Androgen receptor agonism promotes an osteogenic gene program in preadipocytes

PubMed Central

Hartig, Sean M.; Feng, Qin; Ochsner, Scott A.; Xiao, Rui; McKenna, Neil J.; McGuire, Sean E.; He, Bin

2013-01-01

Androgens regulate body composition by interacting with the androgen receptor (AR) to control gene expression in a tissue-specific manner. To identify novel regulatory roles for AR in preadipocytes, we created a 3T3-L1 cell line stably expressing human AR. We found AR expression is required for androgen-mediated inhibition of 3T3-L1 adipogenesis. This inhibition is characterized by decreased lipid accumulation, reduced expression of adipogenic genes, and induction of genes associated with osteoblast differentiation. Collectively, our results suggest androgens promote an osteogenic gene program at the expense of adipocyte differentiation. PMID:23567971

Removing isoflavones from modern soyfood: Why and how?

PubMed

Fernandez-Lopez, Adrian; Lamothe, Valérie; Delample, Mathieu; Denayrolles, Muriel; Bennetau-Pelissero, Catherine

2016-11-01

Estrogenic isoflavones were found, in the 1940s, to disrupt ewe reproduction and were identified in soy-consumers' urine in 1982. This led to controversy about their safety, often supported by current Asian diet measurements, but not by historical data. Traditional Asian recipes of soy were tested while assaying soy glycosilated isoflavones. As these compounds are water-soluble, their concentration is reduced by soaking. Pre-cooking or simmering time-dependently reduces the isoflavone:protein ratio in Tofu. Cooking soy-juice for 15 or 60min decreases the isoflavone:protein ratios in Tofu from 6.90 to 3.57 and 1.80, respectively (p<0.001). Traditional Tempeh contains only 18.07% of the original soybean isoflavones (p<0.001). Soy-juice isoflavones were reduced by ultra-filtration (6.54 vs 1.24 isoflavone:protein; p<0.001). Soy-protein and isoflavones are dissociated by water rinsing and prolonged cooking, but these have no equivalent in modern processes. As regards human health, a precise definition of the safety level of isoflavone intake requires additional studies. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Regulation of steroidogenesis in fetal bovine ovaries: differential effects of LH and FSH.

PubMed

Allen, J J; Herrick, S L; Fortune, J E

2016-11-01

In cattle, primordial follicles form before birth. Fetal ovarian capacity to produce progesterone and estradiol is high before follicle formation begins and decreases around the time follicles first appear (around 90 days of gestation). However, mechanisms that regulate steroid production during this time remain unclear. We hypothesized that LH stimulates progesterone and androgen production and that FSH stimulates aromatization of androgens to estradiol. To test this, we cultured pieces from fetal bovine ovaries for 10 days without or with exogenous hormones and then measured the accumulation of steroids in the culture medium by RIA. LH (100 ng/mL) alone increased the accumulation of progesterone, androstenedione, testosterone and estradiol. FSH (100 ng/mL) alone increased both progesterone and estradiol accumulation, but had no effect on androgens. Exogenous testosterone (0.5 µM) alone greatly increased estradiol accumulation and the combination of testosterone + FSH, but not testosterone + LH, increased estradiol relative to testosterone alone. Interestingly, exogenous testosterone and estradiol decreased progesterone accumulation in a dose-dependent manner. Because the highest dose of estradiol (0.5 µM) decreased progesterone accumulation, but increased both pregnenolone and androstenedione in the same cultures, endogenous estradiol may be a paracrine regulator of steroid synthesis. Together, these results confirm our initial hypotheses and indicate that LH stimulates androgen production in fetal bovine ovaries via the Δ 5 pathway, whereas FSH stimulates aromatization of androgens to estradiol. These results are consistent with the two-cell, two-gonadotropin model of estradiol production by bovine preovulatory follicles, which suggests that the mechanisms regulating ovarian steroid production are established during fetal life. © 2016 Society for Endocrinology.

Nandrolone decreases mu opioid receptor expression in SH-SY5Y human neuroblastoma cells.

PubMed

Guarino, Goffredo; Spampinato, Santi

2008-07-16

Nandrolone and other anabolic androgenic steroids alter the expression and function of neurotransmitter systems and contribute to drug dependence. Nandrolone treatment (10-10 M) caused a time-dependent and concentration-dependent downregulation of mu opioid receptor (MOPr) transcripts in SH-SY5Y human neuroblastoma cells. This effect was prevented by the androgen receptor antagonist hydroxyflutamide. Receptor binding assays confirmed a decrease in MOPr of approximately 40% in nandrolone-treated cells. Treatment with actinomycin D (10 (-5)M), a transcription inhibitor, revealed that nandrolone might regulate MOPr mRNA stability. In SH-SY5Y cells transfected with a human MOPr luciferase promoter/reporter construct, nandrolone did not alter the rate of gene transcription. These results suggest that nandrolone may regulate MOPr expression through posttranscriptional mechanisms requiring the androgen receptor.

Effects of androgen on immunohistochemical localization of androgen receptor and Connexin 43 in mouse ovary.

PubMed

Yang, Mei; Li, Jianhua; An, Yulin; Zhang, Shuiwen

2015-10-01

Androgens have essential roles in the regulation of follicular development and female fertility. Androgen excess is the leading defect in polycystic ovary syndrome (PCOS) patients and involved in the ovarian dysfunction. The aim of this study was to elucidate the regarding regulatory role of androgen in the follicular development of female mouse. Immunohistochemical staining and Western blot analyses were performed to detect androgen receptor (AR) and Connexin 43 (Cx43) expression in ovaries from both control and testosterone-treated group mice. In this study, localizations of AR and Cx43 were dramatically altered in testosterone-treated mouse ovaries. In addition, AR expression was significantly increased, whereas Cx43 expression was markedly decreased after testosterone treatment. Alterations of AR and Cx43 expression by testosterone with concomitant reduction of MII oocytes. Overall, these results suggest the involvement of androgen in the regulation of AR and Cx43 localizations in mouse ovary. Alterations of AR and Cx43 expression by testosterone may affect normal folliculogenesis. Together these findings will enable us to begin understanding the important roles of AR and Cx43 actions in the regulation of follicular development, as well as providing insights into the role of AR and Cx43 actions in the androgen-associated reproductive diseases such as PCOS. Copyright © 2015 Elsevier Ltd. All rights reserved.

Insect-Induced Daidzein, Formononetin and Their Conjugates in Soybean Leaves

PubMed Central

Murakami, Shinichiro; Nakata, Ryu; Aboshi, Takako; Yoshinaga, Naoko; Teraishi, Masayoshi; Okumoto, Yutaka; Ishihara, Atsushi; Morisaka, Hironobu; Huffaker, Alisa; Schmelz, Eric A; Mori, Naoki

2014-01-01

In response to attack by bacterial pathogens, soybean (Gylcine max) leaves accumulate isoflavone aglucones, isoflavone glucosides, and glyceollins. In contrast to pathogens, the dynamics of related insect-inducible metabolites in soybean leaves remain poorly understood. In this study, we analyzed the biochemical responses of soybean leaves to Spodoptera litura (Lepidoptera: Noctuidae) herbivory and also S. litura gut contents, which contain oral secretion elicitors. Following S. litura herbivory, soybean leaves displayed an induced accumulation of the flavone and isoflavone aglycones 4’,7-dihyroxyflavone, daidzein, and formononetin, and also the isoflavone glucoside daidzin. Interestingly, foliar application of S. litura oral secretions also elicited the accumulation of isoflavone aglycones (daidzein and formononetin), isoflavone 7-O-glucosides (daidzin, ononin), and isoflavone 7-O-(6’-O-malonyl-β-glucosides) (malonyldaidzin, malonylononin). Consistent with the up-regulation of the isoflavonoid biosynthetic pathway, folair phenylalanine levels also increased following oral secretion treatment. To establish that these metabolitic changes were the result of de novo biosynthesis, we demonstrated that labeled (13C9) phenylalanine was incorporated into the isoflavone aglucones. These results are consistent with the presence of soybean defense elicitors in S. litura oral secretions. We demonstrate that isoflavone aglycones and isoflavone conjugates are induced in soybean leaves, not only by pathogens as previously demonstrated, but also by foliar insect herbivory. PMID:25000357

Androgen-induced alterations in endometrial proteins crucial in recurrent miscarriages.

PubMed

Rahman, Tanzil Ur; Ullah, Kamran; Guo, Meng-Xi; Pan, Hai-Tao; Liu, Juan; Ren, Jun; Jin, Lu-Yang; Zhou, Yu-Zhong; Cheng, Yi; Sheng, Jian-Zhong; Huang, He-Feng

2018-05-15

High androgen level impairs endometrial receptivity in women experiences the recurrent miscarriage. The mechanism of androgen actions on endometrium is still uncertain. We hypothesized that androgen has a direct effect on the endometrium in women with recurrent miscarriage. In the present study, we assess the impact of androgen (A 2 ) at high concentration (10 -7 M) on Ishikawa cells compared with the physiological concentration of androgen (10 -9 M). To go into deeper analysis, we use global stable isotopes labeled profiling tactic using iTRAQ reagents, followed by 2D LC-MS/MS. We determine 175 non-redundant proteins, and 18 of these were quantified. The analysis of differentially expressed proteins (DEPs) identified 8 up-regulated proteins and 10 down-regulated in the high androgen group. These DEPs were examined by ingenuity pathway (IPA) analysis and established that these proteins might play vital roles in recurrent miscarriage and endometrium receptivity. In addition, proteins cyclin-dependent kinase inhibitor 2a (CDKN2a), endothelial protein C receptor (EPCR), armadillo repeat for velocardiofacial (ARVCF) were independently confirmed using western blot. Knockdown of CDKN2a significantly decreased the expression level of CDKN2a protein in ishikawa cells, and decreased migration ( p < 0.01), invasion ( p < 0.05), proliferation ( p < 0.05), and the rate of Jar spheroid attachment ( p < 0.05) to Ishikawa cell monolayer. The present results suggest that androgen at high concentration could alter the expression levels of proteins related to endometrium development and embryo implantation, which might be a cause of the impaired endometrial receptivity and miscarriage.

Androgen-androgen receptor system improves chronic inflammatory conditions by suppressing monocyte chemoattractant protein-1 gene expression in adipocytes via transcriptional regulation

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

Morooka, Nobukatsu, E-mail: amorooka@gunma-u.ac.jp; Ueguri, Kei; Yee, Karen Kar Lye

Age-related decreases in sex hormones are closely related to chronic inflammation in obesity and metabolic diseases. Particularly, the molecular basis of androgen activity in regulating inflammation and controlling metabolism remains largely unknown. Obese adipocytes secrete monocyte chemoattractant protein-1 (MCP-1), a key chemokine that promotes the infiltration of monocytes/macrophages into adipose tissue, thereby leading to metabolic disorders. Here, we studied the role of androgen-androgen receptor (AR) action in regulating MCP-1 expression in adipose tissue. We observed the induction of Mcp-1 expression in 3T3-L1 adipocytes co-cultured with RAW264.7 macrophages. Additionally, Mcp-1 expression was upregulated by culturing in conditioned medium derived from inflammatorymore » macrophages (M1-Mφ) containing tumor necrosis factor-alpha (TNF-α). We found that sex hormones downregulated TNF-α-induced Mcp-1 and interleukin (Il)-6 expression in 3T3-L1 adipocytes. Furthermore, luciferase-reporter analysis indicated that MCP-1 promoter activity was predominantly suppressed by dihydrotestosterone (DHT)-AR interactions through functional canonical nuclear factor-kappa B (NF-κB) sites, whereas non-canonical NF-κB site containing important flanking sequences exhibited minor contributions to DHT-AR transcriptional repression. These findings suggested that androgen-AR suppressed obesity-induced chronic inflammation in adipose tissue. - Highlights: • DHT, non-aromatizable androgen suppresses Mcp-1 expression in adipocytes. • Mcp-1 transcription was negatively regulated by DHT-AR action. • DHT-AR selectively regulates Mcp-1 transcription through distinct NF-κB sites.« less

Sex hormones regulate cerebral drug metabolism via brain miRNAs: down-regulation of brain CYP2D by androgens reduces the analgesic effects of tramadol

PubMed Central

Li, Jie; Xie, Mengmeng; Wang, Xiaoshuang; Ouyang, Xiufang; Wan, Yu; Dong, Guicheng; Yang, Zheqiong; Yang, Jing; Yue, Jiang

2015-01-01

Background and Purpose Brain cytochrome P450 2D (CYP2D) metabolises exogenous neurotoxins, endogenous substances and neurotransmitters. Brain CYP2D can be regulated in an organ-specific manner, but the possible regulatory mechanisms are poorly understood. We investigated the involvement of miRNAs in the selective regulation of brain CYP2D by testosterone and the corresponding alteration of the pharmacological profiles of tramadol by testosterone. Experimental Approach The regulation of CYP2D and brain-enriched miRNAs by testosterone was investigated using SH-SY5Y cells, U251 cells, and HepG2 cells as well as orchiectomized growth hormone receptor knockout (GHR-KO) mice and rats. Concentration–time curves of tramadol in rat brain were determined using a microdialysis technique. The analgesic action of tramadol was assessed by the tail-flick test in rats. Key Results miR-101 and miR-128-2 bound the 3′-untranslated region of the CYP2D6 mRNA and decreased its level. Testosterone decreased CYP2D6 catalytic function via the up-regulation of miR-101 and miR-128-2 in SH-SY5Y and U251 cells, but not in HepG2 cells. Orchiectomy decreased the levels of miR-101 and miR-128-2 in the hippocampus of male GHR-KO mice, indicating that androgens regulate miRNAs directly, not via the alteration of growth hormone secretion patterns. Changes in the pharmacokinetic and pharmacodynamic profiles of tramadol by orchiectomy was attenuated by either testosterone supplementation or a specific brain CYP2D inhibitor. Conclusions and Implications The selective regulation of brain CYP2D via brain-enriched miRNAs, following changes in androgen levels, such as in testosterone therapy, androgen deprivation therapy and/or ageing may alter the response to centrally active substances. PMID:26031356

Synthesis and Secretion of Isoflavones by Field-Grown Soybean.

PubMed

Sugiyama, Akifumi; Yamazaki, Yumi; Hamamoto, Shoichiro; Takase, Hisabumi; Yazaki, Kazufumi

2017-09-01

Isoflavones play important roles in rhizosphere plant-microbe interactions. Daidzein and genistein secreted by soybean roots induce the symbiotic interaction with rhizobia and may modulate rhizosphere interactions with microbes. Yet despite their important roles, little is known about the biosynthesis, secretion and fate of isoflavones in field-grown soybeans. Here, we analyzed isoflavone contents and the expression of isoflavone biosynthesis genes in field-grown soybeans. In roots, isoflavone contents and composition did not change with crop growth, but the expression of UGT4, an isoflavone-specific 7-O-glucosyltransferase, and of ICHG (isoflavone conjugates hydrolyzing beta-glucosidase) was decreased during the reproductive stages. Isoflavone contents were higher in rhizosphere soil than in bulk soil during both vegetative and reproductive stages, and were comparable in the rhizosphere soil between these two stages. We analyzed the degradation dynamics of daidzein and its glucosides to develop a model for predicting rhizosphere isoflavone contents from the amount of isoflavones secreted in hydroponic culture. Conjugates of daidzein were degraded much faster than daidzein, with degradation rate constants of 8.51 d-1 for malonyldaidzin and 11.6 d-1 for daidzin, vs. 9.15 × 10-2 d-1 for daidzein. The model suggested that secretion of isoflavones into the rhizosphere is higher during vegetative stages than during reproductive stages in field-grown soybean. © The Author 2017. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Glutathione S-transferase Pi mediates proliferation of androgen-independent prostate cancer cells

PubMed Central

Hokaiwado, Naomi; Takeshita, Fumitaka; Naiki-Ito, Aya; Asamoto, Makoto; Ochiya, Takahiro; Shirai, Tomoyuki

2008-01-01

Prostate cancers generally acquire an androgen-independent growth capacity with progression, resulting in resistance to antiandrogen therapy. Therefore, identification of the genes regulated through this process may be important for understanding the mechanisms of prostate carcinogenesis. We here utilized androgen-dependent/independent transplantable tumors, newly established with the ‘transgenic rat adenocarcinoma in prostate’ (TRAP) model, to analyze their gene expression using microarrays. Among the overexpressed genes in androgen-independent prostate cancers compared with the androgen-dependent tumors, glutathione S-transferase pi (GST-pi) was included. In line with this, human prostate cancer cell lines PC3 and DU145 (androgen independent) had higher expression of GST-pi compared with LNCaP (androgen dependent) as determined by semiquantitative reverse transcription–polymerase chain reaction analysis. To investigate the roles of GST-pi expression in androgen-independent human prostate cancers, GST-pi was knocked down by a small interfering RNA (siRNA), resulting in significant decrease of the proliferation rate in the androgen-independent PC3 cell line. In vivo, administration of GST-pi siRNA–atelocollagen complex decreased GST-pi protein expression, resulting in enhanced numbers of TdT mediated dUTP-biotin nick-end labering (TUNEL)-positive apoptotic cells. These findings suggest that GST-pi might play important roles in proliferation of androgen-independent human prostate cancer cells. PMID:18413363

Ca(2+)-Calmodulin regulation of testicular androgen production in Mozambique tilapia (Oreochromis mossambicus).

PubMed

Martins, Rute S T; Fuentes, Juan; Almeida, Olinda; Power, Deborah M; Canario, Adelino V M

2009-06-01

The Ca(2+)-Calmodulin (CaM) signaling pathway has previously been shown to be involved in the regulation of teleost fish ovarian steroidogenesis. However, a putative role of CaM in testicular steroidogenesis and potential targets has not been examined. To examine whether basal steroidogenesis is modulated by Ca(2+) and CaM levels in the testis of Mozambique tilapia (Oreochromis mossambicus) we have incubated testicular fragments in vitro under different conditions and analyzed steroid output. Calcium-free medium with or without EGTA did not affect testicular basal 11-ketotestosterone (11-KT) and testosterone (T) secretion. However, addition of 80microM the CaM inhibitor W7 significantly reduced basal 11-KT, T and androstenedione secretion. Interestingly, the decreased androgen production by 80microM of W7 was accompanied by increased 11-desoxicortisol output and by the activation of cortisol synthesis in the testis, the latter undetected in untreated tissues. However, production of 17,20alpha-dihydroxy-4-pregnen-3-one was unaltered by W7. This suggests that C17,20 desmolase, 21-hydroxylase and possibly 11beta-hydroxysteroid dehydrogenase are targets for CaM. In addition, androgen production was also found to be regulated by the level of cAMP since incubations with forskolin (FK) significantly increased 11-KT and T output. A cross-talk between the cAMP and Ca(2+)-CaM signaling pathways was detected since W7 administration also decreased FK stimulated androgen production. Altogether, these data show that both basal and cAMP stimulated androgen levels were modulated by intracellular Ca(2+)-dependent CaM and that possibly Ca(2+)-CaM determines the shift in steroidogenesis from C21 steroids to androgens.

Reproductive toxicity assessment of chronic dietary exposure to soy isoflavones in male rats.

PubMed

Faqi, Ali S; Johnson, William D; Morrissey, Robert L; McCormick, David L

2004-06-01

Epidemiologic and experimental data suggest that consumption of diets that are rich in isoflavones may decrease cancer risk in the breast, prostate, and other tissues. Isoflavones such as genistein and daidzein are structurally similar to endogenous estrogens, and demonstrate both estrogenic and weak anti-estrogenic activities; these activities may underlie the impaired fertility and reproductive tract disorders reported in animals exposed to high doses of isoflavones. To identify possible effects of isoflavones on male fertility, we evaluated reproductive parameters in Wistar-Unilever rats receiving dietary exposure to PTI G-2535, a characterized mixture of soy-derived isoflavones containing 45% genistein, 23% daidzein, and 4% glycitein. Beginning at 10 weeks of age, rats received chronic dietary exposure to the soy isoflavone mixture (200 or 2000 mg/kg diet) for a minimum of 12 months. Controls received unsupplemented chow diet only for the same period. Dietary exposure to isoflavones induced no gross toxicity or alterations in body weight gain. Absolute and relative weights of the testis and epididymis in groups receiving high or low doses of isoflavones were comparable to those of controls, and histopathologic evaluations demonstrated that testicular morphology was similar in all study groups. Isoflavone exposure had no significant effects on spermatid count, sperm production, or sperm morphology in any group. These data suggest that the reproductive system of adult male rats is relatively insensitive to isoflavone toxicity at dose levels that demonstrate significant activity in cancer chemoprevention, and that male reproductive function is unlikely to be affected by long-term administration of isoflavones for cancer prevention or other purposes. The results of this study conducted in adult male rats differ from the significant alterations in reproductive parameters that have been reported in female rats receiving prenatal or juvenile exposure to isoflavones.

Soya phytoestrogens, genistein and daidzein, decrease apolipoprotein B secretion from HepG2 cells through multiple mechanisms.

PubMed Central

Borradaile, Nica M; de Dreu, Linda E; Wilcox, Lisa J; Edwards, Jane Y; Huff, Murray W

2002-01-01

Diets containing the soya-derived phytoestrogens, genistein and daidzein, decrease plasma cholesterol in humans and experimental animals. The mechanisms responsible for the hypocholesterolaemic effects of these isoflavones are unknown. The present study was conducted to determine if genistein and daidzein regulate hepatocyte cholesterol metabolism and apolipoprotein (apo) B secretion in cultured human hepatoma (HepG2) cells. ApoB secretion was decreased dose-dependently by up to 63% and 71% by genistein and daidzein (100 microM; P<0.0001) respectively. In contrast, no effect on apoAI secretion was observed. Cellular cholesterol synthesis was inhibited 41% by genistein (100 microM; P<0.005) and 18% by daidzein (100 microM; P<0.05), which was associated with significant increases in 3-hydroxy-3-methylglutaryl-CoA reductase mRNA. Cellular cholesterol esterification was decreased 56% by genistein (100 microM; P<0.04) and 29% by daidzein (100 microM; P<0.04); however, mRNA levels for acyl-CoA:cholesterol acyltransferase (ACAT) 1 and ACAT2 were unaffected. At 100 microM, both isoflavones equally inhibited the activities of both forms of ACAT in cells transfected with either ACAT1 or ACAT2. Genistein (100 microM) and daidzein (100 microM) significantly decreased the activity of microsomal triacylglycerol transfer protein (MTP) by 30% and 24% respectively, and significantly decreased MTP mRNA levels by 35% and 55%. Both isoflavones increased low-density lipoprotein (LDL)-receptor mRNA levels by 3- to 6-fold (100 microM; P<0.03) and significantly increased the binding, uptake and degradation of (125)I-labelled LDL, suggesting that enhanced reuptake of newly secreted apoB-containing lipoproteins contributed to the net decrease in apoB secretion. These results indicate that genistein and daidzein inhibit hepatocyte apoB secretion through several mechanisms, including inhibition of cholesterol synthesis and esterification, inhibition of MTP activity and expression and increased expression of the LDL-receptor. PMID:12030847

Sphingosine Kinase-1 Is Central to Androgen-Regulated Prostate Cancer Growth and Survival

PubMed Central

Dayon, Audrey; Brizuela, Leyre; Martin, Claire; Mazerolles, Catherine; Pirot, Nelly; Doumerc, Nicolas; Nogueira, Leonor; Golzio, Muriel; Teissié, Justin; Serre, Guy; Rischmann, Pascal; Malavaud, Bernard; Cuvillier, Olivier

2009-01-01

Background Sphingosine kinase-1 (SphK1) is an oncogenic lipid kinase notably involved in response to anticancer therapies in prostate cancer. Androgens regulate prostate cancer cell proliferation, and androgen deprivation therapy is the standard of care in the management of patients with advanced disease. Here, we explored the role of SphK1 in the regulation of androgen-dependent prostate cancer cell growth and survival. Methodology/Principal Findings Short-term androgen removal induced a rapid and transient SphK1 inhibition associated with a reduced cell growth in vitro and in vivo, an event that was not observed in the hormono-insensitive PC-3 cells. Supporting the critical role of SphK1 inhibition in the rapid effect of androgen depletion, its overexpression could impair the cell growth decrease. Similarly, the addition of dihydrotestosterone (DHT) to androgen-deprived LNCaP cells re-established cell proliferation, through an androgen receptor/PI3K/Akt dependent stimulation of SphK1, and inhibition of SphK1 could markedly impede the effects of DHT. Conversely, long-term removal of androgen support in LNCaP and C4-2B cells resulted in a progressive increase in SphK1 expression and activity throughout the progression to androgen-independence state, which was characterized by the acquisition of a neuroendocrine (NE)-like cell phenotype. Importantly, inhibition of the PI3K/Akt pathway—by negatively impacting SphK1 activity—could prevent NE differentiation in both cell models, an event that could be mimicked by SphK1 inhibitors. Fascinatingly, the reversability of the NE phenotype by exposure to normal medium was linked with a pronounced inhibition of SphK1 activity. Conclusions/Significance We report the first evidence that androgen deprivation induces a differential effect on SphK1 activity in hormone-sensitive prostate cancer cell models. These results also suggest that SphK1 activation upon chronic androgen deprivation may serve as a compensatory mechanism allowing prostate cancer cells to survive in androgen-depleted environment, giving support to its inhibition as a potential therapeutic strategy to delay/prevent the transition to androgen-independent prostate cancer. PMID:19956567

Isoflavone Retention during Processing, Bioaccessibility, and Transport by Caco-2 Cells: Effects of Source and Amount of Fat in a Soy Soft Pretzel

PubMed Central

Simmons, Amber L.; Chitchumroonchokchai, Chureeporn; Vodovotz, Yael; Failla, Mark L.

2014-01-01

The impact of source and amount of lipid used to prepare a soy soft pretzel on the bioaccessibility and transport of isoflavones was investigated using the coupled in vitro digestion/Caco-2 human cell model. Pretzels were prepared without or with 2.9 or 6.0% exogenous lipid from either shortening, canola oil, ground almond, or ground hazelnut. The isoflavone backbone structure was stable during pretzel production, although there was partial conversion from malonyl and acetyl glucosides to simple glucosides and aglycones. Endogenous β-glucosidase activity in ground almond facilitated partial conversion of simple glucosides to aglycones during proofing, resulting in a slight decrease in bioaccessibility of isoflavones as compared with other sources of lipid. Amount and source of lipid did not affect bioaccessibility or uptake and metabolism of isoflavones by Caco-2 cells, although transport across the monolayer was greater with the lesser amount of shortening. These results suggest that the isoflavone structure, but not source or amount of lipid in a soy pretzel, may affect bioavailability of isoflavones. PMID:23167916

Pharmacokinetics of a slow-release formulation of soybean isoflavones in healthy postmenopausal women.

PubMed

Setchell, Kenneth D R; Brzezinski, Amnon; Brown, Nadine M; Desai, Pankaj B; Melhem, Murad; Meredith, Trevor; Zimmer-Nechimias, Linda; Wolfe, Brian; Cohen, Yoram; Blatt, Yoav

2005-03-23

Pharmacokinetic studies of soybean isoflavones have shown that following oral ingestion, the two major isoflavones, daidzin and genistin, are hydrolyzed in the intestine, rapidly absorbed into the peripheral circulation, and eliminated from the body with a terminal half-life of 7-8 h. These characteristics make maintenance of steady-state plasma isoflavone concentrations difficult to attain unless there is repeated daily ingestion of foods or supplements containing isoflavones. In an attempt to sustain more constant plasma isoflavone concentrations, a new slow-release formulation of a soybean isoflavone extract was prepared by microencapsulation with a mixture of hydroxypropylcellulose and ethylcellulose to alter its dissolution characteristics. In vitro experiments confirmed slow aqueous dissolution of isoflavones from this formulation when compared with the conventional isoflavone extract. The pharmacokinetics of this slow-release isoflavone extract was studied in 10 healthy postmenopausal women after oral administration of a single capsule containing the equivalent of 22.3 mg of genistein and 7.47 mg of daidzein expressed as aglycons. A comparison of the key pharmacokinetic parameters obtained in this study with those established in extensive studies performed previously in this laboratory indicated that the mean residence time of genistein and daidzein increased 2-fold with microencapsulation. These findings are indicative of a decreased rate of absorption, consistent with the observed slow in vitro dissolution rate. These findings show that it is feasible to employ polymer matrices that slow the aqueous dissolution for preparing sustained-release formulations of soy isoflavones. Further studies to optimize such formulations are warranted.

The effects of green kiwifruit combined with isoflavones on equol production, bone turnover and gut microflora in healthy postmenopausal women.

PubMed

Kruger, Marlena C; Middlemiss, Catherine; Katsumata, Shinichi; Tousen, Yuko; Ishimi, Yoshiko

2018-01-01

Isoflavone (daidzein and genistein) interventions in postmenopausal women have produced inconsistent skeletal benefits, partly due to population heterogeneity in daidzein metabolism to equol by enteric bacteria. This study assessed changes in microflora and bone turnover in response to isoflavone and ki-wifruit supplementation in New Zealand postmenopausal women. Healthy women 1-10 years post-menopause were randomly allocated to group A (n=16) or B (n=17) for a 16-week crossover trial. Two consecutive 6-week treatment periods had a 2-week lead-in period at intervention commencement and a 2-week washout period between treatments. Treatments prescribed either (1) daily isoflavone supplementation (50 mg/day aglycone daidzein and genistein) alone, or (2) with two green kiwifruit. At treatment baseline and end-point (four time points) the serum bone markers C Telopeptide of Type I collagen (CTx), undercarboxylated os-teocalcin (unOC), and serum and urinary daidzein and equol, were measured. Changes in gut microflora were monitored in a subgroup of the women. Equol producers made up 30% of this study population (equol producers n=10; non-equol producers n=23) with serum equol rising significantly in equol producers. Serum ucOC decreased by 15.5% (p<0.05) after the kiwifruit and isoflavone treatment. There were no changes in serum CTx or in the diversity of the gut microflora. 50 mg/day isoflavones did not reduce bone resorption but kiwifruit and isoflavone consumption decreased serum ucOC levels, possibly due to vitamin K1 and/or other bioactive components of green kiwifruit.

The daidzein metabolite, 6,7,4'-Trihydroxyisoflavone, is a novel inhibitor of PKCα in suppressing solar UV-induced matrix metalloproteinase 1.

PubMed

Lim, Tae-Gyu; Kim, Jong-Eun; Lee, Sung-Young; Park, Jun Seong; Yeom, Myung Hun; Chen, Hanyong; Bode, Ann M; Dong, Zigang; Lee, Ki Won

2014-11-19

Soy isoflavone is an attractive source of functional cosmetic materials with anti-wrinkle, whitening and skin hydration effects. After consumption, the majority of soy isoflavones are converted to their metabolites in the human gastrointestinal tract. To understand the physiological impact of soy isoflavone on the human body, it is necessary to evaluate and address the biological function of its metabolites. In this study, we investigated the effect of 6,7,4'-trihydroxyisoflavone (6,7,4'-THIF), a major metabolite of daidzein, against solar UV (sUV)-induced matrix metalloproteinases (MMPs) in normal human dermal fibroblasts. MMPs play a critical role in the degradation of collagen in skin, thereby accelerating the aging process of skin. The mitogen-activated protein/extracellular signal-regulated kinase (MEK)/extracellular signal-regulated kinase (ERK), mitogen-activated protein kinase (MKK)3/6/p38 and MKK4/c-Jun N-terminal kinases (JNK) signaling pathways are known to modulate MMP-1 function, and their activation by sUV was significantly reduced by 6,7,4'-THIF pretreatment. Our results also indicated that the enzyme activity of protein kinase C (PKC)α, an upstream regulator of MKKs signaling, is suppressed by 6,7,4'-THIF using the in vitro kinase assay. Furthermore, the direct interaction between 6,7,4'-THIF and endogenous PKCα was confirmed using the pull-down assay. Not only sUV-induced MMP-1 expression, but also sUV-induced signaling pathway activation were decreased in PKCα knockdown cells. Overall, we elucidated the inhibitory effect of 6,7,4'-THIF on sUV-induced MMPs and suggest PKCα as its direct molecular target.

Hypogonadism and erectile dysfunction associated with soy product consumption.

PubMed

Siepmann, Timo; Roofeh, Joseph; Kiefer, Florian W; Edelson, David G

2011-01-01

Previous research has focused on the beneficial effects of soy and its active ingredients, isoflavones. For instance, soy consumption has been associated with lower cardiovascular and breast cancer risks. However, the number of reports demonstrating adverse effects of isoflavones due to their estrogenlike properties has increased. We present the case of a 19-y-old type 1 diabetic but otherwise healthy man with sudden onset of loss of libido and erectile dysfunction after the ingestion of large quantities of soy-based products in a vegan-style diet. Blood levels of free and total testosterone and dehydroepiandrosterone (DHEA) were taken at the initial presentation for examination and continuously monitored up to 2 y after discontinuation of the vegan diet. Blood concentrations of free and total testosterone were initially decreased, whereas DHEA was increased. These parameters normalized within 1 y after cessation of the vegan diet. Normalization of testosterone and DHEA levels was paralleled by a constant improvement of symptoms; full sexual function was regained 1 y after cessation of the vegan diet. This case indicates that soy product consumption is related to hypogonadism and erectile dysfunction. To the best of our knowledge, this is the first report of a combination of decreased free testosterone and increased DHEA blood concentrations after consuming a soy-rich diet. Hence, this case emphasizes the impact of isoflavones in the regulation of sex hormones and associated physical alterations. Copyright © 2011 Elsevier Inc. All rights reserved.

Soybean isoflavones ameliorate ischemic cardiomyopathy by activating Nrf2-mediated antioxidant responses.

PubMed

Li, Yang; Zhang, Haiyan

2017-08-01

Ischemic cardiomyopathy (IC) is the major cause of heart failure. Conventional medicine has been proved ineffective with adverse effects. Soybean presents exciting adjunctive therapies and shows protective benefits for IC. However, the molecular mechanisms remain unclear. Isoflavones are the main bioactive components of soybean and may be protective against heart disease. Isoflavones were extracted by using an acidic-ethanol method and analyzed by HPLC. All patients with ischemic stroke were randomly and evenly assigned to two groups: the isoflavone group (80 mg day -1 , n = 100) and control group (80 mg day -1 placebo, n = 100), and the whole period of the experiment was 24 weeks. The effects of soybean isoflavone on brachial flow-mediated dilatation (FMD) were measured. HPLC fractionation shows that isoflavone extracts are mainly composed of 55% genistein, 23% daidzein, and 14% glycitein. Isoflavone therapy reduced more levels of triglyceride and LDL-c in females than in males. FMD was higher in the isoflavone group than in the control group after 24-week therapy (treatment effect 2.0%, 95% CI 0.18-3.0, P = 0.01). The baseline differences were adjusted in FMD and the isoflavone therapies were closely associated with the reduction of FMD impairment at 24 weeks (odds ratio 0.30, 95% CI 0.14-0.85, P = 0.01). The effects of isoflavone on brachial FMD were negatively associated with base FMD (r = -0.65, P < 0.01). Furthermore, isoflavone therapy caused a significant increase in the levels of erythroid-derived 2-like 2 (Nrf2), superoxide dismutase (SOD) and a significant decrease in serum levels of C-reactive protein, 8-isoprostane, malondialdehyde, interleukin-6 and tumor necrosis factor alpha. In contrast, the isoflavones had no effects on the levels of oxidation-related molecules when Nrf2 was silenced. These results suggest that soybean isoflavones ameliorate IC patients by improving their antioxidant capacities via the upregulation of Nrf2.

Androgen receptor and chemokine receptors 4 and 7 form a signaling axis to regulate CXCL12-dependent cellular motility.

PubMed

Hsiao, Jordy J; Ng, Brandon H; Smits, Melinda M; Wang, Jiahui; Jasavala, Rohini J; Martinez, Harryl D; Lee, Jinhee; Alston, Jhullian J; Misonou, Hiroaki; Trimmer, James S; Wright, Michael E

2015-03-31

Identifying cellular signaling pathways that become corrupted in the presence of androgens that increase the metastatic potential of organ-confined tumor cells is critical to devising strategies capable of attenuating the metastatic progression of hormone-naïve, organ-confined tumors. In localized prostate cancers, gene fusions that place ETS-family transcription factors under the control of androgens drive gene expression programs that increase the invasiveness of organ-confined tumor cells. C-X-C chemokine receptor type 4 (CXCR4) is a downstream target of ERG, whose upregulation in prostate-tumor cells contributes to their migration from the prostate gland. Recent evidence suggests that CXCR4-mediated proliferation and metastasis of tumor cells is regulated by CXCR7 through its scavenging of chemokine CXCL12. However, the role of androgens in regulating CXCR4-mediated motility with respect to CXCR7 function in prostate-cancer cells remains unclear. Immunocytochemistry, western blot, and affinity-purification analyses were used to study how androgens influenced the expression, subcellular localization, and function of CXCR7, CXCR4, and androgen receptor (AR) in LNCaP prostate-tumor cells. Moreover, luciferase assays and quantitative polymerase chain reaction (qPCR) were used to study how chemokines CXCL11 and CXCL12 regulate androgen-regulated genes (ARGs) in LNCaP prostate-tumor cells. Lastly, cell motility assays were carried out to determine how androgens influenced CXCR4-dependent motility through CXCL12. Here we show that, in the LNCaP prostate-tumor cell line, androgens coordinate the expression of CXCR4 and CXCR7, thereby promoting CXCL12/CXCR4-mediated cell motility. RNA interference experiments revealed functional interactions between AR and CXCR7 in these cells. Co-localization and affinity-purification experiments support a physical interaction between AR and CXCR7 in LNCaP cells. Unexpectedly, CXCR7 resided in the nuclear compartment and modulated AR-mediated transcription. Moreover, androgen-mediated cell motility correlated positively with the co-localization of CXCR4 and CXCR7 receptors, suggesting that cell migration may be linked to functional CXCR4/CXCR7 heterodimers. Lastly, CXCL12-mediated cell motility was CXCR7-dependent, with CXCR7 expression required for optimal expression of CXCR4 protein. Overall, our results suggest that inhibition of CXCR7 function might decrease the metastatic potential of organ-confined prostate cancers.

Reduction of C-reactive protein with isoflavone supplement reverses endothelial dysfunction in patients with ischaemic stroke.

PubMed

Chan, Yap-Hang; Lau, Kui-Kai; Yiu, Kai-Hang; Li, Sheung-Wai; Chan, Hiu-Ting; Fong, Daniel Yee-Tak; Tam, Sidney; Lau, Chu-Pak; Tse, Hung-Fat

2008-11-01

To investigate the effect of oral isoflavone supplement on vascular endothelial function in patients with established cardiovascular disease. A randomized, double-blinded, placebo-controlled trial was performed to determine the effects of isoflavone supplement (80 mg/day, n = 50) vs. placebo (n = 52) for 12 weeks on brachial flow-mediated dilatation (FMD) in patients with prior ischaemic stroke. Compared with controls, FMD at 12 weeks was significantly greater in isoflavone-treated patients [treatment effect 1.0%, 95% confidence interval (95% CI) 0.1-2.0, P = 0.035]. Adjusted for baseline differences in FMD, isoflavone treatment was independently associated with significantly less impairment of FMD at 12 weeks (odds ratio 0.32, 95% CI 0.13-0.80, P = 0.014). The absolute treatment effect of isoflavone on brachial FMD was inversely related to baseline FMD (r = -0.51, P < 0.001), suggesting that vasoprotective effect of isoflavone was more pronounced in patients with more severe endothelial dysfunction. Moreover, isoflavone treatment for 12 weeks resulted in a significant decrease in serum high-sensitivity (hs)-C-reactive protein level (treatment effect -1.7 mg/L, 95% CI -3.3 to -0.1, P = 0.033). Nevertheless, isoflavone did not have any significant treatment effects on nitroglycerin-mediated dilatation, blood pressure, heart rate, serum levels of fasting glucose and insulin, haemoglobin A1c, and oxidative stress as determined by serum superoxide dismutase, 8-isoprostane, and malondialdehyde (all P > 0.05). This study demonstrated that 12 week isoflavone treatment reduced serum hs-C-reactive protein and improved brachial FMD in patients with clinically manifest atherosclerosis, thus reversing their endothelial dysfunction status. These findings may have important implication for the use of isoflavone for secondary prevention in patients with cardiovascular disease, on top of conventional interventions.

Androgen Receptor-Mediated Growth Suppression of HPr-1AR and PC3-Lenti-AR Prostate Epithelial Cells

PubMed Central

Bolton, Eric C.

2015-01-01

The androgen receptor (AR) mediates the developmental, physiologic, and pathologic effects of androgens including 5α-dihydrotestosterone (DHT). However, the mechanisms whereby AR regulates growth suppression and differentiation of luminal epithelial cells in the prostate gland and proliferation of malignant versions of these cells are not well understood, though they are central to prostate development, homeostasis, and neoplasia. Here, we identify androgen-responsive genes that restrain cell cycle progression and proliferation of human prostate epithelial cell lines (HPr-1AR and PC3-Lenti-AR), and we investigate the mechanisms through which AR regulates their expression. DHT inhibited proliferation of HPr-1AR and PC3-Lenti-AR, and cell cycle analysis revealed a prolonged G1 interval. In the cell cycle, the G1/S-phase transition is initiated by the activity of cyclin D and cyclin-dependent kinase (CDK) complexes, which relieve growth suppression. In HPr-1AR, cyclin D1/2 and CDK4/6 mRNAs were androgen-repressed, whereas CDK inhibitor, CDKN1A, mRNA was androgen-induced. The regulation of these transcripts was AR-dependent, and involved multiple mechanisms. Similar AR-mediated down-regulation of CDK4/6 mRNAs and up-regulation of CDKN1A mRNA occurred in PC3-Lenti-AR. Further, CDK4/6 overexpression suppressed DHT-inhibited cell cycle progression and proliferation of HPr-1AR and PC3-Lenti-AR, whereas CDKN1A overexpression induced cell cycle arrest. We therefore propose that AR-mediated growth suppression of HPr-1AR involves cyclin D1 mRNA decay, transcriptional repression of cyclin D2 and CDK4/6, and transcriptional activation of CDKN1A, which serve to decrease CDK4/6 activity. AR-mediated inhibition of PC3-Lenti-AR proliferation occurs through a similar mechanism, albeit without down-regulation of cyclin D. Our findings provide insight into AR-mediated regulation of prostate epithelial cell proliferation. PMID:26372468

Attempts to increase inosinic acid in broiler meat by using feed additives.

PubMed

Wang, X F; Liu, G H; Cai, H Y; Chang, W H; Ma, J S; Zheng, A J; Zhang, S

2014-11-01

To explore regulation of inosinic acid content in chicken meat as a result of feed additives, 576 one-day-old male Arbor Acres broilers were randomly allotted into 8 dietary treatments including control, purine nucleotide (P), betaine (B), soybean isoflavone (S), purine nucleotide + betaine (PB), purine nucleotide + soybean isoflavone (PS), betaine +soybean isoflavone (BS), and purine nucleotide + betaine + soybean isoflavone (PBS) by a 2 × 2 × 2 factorial arrangement. At d 42 of age, broilers were slaughtered, and growth performance, carcass characteristics, inosinic acid content, and activities of enzyme closely related to inosinic acid metabolism of broilers were measured. The results revealed that these feed additives did not affect ADG and ADFI of the broilers (P > 0.05). However, supplementing purine nucleotides lowered feed/gain of broilers in PS and PBS groups (P < 0.05). There was a significant interaction on feed/gain of broilers between purine nucleotides and soybean isoflavone (P < 0.05). The abdominal fat percentages in groups B, S, BS, and PBS were lower than the control group, respectively (P < 0.05). The thigh muscle percentages of groups P and B were higher than that of group PB (P < 0.05). There were certain interactions on the percentage of thigh muscle (P = 0.05) and abdominal fat (P < 0.05) between P, B, and S groups. Compared with the control group, inosinic acid content in broiler breast meat was improved by using feed additives (P < 0.05). Supplementing purine nucleotides, betaine, soybean isoflavone, and their combinations increased alkaline phosphatase activity in breast meat of broilers (P < 0.05). Purine nucleotides improved the activity of adenosine deaminase, but decreased the activity of 5'-nucleotidase. Soybean isoflavone lowered the activity of alkaline phosphatase. There were no significant interactions on activities of creatine kinase, adenosine deaminase, alkaline phosphatase, and 5'-nucleotidase between these additives (P > 0.05). The umami rating of broiler breast meat increased in conjunction with supplementing these additives. In conclusion, supplementing standard feed with the additives investigated in this study could improve inosinic acid content in chicken meat by increasing synthase activity or inhibiting degradation enzyme activity without inferior growth performance and carcass quality. ©2014 Poultry Science Association Inc.

Differential regulation of insulin-like growth factor-I receptor gene expression by wild type and mutant androgen receptor in prostate cancer cells.

PubMed

Schayek, Hagit; Seti, Hila; Greenberg, Norman M; Sun, Shihua; Werner, Haim; Plymate, Stephen R

2010-07-29

The progression of prostate cancer from an organ-confined, androgen-sensitive disease to a metastatic one is associated with dysregulation of androgen receptor (AR)-regulated target genes and with a decrease in insulin-like growth factor-I receptor (IGF-IR) expression. To investigate the differential effects of wild type (wt) and mutant AR on IGF-IR levels we employed a series of isogenic prostate-derived cell lines and human xenografts. We show that basal and phosphorylated IGF-IR levels progressively decreased as prostate cancer cells became more tumorigenic and metastatic. In addition, we show that wt, but not mutant, AR along with dihydrotestosterone treatment increased IGF-IR promoter activity and endogenous IGF-IR levels. ChIP analysis show enhanced AR binding to the IGF-IR promoter in AR-overexpressing cells. Finally, wt AR-overexpressing cells display an enhanced proliferation rate. In summary, we provide evidence that activated wt AR enhances IGF-IR transcription in prostate cancer cells via a mechanism that involves AR binding to the IGF-IR promoter. AR mutations alter the ability of the mutated protein to regulate IGF-IR expression. Our results suggest that prostate cancer progression is associated with a decrease in IGF-IR expression that could be the result of impaired ability of AR to stimulate IGF-IR gene expression. 2010 Elsevier Ireland Ltd. All rights reserved.

