene expression, including DNA methylation, histone modifications controlling chromatin accessibility, and non-coding RNAs. These effects have been suggested to contribute to cancer preventive potential in in vitro and in vivo studies, affecting several key processes such as DNA repair, cell signaling cascades including Wnt-signaling, induction of apoptosis, cell cycle progression, cell proliferation, migration and invasion, epithelial-mesenchymal transition (EMT), metastasis formation and development of drug-resistance. We here summarize the state-of-the-art of IF affecting the epigenome in major hormone-dependent, urogenital, and gastrointestinal tumor types and in in vivo studies on anti-cancer treatment or developmental aspects, and short-term intervention studies in adults. These data, while often requiring replication, suggest that epigenetic gene regulation represents an important novel target of IF and should be taken into consideration when evaluating the cancer preventive potential of IF in humans.

Impact of Soy Isoflavones on the Epigenome in Cancer Prevention

PubMed Central

Pudenz, Maria; Roth, Kevin; Gerhauser, Clarissa

2014-01-01

Isoflavones (IF) such as genistein are cancer preventive phytochemicals found in soy and other legumes. Epidemiological studies point to a reduced risk for hormone‑dependent cancers in populations following a typical Asian diet rich in soy products. IF act as phytoestrogens and prevent tumorigenesis in rodent models by a broad spectrum of bioactivities. During the past 10 years, IF were shown to target all major epigenetic mechanisms regulating gene expression, including DNA methylation, histone modifications controlling chromatin accessibility, and non-coding RNAs. These effects have been suggested to contribute to cancer preventive potential in in vitro and in vivo studies, affecting several key processes such as DNA repair, cell signaling cascades including Wnt-signaling, induction of apoptosis, cell cycle progression, cell proliferation, migration and invasion, epithelial-mesenchymal transition (EMT), metastasis formation and development of drug-resistance. We here summarize the state-of-the-art of IF affecting the epigenome in major hormone-dependent, urogenital, and gastrointestinal tumor types and in in vivo studies on anti-cancer treatment or developmental aspects, and short-term intervention studies in adults. These data, while often requiring replication, suggest that epigenetic gene regulation represents an important novel target of IF and should be taken into consideration when evaluating the cancer preventive potential of IF in humans. PMID:25322458

Neonatal exposure to daidzein, genistein, or the combination modulates bone development in female CD-1 mice.

PubMed

Kaludjerovic, Jovana; Ward, Wendy E

2009-03-01

Neonatal exposure to genistein (GEN), an isoflavone abundant in soy, favorably modulates bone mineral density (BMD) and bone strength in mice at adulthood. The study objective was to determine whether early exposure to a combination of the soy isoflavones daidzein (DAI) and GEN that naturally exists in soy protein-based infant formula results in greater benefits to bone at adulthood than either treatment alone. Male and female CD-1 mice (n = 8-16 pups per group per gender) were randomized to subcutaneous injections of DAI (2 mg x kg body weight(-1) x d(-1)), GEN (5 mg x kg body weight(-1) x d(-1)), DAI+GEN (7 mg x kg body weight(-1) x d(-1)), diethylstilbesterol (DES; positive control) (2 mg x kg body weight(-1) x d(-1)), or control (CON) from postnatal d 1-5 and were studied to 4 mo of age. BMD, biomechanical bone strength, and bone microarchitecture were assessed at the femur and lumbar vertebrae (LV). Females treated with DAI, GEN, DAI+GEN, or DES had greater (P < 0.05) BMD at the LV compared with CON and vertebra in the DAI and DES group were more resistant to compression fractures. Microstructural analyses demonstrated that treatment with DAI and GEN resulted in greater (P < 0.05) trabecular connectivity and trabecular thickness, respectively, than the CON. In conclusion, neonatal exposure to DAI and/or GEN had a positive effect on the skeleton of female mice at adulthood, but, compared with individual treatments, DAI+GEN did not have a greater benefit to bone in females or males.

Inhibition of in vitro growth and arrest in the G0/G1 phase of HCT8 line human colon cancer cells by kaempferide triglycoside from Dianthus caryophyllus.

PubMed

Martineti, Valentina; Tognarini, Isabella; Azzari, Chiara; Carbonell Sala, Silvia; Clematis, Francesca; Dolci, Marcello; Lanzotti, Virginia; Tonelli, Francesco; Brandi, Maria Luisa; Curir, Paolo

2010-09-01

The effects of phytoestrogens have been studied in the hypothalamic-pituitary-gonadal axis and in various non-gonadal targets. Epidemiologic and experimental evidence indicates a protective effect of phytoestrogens also in colorectal cancer. The mechanism through which estrogenic molecules control colorectal cancer tumorigenesis could possibly involve estrogen receptor beta, the predominantly expressed estrogen receptor subtype in colon mucosa.To validate this hypothesis, we therefore used an engineered human colon cancer cell line induced to overexpress estrogen receptor beta, beside its native cell line, expressing very low levels of ERbeta and not expressing ERalpha; as a phytoestrogenic molecule, we used kaempferide triglycoside, a glycosylated flavonol from a Dianthus caryophyllus cultivar. The inhibitory properties of this molecule toward vegetal cell growth have been previously demonstrated: however, no data on its activity on animal cell or information about the mechanism of this activity are available. Kaempferide triglycoside proved to inhibit the proliferation of native and estrogen receptor beta overexpressing colon cancer cells through a mechanism not mediated by ligand binding dependent estrogen receptor activation. It affected HCT8 cell cycle progression by increasing the G(0)/G(1) cell fraction and in estrogen receptor beta overexpressing cells increased two antioxidant enzymes. Interestingly, the biological effects of this kaempferide triglycoside were strengthened by the presence of high levels of estrogen receptor beta.Pleiotropic molecular effects of phytoestrogens may explain their protective activity against colorectal cancer and may represent an interesting area for future investigation with potential clinical applications. Copyright 2010 John Wiley & Sons, Ltd.

Acute alcohol-induced protection against infarction in rabbit hearts: differences from and similarities to ischemic preconditioning.

PubMed

Krenz, M; Baines, C P; Heusch, G; Downey, J M; Cohen, M V

2001-11-01

Recent studies reveal that brief ethanol exposure induces cardioprotection against simulated ischemia in cardiomyocytes by the activation of protein kinase C- epsilon. The present study tests the ability of ethanol to induce protection in rabbit hearts in which infarct size was the end-point and explores the signal transduction pathways involved. In isolated rabbit hearts, 50 m m ethanol infused for 5 min with 10 min of washout prior to 30 min of regional ischemia reduced infarct size (triphenyltetrazolium chloride staining) by 49%. Neither adenosine receptor blockade with 8-(p -sulfophenyl) theophylline nor the free radical scavenger N-2-mercaptopropionyl glycine inhibited the protection triggered by ethanol. In contrast, protein kinase C inhibition with chelerythrine, protein tyrosine kinase inhibition with genistein, and blockade of ATP-sensitive potassium channels (K(ATP)) with either 5-hydroxydecanoate or glibenclamide did abolish protection. Thus, transient ethanol exposure followed by washout prior to ischemia elicits a preconditioning-like effect involving protein kinase C, at least one protein tyrosine kinase, and K(ATP)channels, but neither adenosine nor free radicals. Copyright 2001 Academic Press.

Differential effect of pure isoflavones and soymilk on estrogen receptor activity in mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rando, Gianpaolo; Ramachandran, Balaji; Rebecchi, Monica

2009-06-15

Background: Because of the complexity of estrogen receptor (ER) physiological activity, the interaction of pure isoflavones or soy-based diets on ER needs to be clearly demonstrated. Objectives: To investigate the effects of the administration of isoflavones as a pure compound or as a component of diet on the ER transcriptional activity in adult mice. Methods: Effects of acute (6 h) and chronic (21 days) oral administration of soy milk, pure genistein and a mix of genistein and daidzein was studied in living ERE-Luc mice. In this animal model, the synthesis of luciferase is under the state of ER transcriptional activity.more » Luciferase activity was measured in living mice by daily bioluminescence imaging sessions and in tissue extracts by enzymatic assay. Results: Acute, oral administration of genistein or soymilk caused a significant increase of ER activity in liver. In a 20 day long treatment, soymilk was more potent than genistein in liver and appeared to extend its influence on ER transcriptional activity in other tissues, such as the digestive tract. A mixture of pure genistein and daidzein at the same concentration as in soymilk failed to induce significant changes during acute and chronic studies suggesting an important, uncharacterized role of the soymilk matrix. Consistent with this observation, synergistic effects of the matrix plus isoflavones were observed in MCF-7 cells stably transfected with the ERE-luc construct. Conclusions: This study underlines the limitations of the analysis of single food components in the evaluation of their effects on estrogen receptor activity and advocates the necessity to use complex organisms for the full comprehension of the effects of compounds altering the endocrine balance.« less

Global gene expression and morphological alterations in the mammary gland after gestational exposure to bisphenol A, genistein and indole-3-carbinol in female Sprague-Dawley offspring

DOE Office of Scientific and Technical Information (OSTI.GOV)

Grassi, Tony F.

This study aimed to evaluate the modifying effects of dietary genistein (GEN) and indole-3-carbinol (I3C) on early mammary gland development in female Sprague-Dawley offspring born to mothers exposed to BPA during gestation. Pregnant rats were treated with BPA25 or 250 μg/kg bw/day from gestational days 10 to 21 with or without dietary intake of GEN (250 mg/kg chow) or I3C (2000 mg/kg chow). At post-natal day (PND) 21, female offspring from different litters were euthanized for mammary gland development and gene expression analyses. Our results indicated that prenatal exposure to BPA25 and 250 did not modify the ductal elongation ofmore » the mammary gland tree or the estrogen receptor alpha (ER-α) expression in terminal end buds (TEBs). However, BPA25-exposed offspring had a higher number of terminal structures (TEBs + TDs) and an increased mammary branching and cell proliferation index in TEBs. Besides that, BPA25 and 250 modulated the expression of several genes in the immature mammary gland that were not changed in a dose dependent manner and involved different clusters of up- and down-regulated genes. Furthermore, BPA25 and BPA250 + I3C-treated groups also had a higher number of enriched functional gene categories. In addition, maternal dietary GEN and I3C in association with BPA exposure produced specific gene expression alterations in the mammary gland and overcome the adverse effect of BPA25, decreasing the branching of the mammary gland. In conclusion, prenatal BPA exposure induced both morphological and gene expression modifications on the mammary gland that dietary intake of GEN and I3C reverted on BPA25-exposed animals. - Highlights: • Gestational BPA and its association with GEN and I3C modify gene expression on the early mammary gland development. • GEN and I3C induced a different gene expression signature than lower BPA dose. • Dietary GEN and I3C countered the adverse effect of lower BPA dose on the cell proliferation and mammary gland

Unique Gene Expression Profiles in the Mammary Gland of Prepubertal and Adult Female Rats Treated With Estradiol or Soy Protein Isolate (SPI)

USDA-ARS?s Scientific Manuscript database

Concerns have arisen regarding infertility and increased breast cancer risk in women consuming soy foods, primarily because of the perceived estrogenicity of soy isoflavones such as genistein and daidzein. Two studies were conducted in mammary gland to determine if consumption of soy products induce...

Timing of Captopril Administration Determines Radiation Protection or Radiation Sensitization in a Murine Model of Total Body Irradiation

DTIC Science & Technology

2010-04-01

Prescribed by ANSI Std Z39-18 senescence and thereby prevent radiation- induced stem cell pool exhaustion. Our laboratory has shown that the isofla- vone...genistein transiently arrests the LT-HSC in the G0/ G1 phases of the cell cycle and reduces radiation- induced genotoxicity, senescence, and stem cell ...captopril- induced radiation protection correlated with tran- sient quiescence (increased G0) of the ST-HSC population and prevention of stem cell pool

Timing of Captopril Administration Determines Radiation Protection or Radiation Sensitization in a Murine Model of Total Body Irradiation

DTIC Science & Technology

2010-01-01

Prescribed by ANSI Std Z39-18 senescence and thereby prevent radiation- induced stem cell pool exhaustion. Our laboratory has shown that the isofla- vone...genistein transiently arrests the LT-HSC in the G0/ G1 phases of the cell cycle and reduces radiation- induced genotoxicity, senescence, and stem cell pool... induced radiation protection correlated with tran- sient quiescence (increased G0) of the ST-HSC population and prevention of stem cell pool

Evidence that simulated microgravity may alter the vascular nonreceptor tyrosine kinase second messenger pathway

NASA Technical Reports Server (NTRS)

Kahwaji, C. I.; Sheibani, S.; Han, S.; Siu, W. O.; Kaka, A. H.; Fathy, T. M.; el-Abbadi, N. H.; Purdy, R. E.

2000-01-01

Simulated microgravity (hind limb unweighting; HU) reduces maximal contractile capacity to norepinephrine (NE) but not 5-hydroxytryptamine (5-HT) in the rat abdominal aorta of male Wistar rats. Our earlier study showed that voltage-operated calcium channels, the MAPK pathway [1], and vasoconstrictive prostaglandins contribute to the NE-induced contraction of control (C) but not HU, aorta rings. Genistein, a general tyrosine kinase inhibitor, caused a significant reduction in vascular contractility in C but not HU arteries. The present study explored the role of protein kinase C (PKC) and extracellular receptor-activated kinase 1 and 2 (ERK1/2) in the HU-induced vascular hyporesponsiveness to NE. Microgravity was simulated in Wistar rats by 20 day HU. The abdominal aorta was removed from control and HU rats, cut into 3 mm rings, and mounted in tissue baths to measure isometric contraction. Protein levels were determined using Western blot analysis. PD98059, a selective MAPKK inhibitor, caused a marked inhibition of NE-induced contraction in both C and HU arteries. Calphostin C, a PKC inhibitor, completely abolished the contractile response to NE in both C and HU tissues. Phosphorylated (activated) ERK1/2 protein mass was greater in C, compared to HU, aortas, and was reduced by genistein only in C tissues. MAPK total protein levels in the rat aorta were increased in the HU-treated, compared to C, animals. These results indicate that PKC represents an early transduction step in the contractile response to NE in the rat abdominal aorta. That inhibition of the step immediately before activation of MAPK reduced contraction in both C and HU tissues, while general tyrosine kinase inhibition with genistein blocked only the control responses, suggests that a nonreceptor tyrosine kinase may be involved in HU-induced vascular hyporesponsiveness to NE.

Potentiation of carbachol-induced detrusor smooth muscle contractions by beta-adrenoceptor activation.

PubMed

Klausner, Adam P; Rourke, Keith F; Miner, Amy S; Ratz, Paul H

2009-03-15

In strips of rabbit bladder free of urothelium, the beta-adrenoceptor agonist, isoproterenol, significantly reduced basal detrusor smooth muscle tone and inhibited contractions produced by low concentrations of the muscarinic receptor agonist, carbachol. During a carbachol concentration-response curve, instead of inhibiting, isoproterenol strengthened contractions produced by high carbachol concentrations. Thus, the carbachol concentration-response curve was shifted by isoproterenol from a shallow, graded relationship, to a steep, switch-like relationship. The tyrosine kinase inhibitor, genistein, inhibited carbachol-induced contractions only in the presence of isoproterenol. Contraction produced by a single high carbachol concentration (1 microM) displayed 1 fast and 1 slow peak. In the presence of isoproterenol, the slow peak was not strengthened, but was delayed, and U-0126 (mitogen-activated protein kinase kinase inhibitor) selectively inhibited this delay concomitantly with inhibition of extracellular signal-regulated kinase (ERK) phosphorylation. Isoproterenol reduced ERK phosphorylation only in the absence of carbachol. These data support the concept that, by inhibiting weak contractions, potentiating strong contractions, and producing a more switch-like concentration-response curve, beta-adrenoceptor stimulation enhanced the effectiveness of muscarinic receptor-induced detrusor smooth muscle contraction. Moreover, beta-adrenoceptor stimulation changed the cellular mechanism by which carbachol produced contraction. The potential significance of multi-receptor and multi-cell crosstalk is discussed.

Ethylene Induced a High Accumulation of Dietary Isoflavones and Expression of Isoflavonoid Biosynthetic Genes in Soybean (Glycine max) Leaves.

PubMed

Yuk, Heung Joo; Song, Yeong Hun; Curtis-Long, Marcus J; Kim, Dae Wook; Woo, Su Gyeong; Lee, Yong Bok; Uddin, Zia; Kim, Cha Young; Park, Ki Hun

2016-10-05

Dietary isoflavones, daidzein and genistein are of huge interest in the nutraceutical field due to their practical application to postmenopause complications. This study is the first report an efficient method to prepare isoflavone rich soybean leaves (soyleaves) which is an edible food stuff in Asian countries. The preharvest treatment of ethylene highly stimulated the level of isoflavone in soyleaves. Annotation and quantification of metabolites were determined by UPLC-Q-TOF-MS and HPLC. Phenolic metabolites of soyleaves are mostly kaempferol glycosides, but not dietary isoflavones. The accumulated isoflavones by ethylene treatment were determined to be daidzin 1, genistin 2, malonyldaidzin 3 and malonylgenistin 4, which were easily hydrolyzed to daidzein and genistein by β-glucosidase. Total content of dietary isoflavones was increased up to 13854 μg/g. The most suitable condition was estimated to be 250 μg/g ethylene or 200 μg/g ethephon (ethylene donor) treatment at the R3 growth stage. The ratio of daidzein and genistein glycosides was approximately 5 to 3. The accumulated isoflavonoid biosynthesis pathway genes were identified within the transcriptome of soyleaves tissues at 1 day after treatment of ethephon. The quantitative RT-PCR analysis of these genes indicated significantly higher expression of CHS, CHI, IFS, HID, IF7GT, and IF7MaT compared to control leaves. These findings suggest that ethylene activates a set of structural genes involved in isoflavonoid biosynthesis, thereby leading to enhanced production of isoflavones in soybean plants.

Testicular Development in Male Rats Is Sensitive to a Soy-Based Diet in the Neonatal Period1

PubMed Central

Napier, India D.; Simon, Liz; Perry, Devin; Cooke, Paul S.; Stocco, Douglas M.; Sepehr, Estatira; Doerge, Daniel R.; Kemppainen, Barbara W.; Morrison, Edward E.; Akingbemi, Benson T.

2014-01-01

ABSTRACT Approximately 30% of infants in the United States are exposed to high doses of isoflavones resulting from soy infant formula consumption. Soybeans contain the isoflavones genistin and daidzin, which are hydrolyzed in the gastrointestinal tract to their genistein and daidzein aglycones. Both aglycones possess hormonal activity and may interfere with male reproductive development. Testosterone, which supports male fertility, is mainly produced by testicular Leydig cells. Our previous studies indicated that perinatal exposure of male rats to isoflavones induced proliferative activity in Leydig cells and increased testosterone concentrations into adulthood. However, the relevance of the neonatal period as part of the perinatal window of isoflavone exposure remains to be established. The present study examined the effects of exposure to isoflavones on male offspring of dams maintained on a casein-based control or whole soybean diet in the neonatal period, that is, Days 2 to 21 postpartum. The results showed that the soybean diet stimulated proliferative activity in developing Leydig cells while suppressing their steroidogenic capacity in adulthood. In addition, isoflavone exposure decreased production of anti-Müllerian hormone by Sertoli cells. Similar to our previous in vitro studies of genistein action in Leydig cells, daidzein induced proliferation and interfered with signaling pathways to suppress steroidogenic activity. Overall, the data showed that the neonatal period is a sensitive window of exposure to isoflavones and support the view that both genistein and daidzein are responsible for biological effects associated with soy-based diets. PMID:24451983

Analysis of regulatory mechanisms of an insulin-inducible SHARP-2 gene by (S)-Equol.

PubMed

Haneishi, Ayumi; Takagi, Katsuhiro; Asano, Kosuke; Yamamoto, Taichi; Tanaka, Takashi; Nakamura, Soichiro; Noguchi, Tamio; Yamada, Kazuya

2012-09-01

Small compounds that activate the insulin-dependent signaling pathway have potential therapeutic applications in controlling type 2 diabetes mellitus. The rat enhancer of split- and hairy-related protein-2 (SHARP-2) is an insulin-inducible transcription factor that decreases expression of the phosphoenolpyruvate carboxykinase gene, a gluconeogenic enzyme gene. In this study, we screened for soybean isoflavones that can induce the rat SHARP-2 gene expression and analyzed their mechanism(s). Genistein and (S)-Equol, a metabolite of daidzein, induced rat SHARP-2 gene expression in H4IIE rat hepatoma cells. The (S)-Equol induction was mediated by both the phosphoinositide 3-kinase- and protein kinase C (PKC)-pathways. When a dominant negative form of atypical PKC lambda (aPKCλ) was expressed, the induction of SHARP-2 mRNA level by (S)-Equol was inhibited. In addition, Western blot analyses showed that (S)-Equol rapidly activated both aPKCλ and classical PKC alpha. Furthermore, the (S)-Equol induction was inhibited by treatment with a RNA polymerase inhibitor or a protein synthesis inhibitor. Finally, a reporter gene assay revealed that the transcriptional stimulation by (S)-Equol was mediated by nucleotide sequences located between -4687 and -4133 of the rat SHARP-2 gene. Thus, we conclude that (S)-Equol is an useful dietary supplement to control type 2 diabetes mellitus. Copyright © 2012 Elsevier Inc. All rights reserved.

Red wine consumption may affect sperm biology: the effects of different concentrations of the phytoestrogen myricetin on human male gamete function.

PubMed

Aquila, Saveria; Santoro, Marta; De Amicis, Francesca; Guido, Carmela; Bonofiglio, Daniela; Lanzino, Marilena; Cesario, Maria Grazia; Perrotta, Ida; Sisci, Diego; Morelli, Catia

2013-02-01

Myricetin is a natural flavonoid, particularly enriched in red wines, whose occurrence is widespread among plants. Despite extensive research, the beneficial effects of Myricetin on human health are still controversial. Here, we tested the estrogen-like effect of the phytoestrogen Myricetin on human ejaculated sperm biology. To this aim, human normozoospermic samples were exposed to increasing concentrations (10 nM, 100 nM, and 1 µM) of Myricetin. Motility, viability, capacitation-associated biochemical changes (i.e., cholesterol efflux and tyrosine phosphorylation), acrosin activity, as well as glucose utilization and fatty-acid oxidation (i.e., glucose and lipid metabolism) were all significantly increased by low doses of Myricetin. Importantly, both estrogen receptors α and β (ERs) and phosphatidylinositol-3-OH kinase (PI3K)/AKT signaling are activated in the presence of Myricetin since these were both abrogated by specific inhibitors of each pathway. Our results show how Myricetin, through ERs and PI3K/AKT signalings, potentiates sperm function. This effect is dose-dependent at low concentrations of Myricetin (up to 100 nM), whereas higher amounts do not seem to improve any further sperm motility, viability, or other tested features, and, in some cases, they reduced or even abrogated the efficacy exerted by lower doses. Further studies are needed to elucidate if high levels of Myricetin, which could be attained even with moderate wine consumption, could synergize with endogenous estrogens in the female reproductive tract, interfering with the physiological sperm fertilization process. Copyright © 2012 Wiley Periodicals, Inc.

Mitigation of lung injury after accidental exposure to radiation.

PubMed

Mahmood, J; Jelveh, S; Calveley, V; Zaidi, A; Doctrow, S R; Hill, R P

2011-12-01

There is a serious need to develop effective mitigators against accidental radiation exposures. In radiation accidents, many people may receive nonuniform whole-body or partial-body irradiation. The lung is one of the more radiosensitive organs, demonstrating pneumonitis and fibrosis that are believed to develop at least partially because of radiation-induced chronic inflammation. Here we addressed the crucial questions of how damage to the lung can be mitigated and whether the response is affected by irradiation to the rest of the body. We examined the widely used dietary supplement genistein given at two dietary levels (750 or 3750 mg/kg) to Fischer rats irradiated with 12 Gy to the lung or 8 Gy to the lung + 4 Gy to the whole body excluding the head and tail (whole torso). We found that genistein had promising mitigating effects on oxidative damage, pneumonitis and fibrosis even at late times (36 weeks) when drug treatment was initiated 1 week after irradiation and stopped at 28 weeks postirradiation. The higher dose of genistein showed no greater beneficial effect. Combined lung and whole-torso irradiation caused more lung-related severe morbidity resulting in euthanasia of the animals than lung irradiation alone.

G Protein-Coupled Estrogen Receptor-Selective Ligands Modulate Endometrial Tumor Growth

PubMed Central

Petrie, Whitney K.; Dennis, Megan K.; Dai, Donghai; Arterburn, Jeffrey B.; Smith, Harriet O.; Hathaway, Helen J.; Prossnitz, Eric R.

2013-01-01

Endometrial carcinoma is the most common cancer of the female reproductive tract. GPER/GPR30 is a 7-transmembrane spanning G protein-coupled receptor that has been identified as the third estrogen receptor, in addition to ERα and ERβ. High GPER expression is predictive of poor survival in endometrial and ovarian cancer, but despite this, the estrogen-mediated signaling pathways and specific estrogen receptors involved in endometrial cancer remain unclear. Here, employing ERα-negative Hec50 endometrial cancer cells, we demonstrate that GPER mediates estrogen-stimulated activation of ERK and PI3K via matrix metalloproteinase activation and subsequent transactivation of the EGFR and that ER-targeted therapeutic agents (4-hydroxytamoxifen, ICI182,780/fulvestrant, and Raloxifene), the phytoestrogen genistein, and the “ERα-selective” agonist propylpyrazole triol also function as GPER agonists. Furthermore, xenograft tumors of Hec50 cells yield enhanced growth with G-1 and estrogen, the latter being inhibited by GPER-selective pharmacologic antagonism with G36. These results have important implications with respect to the use of putatively ER-selective ligands and particularly for the widespread long-term use of “ER-targeted” therapeutics. Moreover, our findings shed light on the potential mechanisms of SERM/SERD side effects reported in many clinical studies. Finally, our results provide the first demonstration that pharmacological inhibition of GPER activity in vivo prevents estrogen-mediated tumor growth. PMID:24379833

An exposure:activity profiling method for interpreting high-throughput screening data for estrogenic activity--proof of concept.

PubMed

Becker, Richard A; Friedman, Katie Paul; Simon, Ted W; Marty, M Sue; Patlewicz, Grace; Rowlands, J Craig

2015-04-01

Rapid high throughput in vitro screening (HTS) assays are now available for characterizing dose-responses in assays that have been selected for their sensitivity in detecting estrogen-related endpoints. For example, EPA's ToxCast™ program recently released endocrine assay results for more than 1800 substances and the interagency Tox21 consortium is in the process of releasing data for approximately 10,000 chemicals. But such activity measurements alone fall short for the purposes of priority setting or screening because the relevant exposure context is not considered. Here, we extend the method of exposure:activity profiling by calculating the exposure:activity ratios (EARs) using human exposure estimates and AC50 values for a range of chemicals tested in a suite of seven estrogenic assays in ToxCast™ and Tox21. To provide additional context, relative estrogenic exposure:activity quotients (REEAQ) were derived by comparing chemical-specific EARs to the EAR of the ubiquitous dietary phytoestrogen, genistein (GEN). Although the activity of a substance in HTS-endocrine assays is not a measure of health hazard or risk, understanding how such a dose compares to human exposures provides a valuable additional metric that can be used in decision-making; substances with small EARs and REEAQs would indicate low priority for further endocrine screening or testing. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

G protein-coupled estrogen receptor-selective ligands modulate endometrial tumor growth.

PubMed

Petrie, Whitney K; Dennis, Megan K; Hu, Chelin; Dai, Donghai; Arterburn, Jeffrey B; Smith, Harriet O; Hathaway, Helen J; Prossnitz, Eric R

2013-01-01

Endometrial carcinoma is the most common cancer of the female reproductive tract. GPER/GPR30 is a 7-transmembrane spanning G protein-coupled receptor that has been identified as the third estrogen receptor, in addition to ERα and ERβ. High GPER expression is predictive of poor survival in endometrial and ovarian cancer, but despite this, the estrogen-mediated signaling pathways and specific estrogen receptors involved in endometrial cancer remain unclear. Here, employing ERα-negative Hec50 endometrial cancer cells, we demonstrate that GPER mediates estrogen-stimulated activation of ERK and PI3K via matrix metalloproteinase activation and subsequent transactivation of the EGFR and that ER-targeted therapeutic agents (4-hydroxytamoxifen, ICI182,780/fulvestrant, and Raloxifene), the phytoestrogen genistein, and the "ERα-selective" agonist propylpyrazole triol also function as GPER agonists. Furthermore, xenograft tumors of Hec50 cells yield enhanced growth with G-1 and estrogen, the latter being inhibited by GPER-selective pharmacologic antagonism with G36. These results have important implications with respect to the use of putatively ER-selective ligands and particularly for the widespread long-term use of "ER-targeted" therapeutics. Moreover, our findings shed light on the potential mechanisms of SERM/SERD side effects reported in many clinical studies. Finally, our results provide the first demonstration that pharmacological inhibition of GPER activity in vivo prevents estrogen-mediated tumor growth.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Teng, Christina T., E-mail: teng1@niehs.nih.gov; Beames, Burton; Alex Merrick, B.

Highlights: • We developed a stable cell line with intact PGC-1α/ERRα axis. • The ERRα repressor, XCT790, down regulates this pathway. • Phytoestrogen, genisten stimulates this pathway. - Abstract: The estrogen-related receptor α (ERRα) and the peroxisome proliferator-activated receptor γ (PPARγ) coactivator 1α (PGC-1α) play critical roles in the control of several physiological functions, including the regulation of genes involved in energy homeostasis. However, little is known about the ability of environmental chemicals to disrupt or modulate this important bioenergetics pathway in humans. The goal of this study was to develop a cell-based assay system with an intact PGC-1α/ERRα axismore » that could be used as a screening assay for detecting such chemicals. To this end, we successfully generated several stable cell lines expressing PGC-1α and showed that the reporter driven by the native ERRα hormone response unit (AAB-Luc) is active in these cell lines and that the activation is PGC-1α-dependent. Furthermore, we show that this activation can be blocked by the ERRα selective inverse agonist, XCT790. In addition, we find that genistein and bisphenol A further stimulate the reporter activity, while kaempferol has minimal effect. These cell lines will be useful for identifying environmental chemicals that modulate this important pathway.« less

2-heptyl-formononetin increases cholesterol and induces hepatic steatosis in mice.

PubMed

Andersen, Charlotte; Schjoldager, Janne G; Tortzen, Christian G; Vegge, Andreas; Hufeldt, Majbritt R; Skaanild, Mette T; Vogensen, Finn K; Kristiansen, Karsten; Hansen, Axel K; Nielsen, John

2013-01-01

Consumption of isoflavones may prevent adiposity, hepatic steatosis, and dyslipidaemia. However, studies in the area are few and primarily with genistein. This study investigated the effects of formononetin and its synthetic analogue, 2-heptyl-formononetin (C7F), on lipid and cholesterol metabolism in C57BL/6J mice. The mice were fed a cholesterol-enriched diet for five weeks to induce hypercholesterolemia and were then fed either the cholesterol-enriched diet or the cholesterol-enriched diet-supplemented formononetin or C7F for three weeks. Body weight and composition, glucose homeostasis, and plasma lipids were compared. In another experiment, mice were fed the above diets for five weeks, and hepatic triglyceride accumulation and gene expression and histology of adipose tissue and liver were examined. Supplementation with C7F increased plasma HDL-cholesterol thereby increasing the plasma level of total cholesterol. Supplementation with formononetin did not affect plasma cholesterol but increased plasma triglycerides levels. Supplementation with formononetin and C7F induced hepatic steatosis. However, formononetin decreased markers of inflammation and liver injury. The development of hepatic steatosis was associated with deregulated expression of hepatic genes involved in lipid and lipoprotein metabolism. In conclusion, supplementation with formononetin and C7F to a cholesterol-enriched diet adversely affected lipid and lipoprotein metabolism in C57BL/6J mice.

2-Heptyl-Formononetin Increases Cholesterol and Induces Hepatic Steatosis in Mice

PubMed Central

Andersen, Charlotte; Schjoldager, Janne G.; Tortzen, Christian G.; Vegge, Andreas; Hufeldt, Majbritt R.; Skaanild, Mette T.; Vogensen, Finn K.; Kristiansen, Karsten; Hansen, Axel K.; Nielsen, John

2013-01-01

Consumption of isoflavones may prevent adiposity, hepatic steatosis, and dyslipidaemia. However, studies in the area are few and primarily with genistein. This study investigated the effects of formononetin and its synthetic analogue, 2-heptyl-formononetin (C7F), on lipid and cholesterol metabolism in C57BL/6J mice. The mice were fed a cholesterol-enriched diet for five weeks to induce hypercholesterolemia and were then fed either the cholesterol-enriched diet or the cholesterol-enriched diet-supplemented formononetin or C7F for three weeks. Body weight and composition, glucose homeostasis, and plasma lipids were compared. In another experiment, mice were fed the above diets for five weeks, and hepatic triglyceride accumulation and gene expression and histology of adipose tissue and liver were examined. Supplementation with C7F increased plasma HDL-cholesterol thereby increasing the plasma level of total cholesterol. Supplementation with formononetin did not affect plasma cholesterol but increased plasma triglycerides levels. Supplementation with formononetin and C7F induced hepatic steatosis. However, formononetin decreased markers of inflammation and liver injury. The development of hepatic steatosis was associated with deregulated expression of hepatic genes involved in lipid and lipoprotein metabolism. In conclusion, supplementation with formononetin and C7F to a cholesterol-enriched diet adversely affected lipid and lipoprotein metabolism in C57BL/6J mice. PMID:23738334

Prevention of Human Mammary Carcinogenesis

DTIC Science & Technology

1995-06-30

selected naturally-occurring agents (-)- epigallocatechin gallate ( EGCG ), indole-3-carbinol (13C) and genistein (GEN) for growth inhibition of 184-B5...mechanisms of BP-induced and GEN-induced alterations in cell cycle are being investigated in the ongoing studies. In addition, effects of 13C and EGCG are...rodent mammary tumorigenesis. The maximally nontoxic doses of EGCG , 13C and GEN identified by initial dose-response experiments, were used. The data

Adding the phytoestrogen Cimicifugae Racemosae to clomiphene induction cycles with timed intercourse in polycystic ovary syndrome improves cycle outcomes and pregnancy rates - a randomized trial.

PubMed

Shahin, Ahmed Y; Mohammed, Safwat A

2014-07-01

Owing to their potential to act as estrogen receptor modulators and interfere with aromatase enzyme in animal studies, phytoestrogens (PE) may be useful as part of ovulation induction for polycystic ovary syndrome (PCOS). Patients <35 years, presenting with infertility and PCOS, were included and randomly allocated to either group I (clomiphene citrate; CC) or group II (CC plus Cimicifugae racemosae; CR). Primary outcome was pregnancy rate. Secondary outcomes included ovulation, midcycle serum estradiol and luteinizing hormone (LH) as well as mid-luteal serum progesterone. Analysis included 98 patients in group I versus 96 patients in group II. Both groups were matched regarding demographics and basic data. Significant differences were elicited when comparing days until HCG injection (15.0 ± 1.7 versus 12.0 ± 1.9, p=0.91), endometrial thickness (mm) (8.5 ± 1.9 versus 12.5 ± 1.9, p<0.001), serum levels of mid-luteal and midcycle estradiol (p<0.001; Figure 2), LH (IU/ml) (p<0.001) as well as mid-luteal progesterone (p<0.001). PE plus CC group had significantly higher clinical pregnancies per cycle (33/192 (17.2%) versus 71/204 (34.8%), p<0.01), compared to the CC only group. Adding CR to clomiphene-induction cycles with timed intercourse in polycystic ovarian syndrome improves cycle outcomes and pregnancy rates.

Soybean supplementation helps reverse age- and scopolamine-induced memory deficits in mice.