Differential regulation of insulin-like growth factor-I receptor gene expression by wild type and mutant androgen receptor in prostate cancer cells

PubMed Central

Schayek, Hagit; Seti, Hila; Greenberg, Norman M.; Sun, Shihua; Werner, Haim; Plymate, Stephen R.

2010-01-01

The progression of prostate cancer from an organ-confined, androgen-sensitive disease to a metastatic one is associated with dysregulation of androgen receptor (AR)-regulated target genes and with a decrease in insulin-like growth factor-I receptor (IGF-IR) expression. To investigate the differential effects of wild type (wt) and mutant AR on IGF-IR levels we employed a series of isogenic prostate-derived cell lines and human xenografts. We show that basal and phosphorylated IGF-IR levels progressively decreased as prostate cancer cells became more tumorigenic and metastatic. In addition, we show that wt, but not mutant, AR along with dihydrotestosterone treatment increased IGF-IR promoter activity and endogenous IGF-IR levels. ChIP analysis show enhanced AR binding to the IGF-IR promoter in AR-overexpressing cells. Finally, wt AR-overexpressing cells display an enhanced proliferation rate. In summary, we provide evidence that activated wt AR enhances IGF-IR transcription in prostate cancer cells via a mechanism that involves AR binding to the IGF-IR promoter. AR mutations alter the ability of the mutated protein to regulate IGF-IR expression. Our results suggest that prostate cancer progression is associated with a decrease in IGF-IR expression that could be the result of impaired ability of AR to stimulate IGF-IR gene expression. PMID:20417685

Effects of soy isoflavone supplements on bone turnover markers in menopausal women: systematic review and meta-analysis of randomized controlled trials.

PubMed

Taku, Kyoko; Melby, Melissa K; Kurzer, Mindy S; Mizuno, Shoichi; Watanabe, Shaw; Ishimi, Yoshiko

2010-08-01

Effects of soy isoflavone supplements on bone turnover markers remain unclear. This up-to-date systematic review and meta-analysis of randomized controlled trials (RCTs) was performed primarily to more completely and precisely clarify the effects on urinary deoxypyridinoline (DPD) and serum bone alkaline phosphatase (BAP) and secondarily to evaluate the effects on other bone turnover markers, compared with placebo in menopausal women. PubMed, CENTRAL, ICHUSHI, and CNKI were searched in June 2009 for relevant studies of RCTs. Data on study design, participants, interventions, and outcomes were extracted and methodological quality of each included trial was assessed. From 3740 identified relevant articles, 10 (887 participants), 10 (1210 participants), and 8 (380 participants) RCTs were selected for meta-analysis of effects on DPD, BAP, and serum osteocalcin (OC), respectively, using Review Manager 5.0.22. Daily ingestion of an average 56 mg soy isoflavones (aglycone equivalents) for 10 weeks to 12 months significantly decreased DPD by 14.1% (95% CI: -26.8% to -1.5%; P=0.03) compared to baseline (heterogeneity: P<0.00001; I(2)=93%; random effects model). The overall effect of soy isoflavones on DPD compared with placebo was a significant decrease of -18.0% (95% CI: -28.4% to -7.7%, P=0.0007; heterogeneity: P=0.0001; I(2)=73%; random effects model). Subgroup analyses and meta-regressions revealed that isoflavone dose and intervention duration did not significantly relate to the variable effects on DPD. Daily supplementation of about 84 mg and 73 mg of soy isoflavones for up to 12 months insignificantly increased BAP by 8.0% (95% CI: -4.2% to 20.2%, P=0.20; heterogeneity: P<0.00001; I(2)=98%) and OC by 10.3% (95% CI: -3.1% to 23.7%, P=0.13; heterogeneity: P=0.002; I(2)=69%) compared with placebo (random effects model), respectively. Soy isoflavone supplements moderately decreased the bone resorption marker DPD, but did not affect bone formation markers BAP and OC in menopausal women. The effects varied between studies, and further studies are needed to address factors relating to the observed effects of soy isoflavones on DPD and to verify effects on other bone turnover markers. Copyright 2010 Elsevier Inc. All rights reserved.

Regulation of Androgen Receptor-Mediated Transcription by RPB5 Binding Protein URI/RMP ▿

PubMed Central

Mita, Paolo; Savas, Jeffrey N.; Djouder, Nabil; Yates, John R.; Ha, Susan; Ruoff, Rachel; Schafler, Eric D.; Nwachukwu, Jerome C.; Tanese, Naoko; Cowan, Nicholas J.; Zavadil, Jiri; Garabedian, Michael J.; Logan, Susan K.

2011-01-01

Androgen receptor (AR)-mediated transcription is modulated by interaction with coregulatory proteins. We demonstrate that the unconventional prefoldin RPB5 interactor (URI) is a new regulator of AR transcription and is critical for antagonist (bicalutamide) action. URI is phosphorylated upon androgen treatment, suggesting communication between the URI and AR signaling pathways. Whereas depletion of URI enhances AR-mediated gene transcription, overexpression of URI suppresses AR transcriptional activation and anchorage-independent prostate cancer cell growth. Repression of AR-mediated transcription is achieved, in part, by URI binding and regulation of androgen receptor trapped clone 27 (Art-27), a previously characterized AR corepressor. Consistent with this idea, genome-wide expression profiling in prostate cancer cells upon depletion of URI or Art-27 reveals substantially overlapping patterns of gene expression. Further, depletion of URI increases the expression of the AR target gene NKX-3.1, decreases the recruitment of Art-27, and increases AR occupancy at the NKX-3.1 promoter. While Art-27 can bind AR directly, URI is bound to chromatin prior to hormone-dependent recruitment of AR, suggesting a role for URI in modulating AR recruitment to target genes. PMID:21730289

Androgen Action via the Androgen Receptor in Neurons Within the Brain Positively Regulates Muscle Mass in Male Mice.

PubMed

Davey, Rachel A; Clarke, Michele V; Russell, Patricia K; Rana, Kesha; Seto, Jane; Roeszler, Kelly N; How, Jackie M Y; Chia, Ling Yeong; North, Kathryn; Zajac, Jeffrey D

2017-10-01

Although it is well established that exogenous androgens have anabolic effects on skeletal muscle mass in humans and mice, data from muscle-specific androgen receptor (AR) knockout (ARKO) mice indicate that myocytic expression of the AR is dispensable for hind-limb muscle mass accrual in males. To identify possible indirect actions of androgens via the AR in neurons to regulate muscle, we generated neuron-ARKO mice in which the dominant DNA binding-dependent actions of the AR are deleted in neurons of the cortex, forebrain, hypothalamus, and olfactory bulb. Serum testosterone and luteinizing hormone levels were elevated twofold in neuron-ARKO males compared with wild-type littermates due to disruption of negative feedback to the hypothalamic-pituitary-gonadal axis. Despite this increase in serum testosterone levels, which was expected to increase muscle mass, the mass of the mixed-fiber gastrocnemius (Gast) and the fast-twitch fiber extensor digitorum longus hind-limb muscles was decreased by 10% in neuron-ARKOs at 12 weeks of age, whereas muscle strength and fatigue of the Gast were unaffected. The mass of the soleus muscle, however, which consists of a high proportion of slow-twitch fibers, was unaffected in neuron-ARKOs, demonstrating a stimulatory action of androgens via the AR in neurons to increase the mass of fast-twitch hind-limb muscles. Furthermore, neuron-ARKOs displayed reductions in voluntary and involuntary physical activity by up to 60%. These data provide evidence for a role of androgens via the AR in neurons to positively regulate fast-twitch hind-limb muscle mass and physical activity in male mice. Copyright © 2017 Endocrine Society.

Green tea polyphenol EGCG blunts androgen receptor function in prostate cancer

PubMed Central

Siddiqui, Imtiaz A.; Asim, Mohammad; Hafeez, Bilal B.; Adhami, Vaqar M.; Tarapore, Rohinton S.; Mukhtar, Hasan

2011-01-01

Androgen deprivation therapy is the major treatment for advanced prostate cancer (PCa). However, it is a temporary remission, and the patients almost inevitably develop hormone refractory prostate cancer (HRPC). HRPC is almost incurable, although most HRPC cells still express androgen receptor (AR) and depend on the AR for growth, making AR a prime drug target. Here, we provide evidence that epigallocatechin-3-gallate (EGCG), the major polyphenol in green tea, is a direct antagonist of androgen action. In silico modeling and FRET-based competition assay showed that EGCG physically interacts with the ligand-binding domain of AR by replacing a high-affinity labeled ligand (IC50 0.4 μM). The functional consequence of this interaction was a decrease in AR-mediated transcriptional activation, which was due to EGCG mediated inhibition of interdomain N-C termini interaction of AR. Treatment with EGCG also repressed the transcriptional activation by a hotspot mutant AR (T877A) expressed ectopically as well as the endogenous AR mutant. As the physiological consequence of AR antagonism, EGCG repressed R1881-induced PCa cell growth. In a xenograft model, EGCG was found to inhibit AR nuclear translocation and protein expression. We also observed a significant down-regulation of androgen-regulated miRNA-21 and up-regulation of a tumor suppressor, miRNA-330, in tumors of mice treated with EGCG. Taken together, we provide evidence that EGCG functionally antagonizes androgen action at multiple levels, resulting in inhibition of PCa growth.—Siddiqui, I. A., Asim, M., Hafeez, B. B., Adhami, V. M., Tarapore, R. S., Mukhtar, H. Green tea polyphenol EGCG blunts androgen receptor function in prostate cancer. PMID:21177307

Absorption and bioeffects of an isoflavone-based supplementation in postmenopausal women

PubMed Central

Pampaloni, Barbara; Bartolini, Silvia; Bartolini, Elisa; Ottanelli, Silva; Masi, Laura; Romani, Annalisa; Tanini, Annalisa; Vignolini, Pamela; Brandi, Maria Luisa

2009-01-01

Epidemiological studies suggest that consumption of isoflavones rich diets can improve several postmenopausal complications. The aim of this study was to investigate the absorption and the efficacy of isoflavonic supplementation in the treatment of menopausal symptoms. 36 postmenopausal women received 75 mg/day of isoflavones in the form of tablets, for six months. 21 subjects concluded the treatment. Plasmatic and urinary samples were collected before and after the treatment, along with a dietary interview. Isoflavones were determined in biological samples and in commercial administered supplements by a HPLC/DAD system. Results showed the presence of genistein (from 0.043 to 1.820 micromol/L) in plasma samples, and of genistein (from 2.486 to 20.363 micromol/24h) and daidzein (from 11.106 to 98.091 micromol/24h) in the urines of the treated women. In the 21 completers the Greene Climateric scale value for hot flushes changed from 3 to 1 or 0. No changes of the endometrial thickness and of the breast tissue were detected. The analysis of the supplement content in the tablets was in agreement with what declared by the producer. Administration of isoflavone supplements produced a decrease of symptoms in this cohort of postmenopausal women monitored for isoflavone absorption. PMID:22461255

TOFA (5-tetradecyl-oxy-2-furoic acid) reduces fatty acid synthesis, inhibits expression of AR, neuropilin-1 and Mcl-1 and kills prostate cancer cells independent of p53 status.

PubMed

Guseva, Natalya V; Rokhlin, Oskar W; Glover, Rebecca A; Cohen, Michael B

2011-07-01

A key player in prostate cancer development and progression is the androgen receptor (AR). Tumor-associated lipogenesis can protect cancer cells from carcinogenic- and therapeutic-associated treatments. Increased synthesis of fatty acids and cholesterol is regulated by androgens through induction of several genes in androgen-responsive cancer cells. Acetyl-CoA-carboxylase-α (ACCA) is a key enzyme in the regulation of fatty acids synthesis. Here we show that AR binds in vivo to intron regions of human ACCA gene. We also show that the level of ACCA protein in LNCaP depends on AR expression and that DHT treatment increases ACCA expression and fatty acid synthesis. Inhibition of ACCA by TOFA (5-tetradecyl-oxy-2-furoic acid) decreases fatty acid synthesis and induces caspase activation and cell death in most PCa cell lines. Our data suggest that TOFA can kill cells via the mitochondrial pathway since we found cytochrome c release after TOFA treatment in androgen sensitive cell lines. The results also imply that the pro-apoptotic effect of TOFA may be mediated via a decrease of neuropilin-1(NRP1) and Mcl-1expression. We have previously reported that Mcl-1 is under AR regulation and plays an important role in resistance to drug-induced apoptosis in prostate cancer cells, and NRP1 is known to regulate Mcl-1 expression. Here, we show for the first time that NRP1 expression is under AR control. Taken together, our data suggest that TOFA is a potent cell death inducing agent in prostate cancer cells.

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®.

Modification of isoflavone profiles in a fermented soy food with almond powder.

PubMed

Park, MinHee; Jeong, Min Kyu; Kim, MiJa; Lee, JaeHwan

2012-01-01

Isoflavone profiles of a fermented soy food, cheonggukjang, were modified using almond powder. Isoflavones were analyzed by high performance liquid chromatography (HPLC) with an ultraviolet detector. Malonyl derivatives of isoflavones decreased and aglycones of isoflavones increased in samples with almond powder for 48 h. As added, almond powder increased from 0%, 5%, and 10% (w/w), amounts of aglycones increased to 21.11%, 26.63%, and 32.45% for 48 h, respectively. β-Glucosidase activity in 5% and 10% almond added samples was significantly higher than samples without addition of almond (P < 0.05). The content of succinyl daidzin and succinyl genistin, new metabolites from isoflavones, in almond-added cheonggukjang was significantly lower than control samples, implying that β-glucosidase activity from almond affected negatively the formation of succinyl derivatives (P < 0.05). Principal component analysis (PCA) for isoflavone distribution showed that first principal component (PC1) and second principal component (PC2) expressed 64.78% and 22.26% of the data variability, respectively. Biotransformation of isoflavones in any fermented soy foods can be achieved using natural products containing high β-glucosidase activity such as almond. The results of this study can help to modify the structural transformation of phytochemicals in any fermented soy foods using natural products. Adjusting the content of almond powder can achieve wanted profiles, for example, high aglycones content. Also, content of metabolites such as succinyl derivatives can be controlled using proper amounts of almond and fermentation time. © 2011 Institute of Food Technologists®

Transcriptional up-regulation of the human androgen receptor by androgen in bone cells.

PubMed

Wiren, K M; Zhang, X; Chang, C; Keenan, E; Orwoll, E S

1997-06-01

Androgen regulation of androgen receptor (AR) expression has been observed in a variety of tissues, generally as inhibition, and is thought to attenuate cellular responses to androgen. AR is expressed in osteoblasts, the bone-forming cell, suggesting direct actions of androgens on bone. Here we characterized the effect of androgen exposure on AR gene expression in human osteoblastic SaOS-2 and U-2 OS cells. Treatment of osteoblastic cells with the nonaromatizable androgen 5alpha-dihydrotestosterone increased AR steady state messenger RNA levels in a time- and dose-dependent fashion. Reporter assays with 2.3 kilobases of the proximal 5'-flanking region of the human AR promoter linked to the chloramphenicol acetyltransferase gene in transfected cultures showed that up-regulation of AR promoter activity by androgen was time and dose dependent. Treatment with other steroid hormones, including progesterone, 17beta-estradiol, and dexamethasone, was without effect. The antiandrogen hydroxyflutamide completely antagonized androgen up-regulation. Thus, in contrast to many other androgen target tissues, androgen exposure increases steady state AR messenger RNA levels in osteoblasts. This regulation occurs at least partially at the level of transcription, is mediated by the 5'-promoter region of the AR gene, and is dependent on functional AR. These results suggest that physiological concentrations of androgens have significant effects on AR expression in skeletal tissue.

Gene expression and adiposity are modified by soy protein in male Zucker diabetic fatty rats.

PubMed

Banz, William J; Davis, Jeremy; Peterson, Richard; Iqbal, Muhammad J

2004-12-01

It has earlier been demonstrated that soy protein diets ameliorate the diabetic phenotype in obese Zucker rats. In this study, we further investigated physiological changes related to adiposity in male Zucker diabetic fatty rats consuming soy-based diets and compared these diets with the insulin-sensitizing drug, rosiglitazone. Transcript abundance of known genes was assessed in the livers to identify potential molecular connections between soy diets and adiposity. Male Zucker diabetic fatty rats were assigned to casein (C) protein, low-isoflavone soy (LIS) protein, high-isoflavone soy (HIS) protein, or C + rosiglitazone (CR) diets. Compared with the C diet, the LIS diet decreased plasma lipids and increased body weight, but did not change liver weight or carcass adiposity. HIS decreased plasma lipids, liver weight, and body weight. CR decreased plasma lipids and increased carcass adiposity and body weight with no effect on liver weight. In LIS livers, 15 genes involved in signaling and lipid metabolism were up-regulated 2-fold or higher. In HIS livers, seven genes had a 2-fold or higher change in abundance. However, in CR livers, none of the genes was significantly changed compared with the C diet. There appears to be a distinct change in gene expression associated with soy diets as compared with C-based diets and rosiglitazone treatment.

Production of Two Novel Methoxy-Isoflavones from Biotransformation of 8-Hydroxydaidzein by Recombinant Escherichia coli Expressing O-Methyltransferase SpOMT2884 from Streptomyces peucetius

PubMed Central

Chiang, Chien-Min; Ding, Hsiou-Yu; Tsai, Ya-Ting; Chang, Te-Sheng

2015-01-01

Biotransformation of 8-hydroxydaidzein by recombinant Escherichia coli expressing O-methyltransferase (OMT) SpOMT2884 from Streptomyces peucetius was investigated. Two metabolites were isolated and identified as 7,4′-dihydroxy-8-methoxy-isoflavone (1) and 8,4′-dihydroxy-7-methoxy-isoflavone (2), based on mass, 1H-nuclear magnetic resonance (NMR) and 13C-NMR spectrophotometric analysis. The maximum production yields of compound (1) and (2) in a 5-L fermenter were 9.3 mg/L and 6.0 mg/L, respectively. The two methoxy-isoflavones showed dose-dependent inhibitory effects on melanogenesis in cultured B16 melanoma cells under non-toxic conditions. Among the effects, compound (1) decreased melanogenesis to 63.5% of the control at 25 μM. This is the first report on the 8-O-methylation activity of OMT toward isoflavones. In addition, the present study also first identified compound (1) with potent melanogenesis inhibitory activity. PMID:26610478

[Soy isoflavones and human health: breast cancer and puberty timing].

PubMed

Valladares, Luis; Garrido, Argelia; Sierralta, Walter

2012-04-01

Accumulated exposure to high levels of estrogen is associated with an increased incidence of breast cancer. Thus, factors such as early puberty, late menopause and hormone replacement therapy are considered to be risk factors, whereas early childbirth, breastfeeding and puberty at a later age are known to consistently decrease the lifetime breast cancer risk. Epidemiological studies suggest that consumption of isoflavones correlates with a lower incidence of breast cancer. Data from human intervention studies show that the effects of isoflavones on early breast cancer markers differ between pre- and post-menopausal women. The reports from experimental animals (rats and mice) on mammary tumors are variable. These results taken together with heterogeneous outcomes of human interventions, have led to a controversy surrounding the intake of isoflavones to reduce breast cancer risk. This review summarizes recent studies and analyzes factors that could explain the variability of results. In mammary tissue, from the cellular endocrine viewpoint, we analyze the effect of isoflavones on the estrogen receptor and their capacity to act as agonists or antagonists. On the issue of puberty timing, we analyze the mechanisms by which girls, but not boys, with higher prepuberal isoflavone intakes appear to enter puberty at a later age.

Soy isoflavones in nutritionally relevant amounts have varied nutrigenomic effects on adipose tissue.

PubMed

Giordano, Elena; Dávalos, Alberto; Crespo, Maria Carmen; Tomé-Carneiro, Joao; Gómez-Coronado, Diego; Visioli, Francesco

2015-01-30

Soy consumption has been suggested to afford protection from cardiovascular disease (CVD). Indeed, accumulated albeit controversial evidence suggests that daily consumption of ≥25 g of soy protein with its associated phytochemicals intact can improve lipid profiles in hypercholesterolemic humans. However, the belief that soy foods and supplements positively impact human health has become increasingly controversial among the general public because of the reported estrogenic activities of soy isoflavones. In this study, we investigated the nutrigenomic actions of soy isoflavones (in nutritionally-relevant amounts) with a specific focus on the adipose tissue, due to its pivotal role in cardiometabolism. Young C57BL/6 mice were maintained for eight weeks under two different diet regimes: (1) purified control diet; or (2) purified control diet supplemented with 0.45 g% soybean dry purified extract (a genistein/daidzein mix). Soy isoflavones increased plasma total cholesterol concentrations and decreased triglyceride ones. Circulating leptin levels was also increased by soy consumption. Differentially expressed genes in adipose tissue were classified according to their role(s) in cellular or metabolic pathways. Our data show that soy isoflavones, administered in nutritionally-relevant amounts, have diverse nutrigenomic effects on adipose tissue. Taking into account the moderate average exposure to such molecules, their impact on cardiovascular health needs to be further investigated to resolve the issue of whether soy consumption does indeed increase or decrease cardiovascular risk.

The Steroid Metabolome in the Isolated Ovarian Follicle and Its Response to Androgen Exposure and Antagonism

PubMed Central

Lebbe, Marie; Taylor, Angela E.; Visser, Jenny A.; Kirkman-Brown, Jackson C.; Woodruff, Teresa K.

2017-01-01

The ovarian follicle is a major site of steroidogenesis, crucially required for normal ovarian function and female reproduction. Our understanding of androgen synthesis and metabolism in the developing follicle has been limited by the sensitivity and specificity issues of previously used assays. Here we used liquid chromatography–tandem mass spectrometry to map the stage-dependent endogenous steroid metabolome in an encapsulated in vitro follicle growth system, from murine secondary through antral follicles. Furthermore, follicles were cultured in the presence of androgen precursors, nonaromatizable active androgen, and androgen receptor (AR) antagonists to assess effects on steroidogenesis and follicle development. Cultured follicles showed a stage-dependent increase in endogenous androgen, estrogen, and progesterone production, and incubations with the sex steroid precursor dehydroepiandrosterone revealed the follicle as capable of active androgen synthesis at early developmental stages. Androgen exposure and antagonism demonstrated AR–mediated effects on follicle growth and antrum formation that followed a biphasic pattern, with low levels of androgens inducing more rapid follicle maturation and high doses inhibiting oocyte maturation and follicle growth. Crucially, our study provides evidence for an intrafollicular feedback circuit regulating steroidogenesis, with decreased follicle androgen synthesis after exogenous androgen exposure and increased androgen output after additional AR antagonist treatment. We propose that this feedback circuit helps maintain an equilibrium of androgen exposure in the developing follicle. The observed biphasic response of follicle growth and function in increasing androgen supplementations has implications for our understanding of polycystic ovary syndrome pathophysiology and the dose-dependent utility of androgens in in vitro fertilization settings. PMID:28323936

Oral isoflavone supplementation on endometrial thickness: a meta-analysis of randomized placebo-controlled trials

PubMed Central

Liu, Jie; Yuan, Feixiang; Gao, Jian; Shan, Boer; Ren, Yulan; Wang, Huaying; Gao, Ying

2016-01-01

Background Isoflavone from soy and other plants modulate hormonal effects in women, and the hormone disorder might result in different caners including endometrial cancer. However, it's effect on the risk of endometrial cancer is still inconclusive. We aimed to assess the effects of isoflavone on endometrial thickness, a risk factor of endometrial cancer in peri- and post-menopausal women. Methods A meta-analysis of randomized controlled trials was conducted to evaluate the effect of oral isoflavone supplementation on endometrial thickness in peri- and post-menopausal women. Electronic searches were performed on the PubMed, Embase, the Cochrane Library, web of science, CINAHL, and WHO ICTRP to August 1st, 2015. Reviews and reference lists of relevant articles were also searched to identify more studies. Summary estimates of standard mean differences (SMD's) and 95%CIs were obtained with random-effects models. Heterogeneity was evaluated with meta-regression and stratified analyses. Results A total of 23 trials were included in the current analysis. The overall results did not show significant change of endometrial thickness after oral isoflavone supplementation (23 studies, 2167subjects; SMD:-0.05; 95%CI:-0.23, 0.13; P=0.60). Stratified analysis suggested that a daily dose of more than 54mg could decrease the endometrial thickness for 0.26mm (10 trials, 984subjects; SMD:-0.26; 95%CI:-0.45, −0.07; P=0.007). Furthermore, isoflavone supplementation significantly decrease the endometrial thickness for 0.23mm in North American studies (7 trials, 726 subjects; SMD:-0.23; 95%CI:-0.44, −0.01; P=0.04), but it suggested an increase for 0.23mm in Asian studies (3 trials, 224 subjects; SMD: 0.23; 95%CI:-0.04, 0.50; P=0.10). Conclusion Oral isoflavone supplementation might have different effects in different populations and at different daily doses. Multiple-centre, larger, and long-term trials are deserved to further evaluate its effect. PMID:26967050

The effects of soy isoflavone on bone density in north region of climacteric Chinese women

PubMed Central

Chi, Xiao-Xing; Zhang, Tao

2013-01-01

Only a few investigations were based on limb bone density. This study evaluated the efficacy of soy isoflavone in the treatment of the principal menopausal disorders, limb bone density and the role of pathway. The research protocol involved the random subdivision of the enrolled sample into two groups of 40 women, who were to receive treatment for 6 months with isoflavone (90 mg/day) and with placebo. All of the patients were asked to fill in a questionnaire concerning their complaints. BMD of the radius and tibia were measured using quantitative ultrasound. Bone metabolism indexes calcium, phosphorus and alkaline phosphatase (ALP) were examined regularly. Serum cytokines interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) examined by ELISA. The results of the score of Kupperman table showed that the isoflavone can lead to a significant reduction in some of the disorders. Compared with placebo, the tibia bone density in isoflavone group increased obviously against the base value before trail. Isoflavone led to a stronger descent of the concentration of ALP and a decrease of IL-6 and TNF-α level than placebo. For climacteric women, soy isoflavone in the dose of 90 mg/day could improve some menopausal syndromes and was effective on increasing limb bone density, which maybe had the relationship with the levels of IL-6, TNF-α and ALP in serum. PMID:24062607

Androgen-responsive gene database: integrated knowledge on androgen-responsive genes.

PubMed

Jiang, Mei; Ma, Yunsheng; Chen, Congcong; Fu, Xuping; Yang, Shu; Li, Xia; Yu, Guohua; Mao, Yumin; Xie, Yi; Li, Yao

2009-11-01

Androgen signaling plays an important role in many biological processes. Androgen Responsive Gene Database (ARGDB) is devoted to providing integrated knowledge on androgen-controlled genes. Gene records were collected on the basis of PubMed literature collections. More than 6000 abstracts and 950 original publications were manually screened, leading to 1785 human genes, 993 mouse genes, and 583 rat genes finally included in the database. All the collected genes were experimentally proved to be regulated by androgen at the expression level or to contain androgen-responsive regions. For each gene important details of the androgen regulation experiments were collected from references, such as expression change, androgen-responsive sequence, response time, tissue/cell type, experimental method, ligand identity, and androgen amount, which will facilitate further evaluation by researchers. Furthermore, the database was integrated with multiple annotation resources, including National Center for Biotechnology Information, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes pathway, to reveal the biological characteristics and significance of androgen-regulated genes. The ARGDB web site is mainly composed of the Browse, Search, Element Scan, and Submission modules. It is user friendly and freely accessible at http://argdb.fudan.edu.cn. Preliminary analysis of the collected data was performed. Many disease pathways, such as prostate carcinogenesis, were found to be enriched in androgen-regulated genes. The discovered androgen-response motifs were similar to those in previous reports. The analysis results are displayed in the web site. In conclusion, ARGDB provides a unified gateway to storage, retrieval, and update of information on androgen-regulated genes.

Ornithine Decarboxylase Activity Is Required for Prostatic Budding in the Developing Mouse Prostate

PubMed Central

Gamat, Melissa; Malinowski, Rita L.; Parkhurst, Linnea J.; Steinke, Laura M.; Marker, Paul C.

2015-01-01

The prostate is a male accessory sex gland that produces secretions in seminal fluid to facilitate fertilization. Prostate secretory function is dependent on androgens, although the mechanism by which androgens exert their effects is still unclear. Polyamines are small cationic molecules that play pivotal roles in DNA transcription, translation and gene regulation. The rate-limiting enzyme in polyamine biosynthesis is ornithine decarboxylase, which is encoded by the gene Odc1. Ornithine decarboxylase mRNA decreases in the prostate upon castration and increases upon administration of androgens. Furthermore, testosterone administered to castrated male mice restores prostate secretory activity, whereas administering testosterone and the ornithine decarboxylase inhibitor D,L-α-difluromethylornithine (DFMO) to castrated males does not restore prostate secretory activity, suggesting that polyamines are required for androgens to exert their effects. To date, no one has examined polyamines in prostate development, which is also androgen dependent. In this study, we showed that ornithine decarboxylase protein was expressed in the epithelium of the ventral, dorsolateral and anterior lobes of the adult mouse prostate. Ornithine decarboxylase protein was also expressed in the urogenital sinus (UGS) epithelium of the male and female embryo prior to prostate development, and expression continued in prostatic epithelial buds as they emerged from the UGS. Inhibiting ornithine decarboxylase using DFMO in UGS organ culture blocked the induction of prostatic buds by androgens, and significantly decreased expression of key prostate transcription factor, Nkx3.1, by androgens. DFMO also significantly decreased the expression of developmental regulatory gene Notch1. Other genes implicated in prostatic development including Sox9, Wif1 and Srd5a2 were unaffected by DFMO. Together these results indicate that Odc1 and polyamines are required for androgens to exert their effect in mediating prostatic bud induction, and are required for the expression of a subset of prostatic developmental regulatory genes including Notch1 and Nkx3.1. PMID:26426536

Effects of soybean isoflavone dosage and exercise on the serum markers of bone metabolism in ovariectomized rats.

PubMed

Liu, Kemin; Ma, Guodong; Lv, Guofeng; Zou, Yuan; Wang, Wencheng; Liu, Lihong; Yan, Ping; Liu, Yanna; Jiang, Lijie; Liu, Yanhuan; Liu, Zhenyu

2007-01-01

This study was designed to determine whether combined treatments with soybean isoflavone dosage and moderate exercise would exhibit synergistically effects on bone metabolism following the onset of menopause. Fifty 12 wk-old female Wistar rats were assigned to five groups: 1) Sham operated (Sham), 2) ovariectomized (OVX), 3) OVX received soybean isoflavone (OVX-IF), 4) OVX exercised (OVX-EXE) and 5) OVX treated with both soybean isoflavone and exercise (OVX-IF-EXE). All rats were fed a normal diet ad libitum. Daily soybean isoflavone dosage was 50 mg/kg body weight. The vehicle was given in Sham, OVX and OVX-EXE groups. The drugs were all oral administered using a stomach tube. Exercising rats were trained on an uphill treadmill at 20 m/min for 1h/day, 5 days/week. The experimental duration consisted of the adaptation periods of 2 weeks and treatment periods of 8 weeks. The results showed that the uterus relative weights in OVX-EXE, OVX-IF and OVX-IF-EXE groups were all lower than those in Sham, they were higher than those in the OVX group. Serum alkaline phosphates (AKP) activities of OVX was significantly increased as compared to that of Sham (p<0.01). OVX-IF and OVX-IF-EXE respectively decreased the Serum alkaline phosphates activities, as compared to that of OVX (p<0.01). The tartrate-resistant acid phosphatase (TRAP) value of OVX was significantly increased as compared to that of Sham (p<0.05). OVX-IF decreased the TRAP as compared to that of OVX (p<0.05). These results suggest soybean isoflavone and resistance exercise both can restrain ovx-induced bone loss. But their mechanisms may be different.

Inverse Regulation of DHT Synthesis Enzymes 5α-Reductase Types 1 and 2 by the Androgen Receptor in Prostate Cancer.

PubMed

Audet-Walsh, Étienne; Yee, Tracey; Tam, Ingrid S; Giguère, Vincent

2017-04-01

5α-Reductase types 1 and 2, encoded by SRD5A1 and SRD5A2, are the two enzymes that can catalyze the conversion of testosterone to dihydrotestosterone, the most potent androgen receptor (AR) agonist in prostate cells. 5α-Reductase type 2 is the predominant isoform expressed in the normal prostate. However, its expression decreases during prostate cancer (PCa) progression, whereas SRD5A1 increases, and the mechanism underlying this transcriptional regulatory switch is still unknown. Interrogation of SRD5A messenger RNA expression in three publicly available data sets confirmed that SRD5A1 is increased in primary and metastatic PCa compared with nontumoral prostate tissues, whereas SRD5A2 is decreased. Activation of AR, a major oncogenic driver of PCa, induced the expression of SRD5A1 from twofold to fourfold in three androgen-responsive PCa cell lines. In contrast, AR repressed SRD5A2 expression in this context. Chromatin-immunoprecipitation studies established that AR is recruited to both SRD5A1 and SRD5A2 genes following androgen stimulation but initiates transcriptional activation only at SRD5A1 as monitored by recruitment of RNA polymerase II and the presence of the H3K27Ac histone mark. Furthermore, we showed that the antiandrogens bicalutamide and enzalutamide block the AR-mediated regulation of both SRD5A1 and SRD5A2, highlighting an additional mechanism explaining their beneficial effects in patients. In summary, we identified an AR-dependent transcriptional regulation that explains the differential expression of 5α-reductase types 1 and 2 during PCa progression. Our work thus defines a mechanism by which androgens control their own synthesis via differential regulatory control of the expression of SRD5A1 and SRD5A2. Copyright © 2017 Endocrine Society.

Regulation of sexual odor preference by sex steroids in the posterodorsal medial amygdala in female rats.

PubMed

Fujiwara, Masaya; Nitta, Asano; Chiba, Atsuhiko

2016-06-01

Our previous study in male rats demonstrated that bilateral administration of flutamide, an androgen receptor (AR) antagonist, into the posterodorsal medial amygdala (MePD) increased the time sniffing male odors to as high as that sniffing estrous odors, eliminating the preference for estrous odors over male odors. This made us speculate that under blockade of AR in the MePD, testosterone-derived estrogen acting on the same brain region arouses interest in male odors which is otherwise suppressed by concomitant action of androgen. In cyclic female rats, endogenous androgen has been thought to be involved in inhibitory regulation of estrogen-activated sexual behavior. Thus, in the present study, we investigated the possibility that in female rats the arousal of interest in male odors is also normally regulated by both estrogen and androgen acting on the MePD, as predicted by our previous study in male rats. Implantation of either the estrogen receptor blocker tamoxifen (TX) or a non-aromatizable androgen 5α-dihydrotestosterone (DHT) into the MePD of ovariectomized, estrogen-primed female rats eliminated preference for male odors over estrous odors by significantly decreasing the time sniffing male odors to as low as that sniffing estrous odors. The subsequent odor discrimination tests confirmed that the DHT and TX administration did not impair the ability to discriminate between male and estrous odors. These results suggest that in estrous female rats estrogen action in the MePD plays critical roles in the expression of the preference for male odors while androgen action in the same brain region interferes with the estrogen action. Copyright © 2016 Elsevier Inc. All rights reserved.

Androgens and esophageal cancer: What do we know?

PubMed

Sukocheva, Olga A; Li, Bin; Due, Steven L; Hussey, Damian J; Watson, David I

2015-05-28

Significant disparities exist between genders for the development and progression of several gastro-intestinal (GI) diseases including cancer. Differences in incidence between men vs women for colon, gastric and hepatocellular cancers suggest a role for steroid sex hormones in regulation of GI carcinogenesis. Involvement of intrinsic gender-linked mechanisms is also possible for esophageal adenocarcinoma as its incidence is disproportionally high among men. However, the cause of the observed gender differences and the potential role of androgens in esophageal carcinogenesis remains unclear, even though the cancer-promoting role of androgen receptors (AR) shown in other cancers such as prostate and bladder suggests this aspect warrants exploration. Several studies have demonstrated expression of ARs in esophageal cancer. However, only one study has suggested a potential link between AR signaling and outcome - poorer prognosis. Two groups have analyzed data from cohorts with prostate cancer and one of these found a decreased incidence of esophageal squamous and adenocarcinoma after androgen deprivation therapy. However, very limited information is available about the effects of androgen and AR-initiated signaling on esophageal cancer cell growth in vitro and in vivo. Possible mechanisms for androgens/AR involvement in the regulation of esophageal cancer growth are considered, and the potential use of AR as a prognostic factor and clinical target is highlighted, although insufficient evidence is available to support clinical trials of novel therapies. As esophageal adenocarcinoma is a gender linked cancer with a large male predominance further studies are warranted to clarify the role of androgens and ARs in shaping intracellular signaling and genomic responses in esophageal cancer.

Soy food and isoflavone intake reduces the risk of cognitive impairment in elderly Japanese women.

PubMed

Nakamoto, Mariko; Otsuka, Rei; Nishita, Yukiko; Tange, Chikako; Tomida, Makiko; Kato, Yuki; Imai, Tomoko; Sakai, Tohru; Ando, Fujiko; Shimokata, Hiroshi

2018-01-18

Data were derived from the National Institute for Longevity Sciences-Longitudinal Study of Aging. Subjects comprised 403 men and 373 women aged 60-81 years at baseline who participated in the follow-up study at least once. Bean, soy product and soy isoflavone intake was assessed using a 3-day dietary record at baseline. Cognitive function was assessed by the Mini-Mental State Examination (MMSE). MMSE scores of ≤23 were used to define cognitive impairment. The relationship between bean, soy product and soy isoflavone intake and cognitive impairment was assessed using a generalized estimating equation. Multivariate-adjusted odds ratios (95% confidence intervals) for cognitive impairment with a 1 s.d. increase in total bean, total soybean and total soy isoflavone intakes were 0.48 (0.28-0.81; p = 0.006), 0.51 (0.32-0.83; p = 0.007), and 0.55 (0.32-0.93; p = 0.026), respectively, in women. Total soybean and soy isoflavone intake might decrease the risk of cognitive impairment in elderly Japanese women.

Soy Consumption and the Risk of Prostate Cancer: An Updated Systematic Review and Meta-Analysis

PubMed Central

Ranard, Katherine M.; Jeon, Sookyoung; Erdman, John W.

2018-01-01

Prostate cancer (PCa) is the second most commonly diagnosed cancer in men, accounting for 15% of all cancers in men worldwide. Asian populations consume soy foods as part of a regular diet, which may contribute to the lower PCa incidence observed in these countries. This meta-analysis provides a comprehensive updated analysis that builds on previously published meta-analyses, demonstrating that soy foods and their isoflavones (genistein and daidzein) are associated with a lower risk of prostate carcinogenesis. Thirty articles were included for analysis of the potential impacts of soy food intake, isoflavone intake, and circulating isoflavone levels, on both primary and advanced PCa. Total soy food (p < 0.001), genistein (p = 0.008), daidzein (p = 0.018), and unfermented soy food (p < 0.001) intakes were significantly associated with a reduced risk of PCa. Fermented soy food intake, total isoflavone intake, and circulating isoflavones were not associated with PCa risk. Neither soy food intake nor circulating isoflavones were associated with advanced PCa risk, although very few studies currently exist to examine potential associations. Combined, this evidence from observational studies shows a statistically significant association between soy consumption and decreased PCa risk. Further studies are required to support soy consumption as a prophylactic dietary approach to reduce PCa carcinogenesis. PMID:29300347

Choline Kinase Alpha as an Androgen Receptor Chaperone and Prostate Cancer Therapeutic Target

PubMed Central

Asim, Mohammad; Massie, Charles E.; Orafidiya, Folake; Pértega-Gomes, Nelma; Warren, Anne Y.; Esmaeili, Mohsen; Selth, Luke A.; Zecchini, Heather I.; Luko, Katarina; Qureshi, Arham; Baridi, Ajoeb; Menon, Suraj; Madhu, Basetti; Escriu, Carlos; Lyons, Scott; Vowler, Sarah L.; Zecchini, Vincent R.; Shaw, Greg; Hessenkemper, Wiebke; Russell, Roslin; Mohammed, Hisham; Stefanos, Niki; Lynch, Andy G.; Grigorenko, Elena; D’Santos, Clive; Taylor, Chris; Lamb, Alastair; Sriranjan, Rouchelle; Yang, Jiali; Stark, Rory; Dehm, Scott M.; Rennie, Paul S.; Carroll, Jason S.; Griffiths, John R.; Tavaré, Simon; Mills, Ian G.; McEwan, Iain J.; Baniahmad, Aria; Tilley, Wayne D.; Neal, David E.

2016-01-01

Background: The androgen receptor (AR) is a major drug target in prostate cancer (PCa). We profiled the AR-regulated kinome to identify clinically relevant and druggable effectors of AR signaling. Methods: Using genome-wide approaches, we interrogated all AR regulated kinases. Among these, choline kinase alpha (CHKA) expression was evaluated in benign (n = 195), prostatic intraepithelial neoplasia (PIN) (n = 153) and prostate cancer (PCa) lesions (n = 359). We interrogated how CHKA regulates AR signaling using biochemical assays and investigated androgen regulation of CHKA expression in men with PCa, both untreated (n = 20) and treated with an androgen biosynthesis inhibitor degarelix (n = 27). We studied the effect of CHKA inhibition on the PCa transcriptome using RNA sequencing and tested the effect of CHKA inhibition on cell growth, clonogenic survival and invasion. Tumor xenografts (n = 6 per group) were generated in mice using genetically engineered prostate cancer cells with inducible CHKA knockdown. Data were analyzed with χ2 tests, Cox regression analysis, and Kaplan-Meier methods. All statistical tests were two-sided. Results: CHKA expression was shown to be androgen regulated in cell lines, xenografts, and human tissue (log fold change from 6.75 to 6.59, P = .002) and was positively associated with tumor stage. CHKA binds directly to the ligand-binding domain (LBD) of AR, enhancing its stability. As such, CHKA is the first kinase identified as an AR chaperone. Inhibition of CHKA repressed the AR transcriptional program including pathways enriched for regulation of protein folding, decreased AR protein levels, and inhibited the growth of PCa cell lines, human PCa explants, and tumor xenografts. Conclusions: CHKA can act as an AR chaperone, providing, to our knowledge, the first evidence for kinases as molecular chaperones, making CHKA both a marker of tumor progression and a potential therapeutic target for PCa. PMID:26657335

Androgen receptor signals regulate UDP-glucuronosyltransferases in the urinary bladder: a potential mechanism of androgen-induced bladder carcinogenesis.

PubMed

Izumi, Koji; Zheng, Yichun; Hsu, Jong-Wei; Chang, Chawnshang; Miyamoto, Hiroshi

2013-02-01

UDP-glucuronosyltransferases (UGTs), major phase II drug metabolism enzymes, play an important role in urinary bladder cancer initiation by detoxifying carcinogens. We aimed to determine if androgens regulate UGT expression via the androgen receptor (AR) pathway in the bladder. Real-time reverse transcription-polymerase chain reaction and Western blot analyses were used to assess UGT1A levels in the normal urothelium SVHUC cell line stably expressed with AR and in bladder tissues from AR knockout (ARKO) and castrated male mice. Immunohistochemistry was also performed in radical cystectomy specimens. Dihydrotestosterone (DHT) treatment in SVHUC-AR reduced mRNA expression of all the UGT1A subtypes (19-75% decrease), and hydroxyflutamide antagonized the DHT effects. In contrast, DHT showed only marginal effects on UGT1A expression in SVHUC-Vector. Of note were higher expression levels of UGT1As in SVHUC-Vector than in SVHUC-AR. In ARKO mice, all the Ugt1a subtypes were up-regulated, compared to wild-type littermates. In wild-type male mice, castration increased the expression of Ugt1a8, Ugt1a9, and Ugt1a10. Additionally, wild-type female mice had higher levels of Ugt1a than wild-type males. Immunohistochemical studies showed strong (3+) UGT1A staining in 11/24 (46%) cancer tissues, which was significantly lower than in corresponding benign tissues [17/18 (94%) cases (P = 0.0009)]. These results suggest that androgen-mediated AR signals promote bladder carcinogenesis by down-regulating the expression of UGTs in the bladder. Copyright © 2011 Wiley Periodicals, Inc.

Establishment of prostate cancer spheres from a prostate cancer cell line after phenethyl isothiocyanate treatment and discovery of androgen-dependent reversible differentiation between sphere and neuroendocrine cells.

PubMed

Chen, Yamei; Cang, Shundong; Han, Liying; Liu, Christina; Yang, Patrick; Solangi, Zeeshan; Lu, Quanyi; Liu, Delong; Chiao, J W

2016-05-03

Prostate cancer can transform from androgen-responsive to an androgen-independent phenotype. The mechanism responsible for the transformation remains unclear. We studied the effects of an epigenetic modulator, phenethyl isothiocyanate (PEITC), on the androgen-responsive LNCaP cells. After treatment with PEITC, floating spheres were formed with characteristics of prostate cancer stem cells (PCSC). These spheres were capable of self-renewal in media with and without androgen. They have been maintained in both types of media as long term cultures. Upon androgen deprivation, the adherent spheres differentiated to neuroendocrine cells (NEC) with decreased proliferation, expression of androgen receptor, and PSA. NEC reverse differentiated to spheres when androgen was replenished. The sphere cells expressed surface marker CD44 and had enhanced histone H3K4 acetylation, DNMT1 down-regulation and GSTP1 activation. We hypothesize that PEITC-mediated alteration in epigenomics of LNCaP cells may give rise to sphere cells, whereas reversible androgenomic alterations govern the shuttling between sphere PCSC and progeny NEC. Our findings identify unrecognized properties of prostate cancer sphere cells with multi-potential plasticity. This system will facilitate development of novel therapeutic agents and allow further exploration into epigenomics and androgenomics governing the transformation to hormone refractory prostate cancer.

A maize gene encoding an NADPH binding enzyme highly homologous to isoflavone reductases is activated in response to sulfur starvation.