PubMed

Bansal, Nitin; Parle, Milind

2010-12-01

Phytoestrogens are nonsteroidal plant compounds that are able to exert estrogenic effects. Soybean is a rich source of phytoestrogens, especially isoflavones. Soy isoflavones are utilized for estrogen replacement therapy. Estrogen is reported to influence several areas of brain that are involved in cognition and behavior. Therefore, the present study was undertaken to examine whether dietary supplementation with soybean improves the cognitive function of mice. Soybean was administered in three different concentrations (2%, 5% and 10% [wt/wt]) in the normal diet to young and mature mice for 60 successive days. The passive avoidance paradigm and the elevated plus maze served as the exteroceptive behavioral models, whereas scopolamine (1.4 mg/kg, i.p.) served as the interoceptive behavioral model. The brain acetylcholinesterase activity (AChE) activity, brain thiobarbituric acid-reactive substances (TBARS), reduced glutathione (GSH), and total blood cholesterol levels were also measured in the present study. The administration of soybean for 60 consecutive days protected (P < .05) the animals from developing memory impairment. Soybean administration also resulted in diminished brain AChE activity, decrease in brain TBARS, and increase in GSH levels, thereby indicating facilitated cholinergic transmission, reduced free radical generation, and enhanced scavenging of free radicals. Thus, soybean appears to be a useful remedy for improving memory and for the management of cognitive deficits owing to its pro-estrogenic, antioxidant, procholinergic, and/or neuroprotective properties.

A simple and robust high-performance liquid chromatography coupled to a diode-array detector method for the analysis of genistein in mouse tissues.

PubMed

Tamames-Tabar, C; Imbuluzqueta, E; Campanero, M A; Horcajada, P; Blanco-Prieto, M J

2013-09-15

A simple liquid-liquid extraction procedure and quantification by high-performance liquid chromatography (HPLC) method coupled to a diode-array detector (DAD) of genistein (GEN) was developed in various mouse biological matrices. 7-ethoxycoumarin was used as internal standard (IS) and peaks were optimally separated using a Kinetex C18 column (2.6μm, 150mm×2.10mm I.D.) at 40°C with an isocratic elution of mobile phase with sodium dihydrogen phosphate 0.01M in water at pH 2.5 and methanol (55:45, v/v), at a flow rate of 0.25mL/min. The injection volume was 10μL. In all cases, the range of GEN recovery was higher than 61%. The low limit of quantification (LLOQ) was 25ng/mL. The linearity of the calibration curves was satisfactory in all cases as shown by correlation coefficients >0.996. The within-day and between-day precisions were <15% and the accuracy ranged in all cases between 90.14% and 106.05%. This method was successfully applied to quantify GEN in liver, spleen, kidney and plasma after intravenous administration of a single dose (30mg/kg) in female BALB/C mice. Copyright © 2013 Elsevier B.V. All rights reserved.

Resveratrol inhibits estrogen-induced breast carcinogenesis through induction of NRF2-mediated protective pathways

PubMed Central

Singh, Bhupendra; Shoulson, Rivka; Chatterjee, Anwesha; Ronghe, Amruta; Bhat, Nimee K.; Dim, Daniel C.; Bhat, Hari K.

2014-01-01

The importance of estrogens in the etiology of breast cancer is widely recognized. Estrogen-induced oxidative stress has been implicated in this carcinogenic process. Resveratrol (Res), a natural antioxidant phytoestrogen has chemopreventive effects against a variety of illnesses including cancer. The objective of the present study was to characterize the mechanism(s) of Res-mediated protection against estrogen-induced breast carcinogenesis. Female August Copenhagen Irish rats were treated with 17β-estradiol (E2), Res and Res + E2 for 8 months. Cotreatment of rats with Res and E2 inhibited E2-mediated proliferative changes in mammary tissues and significantly increased tumor latency and reduced E2-induced breast tumor development. Resveratrol treatment alone or in combination with E2 significantly upregulated expression of nuclear factor erythroid 2-related factor 2 (NRF2) in mammary tissues. Expression of NRF2-regulated antioxidant genes NQO1, SOD3 and OGG1 that are involved in protection against oxidative DNA damage was increased in Res- and Res + E2-treated mammary tissues. Resveratrol also prevented E2-mediated inhibition of detoxification genes AOX1 and FMO1. Inhibition of E2-mediated alterations in NRF2 promoter methylation and expression of NRF2 targeting miR-93 after Res treatment indicated Res-mediated epigenetic regulation of NRF2 during E2-induced breast carcinogenesis. Resveratrol treatment also induced apoptosis and inhibited E2-mediated increase in DNA damage in mammary tissues. Increased apoptosis and decreased DNA damage, cell migration, colony and mammosphere formation in Res- and Res + E2-treated MCF-10A cells suggested a protective role of Res against E2-induced mammary carcinogenesis. Small-interfering RNA-mediated silencing of NRF2 inhibited Res-mediated preventive effects on the colony and mammosphere formation. Taken together, these results suggest that Res inhibits E2-induced breast carcinogenesis via induction of NRF2-mediated protective

Vasoconstriction induced by G1, a G-protein-coupled oestrogen receptor1 (GPER-1) agonist, in the isolated perfused rat kidney.

PubMed

Kurt, Akif Hakan; Buyukafsar, Kansu

2013-02-28

Vascular effects of the G protein-coupled oestrogen receptor1 (GPER-1) agonist, G1 (10(-7)-5×10(-6) M), the main oestrogenic hormone, 17β-estradiol (10(-9)-10(-4) M), the NR3A1 agonist, PPT (10(-8)-10(-5) M), the NR3A2 agonist DPN (10(-8)-10(-5) M), and the classical oestrogen receptor blocker but also a GPER agonist, ICI-182780 (10(-8)-3×10(-6) M), were investigated on the perfusion pressure in the isolated rat kidney. To seek cellular mechanisms involved in GPER-1-induced signalling we tested several compounds including the inhibitors of Rho-kinase (ROCK) (Y-27632), tyrosine kinase (genistein), p38MAPK (SB203580), p44/42MAPK (PD98059), protein kinase C (PKC) (GF109203X), Jun-kinase (JNK) (SP600125), phosphatidylinositol-3-kinase (PI3K) (LY294002), Ca(2+) channels (nifedipine), GPER-1 (G15) and epidermal growth factor (EGF) receptor kinase (AG-1478). Moreover, the effect of saponin (50mg/ml) that was used for endothelium removal was explored on G1-elicited vascular action. G1, 17β-estradiol and ICI-182780 but not PPT and DPN induced vasoconstrictions in basal renal perfusion pressure. In contrast, G1 promoted vasodilatation when the perfusion pressure was elevated in advance by phenylephrine. G1-elicited vasoconstriction was not modified by endothelial removal; however, it was markedly inhibited by GPER-1 antagonist, G15. The vasoconstrictor response to G1 was also significantly attenuated by Y-27632, PD98059, SB203580, GF109203X, genistein, AG-1478, and nifedipine, but not LY294002 and SP600125. Western blotting indicated the expression of GPER-1 in renal artery, medulla and cortex of rat kidney. In conclusion, GPER-1 could substantially modulate vascular responses through a variety of signalling pathways including ROCK, PKC, p38 MAPK, p42/44 MAPK, tyrosine kinase, EGF receptor kinase and VOCC but not JNK or PI3K in isolated perfused rat kidney. Copyright © 2013 Elsevier B.V. All rights reserved.

Epigenetic Effects of Environmental Chemicals Bisphenol A and Phthalates

PubMed Central

Singh, Sher; Li, Steven Shoei-Lung

2012-01-01

The epigenetic effects on DNA methylation, histone modification, and expression of non-coding RNAs (including microRNAs) of environmental chemicals such as bisphenol A (BPA) and phthalates have expanded our understanding of the etiology of human complex diseases such as cancers and diabetes. Multiple lines of evidence from in vitro and in vivo models have established that epigenetic modifications caused by in utero exposure to environmental toxicants can induce alterations in gene expression that may persist throughout life. Epigenetics is an important mechanism in the ability of environmental chemicals to influence health and disease, and BPA and phthalates are epigenetically toxic. The epigenetic effect of BPA was clearly demonstrated in viable yellow mice by decreasing CpG methylation upstream of the Agouti gene, and the hypomethylating effect of BPA was prevented by maternal dietary supplementation with a methyl donor like folic acid or the phytoestrogen genistein. Histone H3 was found to be trimethylated at lysine 27 by BPA effect on EZH2 in a human breast cancer cell line and mice. BPA exposure of human placental cell lines has been shown to alter microRNA expression levels, and specifically, miR-146a was strongly induced by BPA treatment. In human breast cancer MCF7 cells, treatment with the phthalate BBP led to demethylation of estrogen receptor (ESR1) promoter-associated CpG islands, indicating that altered ESR1 mRNA expression by BBP is due to aberrant DNA methylation. Maternal exposure to phthalate DEHP was also shown to increase DNA methylation and expression levels of DNA methyltransferases in mouse testis. Further, some epigenetic effects of BPA and phthalates in female rats were found to be transgenerational. Finally, the available new technologies for global analysis of epigenetic alterations will provide insight into the extent and patterns of alterations between human normal and diseased tissues. In vitro models such as human embryonic stem cells

Epigenetic effects of environmental chemicals bisphenol A and phthalates.

PubMed

Singh, Sher; Li, Steven Shoei-Lung

2012-01-01

The epigenetic effects on DNA methylation, histone modification, and expression of non-coding RNAs (including microRNAs) of environmental chemicals such as bisphenol A (BPA) and phthalates have expanded our understanding of the etiology of human complex diseases such as cancers and diabetes. Multiple lines of evidence from in vitro and in vivo models have established that epigenetic modifications caused by in utero exposure to environmental toxicants can induce alterations in gene expression that may persist throughout life. Epigenetics is an important mechanism in the ability of environmental chemicals to influence health and disease, and BPA and phthalates are epigenetically toxic. The epigenetic effect of BPA was clearly demonstrated in viable yellow mice by decreasing CpG methylation upstream of the Agouti gene, and the hypomethylating effect of BPA was prevented by maternal dietary supplementation with a methyl donor like folic acid or the phytoestrogen genistein. Histone H3 was found to be trimethylated at lysine 27 by BPA effect on EZH2 in a human breast cancer cell line and mice. BPA exposure of human placental cell lines has been shown to alter microRNA expression levels, and specifically, miR-146a was strongly induced by BPA treatment. In human breast cancer MCF7 cells, treatment with the phthalate BBP led to demethylation of estrogen receptor (ESR1) promoter-associated CpG islands, indicating that altered ESR1 mRNA expression by BBP is due to aberrant DNA methylation. Maternal exposure to phthalate DEHP was also shown to increase DNA methylation and expression levels of DNA methyltransferases in mouse testis. Further, some epigenetic effects of BPA and phthalates in female rats were found to be transgenerational. Finally, the available new technologies for global analysis of epigenetic alterations will provide insight into the extent and patterns of alterations between human normal and diseased tissues. In vitro models such as human embryonic stem cells

Effect of protein tyrosine kinase inhibitors on the current through the Ca(V)3.1 channel.

PubMed

Kurejová, Martina; Lacinová, L'ubica

2006-02-01

In the present study, we have investigated the effects of protein tyrosine kinase (PTK) inhibitors on the Ca(V)3.1 calcium channel stably transfected in HEK293 cells using the whole-cell configuration of the patch-clamp technique. We have tested two different tyrosine kinase inhibitors, genistein and tyrphostin AG213, and their inactive analogs, genistin and tyrphostin AG9. Bath application of genistein, but not genistin, decreased the T-type calcium current amplitude in a concentration-dependent manner with an IC(50) of 24.7+/-2.0 microM. This effect of genistein was accompanied by deceleration of channel activation and acceleration of channel inactivation. Intracellular application of neither genistein nor genistin had a significant effect on the calcium current. Extracellular application of 50 microM tyrphostin AG213 and its inactive analogue, tyrphostin AG9, did not affect the current through the Ca(V)3.1 channel. The effect of genistein on the channel was also not affected by the presence of catalytically active PTK, p60(c-src) inside the cell. We have concluded that genistein directly inhibited the channel. This mechanism does not involve a PTK-dependent pathway. The alteration of the channel kinetics by genistein suggests an interaction with the voltage sensor of the channel together with the channel pore occlusion.

Polyphenols and Prostate Cancer Chemoprevention

DTIC Science & Technology

2004-03-01

The polyphenols, catechin, (-)- epigallocatechin -3- gallate ( EGCG ), genistein and resveratrol, are associated with reduced incidences of prostate and...protective effect without adverse effects with possible elevated exposure. The specific aims are 1) to investigate the potential of genistein, EGCG and...genistein, EGCG and resveratrol to regulate sex steroid- and specific growth factor-receptor and ligand expression as mechanism of prostate cancer

Polyphenols and Prostate Cancer Chemoprevention

DTIC Science & Technology

2005-03-01

ABSTRACT (Maximum 200 Words) The goal of this research is to Investigate the potential of (-)- epigallocatechin -3- gallate ( EGCG ), genistein and resveratrol...prostate chemoprevention are the soy isoflavone, genistein, and the tea catechin, (-)- epigallocatechin -3- gallate ( EGCG ). Another polyphenol that has...adenocarcinoma (TRAMP)). The specific aims are 1) to investigate the potential of genistein, EGCG and resveratrol, alone and in combination, to

TNFalpha-induced and berberine-antagonized tight junction barrier impairment via tyrosine kinase, Akt and NFkappaB signaling.

PubMed

Amasheh, Maren; Fromm, Anja; Krug, Susanne M; Amasheh, Salah; Andres, Susanne; Zeitz, Martin; Fromm, Michael; Schulzke, Jörg-Dieter

2010-12-01

TNFα-mediated tight junction defects contribute to diarrhea in inflammatory bowel diseases (IBDs). In our study, the signaling pathways of the TNFα effect on barrier- or pore-forming claudins were analyzed in HT-29/B6 human colon monolayers. Berberine, a herbal therapeutic agent that has been recently established as a therapy for diabetes and hypercholesterinemia, was able to completely antagonize the TNFα-mediated barrier defects in the cell model and in rat colon. Ussing chamber experiments and two-path impedance spectroscopy revealed a decrease of paracellular resistance after TNFα to 11±4%, whereas transcellular resistance was unchanged. The permeability of the paracellular marker fluorescein was increased fourfold. Berberine alone had no effect while it fully prevented the TNFα-induced barrier defects. This effect on resistance was confirmed in rat colon. TNFα removed claudin-1 from the tight junction and increased claudin-2 expression. Berberine prevented TNFα-induced claudin-1 disassembly and upregulation of claudin-2. The effects of berberine were mimicked by genistein plus BAY11-7082, indicating that they are mediated via tyrosine kinase, pAkt and NFκB pathways. In conclusion, the anti-diarrheal effect of berberine is explained by a novel mechanism, suggesting a therapeutic approach against barrier breakdown in intestinal inflammation.

Formononetin-induced apoptosis of human prostate cancer cells through ERK1/2 mitogen-activated protein kinase inactivation.

PubMed

Ye, Y; Hou, R; Chen, J; Mo, L; Zhang, J; Huang, Y; Mo, Z

2012-04-01

Formononetin is a main active component of red clover plants (Trifolium pratense L.), and is considered as a phytoestrogen. Our previous studies demonstrated that formononetin caused cell cycle arrest at the G0/G1 phase by inactivating insulin-like growth factor 1(IGF1)/IGF1R-phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway in MCF-7 cells. In the present study, we investigated the molecular mechanisms involved in the effect of formononetin on prostate cancer cells. Our results suggested that higher concentrations of formononetin inhibited the proliferation of prostate cancer cells (LNCaP and PC-3), while the most striking effect was observed in LNCaP cells. We further found that formononetin inactivated extracellular signal-regulated kinase1/2 (ERK1/2) mitogen-activated protein kinase (MAPK) signaling pathway in a dose-dependent manner, which resulted in increased the expression levels of BCL2-associated X (Bax) mRNA and protein, and induced apoptosis in LNCaP cells. Thus, we concluded that the induced apoptosis effect of formononetin on human prostate cancer cells was related to ERK1/2 MAPK-Bax pathway. Considering that red clover plants were widely used clinically, our results provided the foundation for future development of different concentrations formononetin for treatment of prostate cancer. © Georg Thieme Verlag KG Stuttgart · New York.

Inhibition of c-Jun N-terminal kinase sensitizes tumor cells to flavonoid-induced apoptosis through down-regulation of JunD

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kook, Sung-Ho; Research Center of Bioactive Materials, Chonbuk National University, Chonju 561-756; Son, Young-Ok

Reduction of susceptibility to apoptosis signals is a crucial step in carcinogenesis. Therefore, sensitization of tumor cells to apoptosis is a promising therapeutic strategy. c-Jun NH{sub 2}-terminal kinase (JNK) has been implicated in stress-induced apoptosis. However, many studies also emphasize the role of JNK on cell survival, although its mechanisms are not completely understood. Previously, we found that inhibition of JNK activity promotes flavonoid-mediated apoptosis of human osteosarcoma cells. We thus determined whether inhibition of JNK sensitizes tumor cells to a bioflavonoid-induced apoptosis, and whether this effect of JNK is a general effect. As the results, quercetin and genistein asmore » well as a flavonoid fraction induced apoptosis of tumor cells, which was further accelerated by specific JNK inhibitor, SP600125 or by small interfering RNA specific to JNK1/2. This effect was specific to types of cells because it was further apparent in tumorigenic cell lines. Inhibition of JNK by SP600125 also reduced flavonoid-stimulated nuclear induction of JunD which was known to have protective role in apoptosis, whereas JNK inhibition alone had little effect on apoptosis. The flavonoid-induced apoptosis of tumor cells was significantly enhanced by transfecting them with antisense JunD oligonucleotides. These results suggest that inhibition of JNK facilitates flavonoid-induced apoptosis through down-regulation of JunD, which is further sensitive to tumor cells. Therefore, combination with a specific JNK inhibitor further enhances the anti-cancer and chemopreventive potential of bio-flavonoids.« less

Phosphotyrosine phosphatase and tyrosine kinase inhibition modulate airway pressure-induced lung injury.

PubMed

Parker, J C; Ivey, C L; Tucker, A

1998-11-01

We determined whether drugs which modulate the state of protein tyrosine phosphorylation could alter the threshold for high airway pressure-induced microvascular injury in isolated perfused rat lungs. Lungs were ventilated for successive 30-min periods with peak inflation pressures (PIP) of 7, 20, 30, and 35 cmH2O followed by measurement of the capillary filtration coefficient (Kfc), a sensitive index of hydraulic conductance. In untreated control lungs, Kfc increased by 1.3- and 3.3-fold relative to baseline (7 cmH2O PIP) after ventilation with 30 and 35 cmH2O PIP. However, in lungs treated with 100 microM phenylarsine oxide (a phosphotyrosine phosphatase inhibitor), Kfc increased by 4.7- and 16.4-fold relative to baseline at these PIP values. In lungs treated with 50 microM genistein (a tyrosine kinase inhibitor), Kfc increased significantly only at 35 cmH2O PIP, and the three groups were significantly different from each other. Thus phosphotyrosine phosphatase inhibition increased the susceptibility of rat lungs to high-PIP injury, and tyrosine kinase inhibition attenuated the injury relative to the high-PIP control lungs.

Formononetin-induced apoptosis by activation of Ras/p38 mitogen-activated protein kinase in estrogen receptor-positive human breast cancer cells.

PubMed

Chen, J; Sun, L

2012-12-01

Formononetin is one of the main active components of red clover plants, and considered as a phytoestrogen. Its pharmacological effects in vivo may be either estrogenic or anti-estrogenic, mainly depending upon the estrogen levels. Our recent studies suggested that formononetin inactivated IGF1/IGF1R-PI3K/Akt pathways and decreased cyclin D1 mRNA and protein expression in human breast cancer cells in vitro and in vivo. In the present study, we further investigated the molecular mechanisms involved in the induced apoptosis effect of formononetin on breast cancer cells. Our results suggested that formononetin inhibited the proliferation of ER-positive MCF-7 cells and T47D cells. In contrast, formononetin could not inhibit the cell of growth of ER-negative breast cancer cells such as MDA-MB-435 S cells. We further found that formononetin activated MAPK signaling pathway in a dose-dependent manner, which resulted in the increased ratio of Bax/Bcl-2, and induced apoptosis on MCF-7 cells. However, when MCF-7 cells were pretreated with p38MAPK inhibitor SB203580 before formononetin, apoptosis induced by formononetin was significantly attenuated. Thus, we conclude that the induced apoptosis effect of formononetin on human breast cancer cells were related to Ras-p38MAPK pathway. Considering that red clover plants are widely used clinically, our results provide the foundation for future development of formononetin for treatment of ER-positive breast cancer. © Georg Thieme Verlag KG Stuttgart · New York.

Medical hypothesis: bifunctional genetic-hormonal pathways to breast cancer.

PubMed

Davis, D L; Telang, N T; Osborne, M P; Bradlow, H L

1997-04-01

As inherited germ line mutations, such as loss of BRCA1 or AT, account for less than 5% of all breast cancer, most cases involve acquired somatic perturbations. Cumulative lifetime exposure to bioavailable estradiol links most known risk factors (except radiation) for breast cancer. Based on a series of recent experimental and epidemiologic findings, we hypothesize that the multistep process of breast carcinogenesis results from exposure to endogenous or exogenous hormones, including phytoestrogens that directly or indirectly alter estrogen metabolism. Xenohormones are defined as xenobiotic materials that modify hormonal production; they can work bifunctionally, through genetic or hormonal paths, depending on the periods and extent of exposure. As for genetic paths, xenohormones can modify DNA structure or function. As for hormonal paths, two distinct mechanisms can influence the potential for aberrant cell growth: compounds can directly bind with endogenous hormone or growth factor receptors affecting cell proliferation or compounds can modify breast cell proliferation altering the formation of hormone metabolites that influence epithelial-stromal interaction and growth regulation. Beneficial xenohormones, such as indole-3-carbinol, genistein, and other bioflavonoids, may reduce aberrant breast cell proliferation, and influence the rate of DNA repair or apoptosis and thereby influence the genetic or hormonal microenvironments. Upon validation with appropriate in vitro and in vivo studies, biologic markers of the risk for breast cancer, such as hormone metabolites, total bioavailable estradiol, and free radical generators can enhance cancer detection and prevention.

An updated review of dietary isoflavones: Nutrition, processing, bioavailability and impacts on human health.

PubMed

Zaheer, Khalid; Humayoun Akhtar, M

2017-04-13

Isoflavones (genistein, daidzein, and glycitein) are bioactive compounds with mildly estrogenic properties and often referred to as phytoestrogen. These are present in significant quantities (up to 4-5 mg·g -1 on dry basis) in legumes mainly soybeans, green beans, mung beans. In grains (raw materials) they are present mostly as glycosides, which are poorly absorbed on consumption. Thus, soybeans are processed into various food products for digestibility, taste and bioavailability of nutrients and bioactives. Main processing steps include steaming, cooking, roasting, microbial fermentation that destroy protease inhibitors and also cleaves the glycoside bond to yield absorbable aglycone in the processed soy products, such as miso, natto, soy milk, tofu; and increase shelf lives. Processed soy food products have been an integral part of regular diets in many Asia-Pacific countries for centuries, e.g. China, Japan and Korea. However, in the last two decades, there have been concerted efforts to introduce soy products in western diets for their health benefits with some success. Isoflavones were hailed as magical natural component that attribute to prevent some major prevailing health concerns. Consumption of soy products have been linked to reduction in incidence or severity of chronic diseases such as cardiovascular, breast and prostate cancers, menopausal symptoms, bone loss, etc. Overall, consuming moderate amounts of traditionally prepared and minimally processed soy foods may offer modest health benefits while minimizing potential for any adverse health effects.

Impact of genistein on the gut microbiome of humanized mice and its role in breast tumor inhibition.

PubMed

Paul, Bidisha; Royston, Kendra J; Li, Yuanyuan; Stoll, Matthew L; Skibola, Christine F; Wilson, Landon S; Barnes, Stephen; Morrow, Casey D; Tollefsbol, Trygve O

2017-01-01

Since dietary polyphenols can have beneficial effects in prevention and treatment of cancer, we tested the hypothesis that breast cancer patients' intestinal microbiota is modulated by genistein (GE), an isoflavone found in soy, and that microbial alterations may offset the side effects brought about by chemotherapy. We demonstrated successful humanization of germ-free mice by transplanting fecal samples from breast cancer patients before and after chemotherapy. Mice were then grouped based on chemotherapy status and GE or control diet. We did not find any significant differences between pre-chemotherapy and post-chemotherapy bacterial composition and abundances. Germ-free mice on a GE diet showed differences in microbial composition as compared to mice on control diet. Four weeks after introduction of the customized GE diet, there was distinct clustering of GE-fed mice as compared to the control-fed group. In the gut microbiome of GE-treated humanized mice, there was an increase in abundance of genera Lactococcus and Eubacterium. Phylum Verrucomicrobia showed statistically significant (p = 0.02) differences in abundances between the GE-fed and control-fed groups. There was an increase in bacteria belonging to family Lachnospiraceae and Ruminococcaceae in GE-fed mice. Marked changes were observed in GE catabolism in mice humanized with fecal material from two of three patients' post-chemotherapy with complete disappearance of 4-ethylphenol and 2-(4-hydroxyphenol) propionic acid conjugates. The post-tumor samples did not show any distinct clustering of the gut microbiota between the two diet groups. There was an increase in latency of about 25% for tumor growth of the humanized mice that were on a GE diet as compared to humanized mice on a control diet. The average tumor size for the GE group was significantly decreased compared to the non-GE group. Collectively, our results suggest that the intestinal microbiota becomes altered with a GE diet before induction of

Impact of genistein on the gut microbiome of humanized mice and its role in breast tumor inhibition

PubMed Central

Paul, Bidisha; Royston, Kendra J.; Li, Yuanyuan; Stoll, Matthew L.; Skibola, Christine F.; Wilson, Landon S.; Barnes, Stephen; Morrow, Casey D.

2017-01-01

Since dietary polyphenols can have beneficial effects in prevention and treatment of cancer, we tested the hypothesis that breast cancer patients’ intestinal microbiota is modulated by genistein (GE), an isoflavone found in soy, and that microbial alterations may offset the side effects brought about by chemotherapy. We demonstrated successful humanization of germ-free mice by transplanting fecal samples from breast cancer patients before and after chemotherapy. Mice were then grouped based on chemotherapy status and GE or control diet. We did not find any significant differences between pre-chemotherapy and post-chemotherapy bacterial composition and abundances. Germ-free mice on a GE diet showed differences in microbial composition as compared to mice on control diet. Four weeks after introduction of the customized GE diet, there was distinct clustering of GE-fed mice as compared to the control-fed group. In the gut microbiome of GE-treated humanized mice, there was an increase in abundance of genera Lactococcus and Eubacterium. Phylum Verrucomicrobia showed statistically significant (p = 0.02) differences in abundances between the GE-fed and control-fed groups. There was an increase in bacteria belonging to family Lachnospiraceae and Ruminococcaceae in GE-fed mice. Marked changes were observed in GE catabolism in mice humanized with fecal material from two of three patients’ post-chemotherapy with complete disappearance of 4-ethylphenol and 2-(4-hydroxyphenol) propionic acid conjugates. The post-tumor samples did not show any distinct clustering of the gut microbiota between the two diet groups. There was an increase in latency of about 25% for tumor growth of the humanized mice that were on a GE diet as compared to humanized mice on a control diet. The average tumor size for the GE group was significantly decreased compared to the non-GE group. Collectively, our results suggest that the intestinal microbiota becomes altered with a GE diet before induction

Accumulation of genistein and daidzein, soybean isoflavones implicated in promoting human health, is significantly elevated by irrigation.

PubMed

Bennett, John O; Yu, Oliver; Heatherly, Larry G; Krishnan, Hari B

2004-12-15

late-planted soybeans as much as 2.5-fold. Accumulation of individual isoflavones, daidzein and genistein, was also elevated by irrigation. Because this cultural practice improves the quality traits of seeds, ESPS provides an opportunity for enhancing the quality of soybean.

Estrogenic compounds inhibit gap junctional intercellular communication in mouse Leydig TM3 cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Iwase, Yumiko; Fukata, Hideki; Mori, Chisato

2006-05-01

Some estrogenic compounds are reported to cause testicular disorders in humans and/or experimental animals by direct action on Leydig cells. In carcinogenesis and normal development, gap junctional intercellular communication (GJIC) plays an essential role in maintaining homeostasis. In this study, we examine the effects of diethylstilbestrol (DES, a synthetic estrogen), 17{beta}-estradiol (E{sub 2}, a natural estrogen), and genistein (GEN, a phytoestrogen) on GJIC between mouse Leydig TM3 cells using Lucifer yellow microinjection. The three compounds tested produced GJIC inhibition in the TM3 cells after 24 h. Gradually, 10 {mu}M DES began to inhibit GJIC for 24 h and this effectmore » was observed until 72 h. On the other hand, both 20 {mu}M E{sub 2} and 25 {mu}M GEN rapidly inhibited GJIC in 6 h and 2 h, respectively. The effects continued until 24 h, but weakened by 72 h. Furthermore, a combined effect at {mu}M level between DES and E{sub 2} on GJIC inhibition was observed, but not between GEN and E{sub 2}. DES and E{sub 2} showed GJIC inhibition at low dose levels (nearly physiological estrogen levels) after 72 h, but GEN did not. DES-induced GJIC inhibition at 10 pM and 10 {mu}M was completely counteracted by ICI 182,780 (ICl), an estrogen receptor antagonist. On the other hand, the inhibitory effects on GJIC with E{sub 2} (10 pM and 20 {mu}M) and GEN (25 {mu}M) were partially blocked by ICI or calphostin C, a protein kinase C (PKC) inhibitor, and were completely blocked by the combination of ICI and calphostin C. These results demonstrate that DES inhibits GJIC between Leydig cells via the estrogen receptor (ER), and that E{sub 2} and GEN inhibit GJIC via ER and PKC. These estrogenic compounds may have different individual nongenotoxic mechanism including PKC pathway on testicular carcinogenesis or development.« less

Micellar emulsions composed of mPEG-PCL/MCT as novel nanocarriers for systemic delivery of genistein: a comparative study with micelles

PubMed Central

Zhang, Tianpeng; Wang, Huan; Ye, Yanghuan; Zhang, Xingwang; Wu, Baojian

2015-01-01

Polymeric micelles receive considerable attention as drug delivery vehicles, depending on the versatility in drug solubilization and targeting therapy. However, their use invariably suffers with poor stability both in in vitro and in vivo conditions. Here, we aimed to develop a novel nanocarrier (micellar emulsions, MEs) for a systemic delivery of genistein (Gen), a poorly soluble anticancer agent. Gen-loaded MEs (Gen-MEs) were prepared from methoxy poly(ethylene glycol)-block-(ε-caprolactone) and medium-chain triglycerides (MCT) by solvent-diffusion technique. Nanocarriers were characterized by dynamic light scattering, transmission electron microscopy, and in vitro release. The resulting Gen-MEs were approximately 46 nm in particle size with a narrow distribution. Gen-MEs produced a different in vitro release profile from the counterpart of Gen-ME. The incorporation of MCT significantly enhanced the stability of nanoparticles against dilution with simulated body fluid. Pharmacokinetic study revealed that MEs could notably extend the mean retention time of Gen, 1.57- and 7.38-fold as long as that of micelles and solution formulation, respectively, following intravenous injection. Furthermore, MEs markedly increased the elimination half-life (t1/2β) of Gen, which was 2.63-fold larger than that of Gen solution. Interestingly, Gen distribution in the liver and kidney for MEs group was significantly low relative to the micelle group in the first 2 hours, indicating less perfusion in such two tissues, which well accorded with the elongated mean retention time. Our findings suggested that MEs may be promising carriers as an alternative of micelles to systemically deliver poorly soluble drugs. PMID:26491290

Restoring sensitivity to oxaliplatin by a novel approach in gemcitabine-resistant pancreatic cancer cells in vitro and in vivo

PubMed Central

Banerjee, Sanjeev; Kong, Dejuan; Azmi, Asfar S.; Wang, Zhiwei; Ahmad, Aamir; Sethi, Seema; Sarkar, Fazlul H.

2011-01-01

Oxaliplatin (OxP) has been used in combination therapy with gemcitabine for the treatment of pancreatic cancer (PC), but the beneficial effect was marginal, which is believed to be due to de novo and acquired drug resistance of PC. Here, we report our in vitro and in vivo preclinical evidence in support of chemosensitization of drug-resistant cells by a nontoxic chemopreventive agent (genistein). Genistein pretreatment together with low concentration of OxP showed significant reduction in cell viability and colony formation concomitant with increased apoptosis (p < 0.01), which was highly synergistic. Drug resistance of PC is allegedly linked with both constitutive and OxP-induced activation of NF-κB, and we found that inactivation of (nuclear factor kappa B) NF-κB by genistein before treatment of cells with OxP was required for cell killing, which was consistent with the downregulation of NF-κB and its downstream antiapoptotic genes (Bcl-2, XIAPs and survivin). Most importantly, our in vivo experiments using orthotopic mouse model showed significant reduction in tumor size (p < 0.01) and reduction of locoregional lymph node metastasis by combination treatment. These results were also consistent with inactivation of NF-κB and the downregulation of NF-κB downstream genes, decreased proliferation marker (Ki-67) and increased apoptosis (TUNEL) in tumor remnants, all of which was consistent with in vitro findings. From these results, we conclude that genistein sensitizes drug-resistant PC to OxP, which is mechanistically linked with inactivation of NF-κB signaling, resulting in greater antitumor effects, and thus our data suggest that this approach could be useful in improving the treatment outcome for patients diagnosed with PC. PMID:20824697

Formononetin attenuates osteoclastogenesis via suppressing the RANKL-induced activation of NF-κB, c-Fos, and nuclear factor of activated T-cells cytoplasmic 1 signaling pathway.

PubMed

Huh, Jeong-Eun; Lee, Wong In; Kang, Jung Won; Nam, Dongwoo; Choi, Do-Young; Park, Dong-Suk; Lee, Sang Hoon; Lee, Jae-Dong

2014-11-26

Formononetin (1), a plant-derived phytoestrogen, possesses bone protective properties. To address the potential therapeutic efficacy and mechanism of action of 1, we investigated its antiosteoclastogenic activity and its effect on nuclear factor-kappaB ligand (RANKL)-induced bone-marrow-derived macrophages (BMMs). Compound 1 markedly inhibited RANKL-induced osteoclast differentiation in the absence of cytotoxicity, by regulating the expression of osteoprotegerin (OPG) and RANKL in BMMs and in cocultured osteoblasts. Compound 1 significantly inhibited RANKL-induced tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, monocyte chemoattractant protein-1 (MCP-1), regulated on activation normal T cell expressed and secreted (RANTES), and macrophage inflammatory protein-1α (MIP-1α) in a concentration-dependent manner. These effects were accompanied by a decrease in RANKL-induced activation of the NF-κB p65 subunit, degradation of inhibitor κBα (IκBα), induction of NF-κB, and phosphorylation of AKT, extracellular-signal regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (p38 MAPK). NF-κB siRNA suppressed AKT, ERK, JNK, and p38 MAPK phosphorylation. Furthermore, 1 significantly suppressed c-Fos and nuclear factor of activated T-cells cytoplasmic 1 (NFATc1), key transcription factors during osteoclastogenesis. SP600125, a specific inhibitor of JNK, reduced RANKL-induced expression of phospho-c-Jun, c-Fos, and NFATc1 and inhibited osteoclast formation. These results suggested that 1 acted as an antiresorption agent by blocking osteoclast activation.