PubMed Central

Petrucco, S; Bolchi, A; Foroni, C; Percudani, R; Rossi, G L; Ottonello, S

1996-01-01

we isolated a novel gene that is selectively induced both in roots and shoots in response to sulfur starvation. This gene encodes a cytosolic, monomeric protein of 33 kD that selectively binds NADPH. The predicted polypeptide is highly homologous ( > 70%) to leguminous isoflavone reductases (IFRs), but the maize protein (IRL for isoflavone reductase-like) belongs to a novel family of proteins present in a variety of plants. Anti-IRL antibodies specifically recognize IFR polypeptides, yet the maize protein is unable to use various isoflavonoids as substrates. IRL expression is correlated closely to glutathione availability: it is persistently induced in seedlings whose glutathione content is about fourfold lower than controls, and it is down-regulated rapidly when control levels of glutathione are restored. This glutathione-dependent regulation indicates that maize IRL may play a crucial role in the establishment of a thiol-independent response to oxidative stress under glutathione shortage conditions. PMID:8597660

A maize gene encoding an NADPH binding enzyme highly homologous to isoflavone reductases is activated in response to sulfur starvation.

PubMed

Petrucco, S; Bolchi, A; Foroni, C; Percudani, R; Rossi, G L; Ottonello, S

1996-01-01

we isolated a novel gene that is selectively induced both in roots and shoots in response to sulfur starvation. This gene encodes a cytosolic, monomeric protein of 33 kD that selectively binds NADPH. The predicted polypeptide is highly homologous ( > 70%) to leguminous isoflavone reductases (IFRs), but the maize protein (IRL for isoflavone reductase-like) belongs to a novel family of proteins present in a variety of plants. Anti-IRL antibodies specifically recognize IFR polypeptides, yet the maize protein is unable to use various isoflavonoids as substrates. IRL expression is correlated closely to glutathione availability: it is persistently induced in seedlings whose glutathione content is about fourfold lower than controls, and it is down-regulated rapidly when control levels of glutathione are restored. This glutathione-dependent regulation indicates that maize IRL may play a crucial role in the establishment of a thiol-independent response to oxidative stress under glutathione shortage conditions.

Isoflavones in food supplements: chemical profile, label accordance and permeability study in Caco-2 cells.

PubMed

Almeida, I M C; Rodrigues, F; Sarmento, B; Alves, R C; Oliveira, M B P P

2015-03-01

Consumers nowadays are playing an active role in their health-care. A special case is the increasing number of women, who are reluctant to use exogenous hormone therapy for the treatment of menopausal symptoms and are looking for complementary therapies. However, food supplements are not clearly regulated in Europe. The EFSA has only recently begun to address the issues of botanical safety and purity regulation, leading to a variability of content, standardization, dosage, and purity of available products. In this study, isoflavones (puerarin, daidzin, genistin, daidzein, glycitein, genistein, formononetin, prunetin, and biochanin A) from food supplements (n = 15) for menopausal symptoms relief are evaluated and compared with the labelled information. Only four supplements complied with the recommendations made by the EC on the tolerable thresholds. The intestinal bioavailability of these compounds was investigated using Caco-2 cells. The apparent permeability coefficients of the selected isoflavonoids across the Caco-2 cells were affected by the isoflavone concentration and product matrix.

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

Soy isoflavone supplementation elevates erythrocyte superoxide dismutase, but not plasma ceruloplasmin in postmenopausal breast cancer survivors.

PubMed

DiSilvestro, Robert A; Goodman, Jaime; Dy, Emily; Lavalle, Gregory

2005-02-01

Soy isoflavone antioxidant effects may help prevent breast cancer re-occurrence, but isoflavone estrogen-like actions may increase breast cancer risk. These isoflavone actions can be reflected by effects on two copper enzymes activities, superoxide dismutase 1 (SOD 1), which has antioxidant function relevant to breast cancer prevention, and ceruloplasmin, which has its synthesis up-regulated by estrogen, and for which high values are associated with high breast cancer risk. A soy isoflavone-rich concentrate supplement was examined for effects on these two copper enzyme activities in post-menopausal breast cancer survivors (n = 7) in a crossover design with a placebo (24 days on supplement or placebo; 14 day wash out). The soy concentrate, but not the placebo, increased erythrocyte SOD 1 activities, but not ceruloplasmin activities or protein. The effect on superoxide dismutase activities was not likely due to increased copper intake since analysis of the soy extract showed little copper. The effect on superoxide dismutase was not accompanied by a change in urinary contents of 8-deoxyhydroxyguanosine, a DNA oxidant product, though perhaps this would change with a longer intervention. In summary, in regard to two copper enzyme activities, an isoflavone-rich soy concentrate showed an antioxidant effect considered relevant to breast cancer, but not an effect associated with estrogenic activity and increased breast cancer risk.

Garlic-derived S-allylmercaptocysteine is a novel in vivo antimetastatic agent for androgen-independent prostate cancer.

PubMed

Howard, Edward W; Ling, Ming-Tat; Chua, Chee Wai; Cheung, Hiu Wing; Wang, Xianghong; Wong, Yong Chuan

2007-03-15

There is epidemiologic evidence that high garlic consumption decreases the incidence of prostate cancer, and compounds isolated from garlic have been shown to have cancer-preventive and tumor-suppressive effects. Recent in vitro studies in our laboratory have shown that garlic-derived organosulfur compound S-allylmercaptocysteine suppresses invasion and cell motility of androgen-independent prostate cancer cells via the up-regulation of cell-adhesion molecule E-cadherin. S-allylmercaptocysteine is therefore a potential antimetastatic drug with broad clinical applications that we tested in vivo for the first time in this study. We used a newly established fluorescent orthotopic androgen-independent prostate cancer mouse model to assess the ability of S-allylmercaptocysteine to inhibit tumor growth and dissemination. We showed that oral S-allylmercaptocysteine not only inhibited the growth of primary tumors by up to 71% (P < 0.001) but also reduced the number of lung and adrenal metastases by as much as 85.5% (P = 0.001) without causing notable toxicity. This metastatic suppression was accompanied by a 91% reduction of viable circulating tumor cells (P = 0.041), suggesting that S-allylmercaptocysteine prevents dissemination by decreasing tumor cell intravasation. Our results provide in vivo evidence supporting the potential use of S-allylmercaptocysteine as an E-cadherin up-regulating antimetastatic agent for the treatment of androgen-independent prostate cancer. This is the first report of the in vivo antimetastatic properties of garlic, which may also apply to other cancer types.

Concentrations of isoflavones and their metabolites in the blood of pregnant and non-pregnant heifers fed soy bean.

PubMed

Woclawek-Potocka, Izabela; Piskula, Mariusz Krzysztof; Bah, Mamadou; Siemieniuch, Marta Jolanta; Korzekwa, Anna; Brzezicka, Edyta; Skarzynski, Dariusz Jan

2008-10-01

The present study compared the changes in isoflavones (daidzein and genistein) and their metabolite (equol and para-ethyl-phenol) concentrations in the blood plasma of cyclic and pregnant heifers after feeding with soy bean. Twelve healthy heifers were divided into three groups: cyclic heifers (days 8-12 of the estrous cycle; control group; n=4), an early pregnancy group (2 months pregnant; n=4) and a late pregnancy group (8 months pregnant; n=4). All heifers 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 an HPLC system. In the blood plasma of the early- and late-pregnant heifers, we found lower concentrations and time-dependent decreases in daidzein and genistein in comparison to cyclic heifers (P<0.05). Moreover, we noticed significant increases of equol and para-ethyl-phenol in the blood plasma of the early-pregnant heifers (P<0.05). In contrast, in the blood plasma of the late-pregnant heifers, we did not find an increase in the isoflavone metabolite concentrations compared with the early-pregnant heifers (P>0.05). In conclusion, physiological status (cyclicity or pregnancy) of the females influenced the concentrations of isoflavone metabolites in the blood plasma of the heifers. The stage of pregnancy affects isoflavone absorption, biotransformation and metabolism differently and results in higher concentrations of active metabolites of isoflavones during early pregnancy in comparison to their lower concentrations during late pregnancy. Therefore, we surmise that cows are more sensitive to active isoflavone metabolite actions during early pregnancy than cyclic heifers and heifers in late pregnancy.

Resveratrol Reduces Steroidogenesis in Rat Ovarian Theca-Interstitial Cells: The Role of Inhibition of Akt/PKB Signaling Pathway

PubMed Central

Ortega, Israel; Villanueva, Jesus A.; Wong, Donna H.; Cress, Amanda B.; Sokalska, Anna; Stanley, Scott D.

2012-01-01

Polycystic ovary syndrome is characterized by theca-interstitial hyperplasia and increased expression of steroidogenic genes, leading to excessive androgen production. Resveratrol, a natural polyphenol, promotes apoptosis and reduces rat theca-interstitial cell growth, in part by inhibiting the mevalonate pathway and decreasing the availability of substrates of isoprenylation [farnesyl-pyrophosphate (FPP) and geranylgeranyl-pyrophosphate (GGPP)]. This study evaluated the effect of resveratrol on rat theca-interstitial cell steroidogenesis. Because resveratrol may activate sirtuins, this study also investigated whether steroidogenesis was affected by sirtuin inhibitors (nicotinamide, sirtinol). Theca-interstitial cells were cultured with or without resveratrol (1–10 μm), GGPP (30 μm), FPP (30 μm), nicotinamide (1 mm), and/or sirtinol (10 μm). Resveratrol did not affect progesterone levels but reduced androgen production in a concentration-dependent fashion (androstenedione by up to 78% and androsterone by up to 76%). This inhibitory effect correlated with a decrease in mRNA expression of genes regulating androgen production, especially Cyp17a1 (by up to 73%). GGPP and FPP had no effect on androgen levels and Cyp17a1 mRNA levels and did not alter the effects induced by resveratrol. Similarly, sirtuin inhibitors did not reverse resveratrol-induced inhibition of steroidogenesis. However, resveratrol decreased activity of serine-threonine kinase/protein kinase B pathway, a cell-signaling pathway involved in ovarian steroidogenesis. The present findings indicate that resveratrol reduces androgen production primarily by inhibiting Cyp17a1 mRNA expression, and this inhibition may be mediated, in part, by blocking the activity of the serine-threonine kinase/protein kinase B pathway. These findings may be of clinical relevance to conditions associated with excessive production of androgens by theca cells, such as polycystic ovary syndrome. PMID:22719052

In Silico Analysis Identifies a Novel Role for Androgens in the Regulation of Human Endometrial Apoptosis

PubMed Central

Marshall, Elaine; Lowrey, Jacqueline; MacPherson, Sheila; Maybin, Jacqueline A.; Collins, Frances; Critchley, Hilary O. D.

2011-01-01

Context: The endometrium is a multicellular, steroid-responsive tissue that undergoes dynamic remodeling every menstrual cycle in preparation for implantation and, in absence of pregnancy, menstruation. Androgen receptors are present in the endometrium. Objective: The objective of the study was to investigate the impact of androgens on human endometrial stromal cells (hESC). Design: Bioinformatics was used to identify an androgen-regulated gene set and processes associated with their function. Regulation of target genes and impact of androgens on cell function were validated using primary hESC. Setting: The study was conducted at the University Research Institute. Patients: Endometrium was collected from women with regular menses; tissues were used for recovery of cells, total mRNA, or protein and for immunohistochemistry. Results: A new endometrial androgen target gene set (n = 15) was identified. Bioinformatics revealed 12 of these genes interacted in one pathway and identified an association with control of cell survival. Dynamic androgen-dependent changes in expression of the gene set were detected in hESC with nine significantly down-regulated at 2 and/or 8 h. Treatment of hESC with dihydrotestosterone reduced staurosporine-induced apoptosis and cell migration/proliferation. Conclusions: Rigorous in silico analysis resulted in identification of a group of androgen-regulated genes expressed in human endometrium. Pathway analysis and functional assays suggest androgen-dependent changes in gene expression may have a significant impact on stromal cell proliferation, migration, and survival. These data provide the platform for further studies on the role of circulatory or local androgens in the regulation of endometrial function and identify androgens as candidates in the pathogenesis of common endometrial disorders including polycystic ovarian syndrome, cancer, and endometriosis. PMID:21865353

Insulin hypersecretion together with high luteinizing hormone concentration augments androgen secretion in oral glucose tolerance test in women with polycystic ovarian disease.

PubMed

Anttila, L; Koskinen, P; Jaatinen, T A; Erkkola, R; Irjala, K; Ruutiainen, K

1993-08-01

Female hyperandrogenism is often associated with hyperinsulinaemia and insulin resistance. We evaluated the hormone responses in an oral glucose tolerance test to investigate the interactions of gonadotrophins, insulin, C-peptide and androgens in women with polycystic ovarian disease (PCOD). In 28 patients with ultrasonographically diagnosed PCOD, hyperinsulinaemia and insulin resistance were mainly associated with obesity. Both basal and cumulative sum of insulin to C-peptide ratios were high in obese subjects, suggesting decreasing hepatic removal of insulin caused by obesity. Nevertheless, in some lean PCOD women, despite normal fasting insulin concentrations, insulin hypersecretion existed. The mean concentration of testosterone decreased significantly during the oral glucose tolerance test both in PCOD and control women, and of androstenedione in the PCOD patients only. However, an increase in androgen responses was found in a subgroup of PCOD patients, who had both elevated luteinizing hormone (LH) concentrations and hyperinsulinaemic response to oral glucose. In the remaining PCOD patients an inverse correlation between LH and insulin was found. The patients with hyperinsulinaemia together with LH hypersecretion may represent a subgroup of PCOD with deranged regulation of androgen secretion.

Identification of Novel Androgen-Regulated Pathways and mRNA Isoforms through Genome-Wide Exon-Specific Profiling of the LNCaP Transcriptome

PubMed Central

Carling, Phillippa J.; Buist, Thomas; Zhang, Chaolin; Grellscheid, Sushma N.; Armstrong, Kelly; Stockley, Jacqueline; Simillion, Cedric; Gaughan, Luke; Kalna, Gabriela; Zhang, Michael Q.; Robson, Craig N.; Leung, Hing Y.; Elliott, David J.

2011-01-01

Androgens drive the onset and progression of prostate cancer (PCa) by modulating androgen receptor (AR) transcriptional activity. Although several microarray-based studies have identified androgen-regulated genes, here we identify in-parallel global androgen-dependent changes in both gene and alternative mRNA isoform expression by exon-level analyses of the LNCaP transcriptome. While genome-wide gene expression changes correlated well with previously-published studies, we additionally uncovered a subset of 226 novel androgen-regulated genes. Gene expression pathway analysis of this subset revealed gene clusters associated with, and including the tyrosine kinase LYN, as well as components of the mTOR (mammalian target of rapamycin) pathway, which is commonly dysregulated in cancer. We also identified 1279 putative androgen-regulated alternative events, of which 325 (∼25%) mapped to known alternative splicing events or alternative first/last exons. We selected 30 androgen-dependent alternative events for RT-PCR validation, including mRNAs derived from genes encoding tumour suppressors and cell cycle regulators. Of seven positively-validating events (∼23%), five events involved transcripts derived from alternative promoters of known AR gene targets. In particular, we found a novel androgen-dependent mRNA isoform derived from an alternative internal promoter within the TSC2 tumour suppressor gene, which is predicted to encode a protein lacking an interaction domain required for mTOR inhibition. We confirmed that expression of this alternative TSC2 mRNA isoform was directly regulated by androgens, and chromatin immunoprecipitation indicated recruitment of AR to the alternative promoter region at early timepoints following androgen stimulation, which correlated with expression of alternative transcripts. Together, our data suggest that alternative mRNA isoform expression might mediate the cellular response to androgens, and may have roles in clinical PCa. PMID:22194994

Wnt/Beta-Catenin, Foxa2, and CXCR4 Axis Controls Prostate Cancer Progression

DTIC Science & Technology

2013-07-01

NT1 cells with or without Foxa2 were cultured in 5% strip medium in the presence or absence of androgen. Cell growth curve was measured by WTS...assays. Over-expression of Foxa2 increased NT1 cell growth even in the absence of androgen. Figure 3. knocking-down Foxa2 did not affect PC3 cell ...in NeoTag1 cells decreased AR level; however, AR 6 activity did not change. Foxa2 target genes were up-regulated in NT1 /Foxa2 over-expressing

The pharmacokinetic behavior of the soy isoflavone metabolite S-(-)equol and its diastereoisomer R-(+)equol in healthy adults determined by using stable-isotope-labeled tracers.

PubMed

Setchell, Kenneth Dr; Zhao, Xueheng; Jha, Pinky; Heubi, James E; Brown, Nadine M

2009-10-01

The nonsteroidal estrogen equol occurs as diastereoisomers, S-(-)equol and R-(+)equol, both of which have significant biological actions. S-(-)equol, the naturally occurring enantiomer produced by 20-30% of adults consuming soy foods, has selective affinity for estrogen receptor-beta, whereas both enantiomers modulate androgen action. Little is known about the pharmacokinetics of the diastereoisomers, despite current interest in developing equol as a nutraceutical or pharmaceutical agent. The objective was to compare the pharmacokinetics of S-(-)equol and R-(+)equol by using [13C] stable-isotope-labeled tracers to facilitate the optimization of clinical studies aimed at evaluating the potential of these diastereoisomers in the prevention and treatment of estrogen- and androgen-dependent conditions. A randomized, crossover, open-label study in 12 healthy adults (6 men and 6 women) compared the plasma and urinary pharmacokinetics of orally administered enantiomeric pure forms of S-(-)[2-13C]equol, R-(+)[2-13C]equol, and the racemic mixture. Plasma and urinary [13C]R-equol and [13C]S-equol concentrations were measured by tandem mass spectrometry. Plasma [13C]equol concentration appearance and disappearance curves showed that both enantiomers were rapidly absorbed, attained high circulating concentrations, and had a similar terminal elimination half-life of 7-8 h. The systemic bioavailability and fractional absorption of R-(+)[2-13C]equol were higher than those of S-(-)[2-13C]equol or the racemate. The pharmacokinetics of racemic (+/-)[2-13C]equol were different from those of the individual enantiomers: slower absorption, lower peak plasma concentrations, and lower systemic bioavailability. The high bioavailability of both diastereoisomers contrasts with previous findings for the soy isoflavones daidzein and genistein, both of which have relatively poor bioavailability, and suggests that low doses of equol taken twice daily may be sufficient to achieve biological effects.

Isoflavone and Protein Constituents of Lactic Acid-Fermented Soy Milk Combine to Prevent Dyslipidemia in Rats Fed a High Cholesterol Diet

PubMed Central

Kobayashi, Maki; Egusa, Shintaro; Fukuda, Mitsuru

2014-01-01

A high cholesterol diet induces dyslipidemia. This study investigated whether isoflavone aglycones in lactic acid-fermented soy milk (LFS) improve lipid metabolism in rats fed a high cholesterol diet. Male Sprague-Dawley rats aged seven weeks were fed an AIN-93G diet, a 1% cholesterol diet (a high cholesterol diet), a high-cholesterol diet containing 4% isoflavone extract of LFS (LFS extract diet), a high-cholesterol diet containing 19.4% ethanol-washed LFS (ethanol-washed LFS diet, isoflavone-poor diet), or a high cholesterol diet containing 23.2% intact LFS (intact LFS diet) for five weeks. The plasma total cholesterol (TC) level was increased in the rats fed the LFS extract diet compared with those fed the high cholesterol diet. The TC level was decreased by the intact LFS and ethanol-washed LFS diets. The cholesterol-lowering effect was stronger in the rats fed the intact LFS diet than those fed the ethanol-washed LFS diet. The plasma triglyceride (TG) level was unchanged in the rats fed the LFS extract diet, but it decreased in rats fed the intact LFS and ethanol-washed LFS diets. Although, compared with the high cholesterol diet, the LFS extract and ethanol-washed LFS diets did not reduce hepatic cholesterol and TG, both levels were remarkably lowered by the intact LFS diet. These results suggest that the improvement in lipid metabolism of rats fed a high-cholesterol diet containing LFS isoflavone aglycones is not due to an independent effect but due to a cooperative effect with soy protein. PMID:25514389

The Biochemistry, Chemistry and Physiology of the Isoflavones in Soybeans and their Food Products

PubMed Central

2010-01-01

Abstract In this review of the chemistry, absorption, metabolism, and mechanisms of action of plant isoflavones, emphasis is placed on the isoflavones in soy and the food products derived from them. Soybeans have been part of food history in Asia for several millennia but did not reach the Americas and Europe until the eighteenth century. In the twentieth century, there was a tremendous increase in the cultivation of soybeans in the United States and more recently in South America. Soy foods have entered the U.S. food supply in ever-increasing amounts both in the form of traditional products (soy milk, tofu) and in more subtle ways in dairy and bread/cake products. The isoflavones in non-fermented foods are for the most part in the form of glycoside conjugates. These undergo changes due to different processing procedures. Isoflavones and their metabolites are well absorbed and undergo an enterohepatic circulation. They are often termed phytoestrogens because they bind to the estrogen receptors although weakly compared to physiologic estrogens. This estrogenicity is not the only mechanism by which isoflavones may have bioactivity—they inhibit tyrosine kinases, have antioxidant activity, bind to and activate peroxisome proliferator regulators α and γ, inhibit enzymes in steroid biosynthesis, strongly influence natural killer cell function and the activation of specific T-cell subsets, and inhibit metastasis. These various properties may explain the much lower incidence of hormonally-dependent breast cancer in Asian populations compared to Americans and Europeans. PMID:20235891

Androgen Deficiency During Mid- and Late Pregnancy Alters Progesterone Production and Metabolism in the Porcine Corpus Luteum

PubMed Central

Knapczyk-Stwora, Katarzyna; Ciereszko, Renata E.; Golas, Aniela; Wieciech, Iwona; Slomczynska, Maria

2014-01-01

We determined whether androgen deficiency induced by flutamide treatment during mid- and late pregnancy affects the functions of the porcine corpus luteum (CL). Pregnant gilts were injected with flutamide between days 43 and 49 (gestation day [GD] 50F), days 83 and 89 (GD90F), or days 101 and 107 (GD108F) of gestation. Antiandrogen treatment increased the luteal progesterone concentration in the GD50F group and decreased progesterone content in the GD90F and GD108F groups. Luteal levels of side-chain cleavage cytochrome P450 (CYP11A1) mRNA and protein were significantly downregulated in the GD90F and GD108F groups as compared with the respective controls. The 3β-hydroxysteroid dehydrogenase/Δ5-Δ4 isomerase (HSD3B) mRNA and protein expression were significantly reduced only in the GD108F group as compared with the control. Decreased luteal 20α-hydroxysteroid dehydrogenase (AKR1C1) mRNA and protein levels were observed in the GD50F group. Thus, androgen deficiency during pregnancy in pigs led to CL dysfunction that is marked by decreased progesterone production. Furthermore, exposure to flutamide during late pregnancy downregulated steroidogenic enzymes (CYP11A1 and HSD3B) in pigs. We conclude that androgens are important regulators of CL function during pregnancy. PMID:24429677

Androgen deficiency during mid- and late pregnancy alters progesterone production and metabolism in the porcine corpus luteum.

PubMed

Grzesiak, Malgorzata; Knapczyk-Stwora, Katarzyna; Ciereszko, Renata E; Golas, Aniela; Wieciech, Iwona; Slomczynska, Maria

2014-06-01

We determined whether androgen deficiency induced by flutamide treatment during mid- and late pregnancy affects the functions of the porcine corpus luteum (CL). Pregnant gilts were injected with flutamide between days 43 and 49 (gestation day [GD] 50F), days 83 and 89 (GD90F), or days 101 and 107 (GD108F) of gestation. Antiandrogen treatment increased the luteal progesterone concentration in the GD50F group and decreased progesterone content in the GD90F and GD108F groups. Luteal levels of side-chain cleavage cytochrome P450 (CYP11A1) mRNA and protein were significantly downregulated in the GD90F and GD108F groups as compared with the respective controls. The 3β-hydroxysteroid dehydrogenase/Δ5-Δ4 isomerase (HSD3B) mRNA and protein expression were significantly reduced only in the GD108F group as compared with the control. Decreased luteal 20α-hydroxysteroid dehydrogenase (AKR1C1) mRNA and protein levels were observed in the GD50F group. Thus, androgen deficiency during pregnancy in pigs led to CL dysfunction that is marked by decreased progesterone production. Furthermore, exposure to flutamide during late pregnancy downregulated steroidogenic enzymes (CYP11A1 and HSD3B) in pigs. We conclude that androgens are important regulators of CL function during pregnancy.

Formononetin induces the mitochondrial apoptosis pathway in prostate cancer cells via downregulation of the IGF-1/IGF-1R signaling pathway.

PubMed

Huang, Wen-Jun; Bi, Ling-Yun; Li, Zhen-Zhao; Zhang, Xing; Ye, Yu

2013-12-20

Abstract Context: Formononetin, an isoflavone, can inhibit the proliferation of cancer cells, including those of the prostate. However, its antitumor mechanism remains unclear. Aim: To investigate whether the insulin-like growth factor 1 (IGF-1)/insulin-like growth factor 1 receptor (IGF-1 R) signaling pathway mediates the formononetin antitumor effect on prostate cancer cells. Materials and methods: The viability of PC-3 cells was measured by MTT assay 48 h after formononetin treatment (25, 50 and 100 μM). Formononetin-induced cell apoptosis was measured by Hoechst 33258 staining and flow cytometry. Expression of Bax mRNA was detected by real-time PCR, and the expression levels of Bax and IGF-1 R proteins were detected by western blots. Results: At concentrations >12.5 μM, formononetin significantly inhibited the proliferation of human prostate cancer cells. Formononetin increased Bax mRNA and protein expression levels and decreased the expression levels of pIGF-1 R protein in a dose-dependent manner. Conclusion: High concentrations of formononetin-induced apoptosis in androgen-independent prostate cancer cells through inhibition of the IGF-1/IGF-1 R pathway.

Inhibitor of p52 NF-κB subunit and androgen receptor (AR) interaction reduces growth of human prostate cancer cells by abrogating nuclear translocation of p52 and phosphorylated ARser81

PubMed Central

Mehraein-Ghomi, Farideh; Church, Dawn R.; Schreiber, Cynthia L.; Weichmann, Ashley M.; Basu, Hirak S.; Wilding, George

2015-01-01

Accumulating evidence shows that androgen receptor (AR) activation and signaling plays a key role in growth and progression in all stages of prostate cancer, even under low androgen levels or in the absence of androgen in the castration-resistant prostate cancer. Sustained activation of AR under androgen-deprived conditions may be due to its interaction with co-activators, such as p52 NF-κB subunit, and/or an increase in its stability by phosphorylation that delays its degradation. Here we identified a specific inhibitor of AR/p52 interaction, AR/p52-02, via a high throughput screen based on the reconstitution of Gaussia Luciferase. We found that AR/p52-02 markedly inhibited growth of both castration-resistant C4-2 (IC50 ∼6 μM) and parental androgen-dependent LNCaP (IC50 ∼4 μM) human prostate cancer cells under low androgen conditions. Growth inhibition was associated with significantly reduced nuclear p52 levels and DNA binding activity, as well as decreased phosphorylation of AR at serine 81, increased AR ubiquitination, and decreased AR transcriptional activity as indicated by decreased prostate-specific antigen (PSA) mRNA levels in both cell lines. AR/p52-02 also caused a reduction in levels of p21WAF/CIP1, which is a direct AR targeted gene in that its expression correlates with androgen stimulation and mitogenic proliferation in prostate cancer under physiologic levels of androgen, likely by disrupting the AR signaling axis. The reduced level of cyclinD1 reported previously for this compound may be due to the reduction in nuclear presence and activity of p52, which directly regulates cyclinD1 expression, as well as the reduction in p21WAF/CIP1, since p21WAF/CIP1 is reported to stabilize nuclear cyclinD1 in prostate cancer. Overall, the data suggest that specifically inhibiting the interaction of AR with p52 and blocking activity of p52 and pARser81 may be an effective means of reducing castration-resistant prostate cancer cell growth. PMID:26622945

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.

Bioactive Androgens and Glucuronidated Androgen Metabolites are Associated with Subcutaneous and Ectopic Skeletal Muscle Adiposity among Older Black Men

PubMed Central

Miljkovic, Iva; Cauley, Jane A; Dressen, Amy S; Gordon, Christopher L; Goodpaster, Bret H; Kuller, Lewis H; Bunker, Clareann H; Patrick, Alan L; Wheeler, Victor W; Orwoll, Eric S; Zmuda, Joseph M

2011-01-01

Aging is associated with declining serum levels of androgenic hormones and with increased skeletal muscle fat infiltration, an emerging risk factor for type 2 diabetes mellitus (T2DM). Androgens regulate fat mass and glucose homeostasis, but the effect of androgenic hormones on skeletal muscle fat infiltration is largely unknown. Thus, the aim of the current study was to examine the association of serum androgens and their precursors and metabolites with skeletal muscle fat infiltration and T2DM in a black male population group at high risk of T2DM. Serum androgens, estrogens, and androgen precursors and metabolites were measured using mass spectrometry, and calf skeletal muscle fat distribution [subcutaneous and intermuscular fat; skeletal muscle density] were measured using quantitative computed tomography in 472 Afro-Caribbean men aged 65 and older. Bioactive androgens, testosterone, free testosterone and dihydrotestosterone, were associated with less skeletal muscle fat infiltration (r=−0.14 to −0.18, P<0.05) and increased skeletal muscle density (r=0.10 to 0.14, P<0.05), independent of total adiposity. Additionally, glucuronidated androgen metabolites were associated with less subcutaneous fat (r=−0.11 to −0.15, P<0.05). Multivariate logistic regression analysis identified an increased level of 3α-diol-3 glucuronide (OR=1.38, P<0.01) and a decreased level of dihydrotestosterone (OR=0.66, P<0.01) to be significantly associated with T2DM. Our findings suggest that in elderly black men, independent of total adiposity, bioactive androgens and glucuronidated androgen metabolites may play previously unrecognized role in skeletal muscle fat distribution. Longitudinal studies are needed to further evaluate the relationship between androgens and androgen metabolites with changes in skeletal muscle fat distribution with aging and the incidence of T2DM. PMID:21353258

Soyfood intake in the prevention of breast cancer risk in women: a meta-analysis of observational epidemiological studies.

PubMed

Qin, Li-Qiang; Xu, Jia-Ying; Wang, Pei-Yu; Hoshi, Kazuhiko

2006-12-01

Many studies have suggested that the intake of soy products may protect against the occurrence of breast cancer because of the considerable amount of isoflavones they contain. To review the results of the observational studies, we performed this meta-analysis of the relevant literature. We searched Medline for reports that examined the association between soyfood consumption (or isoflavone intake) and breast cancer risk from January 1966 to April 2006. The random-effects model was used to estimate the pooled relative risk (RR). Twenty-one independent studies (14 case-control studies and 7 cohort studies) were included in the final analysis. The pooled RR of breast cancer for soyfood intake was 0.75 with a 95% CI of 0.59-0.95. As the main types of soyfood in Japan and China, tofu and miso showed clear protective effects. Isoflavone intake resulted in a 20% decrease in risk (RR = 0.81, 95% CI 0.67-0.99). The pooled RR varied little according to study stratification. When the studies published in Japanese and Chinese were added, the inverse associations between soyfood, tofu and breast cancer risk became slightly stronger. The weak association of miso was possibly due to the high concentration of salt in miso soup. In the present analysis, we did not find strong evidence for publication bias in the combination of the studies. This meta-analysis supported the hypotheses that soyfood intake may be associated with a decreased risk of breast cancer due to the isoflavones. Further epidemiological studies need to be conducted with more comprehensive information about the soyfood, and more accurate assessment of the isoflavones.

Relationship between soy and isoflavone intake and periodontal disease: The Freshmen in Dietetic Courses Study II

PubMed Central

Tanaka, Keiko; Sasaki, Satoshi; Murakami, Kentaro; Okubo, Hitomi; Takahashi, Yoshiko; Miyake, Yoshihiro

2008-01-01

Background Much research has shown that soy products inhibited various diseases. However, no published studies have examined the effects of consumption of soy and isoflavones on periodontal disease. The aim of this study was to investigate whether soy and isoflavone intake is associated with the prevalence of periodontal disease. Methods The subjects were 3956 Japanese female students, aged 18 to 22 years, who were taking a dietetic course. Periodontal disease was defined as present when a subject reported diagnosis of the disorder by a dentist. Information on dietary factors was collected using a validated diet history questionnaire. Logistic regression analysis was used to estimate the odds ratios and their confidence intervals of periodontal disease. Adjustment was made for cigarette smoking, toothbrushing frequency, region of residence, and body mass index. Results The prevalence of periodontal disease was 8.0%. Intake of total soy product and tofu was independently associated with a decreased prevalence of periodontal disease; multivariate odds ratios in comparison of the highest with the lowest quintile were 0.68 and 0.68, respectively (95% confidence intervals = 0.47–0.97 and 0.47–0.98, P for trend = 0.01 and 0.004, respectively). A significant inverse dose-response relationship between the intake of isoflavones and the prevalence of periodontal disease was observed, although the difference in the adjusted odds ratio between the extreme quintiles was of borderline significance (P for trend = 0.04). There were no measurable dose-response relationships between consumption of tofu products, fermented soybeans, boiled soybeans, miso, or miso soup and the prevalence of periodontal disease. Conclusion Our findings suggest that soy and isoflavone intake may decrease the likelihood of periodontal disease. Further investigations with objective measures for periodontal disease are needed to confirm our findings. PMID:18226266

Mitochondrial redox signaling by p66Shc is involved in regulating androgenic growth stimulation of human prostate cancer cells

PubMed Central

Veeramani, S; Yuan, T-C; Lin, F-F; Lin, M-F

2009-01-01

p66Shc is shown to negatively regulate the life span in mice through reactive oxygen species (ROS) production. Recent reports, however, revealed that p66Shc protein level is significantly elevated in several human cancer tissues and growth-stimulated carcinoma cells, suggesting a mitogenic and carcinogenic role for p66Shc. In this communication, we demonstrate for the first time that p66Shc mediates androgenic growth signals in androgen-sensitive human prostate cancer cells through mitochondrial ROS production. Growth stimulation of prostate cancer cells with 5α-dihydrotestosterone (DHT) is accompanied by increased p66Shc level and ROS production, which is abolished by antioxidant treatments. However, antioxidant treatments do not affect the transcriptional activity of androgen receptor (AR) as observed by its inability to block DHT-induced prostate-specific antigen expression, an AR-dependent correlate of prostate cancer progression. Elevated expression of p66Shc by cDNA transfection increases the basal cell proliferation and, thus, reduces additional DHT-induced cell proliferation. Furthermore, DHT increases the translocation of p66Shc into mitochondria and its interaction with cytochrome c. Conversely, both redox-negative p66Shc mutant (W134F), which is deficient in cytochrome c interaction, and p66Shc small interfering RNA decrease DHT-induced cell proliferation. These results collectively reveal a novel role for p66Shc–ROS pathway in androgen-induced prostate cancer cell proliferation and, thus, may play a role in early prostate carcinogenesis. PMID:18504439

The tumor suppressor TERE1 (UBIAD1) prenyltransferase regulates the elevated cholesterol phenotype in castration resistant prostate cancer by controlling a program of ligand dependent SXR target genes

PubMed Central

Fredericks, William J.; Sepulveda, Jorge; Lal, Priti; Tomaszewski, John E.; Lin, Ming-Fong; McGarvey, Terry; Rauscher, Frank J; Malkowicz, S. Bruce

2013-01-01

Castrate-Resistant Prostate Cancer (CRPC) is characterized by persistent androgen receptor-driven tumor growth in the apparent absence of systemic androgens. Current evidence suggests that CRPC cells can produce their own androgens from endogenous sterol precursors that act in an intracrine manner to stimulate tumor growth. The mechanisms by which CRPC cells become steroidogenic during tumor progression are not well defined. Herein we describe a novel link between the elevated cholesterol phenotype of CRPC and the TERE1 tumor suppressor protein, a prenyltransferase that synthesizes vitamin K-2, which is a potent endogenous ligand for the SXR nuclear hormone receptor. We show that 50% of primary and metastatic prostate cancer specimens exhibit a loss of TERE1 expression and we establish a correlation between TERE1 expression and cholesterol in the LnCaP-C81 steroidogenic cell model of the CRPC. LnCaP-C81 cells also lack TERE1 protein, and show elevated cholesterol synthetic rates, higher steady state levels of cholesterol, and increased expression of enzymes in the de novo cholesterol biosynthetic pathways than the non-steroidogenic prostate cancer cells. C81 cells also show decreased expression of the SXR nuclear hormone receptor and a panel of directly regulated SXR target genes that govern cholesterol efflux and steroid catabolism. Thus, a combination of increased synthesis, along with decreased efflux and catabolism likely underlies the CRPC phenotype: SXR might coordinately regulate this phenotype. Moreover, TERE1 controls synthesis of vitamin K-2, which is a potent endogenous ligand for SXR activation, strongly suggesting a link between TERE1 levels, K-2 synthesis and SXR target gene regulation. We demonstrate that following ectopic TERE1 expression or induction of endogenous TERE1, the elevated cholesterol levels in C81 cells are reduced. Moreover, reconstitution of TERE1 expression in C81 cells reactivates SXR and switches on a suite of SXR target genes that coordinately promote both cholesterol efflux and androgen catabolism. Thus, loss of TERE1 during tumor progression reduces K-2 levels resulting in reduced transcription of SXR target genes. We propose that TERE1 controls the CPRC phenotype by regulating the endogenous levels of Vitamin K-2 and hence the transcriptional control of a suite of steroidogenic genes via the SXR receptor. These data implicate the TERE1 protein as a previously unrecognized link affecting cholesterol and androgen accumulation that could govern acquisition of the CRPC phenotype. PMID:23919967

Splicing Factor Prp8 Interacts With NES(AR) and Regulates Androgen Receptor in Prostate Cancer Cells.

PubMed

Wang, Dan; Nguyen, Minh M; Masoodi, Khalid Z; Singh, Prabhpreet; Jing, Yifeng; O'Malley, Katherine; Dar, Javid A; Dhir, Rajiv; Wang, Zhou

2015-12-01

Androgen receptor (AR) plays a pivotal role in the development of primary as well as advanced castration-resistant prostate cancer. Previous work in our lab identified a novel nuclear export signal (NES) (NES(AR)) in AR ligand-binding domain essential for AR nucleocytoplasmic trafficking. By characterizing the localization of green fluorescence protein (GFP)-tagged NES(AR), we designed and executed a yeast mutagenesis screen and isolated 7 yeast mutants that failed to display the NES(AR) export function. One of those mutants was identified as the splicing factor pre-mRNA processing factor 8 (Prp8). We further showed that Prp8 could regulate NES(AR) function using short hairpin RNA knockdown of Prp8 coupled with a rapamycin export assay in mammalian cells and knockdown of Prp8 could induce nuclear accumulation of GFP-tagged AR in PC3 cells. Prp8 expression was decreased in castration-resistant LuCaP35 xenograft tumors as compared with androgen-sensitive xenografts. Laser capture microdissection and quantitative PCR showed Prp8 mRNA levels were decreased in human prostate cancer specimens with high Gleason scores. In prostate cancer cells, coimmunoprecipitation and deletion mutagenesis revealed a physical interaction between Prp8 and AR mainly mediated by NES(AR). Luciferase assay with prostate specific antigen promoter-driven reporter demonstrated that Prp8 regulated AR transcription activity in prostate cancer cells. Interestingly, Prp8 knockdown also increased polyubiquitination of endogenous AR. This may be 1 possible mechanism by which it modulates AR activity. These results show that Prp8 is a novel AR cofactor that interacts with NES(AR) and regulates AR function in prostate cancer cells.

Membrane androgen receptor characteristics of human ZIP9 (SLC39A) zinc transporter in prostate cancer cells: Androgen-specific activation and involvement of an inhibitory G protein in zinc and MAP kinase signaling.

PubMed

Thomas, Peter; Pang, Yefei; Dong, Jing

2017-05-15

Characteristics of novel human membrane androgen receptor (mAR), ZIP9 (SLC39A9), were investigated in ZIP9-transfected PC-3 cells (PC3-ZIP9). Ligand blot analysis showed plasma membrane [ 3 H]-T binding corresponds to the position of ZIP9 on Western blots which suggests ZIP9 can bind [ 3 H]-T alone, without a protein partner. Progesterone antagonized testosterone actions, blocking increases in zinc, Erk phosphorylation and apoptosis, further evidence that ZIP9 is specifically activated by androgens. Pre-treatment with GTPγS and pertussis toxin decreased plasma membrane [ 3 H]-T binding and blocked testosterone-induced increases in Erk phosphorylation and intracellular zinc, indicating ZIP9 is coupled to an inhibitory G protein (Gi) that mediates both MAP kinase and zinc signaling. Testosterone treatment of nuclei and mitochondria which express ZIP9 decreased their zinc contents, suggesting ZIP9 also regulates free zinc through releasing it from these intracellular organelles. The results show ZIP9 is a specific Gi coupled-mAR mediating testosterone-induced MAP kinase and zinc signaling in PC3-ZIP9 cells. Copyright © 2017 Elsevier B.V. All rights reserved.

Telomerase as an Androgen Receptor-Regulated Target in Selenium Chemoprevention of Prostate Cancer

DTIC Science & Technology

2010-05-01

TITLE: Telomerase as an Androgen Receptor-Regulated Target in Selenium Chemoprevention of Prostate Cancer PRINCIPAL INVESTIGATOR...May 2009 - 30 Apr 2010 4. TITLE AND SUBTITLE Telomerase as an Androgen Receptor-Regulated Target in Selenium Chemoprevention of Prostate Cancer...telomerase as a potential target of AR signaling suppression by selenium . We found that combination of selenium and bicalutamide produced a robust down

Different profiles of neuroendocrine cell differentiation evolve in the PC-310 human prostate cancer model during long-term androgen deprivation.

PubMed

Jongsma, Johan; Oomen, Monique H; Noordzij, Marinus A; Van Weerden, Wytske M; Martens, Gerard J M; van der Kwast, Theodorus H; Schröder, Fritz H; van Steenbrugge, Gert J

2002-03-01

Neuroendocrine (NE) cells are androgen-independent cells and secrete growth-modulating peptide hormones via a regulated secretory pathway (RSP). We studied NE differentiation after long-term androgen withdrawal in the androgen-dependent human prostate cancer xenograft PC-310. Tumor-bearing nude mice were killed at 0, 2, 5, 7, 14, 21, 47, 84, and 154 days after castration. The half-life of the PC-310 tumor was 10 days, with a stable residual tumor volume of 30--40% after 21 days and longer periods of androgen deprivation. Proliferative activity and prostate-specific antigen serum levels decreased to zero after castration, whereas cell-cycle arrest was manifested by increased p27(kip1) expression. A temporary downregulation of androgen receptor (AR) expression was noted after androgen deprivation. The expression of chromogranin A, secretogranin III, and secretogranin V (7B2) increased 5 days after castration and later. Subsequently, pro-hormone convertase 1 and peptidyl alpha--amidating monooxygenase as well as vascular endothelial growth factor were expressed from 7 days after castration on. Finally, such growth factors as gastrin-releasing peptide and serotonin were expressed in a small part of the NE cells 21 days after castration, but strong expression was induced late during androgen deprivation, that is, 84 and 154 days after castration, respectively. Androgen deprivation of the NE-differentiated PC-310 model induced the formation of NE-differentiated AR(minus sign) and non-NE AR(+) tumor residues. The NE-differentiated cells actively produced growth factors via an RSP that may lead to hormone-refractory disease. The dormant non-NE AR(+) tumor cells were shown to remain androgen sensitive even after long-term androgen deprivation. In the PC-310 xenograft, time-dependent NE differentiation and subsequent maturation were induced after androgen depletion. The androgen-dependent PC-310 xenograft model constitutes an excellent model for studying the role of NE cells in the progression of clinical prostate cancer. Copyright 2002 Wiley-Liss, Inc.

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 lacking. LG isoflavone supplementation resulted in a caloric restriction-like gene expression profile for both producer phenotypes and pointed toward a potential beneficial effect, whereas both supplements induced anti-inflammatory gene expression in equol producers. The study was registered at clinicaltrials.gov as NCT01556737. © 2014 American Society for Nutrition.

Selenium is a Chemotherapeutic Agent for the Treatment of Prostate Cancer

DTIC Science & Technology

2007-12-01

to the AR without decreasing AR levels. Strategic targeting of the AR with ribozymes , antisense oligomers, and small interfering RNAs has been shown... ribozyme . Mol Endrocrinol 1998;12:1558-1566. 20 10. Ko YJ, Devi GR, London CA, et al. Androgen receptor down-regulation in prostate cancer with

Effects of UV-B radiation on the isoflavone accumulation and physiological-biochemical changes of soybean during germination: Physiological-biochemical change of germinated soybean induced by UV-B.

PubMed

Ma, Meng; Wang, Pei; Yang, Runqiang; Gu, Zhenxin

2018-06-01

In this study, the effects of UV-B radiation on the isoflavones accumulation, physiological and nutritional quality, water status, and characteristics of proteins in germinated soybeans were investigated. The results showed that isoflavones content in soybeans increased with appropriate intensity and time of UV-B radiation and decreased with excessive treatment. Fresh weight, length, free amino acids, reducing sugar contents and bulk water (T 23 ) in germinated soybeans decreased with increasing radiation time, indicating that UV-B inhibited the growth and nutrients metabolism of soybean during germination. Cell damage was detected in germinated soybeans with excessive UV-B radiation, as shown by the black spots in cotyledons and the increased intercellular water determined by LF-NMR. Germination resulted in an increase in random coil structures, while UV-B radiation induced no obvious changes in FT-IR spectrum and protein conformation of soybeans. Both UV-B radiation and germination caused the increase in soluble proteins, especially in 1.0-75.0 kDa fraction. Copyright © 2018 Elsevier Ltd. All rights reserved.