Black tea and D. candidum extracts play estrogenic activity via estrogen receptor α-dependent signaling pathway

PubMed Central

Wang, Yongsen; Sun, Jing; Zhang, Kun; Hu, Xin; Sun, Yuchu; Sheng, Jun; Fu, Xueqi

2018-01-01

In recent years, phytoestrogens have been shown as useful selective estrogen receptor modulators. The estrogen-like effects of black tea (BT) and D. candidum (DC), as well as the combination of the two herbs, have remained largely elusive. This study aims to investigate the phytoestrogenic effect of BT and DC extract, and the possible mechanism. The effects on T47D (ER+ cell line) proliferation were evaluated by using MTT assay. The S phase proportion of ER+ cells was determined by using flow cytometry. The estrogen antagonist ICI 182,780 was applied to block the ER function. The activation of ER-mediated PI3K/AKT and ERK signal pathways were observed by using western blot. Expression of ERα and PGR, as well as PS2 and Cyclin D1 were detected by using western blot and real-time quantitative PCR. Firstly, our results found that BT and DC extracts promoted cell proliferation in ER-positive cells, and this effect was ER-dependent. Besides, BT and DC extracts increased the S-phase cell number. Next, PI3K, AKT and ERK pathways below ER were activated by phytoestrogen treatment, and this activation was blocked by the ER antagonist. Moreover, prolonged BT and DC treatments increased the expression of ESR1 and PGR. Consistently, the mRNA levels of not only ESR1 and PGR but also estrogen-dependent effectors ps2 and cyclin D1, were increased by phytoestrogens and blocked by ICI 182,780. Taken Together, BT and DC extracts have phytoestrogenic effects, and this may provide new ideas and experimental basis for the development and application of phytoestrogens. PMID:29422998

Study of cytoskeletal changes induced by okadaic acid in BE(2)-M17 cells by means of a quantitative fluorimetric microplate assay.

PubMed

Leira, F; Alvarez, C; Vieites, J M; Vieytes, M R; Botana, L M

2001-01-01

The diarrhogenic activity of the marine toxin okadaic acid (OA) has been associated to its actin-disrupting effect, which could reflect the loosening of tight junctions in vivo. In this report, we present results obtained using a fluorimetric microplate assay for quantitative measurements of OA-induced changes on F-actin pools in BE(2)-M17 cells. The proposed method shows important advantages over classical methods in terms of rapidity, sensitivity (less than 5000 cells per well) and reproducibility, thus providing a very useful tool for studying F-actin levels in living cells. Results obtained demonstrate a time- and dose-dependent decrease of F-actin pools (IC(50)=100 nM at 1 h) in OA-treated cells, which was partly counteracted by TPA, H89, forskolin, wortmannin, ionomycin and orthovanadate at early stages, but remained unaffected after 24 h of incubation. Cells exposed for 1 h to 1 nM OA showed a slight increase of F-actin pools (1.5-fold), which was blocked by genistein and lavendustin A, thus suggesting a role for tyrosine kinases-dependent pathways in OA-induced polymerization at low concentrations. These results suggest direct interactions of Ser/Thr protein phosphatases with actin-binding proteins in the regulation of actin polymerization, thus indicating that disruption of cytoskeletal structure may be a key mechanism of OA-induced diarrhea.

Evidence for estrogen receptor beta-selective activity of Vitex agnus-castus and isolated flavones.

PubMed

Jarry, Hubertus; Spengler, Barbara; Porzel, Andrea; Schmidt, Juergen; Wuttke, Wolfgang; Christoffel, Volker

2003-10-01

Recent cell culture experiments indicated that extracts of Vitex agnus-castus (VAC) may contain yet unidentified phytoestrogens. Estrogenic actions are mediated via estrogen receptors (ER). To investigate whether VAC compounds bind to the currently known isoforms ERalpha or ERss, ligand binding assays (LBA) were performed. Subtype specific ER-LBA revealed a binding of VAC to ERss only. To isolate the ERss-selective compounds, the extract was fractionated by bio-guidance. The flavonoid apigenin was isolated and identified as the most active ERss-selective phytoestrogen in VAC. Other isolated compounds were vitexin and penduletin. These data demonstrate that the phytoestrogens in VAC are ERss-selective.

An Improved Nonradioactive Screening Method Identifies Genistein and Xanthohumol as Potent Inhibitors of Iodothyronine Deiodinases.

PubMed

Renko, Kostja; Schäche, Sonja; Hoefig, Carolin S; Welsink, Tim; Schwiebert, Christian; Braun, Doreen; Becker, Niels-Peter; Köhrle, Josef; Schomburg, Lutz

2015-08-01

enzymes were monitored with various nonradioactive substrates and confirmed by liquid chromatography-tandem mass spectrometry. The contrast agent and known DIO inhibitor iopanoic acid was characterized as readily accepted substrate by DIO2 and Dio3. In a screening approach using established endocrine disrupting compounds, the natural food ingredient genistein was identified as a further DIO1-specific inhibitor, while xanthohumol turned out to potently block the activity of all three isoenzymes. A rapid nonradioactive screening method based on the Sandell-Kolthoff reaction is suitable for identification of environmental, nutritive and pharmacological compounds modulating activities of human deiodinase enzymes.

Resolution of non-psychogenic epileptic-like seizures utilizing a vasodilatory and anti-inflammatory dietary intervention.

PubMed

Mamo, J C

2016-10-01

A young female subject with ineffective pharmacological regulation of chronic vasoconstrictive-induced epilectic-like seizures was effectively treated with a dietary regimen targeted to promote vasodilatation and attenuate vascular inflammation. The intervention consisted of complete cessation of caffeinated beverages, supplementation with L-arginine to promote vasodilatation, consumption of foods rich in phytoestrogens, minimization of foods enriched with saturated fatty acids, supplementation with vitamin D concomitant with increased ingestion of dairy milk and supplementation with aged garlic extract.

7,3',4'-Trihydroxyisoflavone, a metabolite of the soy isoflavone daidzein, suppresses ultraviolet B-induced skin cancer by targeting Cot and MKK4.

PubMed

Lee, Dong Eun; Lee, Ki Won; Byun, Sanguine; Jung, Sung Keun; Song, Nury; Lim, Sung Hwan; Heo, Yong-Seok; Kim, Jong Eun; Kang, Nam Joo; Kim, Bo Yeon; Bowden, G Tim; Bode, Ann M; Lee, Hyong Joo; Dong, Zigang

2011-04-22

Nonmelanoma skin cancer is one of the most frequently occurring cancers in the United States. Chronic exposure to UVB irradiation is a major cause of this cancer. Daidzein, along with genistein, is a major isoflavone found in soybeans; however, little is known about the chemopreventive effects of daidzein and its metabolites in UVB-induced skin cancer. Here, we found that 7,3',4'-trihydroxyisoflavone (THIF), a major metabolite of daidzein, effectively inhibits UVB-induced cyclooxygenase 2 (COX-2) expression through the inhibition of NF-κB transcription activity in mouse skin epidermal JB6 P+ cells. In contrast, daidzein had no effect on COX-2 expression levels. Data from Western blot and kinase assays showed that 7,3',4'-THIF inhibited Cot and MKK4 activity, thereby suppressing UVB-induced phosphorylation of mitogen-activated protein kinases. Pull-down assays indicated that 7,3',4'-THIF competed with ATP to inhibit Cot or MKK4 activity. Topical application of 7,3',4'-THIF clearly suppressed the incidence and multiplicity of UVB-induced tumors in hairless mouse skin. Hairless mouse skin results also showed that 7,3',4'-THIF inhibits Cot or MKK4 kinase activity directly, resulting in suppressed UVB-induced COX-2 expression. A docking study revealed that 7,3',4'-THIF, but not daidzein, easily docked to the ATP binding site of Cot and MKK4, which is located between the N- and C-lobes of the kinase domain. Collectively, these results provide insight into the biological actions of 7,3',4'-THIF, a potential skin cancer chemopreventive agent.

Involvement of the Tyr kinase/JNK pathway in carbachol-induced bronchial smooth muscle contraction in the rat.

PubMed

Sakai, Hiroyasu; Watanabe, Yu; Honda, Mai; Tsuiki, Rika; Ueda, Yusuke; Nagai, Yuki; Narita, Minoru; Misawa, Miwa; Chiba, Yoshihiko

2013-05-01

Tyrosine (Tyr) kinases and mitogen-activated protein kinases have been thought to participate in the contractile response in various smooth muscles. The aim of the current study was to investigate the involvement of the Tyr kinase pathway in the contraction of bronchial smooth muscle. Ring preparations of bronchi isolated from rats were suspended in an organ bath. Isometric contraction of circular smooth muscle was measured. Immunoblotting was used to examine the phosphorylation of c-Jun N-terminal kinasess (JNKs) in bronchial smooth muscle. To examine the role of mitogen-activated protein kinase(s) in bronchial smooth muscle contraction, the effects of MPAK inhibitors were investigated in this study. The contraction induced by carbachol (CCh) was significantly inhibited by pretreatment with selective Tyr kinase inhibitors (genistein and ST638, n = 6, respectively), and a JNK inhibitor (SP600125, n = 6). The contractions induced by high K depolarization (n = 4), orthovanadate (a potent Tyr phosphatase inhibitor) and sodium fluoride (a G protein activator; NaF) were also significantly inhibited by selective Tyr kinase inhibitors and a JNK inhibitor (n = 4, respectively). However, the contraction induced by calyculin-A was not affected by SP600125. On the other hand, JNKs were phosphorylated by CCh (2.2 ± 0,4 [mean±SEM] fold increase). The JNK phosphorylation induced by CCh was significantly inhibited by SP600125 (n = 4). These findings suggest that the Tyr kinase/JNK pathway may play a role in bronchial smooth muscle contraction. Strategies to inhibit JNK activation may represent a novel therapeutic approach for diseases involving airway obstruction, such as asthma and chronic obstructive pulmonary disease.

Two-signal electrochemical method for evaluation suppression and proliferation of MCF-7 cells based on intracellular purine.

PubMed

Li, Jinlian; Lin, Runxian; Wang, Qian; Gao, Guanggang; Cui, Jiwen; Liu, Jiguang; Wu, Dongmei

2014-07-01

Two electrochemical signals ascribed to xanthine/guanine and hypanthine/adenine in MCF-7 cells were detected at 0.726 and 1.053 V, respectively. Based on the intensity of signals, the genistein-induced proliferation and suppression of MCF-7 cells could be evaluated. The results showed that with the increase of genistein dose at the range of 10(-9) to 10(-6)M, the two electrochemical signals of MCF-7 cell suspension increased due to the proliferation, whereas the tendency at the high dosage range of more than 10(-5)M was decreased. The proliferation and cytotoxicity obtained by the electrochemical method were in agreement with those obtained by cell counting and the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium] method. Thus, the two-signal electrochemical method is an effective way to evaluate the effect of drugs on cell activity based on purine metabolism. Copyright © 2014 Elsevier Inc. All rights reserved.

Blueberries and Tofu: Friend or Foe?

NASA Astrophysics Data System (ADS)

D'Ascoli, Jennifer; Lee, Susanne

2004-03-01

Two flavonoids, naringenin and genistein found in blueberries and soybeans, respectively, scavenge free radicals and exhibit anti- breast and prostate cancer properties. When consumed in foods, these flavonoids usually are subject to heat, yet all biological studies have been performed with unheated molecules. We have explored and will report on the three-dimensional, molecular structure changes we have thermally-induced in naringenin and genistein. We have measured and will discuss the flavonoids' thermodynamic properties as a function of temperature. Several endothermic transformations were observed along with a marked color change that remained when the flavonoids were dissolved in a solvent, indicating their molecular structures had been altered by the heat. Ultraviolet-Visible spectroscopy, and proton and carbon 1-D nuclear magnetic resonance will be presented that show the change was associated with a decrease in electron localization within the molecules. We will explain how such modified structures could scavenge free radicals more effectively and affect breast cancer cell proliferation.

Puerariae radix isoflavones and their metabolites inhibit growth and induce apoptosis in breast cancer cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lin, Y.-J.; Department of Biotechnology, Asia University, Taichung, Taiwan; Graduate Institute of Chinese Medical Science, China Medical University, Taichung, Taiwan

2009-01-23

Puerariae radix (PR) is a popular natural herb and a traditional food in Asia, which has antithrombotic and anti-allergic properties and stimulates estrogenic activity. In the present study, we investigated the effects of the PR isoflavones puerarin, daidzein, and genistein on the growth of breast cancer cells. Our data revealed that after treatment with PR isoflavones, a dose-dependent inhibition of cell growth occurred in HS578T, MDA-MB-231, and MCF-7 cell lines. Results from cell cycle distribution and apoptosis assays revealed that PR isoflavones induced cell apoptosis through a caspase-3-dependent pathway and mediated cell cycle arrest in the G2/M phase. Furthermore, wemore » observed that the serum metabolites of PR (daidzein sulfates/glucuronides) inhibited proliferation of the breast cancer cells at a 50% cell growth inhibition (GI{sub 50}) concentration of 2.35 {mu}M. These results indicate that the daidzein constituent of PR can be metabolized to daidzein sulfates or daidzein glucuronides that exhibit anticancer activities. The protein expression levels of the active forms of caspase-9 and Bax in breast cancer cells were significantly increased by treatment with PR metabolites. These metabolites also increased the protein expression levels of p53 and p21. We therefore suggest that PR may act as a chemopreventive and/or chemotherapeutic agent against breast cancer by reducing cell viability and inducing apoptosis.« less

Dietary isoflavone absorption, excretion, and metabolism in captive cheetahs (Acinonyx jubatus).

PubMed

Whitehouse-Tedd, Katherine M; Cave, Nicholas J; Ugarte, Claudia E; Waldron, Lucy A; Prasain, Jeevan K; Arabshahi, Alireza; Barnes, Stephen; Thomas, David G

2011-12-01

Dietary isoflavones, capable of influencing reproductive parameters in domestic cats (Felis catus), have been detected in commercial diets fed to captive cheetahs (Acinonyx jubatus). However, the absorptive and metabolic capacity of cheetahs towards isoflavones has not yet been studied. Experiments were designed to describe the plasma concentration-time curve, metabolite profile, and urinary and fecal excretion of genistein and daidzein in cheetahs following consumption of isoflavones. Four adult cheetahs were administered a single oral bolus of genistein and daidzein, and five juvenile cheetahs consuming a milk replacer formula found to contain isoflavones were also included. Urine was collected from all animals, and blood and feces were also collected from adult cheetahs following isoflavone exposure. Samples were analyzed for isoflavone metabolite concentration by liquid chromatography-electrospray ionization-multiple reaction ion monitoring mass spectrometry and high-performance liquid chromatography. Sulfate conjugates were the primary metabolites detected of both genistein and daidzein (60-80% of total isoflavones present) in the plasma and urine of cheetahs. A smaller proportion of daidzein was detected as conjugates in the urine of juvenile cheetahs, compared to adult cheetahs. Other metabolites included unconjugated genistein and daidzein, O-desmethylangolensin, and dihydrodaidzein, but not equol. Only 33% of the ingested genistein dose, and 9% of daidzein, was detected in plasma from adult cheetahs. However, of the ingested dose, 67% of genistein and 45% of daidzein were detected in the feces of adults. This study revealed that cheetahs appear efficient in their conjugation of absorbed dietary isoflavones and only a small fraction of ingested dose is absorbed. However, the capacity of the cheetah to conjugate genistein and daidzein with sulfate moieties appears lower than reported in the domestic cat. This may confer greater opportunity for biologic

Targeting the cancer initiating cell: the Achilles' heel of cancer.

PubMed

McCubrey, James A; Chappell, William H; Abrams, Stephen L; Franklin, Richard A; Long, Jacquelyn M; Sattler, Jennifer A; Kempf, C Ruth; Laidler, Piotr; Steelman, Linda S

2011-01-01

We have isolated cell with the cancer initiating cell (CIC) phenotype from PC3 cells. The PC3/(CIC) cells are more resistant than the PC3/(BC) cells to chemotherapeutic drugs such as docetaxel which is used to treat prostate cancer. Thus these prostate CICs could lay dormant and persist even after chemotherapeutic drug treatment. Then when the chemotherapeutic drug is removed, they could potentially repopulate the original tumor site or metastize to a distant site. However, the prostate CICs were not significantly more resistant to drugs which target EGFR, NF-κB, Smo and the natural product genistein. Interesting the prostate CICs could be rendered more sensitive to docetaxel by inclusion of suboptimal doses of genistein, cyclopamine, and EGFR inhibitors. In contrast, addition of suboptimal amounts of genistein, cyclopamine, or EGFR inhibitors did not increase the sensitivity of the PC/(BC) cells to docetaxel. Similar results were observed when combination experiments were performed with cyclopamine and suboptimal doses of either genistein or docetaxel. The BC cells are usually more rapidly proliferating than the CICs. Thus the CICs are not as sensitive to docetaxel which targets replication. In contrast, the CICs could be rendered sensitive to docetaxel or cyclopamine by co-treatment with certain other drugs, including the natural product genistein which is present in the human diet of many people, especially Asians. Genistein is by itself only weakly toxic to prostate and other cancer cells. That is probably one of the big reasons that it can be used as a dietary supplement for prostate and breast cancers. It is clear from our studies that low doses of genistein can increase the sensitivity of prostate CICs to drugs such as docetaxel and cyclopamine, two drugs either used or under consideration for prostate cancer therapy.

Nodulation Characterization and Proteomic Profiling of Bradyrhizobium liaoningense CCBAU05525 in Response to Water-Soluble Humic Materials

PubMed Central

Guo Gao, Tong; Yuan Xu, Yuan; Jiang, Feng; Zhen Li, Bao; Shui Yang, Jin; Tao Wang, En; Li Yuan, Hong

2015-01-01

The lignite biodegradation procedure to produce water-soluble humic materials (WSHM) with a Penicillium stain was established by previous studies in our laboratory. This study researched the effects of WSHM on the growth of Bradyrhizobium liaoningense CCBAU05525 and its nodulation on soybean. Results showed that WSHM enhanced the cell density of CCBAU05525 in culture, and increased the nodule number, nodule fresh weight and nitrogenase activity of the inoculated soybean plants. Then the chemical compounds of WSHM were analyzed and flavonoid analogues were identified in WSHM through tetramethyl ammonium hydroxide (TMAH)-py-GC/MS analysis. Protein expression profiles and nod gene expression of CCBAU05525 in response to WSHM or genistein were compared to illustrate the working mechanism of WSHM. The differently expressed proteins in response to WSHM were involved in nitrogen and carbon metabolism, nucleic acid metabolism, signaling, energy production and some transmembrane transports. WSHM was found more effective than genistein in inducing the nod gene expression. These results demonstrated that WSHM stimulated cell metabolism and nutrient transport, which resulted in increased cell density of CCBAU05525 and prepared the bacteria for better bacteroid development. Furthermore, WSHM had similar but superior functions to flavone in inducing nod gene and nitrogen fixation related proteins expression in CCBAU05525. PMID:26054030

Effects of soy containing diet and isoflavones on cytochrome P450 enzyme expression and activity.

PubMed

Ronis, Martin J J

2016-08-01

Cytochromes P450 (CYPs) play an important role in metabolism and clearance of most clinically utilized drugs and other xenobiotics. They are important in metabolism of endogenous compounds including fatty acids, sterols, steroids and lipid-soluble vitamins. Dietary factors such as phytochemicals are capable of affecting CYP expression and activity, which may be important in diet-drug interactions and in the development of fatty liver disease, cardiovascular disease and cancer. One important diet-CYP interaction is with diets containing plant proteins, particularly soy protein. Soy diets are traditionally consumed in Asian countries and are linked to lower incidence of several cancers and of cardiovascular disease in Asian populations. Soy is also an important protein source in vegetarian and vegan diets and the sole protein source in soy infant formulas. Recent studies suggest that consumption of soy can inhibit induction of CY1 enzymes by polycyclic aromatic hydrocarbons (PAHs) which may contribute to cancer prevention. In addition, there are data to suggest that soy components promiscuously activate several nuclear receptors including PXR, PPAR and LXR resulting in increased expression of CYP3As, CYP4As and CYPs involved in metabolism of cholesterol to bile acids. Such soy-CYP interactions may alter drug pharmacokinetics and therapeutic efficacy and are associated with improved lipid homeostasis and reduced risk of cardiovascular disease. The current review summarizes results from in vitro; in vivo and clinical studies of soy-CYP interactions and examines the evidence linking the effects of soy diets on CYP expression to isoflavone phytoestrogens, particularly, genistein and daidzein that are associated with soy protein.

Breast cancer resistance protein (Bcrp) and the testis—an unexpected turn of events

PubMed Central

Qian, Xiaojing; Cheng, Yan-Ho; Mruk, Dolores D; Cheng, C Yan

2013-01-01

Breast cancer resistance protein (Bcrp) is an ATP-dependent efflux drug transporter. It has a diverse spectrum of hydrophilic and hydrophobic substrates ranging from anticancer, antiviral and antihypertensive drugs, to organic anions, antibiotics, phytoestrogens (e.g., genistein, daidzein, coumestrol), xenoestrogens and steroids (e.g., dehydroepiandrosterone sulfate). Bcrp is an integral membrane protein in cancer and normal cells within multiple organs (e.g., brain, placenta, intestine and testis) that maintains cellular homeostasis by extruding drugs and harmful substances from the inside of cells. In the brain, Bcrp is a major component of the blood–brain barrier located on endothelial cells near tight junctions (TJs). However, Bcrp is absent at the Sertoli cell blood–testis barrier (BTB); instead, it is localized almost exclusively to the endothelial TJ in microvessels in the interstitium and the peritubular myoid cells in the tunica propria. Recent studies have shown that Bcrp is also expressed stage specifically and spatiotemporally by Sertoli and germ cells in the seminiferous epithelium of rat testes, limited only to a testis-specific cell adhesion ultrastructure known as the apical ectoplasmic specialisation (ES) in stage VI–early VIII tubules. These findings suggest that Bcrp is equipped by late spermatids and Sertoli cells to protect late-stage spermatids completing spermiogenesis. Furthermore, Bcrp was found to be associated with F (filamentous)-actin and several actin regulatory proteins at the apical ES and might be involved in the organisation of actin filaments at the apical ES in stage VII–VIII tubules. These findings will be carefully evaluated in this brief review. PMID:23665760

Dietary supplements and prostate cancer: a systematic review of double-blind, placebo-controlled randomised clinical trials.

PubMed

Posadzki, Paul; Lee, Myeong Soo; Onakpoya, Igho; Lee, Hye Won; Ko, Byong Seob; Ernst, Edzard

2013-06-01

Dietary supplements are popular among patients with prostate cancer (PC). The objective of this systematic review was to critically examine double-blind, placebo-controlled randomised clinical trials (RCTs) of non-herbal dietary supplements and vitamins (NHDS) for evidence that prostate specific antigen (PSA) levels were reduced in PC patients. Five databases were searched from their inception through December 2012 to identify studies that met our inclusion criteria. Methodological quality was independently assessed by two reviewers using the Cochrane tool. Eight RCTs met the eligibility criteria and were of high methodological quality. The following supplements were tested: isoflavones (genistein, daidzein, and glycitein), minerals (Se) or vitamins (vitamin D) or a combination of antioxidants, bioflavonoids, carotenoids, lycopenes, minerals (Se, Zn, Cu, and Mg), phytoestrogens, phytosterols, vitamins (B2, B6, B9, B12, C, and E), and other substances (CoQ10 and n-acetyl-l cysteine). Five RCTs reported no significant effects compared with placebo. Two RCTs reported that a combination of antioxidants, isoflavones, lycopenes, minerals, plant oestrogens and vitamins significantly decreased PSA levels compared with placebo. One RCT did not report differences in PSA levels between the groups. In conclusion, the hypothesis that dietary supplements are effective treatments for PC patients is not supported by sound clinical evidence. There are promising data for only two specific remedies, which contained a mixture of ingredients, but even for these supplements, additional high quality evidence is necessary before firm recommendations would be justified. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

EFFECT OF DIETARY FLAVONOID NARINGENIN ON BONES IN RATS WITH OVARIECTOMY-INDUCED OSTEOPOROSIS.

PubMed

Kaczmarczyk-Sedlak, Ilona; Wojnar, Weronika; Zych, Maria; Ozimina-Kamińska, Ewa; Bońka, Anna

2016-07-01

Naringenin is a dietary flavanone which can be found in many products such as citrus fruits. This substance reveals multiple pharmacological activities such as antiinflammatory and antioxidative. During the menopause, the estrogen deficiency occurs, thus naringenin, which is also considered as a phytoestrogen, may be useful in the treatment of menopause-associated osteoporosis. The aim of the presented study was to examine the effect of naringenin on the mechanical properties, chemical composition and the histomorphological parameters of bones in the rats with ovariectomy-induced osteoporosis. The female Wistar rats were divided into 4 groups: sham-operated, ovariectomized, ovariectoiized treated with estradiol (0.2 mg/kg p.o.) and ovariectomized treated with naringenin (50 mg/kg p.o.), and the tested substances were administered for 4 weeks. The obtained results show that ovariectomy caused the characteristic changes in the skeletal system of rats - there was deterioration in mechanics, chemistry and histomorphometry. The estradiol administered to the rats served as positive control for the experiment. Administration of naringenin to the ovariectomized rats affected neither the bone chemical content nor the mechanical properties, however, there was a slight improvement in the bone microarchitecture in the tissue affected by osteoporosis. It can be concluded that the intake of naringenin in dietary products is not harmful and may even bring beneficial effect on the bones histomorphometry during postmenopausal osteoporosis.

Molecular basis of 'hypoxic' breast cancer cell radio-sensitization: phytochemicals converge on radiation induced Rel signaling.

PubMed

Aravindan, Sheeja; Natarajan, Mohan; Herman, Terence S; Awasthi, Vibhudutta; Aravindan, Natarajan

2013-03-04

Heterogeneously distributed hypoxic areas are a characteristic property of locally advanced breast cancers (BCa) and generally associated with therapeutic resistance, metastases, and poor patient survival. About 50% of locally advanced BCa, where radiotherapy is less effective are suggested to be due to hypoxic regions. In this study, we investigated the potential of bioactive phytochemicals in radio-sensitizing hypoxic BCa cells. Hypoxic (O2-2.5%; N2-92.5%; CO2-5%) MCF-7 cells were exposed to 4 Gy radiation (IR) alone or after pretreatment with Curcumin (CUR), curcumin analog EF24, neem leaf extract (NLE), Genistein (GEN), Resveratrol (RES) or raspberry extract (RSE). The cells were examined for inhibition of NFκB activity, transcriptional modulation of 88 NFκB signaling pathway genes, activation and cellular localization of radio-responsive NFκB related mediators, eNos, Erk1/2, SOD2, Akt1/2/3, p50, p65, pIκBα, TNFα, Birc-1, -2, -5 and associated induction of cell death. EMSA revealed that cells exposed to phytochemicals showed complete suppression of IR-induced NFκB. Relatively, cells exposed EF24 revealed a robust inhibition of IR-induced NFκB. QPCR profiling showed induced expression of 53 NFκB signaling pathway genes after IR. Conversely, 53, 50, 53, 53, 53 and 53 of IR-induced genes were inhibited with EF24, NLE, CUR, GEN, RES and RSE respectively. In addition, 25, 29, 24, 16, 11 and 21 of 35 IR-suppressed genes were further inhibited with EF24, NLE, CUR, GEN, RES and RSE respectively. Immunoblotting revealed a significant attenuating effect of IR-modulated radio-responsive eNos, Erk1/2, SOD2, Akt1/2/3, p50, p65, pIκBα, TNFα, Birc-1, -2 and -5 with EF24, NLE, CUR, GEN, RES or RSE. Annexin V-FITC staining showed a consistent and significant induction of IR-induced cell death with these phytochemicals. Notably, EF24 robustly conferred IR-induced cell death. Together, these data identifies the potential hypoxic cell radio-sensitizers and further

Arctigenin, a dietary phytoestrogen, induces apoptosis of estrogen receptor-negative breast cancer cells through the ROS/p38 MAPK pathway and epigenetic regulation.

PubMed

Hsieh, Chia-Jung; Kuo, Po-Lin; Hsu, Ying-Chan; Huang, Ya-Fang; Tsai, Eing-Mei; Hsu, Ya-Ling

2014-02-01

This study investigates the anticancer effect of arctigenin (ATG), a natural lignan product of Arctium lappa L., in human breast cancer MDA-MB-231 cells. Results indicate that ATG inhibits MDA-MB-231 cell growth by inducing apoptosis in vitro and in vivo. ATG triggers the mitochondrial caspase-independent pathways, as indicated by changes in Bax/Bcl-2 ratio, resulting in AIF and EndoG nuclear translocation. ATG increased cellular reactive oxygen species (ROS) production by increasing p22(phox)/NADPH oxidase 1 interaction and decreasing glutathione level. ATG clearly increases the activation of p38 MAPK, but not JNK and ERK1/2. Antioxidant EUK-8, a synthetic catalytic superoxide and hydrogen peroxide scavenger, significantly decreases ATG-mediated p38 activation and apoptosis. Blocking p38 with a specific inhibitor suppresses ATG-mediated Bcl-2 downregulation and apoptosis. Moreover, ATG activates ATF-2, a transcription factor activated by p38, and then upregulates histone H3K9 trimethylation in the Bcl-2 gene promoter region, resulting in Bcl-2 downregulation. Taken together, the results demonstrate that ATG induces apoptosis of MDA-MB-231 cells via the ROS/p38 MAPK pathway and epigenetic regulation of Bcl-2 by upregulation of histone H3K9 trimethylation. Crown Copyright © 2013. Published by Elsevier Inc. All rights reserved.

Method development for the determination of coumarin compounds by capillary electrophoresis with indirect laser-induced fluorescence detection.

PubMed

Wang, Weiping; Tang, Jianghong; Wang, Shumin; Zhou, Lei; Hu, Zhide

2007-04-27

A capillary zone electrophoresis (CZE) with indirect laser-induced fluorescence detection (ILIFD) method is described for the simultaneous determination of esculin, esculetin, isofraxidin, genistein, naringin and sophoricoside. The baseline separation was achieved within 5 min with running buffer (pH 9.4) composed of 5mM borate, 20% methanol (v/v) as organic modifier, 10(-7)M fluorescein sodium as background fluorophore and 20 kV of applied voltage at 30 degrees C of cartridge temperature. Good linearity relationships (correlation coefficients >0.9900) between the second-order derivative peak-heights (RFU) and concentrations of the analytes (mol L(-1)) were obtained. The detection limits for all analytes in second-order derivative electrophoregrams were in the range of 3.8-15 microM. The RSD data of intra-day for migration times and second-order derivative peak-height were less than 0.95 and 5.02%, respectively. This developed method was applied to the analysis of the courmin compounds in herb plants with recoveries in the range of 94.7-102.1%. In this work, although the detection sensitivity was lower than that of direct LIF, yet the method would extend the application range of LIF detection.

Isoflavone supplement composition and equol producer status affect gene expression in adipose tissue: a double-blind, randomized, placebo-controlled crossover trial in postmenopausal women.

PubMed

van der Velpen, Vera; Geelen, Anouk; Hollman, Peter C H; Schouten, Evert G; van 't Veer, Pieter; Afman, Lydia A

2014-11-01

Isoflavone supplements, consumed by women experiencing menopausal symptoms, are suggested to have positive effects on menopause-related adiposity and cardiovascular disease risk profile, but discussions about their safety are still ongoing. The objective was to study the effects of an 8-wk consumption of 2 different isoflavone supplements compared with placebo on whole-genome gene expression in the adipose tissue of postmenopausal women. This double-blind, randomized, placebo-controlled crossover intervention consisted of 2 substudies, one with a low-genistein (LG) supplement (56% daidzein + daidzin, 16% genistein + genistin, and 28% glycitein + glycitin) and the other with a high-genistein (HG) supplement (49% daidzein + daidzin, 41% genistein + genistin, and 10% glycitein + glycitin). Both supplements provided ∼ 100 mg isoflavones/d (aglycone equivalents). After the 8-wk isoflavone and placebo period, whole-genome arrays were performed in subcutaneous adipose tissue of postmenopausal women (n = 26 after LG, n = 31 after HG). Participants were randomized by equol-producing phenotype, and data analysis was performed per substudy for equol producers and nonproducers separately. Gene set enrichment analysis showed downregulation of expression of energy metabolism-related genes after LG supplementation (n = 24) in both equol-producing phenotypes and oppositely regulated expression for equol producers (down) and nonproducers (up) after HG supplementation (n = 31). Expression of inflammation-related genes was upregulated in equol producers but downregulated in nonproducers, independent of supplement type. Only 4.4-7.0% of the genes with significantly changed expression were estrogen responsive. Body weight, adipocyte size, and plasma lipid profile were not affected by isoflavone supplementation. Effects of isoflavones on adipose tissue gene expression were influenced by supplement composition and equol-producing phenotype, whereas estrogen-responsive effects were

Targeted Metabolomics Identifies Pharmacodynamic Biomarkers for BIO 300 Mitigation of Radiation-Induced Lung Injury.

PubMed

Jones, Jace W; Jackson, Isabel L; Vujaskovic, Zeljko; Kaytor, Michael D; Kane, Maureen A

2017-12-01

Biomarkers serve a number of purposes during drug development including defining the natural history of injury/disease, serving as a secondary endpoint or trigger for intervention, and/or aiding in the selection of an effective dose in humans. BIO 300 is a patent-protected pharmaceutical formulation of nanoparticles of synthetic genistein being developed by Humanetics Corporation. The primary goal of this metabolomic discovery experiment was to identify biomarkers that correlate with radiation-induced lung injury and BIO 300 efficacy for mitigating tissue damage based upon the primary endpoint of survival. High-throughput targeted metabolomics of lung tissue from male C57L/J mice exposed to 12.5 Gy whole thorax lung irradiation, treated daily with 400 mg/kg BIO 300 for either 2 weeks or 6 weeks starting 24 h post radiation exposure, were assayed at 180 d post-radiation to identify potential biomarkers. A panel of lung metabolites that are responsive to radiation and able to distinguish an efficacious treatment schedule of BIO 300 from a non-efficacious treatment schedule in terms of 180 d survival were identified. These metabolites represent potential biomarkers that could be further validated for use in drug development of BIO 300 and in the translation of dose from animal to human.