Up-regulation of miR-200 and let-7 by natural agents leads to the reversal of epithelial-mesenchymal transition in gemcitabine-resistant pancreatic cancer cells

PubMed Central

Li, Yiwei; VandenBoom, Timothy G.; Kong, Dejuan; Wang, Zhiwei; Ali, Shadan; Philip, Philip A.; Sarkar, Fazlul H.

2009-01-01

Pancreatic cancer (PC) is the fourth most common cause of cancer death in the United States and the aggressiveness of PC is in part due to its intrinsic and extrinsic drug resistance characteristics, which is also associated with the acquisition of epithelial-to-mesenchymal transition (EMT). Emerging evidence also suggest that the processes of EMT is regulated by the expression status of many microRNAs (miRNAs), which are believed to function as key regulators of various biological and pathological processes during tumor development and progression. In the present study, we compared the expression of miRNAs between gemcitabine-sensitive and gemcitabine-resistant PC cells, and investigated whether the treatment of cells with “natural agents” [3,3′-diinodolylmethane (DIM) or isoflavone] could affect the expression of miRNAs. We found that the expression of miR-200b, miR-200c, let-7b, let-7c, let-7d, and let-7e was significantly down-regulated in gemcitabine-resistant cells that showed EMT characteristics such as elongated fibroblastoid morphology, lower expression of epithelial marker E-cadherin, and higher expression of mesenchymal markers such as vimentin and ZEB1. Moreover, we found that re-expression of miR-200 by transfection studies or treatment of gemcitabine-resistant cells with either DIM or isoflavone resulted in the down-regulation of ZEB1, slug, and vimentin, which was consistent with morphological reversal of EMT phenotype leading to epithelial morphology. These results provide experimental evidence, for the first time, that DIM and isoflavone could function as miRNA regulators leading to the reversal of EMT phenotype, which is likely to be important for designing novel therapies for PC. PMID:19654291

Soy isoflavone intake and stomach cancer risk in Japan: From the Takayama study.

PubMed

Wada, Keiko; Tsuji, Michiko; Tamura, Takashi; Konishi, Kie; Kawachi, Toshiaki; Hori, Akihiro; Tanabashi, Shinobu; Matsushita, Shogen; Tokimitsu, Naoki; Nagata, Chisato

2015-08-15

Although several experimental studies suggested that soy isoflavone intake inhibits the growth of stomach cancer, previous epidemiological studies have observed inconsistent results. We evaluated the associations of soy or isoflavone intake with stomach cancer incidence after considering several lifestyle factors, including salt intake, in a population-based prospective cohort study in Japan. Subjects were 14,219 men and 16,573 women aged 35 years or older in September 1992. Soy and isoflavone intakes, assessed with a validated food-frequency questionnaire, were controlled for the total energy intake. Cancer incidence was mainly confirmed through regional population-based cancer registries. Until March 2008, 441 men and 237 women developed stomach cancer. After adjustments for multiple confounders, a significantly decreased relative risk of stomach cancer was observed in the highest vs. lowest quartile of soy intake; the estimated hazard ratios were 0.71 (95% CI: 0.53, 0.96) for men (p for trend = 0.039) and 0.58 (95% CI: 0.36, 0.94) for women (p for trend = 0.003). Similar inverse associations between isoflavone intake and stomach cancer risk were also observed in women. Higher intake of non-fermented soy foods was significantly associated with a lower risk of stomach cancer (p for trend: 0.022 in men and 0.005 in women), whereas there was no significant association between the intake of fermented soy foods and a risk of stomach cancer. These results suggest that a high intake of soy isoflavone, mainly nonfermented soy foods, have a protective effect against stomach cancer. © 2015 UICC.

Isoflavones enhance interleukin-17 gene expression via retinoic acid receptor-related orphan receptors α and γ

PubMed Central

Kojima, Hiroyuki; Takeda, Yukimasa; Muromoto, Ryuta; Takahashi, Miki; Hirao, Toru; Takeuchi, Shinji; Jetten, Anton M.; Matsuda, Tadashi

2018-01-01

The retinoic acid receptor-related orphan receptors α and γ (RORα and RORγ), are key regulators of helper T (Th)17 cell differentiation, which is involved in the innate immune system and autoimmune disorders. In this study, we investigated the effects of isoflavones on RORα/γ activity and the gene expression of interleukin (IL)-17, which mediates the function of Th17 cells. In doxycycline-inducible CHO stable cell lines, we found that four isoflavones, biochanin A (BA), genistein, formononetin, and daidzein, enhanced RORα- or RORγ-mediated transcriptional activity in a dose-dependent manner. In an activation assay of the Il17a promoter using Jurkat cells, these compounds enhanced the RORα- or RORγ-mediated activation of the Il17a promoter at concentrations of 1 × 10−6 M to 1 × 10−5 M. In mammalian two-hybrid assays, the four isoflavones enhanced the interaction between the RORα- or RORγ-ligand binding domain and the co-activator LXXLL peptide in a dose-dependent manner. In addition, these isoflavones potently enhanced Il17a mRNA expression in mouse T lymphoma EL4 cells treated with phorbol myristate acetate and ionomycin, but showed slight enhancement of Il17a gene expression in RORα/γ-knockdown EL4 cells. Immunoprecipitation and immunoblotting assays also revealed that BA enhanced the interaction between RORγt and SRC-1, which is a co-activator for nuclear receptors. Taken together, these results suggest that the isoflavones have the ability to enhance IL-17 gene expression by stabilizing the interactions between RORα/γ and co-activators. This also provides the first evidence that dietary chemicals can enhance IL-17 gene expression in immune cells. PMID:25583575

Reciprocal feedback regulation of PI3K and androgen receptor signaling in PTEN-deficient prostate cancer.

PubMed

Carver, Brett S; Chapinski, Caren; Wongvipat, John; Hieronymus, Haley; Chen, Yu; Chandarlapaty, Sarat; Arora, Vivek K; Le, Carl; Koutcher, Jason; Scher, Howard; Scardino, Peter T; Rosen, Neal; Sawyers, Charles L

2011-05-17

Prostate cancer is characterized by its dependence on androgen receptor (AR) and frequent activation of PI3K signaling. We find that AR transcriptional output is decreased in human and murine tumors with PTEN deletion and that PI3K pathway inhibition activates AR signaling by relieving feedback inhibition of HER kinases. Similarly, AR inhibition activates AKT signaling by reducing levels of the AKT phosphatase PHLPP. Thus, these two oncogenic pathways cross-regulate each other by reciprocal feedback. Inhibition of one activates the other, thereby maintaining tumor cell survival. However, combined pharmacologic inhibition of PI3K and AR signaling caused near-complete prostate cancer regressions in a Pten-deficient murine prostate cancer model and in human prostate cancer xenografts, indicating that both pathways coordinately support survival. Copyright © 2011 Elsevier Inc. All rights reserved.

Red clover-derived isoflavones and mammographic breast density: a double-blind, randomized, placebo-controlled trial [ISRCTN42940165

PubMed Central

Atkinson, Charlotte; Warren, Ruth ML; Sala, Evis; Dowsett, Mitch; Dunning, Alison M; Healey, Catherine S; Runswick, Shirley; Day, Nicholas E; Bingham, Sheila A

2004-01-01

Introduction Isoflavones are hypothesized to protect against breast cancer, but it is not clear whether they act as oestrogens or anti-oestrogens in breast tissue. Our aim was to determine the effects of taking a red clover-derived isoflavone supplement daily for 1 year on mammographic breast density. Effects on oestradiol, follicle-stimulating hormone (FSH), luteinizing hormone (LH), lymphocyte tyrosine kinase activity and menopausal symptoms were also assessed. Methods A total of 205 women (age range 49–65 years) with Wolfe P2 or DY mammographic breast patterns were randomly assigned to receive either a red clover-derived isoflavone tablet (26 mg biochanin A, 16 mg formononetin, 1 mg genistein and 0.5 mg daidzein) or placebo. Change in mammographic breast density, serum oestradiol, FSH, LH, menopausal symptoms and lymphocyte tyrosine kinase activity from baseline to 12 months were assessed. Results A total of 177 women completed the trial. Mammographic breast density decreased in both groups but the difference between the treatment and placebo was not statistically significant. There was a significant interaction between treatment group and oestrogen receptor (ESR1) PvuII polymorphism for the change in estimated percentage breast density (mean ± standard deviation): TT isoflavone 1.4 ± 12.3% and TT placebo -9.6 ± 14.2%; CT isoflavone -5.2 ± 12.0% and CT placebo -2.8 ± 10.3%; and CC isoflavone -3.4 ± 9.7% and CC placebo -1.1 ± 9.5%. There were no statistically significant treatment effects on oestradiol, FSH, or LH (assessed only in postmenopausal women), or on lymphocyte tyrosine kinase activity. Baseline levels of menopausal symptoms were low, and there were no statistically significant treatment effects on frequency of hot flushes or other menopausal symptoms. Conclusion In contrast to studies showing that conventional hormone replacement therapies increase mammographic breast density, the isoflavone supplement did not increase mammographic breast density in this population of women. Furthermore, there were no effects on oestradiol, gonadotrophins, lymphocyte tyrosine kinase activity, or menopausal symptoms. PMID:15084240

[Effect of milk product with soy isoflavones on quality of life and bone metabolism in postmenopausal Spanish women: randomized trial].

PubMed

García-Martín, Antonia; Quesada Charneco, Miguel; Alvárez Guisado, Alejandro; Jiménez Moleón, José Juan; Fonollá Joya, Juristo; Muñoz-Torres, Manuel

2012-02-04

To analyze the effects of nutritional intervention with a milk product enriched with soy isoflavones on quality of life and bone metabolism in postmenopausal Spanish women. We performed a double-blind controlled randomized trial in ninety-nine postmenopausal women. Group S women (n=48) were randomized to consume milk product enriched with soy isoflavone (50 mg/day) while group C (n=51) consumed product control for 12 months. Parameters of quality of life (Cervantes scale), markers of bone metabolism and bone mass estimated by ultrasound of the calcaneus (QUS) were evaluated. Overall, there was an improvement in the domains menopause (P=.015) and vasomotor symptoms (P<.001). S group emphasized the assessment of vasomotor symptoms (P=.001) and differed positively from group C in health (P=.019), sex (P=.021) and partner (P=.002). Serum levels TRAP (P<.001) and OPG (P=.007) decreased and concentrations of 25-OH-vitamin D increased (P<.001) without differences between groups. In the assessment of QUS, there was an increase in estimated bone mineral density in group S (P=.040), whereas in group C there were no significant differences. Daily consumption of these milk products increases levels of 25-OH-vitamin D and decreases bone metabolism markers. Additional supplementation with soy isoflavones seems to improve quality of life and bone mass in Spanish postmenopausal women. Copyright © 2010 Elsevier España, S.L. All rights reserved.

A casein diet added isoflavone-enriched soy protein favorably affects biomarkers of steatohepatitis in obese Zucker rats.

PubMed

Gudbrandsen, Oddrun Anita; Wergedahl, Hege; Berge, Rolf Kristian

2009-05-01

Dietary supplementation of a soy protein enriched with isoflavones (HDI) has been shown to improve fatty liver in obese rats. The main objective of this study was to investigate whether HDI would influence the inflammatory status in livers of obese rats with fatty liver. Male obese Zucker fa/fa rats were fed casein (controls) or casein supplemented with HDI (containing 4.00 g of genistein and 4.50 g of daidzein per kilogram of diet) for 6 wk. The HDI-fed rats had a markedly lower hepatic concentration of triacylglycerol when compared with controls. The decreased aspartate transaminase/alanine transaminase ratio in plasma, together with lower circulating levels of alkaline phosphatase and bile acids after HDI feeding, implied an improved hepatitis. This was supported by decreased plasma and hepatic mRNA levels of tumor necrosis factor-alpha, lower plasma levels of interleukin-1beta and monocyte chemoattractant protein-1, and an increased anti-inflammatory fatty acid index in plasma. HDI also seemed to protect the rats from oxidative damage, because the level of lipid peroxides in triacylglycerol-rich lipoproteins after in vitro copper oxidation was lower for HDI-fed rats when compared with controls. These results show that isoflavone-enriched soy protein favorably affects biomarkers of hepatic inflammation in obese Zucker fa/fa rats with fatty liver. Thus, dietary soy proteins enriched in isoflavones may be a promising agent to improve steatohepatitis in patients.

Androgen Ablation Augments Prostate Cancer Vaccine Immunogenicity Only When Applied After Immunization

PubMed Central

Koh, Yi T.; Gray, Andrew; Higgins, Sean A.; Hubby, Bolyn; Kast, W. Martin

2009-01-01

Background Androgen ablation (AA) causes apoptosis of normal and neoplastic prostate cells. It is a standard treatment for advanced prostate cancer. Androgen ablation-mediated immunological effects include bone marrow hyperplasia, thymic regeneration, T and B cell lymphopoeisis and restoration of age-related peripheral T cell dysfunction. Androgens also regulate the transcription of several cytokines. Dendritic cells (DC) are the most potent antigen presenting cells that can activate antigen-specific naïve T cells. Despite myriad clinical trials involving DC-based prostate cancer immunotherapies, the effects of AA on DC function remain largely uncharacterized. Therefore, we investigated the effects of AA on DC and whether it could improve the efficacy of prostate cancer immunotherapy. Methods Cytokine expression changes due to AA were quantified by multiplex ELISA. Flow cytometry was used to assess AA-mediated effects on DC maturation and expression of costimulatory markers. Mixed leukocyte reactions and cell-mediated lysis assays elucidated the role of androgens in DC function. The effect of AA on the efficacy of vaccination against a prostate tumor-associated antigen was tested using Elispot assays. Results Androgen ablation increased dendritic cell maturation and costimulatory marker expression, but had no effect on DC costimulatory function. However, DC isolated from castrated mice increased the expression of key cytokines by antigen-experienced T cells while decreasing their expression in naïve cells. Finally, androgen ablation improved immune responses to vaccination only when applied after immunization. Conclusion Androgen ablation causes differential effects of DC on primary and secondary T cell responses, thus augmenting vaccine immunogenicity only when applied after immunization. PMID:19143030

Modulation of Androgen Receptor Signaling in Hormonal Therapy-Resistant Prostate Cancer Cell Lines

PubMed Central

Marques, Rute B.; Dits, Natasja F.; Erkens-Schulze, Sigrun; van IJcken, Wilfred F. J.; van Weerden, Wytske M.; Jenster, Guido

2011-01-01

Background Prostate epithelial cells depend on androgens for survival and function. In (early) prostate cancer (PCa) androgens also regulate tumor growth, which is exploited by hormonal therapies in metastatic disease. The aim of the present study was to characterize the androgen receptor (AR) response in hormonal therapy-resistant PC346 cells and identify potential disease markers. Methodology/Principal Findings Human 19K oligoarrays were used to establish the androgen-regulated expression profile of androgen-responsive PC346C cells and its derivative therapy-resistant sublines: PC346DCC (vestigial AR levels), PC346Flu1 (AR overexpression) and PC346Flu2 (T877A AR mutation). In total, 107 transcripts were differentially-expressed in PC346C and derivatives after R1881 or hydroxyflutamide stimulations. The AR-regulated expression profiles reflected the AR modifications of respective therapy-resistant sublines: AR overexpression resulted in stronger and broader transcriptional response to R1881 stimulation, AR down-regulation correlated with deficient response of AR-target genes and the T877A mutation resulted in transcriptional response to both R1881 and hydroxyflutamide. This AR-target signature was linked to multiple publicly available cell line and tumor derived PCa databases, revealing that distinct functional clusters were differentially modulated during PCa progression. Differentiation and secretory functions were up-regulated in primary PCa but repressed in metastasis, whereas proliferation, cytoskeletal remodeling and adhesion were overexpressed in metastasis. Finally, the androgen-regulated genes ENDOD1, MCCC2 and ACSL3 were selected as potential disease markers for RT-PCR quantification in a distinct set of human prostate specimens. ENDOD1 and ACSL3 showed down-regulation in high-grade and metastatic PCa, while MCCC2 was overexpressed in low-grade PCa. Conclusions/Significance AR modifications altered the transcriptional response to (anti)androgens in therapy-resistant cells. Furthermore, selective down-regulation of genes involved in differentiation and up-regulation of genes promoting proliferation and invasion suggest a disturbed balance between the growth and differentiation functions of the AR pathway during PCa progression. These findings may have implications in the current treatment and development of novel therapeutical approaches for metastatic PCa. PMID:21829708

Androgen Regulation of p27 in the Normal and Neoplastic Prostate

DTIC Science & Technology

1999-09-01

IL-6 (50) or the flavanoid antioxidant silibinin (5 1) results in increased p27KIP’ expression associated with G1 arrest and neuroendocrine...Commun 257:609-614. 51. Zi X, Agarwal R 1999 Silibinin decreases prostate-specific antigen with cell growth inhibition via GI arrest, leading to

Androgen Regulation of 5α-Reductase Isoenzymes in Prostate Cancer: Implications for Prostate Cancer Prevention

PubMed Central

Li, Jin; Ding, Zhiyong; Wang, Zhengxin; Lu, Jing-Fang; Maity, Sankar N.; Navone, Nora M.; Logothetis, Christopher J.; Mills, Gordon B.; Kim, Jeri

2011-01-01

The enzyme 5α-reductase, which converts testosterone to dihydrotestosterone (DHT), performs key functions in the androgen receptor (AR) signaling pathway. The three isoenzymes of 5α-reductase identified to date are encoded by different genes: SRD5A1, SRD5A2, and SRD5A3. In this study, we investigated mechanisms underlying androgen regulation of 5α-reductase isoenzyme expression in human prostate cells. We found that androgen regulates the mRNA level of 5α-reductase isoenzymes in a cell type–specific manner, that such regulation occurs at the transcriptional level, and that AR is necessary for this regulation. In addition, our results suggest that AR is recruited to a negative androgen response element (nARE) on the promoter of SRD5A3 in vivo and directly binds to the nARE in vitro. The different expression levels of 5α-reductase isoenzymes may confer response or resistance to 5α-reductase inhibitors and thus may have importance in prostate cancer prevention. PMID:22194926

Androgens trigger different growth responses in genetically identical human hair follicles in organ culture that reflect their epigenetic diversity in life.

PubMed

Miranda, Benjamin H; Charlesworth, Matthew R; Tobin, Desmond J; Sharpe, David T; Randall, Valerie A

2018-02-01

Male sex hormones-androgens-regulate male physique development. Without androgen signaling, genetic males appear female. During puberty, increasing androgens harness the hair follicle's unique regenerative ability to replace many tiny vellus hairs with larger, darker terminal hairs ( e.g., beard). Follicle response is epigenetically varied: some remain unaffected ( e.g., eyelashes) or are inhibited, causing balding. How sex steroid hormones alter such developmental processes is unclear, despite high incidences of hormone-driven cancer, hirsutism, and alopecia. Unfortunately, existing development models are not androgen sensitive. Here, we use hair follicles to establish an androgen-responsive human organ culture model. We show that women's intermediate facial follicles respond to men's higher androgen levels by synthesizing more hair over several days, unlike donor-matched, androgen-insensitive, terminal follicles. We demonstrate that androgen receptors-androgen-activated gene transcription regulators-are required and are present in vivo within these follicles. This is the first human organ that involves multiple cell types that responds appropriately to hormones in prolonged culture, in a way which mirrors its natural behavior. Thus, intermediate hair follicles offer a hormone-switchable human model with exceptional, unique availability of genetically identical, but epigenetically hormone-insensitive, terminal follicles. This should enable advances in understanding sex steroid hormone signaling, gene regulation, and developmental and regenerative systems and facilitate better therapies for hormone-dependent disorders.-Miranda, B. H., Charlesworth, M. R., Tobin, D. J., Sharpe, D. T., Randall, V. A. Androgens trigger different growth responses in genetically identical human hair follicles in organ culture that reflect their epigenetic diversity in life.

Bypass Mechanisms of the Androgen Receptor Pathway in Therapy-Resistant Prostate Cancer Cell Models

PubMed Central

Marques, Rute B.; Dits, Natasja F.; Erkens-Schulze, Sigrun; van Weerden, Wytske M.; Jenster, Guido

2010-01-01

Background Prostate cancer is initially dependent on androgens for survival and growth, making hormonal therapy the cornerstone treatment for late-stage tumors. However, despite initial remission, the cancer will inevitably recur. The present study was designed to investigate how androgen-dependent prostate cancer cells eventually survive and resume growth under androgen-deprived and antiandrogen supplemented conditions. As model system, we used the androgen-responsive PC346C cell line and its therapy-resistant sublines: PC346DCC, PC346Flu1 and PC346Flu2. Methodology/Principal Findings Microarray technology was used to analyze differences in gene expression between the androgen-responsive and therapy-resistant PC346 cell lines. Microarray analysis revealed 487 transcripts differentially-expressed between the androgen-responsive and the therapy-resistant cell lines. Most of these genes were common to all three therapy-resistant sublines and only a minority (∼5%) was androgen-regulated. Pathway analysis revealed enrichment in functions involving cellular movement, cell growth and cell death, as well as association with cancer and reproductive system disease. PC346DCC expressed residual levels of androgen receptor (AR) and showed significant down-regulation of androgen-regulated genes (p-value = 10−7). Up-regulation of VAV3 and TWIST1 oncogenes and repression of the DKK3 tumor-suppressor was observed in PC346DCC, suggesting a potential AR bypass mechanism. Subsequent validation of these three genes in patient samples confirmed that expression was deregulated during prostate cancer progression. Conclusions/Significance Therapy-resistant growth may result from adaptations in the AR pathway, but androgen-independence may also be achieved by alternative survival mechanisms. Here we identified TWIST1, VAV3 and DKK3 as potential players in the bypassing of the AR pathway, making them good candidates as biomarkers and novel therapeutical targets. PMID:20976069

Multivalent Peptidomimetic Conjugates as Inhibitors of Androgen Receptor Function in Therapy Resistant Prostate Cancer

DTIC Science & Technology

2016-10-01

hormones that play a critical role in stimulating prostate cancer growth . Androgens activate a protein called the androgen receptor (AR), which...5-15 3 1. INTRODUCTION: Androgens are hormones that play a critical role in stimulating prostate cancer growth . Androgens...regulates genes involved in cell growth . Although powerful anti-androgen drugs can be administered to block AR action and have been used successfully to

[Soy isoflavones with supplemental calcium provide protection against the loss of bone mass and influence insulin-like growth factor (IGF)-I after ovariectomy in rat].

PubMed

Cheng, Mao-wei; Liu, Jia-fa; Yi, Guo-qin; Zhang, Xi-ping; Zhu, Qing-hua; Liu, Lie-gang

2006-09-01

To compare the effects of soy isoflavone with supplemental calcium to soy isoflavone or Ca alone on preservation of bone mineral density (BMD) and the expression of insulin-like growth factor (IGF)-I. Sprague-Dawley (SD) female Rats, 6 months old, were ovariectomized and randomized into five groups: sham-operated group (n = 10) or ovx (n = 40) group. Shams were fed a 3.272 g/kg Ca diet. Ovx rats were randomized to a 3.272 g/kg Ca diet alone (OVX) or with soy isoflavone (SI) extract (37.95 mg/kg.bw) or to a supplemental Ca diet (Ca, 4.676 g/kg) alone or a supplemental Ca diet with the isoflavone extract (SI + Ca) for 12 weeks. BMD of femur was measured by scanner of bone mineral density. The level of IGF-1 mRNA expression was measured by reverse transcriptase-polymerase chain reaction (RT-PCR), respectively. There was no significant difference between group Sham (0.267 +/- 0.008) and group SI + Ca (0.263 +/- 0.007) g/cm(2) (P > 0.05) on femur BMD of distal end. Femur BMD of distal end in group Sham and group SI + Ca was greater (P < 0.05) as compared to group OVX (0.245 +/- 0.005) g/cm(2), SI (0.258 +/- 0.011) g/cm(2) or Ca (0.255 +/- 0.004) g/cm(2), P < 0.05. The liver tissue IGF-1 mRNA contents (IGF-1 cDNA/B-actin cDNA) were significantly decreased in group Sham (0.200 +/- 0.023) g/cm(2), SI (0.278 +/- 0.019) g/cm(2), Ca (0.302 +/- 0.026) g/cm(2) or SI + Ca (0.231 +/- 0.025) g/cm(2) as compared to group OVX (0.362 +/- 0.031) g/cm(2), P < 0.05; The liver tissue IGF-1 mRNA contents (IGF-1 cDNA/B-actin cDNA) were significantly decreased in group SI + Ca (0.231 +/- 0.025) g/cm(2) compared to group SI (0.278 +/- 0.019) g/cm(2) and Ca (0.302 +/- 0.026) g/cm(2), P < 0.05. Soy isoflavones combined with supplemental Ca are more protective against the loss of femur BMD than soy isoflavones or supplemental Ca diet alone. The dose of SI (37.95 mg/kg.bw) might significantly restrain the rising of the liver tissue IGF-1 mRNA contents caused by ovariectomy.

Prostate Androgen-Regulated Mucin-Like protein 1: A Novel Regulator of Progesterone Metabolism

PubMed Central

Park, Ji Yeon; Jang, Hyein; Curry, Thomas E.; Sakamoto, Aiko

2013-01-01

The LH surge reprograms preovulatory follicular cells to become terminally differentiated luteal cells which produce high levels of progesterone and become resistant to apoptosis. PARM1 (prostate androgen regulated mucin-like protein 1) has been implicated in cell differentiation and cell survival in nonovarian cells, but little is known about PARM1 in the ovary. This study demonstrated that the LH surge induced a dramatic increase in Parm1 expression in periovulatory follicles and newly forming CL in both cycling and immature rat models. We further demonstrated that hCG increases Parm1 expression in granulosa cell cultures. The in vitro up-regulation of Parm1 expression was mediated by hCG-activated multiple signaling pathways and transcriptional activation of this gene. Parm1 knockdown increased the viability of cultured granulosa cells but resulted in a decrease in progesterone levels. The inhibitory effect of Parm1 silencing on progesterone was reversed by adenoviral mediated add-back expression of Parm1. Parm1 silencing had little effect on the expression of genes involved in progesterone biosynthesis and metabolism such as Scarb1, Ldlr, Vldlr, Scp2, Star, Cyp11a1, Hsd3b, and Srd5a1, while decreasing the expression of Akr1c3. Analyses of culture media steroid levels revealed that Parm1 knockdown had no effect on pregnenolone levels, while resulting in time-dependent decreases in progesterone and 20α-dihydroprogesterone and accelerated accumulation of 5α-pregnanediol. This study revealed that the up-regulation of Parm1 expression promotes progesterone and 20α-dihydroprogesterone accumulation in luteinizing granulosa cells by inhibiting progesterone catabolism to 5α-pregnanediol. PARM1 contributes to ovulation and/or luteal function by acting as a novel regulator of progesterone metabolism. PMID:24085821

Bioavailability, disposition, and dose-response effects of soy isoflavones when consumed by healthy women at physiologically typical dietary intakes.

PubMed

Setchell, Kenneth D R; Brown, Nadine Maynard; Desai, Pankaj B; Zimmer-Nechimias, Linda; Wolfe, Brian; Jakate, Abhijeet S; Creutzinger, Vivian; Heubi, James E

2003-04-01

The pharmacokinetics of isoflavones in 10 healthy women were determined from serum appearance/disappearance concentration profiles and urinary excretions after single-bolus ingestion of 10, 20 or 40 g of soy nuts delivering increasing amounts of the conjugated forms of daidzein (6.6, 13.2 and 26.4 mg) and genistein (9.8, 19.6 and 39.2 mg). Peak serum daidzein and genistein concentrations were attained after 4-8 h, and elimination half-lives were 8.0 and 10.1 h, respectively. There were no differences in the pharmacokinetics of daidzein and genistein between pre- and postmenopausal women, indicating absorption and disposition of isoflavones to be independent of age or menopausal status. A curvilinear relationship was observed between the bioavailability of daidzein and genistein, apparent from the area under the curve to infinity (AUC(inf)) of the serum concentration-time profiles and the amount of isoflavones ingested. The mean fraction of the isoflavones excreted in urine decreased with increasing intake when expressed as a percentage of the administered dose (63.2 +/- 8.0, 54.4 +/- 8.1 and 44.0 +/- 4.3%, respectively, for daidzein, and correspondingly, 25.2 +/- 5.3, 13.4 +/- 2.1 and 15.8 +/- 2.7% for genistein), underscoring the trend toward nonlinear pharmacokinetics. Equol was identified as a metabolite in 30% of women; it was present consistently in urine and blood from the same subjects. Its delayed appearance was consistent with colonic synthesis. On the basis of the pharmacokinetics, optimum steady-state serum isoflavone concentrations would be expected from modest intakes of soy foods consumed regularly throughout the day rather than from a single highly enriched product.

Decrease in lean body mass in men with prostate cancer receiving androgen deprivation therapy: mechanism and biomarkers.

PubMed

Hara, Noboru; Ishizaki, Fumio; Saito, Toshihiro; Nishiyama, Tsutomu; Kawasaki, Takashi; Takahashi, Kota

2013-02-01

To elucidate the mechanism of the androgen deprivation therapy (ADT)-related decrease in lean body mass (LBM). The LBM and blood samples were studied before and after 6 months of ADT in 72 patients with localized prostate cancer. The LBM was assessed using a foot-to-foot bioelectrical impedance analyzer. Before ADT, the LBM correlated with none of the serum sex steroid levels; however, it correlated closely with serum 5α-androstane-3α,17β-diol glucuronide (Spearman's rank correlation coefficient = 0.409, P = .001) and insulin-like growth factor-1 (IGF-I, Spearman's rank correlation coefficient = 0.329, P = .005). After ADT, the LBM decreased by 0.9% (P = .036), and the serum testosterone and dihydrotestosterone had decreased by 96.8% and 94.3%, respectively (P <.001 for both), and the IGF-I had increased by 11.6% (from 19.9 to 22.2 nmol/L, P = .001). The serum 1,25-dihydroxyvitamin D3 [1,25(OH)2D] levels decreased after ADT by 9.8% (from 66.2 to 59.7 pg/mL, P = .008), and the post-treatment LBM correlated inversely with 1,25(OH)2D (Spearman's rank correlation coefficient = -0.343, P = .003). The post-treatment LBM was dissociated with 5α-androstane-3α,17β-diol glucuronide and IGF-I. The pretreatment and post-treatment LBMs both correlated inversely with serum sex hormone-binding globulin (P = .024 and P = .016, respectively). The deficiency in androgen levels was suggested to be a link to the ADT-related decrease in LBM; the androgen metabolite 5α-androstane-3α,17β-diol glucuronide has a potential value for assessing the LBM in untreated men. IGF-I also promotes muscle building and is positively regulated during ADT. Sex hormone-binding globulin possibly accelerates the ADT-related decrease in LBM. Although the mechanism for the decrease in 1,25(OH)2D and its inverse correlation with LBM during ADT is unclear, 1,25(OH)2D might be a biomarker reflecting the ADT-related decrease in LBM. Copyright © 2013 Elsevier Inc. All rights reserved.

Testosterone regulation of Akt/mTORC1/FoxO3a Signaling in Skeletal Muscle

PubMed Central

White, James P.; Gao, Song; Puppa, Melissa J.; Sato, Shuichi; Welle, Stephen L.; Carson, James A.

2012-01-01

Low endogenous testosterone production, known as hypogonadism is commonly associated with conditions inducing muscle wasting. Akt signaling can control skeletal muscle mass through mTOR regulation of protein synthesis and FoxO regulation of protein degradation, and this pathway has been previously identified as a target of androgen signaling. However, the testosterone sensitivity of Akt/mTOR signaling requires further understanding in order to grasp the significance of varied testosterone levels seen with wasting disease on muscle protein turnover regulation. Therefore, the purpose of this study is to determine the effect of androgen availability on muscle Akt/mTORC1/FoxO3a regulation in skeletal muscle and cultured C2C12 myotubes. C57BL/6 mice were either castrated for 42 days or castrated and treated with the nandrolone decanoate (ND) (6 mg/kg bw/wk). Testosterone loss (TL) significantly decreased volitional grip strength, body weight, and gastrocnemius (GAS) muscle mass, and ND reversed these changes. Related to muscle mass regulation, TL decreased muscle IGF-1 mRNA, the rate of myofibrillar protein synthesis, Akt phosphorylation, and the phosphorylation of Akt targets, GSK3β, PRAS40 and FoxO3a. TL induced expression of FoxO transcriptional targets, MuRF1, atrogin1 and REDD1. Muscle AMPK and raptor phosphorylation, mTOR inhibitors, were not altered by low testosterone. ND restored IGF-1 expression and Akt/mTORC1 signaling while repressing expression of FoxO transcriptional targets. Testosterone (T) sensitivity of Akt/mTORC1 signaling was examined in C2C12 myotubes, and mTOR phosphorylation was induced independent of Akt activation at low T concentrations, while a higher T concentration was required to activate Akt signaling. Interestingly, low concentration T was sufficient to amplify myotube mTOR and Akt signaling after 24h of T withdrawal, demonstrating the potential in cultured myotubes for a T initiated positive feedback mechanism to amplify Akt/mTOR signaling. In summary, androgen withdrawal decreases muscle myofibrillar protein synthesis through Akt/mTORC1 signaling, which is independent of AMPK activation, and readily reversible by anabolic steroid administration. Acute Akt activation in C2C12 myotubes is sensitive to a high concentration of testosterone, and low concentrations of testosterone can activate mTOR signaling independent of Akt. PMID:23116773

Multivalent Peptidomimetic Conjugates as Inhibitors of Androgen Receptor Function in Therapy-Resistant Prostate Cancer

DTIC Science & Technology

2017-10-01

Requirements ........................ 5 9. Appendices ......................................................... none 1. INTRODUCTION: Androgens are ...hormones that play a critical role in stimulating prostate cancer growth. Androgens activate a protein called the androgen receptor ( AR ), which...regulates genes involved in cell growth. Although powerful anti-androgen drugs can be administered to block AR action and have been used successfully to

Efficacy and safety of a phytoestrogen preparation derived from Glycine max (L.) Merr in climacteric symptomatology: a multicentric, open, prospective and non-randomized trial.

PubMed

Albert, A; Altabre, C; Baró, F; Buendía, E; Cabero, A; Cancelo, M J; Castelo-Branco, C; Chantre, P; Duran, M; Haya, J; Imbert, P; Julía, D; Lanchares, J L; Llaneza, P; Manubens, M; Miñano, A; Quereda, F; Ribes, C; Vázquez, F

2002-03-01

A multicentric, open, prospective, observational and no-randomized clinical trial was carried out in Spain with 190 postmenopausal women receiving a soy preparation rich in isoflavones (PHYTO SOYA, capsules containing 17.5 mg isoflavones). The main object of the present study was to investigate its efficacy in alleviating the symptomatology derived from the lack of estrogen, mainly hot flushes, but also other symptoms such as sleep disorder, anxiety, depression, vaginal dryness, loss of libido and bone pain. Each patient received 35 mg isoflavones per day in two doses. During the four months' treatment, a statistically significant decrease in the number of hot flushes with PHYTO SOYA was experienced by 80.82% women; only 5,48% patients did not improve with the treatment. The average reduction was 47.8%, which is equivalent to 4 hot flushes. All the other studied parameters also showed a statistically significant decrease. No severe side-effects were reported and tolerance was excellent. Treatment with PHYTO SOYA resulted in a significant improvement of the symptomatology that accompanies the lack of estrogen during menopause.

Estrogen receptor beta-mediated proliferative inhibition and apoptosis in human breast cancer by calycosin and formononetin.

PubMed

Chen, Jian; Zhao, Xinge; Ye, Yu; Wang, Yong; Tian, Jing

2013-01-01

Calycosin and formononetin are two main components of isoflavones. In our previous studies, we have respectively reported their antitumor activities on breast cancer cell MCF-7. To further investigate the feasibility of isoflavones in clinically treating breast carcinoma, here we specifically focused on the comparison between calycosin and formononetin, along with the relevant mechanism. ER-positive (MCF-7, T-47D) and ER-negative breast cancer cells (MDA-231, MDA-435) were respectively treated with calycosin or formononetin. Cell proliferation and apoptosis were measured by MTT assay and flow cytometry. mRNA levels of ER beta (ERβ) and miR-375 were quantifed by real-time PCR. Expression of ERβ and insulin-like growth factor 1 receptor (IGF-1R), and activation of poly (ADP-ribose) polymerase 1 (PARP-1) were determined by Western blotting. Both calycosin and formononetin impaired proliferation and triggered apoptosis of ER-positive breast cancer cells (MCF-7, T-47D) in a time- and dose-dependent manner, especially in the treatment with calycosin. However, no such effect was observed in ER-negative breast cancer cells, indicating the correlation between isoflavones-induced inhibitory effect and ERs. Thus calycosin and most sensitive MCF-7 cells were used to study the relevant signaling pathway. After the treatment of calycosin, ERβ expression was significantly increased in MCF-7 cells, followed by decrease of IGF-1R, activation of PARP-1 cleavage and downregulation of miR-375. Calycosin has an advantage on inhibiting breast cancer growth in comparison with formononetin, which is obtained by ERβ-mediated regulation of IGF-1R signaling pathways and miR-375 expression. © 2014 S. Karger AG, Basel.

Up-Regulation of Follistatin-Like 1 By the Androgen Receptor and Melanoma Antigen-A11 in Prostate Cancer.

PubMed

Su, Shifeng; Parris, Amanda B; Grossman, Gail; Mohler, James L; Wang, Zengjun; Wilson, Elizabeth M

2017-04-01

High affinity androgen binding to the androgen receptor (AR) activates genes required for male sex differentiation and promotes the development and progression of prostate cancer. Human AR transcriptional activity involves interactions with coregulatory proteins that include primate-specific melanoma antigen-A11 (MAGE-A11), a coactivator that increases AR transcriptional activity during prostate cancer progression to castration-resistant/recurrent prostate cancer (CRPC). Microarray analysis and quantitative RT-PCR were performed to identify androgen-regulated MAGE-A11-dependent genes in LAPC-4 prostate cancer cells after lentivirus shRNA knockdown of MAGE-A11. Chromatin immunoprecipitation was used to assess androgen-dependent AR recruitment, and immunocytochemistry to localize an androgen-dependent protein in prostate cancer cells and tissue and in the CWR22 human prostate cancer xenograft. Microarray analysis of androgen-treated LAPC-4 prostate cancer cells indicated follistatin-like 1 (FSTL1) is up-regulated by MAGE-A11. Androgen-dependent up-regulation of FSTL1 was inhibited in LAPC-4 cells by lentivirus shRNA knockdown of AR or MAGE-A11. Chromatin immunoprecipitation demonstrated AR recruitment to intron 10 of the FSTL1 gene that contains a classical consensus androgen response element. Increased levels of FSTL1 protein in LAPC-4 cells correlated with higher levels of MAGE-A11 relative to other prostate cancer cells. FSTL1 mRNA levels increased in CRPC and castration-recurrent CWR22 xenografts in association with predominantly nuclear FSTL1. Increased nuclear localization of FSTL1 in prostate cancer was suggested by predominantly cytoplasmic FSTL1 in benign prostate epithelial cells and predominantly nuclear FSTL1 in epithelial cells in CRPC tissue and the castration-recurrent CWR22 xenograft. AR expression studies showed nuclear colocalization of AR and endogenous FSTL1 in response to androgen. AR and MAGE-A11 cooperate in the up-regulation of FSTL1 to promote growth and progression of CRPC. Prostate 77:505-516, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Effect of water-to-bean ratio on the contents and compositions of isoflavones in tofu.

PubMed

Kao, Fuh-Juin; Su, Nan-Wei; Lee, Min-Hsiung

2004-04-21

The present study investigated the changes of the bioavailable isoflavones, including daidzin, genistin, daidzein, and genistein, during the making of tofu. The amount of extracted daidzin and genistin in soy milk increased with increasing water-to-bean ratios from 5 to 9 and reached the maximum level at the ratios of 9-11. On the other hand, the amount of extracted free isoflavones (daidzein and genistein) was not affected by the water-to-bean ratio at the range of 5-11, and their extracted amounts in soy milk were 2-4-fold those in raw soybean. It is suggested that these free isoflavones are mainly derived from daidzin, genistin, malonyldaidzin, and malonylgenistin through enzymatic hydrolysis during the making of soy milk. Tofu made with water-to-bean ratios of 9:1 and 10:1 had the maximal retentions of daidzin and genistin, which were due to the fine homogeneous network microstructure that is supposed to be more effectively retained through hydrophilic interaction with protein. On the contrary, the retained amount of free isoflavones decreased significantly as the water-to-bean ratio increased from 7 to 11, due to their weakening hydrophobic interaction with protein. In this study it was found that the homogeneous microstructure of tofu improved the retention of hydrophilic daidzin and genistin and that the increased amount of drained water does not significantly reduce their retention in the final tofu products as generally imagined.

Soy isoflavones interfere with thyroid hormone homeostasis in orchidectomized middle-aged rats

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

Šošić-Jurjević, Branka, E-mail: brankasj@ibiss.bg.ac.rs; Filipović, Branko; Wirth, Eva Katrin

We previously reported that genistein (G) and daidzein (D) administered subcutaneously (10 mg/kg) induce changes in the angio-follicular units of the thyroid gland, reduce concentration of total thyroid hormones (TH) and increase thyrotropin (TSH) in serum of orchidectomized middle-aged (16-month-old) rats. To further investigate these effects, we now examined expression levels of the thyroglobulin (Tg), thyroperoxidase (Tpo), vascular endothelial growth factor A (Vegfa) and deiodinase type 1 (Dio 1) genes in the thyroid; in the pituitary, genes involved in TH feedback control (Tsh β, Dio 1, Dio 2, Trh receptor); and in the liver and kidney, expression of T{sub 3}-activatedmore » genes Dio 1 and Spot 14, as well as transthyretin (Ttr), by quantitative real-time PCR. We also analyzed TPO-immunopositivity and immunofluorescence of T{sub 4} bound to Tg, determined thyroid T{sub 4} levels and measured deiodinase enzyme activities in examined organs. Decreased expression of Tg and Tpo genes (p < 0.05) correlated with immunohistochemical staining results, and together with decreased serum total T{sub 4} levels, indicates decreased Tg and TH synthesis following treatments with both isoflavones. However, expression of Spot 14 (p < 0.05) gene in liver and kidney was up-regulated, and liver Dio 1 expression and activity (p < 0.05) increased. At the level of pituitary, no significant change in gene expression levels, or Dio 1 and 2 enzyme activities was observed. In conclusion, both G and D impaired Tg and TH synthesis, but at the same time increased tissue availability of TH in peripheral tissues of Orx middle-aged rats. - Highlights: • We tested how genistein and daidzein interfere with thyroid hormone homeostasis. • Thyroid: decreased expression of Tg and TPO genes correlated with IHC results. • Serum: total T{sub 4} reduced and TSH increased. • Liver and kidney: expression of Spot 14 and liver Dio 1 activity increased. • Pituitary: expression of T{sub 3}-regulated genes and Dio 1 and 2 activities unchanged.« less

Androgen dependent mechanisms of pro-angiogenic networks in placental and tumor development.

PubMed

Metzler, Veronika M; de Brot, Simone; Robinson, Robert S; Jeyapalan, Jennie N; Rakha, Emad; Walton, Thomas; Gardner, David S; Lund, Emma F; Whitchurch, Jonathan; Haigh, Daisy; Lochray, Jack M; Robinson, Brian D; Allegrucci, Cinzia; Fray, Rupert G; Persson, Jenny L; Ødum, Niels; Miftakhova, Regina R; Rizvanov, Albert A; Hughes, Ieuan A; Tadokoro-Cuccaro, Rieko; Heery, David M; Rutland, Catrin S; Mongan, Nigel P

2017-08-01

The placenta and tumors share important characteristics, including a requirement to establish effective angiogenesis. In the case of the placenta, optimal angiogenesis is required to sustain the blood flow required to maintain a successful pregnancy, whereas in tumors establishing new blood supplies is considered a key step in supporting metastases. Therefore the development of novel angiogenesis inhibitors has been an area of active research in oncology. A subset of the molecular processes regulating angiogenesis are well understood in the context of both early placentation and tumorigenesis. In this review we focus on the well-established role of androgen regulation of angiogenesis in cancer and relate these mechanisms to placental angiogenesis. The physiological actions of androgens are mediated by the androgen receptor (AR), a ligand dependent transcription factor. Androgens and the AR are essential for normal male embryonic development, puberty and lifelong health. Defects in androgen signalling are associated with a diverse range of clinical disorders in men and women including disorders of sex development (DSD), polycystic ovary syndrome in women and many cancers. We summarize the diverse molecular mechanisms of androgen regulation of angiogenesis and infer the potential significance of these pathways to normal and pathogenic placental function. Finally, we offer potential research applications of androgen-targeting molecules developed to treat cancer as investigative tools to help further delineate the role of androgen signalling in placental function and maternal and offspring health in animal models. Copyright © 2017 Elsevier Ltd. All rights reserved.

SREBF1 Activity is Regulated by an AR/mTOR Nuclear Axis in Prostate Cancer.

PubMed

Audet-Walsh, Etienne; Vernier, Mathieu; Yee, Tracey; Laflamme, Chloe E; Li, Susan; Chen, Yonghong; Giguere, Vincent

2018-05-21

Reprogramming of cellular metabolism is an important feature of prostate cancer (PCa), including altered lipid metabolism. Recently, it was observed that the nuclear fraction of mTOR is essential for the androgen-mediated metabolic reprogramming of PCa cells. Herein, it is demonstrated that the androgen receptor (AR) and mTOR bind to regulatory regions of sterol regulatory element binding transcription factor 1 (SREBF1) to control its expression, while dual activation of these signaling pathways also promotes SREBF1 cleavage and its translocation to the nucleus. Consequently, SREBF1 recruitment to regulatory regions of its target genes is induced upon treatment with the synthetic androgen R1881, an effect abrogated upon inhibition of the mTOR signaling pathway. In turn, pharmacological and genetic inhibition of SREBF1 activity impairs the androgen-mediated induction of the key lipogenic genes fatty acid synthase (FASN) and stearoyl-CoA desaturase (SCD1). Consistent with these observations, the expression of SREBF1, FASN and SCD1 is significantly correlated in human PCa tumor clinical specimens. Functionally, blockade of SREBF1 activity reduces the androgen-driven lipid accumulation. Interestingly, decreased triglyceride accumulation observed upon SREBF1 inhibition is paralleled by an increase in mitochondrial respiration, indicating a potential rewiring of citrate metabolism in PCa cells. Altogether, these data define an AR/mTOR nuclear axis, in the context of PCa, as a novel pathway regulating SREBF1 activity and citrate metabolism. The finding that an AR/mTOR complex promotes SREBP expression and activity enhances our understanding of the metabolic adaptation necessary for prostate cancer cell growth and suggests novel therapeutic approaches to target metabolic vulnerabilities in tumors. Copyright ©2018, American Association for Cancer Research.

Gain in Transcriptional Activity by Primate-specific Coevolution of Melanoma Antigen-A11 and Its Interaction Site in Androgen Receptor*

PubMed Central

Liu, Qiang; Su, Shifeng; Blackwelder, Amanda J.; Minges, John T.; Wilson, Elizabeth M.

2011-01-01

Male sex development and growth occur in response to high affinity androgen binding to the androgen receptor (AR). In contrast to complete amino acid sequence conservation in the AR DNA and ligand binding domains among mammals, a primate-specific difference in the AR NH2-terminal region that regulates the NH2- and carboxyl-terminal (N/C) interaction enables direct binding to melanoma antigen-A11 (MAGE-11), an AR coregulator that is also primate-specific. Human, mouse, and rat AR share the same NH2-terminal 23FQNLF27 sequence that mediates the androgen-dependent N/C interaction. However, the mouse and rat AR FXXLF motif is flanked by Ala33 that evolved to Val33 in primates. Human AR Val33 was required to interact directly with MAGE-11 and for the inhibitory effect of the AR N/C interaction on activation function 2 that was relieved by MAGE-11. The functional importance of MAGE-11 was indicated by decreased human AR regulation of an androgen-dependent endogenous gene using lentivirus short hairpin RNAs and by the greater transcriptional strength of human compared with mouse AR. MAGE-11 increased progesterone and glucocorticoid receptor activity independently of binding an FXXLF motif by interacting with p300 and p160 coactivators. We conclude that the coevolution of the AR NH2-terminal sequence and MAGE-11 expression among primates provides increased regulatory control over activation domain dominance. Primate-specific expression of MAGE-11 results in greater steroid receptor transcriptional activity through direct interactions with the human AR FXXLF motif region and indirectly through steroid receptor-associated p300 and p160 coactivators. PMID:21730049

Selective Androgen Receptor Downregulators (SARDs): A New Prostate Cancer Therapy

DTIC Science & Technology

2006-10-01

of the androgen receptor messenger RNA and functional inhibition of androgen receptor activity by a hammerhead ribozyme . Mol Endocrinol, 12: 1558...cleavage of the androgen receptor messenger RNA and functional inhibition of androgen receptor activity by a hammerhead ribozyme . Mol Endocrinol...used to down-regulate the AR include antisense oligonucleotides (9, 10), ribozyme treatments (11, 12), AR dominant negatives (13) and small

Overexpression of HepaCAM inhibits cell viability and motility through suppressing nucleus translocation of androgen receptor and ERK signaling in prostate cancer.

PubMed

Song, Xuedong; Wang, Yin; Du, Hongfei; Fan, Yanru; Yang, Xue; Wang, Xiaorong; Wu, Xiaohou; Luo, Chunli

2014-07-01

HepaCAM is suppressed in a variety of human cancers, and involved in cell adhesion, growth, migration, invasion, and survival. However, the expression and function of HepaCAM in prostate cancer are still unknown. HepaCAM expression has been detected by RT-PCR, Western blotting and immunohistochemistry staining in prostate cell lines RWPE-1, LNCap, DU145, PC3, and in 75 human prostate tissue specimens, respectively. Meanwhile, the cell proliferation ability was detected by WST-8 assay. The role of HepaCAM in prostate cancer cell migration and invasion was examined by wound healing and transwell assay. And flow cytometry was used to observe the apoptosis of prostate cancer cells. Then we detected changes of Androgen Receptor translocation and ERK signaling using immunofluorescence staining and western blot after overexpression of HepaCAM. The HepaCAM expression was significantly down-regulated in prostate cancer tissues and undetected in prostate cancer cells. However, the low HepaCAM expression was not statistically associated with clinicopathological characteristics of prostate cancer. Overexpression of HepaCAM in prostate cancer cells decreased the cell proliferation, migration and invasion, and induced the cell apoptosis. Meanwhile, HepaCAM prevented the androgen receptor translocation from the cytoplasm to the nucleus and down-regulated the MAPK/ERK signaling. Our results suggested that HepaCAM acted as a tumor suppressor in prostate cancer. HepaCAM inhibited cell viability and motility which might be through suppressing the nuclear translocation of Androgen Receptor and down-regulating the ERK signaling. Therefore, it was indicated that HepaCAM may be a potential therapeutic target for prostate cancer. © 2014 Wiley Periodicals, Inc.

Expression and potential role of the peptide orexin-A in prostate cancer

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

Valiante, Salvatore; Liguori, Giovanna; Tafuri, Simona

The peptides orexin-A and orexin-B and their G protein-coupled OX1 and OX2 receptors are involved in multiple physiological processes in the central nervous system and peripheral organs. Altered expression or signaling dysregulation of orexins and their receptors have been associated with a wide range of human diseases including narcolepsy, obesity, drug addiction, and cancer. Although orexin-A, its precursor molecule prepro-orexin and OX1 receptor have been detected in the human normal and hyperplastic prostate tissues, their expression and function in the prostate cancer (PCa) remains to be addressed. Here, we demonstrate for the first time the immunohistochemical localization of orexin-A inmore » human PCa specimens, and the expression of prepro-orexin and OX1 receptor at both protein and mRNA levels in these tissues. Orexin-A administration to the human androgen-dependent prostate carcinoma cells LNCaP up-regulates OX1 receptor expression resulting in a decrease of cell survival. Noteworthy, nanomolar concentrations of the peptide counteract the testosterone-induced nuclear translocation of the androgen receptor in the cells: the orexin-A action is prevented by the addition of the OX1 receptor antagonist SB-408124 to the test system. These findings indicate that orexin-A/OX1 receptor interaction interferes with the activity of the androgen receptor which regulates PCa onset and progression, thus suggesting that orexin-A and its receptor might represent novel therapeutic targets to challenge this aggressive cancer. - Highlights: • Orexin-A and OX1 receptor are present in human cancer prostate tissues. • Orexin-A up-regulates OX1 receptor expression in LNCaP cells. • Orexin-A inhibits testosterone-induced nuclear translocation of androgen receptor.« less

Lesson learned from nature for the development of novel anti-cancer agents: implication of isoflavone, curcumin, and their synthetic analogs.

PubMed

Sarkar, Fazlul H; Li, Yiwei; Wang, Zhiwei; Padhye, Subhash

2010-06-01

In recent years, naturally occurring dietary compounds have received greater attention in the field of cancer prevention and treatment research. Among them, isoflavone genistein and curcumin are very promising anti-cancer agents because of their non-toxic and potent anti-cancer properties. However, it is important to note that the low water solubility, poor in vivo bioavailability and unacceptable pharmacokinetic profile of these natural compounds limit their efficacy as anti-cancer agents for solid tumors. Therefore, the development of synthetic analogs of isoflavone and curcumin based on the structure-activity assay, and the encapsulation of isoflavone and curcumin with liposome or nanoparticle for enhancing the anti-tumor activity of these natural agents, is an exciting area of research. Emerging in vitro and in vivo studies clearly suggest that these analogs and formulations of natural compounds could be much more potent for the prevention and/or treatment of various cancers. In this review article, we will summarize the current knowledge regarding the anti-cancer effect of natural compounds and their analogs, the regulation of cell signaling by these agents, and the structure-activity relationship for better design of novel anti-cancer agents, which could open newer avenues for the prevention of tumor progression and/or treatment of human malignancies.

Lesson Learned from Nature for the Development of Novel Anti-Cancer Agents: Implication of Isoflavone, Curcumin, and their Synthetic Analogs

PubMed Central

Sarkar, Fazlul H.; Li, Yiwei; Wang, Zhiwei; Padhye, Subhash

2011-01-01

In recent years, naturally occurring dietary compounds have received greater attention in the field of cancer prevention and treatment research. Among them, isoflavone genistein and curcumin are very promising anti-cancer agents because of their non-toxic and potent anti-cancer properties. However, it is important to note that the low water solubility, poor in vivo bioavailability and unacceptable pharmacokinetic profile of these natural compounds limit their efficacy as anti-cancer agents for solid tumors. Therefore, the development of synthetic analogs of isoflavone and curcumin based on the structure-activity assay, and the encapsulation of isoflavone and curcumin with liposome or nanoparticle for enhancing the anti-tumor activity of these natural agents, is an exciting area of research. Emerging in vitro and in vivo studies clearly suggest that these analogs and formulations of natural compounds could be much more potent for the prevention and/or treatment of various cancers. In this review article, we will summarize the current knowledge regarding the anti-cancer effect of natural compounds and their analogs, the regulation of cell signaling by these agents, and the structure-activity relationship for better design of novel anti-cancer agents, which could open newer avenues for the prevention of tumor progression and/or treatment of human malignancies. PMID:20345353

High-content screening identifies Src family kinases as potential regulators of AR-V7 expression and androgen-independent cell growth

PubMed Central

Szafran, Adam T.; Stephan, Cliff; Bolt, Michael; Mancini, Maureen G.; Marcelli, Marco; Mancini, Michael A.

2018-01-01

Background AR-V7 is an androgen receptor (AR) splice variant that lacks the ligand-binding domain and is isolated from prostate cancer cell lines. Increased expression of AR-V7 is associated with the transition from hormone-sensitive prostate cancer to more advanced castration-resistant prostate cancer (CRPC). Due to the loss of the ligand-binding domain, AR-V7 is not responsive to traditional AR-targeted therapies, and the mechanisms that regulate AR-V7 are still incompletely understood. Therefore, we aimed to explore existing classes of small molecules that may regulate AR-V7 expression and intracellular localization and their potential therapeutic role in CRPC. Methods We used AR high-content analysis (AR-HCA) to characterize the effects of a focused library of well-characterized clinical compounds on AR-V7 expression at the single-cell level in PC3 prostate cancer cells stably expressing green fluorescent protein (GFP)-AR-V7 (GFP-AR-V7:PC3). In parallel, an orthogonal AR-HCA screen of a small interfering (si)RNA library targeting 635 protein kinases was performed in GFP-AR-V7:PC3. The effect of the Src-Abl inhibitor PD 180970 was further characterized using cell-proliferation assays, quantitative PCR, and western blot analysis in multiple hormone-sensitive and CRPC cell lines. Results Compounds that tended to target Akt, Abl, and Src family kinases (SFKs) decreased overall AR-V7 expression, nuclear translocation, absolute nuclear level, and/or altered nuclear distribution. We identified 20 protein kinases that, when knocked down, either decreased nuclear GFP-AR-V7 levels or altered AR-V7 nuclear distribution, a set that included the SFKs Src and Fyn. The Src-Abl dual kinase inhibitor PD180970 decreased expression of AR-V7 by greater than 46% and decreased ligand-independent transcription of AR target genes in the 22RV1 human prostate carcinoma cell line. Further, PD180970 inhibited androgen-independent cell proliferation in endogenous–AR-V7–expressing prostate cancer cell lines and also overcame bicalutamide resistance observed in the 22RV1 cell line. Conclusions SFKs, especially Src and Fyn, may be important upstream regulators of AR-V7 expression and represent promising targets in a subset of CRPCs expressing high levels of AR-V7. PMID:27699828

Selective Androgen Receptor Down-Regulators (SARDs): A New Prostate Cancer Therapy

DTIC Science & Technology

2007-10-01

PCa (9). Thus far, the techniques that have been used to down-regulate the AR include antisense oligonucleotides (10, 11), ribozyme treatments (12...Our findings suggest that ICI may present a useful treatment option for patients with AR-dependent PCa. Unlike the ribozyme , antisense, siRNA, or...Catalytic cleavage of the androgen receptor messenger RNA and functional inhibition of androgen receptor activity by a hammerhead ribozyme . Mol Endocrinol

Hypochlorite Oxidation of Select Androgenic Steroids

EPA Science Inventory

Steroid hormones are vital for regulation of various biological functions including sexual development. Elevated concentrations of natural and synthetic androgenic steroids have been shown to adversely affect normal development in indigenous aqueous species. Androgens and their s...

Determination of Total Soy Isoflavones in Dietary Supplements, Supplement Ingredients, and Soy Foods by High-Performance Liquid Chromatography with Ultraviolet Detection: Collaborative Study

PubMed Central

Collison, Mark W.

2008-01-01

An interlaboratory study was conducted to evaluate a method for determining total soy isoflavones in dietary supplements, dietary supplement ingredients, and soy foods. Isoflavones were extracted using aqueous acetonitrile containing a small amount of dimethylsulfoxide (DMSO) and all 12 of the naturally occuring isoflavones in soy were determined by high-performance liquid Chromatography (HPLC) with UV detection using apigenin as an internal standard. Fifteen samples (6 pairs of blind duplicates plus 3 additional samples) of soy isoflavone ingredients, soy isoflavone dietary supplements, soy flour, and soy protein products were successfully analyzed by 13 collaborating laboratories in 6 countries. For repeatability, the relative standard deviations (RSDr) ranged from 1.07 for samples containing over 400 mg/g total isoflavones to 3.31 for samples containing 0.87 mg/g total isoflavones, and for reproducibility the RSDR values ranged from 2.29 for samples containing over 400 mg/g total isoflavones to 9.36 for samples containing 0.87 mg/g total isoflavones. HorRat values ranged from 1.00 to 1.62 for all samples containing at least 0.8 mg/g total isoflavones. One sample, containing very low total isoflavones (<0.05 mg/g), gave RSDR values of 175 and a HorRat value of 17.6. This sample was deemed to be below the usable range of the method. The method provides accurate and precise results for analysis of soy isoflavones in dietary supplements and soy foods. PMID:18567292

Determination of total soy isoflavones in dietary supplements, supplement ingredients, and soy foods by high-performance liquid chromatography with ultraviolet detection: collaborative study.

PubMed

Collison, Mark W

2008-01-01

An interlaboratory study was conducted to evaluate a method for determining total soy isoflavones in dietary supplements, dietary supplement ingredients, and soy foods. Isoflavones were extracted using aqueous acetonitrile containing a small amount of dimethylsulfoxide (DMSO) and all 12 of the naturally occuring isoflavones in soy were determined by high-performance liquid chromatography (HPLC) with UV detection using apigenin as an internal standard. Fifteen samples (6 pairs of blind duplicates plus 3 additional samples) of soy isoflavone ingredients, soy isoflavone dietary supplements, soy flour, and soy protein products were successfully analyzed by 13 collaborating laboratories in 6 countries. For repeatability, the relative standard deviations (RSDr) ranged from 1.07 for samples containing over 400 mglg total isoflavones to 3.31 for samples containing 0.87 mg/g total isoflavones, and for reproducibility the RSDR values ranged from 2.29 for samples containing over 400 mg/g total isoflavones to 9.36 for samples containing 0.87 mg/g total isoflavones. HorRat values ranged from 1.00 to 1.62 for all samples containing at least 0.8 mg/g total isoflavones. One sample, containing very low total isoflavones (< 0.05 mg/g), gave RSDR values of 175 and a HorRat value of 17.6. This sample was deemed to be below the usable range of the method. The method provides accurate and precise results for analysis of soy isoflavones in dietary supplements and soy foods.

[Soya isoflavones and evidences on cardiovascular protection].

PubMed

González Cañete, Natalia; Durán Agüero, Samuel

2014-06-01

Soya isoflavones represent a group of non-nutritive, bioactive compounds, of non-steroidal phenolic nature that are present in soy bean and derived foods. They share with other compounds the capacity of binding to estrogenic receptors from different cells and tissues so that they may act as phytoestrogens. The current interest in these compounds comes from the knowledge that in Asian populations with high levels of their consumption the prevalence of cancer and cardiovascular disease is lower, as compared to the Western countries populations. This cardiovascular benefit would be the result not only of the modulation of plasma lipids, which is a widely studied mechanism. This paper reviews the published evidence about the beneficial effects of soya isoflavones and the different mechanisms of action that would benefit cardiovascular health and that surpass the mechanisms traditionally approached such as the modulation of plasma lipids, and that implicate the regulation of cellular and enzymatic functions in situations such as inflammation, thrombosis, and atherosclerotic progression. Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.

A MATHEMATICAL MODEL FOR THE ANDROGENIC REGULATION OF THE PROSTATE IN INTACT AND CASTRATE ADULT MALE RATS

EPA Science Inventory

An abstract that provides understanding for a mathematical model by Barton and Anderson, for the dynamics of androgenic synthesis, transport, metabolism, and regulation of the rodent ventral prostate.

Human Prostatic Acid Phosphatase: Structure, Function and Regulation

PubMed Central

Muniyan, Sakthivel; Chaturvedi, Nagendra K.; Dwyer, Jennifer G.; LaGrange, Chad A.; Chaney, William G.; Lin, Ming-Fong

2013-01-01

Human prostatic acid phosphatase (PAcP) is a 100 kDa glycoprotein composed of two subunits. Recent advances demonstrate that cellular PAcP (cPAcP) functions as a protein tyrosine phosphatase by dephosphorylating ErbB-2/Neu/HER-2 at the phosphotyrosine residues in prostate cancer (PCa) cells, which results in reduced tumorigenicity. Further, the interaction of cPAcP and ErbB-2 regulates androgen sensitivity of PCa cells. Knockdown of cPAcP expression allows androgen-sensitive PCa cells to develop the castration-resistant phenotype, where cells proliferate under an androgen-reduced condition. Thus, cPAcP has a significant influence on PCa cell growth. Interestingly, promoter analysis suggests that PAcP expression can be regulated by NF-κB, via a novel binding sequence in an androgen-independent manner. Further understanding of PAcP function and regulation of expression will have a significant impact on understanding PCa progression and therapy. PMID:23698773

Soy isoflavones inducing overt hypothyroidism in a patient with chronic lymphocytic thyroiditis: a case report.

PubMed

Nakamura, Yuya; Ohsawa, Isao; Goto, Yoshikazu; Tsuji, Mayumi; Oguchi, Tatsunori; Sato, Naoki; Kiuchi, Yuji; Fukumura, Motonori; Inagaki, Masahiro; Gotoh, Hiromichi

2017-09-05

Many people have thyroid conditions that make them susceptible to hypothyroidism. If the foods they eat may interfere with the production of thyroid hormone, which can lead to development of serious hypothyroidism. The danger of health drinks should always be noted. A 72-year-old Japanese woman was previously diagnosed with chronic lymphocytic thyroiditis caused by a goiter and had an elevated thyroid-stimulating hormone level (6.56 μIU/ml), a high anti-thyroid peroxidase antibody level (>600 IU/ml), and a high antithyroglobulin level (> 4000 IU/ml) but normal levels of free triiodothyronine (3.08 pg/ml) and thyroxine (1.18 ng/ml). She presented to our hospital with sudden-onset general malaise, edema, and hoarseness with an elevated thyroid-stimulating hormone (373.3 μIU/ml) level and very low triiodothyronine (< 0.26 pg/ml) and thyroxine (0.10 ng/ml) levels. It was determined that for 6 months she had been consuming a processed, solved health drink ("barley young leaf") in amounts of 9 g/day, which included soybean and kale powder extract. Hypothyroidism might be affected by ingredients of health drinks. She discontinued consumption of the health drink immediately and began taking 12.5 μg of levothyroxine. The amount of levothyroxine was gradually increased every 3 days up to 100 μg. At day 61, her thyroid-stimulating hormone level had decreased (6.12 μIU/ml), her free triiodothyronine (2.69 pg/ml) and thyroxine (1.56 ng/ml) levels had increased, and her general condition was improved. Among risky foods lowering thyroid function, some experimental studies have revealed that isoflavones reduce thyroid function. Therefore, we measured the presence of isoflavones in the patient's frozen serum with thin-layer chromatography. After she discontinued consumption of the health drink, two components quickly disappeared, and the other three components gradually decreased. On the basis of developing solvent composition and a positive ferric chloride reaction in thin-layer chromatography experiment, the five ingredients that disappeared or decreased were highly suspected to be soy isoflavones. This case emphasizes that consuming health drinks that include soy isoflavone powder extracts can lead to severe hypothyroidism.

SYSTEMS MODELING OF PROSTATE REGULATION AND ...

EPA Pesticide Factsheets

The prostate is an androgen-dependent tissue that is an important site of disease in human males as well as an important indicator of androgen status in animals. The rat prostate is used for studying antiandrogenic drugs as well as for evaluation of endocrine disruption (e.g., Hershberger Assay). Pubertal changes in the prostate have been observed to be as sensitive to environmental antiandrogens as in utero effects. The goal of this research is to model the biology of prostate androgen function on a systems level to determine the factors responsible for the dose-response observable with androgens and antiandrogens in the male rat. This includes investigation of the roles of positive and negative feedback loops in prostatic response following castration and dosing with testosterone and/or antiandrogens. A biologically-based, systems-level model will be developed describing the regulation of the prostate by androgens. The model will extend an existing model for the male rat central axis, which describes feedback between luteinizing hormone and testosterone production in the testes, to include the prostate and conversion of testosterone to dihydrotestosterone (DHT). The prostate model will describe binding of androgens to the androgen receptor, 5α-reductase catalyzed production of DHT, and gene regulation affecting cell proliferation, apoptosis, and prostatic fluid production. The model will combine pharmacokinetic models for endogenous hormones (i.e., testost

Exploring Androgen-Regulated Pathways in Teleost Fish Using Transcriptomics and Proteomics

PubMed Central

Martyniuk, Christopher J.; Denslow, Nancy D.

2012-01-01

In the environment, there are aquatic pollutants that disrupt androgen signaling in fish. Laboratory and field-based experiments have utilized omics technologies to characterize the molecular mechanisms underlying androgen-receptor agonism/antagonism. Transcriptomics and proteomics studies with 17β-trenbolone, a growth-promoting pharmaceutical found in water systems surrounding cattle feed lots, and androgens such as 17α-methyltestosterone and 17α-methyldihydrotestosterone, have been conducted in ovary and liver of fish that include the fathead minnow (FHM) (Pimephales promelas), common carp (Cyprinus carpio), Qurt medaka (Oryzias latipes), and zebrafish (Danio rerio). In this mini-review, we survey recent omics studies in fish and reveal that, despite the diversity of species and tissues examined, there are common cellular responses that are observed with waterborne androgenic treatments. Recurring themes in gene ontology include apoptosis, transport and oxidation of lipids, synthesis and transport of hormones, immune response, protein metabolism, and cell proliferation. However, we also discuss other mechanisms other than androgen receptor (AR) activation, such as responses to toxicant stress, estrogen receptor agonism, aromatization of androgens into estrogens, and inhibitory feedback mechanisms by high levels of androgens that may also explain molecular responses in fish. To further explore androgen-responsive protein networks, a sub-network enrichment analysis was performed on protein data collected from the livers of female FHMs exposed to 17β-trenbolone. We construct a putative AR-regulated protein/cell process network in the liver that includes B-lymphocyte differentiation, xenobiotic clearance, low-density lipoprotein oxidation, proliferation of smooth muscle cells, and permeability of blood vessels. We demonstrate that construction of protein networks can offer insight into cell processes that are potentially regulated by androgens. PMID:22596056

A Multiscale, Mechanism-Driven, Dynamic Model for the Effects of 5α-Reductase Inhibition on Prostate Maintenance

PubMed Central

Zager, Michael G.; Barton, Hugh A.

2012-01-01

A systems-level mathematical model is presented that describes the effects of inhibiting the enzyme 5α-reductase (5aR) on the ventral prostate of the adult male rat under chronic administration of the 5aR inhibitor, finasteride. 5aR is essential for androgen regulation in males, both in normal conditions and disease states. The hormone kinetics and downstream effects on reproductive organs associated with perturbing androgen regulation are complex and not necessarily intuitive. Inhibition of 5aR decreases the metabolism of testosterone (T) to the potent androgen 5α-dihydrotestosterone (DHT). This results in decreased cell proliferation, fluid production and 5aR expression as well as increased apoptosis in the ventral prostate. These regulatory changes collectively result in decreased prostate size and function, which can be beneficial to men suffering from benign prostatic hyperplasia (BPH) and could play a role in prostate cancer. There are two distinct isoforms of 5aR in male humans and rats, and thus developing a 5aR inhibitor is a challenging pursuit. Several inhibitors are on the market for treatment of BPH, including finasteride and dutasteride. In this effort, comparisons of simulated vs. experimental T and DHT levels and prostate size are depicted, demonstrating the model accurately described an approximate 77% decrease in prostate size and nearly complete depletion of prostatic DHT following 21 days of daily finasteride dosing in rats. This implies T alone is not capable of maintaining a normal prostate size. Further model analysis suggests the possibility of alternative dosing strategies resulting in similar or greater effects on prostate size, due to complex kinetics between T, DHT and gene occupancy. With appropriate scaling and parameterization for humans, this model provides a multiscale modeling platform for drug discovery teams to test and generate hypotheses about drugging strategies for indications like BPH and prostate cancer, such as compound binding properties, dosing regimens, and target validation. PMID:22970204

Altered prostate epithelial development and IGF-1 signal in mice lacking the androgen receptor in stromal smooth muscle cells.

PubMed

Yu, Shengqiang; Zhang, Caixia; Lin, Chiu-Chun; Niu, Yuanjie; Lai, Kuo-Pao; Chang, Hong-chiang; Yeh, Shauh-Der; Chang, Chawnshang; Yeh, Shuyuan

2011-04-01

Androgens and the androgen receptor (AR) play critical roles in the prostate development via mesenchymal-epithelial interactions. Smooth muscle cells (SMC), differentiated from mesenchyme, are one of the basic components of the prostate stroma. However, the roles of smooth muscle AR in prostate development are still obscure. We established the smooth muscle selective AR knockout (SM-ARKO) mouse model using the Cre-loxP system, and confirmed the ARKO efficiency at RNA, DNA and protein levels. Then, we observed the prostate morphology changes, and determined the epithelial proliferation, apoptosis, and differentiation. We also knocked down the AR in a prostate smooth muscle cell line (PS-1) to confirm the in vivo findings and to probe the mechanism. The AR was selectively and efficiently knocked out in the anterior prostates of SM-ARKO mouse. The SM-ARKO prostates have defects with loss of infolding structures, and decrease of epithelial proliferation, but with little change of apoptosis and differentiation. The mechanism studies showed that IGF-1 expression level decreased in the SM-ARKO prostates and AR-knockdown PS-1 cells. The decreased IGF-1 expression might contribute to the defective development of SM-ARKO prostates. The AR in SMCs plays important roles in the prostate development via the regulation of IGF-1 signal. Copyright © 2010 Wiley-Liss, Inc.

Nonsteroidal Selective Androgen Receptor Modulators and Selective Estrogen Receptor β Agonists Moderate Cognitive Deficits and Amyloid-β Levels in a Mouse Model of Alzheimer’s Disease

PubMed Central

2013-01-01

Decreases of the sex steroids, testosterone and estrogen, are associated with increased risk of Alzheimer’s disease. Testosterone and estrogen supplementation improves cognitive deficits in animal models of Alzheimer’s disease. Sex hormones play a role in the regulation of amyloid-β via induction of the amyloid-β degrading enzymes neprilysin and insulin-degrading enzyme. To mimic the effect of dihydrotestosterone (DHT), we administered a selective androgen receptor agonist, ACP-105, alone and in combination with the selective estrogen receptor β (ERβ) agonist AC-186 to male gonadectomized triple transgenic mice. We assessed long-term spatial memory in the Morris water maze, spontaneous locomotion, and anxiety-like behavior in the open field and in the elevated plus maze. We found that ACP-105 given alone decreases anxiety-like behavior. Furthermore, when ACP-105 is administered in combination with AC-186, they increase the amyloid-β degrading enzymes neprilysin and insulin-degrading enzyme and decrease amyloid-β levels in the brain as well as improve cognition. Interestingly, the androgen receptor level in the brain was increased by chronic treatment with the same combination treatment, ACP-105 and AC-186, not seen with DHT or ACP-105 alone. Based on these results, the beneficial effect of the selective ERβ agonist as a potential therapeutic for Alzheimer’s disease warrants further investigation. PMID:24020966

Is the suppressive effect of cyproterone acetate on serum anti-Müllerian-hormone levels in women with polycystic ovary syndrome stronger than under oral contraceptive pill?

PubMed

Plouvier, Pauline; Peigné, Maëliss; Gronier, Héloïse; Robin, Geoffroy; Catteau-Jonard, Sophie; Dewailly, Didier

2016-08-01

To compare the suppressive effect of anti-androgen therapy by cyproterone acetate (CPA) and by oral contraceptive pill (OCP) on anti-müllerian hormone (AMH) levels in women with polycystic ovary syndrome (PCOS) in order to detect a putative direct anti-androgen effect on AMH excess. This is a prospective longitudinal study including 58 women with PCOS between January 2010 and April 2014 at the Lille University Hospital. A total of 47 women with clinical hyperandrogenism were treated by CPA (50 mg/d was administered 20 days out of 28) and 11 women with PCOS but without clinical hyperandrogenism received OCP. Serum AHM levels at baseline were similar in CPA and OCP groups (median [5-95th percentiles]: 60.4 pmol/l [25.1-200.2] versus 58 pmol/l [27.6-100], respectively, p = 0.39). After 3 months of treatment, serum AMH levels decreased significantly by 28% ± 20% and by 22% ± 27% in CPA and OCP groups, respectively. The decrease under both treatments was similar (p = 0.48). That any anti-androgen effect could be observed on AMH in our CPA group in addition to the gonadotropin-suppressing effect suggests that either androgens are not involved in AMH regulation or that they act by interfering with gonadotropin effects on granulosa cells.

The Effect of Levonorgestrel on Fibrinolytic Factors in Human Endometrial Endothelial Cells.

PubMed

Pakrashi, Tarita; Taylor, Joelle E; Nelson, Ashley; Archer, David F; Jacot, Terry

2016-11-01

The levonorgestrel-releasing intrauterine system is considered a highly effective treatment of heavy menstrual bleeding (HMB). While LNG has established effects on the stromal and glandular compartments of the endometrial tissue, its effect on the endometrial endothelial cells has not been investigated. We examined whether LNG regulates fibrinolytic factors, tissue plasminogen activator (tPA), and urokinase plasminogen activator (uPA) secreted by human endometrial endothelial cells (HEECs) and determined the steroid receptor through which LNG exerts its effect on the endothelium. The HEECs were treated with LNG or progesterone and levels of tPA and plasminogen activator inhibitor 1 (PAI-1) measured. The HEECs were specifically examined for the presence of androgen receptors through Western blot. Levonorgestrel ± flutamide were added to HEECs and the levels of tPA and uPA were examined. An enzyme-linked immunosorbent assay performed on culture media confirmed a statistically significant decrease in tPA levels in cells treated with LNG (77.80% ± 8.0% of control; n = 5, P < .05 vs control) but not progesterone. The androgen receptor (110 kDa) was detected in HEEC lysates. The decrease in tPA was blocked by the addition of flutamide (101.3% ± 16% of control), a classic nonsteroidal androgen receptor blocker. There was no change in uPA or PAI-1 levels in cells treated with LNG. Levonorgestrel decreases tPA levels through the androgen receptor in HEECs. Thus, LNG inhibits tPA secretion by the endometrial endothelial cell. This response suggests reduction in HMB with LNG-IUS could reflect an LNG-mediated promotion of hemostasis. © The Author(s) 2016.

The Early Effects of Rapid Androgen Deprivation on Human Prostate Cancer.

PubMed

Shaw, Greg L; Whitaker, Hayley; Corcoran, Marie; Dunning, Mark J; Luxton, Hayley; Kay, Jonathan; Massie, Charlie E; Miller, Jodi L; Lamb, Alastair D; Ross-Adams, Helen; Russell, Roslin; Nelson, Adam W; Eldridge, Matthew D; Lynch, Andrew G; Ramos-Montoya, Antonio; Mills, Ian G; Taylor, Angela E; Arlt, Wiebke; Shah, Nimish; Warren, Anne Y; Neal, David E

2016-08-01

The androgen receptor (AR) is the dominant growth factor in prostate cancer (PCa). Therefore, understanding how ARs regulate the human transcriptome is of paramount importance. The early effects of castration on human PCa have not previously been studied 27 patients medically castrated with degarelix 7 d before radical prostatectomy. We used mass spectrometry, immunohistochemistry, and gene expression array (validated by reverse transcription-polymerase chain reaction) to compare resected tumour with matched, controlled, untreated PCa tissue. All patients had levels of serum androgen, with reduced levels of intraprostatic androgen at prostatectomy. We observed differential expression of known androgen-regulated genes (TMPRSS2, KLK3, CAMKK2, FKBP5). We identified 749 genes downregulated and 908 genes upregulated following castration. AR regulation of α-methylacyl-CoA racemase expression and three other genes (FAM129A, RAB27A, and KIAA0101) was confirmed. Upregulation of oestrogen receptor 1 (ESR1) expression was observed in malignant epithelia and was associated with differential expression of ESR1-regulated genes and correlated with proliferation (Ki-67 expression). This first-in-man study defines the rapid gene expression changes taking place in prostate cancer (PCa) following castration. Expression levels of the genes that the androgen receptor regulates are predictive of treatment outcome. Upregulation of oestrogen receptor 1 is a mechanism by which PCa cells may survive despite castration. Copyright © 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Multivalent Peptidomimetic Conjugates as Inhibitors of Androgen Receptor Function in Therapy-Resistant Prostate Cancer

DTIC Science & Technology

2016-10-01

STATEMENT: Approved for Public Release; Distribution Unlimited The views, opinions and/or findings contained in this report are those of the author...Androgens are hormones that play a critical role in stimulating prostate cancer growth. Androgens activate a protein called the androgen receptor ( AR ), which...regulates genes involved in cell growth. Although powerful anti-androgen drugs can be administered to block AR action and have been used

14-3-3η Amplifies Androgen Receptor Actions in Prostate Cancer

PubMed Central

Titus, Mark A.; Tan, Jiann-an; Gregory, Christopher W.; Ford, O. Harris; Subramanian, Romesh R.; Fu, Haian; Wilson, Elizabeth M.; Mohler, James L.; French, Frank S.

2009-01-01

Purpose Androgen receptor (AR) abundance and AR-regulated gene expression in castration-recurrent prostate cancer (CaP) are indicative of AR activation in the absence of testicular androgen. AR transactivation of target genes in castration-recurrent CaP occurs in part through mitogen signaling that amplifies the actions of AR and its coregulators. Herein we report on the role of 14-3-3η in AR action. Experimental Design and Results AR and 14-3-3η co-localized in COS cell nuclei with and without androgen and 14-3-3η promoted AR nuclear localization in the absence of androgen. 14-3-3η interacted with AR in cell-free binding and coimmunoprecipitation assays. In the recurrent human CaP cell line, CWR-R1, native endogenous AR transcriptional activation was stimulated by 14-3-3η at low DHT concentrations and was increased by EGF. Moreover, the DHT and EGF dependent increase in AR transactivation was inhibited by a dominant negative 14-3-3η. In the CWR22 CaP xenograft model, 14-3-3η expression was increased by androgen, suggesting a feed-forward mechanism that potentiates both 14-3-3η and AR actions. 14-3-3η mRNA and protein decreased following castration of tumor bearing mice and increased in tumors of castrate mice after treatment with testosterone. CWR22 tumors that recurred 5 months after castration contained 14-3-3η levels similar to the androgen-stimulated tumors removed before castration. In a human prostate tissue microarray of clinical specimens, 14-3-3η localized with AR in nuclei and the similar amounts expressed in castration-recurrent CaP, androgen-stimulated CaP and benign prostatic hyperplasia were consistent with AR activation in recurrent CaP. Conclusion 14-3-3η enhances androgen and mitogen induced AR transcriptional activity in castration-recurrent CaP. PMID:19996220

Determination of 15 isoflavone isomers in soy foods and supplements by high-performance liquid chromatography.

PubMed

Yanaka, Kaoru; Takebayashi, Jun; Matsumoto, Teruki; Ishimi, Yoshiko

2012-04-25

Soy isoflavone is the generic name for the isoflavones found in soy. We determined the concentrations of 15 soy isoflavone species, including 3 succinyl glucosides, in 22 soy foods and isoflavone supplements by high-performance liquid chromatography (HPLC). The total isoflavone contents in 14 soy foods and 8 supplements ranged from 45 to 735 μg/g and from 1,304 to 90,224 μg/g, respectively. Higher amounts of succinyl glucosides were detected in natto, a typical fermented soy product in Japan; these ranged from 30 to 80 μg/g and comprised 4.1-10.9% of the total isoflavone content. In soy powder, 59 μg/g of succinyl glucosides were detected, equivalent to 4.6% of the total isoflavone content. These data suggest that the total isoflavone contents may be underestimated in the previous studies that have not included succinyl glucosides, especially for Bacillus subtilis -fermented soy food products.

Steroidal androgens and nonsteroidal, tissue-selective androgen receptor modulator, S-22, regulate androgen receptor function through distinct genomic and nongenomic signaling pathways.

PubMed

Narayanan, Ramesh; Coss, Christopher C; Yepuru, Muralimohan; Kearbey, Jeffrey D; Miller, Duane D; Dalton, James T

2008-11-01

Androgen receptor (AR) ligands are important for the development and function of several tissues and organs. However, the poor oral bioavailability, pharmacokinetic properties, and receptor cross-reactivity of testosterone, coupled with side effects, place limits on its clinical use. Selective AR modulators (SARMs) elicit anabolic effects in muscle and bone, sparing reproductive organs like the prostate. However, molecular mechanisms underlying the tissue selectivity remain ambiguous. We performed a variety of in vitro studies to compare and define the molecular mechanisms of an aryl propionamide SARM, S-22, as compared with dihydrotestosterone (DHT). Studies indicated that S-22 increased levator ani muscle weight but decreased the size of prostate in rats. Analysis of the upstream intracellular signaling events indicated that S-22 and DHT mediated their actions through distinct pathways. Modulation of these pathways altered the recruitment of AR and its cofactors to the PSA enhancer in a ligand-dependent fashion. In addition, S-22 induced Xenopus laevis oocyte maturation and rapid phosphorylation of several kinases, through pathways distinct from steroids. These studies reveal novel differences in the molecular mechanisms by which S-22, a nonsteroidal SARM, and DHT mediate their pharmacological effects.

Characterisation of soy isoflavones and screening for novel malonyl glycosides using high-performance liquid chromatography-electrospray ionisation-mass spectrometry.

PubMed

Gu, L; Gu, W

2001-01-01

HPLC combined with electrospray ionisation (ESI)-MS and photodiode array detection has been employed to study the isoflavone components of soy. All of the known soy isoflavones separated by HPLC were identified and characterised, and three novel isoflavones were detected and screened out. These minor isoflavones were deduced to be isomers of 6"-O-malonyl isoflavone glycosides, based on the ESI-MS and UV data, in which the malonyl group is attached at a position other than the 6" position of the glycosyl moiety of the molecule. These novel malonyl glycosides are as thermally labile as the 6"-O-malonyl glycosides, being converted into known isoflavone glycosides after heating in aqueous ethanol. The advantages of HPLC-ESI-MS in detection of novel isoflavones from plant extracts are reviewed.

Regulation of apical blebbing in the porcine epididymis.

PubMed

Hughes, Jennifer R; Berger, Trish

2018-03-01

Apical blebbing, a non-classical secretion mechanism, occurs in the mature porcine epididymis as part of its normal function. Proteins secreted by this mechanism contribute to the modification of the sperm plasma membrane during epididymal transit and are thought to contribute to acquisition of fertilizing ability. However, little is known about the regulation of this secretion mechanism in an in vivo model. Previous work demonstrated apical blebbing in the epididymis developed pubertally, suggesting androgens, sperm or other luminal factors regulated this process. Hence, the objective was to evaluate the hypothesized regulation of apical blebbing in the epididymis of pubertal boars by androgens and luminal factors. Androgen receptor blockade (flutamide) and surgical interventions (efferent duct ligation, orchidectomy or transection of the caput epididymis) were used to alter signaling, and the subsequent effects on apical blebbing were evaluated histologically. Apical blebbing was not altered by androgen receptor blockade with flutamide, but was significantly reduced 24 h after efferent duct ligation and after orchidectomy, treatments that eliminated luminal flow from the testis (P < 0.05). Like efferent duct ligation, epididymal transection altered luminal flow without removing the androgen source and significantly reduced the appearance of apical blebbing (P < 0.05). In conclusion, apical blebbing in the porcine epididymis appears to be regulated by luminal factors. © 2017 Anatomical Society.

Therapeutic targeting of angiotensin II receptor type 1 to regulate androgen receptor in prostate cancer.

PubMed

Takahashi, Satoru; Uemura, Hiroji; Seeni, Azman; Tang, Mingxi; Komiya, Masami; Long, Ne; Ishiguro, Hitoshi; Kubota, Yoshinobu; Shirai, Tomoyuki

2012-10-01

With the limited strategies for curative treatment of castration-resistant prostate cancer (CRPC), public interest has focused on the potential prevention of prostate cancer. Recent studies have demonstrated that an angiotensin II receptor blocker (ARB) has the potential to decrease serum prostate-specific antigen (PSA) level and improve performance status in CRPC patients. These facts prompted us to investigate the direct effects of ARBs on prostate cancer growth and progression. Transgenic rat for adenocarcinoma of prostate (TRAP) model established in our laboratory was used. TRAP rats of 3 weeks of age received ARB (telmisartan or candesartan) at the concentration of 2 or 10 mg/kg/day in drinking water for 12 weeks. In vitro analyses for cell growth, ubiquitylation or reporter gene assay were performed using LNCaP cells. We found that both telmisartan and candesartan attenuated prostate carcinogenesis in TRAP rats by augmentation of apoptosis resulting from activation of caspases, inactivation of p38 MAPK and down-regulation of the androgen receptor (AR). Further, microarray analysis demonstrated up-regulation of estrogen receptor β (ERβ) by ARB treatment. In both parental and androgen-independent LNCaP cells, ARB inhibited both cell growth and AR-mediated transcriptional activity. ARB also exerted a mild additional effect on AR-mediated transcriptional activation by the ERβ up-regulation. An intervention study revealed that PSA progression was prolonged in prostate cancer patients given an ARB compared with placebo control. These data provide a new concept that ARBs are promising potential chemopreventive and chemotherapeutic agents for prostate cancer. Copyright © 2012 Wiley Periodicals, Inc.

Higher bioavailability of isoflavones after a single ingestion of a soya-based supplement than a soya-based food in young healthy males.

PubMed

Vergne, Sébastien; Bennetau-Pelissero, Catherine; Lamothe, Valérie; Chantre, Philippe; Potier, Mylène; Asselineau, Julien; Perez, Paul; Durand, Marlène; Moore, Nicholas; Sauvant, Patrick

2008-02-01

Soya isoflavones, genistein and daidzein, are the focus of numerous studies investigating their potential effects on health and results remain controversial. Bioavailability is clearly a crucial factor influencing their bioefficacy and could explain these discrepancies. This study aimed at assessing: (1) the isoflavone content of sixty-nine European soya-derivative products sold on the French market; (2) the bioavailability of isoflavones comparing supplement with food. Twelve healthy volunteers were recruited in a randomized two-way crossover trial and received 35 mg isoflavones equivalent aglycone either through supplements or through cheese, both containing different patterns of isoflavone conjugates and different daidzein:genistein ratios. A specific ELISA method was used to assess the plasma and urinary concentrations of isoflavones and thus the pharmacokinetic parameters, which were then normalized to mg of each isoflavone ingested. Results showed that the normalized Cmax of daidzein (P = 0.002) and similarly the normalized AUC0 --> infinity and Cmax of genistein (P = 0.002) from soya-based capsules were higher than that from soya-based cheese. In conclusion, this work completes studies on isoflavone bioavailability and presents new data regarding isoflavone concentrations in soya-derivative products. Assuming that isoflavone conjugation patterns do not influence isoflavone bioavailability, this study shows that isoflavones contained in capsules are more bioavailable than those contained in soya-based cheese. Although the supplement is more bioavailable, the relative importance of this is difficult to interpret as there is little evidence that supplements are biologically active in human subjects to date and further studies will be necessary for this specific supplement to prove its efficacy.

Variations in isoflavone levels in soy foods and soy protein isolates and issues related to isoflavone databases and food labeling.

PubMed

Setchell, Kenneth D R; Cole, Sidney J

2003-07-02

The reliability of databases on the isoflavone composition of foods designed to estimate dietary intakes is contingent on the assumption that soy foods are consistent in their isoflavone content. To validate this, total and individual isoflavone compositions were determined by HPLC for two different soy protein isolates used in the commercial manufacture of soy foods over a 3-year period (n = 30/isolate) and 85 samples of 40 different brands of soy milks. Total isoflavone concentrations differed markedly between the soy protein isolates, varying by 200-300% over 3 years, whereas the protein content varied by only 3%. Total isoflavone content varied by up to 5-fold among different commercial soy milks and was not consistent between repeat purchases. Whole soybean milks had significantly higher isoflavone levels than those made from soy protein isolates (mean +/- SD, 63.6 +/- 21.9 mg/L, n = 43, vs 30.2 +/- 5.8 mg/L, n = 38, respectively, p < 0.0001), although some isolated soy protein-based milks were similar in content to "whole bean" varieties. The ratio of genistein to daidzein isoflavone forms was higher in isolated soy protein-based versus "whole bean" soy milks (2.72 +/- 0.24 vs 1.62 +/- 0.47, respectively, p < 0.0001), and the greatest variability in isoflavone content was observed among brands of whole bean soy milks. These studies illustrate large variability in the isoflavone content of isolated soy proteins used in food manufacture and in commercial soy milks and reinforce the need to accurately determine the isoflavone content of foods used in dietary intervention studies while exposing the limitations of food databases for estimating daily isoflavone intakes.