7,3′,4′-Trihydroxyisoflavone, a Metabolite of the Soy Isoflavone Daidzein, Suppresses Ultraviolet B-induced Skin Cancer by Targeting Cot and MKK4*

PubMed Central

Lee, Dong Eun; Lee, Ki Won; Byun, Sanguine; Jung, Sung Keun; Song, Nury; Lim, Sung Hwan; Heo, Yong-Seok; Kim, Jong Eun; Kang, Nam Joo; Kim, Bo Yeon; Bowden, G. Tim; Bode, Ann M.; Lee, Hyong Joo; Dong, Zigang

2011-01-01

Nonmelanoma skin cancer is one of the most frequently occurring cancers in the United States. Chronic exposure to UVB irradiation is a major cause of this cancer. Daidzein, along with genistein, is a major isoflavone found in soybeans; however, little is known about the chemopreventive effects of daidzein and its metabolites in UVB-induced skin cancer. Here, we found that 7,3′,4′-trihydroxyisoflavone (THIF), a major metabolite of daidzein, effectively inhibits UVB-induced cyclooxygenase 2 (COX-2) expression through the inhibition of NF-κB transcription activity in mouse skin epidermal JB6 P+ cells. In contrast, daidzein had no effect on COX-2 expression levels. Data from Western blot and kinase assays showed that 7,3′,4′-THIF inhibited Cot and MKK4 activity, thereby suppressing UVB-induced phosphorylation of mitogen-activated protein kinases. Pull-down assays indicated that 7,3′,4′-THIF competed with ATP to inhibit Cot or MKK4 activity. Topical application of 7,3′,4′-THIF clearly suppressed the incidence and multiplicity of UVB-induced tumors in hairless mouse skin. Hairless mouse skin results also showed that 7,3′,4′-THIF inhibits Cot or MKK4 kinase activity directly, resulting in suppressed UVB-induced COX-2 expression. A docking study revealed that 7,3′,4′-THIF, but not daidzein, easily docked to the ATP binding site of Cot and MKK4, which is located between the N- and C-lobes of the kinase domain. Collectively, these results provide insight into the biological actions of 7,3′,4′-THIF, a potential skin cancer chemopreventive agent. PMID:21378167

Molecular basis of ‘hypoxic’ breast cancer cell radio-sensitization: phytochemicals converge on radiation induced Rel signaling

PubMed Central

2013-01-01

Background Heterogeneously distributed hypoxic areas are a characteristic property of locally advanced breast cancers (BCa) and generally associated with therapeutic resistance, metastases, and poor patient survival. About 50% of locally advanced BCa, where radiotherapy is less effective are suggested to be due to hypoxic regions. In this study, we investigated the potential of bioactive phytochemicals in radio-sensitizing hypoxic BCa cells. Methods Hypoxic (O2-2.5%; N2-92.5%; CO2-5%) MCF-7 cells were exposed to 4 Gy radiation (IR) alone or after pretreatment with Curcumin (CUR), curcumin analog EF24, neem leaf extract (NLE), Genistein (GEN), Resveratrol (RES) or raspberry extract (RSE). The cells were examined for inhibition of NFκB activity, transcriptional modulation of 88 NFκB signaling pathway genes, activation and cellular localization of radio-responsive NFκB related mediators, eNos, Erk1/2, SOD2, Akt1/2/3, p50, p65, pIκBα, TNFα, Birc-1, -2, -5 and associated induction of cell death. Results EMSA revealed that cells exposed to phytochemicals showed complete suppression of IR-induced NFκB. Relatively, cells exposed EF24 revealed a robust inhibition of IR-induced NFκB. QPCR profiling showed induced expression of 53 NFκB signaling pathway genes after IR. Conversely, 53, 50, 53, 53, 53 and 53 of IR-induced genes were inhibited with EF24, NLE, CUR, GEN, RES and RSE respectively. In addition, 25, 29, 24, 16, 11 and 21 of 35 IR-suppressed genes were further inhibited with EF24, NLE, CUR, GEN, RES and RSE respectively. Immunoblotting revealed a significant attenuating effect of IR-modulated radio-responsive eNos, Erk1/2, SOD2, Akt1/2/3, p50, p65, pIκBα, TNFα, Birc-1, -2 and −5 with EF24, NLE, CUR, GEN, RES or RSE. Annexin V-FITC staining showed a consistent and significant induction of IR-induced cell death with these phytochemicals. Notably, EF24 robustly conferred IR-induced cell death. Conclusions Together, these data identifies the potential

Effects of tyrosine kinase and phosphatase inhibitors on mitosis progression in synchronized tobacco BY-2 cells.

PubMed

Sheremet, Ya A; Yemets, A I; Azmi, A; Vissenberg, K; Verbelen, J P; Blume, Ya B

2012-01-01

To test whether reversible tubulin phosphorylation plays any role in the process of plant mitosis the effects of inhibitors of tyrosine kinases, herbimycin A, genistein and tyrphostin AG 18, and of an inhibitor of tyrosine phosphatases, sodium orthovanadate, on microtubule organization and mitosis progression in a synchronized BY-2 culture has been investigated. It was found that treatment with inhibitors of tyrosine kinases of BY-2 cells at the G2/M transition did not lead to visible disturbances of mitotic microtubule structures, while it did reduce the frequency of their appearance. We assume that a decreased tyrosine phosphorylation level could alter the microtubule dynamic instability parameters during interphase/prophase transition. All types of tyrosine kinase inhibitors used caused a prophase delay: herbimycin A and genistein for 2 h, and tyrphostin AG18 for 1 h. Thereafter the peak of mitosis was displaced for 1 h by herbimycin A or genistein exposure, but after tyrphostin AG18 treatment the timing of the mitosis-peak was comparable to that in control cells. Enhancement of tyrosine phosphorylation induced by the tyrosine phosphatase inhibitor resulted in the opposite effect on BY-2 mitosis transition. Culture treatment with sodium orthovanadate during 1 h resulted in an accelerated start of the prophase and did not lead to the alteration in time of the mitotic index peak formation, as compared to control cells. We suppose that the reversible tyrosine phosphorylation can be involved in the regulation of interphase to M phase transition possibly through regulation of microtubule dynamics in plant cells.

Anthropogenic pressure in a Portuguese river: Endocrine-disrupting compounds, trace elements and nutrients.

PubMed

Ribeiro, Cláudia M R; Maia, Alexandra S; Ribeiro, Ana R; Couto, Cristina; Almeida, Agostinho A; Santos, Mariana; Tiritan, Maria E

2016-10-14

Natural organic compounds such as phytoestrogens and phytosterols found in various plants, as well as mycotoxins produced by fungi, can be found in aquatic environments. The aim of this study was to investigate the occurrence of three different classes of natural estrogenic compounds, i.e., phytoestrogens, phytosterols and mycotoxins, in estuarine water samples from the Ave River estuary. For that, water samples were collected at five sampling points distributed along the estuary at low tide, during 1 year, processed by solid-phase extraction (SPE) and analyzed by gas chromatography coupled to mass spectrometry (GC-MS). To correlate the presence of phytoestrogens and phytosterols in the estuarine water, local flora was collected on riverside. Trace elements content and physicochemical parameters such as nutrients and dissolved oxygen were also determined seasonally at each sampling point, to give insights for the evaluation of water quality and anthropogenic pressure. Both phytoestrogens and phytosterols showed a seasonal variation, with the highest values observed in spring and summer and the lowest in winter. Daidzein (DAID) was found up to 404.0 ng L(-1) in spring and coumestrol (COUM) was found up to 165.0 ng L(-1) in summer. The mycotoxin deoxynivalenol (DON) was ubiquitously determined with values ranging from 59.5 to 642.4 ng L(-1). Nutrients and metals distribution and concentration varied among sampling stations and seasons. This study revealed for the first time the presence of mycotoxins, various classes of phytoestrogens and stigmasterol (STG) in estuarine water from the Ave River (Portugal), and the evaluation of the water quality confirmed that this estuary is still highly impacted by anthropogenic activities.

Antioxidant Therapy for Men With Asymptomatic Prostate Cancer

DTIC Science & Technology

2004-05-01

3 Hct (%) 42 ±3 41± 4 Hgb (g/dL) 14 ± 1 14± 1 Platlets (K/uL) 239 ± 49 278± 80 Lipid Profile T. Cholesterol (mg/dL) 190 ± 39 191 ± 32 HDL (mg/dL) 45...Wiseman, H., et al., Isoflavone phytoestrogens consumed in soy decrease F(2)-isoprostane concentrations and increase resistance of low- density lipoprotein ...Sukhatme, V. P. High cell density induces vascular endothelial growth factor expression via protein tyrosine phosphorylation. Gene Expr, 7: 53-60, 1998

An Enzyme-linked Immunosorbent Assay for Genistein 7-O-[α-rhamnopyranosyl-(1→6)]-β-glucopyranoside Determination in Derris scandens using a Polyclonal Antibody.

PubMed

Jutathis, Kamonthip; Kitisripanya, Tharita; Udomsin, Orain; Inyai, Chadathorn; Sritularak, Boonchoo; Tanaka, Hiroyuki; Putalun, Waraporn

2016-11-01

Genistein 7-O-[α-rhamnopyranosyl-(1→6)]-β-glucopyranoside (GTG) is a major bioactive compound in Derris scandens. It is responsible for anti-inflammatory activity by inhibition of cyclooxygenase and lipoxygenase. There are many commercial products of D. scandens available in Thailand. To develop an enzyme-linked immunosorbent assay (ELISA) for the quantitative analysis of GTG in plant material and derived products using a polyclonal antibody. An immunogen was synthesised by conjugating GTG with a carrier protein. The polyclonal antibody against GTG (GTG-PAb) was produced in New Zealand white rabbits. The ELISA method was validated for specificity, sensitivity, accuracy, precision and correlation with HPLC. The polyclonal antibody was specific to GTG and genistin within the range of compounds tested. The GTG ELISA was applied in the range 0.04-10.00 μg/mL with a limit of detection of 0.03 μg/mL. The recovery of GTG in spiked Derris scandens extracts ranged from 100.7 to 107.0%, with a coefficient of variation less than 7.0%. The intra- and inter-assay variations were less than 5.0%. The ELISA showed a good correlation with HPLC-UV analysis for GTG determination in samples, with a coefficient of determination (r 2 ) of 0.9880. An ELISA was established for GTG determination in Derris scandens. The GTG-PAb can react with GTG and genistin, but genistin has not been found in the plant. Therefore, the ELISA can be used for high throughput quality control of GTG content in D. scandens and its products. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Mechanisms mediating substance P-induced contraction in the rat iris in vitro.

PubMed

Grumann-Júnior, A; Dias, M A; Alves, R V; Boteon, J E; Calixto, J B

2000-06-01

To determine some of the mechanisms by which substance P (SP) induces contraction in the isolated rat iris. Rings of rat iris were mounted in a 5-ml organ chamber containing Krebs solution at 37 degrees C under basal tension of 75 mg, and isometric tension was recorded. Substance P produced graded contraction in the rat iris, being approximately 40-fold more potent than carbachol. Peptidase inhibitors (captopril, phosphoramidon, thiorphan) did not affect the SP response. The SP contraction was dependent on external Ca2+ by a mechanism resistant to both nifedipine and omega-conotoxin GVIA. Atropine and tetrodotoxin significantly shifted the SP response to the right (three- and fivefold, respectively). Neither phorbol nor genistein altered the SP-induced contraction, whereas staurosporine caused a weak inhibition. Indomethacin, pyrilamine, guanethidine, 8-37 calcitonin gene-related peptide (CGRP) fragment, and NG-nitro-L-arginine methyl ester had no effect on SP response. All the natural tachykinin agonists caused concentration-dependent contraction in rat iris with similar maximal responses. The NK3 selective agonist senktide caused graded contraction, being approximately 150-fold more active than the NK2 selective agonist [beta-ala] NKA. The NK1 selective agonist SP methyl ester induced a small contraction. The NK3 and NK2 antagonists SR 142801 and SR 48968 shifted the SP response to the right. Schilds plots gave pA2 (negative logarithm of the molar concentration of antagonist causing a twofold rightward displacement of the concentration response curves) values of 9.37 and 7.97 and slopes of 0.70 and 1.02, respectively. Substance P produces a potent contraction in the isolated rat iris that seems to depend on the neural release of acetylcholine by tetrodotoxin-sensitive mechanisms. Its response relies largely on external Ca2+, through mechanisms independent of activation of L- or N-type Ca2+ channels, and is probably mediated via activation of NK3 and NK2 receptors.

Inducible De Novo Biosynthesis of Isoflavonoids in Soybean Leaves by Spodoptera litura Derived Elicitors: Tracer Techniques Aided by High Resolution LCMS.

PubMed

Nakata, Ryu; Kimura, Yuki; Aoki, Kenta; Yoshinaga, Naoko; Teraishi, Masayoshi; Okumoto, Yutaka; Huffaker, Alisa; Schmelz, Eric A; Mori, Naoki

2016-12-01

Isoflavonoids are a characteristic family of natural products in legumes known to mediate a range of plant-biotic interactions. For example, in soybean (Glycine max: Fabaceae) multiple isoflavones are induced and accumulate in leaves following attack by Spodoptera litura (Lepidoptera: Noctuidae) larvae. To quantitatively examine patterns of activated de novo biosynthesis, soybean (Var. Enrei) leaves were treated with a combination of plant defense elicitors present in S. litura gut content extracts and L-α-[ 13 C 9 , 15 N]phenylalanine as a traceable isoflavonoid precursor. Combined treatments promoted significant increases in 13 C-labeled isoflavone aglycones (daidzein, formononetin, and genistein), 13 C-labeled isoflavone 7-O-glucosides (daidzin, ononin, and genistin), and 13 C-labeled isoflavone 7-O-(6″-O-malonyl-β-glucosides) (malonyldaidzin, malonylononin, and malonylgenistin). In contrast levels of 13 C-labeled flavones and flavonol (4',7-dihydroxyflavone, kaempferol, and apigenin) were not significantly altered. Curiously, application of fatty acid-amino acid conjugate (FAC) elicitors present in S. litura gut contents, namely N-linolenoyl-L-glutamine and N-linoleoyl-L-glutamine, both promoted the induced accumulation of isoflavone 7-O-glucosides and isoflavone 7-O-(6″-O-malonyl-β-glucosides), but not isoflavone aglycones in the leaves. These results demonstrate that at least two separate reactions are involved in elicitor-induced soybean leaf responses to the S. litura gut contents: one is the de novo biosynthesis of isoflavone conjugates induced by FACs, and the other is the hydrolysis of the isoflavone conjugates to yield isoflavone aglycones. Gut content extracts alone displayed no hydrolytic activity. The quantitative analysis of isoflavone de novo biosynthesis, with respect to both aglycones and conjugates, affords a useful bioassay system for the discovery of additional plant defense elicitor(s) in S. litura gut contents that specifically

The effects of Sutaehwan-Gami on menopausal symptoms induced by ovariectomy in rats.

PubMed

Kim, Dong-Il; Choi, Min Sun; Pak, Sok Cheon; Lee, Seung-Bok; Jeon, Songhee

2012-11-23

This study was undertaken to evaluate the beneficial effects of a modified prescription of Sutaehwan named Sutaehwan-Gami (SG), created by adding Rhizoma dioscoreae and Carthami semen to Sutaehwan, on menopausal symptoms. To evaluate the estrogenic effect of SG, we first examined estrogen receptor (ER) activation by SG treatment in breast adenocarcinoma cells and confirmed the estrogenic effect of SG in vivo ovariectomized rats. The animals were randomized into four groups: Sham operated group (Sham), saline treated ovariectomized group (OVX), SG treated group (SG) and raloxifene treated group (RLX). Animals were provided with SG at a dose of 500 mg/kg bw/day and RLX at a dose of 5.4 mg/kg bw/day with standard rat pellets for 3 months. SG significantly increased ERα phosphorylation, and its downstream effectors, extracellular signal-regulated kinase (ERK) and protein kinase B (Akt) phosphorylation in breast adenocarcinoma cells. Treatment with SG reversed ovariectomy-induced uterine weight reduction and weight gain. Decreases in the levels of GOT and GPT were observed in the SG group. The significantly reduced E2β level in OVX rats was raised by treatment with SG. Moreover, SG significantly increased the phosphorylation levels of ERK and Akt in the uterus. Taken together, these data indicate that SG has phytoestrogen-like properties through ERK and Akt activation, implying that it could be protective and beneficial for the management of menopausal symptoms.

Activation of the EGFR/p38/JNK Pathway by Mitochondrial-Derived Hydrogen Peroxide Contributes To Oxygen-induced Contraction Of Ductus Arteriosus

PubMed Central

Hong, Zhigang; Cabrera, Jésus A; Mahapatra, Saswati; Kutty, Shelby; Weir, E. Kenneth; Archer, Stephen L.

2014-01-01

Oxygen-induced contraction of the ductus arteriosus (DA) involves a mitochondrial oxygen-sensor, which signals pO2 in the DA smooth muscle cell (DASMC) by increasing production of diffusible hydrogen peroxide (H2O2). H2O2 stimulates vasoconstriction by regulating ion channels and rho kinase, leading to calcium influx and calcium sensitization. Because epidermal growth factor receptor (EGFR) signaling is also redox regulated and participates in oxygen sensing and vasoconstriction in other systems, we explored the role of the EGFR and its signaling cascade (p38 and JNK) in DA contraction. Experiments were performed in DA rings isolated from full-term New Zealand White rabbits and human DASMC. In human DASMCs increasing pO2 from hypoxia to normoxia (40 to 100 mmHg) significantly increased cytosolic calcium, p<0.01. This normoxic rise in intracellular calcium was mimicked by EGF and inhibited by EGFR siRNA. In DA rings, EGF caused contraction whilst the specific EGFR inhibitor (AG1478) and the tyrosine kinase inhibitors (genistein or tyrphostin A23) selectively attenuated oxygen-induced contraction (p <0.01). Conversely, orthovanadate, a tyrosine phosphatase inhibitor known to activate EGFR signaling, caused dose-dependent contraction of hypoxic DA and superimposed increases in oxygen caused minimal additional contraction. Ansomycin, an activator of EGFR’s downstream kinases, p38 and JNK, caused DA contraction; conversely, oxygen-induced DA contraction was blocked by inhibitors of p38 MAPK (SB203580) or JNK (JNK inhibitor II). O2-induced phosphorylation of EGFR occurred within 5-minutes of increasing pO2 and was inhibited by mitochondrial-targeted overexpression of catalase. AG1478 prevented the oxygen-induced p38 and JNK phosphorylation. In conclusion, O2-induced EGFR transactivation initiates p38/JNK-mediated increases in cytosolic calcium and contributes to DA contraction. The EGFR/p38/JNK pathway is regulated by mitochondrial redox signaling and is a promising

Soy isoflavone phase II metabolism differs between rodents and humans: implications for the effect on breast cancer risk1234

PubMed Central

Brown, Nadine M; Zhao, Xueheng; Lindley, Stephanie L; Heubi, James E; King, Eileen C; Messina, Mark J

2011-01-01

Background: Human and animal studies have produced conflicting results with regard to the effect of soy isoflavones on breast cancer risk. This may be due to differences in isoflavone metabolism. Objective: The objective of this study was to determine whether soy isoflavone phase II metabolism differs between humans and rodents. Design: Circulating total and unconjugated isoflavone concentrations were determined by mass spectrometry in plasma samples from 7 separate studies: 1) in Sprague-Dawley rats and in 3 strains of mice fed commercial soy-containing diets; 2) in Sprague-Dawley rats gavaged with genistein; 3) in healthy adults who consumed single servings of soy nuts, soy milk, and tempeh; 4) in healthy adults subchronically given soy milk; 5) in healthy women orally administered 50 mg genistein; 6) in healthy women orally administered 20 mg pure S-(-)equol; and 7) in 6-mo-old infants fed soy infant formula and later, at age 3 y, a soy germ isoflavone supplement. Results: The proportion of unconjugated genistein in plasma from adults and infants who consumed different soy foods, pure genistein, or an isoflavone supplement was <1% in steady state and <2% at peak concentrations. By contrast, rodents fed soy-containing diets conjugate isoflavones less efficiently. The plasma percentages of unconjugated genistein concentrations in Sprague-Dawley rats and C57BL/6, nude, and transgenic AngptL4B6 mice were 4.0 ± 0.6%, 4.6 ± 0.6%, 11.6 ± 0%, and 30.1 ± 4.3%, respectively, which represent 20, 23, 58, and 150 times that in humans. Conclusion: The markedly higher circulating concentrations of biologically active (unconjugated) genistein in certain strains of mice cast doubt on the value of the use of these rodents for gaining insight into the effects of isoflavones in humans, especially with regard to the effects on breast tissue. PMID:21955647

Soy isoflavone phase II metabolism differs between rodents and humans: implications for the effect on breast cancer risk.