Epigenetic Machinery Regulates Alternative Splicing of Androgen Receptor (AR) Gene in Castration Resistant Prostate Cancer

DTIC Science & Technology

2017-09-01

AWARD NUMBER: W81XWH-16-1-0531 TITLE: Epigenetic machinery regulates alternative splicing of androgen receptor ( AR ) gene in castration...DISTRIBUTION STATEMENT: Approved for Public Release Distribution Unlimited The views, opinions and/or findings contained in this report are those of...One of the reasons for the resistance to ADT and newer anti-androgen drugs is the emergence of constitutively active AR variants ( AR -Vs) such as AR

Differential display RT PCR of total RNA from human foreskin fibroblasts for investigation of androgen-dependent gene expression

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

Nitsche, E.M.; Moquin, A.; Adams, P.S.

1996-05-03

Male sexual differentiation is a process that involves androgen action via the androgen receptor. Defects in the androgen receptor, many resulting from point mutations in the androgen receptor gene, lead to varying degrees of impaired masculinization in chromosomally male individuals. To date no specific androgen regulated morphogens involved in this process have been identified and no marker genes are known that would help to predict further virilization in infants with partial androgen insensitivity. In the present study we first show data on androgen regulated gene expression investigated by differential display reverse transcription PCR (dd RT PCR) on total RNA frommore » human neonatal genital skin fibroblasts cultured in the presence or absence of 100 nM testosterone. Using three different primer combinations, 54 cDNAs appeared to be regulated by androgens. Most of these sequences show the characteristics of expressed mRNAs but showed no homology to sequences in the database. However 15 clones with significant homology to previously cloned sequences were identified. Seven cDNAs appear to be induced by androgen withdrawal. Of these, five are similar to ETS (expression tagged sequences) from unknown genes; the other two show significant homology to the cDNAs of ubiquitin and human guanylate binding protein 2 (GBP-2). In addition, we have identified 8 cDNA clones which show homologies to other sequences in the database and appear to be upregulated in the presence of testosterone. Three differential expressed sequences show significant homology to the cDNAs of L-plastin and one to the cDNA of testican. This latter gene codes for a proteoglycan involved in cell social behavior and therefore of special interest in this context. The results of this study are of interest in further investigation of normal and disturbed androgen-dependent gene expression. 49 refs., 2 figs., 5 tabs.« less

Androgen-induced Long Noncoding RNA (lncRNA) SOCS2-AS1 Promotes Cell Growth and Inhibits Apoptosis in Prostate Cancer Cells*

PubMed Central

Misawa, Aya; Takayama, Ken-ichi; Urano, Tomohiko; Inoue, Satoshi

2016-01-01

Long noncoding RNAs (lncRNA) have been associated with the development of cancer. However, the interplay between lncRNAs and androgen receptor (AR) signaling in prostate cancer is still unclear. Here, we identified lncRNAs induced by androgen in AR-positive prostate cancer cells, where induction was abolished by AR knockdown as well as an anti-androgen, bicalutamide. By combining these data, we identified an androgen-regulated lncRNA, suppressor of cytokine signaling 2-antisense transcript 1 (SOCS2-AS1), the expression of which was higher in castration-resistant prostate cancer model cells, i.e. long-term androgen-deprived (LTAD) cells, than in parental androgen-dependent LNCaP cells. SOCS2-AS1 promoted castration-resistant and androgen-dependent cell growth. We found that SOCS2-AS1 knockdown up-regulated genes related to the apoptosis pathway, including tumor necrosis factor superfamily 10 (TNFSF10), and sensitized prostate cancer cells to docetaxel treatment. Moreover, we also demonstrated that SOCS2-AS1 promotes androgen signaling by modulating the epigenetic control for AR target genes including TNFSF10. These findings suggest that SOCS2-AS1 plays an important role in the development of castration-resistant prostate cancer by repressing apoptosis. PMID:27342777

Resveratrol, piceatannol and analogs inhibit activation of both wild-type and T877A mutant androgen receptor.

PubMed

Lundqvist, Johan; Tringali, Corrado; Oskarsson, Agneta

2017-11-01

Prostate cancer growth and progression are mainly dependent on androgens and many current prostate cancer treatment options target the synthesis or function of androgens. We have previously reported that resveratrol and synthetic analogs of resveratrol with a higher bioavailability inhibit the synthesis of androgens in human adrenocortical H295R cells. Now we have studied the antiandrogenic properties of resveratrol, piceatannol and analogs in two different prostate cell lines; LNCaP and RWPE. LNCaP carry a T877A mutation in the androgen receptor while RWPE has a wild-type androgen receptor. We found that resveratrol, piceatannol and all studied analogs were able to inhibit a dihydrotestosterone-induced activation of the androgen receptor, showing that they act as antiandrogens. In LNCaP cells, all studied compounds were able to statistically significantly decrease the androgenic signaling in concentrations ≥1μM and the synthetic analogs trimethylresveratrol (RSVTM) and tetramethylpiceatannol (PICTM) were the most potent compounds. RWPE cells were not as responsive to the studied compounds as the LNCaP cells. A statistically significant decrease in the androgenic signaling was observed at concentrations ≤5μM for most compounds and RSVTM was found to be the most potent compound. Further, we studied the effects of resveratrol, piceatannol and analogs on the levels of prostate-specific antigen (PSA) in LNCaP cells and found that all studied compounds decreased the level of PSA and that the synthetic analogs diacetylresveratrol (RSVDA), triacetylresveratrol (RSVTA) and RSVTM were the most potent compounds, decreasing the PSA level by approx. 50% at concentrations ≥10μM. In a cell-free receptor binding assay we were unable to show binding of resveratrol or analogs to the ligand binding domain of the androgen receptor, indicating that the observed effects are mediated via other mechanisms than direct ligand competition. We conclude that the resveratrol, piceatannol and analogs are highly interesting for chemoprevention of prostate cancer, since they have a high potency both as inhibitors of androgen synthesis and androgen receptor activation. Copyright © 2017 Elsevier Ltd. All rights reserved.

Equol is more active than soy isoflavone itself to compete for binding to thromboxane A(2) receptor in human platelets.

PubMed

Muñoz, Yenny; Garrido, Argelia; Valladares, Luis

2009-03-01

Several dietary intervention studies examining the health effect of soy isoflavones allude to the importance of equol in establishing the cardiovascular response to soy protein. Although, the specific mechanism by which this action occurs has not been established. The aim of this study was to investigate the inhibitory effect of soy-isoflavones and the metabolite of daidzein, equol, on agonist-induced platelet responses dependent on thromboxane A(2) (TxA(2)) receptor. Competitive radioligand binding assay was used to screen for affinity of these compounds to the TxA(2) receptor. The effect of equol on platelet activation, evaluate through of release of the ATP, by analogs of TxA(2) was analyzed. The effect of equol on platelet aggregation was investigated with ADP, U46619 (a TxA(2) mimic) and the calcium ionophore A23187. The data showed that aglycone isoflavones and equol bind to TxA(2) receptor in the micromol/L range, whereas their glucoside derivates had very low binding activity for this receptor. Under equilibrium conditions, the following order of the relative affinity in inhibiting [(3)H]-SQ29585 binding was: equol>genistein>daidzein>glycitein>genistin, daidzin, glycitin. Equol interaction was reversible and competitive for labeled-SQ29548 with not apparent decrease in the number of TxA(2) binding sites. In addition, from platelet activation studies, equol effectively inhibited ATP secretion elicited by the TxA(2) analog U46619. On the other hand, equol inhibited the platelet aggregation induced by U46619 and A23187, while it failed to inhibit that induced by ADP. The aglycone isoflavones from soy, and particularly equol, have been found to have biological effects attributable to thromboxane A(2) receptor antagonism. These findings may help elucidate how dietary isoflavone modulate platelet function and explain why soy-rich foods are claimed to have beneficial effects in the prevention of thrombotic events.

Large inter-individual variation in isoflavone plasma concentration limits use of isoflavone intake data for risk assessment

PubMed Central

van der Velpen, V; Hollman, P C; van Nielen, M; Schouten, E G; Mensink, M; van't Veer, P; Geelen, A

2014-01-01

Background/objectives: Isoflavones are present in soy foods and soy-based supplements. Despite low plasma isoflavone concentrations in the general Western population, concentrations in supplement users exceed those suggested to be beneficial for health in Asian populations, raising concerns for adverse effects. To aid risk assessment, quantification of the relation between isoflavone intake and plasma concentrations is essential. Subjects/methods: Plasma samples were collected from postmenopausal women in three placebo-controlled crossover studies with 8-week periods for supplements (two studies, ~100 mg isoflavones/day, n=88) or 4-week periods for soy foods (one study, ~48 mg isoflavones/day, n=15). Plasma isoflavone concentrations (daidzein, equol, genistein and glycitein) were quantified using high-performance liquid chromatography and electrochemical detection. The association between plasma concentrations and isoflavone intake, equol producer status, intake–producer interaction and background dietary intake was assessed based on the assumption of a log-linear relation. Results: Median plasma total isoflavone concentrations after the soy food and supplement interventions were respectively 2.16 and 3.47 μmol/l for equol producers and 1.30 and 2.39 μmol/l for non-producers. Regression analysis showed that doubling isoflavone intake increased plasma concentrations by 55–62% (±s.e. 1–2%, R2>0.87) for daidzein, genistein, equol (only for producers) and total isoflavones; for glycitein the association was weaker (15±1%, R2=0.48). Adjustments for energy, carbohydrate and fat intake did not affect these estimates. Inter-individual variation, estimated based on repeated measures in one of the studies, was 30–96%. Conclusions: Although the relation between isoflavone intake and plasma concentrations was adequately quantified, the use of isoflavone intake data for risk assessment needs caution due to large inter-individual variation in plasma concentrations. PMID:24939433

Androgens are bronchoactive drugs that act by relaxing airway smooth muscle and preventing bronchospasm.

PubMed

Montaño, Luis M; Espinoza, Julia; Flores-Soto, Edgar; Chávez, Jaime; Perusquía, Mercedes

2014-07-01

Changes in the androgen levels in asthmatic men may be associated with the severity of asthma. Androgens induce a nongenomic relaxation in airway smooth muscle, but the underlying mechanisms remain unclear. The aim of this study was to investigate the potential bronchorelaxing action of testosterone (TES) and its metabolites (5α- and 5β-dihydrotestosterone (DHT). A preventive effect on ovalbumin (OVA)-induced bronchospasm was observed in sensitized guinea pigs for each androgen. Androgens were studied in response to bronchoconstrictors: carbachol (CCh) and KCl in isolated trachea rings with and without epithelium from non-sensitized and sensitized animals as well as on OVA-induced contraction. Androgens concentration-dependently abolished the contraction in response to CCh, KCl, and OVA. There were significant differences in the sensitivity to the relaxation induced by each androgen. 5β-DHT was more potent for relaxing KCl-induced contraction, while TES and 5α-DHT were more potent for CCh- and OVA-induced contraction. No differences were found in preparations with and without epithelium or in the presence of a nitric oxide (NO) synthase inhibitor or an inhibitor of K(+) channels. These data indicate the absence of involvement of the epithelium-, NO- and K(+) channels-dependent pathway in androgen-induced relaxation. However, in dissociated tracheal myocytes loaded with the calcium-binding fluorescent dye Fura -2, physiological concentrations of androgens decreased the KCl-induced [Ca(2+)]i increment. 5β-DHT was the most potent at decreasing KCl-induced [Ca(2+)]i increment and preventing bronchospasm. We suggest that androgen-induced brochorelaxation was mediated via decreased Ca(2+) influx through L-type Ca(2+)channels but additional Ca(2+) entry blockade may be involved. Molecular changes in androgen structure may determine its preferential site of action. © 2014 Society for Endocrinology.

Aging up-regulates ARA55 in stromal cells, inducing androgen-mediated prostate cancer cell proliferation and migration.

PubMed

Zou, Qingsong; Cui, Di; Liang, Shengjie; Xia, Shujie; Jing, Yifeng; Han, Bangmin

2016-06-01

Stromal cells in the peripheral zone (PZ) of the prostate from older males (PZ-old) could significantly promote Prostate cancer (PCa) growth compared with stromal cells from young males (PZ-young). But the mechanism is still unknown. In the co-culture system with PZ-old cells, Pc3/Du145 cells showed advanced proliferation and migration after Dihydrotestosterone (DHT) incubation, but DHT didn't show the similar effect in PZ-young co-culture system. Also, higher androgen/AR signal pathway activity and AR-related cytokines secretion (FGF-2, KGF, IGF-1) were found in PZ-old cells. As AR exprssison was equivalent in PZ-old and PZ-young cells, we focused on Androgen receptor associated protein-55(ARA55), a stromal-specific androgen receptor (AR) coactivator. ARA55 expression was higher in PZ-old cells compared with PZ-young cells in vitro. After knocking down ARA55 expression in PZ-old cells, the PCa growth- promoting effect from the PZ-old cells was diminished, which may be explained by the decreased the progressive cytokines secretion (FGF-2, KGF, IGF-1) from PZ-old stromal cells. In vivo, the consistent results were also found: PZ-old cells promoted prostate cancer cells growth, but this effect receded when knocking down ARA55 expression in PZ-old cells. From our study, we found PZ stromal cells presented age-related effects in proliferation and migration of prostate cancer cells in the androgen/AR dependent manner. As aging increased, more ARA55 were expressed in PZ stromal cells, leading to more sensitive androgen/androgen receptor (AR) signal pathway, then constituting a more feasible environment to cancer cells.

Alternative male reproductive tactics and the immunocompetence handicap in the Azorean rock-pool blenny, Parablennius parvicornis

PubMed Central

Ros, Albert F.H; Bouton, Niels; Santos, Ricardo S; Oliveira, Rui F

2006-01-01

In the Azorean rock-pool blenny (Parablennius parvicornis) reproductively active males display alternative morphotypes, which differ in the expression of secondary sexual characters (SSC). Males expressing SSC, the M+ morphotype, have high androgen levels and compete for crevices that will be visited by females to spawn. M+ males holding nests court females and care for the eggs. Males with low expression of SSC, the M− morphotype, have low levels of androgens and reproduce by stealing fertilizations from the M+ males. Based on the hypothesis that androgens are immunosuppressive, we expected these morphotypes to differ in immunocompetence. To test this hypothesis, we conducted a field study in which we collected repeated blood samples to monitor leukocyte populations (blood smears), and to measure the primary antibody response of males that were experimentally challenged with a foreign non-pathogenic antigen (sheep red blood cells). Circulating levels of 11-ketotestosterone and testosterone were higher in M+ males than in M− males. Neither granulocyte nor thrombocyte counts did covariate with androgens or male tactic. In contrast, lymphocyte counts and humoral antibody response were negatively correlated with body size, and as expected, both were lower in M+ than in M− males. Interestingly, in M+ males androgen levels decreased after immunization, and this was less in nest-holder males than in M+ males that were floating around in the pools. Within each morphotype we found no relationship between androgens and immunocompetence. The latter result is not supportive for androgen regulated immunosuppression in M+ males. A possible alternative is enhancement of immunity in M− males. These males had relatively high levels of injuries in comparison with M+ males. High immunity might be a consequence of high infection rate because of such injuries. PMID:16627274

Isoflavone profile in soymilk as affected by soybean variety, grinding, and heat-processing methods.

PubMed

Zhang, Yan; Chang, Sam K C; Liu, Zhisheng

2015-05-01

Isoflavones impart health benefits and their overall content and profile in foods are greatly influenced at each step during processing. In this study, 2 soybean varieties (Prosoy and black soybean) were processed with 3 different grinding (ambient, cold, and hot grinding) and heating methods (traditional stove cooking, 1-phase UHT, and 2-phase UHT) for soymilk making. The results showed after cold, ambient, and hot grinding, the total isoflavones were 3917, 5013, and 5949 nmol/g for Prosoy; the total isoflavones were 4073, 3966, and 4284 nmol/g for black soybean. Grinding could significantly increase isoflavone extraction. The grinding process had a destructive effect on isoflavones and this effect varied with grinding temperature. Different heating methods had different effects on different isoflavone forms. Two soybean varieties showed distinct patterns with respect to the change of isoflavone profile during processing. © 2015 Institute of Food Technologists®

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.

Zebrafish (Danio rerio) androgen receptor: sequence homology and up-regulation by the fungicide vinclozolin.

PubMed

Smolinsky, Amanda N; Doughman, Jennifer M; Kratzke, Liên-Thành C; Lassiter, Christopher S

2010-03-01

Steroid hormones regulate gene expression in organisms by binding to receptor proteins. These hormones include the androgens, which signal through androgen receptors (ARs). Endocrine disrupters (EDCs) are chemicals in the environment that adversely affect organisms by binding to nuclear receptors, including ARs. Vinclozolin, a fungicide used on fruit and vegetable crops, is a known anti-androgen, a type of EDC that blocks signals from testosterone and its derivatives. In order to better understand the effects of EDCs, further research on androgen receptors and other hormone signaling pathways is necessary. In this study, we demonstrate the evolutionary conservation between the genomic structure of the human and zebrafish ar genes and find that ar mRNA expression increases in zebrafish embryos exposed to vinclozolin, which may be evolutionarily conserved as well. At 48 and 72 h post-fertilization, vinclozolin-treated embryos express ar mRNA 8-fold higher than the control level. These findings suggest that zebrafish embryos attempt to compensate for the presence of an anti-androgen by increasing the number of androgen receptors available.

Metabolite changes in nine different soybean varieties grown under field and greenhouse conditions.

PubMed

Maria John, K M; Natarajan, Savithiry; Luthria, Devanand L

2016-11-15

Global food security remains a worldwide concern due to changing climate, increasing population, and reduced agriculture acreages. Greenhouse cultivation increases productivity by extending growing seasons, reducing pest infestations and providing protection against short term drastic weather fluctuations like frost, heat, rain, and wind. In the present study, we examined and compared the metabolic responses of nine soybean varieties grown under field and greenhouse conditions. Extracts were assayed by GC-FID, GC-MS, and LC-MS for the identification of 10 primary (amino acids, organic acids, and sugars) and 10 secondary (isoflavones, fatty acid methyl esters) metabolites. Sugar molecules (glucose, sucrose, and pinitol) and isoflavone aglycons were increased but the isoflavones glucoside content decreased in the greenhouse cultivated soybeans. The amino acids and organic acids varied between the varieties. The results show that clustering (PCA and PLS-DA) patterns of soybean metabolites were significantly influenced by the genetic variation and growing conditions. Published by Elsevier Ltd.

Developing Laryngeal Muscle of Xenopus laevis as a Model System: Androgen-Driven Myogenesis Controls Fiber Type Transformation

PubMed Central

Nasipak, Brian; Kelley, Darcy B.

2014-01-01

The developmental programs that contribute to myogenic stem cell proliferation and muscle fiber differentiation control fiber numbers and twitch type. In this study, we describe the use of an experimental model system—androgen-regulated laryngeal muscle of juvenile clawed frogs, Xenopus laevis—to examine the contribution of proliferation by specific populations of myogenic stem cells to expression of the larynx-specific myosin heavy chain isoform, LM. Androgen treatment of juveniles (Stage PM0) resulted in up-regulation of an early (Myf-5) and a late (myogenin) myogenic regulatory factor; the time course of LM up-regulation tracked that of myogenin. Myogenic stem cells stimulated to proliferate by androgen include a population that expresses Pax-7, a marker for the satellite cell myogenic stem cell population. Since androgen can switch muscle fiber types from fast to slow even in denervated larynges, we developed an ex vivo culture system to explore the relation between proliferation and LM expression. Cultured whole larynges maintain sensitivity to androgen, increasing in size and LM expression. Blockade of cell proliferation with cis-platin prevents the switch from slow to fast twitch muscle fibers as assayed by ATPase activity. Blockade of cell proliferation in vivo also resulted in inhibition of LM expression. Thus, both in vivo and ex vivo, inhibition of myogenic stem cell proliferation blocks androgen-induced LM expression and fiber type switching in juveniles. PMID:21954146

Isoflavones inhibit poly(I:C)-induced serum, brain, and skin inflammatory mediators - relevance to chronic fatigue syndrome.

PubMed

Vasiadi, Magdalini; Newman, Jennifer; Theoharides, Theoharis C

2014-10-31

Chronic Fatigue Syndrome (CFS) is a neuroimmunoendocrine disease affecting about 1% of the US population, mostly women. It is characterized by debilitating fatigue for six or more months in the absence of cancer or other systemic diseases. Many CFS patients also have fibromyalgia and skin hypersensitivity that worsen with stress. Corticotropin-releasing hormone (CRH) and neurotensin (NT), secreted under stress, activate mast cells (MC) necessary for allergic reactions to release inflammatory mediators that could contribute to CFS symptoms. To investigate the effect of isoflavones on the action of polyinosinic:polycytidylic acid (poly(I:C)), with or without swim stress, on mouse locomotor activity and inflammatory mediator expression, as well as on human MC activation. Female C57BL/6 mice were randomly divided into four groups: (a) control/no-swim, (b) control/swim, (c) polyinosinic:polycytidylic acid (poly(I:C))/no swim, and (d) polyinosinic:polycytidylic acid (poly(I:C))/swim. Mice were provided with chow low or high in isoflavones for 2 weeks prior to ip injection with 20 mg/kg poly(I:C) followed or not by swim stress for 15 minutes. Locomotor activity was monitored overnight and animals were sacrificed the following day. Brain and skin gene expression, as well as serum levels, of inflammatory mediators were measured. Data were analyzed using the non-parametric Mann-Whitney U-test. Poly(I:C)-treated mice had decreased locomotor activity over 24 hours, and increased serum levels of TNF-α, IL-6, KC (IL-8/CXCL8 murine homolog), CCL2,3,4,5, CXCL10, as well as brain and skin gene expression of TNF, IL-6, KC (Cxcl1, IL8 murine homolog), CCL2, CCL4, CCL5 and CXCL10. Histidine decarboxylase (HDC) and NT expression were also increased, but only in the skin, over the same period. High isoflavone diet reversed these effects. Poly(I:C) treatment decreased mouse locomotor activity and increased serum levels and brain and skin gene expression of inflammatory mediators. These effects were inhibited by isoflavones that may prove useful in CFS.

Trichosanthes kirilowii Exerts Androgenic Activity via Regulation of PSA and KLK2 in 22Rv1 Prostate Cancer Cells.

PubMed

Jeong, Soo-Jin; Choi, Ji-Yoon; Dong, Mi-Sook; Seo, Chang-Seob; Shin, Hyeun-Kyoo

2017-01-01

The androgen comprises a group of hormones that play roles in male reproductive activity as well as personal characteristics. We investigated the androgenic activity of various herbal medicines in human prostate cancer 22Rv1 cells. Herbal extracts of Trichosanthes kirilowii (TK), Asarum sieboldii (AS), Sanguisorba officinalis (SO), and Xanthium strumarium (XS) were selected to have androgenic effects based on a preliminary in vitro screening system. TK, AS, SO, and XS enhanced the proliferation of 22Rv1 cells without having cytotoxic effects. All tested herbal extracts increased androgen receptor (AR)-induced transcriptional activity in the absence or presence of dihydrotestosterone (DHT). In an AR-binding assay, TK, but not AS, SO, or XS, produced a significant inhibition of AR binding activity, indicating it has androgenic activity. Additionally, TK treatment positively regulated mRNA expression of the AR-related molecular targets prostate-specific antigen (PSA) and kallikrein 2 (KLK2) compared with untreated control. Taken together, TK-enhanced AR-mediated transcriptional activity might be an attractive candidate drug for treating androgen-related diseases. Trichosantheskirilowii (TK), Asarumsieboldii (AS), Sanguisorbaofficinalis (SO), and Xanthium strumarium (XS) enhanced the proliferation of 22Rv1 cells without having cytotoxic effects.TK, AS, SO, and XS increased androgen receptor (AR)-induced transcriptional activity.TK, but not AS, SO, or XS, produced a significant inhibition against AR-binding activity.TK treatment positively regulated mRNA expression of the AR-related molecular targets prostate-specific antigen and kallikrein 2. Abbreviations used: BPH: benign prostatic hyperplasia; AR: androgen receptor; DHT: dihydrotestosterone; PSA: prostate-specific antigen; TK: Trichosanthes kirilowii; AS: Asarum sieboldii; SO: Sanguisorba officinalis; XS: Xanthium strumarium; ATCC: American Type Culture Collection; FBS: fetal bovine serum; PBS: phosphate-buffered saline; SD: standard deviation; ARE: androgenresponsive element; KLK: kallikrein.

An in vivo assay performed using multiple biomarkers related to testosterone synthesis and conversion for assessing the androgenic potency of refuse leachate.

PubMed

Gong, Yufeng; Tian, Hua; Dong, Yifei; Zhang, Xiaona; Wang, Wei; Ru, Shaoguo

2017-01-01

Refuse leachate is likely an important source of androgens. However, common in vitro bioassays underestimate the potential androgenic activity of leachate, owing to non-receptor-mediated mechanisms that modify the balance of sex hormones and promote the accumulation of endogenous androgens. This study aimed to develop an in vivo assay by using multiple biomarkers related to testosterone synthesis and conversion for assessing the potential androgenic activity of refuse leachate sampled from a municipal solid waste treatment plant in Qingdao, China. The results indicated that exposure to leachate increased the levels of testosterone and luteinizing hormone, but decreased those of 17β-estradiol in both male and female goldfish (Carassius auratus), suggesting a potential androgenic activity. Further, Leydig cell hyperplasia and decreased gonadal P450 aromatase mRNA levels were observed; these alterations might promote the biosynthesis of testosterone and hinder the conversion of testosterone to 17β-estradiol, which in turn enhance testosterone accumulation. Exposure to leachate also resulted in reproductive impairments, including decreased gonadosomatic index and plasma vitellogenin levels of female goldfish, as well as decreased testicular enzyme activities in male goldfish. The integrated use of biochemical, molecular, and histological markers not only improved our understanding of the androgenic effects of leachate but also verified the reliability and validity of the results. Therefore, the in vivo bioassay described in this study might allow the investigation of the androgenic effects of other complex contaminant mixtures in the future. Copyright © 2016 Elsevier Inc. All rights reserved.

Dissociable Effects on Birdsong of Androgen Signaling in Cortex-Like Brain Regions of Canaries

PubMed Central

2017-01-01

The neural basis of how learned vocalizations change during development and in adulthood represents a major challenge facing cognitive neuroscience. This plasticity in the degree to which learned vocalizations can change in both humans and songbirds is linked to the actions of sex steroid hormones during ontogeny but also in adulthood in the context of seasonal changes in birdsong. We investigated the role of steroid hormone signaling in the brain on distinct features of birdsong using adult male canaries (Serinus canaria), which show extensive seasonal vocal plasticity as adults. Specifically, we bilaterally implanted the potent androgen receptor antagonist flutamide in two key brain regions that control birdsong. We show that androgen signaling in the motor cortical-like brain region, the robust nucleus of the arcopallium (RA), controls syllable and trill bandwidth stereotypy, while not significantly affecting higher order features of song such syllable-type usage (i.e., how many times each syllable type is used) or syllable sequences. In contrast, androgen signaling in the premotor cortical-like brain region, HVC (proper name), controls song variability by increasing the variability of syllable-type usage and syllable sequences, while having no effect on syllable or trill bandwidth stereotypy. Other aspects of song, such as the duration of trills and the number of syllables per song, were also differentially affected by androgen signaling in HVC versus RA. These results implicate androgens in regulating distinct features of complex motor output in a precise and nonredundant manner. SIGNIFICANCE STATEMENT Vocal plasticity is linked to the actions of sex steroid hormones, but the precise mechanisms are unclear. We investigated this question in adult male canaries (Serinus canaria), which show extensive vocal plasticity throughout their life. We show that androgens in two cortex-like vocal control brain regions regulate distinct aspects of vocal plasticity. For example, in HVC (proper name), androgens regulate variability in syntax but not phonology, whereas androgens in the robust nucleus of the arcopallium (RA) regulate variability in phonology but not syntax. Temporal aspects of song were also differentially affected by androgen signaling in HVC versus RA. Thus, androgen signaling may reduce vocal plasticity by acting in a nonredundant and precise manner in the brain. PMID:28821656

Androgen dynamics in vitro in the human prostate gland. Effect of cyproterone and cyproterone acetate

PubMed Central

Giorgi, Eleonora P.; Shirley, I. M.; Grant, J. K.; Stewart, Joan C.

1973-01-01

Hyperplastic and adenocarcinomatous human prostatic tissue was superfused in vitro with radioactively labelled androst-4-ene-3,17-dione, testosterone and 5α-dihydrotestosterone (17β-hydroxy-5α-androstan-3-one), with and without addition of the anti-androgens cyproterone and cyproterone acetate. Cyproterone competitively inhibited the entry of the androgens into the majority of the tissues, whereas cyproterone acetate increased this entry. These findings indicated that transport of androstenedione, testosterone and 5α-dihydrotestosterone into prostatic tissue is performed by a specific mechanism, possibly involving a carrier situated in the cell membrane. The extent of metabolism of the three androgens was also modified: formation of 5α-dihydrotestosterone from testosterone, and of the latter from androstenedione, was decreased by cyproterone and increased by the acetate. Acetate was more effective than cyproterone in decreasing the `uptake' of the perfused androgens by the tissue; at the same time, it increased the androgen clearance from the tissue. As cyproterone acetate is the more potent of the two anti-androgens, the possibility that these findings in vitro are related to the different anti-androgenic potency exhibited by the two compounds in vivo is discussed. `Uptake' of the two anti-androgens and the response to their action on androgen dynamics were similar in adenocarcinomatous and hyperplastic glands. PMID:4125095

Androgen Receptor and its Splice Variant, AR-V7, Differentially Regulate FOXA1 Sensitive Genes in LNCaP Prostate Cancer Cells

PubMed Central

Krause, William C.; Shafi, Ayesha A.; Nakka, Manjula; Weigel, Nancy L.

2014-01-01

Prostate cancer (PCa) is an androgen-dependent disease, and tumors that are resistant to androgen ablation therapy often remain androgen receptor (AR) dependent. Among the contributors to castration-resistant PCa are AR splice variants that lack the ligand-binding domain (LBD). Instead, they have small amounts of unique sequence derived from cryptic exons or from out of frame translation. The AR-V7 (or AR3) variant is constitutively active and is expressed under conditions consistent with CRPC. AR-V7 is reported to regulate a transcriptional program that is similar but not identical to that of AR. However, it is unknown whether these differences are due to the unique sequence in AR-V7, or simply to loss of the LBD. To examine transcriptional regulation by AR-V7, we have used lentiviruses encoding AR-V7 (amino acids 1-627 of AR with the 16 amino acids unique to the variant) to prepare a derivative of the androgen-dependent LNCaP cells with inducible expression of AR-V7. An additional cell line was generated with regulated expression of AR-NTD (amino acids 1-660 of AR); this mutant lacks the LBD but does not have the AR-V7 specific sequence. We find that AR and AR-V7 have distinct activities on target genes that are co-regulated by FOXA1. Transcripts regulated by AR-V7 were similarly regulated by AR-NTD, indicating that loss of the LBD is sufficient for the observed differences. Differential regulation of target genes correlates with preferential recruitment of AR or AR-V7 to specific cis-regulatory DNA sequences providing an explanation for some of the observed differences in target gene regulation. PMID:25008967

Optimization of soy isoflavone extraction with different solvents using the simplex-centroid mixture design.

PubMed

Yoshiara, Luciane Yuri; Madeira, Tiago Bervelieri; Delaroza, Fernanda; da Silva, Josemeyre Bonifácio; Ida, Elza Iouko

2012-12-01

The objective of this study was to optimize the extraction of different isoflavone forms (glycosidic, malonyl-glycosidic, aglycone and total) from defatted cotyledon soy flour using the simplex-centroid experimental design with four solvents of varying polarity (water, acetone, ethanol and acetonitrile). The obtained extracts were then analysed by high-performance liquid chromatography. The profile of the different soy isoflavones forms varied with different extractions solvents. Varying the solvent or mixture used, the extraction of different isoflavones was optimized using the centroid-simplex mixture design. The special cubic model best fitted to the four solvents and its combination for soy isoflavones extraction. For glycosidic isoflavones extraction, the polar ternary mixture (water, acetone and acetonitrile) achieved the best extraction; malonyl-glycosidic forms were better extracted with mixtures of water, acetone and ethanol. Aglycone isoflavones, water and acetone mixture were best extracted and total isoflavones, the best solvents were ternary mixture of water, acetone and ethanol.

Songbird chemical signals reflect uropygial gland androgen sensitivity and predict aggression: implications for the role of the periphery in chemosignaling.

PubMed

Whittaker, Danielle J; Rosvall, Kimberly A; Slowinski, Samuel P; Soini, Helena A; Novotny, Milos V; Ketterson, Ellen D

2018-01-01

Chemical signals can provide useful information to potential mates and rivals. The production mechanisms of these signals are poorly understood in birds, despite emerging evidence that volatile compounds from preen oil may serve as chemosignals. Steroid hormones, including testosterone (T), may influence the production of these signals, yet variation in circulating T only partly accounts for this variation. We hypothesized that odor is a T-mediated signal of an individual's phenotype, regulated in part by androgen sensitivity in the uropygial gland. We quantified natural variation in chemosignals, T, uropygial gland androgen sensitivity, and aggressive behavior in dark-eyed juncos (Junco hyemalis). The interaction between circulating T and androgen receptor transcript abundance significantly correlated with volatile concentrations in male, but not female, preen oil. In both sexes, odorant variables correlated with aggressive response to an intruder. Our results suggest that preen oil volatiles could function as signals of aggressive intent, and, at least in males, may be regulated by local androgen receptor signaling in the uropygial gland. Because these behavioral and chemical traits have been linked with reproductive success, local regulation of androgen sensitivity in the periphery has the potential to be a target of selection in the evolution of avian olfactory signaling.

SOCS3 Modulates the Response to Enzalutamide and Is Regulated by Androgen Receptor Signaling and CpG Methylation in Prostate Cancer Cells.

PubMed

Handle, Florian; Erb, Holger H H; Luef, Birgit; Hoefer, Julia; Dietrich, Dimo; Parson, Walther; Kristiansen, Glen; Santer, Frédéric R; Culig, Zoran

2016-06-01

The proinflammatory cytokine IL6 is associated with bad prognosis in prostate cancer and implicated in progression to castration resistance. Suppressor of cytokine signaling 3 (SOCS3) is an IL6-induced negative feedback regulator of the IL6/Janus kinase (JAK)/STAT3 pathway. This study reveals that the SOCS3 promoter is hypermethylated in cancerous regions compared with adjacent benign tissue in prostate cancer using methylation-specific qPCR. A series of in vitro experiments was performed to assess the functional impact of low SOCS3 expression during anti-androgen treatment. Using lentivirus-mediated knockdown, it was demonstrated for the first time that SOCS3 regulates IL6/JAK/STAT3 signaling in androgen receptor-positive LNCaP cells. In addition, SOCS3 mRNA is upregulated by the anti-androgens bicalutamide and enzalutamide. This effect is caused by androgen receptor-mediated suppression of IL6ST and JAK1 expression, which leads to altered STAT3 signaling. Functionally, knockdown of SOCS3 led to enhanced androgen receptor activity after 3 weeks of enzalutamide treatment in an inflammatory setting. Furthermore, the stemness/self-renewal associated genes SOX2 and NANOG were strongly upregulated by the long-term treatment, and modulation of SOCS3 expression was sufficient to counteract this effect. These findings prove that SOCS3 plays an important role during anti-androgen treatment in an inflammatory environment. SOCS3 is frequently inactivated by promoter hypermethylation in prostate cancer, which disrupts the feedback regulation of IL6 signaling and leads to reduced efficacy of enzalutamide in the presence of inflammatory cytokines. Mol Cancer Res; 14(6); 574-85. ©2016 AACR. ©2016 American Association for Cancer Research.

Adolescent Anabolic/Androgenic Steroids: Aggression and Anxiety During Exposure Predict Behavioral Responding During Withdrawal in Syrian Hamsters (Mesocricetus auratus)

PubMed Central

Ricci, Lesley A.; Morrison, Thomas R.; Melloni, Richard H.

2014-01-01

In the U.S. and worldwide anabolic/androgenic steroid use remains high in the adolescent population. This is concerning given that anabolic/androgenic steroid use is associated with a higher incidence of aggressive behavior during exposure and anxiety during withdrawal. This study uses pubertal Syrian hamsters (Mesocricetus auratus) to investigate the hypothesis that an inverse behavioral relationship exists between anabolic/androgenic steroid-induced aggression and anxiety across adolescent exposure and withdrawal. In the first experiment, we examined aggression and anxiety during adolescent anabolic/androgenic steroid exposure and withdrawal. Adolescent anabolic/androgenic steroid administration produced significant increases in aggression and decreases in anxiety during the exposure period followed by significant decreases in aggression and increases in anxiety during anabolic/androgenic steroid withdrawal. In a second experiment, anabolic/androgenic steroid exposed animals were separated into groups based on their aggressive response during the exposure period and then tested for anxiety during exposure and then for both aggression and anxiety during withdrawal. Data were analyzed using a within subjects repeated measures predictive analysis. Linear regression analysis revealed that the difference in aggressive responding between the anabolic/androgenic steroid exposure and withdrawal periods was a significant predictor of differences in anxiety for both days of testing. Moreover, the combined data suggest that the decrease in aggressive behavior from exposure to withdrawal predicts an increase in anxiety-like responding within these same animals during this time span. Together these findings indicate that early anabolic/androgenic steroid exposure has potent aggression- and anxiety- eliciting effects and that these behavioral changes occur alongside a predictive relationship that exists between these two behaviors over time. PMID:24126136

[A study on isoflavones intake from soy foods and perimenstrual symptoms].

PubMed

Kim, Hae Won; Khil, Jin Mo

2007-04-01

This study was conducted to explore the relationship between isoflavones intake from soy foods and perimenstrual symptoms among women. The research design was a cross sectional study. Subjects consisted of 245 women living in Korea, aged 19-49 years. The measurement tools were MDQ and FFQ. Frequently consumed soy isoflavones foods were rice with soybeans, soybean paste stew, and soy paste with tofu. The amounts of soy isoflavones foods consumed in order from highest to lowest were rice with soybeans, soybean paste stew, seasoned soybean sprouts, and soy paste with tofu. Subjects were divided into three groups by isoflavones intake levels; the small intake group, moderate intake group, and large intake group. There were significant differences in some menstrual symptoms, and postmenstrual symptoms by isoflavones intake levels. In general, the moderate isoflavones intake group showed lower scores in some menstrual symptoms and postmenstrual periods compared to the small and large intake groups. These results suggest some positive health effects of isoflavones from soy foods on perimenstrual symptoms. More accurate, objective measurement needs to be applied and more investigation of soy isoflavones effects on many aspects of women's health need to be done in a future study.

Frequency of soy food consumption and serum isoflavone concentrations among Chinese women in Shanghai.

PubMed

Frankenfeld, Cara L; Lampe, Johanna W; Shannon, Jackilen; Gao, Dao L; Ray, Roberta M; Prunty, Joann; Kalhorn, Thomas F; Wähälä, Kristiina; Patterson, Ruth E; Thomas, David B

2004-09-01

The food-frequency questionnaire (FFQ) can be an efficient tool to evaluate dietary intake in large, population-based studies, especially for specific foods. The objective of this study was to validate the assessment of soy and isoflavone (daidzein and genistein) intakes, measured by an FFQ, by comparing intakes with serum isoflavone concentrations. Soy and isoflavone intakes and serum isoflavone concentrations were determined as part of a case-control study of dietary factors and risks of benign breast disease and breast cancer. The FFQ, administered during an in-person interview, included six soy-specific line items. Blood was drawn within one week of FFQ completion. In total, 1823 women living in Shanghai, People's Republic of China. In this population, soybean milk, fresh bean curd and other bean foods were eaten once per week, and fermented bean curd, fried bean curd puff and soybeans were eaten less than once per week. A significant linear trend (P<0.01) in serum isoflavone concentrations across increasing categories of soy and isoflavone intakes was observed, indicating that soy and isoflavone intakes, measured by the FFQ, well distinguished serum isoflavone concentrations. Linear trends were also observed in both case and control groups in stratified analyses, suggesting little differential bias by case-control status. The results suggest that the FFQ provides a useful marker of soy food consumption and isoflavone exposure in this population.

Dietary sources and determinants of soy isoflavone intake among midlife Chinese Women in Hong Kong.

PubMed

Chan, Sieu-gaen; Ho, Suzanne C; Kreiger, Nancy; Darlington, Gerarda; So, Kam F; Chong, Portia Y Y

2007-11-01

The dietary sources, intake levels, and determinants of soy isoflavone intake were examined using 3217 dietary recalls (DR) collected from 141 Hong Kong Chinese women aged 50-61 y. Multiple-pass 24-h DR were administered by phone by trained interviewers on 23 random, nonconsecutive days to participants over a 12-mo period from 2001 to 2002. We calculated isoflavone intake using analytical values in the Chinese University of Hong Kong Soy Isoflavone Database. Results indicated that the daily intake of total isoflavones was 7.8 +/- 5.6 mg in the study population. Non-Cantonese women had a higher intake of 10.7 +/- 7.6 mg compared with 7.3 +/- 5.0 mg in Cantonese women (P = 0.04). Altogether, 22 foods contributed approximately 90% of the total isoflavone intake. Soft tofu alone accounted for approximately 21% of the isoflavone intake, followed by bean curd skin (7.1%), name-brand soybean milk (6.3%), homemade soybean milk (6.2%), and generic soybean milk (5.8%). Combined, these 5 food items contributed 46% of the total dietary isoflavones. Multiple linear regression analysis indicated dialect group, self-reported health, and age group were significant independent predictors of soy isoflavone consumption. The data provide the basis for elucidating the patterns, determinants, and assessment of dietary soy isoflavone intake in Asian women.

Multivalent Peptidomimetic Conjugates as Inhibitors of Androgen Receptor Function in Therapy-Resistant Prostate Cancer

DTIC Science & Technology

2016-10-01

STATEMENT: Approved for Public Release; Distribution Unlimited The views, opinions and/or findings contained in this report are those of the author(s) and...AVAILABILITY STATEMENT Approved for Public Release; Distribution Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT Androgens are hormones that play a critical...role in stimulating prostate cancer growth. Androgens activate a protein called the androgen receptor ( AR ), which regulates genes involved in cell

Soy and isoflavone consumption and risk of gastrointestinal cancer: a systematic review and meta-analysis.

PubMed

Tse, Genevieve; Eslick, Guy D

2016-02-01

Evidence suggests that soy foods have chemoprotective properties that may reduce the risk of certain cancers such as breast and prostate cancer. However, data involving gastrointestinal (GI) have been limited, and the evidence remains controversial. This study aims to determine the potential relationship between dietary soy intake and GI cancer risk with an evaluation of the effects of isoflavone as an active soy constituent. Relevant studies were identified after literature search via electronic databases through May 2014. Subgroup analysis for isoflavone intake (studies n = 10) was performed. Covariants including gender types, anatomical subsites and preparation methods were also evaluated. Pooled adjusted odds ratios (ORs) comparing highest and lowest categories of dietary pattern scores were calculated using a random effects model. Twenty-two case-control and 18 cohort studies were included for meta-analysis, which contained a total of 633,476 participants and 13,639 GI cancer cases. The combined OR was calculated as 0.93 (95% CI 0.87-0.99; p value heterogeneity = 0.01), showing only a slight decrease in risk, the association was stronger for colon cancer (OR 0.92; 95% CI 0.96-0.99; p value heterogeneity = 0.163) and colorectal cancer (CRC) (OR 0.92; 95% CI 0.87-0.97; p value heterogeneity = 0.3). Subgroup analysis for isoflavone intake showed a statistically significant risk reduction with a risk estimate of 0.73 (95% CI 0.59-0.92; p value heterogeneity = 0), and particularly for CRC (OR 0.76; 95% CI 0.59-0.98; p value heterogeneity = 0). This study provides evidence that soy intake as a food group is only associated with a small reduction in GI cancer risk. Separate analysis for dietary isoflavone intakes suggests a stronger inverse association.

Effects of age and soybean isoflavones on hepatic cholesterol metabolism and thyroid hormone availability in acyclic female rats.

PubMed

Šošić-Jurjević, Branka; Lütjohann, Dieter; Jarić, Ivana; Miler, Marko; Vojnović Milutinović, Danijela; Filipović, Branko; Ajdžanović, Vladimir; Renko, Kostja; Wirth, Eva Katrin; Janković, Snežana; Kӧhrle, Josef; Milošević, Verica

2017-06-01

Soy-food and its isoflavones, genistein (G) and daidzein (D), were reported to exert mild cholesterol-lowering effect, but the underlying mechanism is still unclear. In this research, first we studied age-related alterations in hepatic cholesterol metabolism of acyclic middle-aged (MA) female rats. Then we tested if purified isoflavones may prevent or reverse these changes, and whether putative changes in hepatic thyroid hormone availability may be associated with this effect. Serum and hepatic total cholesterol (TChol), bile acid and cholesterol precursors, as well as serum TSH and T 4 concentrations, hepatic deiodinase (Dio) 1 enzyme activity and MCT8 protein expression were determined by comparing data obtained for MA with young adult (YA) intact (IC) females. Effects of subcutaneously administered G or D (35mg/kg) to MA rats were evaluated versus vehicle-treated MA females. MA IC females were characterized by: higher (p<0.05) serum TChol, lower (p<0.05) hepatic TChol and its biosynthetic precursors, lower (p<0.05) hepatic 7α-hydroxycholesterol but elevated (p<0.05) 27- and 24-hydroxycholesterol in comparison to YA IC. Both isoflavone treatments decreased (p<0.05) hepatic 27-hydroxycholesterol, G being more effective than D, without affecting any other parameter of Chol metabolism. Only G elevated hepatic Dio1 activity (p<0.05). In conclusion, age-related hypercholesteremia was associated with lower hepatic Chol synthesis and shift from main neutral (lower 7α-hydroxycholesterol) to alternative acidic pathway (higher 27-hydroxycholesterol) of Chol degradation to bile acid. Both isoflavones lowered hepatic 27-hydroxycholesterol, which may be considered beneficial. Only G treatment increased hepatic Dio1 activity, thus indicating local increase in thyroid hormones, obviously insufficient to induce prominent cholesterol-lowering effect. Copyright © 2017 Elsevier Inc. All rights reserved.

Modeling Truncated AR Expression in a Natural Androgen Responsive Environment and Identification of RHOB as a Direct Transcriptional Target

PubMed Central

Tsai, Hui-Chi; Boucher, David L.; Martinez, Anthony; Tepper, Clifford G.; Kung, Hsing-Jien

2012-01-01

Recent studies identifying putative truncated androgen receptor isoforms with ligand-independent activity have shed new light on the acquisition of androgen depletion independent (ADI) growth of prostate cancer. In this study, we present a model system in which a C-terminally truncated variant of androgen receptor (TC-AR) is inducibly expressed in LNCaP, an androgen-dependent cell line, which expresses little truncated receptor. We observed that when TC-AR is overexpressed, the endogenous full length receptor (FL-AR) is transcriptionally downmodulated. This in essence allows us to “replace” FL-AR with TC-AR and compare their individual properties in exactly the same genetic and cellular background, which has not been performed before. We show that the TC-AR translocates to the nucleus, activates transcription of AR target genes in the absence of DHT and is sufficient to confer ADI growth to the normally androgen dependent LNCaP line. We also show that while there is significant overlap in the genes regulated by FL- and TC-AR there are also differences in the respective suites of target genes with each AR form regulating genes that the other does not. Among the genes uniquely activated by TC-AR is RHOB which is shown to be involved in the increased migration and morphological changes observed in LN/TC-AR, suggesting a role of RHOB in the regulation of androgen-independent behavior of prostate cancer cells. PMID:23209612

Mitigation of ergot vasoconstriction by clover isoflavones in goats (Capra hircus)

USDA-ARS?s Scientific Manuscript database

Ergot alkaloids produced by a fungal endophyte (Epichloë coenophiala; formerly Neotyphodium coenphialum) that infects tall fescue (Lolium arundinaceum) can induce persistent constriction of the vasculature in ruminants, hindering their capability to thermo-regulate core body temperature. There is e...

High-Content Screening Identifies Src Family Kinases as Potential Regulators of AR-V7 Expression and Androgen-Independent Cell Growth.

PubMed

Szafran, Adam T; Stephan, Cliff; Bolt, Michael; Mancini, Maureen G; Marcelli, Marco; Mancini, Michael A

2017-01-01

AR-V7 is an androgen receptor (AR) splice variant that lacks the ligand-binding domain and is isolated from prostate cancer cell lines. Increased expression of AR-V7 is associated with the transition from hormone-sensitive prostate cancer to more advanced castration-resistant prostate cancer (CRPC). Due to the loss of the ligand-binding domain, AR-V7 is not responsive to traditional AR-targeted therapies, and the mechanisms that regulate AR-V7 are still incompletely understood. Therefore, we aimed to explore existing classes of small molecules that may regulate AR-V7 expression and intracellular localization and their potential therapeutic role in CRPC. We used AR high-content analysis (AR-HCA) to characterize the effects of a focused library of well-characterized clinical compounds on AR-V7 expression at the single-cell level in PC3 prostate cancer cells stably expressing green fluorescent protein (GFP)-AR-V7 (GFP-AR-V7:PC3). In parallel, an orthogonal AR-HCA screen of a small interfering (si)RNA library targeting 635 protein kinases was performed in GFP-AR-V7:PC3. The effect of the Src-Abl inhibitor PD 180970 was further characterized using cell-proliferation assays, quantitative PCR, and western blot analysis in multiple hormone-sensitive and CRPC cell lines. Compounds that tended to target Akt, Abl, and Src family kinases (SFKs) decreased overall AR-V7 expression, nuclear translocation, absolute nuclear level, and/or altered nuclear distribution. We identified 20 protein kinases that, when knocked down, either decreased nuclear GFP-AR-V7 levels or altered AR-V7 nuclear distribution, a set that included the SFKs Src and Fyn. The Src-Abl dual kinase inhibitor PD180970 decreased expression of AR-V7 by greater than 46% and decreased ligand-independent transcription of AR target genes in the 22RV1 human prostate carcinoma cell line. Further, PD180970 inhibited androgen-independent cell proliferation in endogenous-AR-V7-expressing prostate cancer cell lines and also overcame bicalutamide resistance observed in the 22RV1 cell line. SFKs, especially Src and Fyn, may be important upstream regulators of AR-V7 expression and represent promising targets in a subset of CRPCs expressing high levels of AR-V7. Prostate 77:82-93, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Expanding the therapeutic use of androgens via selective androgen receptor modulators (SARMs)

PubMed Central

Gao, Wenqing; Dalton, James T.

2007-01-01

Selective androgen receptor modulators (SARMs) are a novel class of androgen receptor (AR) ligands that might change the future of androgen therapy dramatically. With improved pharmacokinetic characteristics and tissue-selective pharmacological activities, SARMs are expected to greatly extend the clinical applications of androgens to osteoporosis, muscle wasting, male contraception and diseases of the prostate. Mechanistic studies with currently available SARMs will help to define the contributions of differential tissue distribution, tissue-specific expression of 5α-reductase, ligand-specific regulation of gene expression and AR interactions with tissue-specific coactivators to their observed tissue selectivity, and lead to even greater expansion of selective anabolic therapies. PMID:17331889

Simultaneous inhibition of aryl hydrocarbon receptor (AhR) and Src abolishes androgen receptor signaling.

PubMed

Ghotbaddini, Maryam; Cisse, Keyana; Carey, Alexis; Powell, Joann B

2017-01-01

Altered c-Src activity has been strongly implicated in the development, growth, progression, and metastasis of human cancers including prostate cancer. Src is known to regulate several biological functions of tumor cells, including proliferation. There are several Src inhibitors under evaluation for clinical effectiveness but have shown little activity in monotherapy trials of solid tumors. Combination studies are being explored by in vitro analysis and in clinical trials. Here we investigate the effect of simultaneous inhibition of the aryl hydrocarbon receptor (AhR) and Src on androgen receptor (AR) signaling in prostate cancer cells. AhR has also been reported to interact with the Src signaling pathway during prostate development. c-Src protein kinase is associated with the AhR complex in the cytosol and upon ligand binding to AhR, c-Src is activated and released from the complex. AhR has also been shown to regulate AR signaling which remains functionally important in the development and progression of prostate cancer. We provide evidence that co-inhibition of AhR and Src abolish AR activity. Evaluation of total protein and cellular fractions revealed decreased pAR expression and AR nuclear localization. Assays utilizing an androgen responsive element (ARE) and qRT-PCR analysis of AR genes revealed decreased AR promoter activity and transcriptional activity in the presence of both AhR and Src inhibitors. Furthermore, co-inhibition of AhR and Src reduced the growth of prostate cancer cells compared to individual treatments. Several studies have revealed that AhR and Src individually inhibit cellular proliferation. However, this study is the first to suggest simultaneous inhibition of AhR and Src to inhibit AR signaling and prostate cancer cell growth.

Polymorphisms of steroid 5-alpha-reductase type I (SRD5A1) gene are associated to peripheral arterial disease.

PubMed

Signorelli, S S; Barresi, V; Musso, N; Anzaldi, M; Croce, E; Fiore, V; Condorelli, D F

2008-12-01

Although animal studies support the hypothesis that androgenic biological actions may affect experimental atherosclerosis progression, evidence for a relationship between androgen effects and peripheral arterial disease (PAD), a common clinical form of atherosclerosis, is weak or contradictory. Testosterone, the main androgen hormone, is converted in a 5alpha-reduced form by enzymatic activities in the target cells and some specific actions are mediated by such metabolites. Steroid 5-alpha reductase isoenzymes (SRD5A1 and SRD5A2) catalyze the conversion to the bioactive potent androgen dihydrotestosterone and other reduced metabolites and represent relevant regulators of local hormonal actions. In the present study we tested for the association of selected single nucleotide polymorphisms (SNP) of SRD5A1 and SRD5A2 with symptomatic PAD patients. Two different SNP in the SRD5A1 were significantly associated which the PAD phenotype (p<0.03, odds ratio 1.73), while no association was found between PAD phenotypes and SRD5A2. Since the examined SRDA1 gene variant was previously associated with a low enzymatic activity, we suggest that a decreased local enzymatic conversion of testosterone may contribute to PAD genetic susceptibility.

Plasmacytoid dendritic cell interferon-α production to R-848 stimulation is decreased in male infants.

PubMed

Wang, Jennifer P; Zhang, Lei; Madera, Rachel F; Woda, Marcia; Libraty, Daniel H

2012-07-06

Sex differences in response to microbial infections, especially viral ones, may be associated with Toll-like receptor (TLR)-mediated responses by plasmacytoid dendritic cells (pDCs). In this study, we identified sex differences in human infant pDC interferon-α production following challenge with the TLR7/8 agonist R-848. Male pDC responses were significantly lower than those of females during early infancy. This difference may be attributed to the androgen surge experienced by males during the early infancy period. Pretreatment of human pDCs with dihydrotestosterone produced a significant reduction in interferon-α production following R-848 challenge. Androgen-mediated regulation of pDC TLR7-driven innate immune responses may contribute to the observed sex differences in response to infections during early infancy.

Phosphorylation of Isoflavones by Bacillus subtilis BCRC 80517 May Represent Xenobiotic Metabolism.

PubMed

Hsu, Chen; Wu, Bo-Yuan; Chang, Yu-Chuan; Chang, Chi-Fon; Chiou, Tai-Ying; Su, Nan-Wei

2018-01-10

The soy isoflavones daidzein (DAI) and genistein (GEN) have beneficial effects on human health. However, their oral bioavailability is hampered by their low aqueous solubility. Our previous study revealed two water-soluble phosphorylated conjugates of isoflavones, daidzein 7-O-phosphate and genistein 7-O-phosphate, generated via biotransformation by Bacillus subtilis BCRC80517 cultivated with isoflavones. In this study, two novel derivatives of isoflavones, daidzein 4'-O-phosphate and genistein 4'-O-phosphate, were identified by HPLC-ESI-MS/MS and 1 H, 13 C, and 31 P NMR, and their biotransformation roadmaps were proposed. Primarily, isoflavone glucosides were deglycosylated and then phosphorylated predominantly into 7-O-phosphate conjugates with traces of 4'-O-phosphate conjugates. Inevitably, trace quantities of glucosides were converted into 6″-O-succinyl glucosides. GEN was more efficiently phosphorylated than DAI. Nevertheless, the presence of GEN prolonged the time until the exponential phase of cell growth, whereas the other isoflavones showed little effect on cell growth. Our findings provide new insights into the novel microbial phosphorylation of isoflavones involved in xenobiotic metabolism.

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.

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 promote hydrolysis of isoflavone conjugates.

Can soy intake affect serum uric acid level? Pooled analysis from two 6-month randomized controlled trials among Chinese postmenopausal women with prediabetes or prehypertension.

PubMed

Liu, Z M; Ho, C S; Chen, Y M; Woo, J

2015-02-01

Hyperuricemia is a recognized risk factor for cardiovascular diseases. Soy foods contain a moderate amount of purine and may predispose to raised serum uric acid (UA). However, no study has examined the long-term effect of soy intake on UA levels. We examined whether consumption of soy foods and isoflavone extracts for 6 months altered serum UA. The analysis included two randomized controlled trials (soy protein trial and whole soy trial) among total 450 postmenopausal women with either prehypertension or prediabetes. We conducted a pooled analysis by combining participants from both the soy flour and soy protein groups (combined soy foods group), participants from both the isoflavone and daidzein groups (combined isoflavone group) and participants from both milk placebo groups. Fasting venous samples were obtained at baseline and the end of the trial for serum UA analysis. In the pooled data, 417 subjects completed the study according to protocol. The baseline serum UA levels were comparable among the three combined groups. There was a lower decrease in UA levels among women in the combined soy foods group compared with women in the other two groups (p = 0.028 and 0.026). The net decrease and % decrease in UA were 14.5 μmol/L (95 % CI 1.93-25.6, p = 0.023) or 4.9 % (95 % CI 1.3-8.5 %, p = 0.023) between the combined soy foods group and placebo group. Among Chinese postmenopausal women with either prehypertension or prediabetes, soy intake did not increase urate levels.

Androgen Receptor Roles in Insulin Resistance and Obesity in Males: The Linkage of Androgen-Deprivation Therapy to Metabolic Syndrome

PubMed Central

Yu, I-Chen; Lin, Hung-Yun; Sparks, Janet D.; Yeh, Shuyuan

2014-01-01

Prostate cancer (PCa) is one of the most frequently diagnosed malignancies in men. Androgen-deprivation therapy (ADT) is the first-line treatment and fundamental management for men with advanced PCa to suppress functions of androgen/androgen receptor (AR) signaling. ADT is effective at improving cancer symptoms and prolonging survival. However, epidemiological and clinical studies support the notion that testosterone deficiency in men leads to the development of metabolic syndrome that increases cardiovascular disease risk. The underlying mechanisms by which androgen/AR signaling regulates metabolic homeostasis in men are complex, and in this review, we discuss molecular mechanisms mediated by AR signaling that link ADT to metabolic syndrome. Results derived from various AR knockout mouse models reveal tissue-specific AR signaling that is involved in regulation of metabolism. These data suggest that steps be taken early to manage metabolic complications associated with PCa patients receiving ADT, which could be accomplished using tissue-selective modulation of AR signaling and by treatment with insulin-sensitizing agents. PMID:25249645

The Hsp90 Inhibitor, 17-AAG, Prevents the Ligand-Independent Nuclear Localization of Androgen Receptor in Refractory Prostate Cancer Cells

PubMed Central

Saporita, Anthony J.; Ai, Junkui; Wang, Zhou

2010-01-01

BACKGROUND Androgen receptor (AR) is the key molecule in androgen-refractory prostate cancer. Despite androgen ablative conditions, AR remains active and is necessary for the growth of androgen-refractory prostate cancer cells. Nuclear localization of AR is a prerequisite for its transcriptional activation. We examined AR localization in androgen-dependent and androgen-refractory prostate cancer cells. METHODS AND RESULTS We demonstrate increased nuclear localization of a GFP-tagged AR in the absence of hormone in androgen-refractory C4-2 cells compared to parental androgen-sensitive human prostate cancer LNCaP cells. Analysis of AR mutants impaired in ligand-binding indicates that the nuclear localization of AR in C4-2 cells is truly androgen-independent. The hsp90 inhibitor, 17-allylamino-17-demethoxygeldanamycin (17-AAG), inhibits basal PSA expression and disrupts the ligand-independent nuclear localization of AR at doses much lower than required to inhibit androgen-induced nuclear import. CONCLUSIONS Hsp90 is a key regulator of ligand-independent nuclear localization and activation of AR in androgen-refractory prostate cancer cells. PMID:17221841

Involvement of androgens in ovarian health and disease

PubMed Central

Lebbe, M.; Woodruff, T.K.

2013-01-01

In women, ovary and adrenal gland produce androgens. Androgens are essential drivers of the primordial to antral follicle development, prior to serving as substrate for estrogen production in the later stages of folliculogenesis. Androgens play a crucial role in the follicular–stromal intertalk by fine tuning the extracellular matrix and vessel content of the ovarian stroma. Local auto-and paracrine factors regulate androgen synthesis in the pre-antral follicle. Androgen excess is a hallmark of polycystic ovary syndrome and is a key contributor in the exaggerated antral follicle formation, stromal hyperplasia and hypervascularity. Hyperandrogenaemia overrides the follicular–stromal dialog, resulting in follicular arrest and disturbed ovulation. On the other hand, androgen deficiency is likely to have a negative impact on fertility as well, and further research is needed to examine the benefits of androgen-replacement therapy in subfertility. PMID:24026057

RNA splicing and splicing regulator changes in prostate cancer pathology.

PubMed

Munkley, Jennifer; Livermore, Karen; Rajan, Prabhakar; Elliott, David J

2017-09-01

Changes in mRNA splice patterns have been associated with key pathological mechanisms in prostate cancer progression. The androgen receptor (abbreviated AR) transcription factor is a major driver of prostate cancer pathology and activated by androgen steroid hormones. Selection of alternative promoters by the activated AR can critically alter gene function by switching mRNA isoform production, including creating a pro-oncogenic isoform of the normally tumour suppressor gene TSC2. A number of androgen-regulated genes generate alternatively spliced mRNA isoforms, including a prostate-specific splice isoform of ST6GALNAC1 mRNA. ST6GALNAC1 encodes a sialyltransferase that catalyses the synthesis of the cancer-associated sTn antigen important for cell mobility. Genetic rearrangements occurring early in prostate cancer development place ERG oncogene expression under the control of the androgen-regulated TMPRSS2 promoter to hijack cell behaviour. This TMPRSS2-ERG fusion gene shows different patterns of alternative splicing in invasive versus localised prostate cancer. Alternative AR mRNA isoforms play a key role in the generation of prostate cancer drug resistance, by providing a mechanism through which prostate cancer cells can grow in limited serum androgen concentrations. A number of splicing regulator proteins change expression patterns in prostate cancer and may help drive key stages of disease progression. Up-regulation of SRRM4 establishes neuronal splicing patterns in neuroendocrine prostate cancer. The splicing regulators Sam68 and Tra2β increase expression in prostate cancer. The SR protein kinase SRPK1 that modulates the activity of SR proteins is up-regulated in prostate cancer and has already given encouraging results as a potential therapeutic target in mouse models.

Trichosanthes kirilowii Exerts Androgenic Activity via Regulation of PSA and KLK2 in 22Rv1 Prostate Cancer Cells

PubMed Central

Jeong, Soo-Jin; Choi, Ji-Yoon; Dong, Mi-Sook; Seo, Chang-Seob; Shin, Hyeun-Kyoo

2017-01-01

Background: The androgen comprises a group of hormones that play roles in male reproductive activity as well as personal characteristics. Objective: We investigated the androgenic activity of various herbal medicines in human prostate cancer 22Rv1 cells. Materials and Methods: Herbal extracts of Trichosanthes kirilowii (TK), Asarum sieboldii (AS), Sanguisorba officinalis (SO), and Xanthium strumarium (XS) were selected to have androgenic effects based on a preliminary in vitro screening system. Results: TK, AS, SO, and XS enhanced the proliferation of 22Rv1 cells without having cytotoxic effects. All tested herbal extracts increased androgen receptor (AR)-induced transcriptional activity in the absence or presence of dihydrotestosterone (DHT). In an AR-binding assay, TK, but not AS, SO, or XS, produced a significant inhibition of AR binding activity, indicating it has androgenic activity. Additionally, TK treatment positively regulated mRNA expression of the AR-related molecular targets prostate-specific antigen (PSA) and kallikrein 2 (KLK2) compared with untreated control. Conclusion: Taken together, TK-enhanced AR-mediated transcriptional activity might be an attractive candidate drug for treating androgen-related diseases. SUMMARY Trichosantheskirilowii (TK), Asarumsieboldii (AS), Sanguisorbaofficinalis (SO), and Xanthium strumarium (XS) enhanced the proliferation of 22Rv1 cells without having cytotoxic effects.TK, AS, SO, and XS increased androgen receptor (AR)-induced transcriptional activity.TK, but not AS, SO, or XS, produced a significant inhibition against AR-binding activity.TK treatment positively regulated mRNA expression of the AR-related molecular targets prostate-specific antigen and kallikrein 2. Abbreviations used: BPH: benign prostatic hyperplasia; AR: androgen receptor; DHT: dihydrotestosterone; PSA: prostate-specific antigen; TK: Trichosanthes kirilowii; AS: Asarum sieboldii; SO: Sanguisorba officinalis; XS: Xanthium strumarium; ATCC: American Type Culture Collection; FBS: fetal bovine serum; PBS: phosphate-buffered saline; SD: standard deviation; ARE: androgenresponsive element; KLK: kallikrein PMID:28216900

Vasopressin differentially modulates aggression and anxiety in adolescent hamsters administered anabolic steroids.

PubMed

Morrison, Thomas R; Ricci, Lesley A; Melloni, Richard H

2016-11-01

Adolescent Syrian hamsters (Mesocricetus auratus) treated with anabolic/androgenic steroids display increased offensive aggression and decreased anxiety correlated with an increase in vasopressin afferent development, synthesis, and neural signaling within the anterior hypothalamus. Upon withdrawal from anabolic/androgenic steroids, this neurobehavioral relationship shifts as hamsters display decreased offensive aggression and increased anxiety correlated with a decrease in anterior hypothalamic vasopressin. This study investigated the hypothesis that alterations in anterior hypothalamic vasopressin neural signaling modulate behavioral shifting between adolescent anabolic/androgenic steroid-induced offensive aggression and anxiety. To test this, adolescent male hamsters were administered anabolic/androgenic steroids and tested for offensive aggression or anxiety following direct pharmacological manipulation of vasopressin V1A receptor signaling within the anterior hypothalamus. Blockade of anterior hypothalamic vasopressin V1A receptor signaling suppressed offensive aggression and enhanced general and social anxiety in hamsters administered anabolic/androgenic steroids during adolescence, effectively reversing the pattern of behavioral response pattern normally observed during the adolescent exposure period. Conversely, activation of anterior hypothalamic vasopressin V1A receptor signaling enhanced offensive aggression in hamsters exposed to anabolic/androgenic steroids during adolescence. Together, these findings suggest that the state of vasopressin neural development and signaling in the anterior hypothalamus plays an important role in behavioral shifting between aggression and anxiety following adolescent exposure to anabolic/androgenic steroids. Copyright © 2016 Elsevier Inc. All rights reserved.

Vasopressin Differentially Modulates Aggression and Anxiety in Adolescent Hamsters Administered Anabolic Steroids

PubMed Central

Morrison, Thomas R.; Ricci, Lesley A.; Melloni, Richard H.

2016-01-01

Adolescent Syrian hamsters (Mesocricetus auratus) treated with anabolic/androgenic steroids display increased offensive aggression and decreased anxiety correlated with an increase in vasopressin afferent development, synthesis, and neural signaling within the anterior hypothalamus. Upon withdrawal from anabolic/androgenic steroids, this neurobehavioral relationship shifts as hamsters display decreased offensive aggression and increased anxiety correlated with a decrease in anterior hypothalamic vasopressin. This study investigated the hypothesis that alterations in anterior hypothalamic vasopressin neural signaling modulate behavioral shifting between adolescent anabolic/androgenic steroid-induced offensive aggression and anxiety. To test this, adolescent male hamsters were administered anabolic/androgenic steroids and tested for offensive aggression or anxiety following direct pharmacological manipulation of vasopressin V1A receptor signaling within the anterior hypothalamus. Blockade of anterior hypothalamic vasopressin V1A receptor signaling suppressed offensive aggression and enhanced general and social anxiety in hamsters administered anabolic/androgenic steroids during adolescence, effectively reversing the pattern of behavioral response pattern normally observed during the adolescent exposure period. Conversely, activation of anterior hypothalamic vasopressin V1A receptor signaling enhanced offensive aggression in hamsters exposed to anabolic/androgenic steroids during adolescence. Together, these findings suggest that the state of vasopressin neural development and signaling in the anterior hypothalamus plays an important role in behavioral shifting between aggression and anxiety following adolescent exposure to anabolic/androgenic steroids. PMID:27149949

Relationships between yolk androgens and nest density, laying date, and laying order in Western Burrowing Owls (Athene cunicularia hypugaea)

USGS Publications Warehouse

Welty, J.L.; Belthoff, J.R.; Egbert, J.; Schwabl, H.

2012-01-01

Increases in yolk androgens within and among avian clutches have been correlated with decreased incubation time, increased aggression within a nest, increased begging behaviour, decreased immune response, and decreased life span. Although the mechanisms that lead to variability in yolk androgens within and between clutches are not completely known, yolk androgens can be a function of both social and environmental conditions. We were interested in if and how nesting density, laying date, and laying order influenced yolk androgens in Western Burrowing Owls (Athene cunicularia hypugaea (Bonaparte, 1825)) in which nest density varies considerably. In 2006 and 2007, we used radioimmunoassay to quantify the concentrations of testosterone, 5a-dihydrotestosterone, and androstenedione in the egg yolks from one early and one latelaid egg in 47 nests of Burrowing Owls located in the Morley Nelson Snake River Birds of Prey National Conservation Area in southern Idaho. Nesting density had no detectable effect on yolk androgens. Yolk androgens varied temporally and peaked in the middle of the laying season while being low before and after this time period. Within nests, late-laid eggs had higher testosterone and dihydrotestosterone than early-laid eggs; adrostendione exhibited a similar pattern in one but not both years of our study. It is possible that the seasonal pattern in yolk androgens that we observed is related to aspects of mate quality for females or declining chances of fledging success for later nesting females, whereas rises in egg androgens between early and late eggs within clutches could reflect a mechanism to assist nestlings from late-laid eggs that hatch one to several days after their siblings to better compete for resources within the nest or promote survival in the presence of larger siblings.

Vascular Endothelial Growth Factor and Angiopoietin are Required for Prostate Regeneration.

PubMed Central

Wang, Gui-min; Kovalenko, Bruce; Huang, Yili; Moscatelli, David

2007-01-01

BACKGROUND The regulation of the prostate size by androgens may be partly the result of androgen effects on the prostatic vasculature. We examined the effect of changes in androgen levels on the expression of a variety of angiogenic factors in the mouse prostate and determined if vascular endothelial growth factor (VEGF)-A and the angiopoietins are involved in the vascular response to androgens. METHODS Expression of angiogenic factors in prostate was quantitated using real-time PCR at different times after castration and after administration of testosterone to castrated mice. Angiopoietins were localized in prostate by immunohistochemistry and in situ hybridization. The roles of VEGF and the angiopoietins in regeneration of the prostate were examined in mice inoculated with cells expressing soluble VEGF receptor-2 or soluble Tie-2. RESULTS Castration resulted in a decrease in VEGF-A, VEGF-B, VEGF-C, placenta growth factor, FGF-2, and FGF-8 expression after one day. In contrast, VEGF-D mRNA levels increased. No changes in angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2), hepatocyte growth factor, VEGF receptor-1, VEGF receptor-2 or tie-2 mRNA levels were observed. Administration of testosterone to castrated mice had the opposite effect on expression of these angiogenic factors. Ang-2 was expressed predominately in prostate epithelial cells whereas Ang-1 was expressed in epithelium and smooth muscle. Inoculation of mice with cells expressing soluble VEGF receptor-2 or Tie-2 blocked the increase in vascular density normally observed after administration of testosterone to castrated mice. The soluble receptors also blocked the increase in prostate weight and proliferation of prostatic epithelial cells. CONCLUSION VEGF-A and angiopoietins are required for the vascular response to androgens and for the ability of the prostate to regenerate in response to androgens. PMID:17221843

Testosterone differentially regulates targets of lipid and glucose metabolism in liver, muscle and adipose tissues of the testicular feminised mouse.

PubMed

Kelly, Daniel M; Akhtar, Samia; Sellers, Donna J; Muraleedharan, Vakkat; Channer, Kevin S; Jones, T Hugh

2016-11-01

Testosterone deficiency is commonly associated with obesity, metabolic syndrome, type 2 diabetes and their clinical consequences-hepatic steatosis and atherosclerosis. The testicular feminised mouse (non-functional androgen receptor and low testosterone) develops fatty liver and aortic lipid streaks on a high-fat diet, whereas androgen-replete XY littermate controls do not. Testosterone treatment ameliorates these effects, although the underlying mechanisms remain unknown. We compared the influence of testosterone on the expression of regulatory targets of glucose, cholesterol and lipid metabolism in muscle, liver, abdominal subcutaneous and visceral adipose tissue. Testicular feminised mice displayed significantly reduced GLUT4 in muscle and glycolytic enzymes in muscle, liver and abdominal subcutaneous but not visceral adipose tissue. Lipoprotein lipase required for fatty acid uptake was only reduced in subcutaneous adipose tissue; enzymes of fatty acid synthesis were increased in liver and subcutaneous tissue. Stearoyl-CoA desaturase-1 that catalyses oleic acid synthesis and is associated with insulin resistance was increased in visceral adipose tissue and cholesterol efflux components (ABCA1, apoE) were decreased in subcutaneous and liver tissue. Master regulator nuclear receptors involved in metabolism-Liver X receptor expression was suppressed in all tissues except visceral adipose tissue, whereas PPARγ was lower in abdominal subcutaneous and visceral adipose tissue and PPARα only in abdominal subcutaneous. Testosterone treatment improved the expression (androgen receptor independent) of some targets but not all. These exploratory data suggest that androgen deficiency may reduce the buffering capability for glucose uptake and utilisation in abdominal subcutaneous and muscle and fatty acids in abdominal subcutaneous. This would lead to an overspill and uptake of excess glucose and triglycerides into visceral adipose tissue, liver and arterial walls.

In Vitro Androgen Bioassays as a Detection Method for Designer Androgens

PubMed Central

Cooper, Elliot R.; McGrath, Kristine C. Y.; Heather, Alison K.

2013-01-01

Androgens are the class of sex steroids responsible for male sexual characteristics, including increased muscle mass and decreased fat mass. Illicit use of androgen doping can be an attractive option for those looking to enhance sporting performance and/or physical appearance. The use of in vitro bioassays to detect androgens, especially designer or proandrogens, is becoming increasingly important in combating androgen doping associated with nutritional supplements. The nutritional sports supplement market has grown rapidly throughout the past decade. Many of these supplements contain androgens, designer androgens or proandrogens. Many designer or proandrogens cannot be detected by the standard highly-sensitive screening methods such as gas chromatography-mass spectrometry because their chemical structure is unknown. However, in vitro androgen bioassays can detect designer and proandrogens as these assays are not reliant on knowing the chemical structure but instead are based on androgen receptor activation. For these reasons, it may be advantageous to use routine androgen bioassay screening of nutraceutical samples to help curb the increasing problem of androgen doping. PMID:23389345

An AKT activity threshold regulates androgen-dependent and androgen-independent PSA expression in prostate cancer cell lines.

PubMed

Paliouras, Miltiadis; Diamandis, Eleftherios P

2008-06-01

The androgen receptor (AR) plays an important role in early prostate cancer by activating transcription of a number of genes participating in cell proliferation and growth and cancer progression. However, as the cancer progresses, prostate cancer cells transform from an androgen-dependent to an androgen-independent state. Androgen-independent prostate cancer can manifest itself in several forms, including a percentage of cancers that show reduced levels of prostate-specific antigen (PSA) and can progress without the need for the ligand or active receptor. Therefore, our goal was to examine the role of intracellular signaling pathways in an androgen-independent prostate cancer in vitro model. Using the cell line PC3(AR)(2), we stimulated cells with 5-alpha-dihydrotestosterone (DHT) and epidermal growth factor (EGF) and then analyzed PSA expression. We observed lower PSA expression when cells were jointly stimulated with DHT and EGF, and this was associated with an increase in AKT activity. We examined the role of AKT in AR activity and PSA expression by creating stable PC3(AR)(2) cell lines transfected with a PI3K-Ras-effector loop mutant. These cell lines showed lower DHT-stimulated PSA expression that correlated to changes in the phosphorylated state of AR. Therefore, we propose an in vitro androgen-independent model in which a PI3K/AKT activity threshold and subsequent AR transactivation regulate PSA expression.

Effects of baking on cyanidin-3-glucoside content and antioxidant properties of black and yellow soybean crackers.

PubMed

Slavin, Margaret; Lu, Yingjian; Kaplan, Nicholas; Yu, Liangli Lucy

2013-11-15

Black soybean is a potential functional food ingredient with high anthocyanin content, but the ability to maintain anthocyanin content under dry heat processing has not been reported. This study investigated the effects of soybean seed coat colour and baking time-temperature combinations on the extractable antioxidant properties of a soy cracker food model. Crackers prepared with black soybeans had significantly higher TPC, total isoflavones, and peroxyl, hydroxyl, and ABTS(+) radical scavenging abilities than their yellow counterparts, at all time-temperature combinations. Cyanidin-3-glucoside (C3G) was detected only in black soybean crackers, and all baking treatments significantly decreased C3G. The greatest losses occurred at the low temperature×long time and high temperature×short time, the smallest loss with moderate temperature×short/medium time. The high temperature treatment altered phenolic acid and isoflavone profiles; however, total isoflavones were unaffected. Overall results suggest that moderate baking temperature at minimal time may best preserve anthocyanin and other phenolics in baked black soybean crackers. Copyright © 2013 Elsevier Ltd. All rights reserved.

Androgens regulate scarless repair of the endometrial "wound" in a mouse model of menstruation.

PubMed

Cousins, Fiona L; Kirkwood, Phoebe M; Murray, Alison A; Collins, Frances; Gibson, Douglas A; Saunders, Philippa T K

2016-08-01

The human endometrium undergoes regular cycles of synchronous tissue shedding (wounding) and repair that occur during menstruation before estrogen-dependent regeneration. Endometrial repair is normally both rapid and scarless. Androgens regulate cutaneous wound healing, but their role in endometrial repair is unknown. We used a murine model of simulated menses; mice were treated with a single dose of the nonaromatizable androgen dihydrotestosterone (DHT; 200 µg/mouse) to coincide with initiation of tissue breakdown. DHT altered the duration of vaginal bleeding and delayed restoration of the luminal epithelium. Analysis of uterine mRNAs 24 h after administration of DHT identified significant changes in metalloproteinases (Mmp3 and -9; P < 0.01), a snail family member (Snai3; P < 0.001), and osteopontin (Spp1; P < 0.001). Chromatin immunoprecipitation analysis identified putative androgen receptor (AR) binding sites in the proximal promoters of Mmp9, Snai3, and Spp1. Striking spatial and temporal changes in immunoexpression of matrix metalloproteinase (MMP) 3/9 and caspase 3 were detected after DHT treatment. These data represent a paradigm shift in our understanding of the role of androgens in endometrial repair and suggest that androgens may have direct impacts on endometrial tissue integrity. These studies provide evidence that the AR is a potential target for drug therapy to treat conditions associated with aberrant endometrial repair processes.-Cousins, F. L., Kirkwood, P. M., Murray, A. A., Collins, F., Gibson, D. A., Saunders, P. T. K. Androgens regulate scarless repair of the endometrial "wound" in a mouse model of menstruation. © The Author(s).

Decreased steroid hormone synthesis from inorganic nitrite and nitrate: studies in vitro and in vivo.

PubMed

Panesar, N S; Chan, K W

2000-12-15

Nitrites and nitrates are consumed nonchalantly in diet. Organic nitrates are also used as vasodilators in angina pectoris, but the therapy is associated with tolerance whose mechanism remains elusive. Previously, we found inorganic nitrate inhibited steroidogenesis in vitro. Because adrenocorticoids regulate water and electrolyte metabolism, tolerance may ensue from steroid deficiency. We have studied the effects of nitrite and nitrate on in vitro synthesis and in vivo blood levels of steroid hormones. In vitro, nitrite was more potent than nitrate in inhibiting human chorionic gonadotropin (hCG)-stimulated androgen synthesis by Mouse Leydig Tumor cells. At concentrations above 42 mM, nitrite completely inhibited androgen synthesis, and, unlike nitrate, the inhibition was irreversible by increasing hCG concentration. The cAMP production remained intact but reduced with both ions. The nitric oxide (NO) scavenger, 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxy-3-oxide (c-PTIO) significantly increased hCG- or cAMP-stimulated androgen synthesis in all buffers, suggesting that NO is a chemical species directly involved in the nitrite/nitrate-induced inhibition. This is further supported by c-PTIO countering the inhibitory action of methylene blue on androgen synthesis. Rats given distilled water containing 50 mg/L NaNO(2) or NaNO(3) for 4 weeks drank significantly less daily. At the end, their blood corticosterone and testosterone levels were significantly decreased. The adrenocortical histology showed bigger lipid droplets, which are pathogonomic of impaired steroidogenesis. Nitrite and nitrate are metabolized to NO, which binds heme in cytochrome P450 enzymes, thereby inhibiting steroidogenesis. Therapeutic nitrates likewise may decrease adrenal (and gonadal) steroidogenesis. Cortisol deficiency would impair water excretion causing volume expansion, and aldosterone deficiency would cause sodium loss and raised renin. Paradoxically, volume expansion without sodium retention and raised renin has all been reported in tolerance. Copyright 2000 Academic Press.

Exposure of growing and adult captive cheetahs (Acinonyx jubatus) to dietary isoflavones: twenty years later.

PubMed

Bell, K M; Rutherfurd, S M; Hendriks, W H

2010-12-01

Dietary isoflavones are associated with oestrogenic and anti-oestrogenic effects, and have been linked to infertility in cheetahs. This study aimed to determine the isoflavone content of commercially prepared diets consumed by captive cheetahs. Sixteen international zoological facilities provided diets, and the isoflavone content of each diet was determined by acid hydrolysis and HPLC quantification. Proximate nutritional composition was also determined. Over half the diets analysed contained detectable concentrations of isoflavones, whereby total isoflavone content ranged from 1.75-183 mg/kg dry matter. The zoo-specific diets were calculated to deliver a median isoflavone dose of 0.07 mg/kg body weight (BW) and a maximum of 1.95 mg/kg BW to captive cheetahs. On a metabolic body weight basis this equates to a maximum of 4.90-5.43 mg/kg(0.75) . Some diets prepared for hand-rearing neonatal cheetahs could expose neonates to doses of up to 4.24 mg/kg BW (or 4.24-6.33 mg/kg(0.75) for cubs under 3 months of age). Only one of six zoo-specific diets was found to deliver isoflavones in doses shown to possess biological activity in other species. Therefore, on average, dietary isoflavones were not found in commercially prepared diets consumed by captive cheetahs in concentrations predicted to cause physiological changes. However, a small proportion of these diets, including hand-rearing formulas, contained elevated isoflavones concentrations which may influence cheetah fertility, behaviour or other physiological parameters. © 2010 Blackwell Verlag GmbH.

Influence of 10 wk of soy consumption on plasma concentrations and excretion of isoflavonoids and on gut microflora metabolism in healthy adults.

PubMed

Wiseman, Helen; Casey, Karen; Bowey, Elizabeth A; Duffy, Rosanna; Davies, Margaret; Rowland, Ian R; Lloyd, Antony S; Murray, Alistair; Thompson, Richard; Clarke, Don B

2004-09-01

Little information is currently available on the role of the gut microflora in modulating isoflavone bioavailability or on sex differences in isoflavone metabolism and bioavailability. We sought to determine whether chronic soy consumption influences isoflavone bioavailability as judged by plasma isoflavone concentrations and modified gut microflora activities [beta-glucoside hydrolysis and equol and O-desmethylangolensin (O-DMA) production]. We also examined whether sex differences in isoflavone metabolism exist. A randomized, parallel, controlled study design was used to compare a high-soy diet (104 +/- 24 mg total isoflavones/d) with a low-soy diet (0.54 +/- 0.58 mg total isoflavones/d) in 76 healthy young adults for 10 wk. Concentrations of isoflavones and their gut microflora metabolites in the plasma, urine, and feces were significantly higher in the subjects who consumed the high-soy diet than in those who consumed the low-soy diet. Concentrations of O-DMA in plasma and urine were higher in the men than in the women. Fecal bacteria from subjects consuming both diets could convert daidzein to equol ex vivo. Fecal beta-glucosidase activity was significantly higher in the subjects who consumed the high-soy diet than in those who consumed the low-soy diet. Although interindividual variation in isoflavone metabolism was high, intraindividual variation was low. Only concentrations of O-DMA in plasma and urine appeared to be influenced by sex. Chronic soy consumption does not appear to induce many significant changes to the gut metabolism of isoflavones other than higher beta-glucosidase activity.

Relationship between daily isoflavone intake and sleep in Japanese adults: a cross-sectional study.

PubMed

Cui, Yufei; Niu, Kaijun; Huang, Cong; Momma, Haruki; Guan, Lei; Kobayashi, Yoritoshi; Guo, Hui; Chujo, Masahiko; Otomo, Atsushi; Nagatomi, Ryoichi

2015-12-29

Isoflavones comprise a class of phytoestrogens that resemble human estrogen in chemical structure, and have weak estrogenic effects. Because estrogen modulates sleep duration and quality, we hypothesized that isoflavones would have a beneficial effect on sleep status in a way similar to estrogen. We conducted a cross-sectional study to investigate the relationship between daily isoflavone intake and sleep status in Japanese subjects. Our study included 1076 Japanese adults aged 20-78 years. Daily isoflavone intake was assessed using a brief self-administered diet history questionnaire, and sleep was evaluated using a self-reported questionnaire. The prevalence of regular sleep duration (7-8 h/day) and sufficient sleep quality were 13.3% and 56.2%, respectively. After adjusting for potential confounding factors, the odds ratios (95% CIs) for optimal sleep duration (7-8 h) when higher isoflavone intakes (Q2-Q4) were compared with low isoflavone intake (Q1) were Q2: 0.94 (0.53-1.56); Q3: 1.28 (0.73-2.24); and Q4: 1.84 (1.06-3.18) (p for trend = 0.013). In the final adjusted model, sufficient sleep quality across categories of isoflavone intake was Q1: 1.00 (reference); Q2: 1.30 (0.91-1.84); Q3: 1.48 (1.03-2.12); and Q4: 1.78 (1.22-2.60); (p for trend = 0.002). Higher daily isoflavone intake was positively associated with optimal sleep duration and quality in a Japanese population. This finding suggests that daily isoflavone intake may have a potentially beneficial effect on sleep status.

Prevalence of the equol-producer phenotype and its relationship with dietary isoflavone and serum lipids in healthy Chinese adults.

PubMed

Liu, Baohua; Qin, Liqiang; Liu, Aiping; Uchiyama, Shigeto; Ueno, Tomomi; Li, Xuetuo; Wang, Peiyu

2010-01-01

Studies have suggested that daidzein-metabolizing phenotypes have beneficial effects on a range of health outcomes. We investigated the prevalence of equol producers and the relationship of equol phenotype with habitual isoflavone consumption and serum lipid concentrations in 200 Chinese adults in Beijing. After the baseline survey and dietary records, 200 healthy adults in Beijing were challenged with a soy-isoflavone supplement for 3 days; 24-hour urine samples were collected before and after the challenge. Isoflavones and their metabolites in urine were measured to determine equol phenotype. Serum lipids, uric acid, and other biochemical markers were also measured. Only 26.8% of the participants excreted equol when on a regular diet, as compared with 60.4% after the challenge. After the challenge, urinary isoflavonoid excretion increased in all participants, while equol excretion increased only in equol producers. Isoflavone intake was correlated with urinary isoflavone (range r = 0.49-0.58, P < 0.01). As compared with nonproducers, equol producers were less likely to consume cereals (P < 0.001). There was no significant correlation between serum lipids and isoflavone intake. Serum lipids were not significantly affected by equol phenotype. Urinary equol excretion was detected in about 25% of participants under their usual dietary conditions. Their potential to produce equol was increased after the challenge. Urinary isoflavone levels may serve as a useful biomarker for isoflavone intake in populations. We observed an association between equol phenotype and cereal intake. Our findings also suggest that dietary isoflavone intake has no significant effect on serum lipids in healthy participants, regardless of equol phenotype.

Exposure to isoflavone-containing soy products and endothelial function: a Bayesian meta-analysis of randomized controlled trials.

PubMed

Beavers, D P; Beavers, K M; Miller, M; Stamey, J; Messina, M J

2012-03-01

To determine whether and to what degree exposure to isoflavone-containing soy products affects EF. Endothelial dysfunction has been identified as an independent coronary heart disease risk factor and a strong predictor of long-term cardiovascular morbidity and mortality. Data on the effects of exposure to isoflavone-containing soy products on EF are conflicting. A comprehensive literature search was conducted using the PUBMED database (National Library of Medicine, Bethesda, MD) inclusively through August 21, 2009 on RCTs using the keywords: soy, isoflavone, phytoestrogen, EF, flow mediated vasodilation, and FMD. A Bayesian meta-analysis was conducted to provide a comprehensive account of the effect of isoflavone-containing soy products on EF, as measured by FMD. A total of 17 RCTs were selected as having sufficient data for study inclusion. The overall mean absolute change in FMD (95% Bayesian CI) for isoflavone-containing soy product interventions was 1.15% (-0.52, 2.75). When the effects of separate interventions were considered, the treatment effect for isolated isoflavones was 1.98% (0.07, 3.97) compared to 0.72% (-1.39, 2.90) for isoflavone-containing soy protein. The models were not improved when considering study-specific effects such as cuff measurement location, prescribed dietary modification, and impaired baseline FMD. Cumulative evidence from the RCTs included in this meta-analysis indicates that exposure to soy isoflavones can modestly, but significantly, improve EF as measured by FMD. Therefore, exposure to isoflavone supplements may beneficially influence vascular health. Copyright © 2010 Elsevier B.V. All rights reserved.

The effects of soy milk and isoflavone supplements on cognitive performance in healthy, postmenopausal women.

PubMed

Fournier, L R; Ryan Borchers, T A; Robison, L M; Wiediger, M; Park, J S; Chew, B P; McGuire, M K; Sclar, D A; Skaer, T L; Beerman, K A

2007-01-01

The decline in estrogen concentrations in women after menopause can contribute to health related changes including impairments in cognition, especially memory. Because of the health concerns related to hormone replacement therapy (HRT), alternative approaches to treat menopausal symptoms, such as nutritional supplements and/or diet containing isoflavones, are of interest. This study investigated whether soy isoflavones (soy milk and supplement) could improve cognitive functioning in healthy, postmenopausal women. PARTICIPANTS, INTERVENTION AND DESIGN: A total of 79 postmenopausal women, 48-65 years of age, completed a double-blind, placebo-controlled trial in which they were randomly assigned to one of three experimental groups: cow's milk and a placebo supplement (control); soy milk and placebo supplement (soy milk, 72 mg isoflavones/day); or cow's milk and isoflavone supplement (isoflavone supplement, 70 mg isoflavones/day). Cognitive functioning was assessed using various cognitive tasks before the intervention (baseline) and after the intervention (test). In contrast to predictions, soy isoflavones did not improve selective attention (Stroop task), visual long-term memory (pattern recognition), short-term visuospatial memory (Benton Visual Retention Test), or visuo-spatial working memory (color match task). Also, the soy milk group showed a decline in verbal working memory (Digit Ordering Task) compared to the soy supplement and control groups. Soy isoflavones consumed as a food or supplement over a 16-week period did not improve or appreciably affect cognitive functioning in healthy, postmenopausal women.