PubMed

Setchell, Kenneth D R; Brown, Nadine M; Zhao, Xueheng; Lindley, Stephanie L; Heubi, James E; King, Eileen C; Messina, Mark J

2011-11-01

Human and animal studies have produced conflicting results with regard to the effect of soy isoflavones on breast cancer risk. This may be due to differences in isoflavone metabolism. The objective of this study was to determine whether soy isoflavone phase II metabolism differs between humans and rodents. Circulating total and unconjugated isoflavone concentrations were determined by mass spectrometry in plasma samples from 7 separate studies: 1) in Sprague-Dawley rats and in 3 strains of mice fed commercial soy-containing diets; 2) in Sprague-Dawley rats gavaged with genistein; 3) in healthy adults who consumed single servings of soy nuts, soy milk, and tempeh; 4) in healthy adults subchronically given soy milk; 5) in healthy women orally administered 50 mg genistein; 6) in healthy women orally administered 20 mg pure S-(-)equol; and 7) in 6-mo-old infants fed soy infant formula and later, at age 3 y, a soy germ isoflavone supplement. The proportion of unconjugated genistein in plasma from adults and infants who consumed different soy foods, pure genistein, or an isoflavone supplement was <1% in steady state and <2% at peak concentrations. By contrast, rodents fed soy-containing diets conjugate isoflavones less efficiently. The plasma percentages of unconjugated genistein concentrations in Sprague-Dawley rats and C57BL/6, nude, and transgenic AngptL4B6 mice were 4.0 ± 0.6%, 4.6 ± 0.6%, 11.6 ± 0%, and 30.1 ± 4.3%, respectively, which represent 20, 23, 58, and 150 times that in humans. The markedly higher circulating concentrations of biologically active (unconjugated) genistein in certain strains of mice cast doubt on the value of the use of these rodents for gaining insight into the effects of isoflavones in humans, especially with regard to the effects on breast tissue.

Effects of Vitex agnus-castus fruit on sex hormones and antioxidant indices in a d-galactose-induced aging female mouse model.

PubMed

Ahangarpour, Akram; Najimi, Seyedeh Asma; Farbood, Yaghoob

2016-11-01

Aging is associated with the loss of endocrine function. In this study, Vitex agnus-castus (Vitex), which has antioxidant effects and high levels of phytoestrogen, was investigated with regard to the hypothalamic-pituitary-gonadal axis and antioxidant indices in natural aging and in a d-galactose induced aging model in female mice. The mice were subcutaneously injected with d-galactose (500 mg/kg/d for 45 days). Extract of Vitex (600 mg/kg/bid for 7 days by gavage) was used to treat d-galactose-induced aging and natural aging in mice. Seventy-two female NMRI mice (48 3-month-old normal mice and 24 18-24-month-old mice), weighing 30-35 g were randomly divided into six groups: control, Vitex, d-galactose, Vitex + d-galactose, Aging, and Vitex + Aging. The antioxidant indices and sex hormone levels were subsequently measured by enzyme-linked immunosorbent assay kits. Body weight and the levels of malondialdehyde (MDA), follicle-stimulating hormone, and luteinizing hormone levels were significantly increased in the d-galactose aging and natural aging groups, whereas catalase and superoxide dismutase (SOD) activity and estrogen level were significantly decreased in these same groups. d-Galactose can also disrupt the estrous cycle and damage the uterus and ovarian tissues. Vitex could effectively attenuate these alterations. Vitex improved some aging events in the reproductive system of female mice. Therefore, because of its apparent antiaging effects, Vitex can be suitable for some aging problems such as oxidative stress, female sex hormone deficiency, and an atrophic endometrium. Copyright © 2016. Published by Elsevier Taiwan LLC.

Genistein promotes insulin action through adenosine monophosphate-activated protein kinase activation and p70 ribosomal protein S6 kinase 1 inhibition in the skeletal muscle of mice fed a high energy diet.

PubMed

Arunkumar, Elumalai; Anuradha, Carani Venkatraman

2012-08-01

Genistein (GEN), a soy isoflavone, exerts insulin-sensitizing actions in animals; however, the underlying mechanisms have not been determined. Because GEN is a known activator of adenosine monophosphate-activated protein kinase (AMPK), we hypothesize that GEN activates insulin signaling through AMPK activation. To test this hypothesis, a high fat-high fructose diet (HFFD)-fed mice model of insulin resistance was administered GEN, and the insulin signaling pathway proteins in the skeletal muscle were examined. Hyperglycemia and hyperinsulinemia observed in HFFD-fed mice were significantly lowered by GEN. GEN increased insulin-stimulated tyrosine phosphorylation of insulin receptor-β and insulin receptor substrate (IRS) 1 but down-regulated IRS-1 serine phosphorylation in the skeletal muscle of HFFD-fed mice. Furthermore, GEN treatment improved muscle IRS-1-associated phospatidylinositol-3 kinase expression, phosphorylation of Akt at Ser(473), and translocation of glucose transporter subtype 4. Phosphorylation of AMPK at Thr(172) and acetyl coenzyme A carboxylase (ACC) at Ser(79) was augmented, whereas phosphorylation of p70 ribosomal protein S6 kinase 1 at Thr(389) was significantly decreased after GEN treatment in the skeletal muscle of HFFD-fed mice. These results suggest that GEN might improve insulin action in the skeletal muscle by targeting AMPK. Copyright © 2012 Elsevier Inc. All rights reserved.

Isoliquiritigenin induces growth inhibition and apoptosis through downregulating arachidonic acid metabolic network and the deactivation of PI3K/Akt in human breast cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, Ying; Zhao, Haixia; Wang, Yuzhong

Arachidonic acid (AA)-derived eicosanoids and its downstream pathways have been demonstrated to play crucial roles in growth control of breast cancer. Here, we demonstrate that isoliquiritigenin, a flavonoid phytoestrogen from licorice, induces growth inhibition and apoptosis through downregulating multiple key enzymes in AA metabolic network and the deactivation of PI3K/Akt in human breast cancer. Isoliquiritigenin diminished cell viability, 5-bromo-2′-deoxyuridine (BrdU) incorporation, and clonogenic ability in both MCF-7 and MDA-MB-231cells, and induced apoptosis as evidenced by an analysis of cytoplasmic histone-associated DNA fragmentation, flow cytometry and hoechst staining. Furthermore, isoliquiritigenin inhibited mRNA expression of multiple forms of AA-metabolizing enzymes, including phospholipasemore » A2 (PLA2), cyclooxygenases (COX)-2 and cytochrome P450 (CYP) 4A, and decreased secretion of their products, including prostaglandin E{sub 2} (PGE{sub 2}) and 20-hydroxyeicosatetraenoic acid (20-HETE), without affecting COX-1, 5-lipoxygenase (5-LOX), 5-lipoxygenase activating protein (FLAP), and leukotriene B{sub 4} (LTB{sub 4}). In addition, it downregulated the levels of phospho-PI3K, phospho-PDK (Ser{sup 241}), phospho-Akt (Thr{sup 308}), phospho-Bad (Ser{sup 136}), and Bcl-x{sub L} expression, thereby activating caspase cascades and eventually cleaving poly(ADP-ribose) polymerase (PARP). Conversely, the addition of exogenous eicosanoids, including PGE{sub 2}, LTB{sub 4} and a 20-HETE analog (WIT003), and caspase inhibitors, or overexpression of constitutively active Akt reversed isoliquiritigenin-induced apoptosis. Notably, isoliquiritigenin induced growth inhibition and apoptosis of MDA-MB-231 human breast cancer xenografts in nude mice, together with decreased intratumoral levels of eicosanoids and phospho-Akt (Thr{sup 308}). Collectively, these data suggest that isoliquiritigenin induces growth inhibition and apoptosis through downregulating AA

Effect of formononetin on mechanical properties and chemical composition of bones in rats with ovariectomy-induced osteoporosis.

PubMed

Kaczmarczyk-Sedlak, Ilona; Wojnar, Weronika; Zych, Maria; Ozimina-Kamińska, Ewa; Taranowicz, Joanna; Siwek, Agata

2013-01-01

Formononetin is a naturally occurring isoflavone, which can be found in low concentrations in many dietary products, but the greatest sources of this substance are Astragalus membranaceus, Trifolium pratense, Glycyrrhiza glabra, and Pueraria lobata, which all belong to Fabaceae family. Due to its structural similarity to 17 β -estradiol, it can mimic estradiol's effect and therefore is considered as a "phytoestrogen." The aim of this study was to examine the effect of formononetin on mechanical properties and chemical composition of bones in rats with ovariectomy-induced osteoporosis. 12-week-old female rats were divided into 4 groups: sham-operated, ovariectomized, ovariectomized treated with estradiol (0.2 mg/kg) and ovariectomized treated with formononetin (10 mg/kg). Analyzed substances were administered orally for 4 weeks. Ovariectomy caused osteoporotic changes, which can be observed in bone biomechanical features (decrease of maximum load and fracture load and increase of displacements for maximum and fracture loads) and bone chemical composition (increase of water and organic fraction content, while a decrease of minerals takes place). Supplementation with formononetin resulted in slightly enhanced bone mechanical properties and bone chemistry improvement (significantly lower water content and insignificantly higher mineral fraction content). To summarize, administration of formononetin to ovariectomized rats shows beneficial effect on bone biomechanical features and chemistry; thus, it can prevent osteoporosis development.

Effect of Formononetin on Mechanical Properties and Chemical Composition of Bones in Rats with Ovariectomy-Induced Osteoporosis

PubMed Central

Kaczmarczyk-Sedlak, Ilona; Wojnar, Weronika; Zych, Maria; Ozimina-Kamińska, Ewa; Taranowicz, Joanna; Siwek, Agata

2013-01-01

Formononetin is a naturally occurring isoflavone, which can be found in low concentrations in many dietary products, but the greatest sources of this substance are Astragalus membranaceus, Trifolium pratense, Glycyrrhiza glabra, and Pueraria lobata, which all belong to Fabaceae family. Due to its structural similarity to 17β-estradiol, it can mimic estradiol's effect and therefore is considered as a “phytoestrogen.” The aim of this study was to examine the effect of formononetin on mechanical properties and chemical composition of bones in rats with ovariectomy-induced osteoporosis. 12-week-old female rats were divided into 4 groups: sham-operated, ovariectomized, ovariectomized treated with estradiol (0.2 mg/kg) and ovariectomized treated with formononetin (10 mg/kg). Analyzed substances were administered orally for 4 weeks. Ovariectomy caused osteoporotic changes, which can be observed in bone biomechanical features (decrease of maximum load and fracture load and increase of displacements for maximum and fracture loads) and bone chemical composition (increase of water and organic fraction content, while a decrease of minerals takes place). Supplementation with formononetin resulted in slightly enhanced bone mechanical properties and bone chemistry improvement (significantly lower water content and insignificantly higher mineral fraction content). To summarize, administration of formononetin to ovariectomized rats shows beneficial effect on bone biomechanical features and chemistry; thus, it can prevent osteoporosis development. PMID:23762138

Development of a soy food frequency questionnaire to estimate isoflavone consumption in US adults.

PubMed

Kirk, P; Patterson, R E; Lampe, J

1999-05-01

To develop a dietary assessment instrument to measure soy food consumption and isoflavone intake and test it for reliability. A soy food frequency questionnaire, designed for use in this study, was administered twice to participants, separated by a 2-week interval. The questionnaire was tested for reproducibility of estimates of soy food consumption and isoflavone (genistein and daidzein) intake. A convenience sample of 51 faculty, staff, and students was recruited from a naturopathic university. Intraclass correlation coefficients were used to assess reproducibility of estimates of soy food intake and genistein and daidzein intake. Correlation coefficients comparing mean soy food servings per month between the 2 administrations of the questionnaire ranged from 0.50 for soy yogurt to 0.89 for tempeh. Correlation coefficients for genistein and daidzein intake estimated by the 2 administrations of the questionnaire were the same: 0.89. Mean intake (+/- standard deviation) of genistein and daidzein was 7 +/- 10 and 4 +/- 6 mg/day, respectively. Fifteen soy foods contributed 95% of the total genistein and daidzein intake: tofu, soy yogurt, tempeh, soy milk, low-fat tofu, soy flour, miso, soy protein isolate, low-fat soy milk, veggie soy burger, textured vegetable protein, miso soup, cooked soybeans, soy hot dogs, and natto (fermented soy beans). The soy food frequency questionnaire developed in this study provided highly reproducible estimates of soy food consumption and isoflavone intake. This instrument may be a useful tool in studies of the associations between isoflavone exposure and risk for chronic disease.

Production of dihydrodaidzein and dihydrogenistein by a novel oxygen-tolerant bovine rumen bacterium in the presence of atmospheric oxygen.

PubMed

Zhao, Hui; Wang, Xiu-Ling; Zhang, Hong-Lei; Li, Chao-Dong; Wang, Shi-Ying

2011-11-01

The original bovine rumen bacterial strain Niu-O16, capable of anaerobically bioconverting isoflavones daidzein and genistein to dihydrodaidzein (DHD) and dihydrogenistein (DHG), respectively, is a rod-shaped obligate anaerobic bacterium. After a long-term domestication, an oxygen-tolerant bacterium, which we named Aeroto-Niu-O16 was obtained. Strain Aeroto-Niu-O16, which can grow in the presence of atmospheric oxygen, differed from the original obligate anaerobic bacterium Niu-O16 by various characteristics, including a change in bacterial shape (from rod to filament), in biochemical traits (from indole negative to indole positive and from amylohydrolysis positive to negative), and point mutations in 16S rRNA gene (G398A and G438A). We found that strain Aeroto-Niu-O16 not only grew aerobically but also converted isoflavones daidzein and genistein to DHD and DHG in the presence of atmospheric oxygen. The bioconversion rate of daidzein and genistein by strain Aeroto-Niu-O16 was 60.3% and 74.1%, respectively. And the maximum bioconversion capacity for daidzein was 1.2 and 1.6 mM for genistein. Furthermore, when we added ascorbic acid (0.15%, m/v) in the cultural medium, the bioconversion rate of daidzein was increased from 60.3% to 71.7%, and that of genistein from 74.1% to 89.2%. This is the first reported oxygen-tolerant isoflavone biotransforming pure culture capable of both growing and executing the reductive activity under aerobic conditions. © Springer-Verlag 2011

Hepatoprotective Effects of Sophoricoside against Fructose-Induced Liver Injury via Regulating Lipid Metabolism, Oxidation, and Inflammation in Mice.

PubMed

Li, Wenfeng; Lu, Yalong

2018-02-01

The dried fruit of Sophora japonica L. is a traditional Chinese herb tea rich in sophoricoside that is an isoflavone glycoside. The aim of current study was to investigate the hepatic protective effect of sophoricoside in high fructose (HF) diet fed mice. Healthy male mice were fed 30% fructose water and treated 80 and 160 mg/kg·bw sophoricoside continuously for 8 wk. Our data showed that administration of sophoricoside at 80 and 160 mg/kg·bw observably decreased the body weight and liver weight in HF-fed mice. It was found that the treatment of sophoricoside decreased the hepatic cholesterol and triglyceride levels, and serum low-density lipoprotein-cholesterol and apolipoprotein-B levels, and elevated the serum high-density lipoprotein-cholesterol and apolipoprotein-A1 levels. Moreover, the administration of sophoricoside decreased the HF-caused elevations of hepatic malonaldehyde, interleukin-1 and tumor necrosis factor-α levels, while increased the HF-induced decreases of hepatic superoxide dismutase and glutathione peroxidase activities. Meanwhile, serum aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase activities were reduced by treatment of sophoricoside in HF-fed mice. Histopathology of hematoxylin and eosin (H&E) and oil red O staining of liver tissues also confirmed the beneficial effects of sophoricoside against liver injury induced by HF-diet in mice. These findings indicated that sophoricoside may be a novel natural isoflavone for alleviating HF-induced liver injury. Fruit of Sophora japonica L. is a traditional herb tea and it recently becomes popular in China. Sophoricoside is an isoflavone glycoside (Genistein-4'-O-β-d-glucopyranoside) isolated from S. japonical L, and it possessed differential effects on the body health. The ingestion of sophoricoside or sophora fruit tea may be a novel strategy to prevent non-alcoholic fatty liver disease. © 2018 Institute of Food Technologists®.

UV-radiation-induced electron emission by hormones. Hypothesis for specific communication mechanisms

NASA Astrophysics Data System (ADS)

Getoff, Nikola

2009-11-01

The highlights of recently observed electron emission from electronically excited sexual hormones (17β-estradiol, progesterone, testosterone) and the phytohormone genistein in polar media are briefly reviewed. The electron yield, Q(e aq-), dependence from substrate concentration, hormone structure, polarity of solvent, absorbed energy and temperature are discussed. The hormones reactivity with e aq- and efficiency in electron transfer ensure them the ability to communicate with other biological systems in an organism. A hypothesis is presented for the explanation of the mechanisms of the distinct recognition of signals transmitted by electrons, originating from different types of hormones to receiving centres. Biological consequences of the electron emission in respect to cancer are mentioned.