Determination of isoflavones in soy and selected foods containing soy by extraction, saponification, and liquid chromatography: collaborative study.

PubMed

Klump, S P; Allred, M C; MacDonald, J L; Ballam, J M

2001-01-01

Isoflavones are biologically active compounds occurring naturally in a variety of plants, with relatively high levels found in soybeans. Twelve laboratories participated in a collaborative study to determine the aglycon isoflavone content of 8 test samples of soy and foods containing soy. The analytical method for the determination of isoflavones incorporates a mild saponification step that reduces the number of analytes measured and permits quantitation versus commercially available, stable reference standards. Test samples were extracted at 65 degrees C with methanol-water (80 + 20), saponified with dilute sodium hydroxide solution, and analyzed by reversed-phase liquid chromatography with UV detection at 260 nm. Isoflavone results were reported as microg/aglycon/g or microg aglycon equivalents/g. The 8 test samples included 2 blind duplicates and 4 single test samples with total isoflavone concentrations ranging from approximately 50 to 3000 microg/g. Test samples of soy ingredients and products made with soy were distributed to collaborators with appropriate reference standards. Collaborators were asked to analyze test samples in duplicate on 2 separate days. The data were analyzed for individual isoflavone components, subtotals of daidzin-daidzein, glycitin-glycitein, and genistin-genistein, and total isoflavones. The relative standard deviation (RSD) for repeatability was 1.8-7.1%, and the RSD for reproducibility was 3.2-16.1% for total isoflavone values of 47-3099 microg/g.

Omega-3 versus isoflavones in the control of vasomotor symptoms in postmenopausal women.

PubMed

Palacios, S; Lilue, M; Mejia, A; Menendez, C

2017-12-01

Determine the efficacy and tolerability of omega-3 fatty acids versus soybean isoflavones in reducing the vasomotor symptoms (VMSs) frequency in postmenopausal women. A randomized, prospective, two-arm study was performed in healthy postmenopausal women aged 45-65. The two arms were: two capsules/day of omega-3 (425 mg of omega-3/capsule) administered orally (n = 38) and two tablets/day of soybean isoflavones (54.4 mg of isoflavones/tablet) (n = 30), over 16 weeks. The mean baseline frequency of moderate and severe VMSs per week in the omega-3 group was 24.56 and 23.90, respectively, and 19.65 and 19.51 in the isoflavone group. After 4 months, the reduction in moderate and severe hot flashes with omega-3 was significant (p < .001), whereas in the case of isoflavones, there was a significant difference in severe (p = .02) hot flashes after 4 months, but not in moderate hot flashes (p = .077). Omega-3 did not demonstrate significant efficacy differences versus isoflavones over time. The use of omega-3 has a beneficial effect on hot flash reduction after 4 months of treatment. This is comparable to the benefits found with soybean isoflavones after 3-4 weeks and after 4 months in severe hot flash women, but higher than those found with soybean isoflavones in moderate symptom women.

Isoflavonoid content of Hong Kong soy foods.

PubMed

Chan, Sieu G; Murphy, Patricia A; Ho, Suzanne C; Kreiger, Nancy; Darlington, Gerarda; So, Edwin K F; Chong, Portia Y Y

2009-06-24

Progress in understanding the effects of dietary soy isoflavones on chronic disease prevention in the Hong Kong Chinese population has been hampered by the lack of a comprehensive soy isoflavone database. In this study, we determined the concentrations and distribution of isoflavones in 47 foods included in a soy food frequency questionnaire by reverse-phase HPLC. Results indicated that most soy products contained isoflavones ranging from 1 mg of aglucon equivalents/100 g of wet weight (bean strip noodle and egg bean curd) to 80 mg of aglucon equivalents/100 g of wet weight (oyster sauce soybean and sweet bean curd sheet). Among our food groups, mean isoflavone concentrations were lowest in the soy milk group (9.99 mg of aglucon equivalents/100 g of wet weight) and highest in the bean curd skin group (40 mg of aglucon equivalents/100 g of wet weight). The conjugation patterns of isoflavones varied within and between food groups as influenced by the types of soybeans and the processing or cooking techniques used. The isoflavone concentrations reported herein will be useful for ascertaining the relationship between exposure to dietary soy isoflavones and health effects in the Chinese population.

Soybean isoflavone ameliorates β-amyloid 1-42-induced learning and memory deficit in rats by protecting synaptic structure and function.

PubMed

Ding, Juan; Xi, Yuan-Di; Zhang, Dan-Di; Zhao, Xia; Liu, Jin-Meng; Li, Chao-Qun; Han, Jing; Xiao, Rong

2013-12-01

This research aims to investigate whether soybean isoflavone (SIF) could alleviate the learning and memory deficit induced by β-amyloid peptides 1-42 (Aβ 1-42) by protecting the synapses of rats. Adult male Wistar rats were randomly allocated to the following groups: (1) control group; (2) Aβ 1-42 group; (3) SIF group; (4) SIF + Aβ 1-42 group (SIF pretreatment group) according to body weight. The 80 mg/kg/day of SIF was administered orally by gavage to the rats in SIF and SIF+Aβ 1-42 groups. Aβ 1-42 was injected into the lateral cerebral ventricle of rats in Aβ 1-42 and SIF+Aβ 1-42 groups. The ability of learning and memory, ultramicrostructure of hippocampal synapses, and expression of synaptic related proteins were investigated. The Morris water maze results showed the escape latency and total distance were decreased in the rats of SIF pretreatment group compared to the rats in Aβ1-42 group. Furthermore, SIF pretreatment could alleviate the synaptic structural damage and antagonize the down-regulation expressions of below proteins induced by Aβ1-42: (1) mRNA and protein of the synaptophysin and postsynaptic density protein 95 (PSD-95); (2) protein of calmodulin (CaM), Ca(2+) /calmodulin-dependent protein kinase II (CaMK II), and cAMP response element binding protein (CREB); (3) phosphorylation levels of CaMK II and CREB (pCAMK II, pCREB). These results suggested that SIF pretreatment could ameliorate the impairment of learning and memory ability in rats induced by Aβ 1-42, and its mechanism might be associated with the protection of synaptic plasticity by improving the synaptic structure and regulating the synaptic related proteins. Copyright © 2013 Wiley Periodicals, Inc.

The antiestrogen ICI 182,780 decreases the expression of estrogen receptor-alpha but has no effect on estrogen receptor-beta and androgen receptor in rat efferent ductules

PubMed Central

Oliveira, Cleida A; Nie, Rong; Carnes, Kay; Franca, Luiz R; Prins, Gail S; Saunders, Philippa TK; Hess, Rex A

2003-01-01

Background The antiestrogen ICI 182,780 has been used successfully as an alternative experimental model for the study of estrogen action in the rodent adult male reproductive tract. Although ICI 182,780 causes severe alterations in testicular and efferent ductule morphology and function, the effects on the expression of estrogen and androgen receptors in the male have not been shown. Methods In the present study, adult male rats were treated with ICI 182,780 for 7 to 150 days, to evaluate the time-response effects of the treatment on the pattern of ERα, ERβ and AR protein expression in the efferent ductules. The receptors were localized using immunohistochemistry. Results ERα, ERβ and AR have distinct cellular distribution in the testis and efferent ductules. Staining for ERα is nearly opposite of that for ERβ, as ERα shows an increase in staining intensity from proximal to distal efferent ductules, whereas ERβ shows the reverse. Androgen receptor follows that of ERα. ICI 182,780 caused a gradual but dramatic decrease in ERα expression in the testis and efferent ductules, but no change in ERβ and AR expression. Conclusions The differential response of ERα and ERβ proteins to ICI 182,780 indicates that these receptors are regulated by different mechanisms in the male reproductive tract. PMID:14613549

Nucleoporin 62 and Ca(2+)/calmodulin dependent kinase kinase 2 regulate androgen receptor activity in castrate resistant prostate cancer cells.

PubMed

Karacosta, Loukia G; Kuroski, Laura A; Hofmann, Wilma A; Azabdaftari, Gissou; Mastri, Michalis; Gocher, Angela M; Dai, Shuhang; Hoste, Allen J; Edelman, Arthur M

2016-02-15

Re-activation of the transcriptional activity of the androgen receptor (AR) is an important factor mediating progression from androgen-responsive to castrate-resistant prostate cancer (CRPC). However, the mechanisms regulating AR activity in CRPC remain incompletely understood. Ca(2+) /calmodulin-dependent kinase kinase (CaMKK) 2 was previously shown to regulate AR activity in androgen-responsive prostate cancer cells. Our objective was to further explore the basis of this regulation in CRPC cells. The abundance of CaMKK2 in nuclear fractions of androgen-responsive prostate cancer and CRPC, cells were determined by subcellular fractionation and Western blotting. CaMKK2 association with nuclear pore complexes (NPCs) and nucleoporins (Nups) including Nup62, were imaged by structured illumination and super-resolution fluorescence microscopy and co-immunoprecipitation, respectively. The abundance and subcellular localization of CaMKK2 and Nup62 in human clinical specimens of prostate cancer was visualized by immunohistochemistry. The role of Nups in the growth and viability of CRPC cells was assessed by RNA interference and cell counting. The involvement of CaMKK2 and Nup62 in regulating AR transcriptional activity was addressed by RNA interference, chromatin immunoprecipitation, androgen response element reporter assay, and Western blotting. CaMKK2 was expressed at higher levels in the nuclear fraction of CPRC C4-2 cells, than in that of androgen-responsive LNCaP cells. In C4-2 cells, CaMKK2 associated with NPCs of the nuclear envelope and physically interacted with Nup62. CaMKK2 and Nup62 demonstrated pronounced, and similar increases in both expression and perinuclear/nuclear localization in human clinical specimens of advanced prostate cancer relative to normal prostate. Knockdown of Nup62, but not of Nups, 98 or 88, reduced growth and viability of C4-2 cells. Knockdown of Nup62 produced a greater reduction of the growth and viability of C4-2 cells than of non-neoplastic RWPE-1 prostatic cells. Nup62, CaMKK2, and the AR were recruited to androgen response elements of the AR target genes, prostate specific antigen, and transmembrane protease, serine 2. Knockdown of CaMKK2 and Nup62 reduced prostate specific antigen expression and AR transcriptional activity driven by androgen response elements from the prostate-specific probasin gene promoter. Nup62 and CaMKK2 are required for optimal AR transcriptional activity and a potential mechanism for AR re-activation in CRPC. © 2015 Wiley Periodicals, Inc.

Elevated YKL40 is associated with advanced prostate cancer (PCa) and positively regulates invasion and migration of PCa cells

PubMed Central

Jeet, Varinder; Tevz, Gregor; Lehman, Melanie; Hollier, Brett; Nelson, Colleen

2014-01-01

Chitinase 3-like 1 (CHI3L1 or YKL40) is a secreted glycoprotein highly expressed in tumours from patients with advanced stage cancers, including prostate cancer (PCa). The exact function of YKL40 is poorly understood, but it has been shown to play an important role in promoting tumour angiogenesis and metastasis. The therapeutic value and biological function of YKL40 are unknown in PCa. The objective of this study was to examine the expression and function of YKL40 in PCa. Gene expression analysis demonstrated that YKL40 was highly expressed in metastatic PCa cells when compared with less invasive and normal prostate epithelial cell lines. In addition, the expression was primarily limited to androgen receptor-positive cell lines. Evaluation of YKL40 tissue expression in PCa patients showed a progressive increase in patients with aggressive disease when compared with those with less aggressive cancers and normal controls. Treatment of LNCaP and C4-2B cells with androgens increased YKL40 expression, whereas treatment with an anti-androgen agent decreased the gene expression of YKL40 in androgen-sensitive LNCaP cells. Furthermore, knockdown of YKL40 significantly decreased invasion and migration of PCa cells, whereas overexpression rendered them more invasive and migratory, which was commensurate with an enhancement in the anchorage-independent growth of cells. To our knowledge, this study characterises the role of YKL40 for the first time in PCa. Together, these results suggest that YKL40 plays an important role in PCa progression and thus inhibition of YKL40 may be a potential therapeutic strategy for the treatment of PCa. PMID:24981110

Elevated YKL40 is associated with advanced prostate cancer (PCa) and positively regulates invasion and migration of PCa cells.

PubMed

Jeet, Varinder; Tevz, Gregor; Lehman, Melanie; Hollier, Brett; Nelson, Colleen

2014-10-01

Chitinase 3-like 1 (CHI3L1 or YKL40) is a secreted glycoprotein highly expressed in tumours from patients with advanced stage cancers, including prostate cancer (PCa). The exact function of YKL40 is poorly understood, but it has been shown to play an important role in promoting tumour angiogenesis and metastasis. The therapeutic value and biological function of YKL40 are unknown in PCa. The objective of this study was to examine the expression and function of YKL40 in PCa. Gene expression analysis demonstrated that YKL40 was highly expressed in metastatic PCa cells when compared with less invasive and normal prostate epithelial cell lines. In addition, the expression was primarily limited to androgen receptor-positive cell lines. Evaluation of YKL40 tissue expression in PCa patients showed a progressive increase in patients with aggressive disease when compared with those with less aggressive cancers and normal controls. Treatment of LNCaP and C4-2B cells with androgens increased YKL40 expression, whereas treatment with an anti-androgen agent decreased the gene expression of YKL40 in androgen-sensitive LNCaP cells. Furthermore, knockdown of YKL40 significantly decreased invasion and migration of PCa cells, whereas overexpression rendered them more invasive and migratory, which was commensurate with an enhancement in the anchorage-independent growth of cells. To our knowledge, this study characterises the role of YKL40 for the first time in PCa. Together, these results suggest that YKL40 plays an important role in PCa progression and thus inhibition of YKL40 may be a potential therapeutic strategy for the treatment of PCa. © 2014 The authors.

Orchidectomy of middle-aged rats decreases liver deiodinase 1 and pituitary deiodinase 2 activity.

PubMed

Sosic-Jurjevic, Branka; Filipovic, Branko; Renko, Kostja; Ajdzanovic, Vladimir; Manojlovic-Stojanoski, Milica; Milosevic, Verica; Köhrle, Josef

2012-11-01

Endogenous androgens are involved in regulation of thyroid function and metabolism of thyroid hormones. As serum testosterone level progressively declines with age, this regulation may change. We tested how androgen deprivation, achieved by orchidectomy, affects thyroid homeostasis in middle-aged rats. Fifteen-month-old Wistar rats were orchidectomized (Orx) or sham-operated under ketamine anesthesia (15 mg/kg body weight). Five weeks after the surgery, animals were decapitated. Thyroids were used for histomorphometric and ultrastructural examinations and together with livers and pituitaries for real-time quantitative PCR and deiodinase (DIO) activity measurements. Serum testosterone, TSH, l-thyroxine (T(4)), and cholesterol (Chol) levels were determined. As expected, middle-aged control rats had lower (P<0.05) testosterone and T(4) compared with 3-month-old males. In the Orx middle-aged group, we detected diminished serum testosterone (P<0.05), no change in TSH and T(4) levels, and higher Chol level (P<0.05), in comparison with age-matched controls. Histomorphometric analysis of thyroid tissue revealed decreased relative volume densities of follicles and colloid (P<0.05). Relevant gene expressions and DIO1 enzyme activity were not changed in the thyroids of Orx rats. Liver Dio1 gene expression and DIO1 activity were decreased (P<0.05) in comparison with the control values. Pituitary levels of TSHβ, Dio1, and Dio2 mRNAs did not change, while DIO2 activity decreased (P<0.05). In conclusion, orchidectomy of middle-aged rats affected thyroid structure with no effect on serum T(4) and TSH. However, decreased liver DIO1 and pituitary DIO2 enzyme activities indicate compensatory-adaptive changes in local T(3) production.

Androgens inhibit adipogenesis during human adipose stem cell commitment to predipocyte formation

PubMed Central

Chazenbalk, Gregorio; Singh, Prapti; Irge, Dana; Shah, Amy; Abbott, David H; Dumesic, Daniel A

2013-01-01

Androgens play a pivotal role in the regulation of body fat distribution. Adipogenesis is a process whereby multipotent adipose stem cells (ASCs) initially become preadipocytes (ASC commitment to preadipocytes) before differentiating into adipocytes. Androgens inhibit human (h) subcutaneous (SC) abdominal preadipocyte differentiation in both sexes, but their effects on hASC commitment to preadipocyte formation is unknown. We therefore examined whether androgen exposure to human (h) ASCs, isolated from SC abdominal adipose of nonobese women, impairs their commitment to preadipocyte formation and/or subsequent differentiation into adipocytes. For this, isolated hASCs from SC abdominal lipoaspirate were cultured in adipogenesis-inducing medium for 0.5–14 days in the presence of testosterone (T, 0–100 nM) or dihydrotestosterone (DHT, 0–50 nM). Adipogenesis was determined by immunofluorescence microscopy and by quantification of adipogenically relevant transcriptional factors, PPARγ, C/EBPα and C/EBPβ. We found that a 3-day exposure of hASCs to T (50 nM) or DHT (5 nM) in adipogenesis-inducing medium impaired lipid acquisition and decreased PPARγ, C/EBPα and C/EBPβ gene expression. The inhibitory effects of T and DHT at this early-stage of adipocyte differentiation, were partially and completely reversed by flutamide (F, 100 nM), respectively. The effect of androgens on hASC commitment to a preadipocyte phenotype was examined via activation of BMP4 signaling. T (50 nM) and DHT (5nM) significantly inhibited the stimulatory effect of BMP4-induced ASC commitment to the preadipocyte phenotype, as regards PPARγ and C/EBPα gene expression. Our findings indicate that androgens, in part through androgen receptor action, impair BMP4-induced commitment of SC hASCs to preadipocytes and also reduce early-stage adipocyte differentiation, perhaps limiting adipocyte numbers and fat storage in SC abdominal adipose. PMID:23707571

Aromatase inhibitor letrozole downregulates steroid receptor coactivator-1 in specific brain regions that primarily related to memory, neuroendocrine and integration.

PubMed

Bian, Chen; Zhao, Yangang; Guo, Qiang; Xiong, Ying; Cai, Wenqin; Zhang, Jiqiang

2014-05-01

As one of the third generation of aromatase inhibitors, letrozole is a favored drug for the treatment of hormone receptor-positive breast cancer with some adverse effects on the nervous system, but the knowledge is limited and the results are controversial, the mechanism underlying its central action is also unclear. Accumulated evidences have demonstrated that estrogens derived from androgens by aromatase play profound roles in the brain through their receptors, which needs coactivator for the transcription regulation, among which steroid receptor coactivator-1 (SRC-1) has been shown to be multifunctional potentials in the brain, but whether it is regulated by letrozole is currently unknown. In this study, we examined letrozole regulation on SRC-1 expression in adult mice brain using immunohistochemistry. The results showed that letrozole induced dramatic decrease of SRC-1 in the medial septal, hippocampus, medial habenular nucleus, arcuate hypothalamic nucleus and superior colliculus (p<0.01). Significant decrease was detected in the dorsal lateral septal nucleus, bed nucleus of stria terminalis, ventral taenia tecta, dorsomedial and ventromedial hypothalamic nuclei, dorsomedial periaqueductal gray, superior paraolivary nucleus and pontine nucleus (p<0.05). In the hippocampus, levels of estradiol content, androgen receptor, estrogen receptor α and β also decreased significantly after letrozole injection. The above results demonstrated letrozole downregulation of SRC-1 in specific regions that are primarily related to learning and memory, cognition and mood, neuroendocrine as well as information integration, indicating that SRC-1 may be one important downstream central target of letrozole. Furthermore, these potential central adverse effects of letrozole should be taken into serious considerations. Copyright © 2014 Elsevier Ltd. All rights reserved.

Comparative effect of soy protein, soy isoflavones, and 17beta-estradiol on bone metabolism in adult ovariectomized rats.

PubMed

Cai, David J; Zhao, Yongdong; Glasier, Jennifer; Cullen, Diane; Barnes, Stephen; Turner, Charles H; Wastney, Meryl; Weaver, Connie M

2005-05-01

This study provided a comprehensive investigation on the effect of soy protein and soy isoflavones on both calcium and bone metabolism in virgin adult rats. The measurements included bone histology, calcium kinetic modeling, calcium balance, bone densitometry, and whole body densitometry. Results confirmed the bone-preserving effect of estrogen but did not support a bone-sparing role of soy isoflavones. Several animal and short-term human studies have indicated that soy protein isolate enriched with isoflavones may be used as an alternative therapy to estrogen replacement therapy. However, none of the previous studies have investigated this estrogenic effect on both calcium and bone metabolism in animals or humans, which is essential in ascertaining the mode of action of isoflavones. This study was designed to determine the effects of soy protein versus isoflavones on calcium and bone metabolism in an ovariectomized rat model. Unmated 6-month-old ovariectomized and sham-operated female Sprague-Dawley rats were randomly assigned to nine groups (16 rats/group) and pair-fed soy- or casein-based diets with or without isoflavones for 8 weeks. A reference group was administered estrogen through subcutaneous implants (20-35 pg/liter plasma). Bone densitometry, histomorphometry, and mechanical testing were used to study bone metabolism and quality. Calcium metabolism was studied using calcium tracer balance and kinetics. After ovariectomy, estrogen prevented bone loss in trabecular bone and suppressed formation on both trabecular and cortical bone surfaces. Isoflavones given as enriched soy protein isolate or supplements did not prevent trabecular bone loss. Combining isoflavones with estrogen had no additional benefits over estrogen alone. There were no differences in response to isoflavones caused by protein source. None of the treatments significantly affected either total Ca balance or (45)Ca absorption. However, soy protein showed significant effects on reducing urinary loss of Ca in animals, irrespective of isoflavone level, perhaps because of the lower amount of sulfur-containing amino acids in soy protein. Estrogen, but not isoflavones at the levels tested, suppressed bone remodeling in both trabecular and cortical bone after ovariectomy.

Androgen Stimulates Growth of Mouse Preantral Follicles In Vitro: Interaction With Follicle-Stimulating Hormone and With Growth Factors of the TGFβ Superfamily

PubMed Central

Laird, Mhairi; Thomson, Kacie; Fenwick, Mark; Mora, Jocelyn; Hardy, Kate

2017-01-01

Androgens are essential for the normal function of mature antral follicles but also have a role in the early stages of follicle development. Polycystic ovary syndrome (PCOS), the most common cause of anovulatory infertility, is characterized by androgen excess and aberrant follicle development that includes accelerated early follicle growth. We have examined the effects of testosterone and dihydrotestosterone (DHT) on development of isolated mouse preantral follicles in culture with the specific aim of investigating interaction with follicle-stimulating hormone (FSH), the steroidogenic pathway, and growth factors of the TGFβ superfamily that are known to have a role in early follicle development. Both testosterone and DHT stimulated follicle growth and augmented FSH-induced growth and increased the incidence of antrum formation among the granulosa cell layers of these preantral follicles after 72 hours in culture. Effects of both androgens were reversed by the androgen receptor antagonist flutamide. FSH receptor expression was increased in response to both testosterone and DHT, as was that of Star, whereas Cyp11a1 was down-regulated. The key androgen-induced changes in the TGFβ signaling pathway were down-regulation of Amh, Bmp15, and their receptors. Inhibition of Alk6 (Bmpr1b), a putative partner for Amhr2 and Bmpr2, by dorsomorphin resulted in augmentation of androgen-stimulated growth and modification of androgen-induced gene expression. Our findings point to varied effects of androgen on preantral follicle growth and function, including interaction with FSH-activated growth and steroidogenesis, and, importantly, implicate the intrafollicular TGFβ system as a key mediator of androgen action. These findings provide insight into abnormal early follicle development in PCOS. PMID:28324051

Androgen Stimulates Growth of Mouse Preantral Follicles In Vitro: Interaction With Follicle-Stimulating Hormone and With Growth Factors of the TGFβ Superfamily.

PubMed

Laird, Mhairi; Thomson, Kacie; Fenwick, Mark; Mora, Jocelyn; Franks, Stephen; Hardy, Kate

2017-04-01

Androgens are essential for the normal function of mature antral follicles but also have a role in the early stages of follicle development. Polycystic ovary syndrome (PCOS), the most common cause of anovulatory infertility, is characterized by androgen excess and aberrant follicle development that includes accelerated early follicle growth. We have examined the effects of testosterone and dihydrotestosterone (DHT) on development of isolated mouse preantral follicles in culture with the specific aim of investigating interaction with follicle-stimulating hormone (FSH), the steroidogenic pathway, and growth factors of the TGFβ superfamily that are known to have a role in early follicle development. Both testosterone and DHT stimulated follicle growth and augmented FSH-induced growth and increased the incidence of antrum formation among the granulosa cell layers of these preantral follicles after 72 hours in culture. Effects of both androgens were reversed by the androgen receptor antagonist flutamide. FSH receptor expression was increased in response to both testosterone and DHT, as was that of Star, whereas Cyp11a1 was down-regulated. The key androgen-induced changes in the TGFβ signaling pathway were down-regulation of Amh, Bmp15, and their receptors. Inhibition of Alk6 (Bmpr1b), a putative partner for Amhr2 and Bmpr2, by dorsomorphin resulted in augmentation of androgen-stimulated growth and modification of androgen-induced gene expression. Our findings point to varied effects of androgen on preantral follicle growth and function, including interaction with FSH-activated growth and steroidogenesis, and, importantly, implicate the intrafollicular TGFβ system as a key mediator of androgen action. These findings provide insight into abnormal early follicle development in PCOS.

Regulation of protein kinase C-related kinase (PRK) signalling by the TPα and TPβ isoforms of the human thromboxane A2 receptor: Implications for thromboxane- and androgen- dependent neoplastic and epigenetic responses in prostate cancer.

PubMed

O'Sullivan, Aine G; Mulvaney, Eamon P; Kinsella, B Therese

2017-04-01

The prostanoid thromboxane (TX) A 2 and its T Prostanoid receptor (the TP) are increasingly implicated in prostate cancer (PCa). Mechanistically, we recently discovered that both TPα and TPβ form functional signalling complexes with members of the protein kinase C-related kinase (PRK) family, AGC- kinases essential for the epigenetic regulation of androgen receptor (AR)-dependent transcription and promising therapeutic targets for treatment of castrate-resistant prostate cancer (CRPC). Critically, similar to androgens, activation of the PRKs through the TXA 2 /TP signalling axis induces phosphorylation of histone H3 at Thr11 (H3Thr11), a marker of androgen-induced chromatin remodelling and transcriptional activation, raising the possibility that TXA 2 -TP signalling can mimic and/or enhance AR-induced cellular changes even in the absence of circulating androgens such as in CRPC. Hence the aim of the current study was to investigate whether TXA 2 /TP-induced PRK activation can mimic and/or enhance AR-mediated cellular responses in the model androgen-responsive prostate adenocarcinoma LNCaP cell line. We reveal that TXA 2 /TP signalling can act as a neoplastic- and epigenetic-regulator, promoting and enhancing both AR-associated chromatin remodelling (H3Thr11 phosphorylation, WDR5 recruitment and acetylation of histone H4 at lysine 16) and AR-mediated transcriptional activation (e.g of the KLK3/prostate-specific antigen and TMPRSS2 genes) through mechanisms involving TPα/TPβ mediated-PRK1 and PRK2, but not PRK3, signalling complexes. Overall, these data demonstrate that TPα/TPβ can act as neoplastic and epigenetic regulators by mimicking and/or enhancing the actions of androgens within the prostate and provides further mechanistic insights into the role of the TXA 2 /TP signalling axis in PCa, including potentially in CRPC. Copyright © 2017 Elsevier B.V. All rights reserved.

Effects of dietary traditional fermented soybean on reproductive hormones, lipids, and glucose among postmenopausal women in northern Thailand.

PubMed

Sapbamrer, Ratana; Visavarungroj, Nuwat; Suttajit, Maitree

2013-01-01

Isoflavone in soybean and its products have numerous beneficial health effects. A number of clinical studies have demonstrated that dietary soy isoflavone can relieve menopausal symptoms, lower risks of breast cancer, and lower cholesterol and glucose. Among the various effects of isoflavone, the role of cholesterol and glucose reduction seems to be well documented; however, other effects such as reproductive hormones were inconclusive and inconsistent. The main objective of the present study was to investigate the effects of six-month dietary traditional fermented soybean intake on BMI, reproductive hormones, lipids, and glucose among postmenopausal women. Subjects were women with their last menstrual period occurring at least 12 months prior to selection by interview and health screening from Baan Tham Village, Phayao Province, Thailand. A total of 60 women were divided into 2 groups: experimental group (n=31) and reference group (n=29). The experimental group was permitted to continue their usual diet, and supplemented with fermented soybean for 6 months. The fermented soybean provided approximately 60 mg of isoflavone per day. The remarkable findings were that dietary fermented soybean had favorable effects on progesterone and cholesterol, but had no effects on estradiol, glucose, and triglycerides. Although estradiol and glucose in the experimental group did not change, a decrease of estradiol and an increase of glucose were found in the reference group. Our results, therefore, suggest that fermented soybean may have beneficial effects on reproductive hormones and cholesterol, and they would be warrant further detail investigations.

Metabolomic changes in follicular fluid induced by soy isoflavones administered to rats from weaning until sexual maturity

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

Wang, Wenxiang; Zhang, Wenchang, E-mail: wenchang2002@sina.com; Liu, Jin

Female Wistar rats at 21 days of age were treated with one of three concentrations of soy isoflavones (SIF) (50, 100 or 200 mg/kg body weight, orally, once per day) from weaning until sexual maturity (3 months) in order to evaluate the influence of SIF on ovarian follicle development. After treatment, the serum sex hormone levels and enumeration of ovarian follicles of the ovary were measured. The metabolic profile of follicular fluid was determined using HPLC-MS. Principal component analysis (PCA) and partial least-squares-discriminant analysis (PLS-DA) was used to identify differences in metabolites and reveal useful toxic biomarkers. The results indicatedmore » that modest doses of SIF affect ovarian follicle development, as demonstrated by decreased serum estradiol levels and increases in both ovarian follicle atresia and corpora lutea number in the ovary. SIF treatment-related metabolic alterations in follicular fluid were also found in the PCA and PLS-DA models. The 24 most significantly altered metabolites were identified, including primary sex hormones, amino acids, fatty acids and metabolites involved in energy metabolism. These findings may indicate that soy isoflavones affect ovarian follicle development by inducing metabolomic variations in the follicular fluid. - Highlights: ► Modest doses of soy isoflavones (SIF) do affect ovarian follicle development. ► SIF treatment-related metabolic alterations in follicular fluid were found. ► The 24 most significantly altered metabolites were identified.« less

Androgen dynamics in vitro in the human prostate gland. Effect of oestradiol-17β

PubMed Central

Giorgi, Eleonora P.; Stewart, Joan C.; Grant, J. K.; Shirley, I. M.

1972-01-01

Normal, hyperplastic and adenocarcinomatous human prostatic tissue was perfused in vitro with radioactively labelled androstenedione, testosterone and 5α-dihydrotestosterone with and without added oestradiol-17β. Various parameters of tissue–steroid relationship were measured at the steady state. When oestradiol (0.11 or 0.22μmol/l) was added to the perfusing medium, the entry of the steroids into the tissue and their metabolism was increased in the majority of the glands studied. The `uptake' of all the steroids varied, in response to the addition of oestradiol, in both normal and adenocarcinomatous glands in a way differing from the response of hyperplastic glands. As a consequence, the tissue clearance of the steroids, particularly of androstenedione and testosterone, increased in normal and adenocarcinomatous glands in the presence of oestradiol, and decreased in the hyperplastic tissues. At a concentration 0.33μmol/l, oestradiol decreased the entry of the steroids in all the tissues studied, while the clearance of steroids tended to decrease. The significance of these findings in terms of the regulation of androgen dynamics in vivo in the normal and diseased human prostate, with particular regard to the response to oestrogen treatment, is discussed. PMID:5075225

Prospective observational study of isoflavone and the risk of stroke recurrence: potential clinical implications beyond vascular function.

PubMed

Chan, Y-H; Lau, K-K; Yiu, K-H; Siu, C-W; Chan, H-T; Li, S-W; Tam, S; Lam, T-H; Lau, C-P; Tse, H-F

2012-04-01

Whether isoflavone has any effect on recurrent cardiovascular events is unknown. To investigate the relations between isoflavone intake and the risk of stroke recurrence. We recruited 127 consecutive patients with prior history of atherothrombotic/ hemorrhagic stroke (mean age: 67 ± 11 years, 69% male) and prospectively followed up for a mean duration of 30 months. Stroke recurrence and major adverse cardiovascular events (MACE) were documented. Brachial flow-mediated dilatation (FMD) was measured using high-resolution ultrasound. Isoflavone intake was estimated using a validated food frequency questionnaire. Median isoflavone intake was 6.9 (range: 2.1 - 14.5) mg/day. Isoflavone intake was independently associated with increased FMD (Pearson R=0.23, p=0.012). At 30 months, there were 10 stroke recurrence and 12 MACE. Kaplan-Meier analysis showed that patients with isoflavone intake higher than median value had significantly longer median stroke recurrence-free survival time (19.0 [range: 10.4 - 27.6] mth versus 5.0 [range: 4.1 - 5.9] mth, p=0.021) and MACE-free survival time (19.0 [range: 10.4 - 27.6] mth versus 4.0 [range: 2.4 - 5.6] mth, p=0.013). Using multivariate cox regression, higher isoflavone intake was an independent predictor for lower risk of stroke recurrence (hazards ratio 0.18 [95%CI: 0.03 - 0.95], risk reduction 82%, p=0.043) and MACE (hazards ratio 0.16 [95%CI: 0.03 - 0.84], risk reduction 84%, p=0.030). Higher isoflavone intake in stroke patients was associated with prolonged recurrence-free survival, and reduced risk of stroke recurrence and MACE independent of baseline vascular function. Whether isoflavone may confer clinically significant secondary protection in stroke patients should be further investigated in a randomized controlled trial.

Variable Isoflavone Contents of Red Clover Products Affect Intestinal Disposition of Biochanin A, Formononetin, Genistein and Daidzein

PubMed Central

Wang, Stephen W.J.; Chen, Yan; Joseph, Tiby; Hu, Ming

2009-01-01

Marketed red clover products use a wide variety of labels and the isoflavone contents from the lable is ambiguous. In the present study, we analyzed the content of various isoflavone products, and determined a) the content and b) how sample matrix of red clover products affects intestinal disposition of main isoflavones within it using the human intestinal Caco-2 cell model. Analysis using high and ultra-performance liquid chromatography indicates that the isoflavone content varied significantly (p<0.05) between the chosen products. Consequently, rates of isoflavone absorption across the Caco-2 cell monolayers varied (p<0.05) greatly. Unexpectedly, permeabilities of biochanin A and formononetin (two key biomarkers) were found to be significantly affected (p<0.05) by the product matrix. As expected, biochanin A was the only isoflavone with noticeable metabolite peaks in both apical and basolateral sides. Interestingly, rates of metabolism and the polarity of the glucuronidated biochanin A excretion were also significantly altered (p<0.05) by product matrix. Studies using breast cancer resistance protein inhibitor dipyridamole showed that both the apical and basolateral excretion of biochanin A glucuronides were significantly (P<0.05) reduced (7.5 and 9.4-fold, respectively) when dipyridamole is present. This provides evidence that BCRP is the main transporter responsible for the apical efflux of isoflavone glucuronides. In conclusion, the isoflavone contents of the marketed red clover products are highly variable, and product matrix significantly affected intestinal disposition of red clover isoflavones by altering their absorption rates, permeabilities, biochanin A glucuronide excretion rates, and the polarity of biochanin A glucuronide excretion. This research provides scientific evidence to support the standardization effort so that consumers can make intelligent product choices. PMID:18370585

Soy isoflavone intake is associated with risk of Kawasaki disease

PubMed Central

Portman, Michael A.; Navarro, Sandi L.; Bruce, Margaret E.; Lampe, Johanna W.

2016-01-01

Kawasaki disease (KD) is an acute vasculitis affecting children. Incidence of KD varies according to ethnicity and is highest in Asian populations. Although genetic differences may explain this variation, dietary or environmental factors could also be responsible. The objectives of this study were to determine dietary soy and isoflavone consumption in a cohort of KD children just before disease onset and their mothers' intake during pregnancy and nursing. We tested the hypothesis that soy isoflavone consumption is associated with risk of KD in US children, potentially explaining some of the ethnic-cultural variation in incidence. We evaluated soy food intake and isoflavone consumption in nearly 200 US KD cases and 200 age-matched controls using a food frequency questionnaire for children and in their mothers. We used a logistic regression model to test the association of isoflavones and KD. Maternal surveys on soy intake during pregnancy and nursing showed no significant differences in isoflavone consumption between groups. However, we identified significantly increased KD risk in children for total isoflavone (odds ratio [OR], 2.33; 95%confidence interval [CI], 1.37–3.96) and genistein (OR, 2.46; 95% CI, 1.46–4.16) intakes, when comparing high soy consumers vs nonconsumers. In addition, significantly increased KD risk occurred in Asian-American children with the highest consumption (total isoflavones: OR, 7.29; 95% CI, 1.73–30.75; genistein: OR, 8.33; 95% CI, 1.92–36.24) compared to whites. These findings indicate that childhood dietary isoflavone consumption, but not maternal isoflavone intake during pregnancy and nursing, relates to KD risk in an ethnically diverse US population. PMID:27440537

Estradiol causes the rapid accumulation of cAMP in human prostate.

PubMed Central

Nakhla, A M; Khan, M S; Romas, N P; Rosner, W

1994-01-01

Androgens are widely acknowledged to be central to the pathogenesis of benign prostatic hypertrophy (BPH). However, BPH increases in prevalence as men age, at precisely the stage of life when plasma androgens are decreasing. The decrease in total plasma androgens is amplified by an age-related increase in plasma sex hormone-binding globulin (SHBG) that results in a relatively greater decrease in free androgens than in total androgens. In addition, estrogens have long been suspected to be important in BPH, but a direct effect on the human prostate has never been demonstrated. We present data that are consistent with a role for estradiol, and for a decrease in androgens and an increase in SHBG, in the pathogenesis of BPH. We show that estradiol, but not dihydrotestosterone, acts in concert with SHBG to produce an 8-fold increase in intracellular cAMP in human BPH tissue. This increase is not blocked by an antiestrogen and is not provoked by an estrogen (diethylstilbestrol) that does not bind to SHBG, thus excluding the classic estrogen receptor as being operative in these events. Conversely, dihydrotestosterone, which blocks the binding of estradiol to SHBG, completely negates the effect of estradiol. Finally, we demonstrate that the SHBG-steroid-responsive second-messenger system is primarily localized to the prostatic stromal cells and not to the prostatic epithelial cells. Thus, we have shown a cell-specific, powerful, nontranscriptional effect of estradiol on the human prostate. PMID:7515502

Clinical Usefulness of the Histoculture Drug Response Assay for Prostate Cancer and Benign Prostate Hypertrophy (BPH).

PubMed

Hoffman, Robert M

2018-01-01

The histoculture drug response assay (HDRA) has been adapted to determine androgen sensitivity in Gelfoam histoculture of human benign prostatic tissue as well as prostate cancer. Gelfoam histoculture was used to measure androgen-independent and androgen-dependent growth of benign and malignant prostate tissue. The androgen-sensitivity index was significantly higher in 23 paired specimens of prostate cancer compared to benign prostate hypertrophy (BPH). Genistein decreased the androgen-sensitivity index of BPH and prostate cancer in Gelfoam ® histoculture in a dose-dependent manner.

Postnatal expression and androgen regulation of HOXBES2 homeoprotein in rat epididymis.

PubMed

Prabagaran, Esakki; Hegde, Uma C; Moodbidri, Sudhir B; Bandivdekar, Atmaram H; Raghavan, Vijaya P

2007-01-01

The multifunctional and androgen-regulated epididymis is known to provide a conducive microenvironment for the maturation and storage of mature spermatozoa. HOXB2 homeodomain-containing epididymis-specific sperm protein (HOXBES2), a molecule first reported by our group, exhibits cell- and region-specific expression. It was found in the cytoplasm of the principal epithelial cells with maximum in the distal segments of the rat epididymis. The present study was undertaken to determine whether HOXBES2 expression is regulated by androgens and postnatal epididymal development. Toward this, the epididymis was disallowed access to circulating androgens either by chemical or biologic castration. In bilaterally orchidectomized animals, the levels of immunoreactive HOXBES2 declined to <5 % of those seen in sham-operated animals. Exogenous dihydrotestosterone (DHT) supplementation (250 microg/kg body weight) for 7 days restored the expression levels to >or= 90 % of that observed in intact animals. Ethylene dimethane sulfonate (EDS) administration completely abolished HOXBES2 expression in the epididymis, and supplementation with DHT or DHT + estradiol for 10 days re-established HOXBES2 expression to near normalcy. However, in the estradiol alone-supplemented EDS-treated group, HOXBES2 remained undetected. The unaltered HOXBES2 expression following efferent duct ligation suggested that HOXBES2 is not critically dependent on testicular factors. During postnatal development, protein expression in the epididymis begins to appear from day 40 and 50 and increased from day 60 onward, coinciding with the mature levels of circulating androgens and the well-differentiated epididymis. Thus, the data obtained from this study suggests that HOXBES2 expression could be regulated by androgens, and its expression level is closely associated with the postnatal development of the epididymis.

Plasmacytoid dendritic cell interferon-α production to R-848 stimulation is decreased in male infants

PubMed Central

2012-01-01

Background Sex differences in response to microbial infections, especially viral ones, may be associated with Toll-like receptor (TLR)-mediated responses by plasmacytoid dendritic cells (pDCs). Results In this study, we identified sex differences in human infant pDC interferon-α production following challenge with the TLR7/8 agonist R-848. Male pDC responses were significantly lower than those of females during early infancy. This difference may be attributed to the androgen surge experienced by males during the early infancy period. Pretreatment of human pDCs with dihydrotestosterone produced a significant reduction in interferon-α production following R-848 challenge. Conclusions Androgen-mediated regulation of pDC TLR7-driven innate immune responses may contribute to the observed sex differences in response to infections during early infancy. PMID:22769054

Cytosolic androgen receptor in regenerating rat levator ani muscle.

PubMed Central

Max, S R; Mufti, S; Carlson, B M

1981-01-01

The development of the cytosolic androgen receptor was studied after degeneration and regeneration of the rat levator ani muscle after a crush lesion. Muscle regeneration appears to recapitulate myogenesis in many respects. It therefore provides a model tissue in sufficiently in large quantity for investigating the ontogenesis of the androgen receptor. The receptor in the cytosol of the normal levator ani muscle has binding characteristics similar to those of the cytosolic receptor in other androgen-sensitive tissues. By day 3 after a crush lesion of the levator ani muscle, androgen binding decreased to 25% of control values. This decrease was followed by a 4-5 fold increase in hormone binding, which attained control values by day 7 after crush. Androgen binding remained stable at the control value up to day 60 after crushing. These results were correlated with the morphological development of the regenerating muscle after crushing. It is concluded that there is little, if any, androgen receptor present in the early myoblastic stages of regeneration; rather, synthesis of the receptor may occur after the fusion of myoblasts and during the differentiation of myotubes into cross-striated muscle fibres. Images PLATE 1 PLATE 2 PMID:6977357

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.

Regulation of androgen receptor and histone deacetylase 1 by Mdm2-mediated ubiquitylation.

PubMed

Gaughan, Luke; Logan, Ian R; Neal, David E; Robson, Craig N

2005-01-01

The androgen receptor (AR) is a member of the nuclear hormone receptor family of transcription factors and plays a critical role in regulating the expression of genes involved in androgen-dependent and -independent tumour formation. Regulation of the AR is achieved by alternate binding of either histone acetyltransferase (HAT)-containing co-activator proteins, or histone deacetylase 1 (HDAC1). Factors that control AR stability may also constitute an important regulatory mechanism, a notion that has been confirmed with the finding that the AR is a direct target for Mdm2-mediated ubiquitylation and proteolysis. Using chromatin immunoprecipitation (ChIP) and re-ChIP analyses, we show that Mdm2 associates with AR and HDAC1 at the active androgen-responsive PSA promoter in LNCaP prostate cancer cells. Furthermore, we demonstrate that Mdm2-mediated modification of AR and HDAC1 catalyses protein destabilization and attenuates AR sactivity, suggesting that ubiquitylation of the AR and HDAC1 may constitute an additional mechanism for regulating AR function. We also show that HDAC1 and Mdm2 function co-operatively to reduce AR-mediated transcription that is attenuated by the HAT activity of the AR co-activator Tip60, suggesting interplay between acetylation status and receptor ubiquitylation in AR regulation. In all, our data indicates a novel role for Mdm2 in regulating components of the AR transcriptosome.

FOXM1 promotes the progression of prostate cancer by regulating PSA gene transcription.

PubMed

Liu, Youhong; Liu, Yijun; Yuan, Bowen; Yin, Linglong; Peng, Yuchong; Yu, Xiaohui; Zhou, Weibing; Gong, Zhicheng; Liu, Jianye; He, Leye; Li, Xiong

2017-03-07

Androgen/AR is the primary contributor to prostate cancer (PCa) progression by regulating Prostate Specific Antigen (PSA) gene transcription. The disease inevitably evolves to androgen-independent (AI) status. Other mechanisms by which PSA is regulated and develops to AI have not yet been fully determined. FOXM1 is a cell proliferation-specific transcription factor highly expressed in PCa cells compared to non-malignant prostate epithelial cells, suggesting that the aberrant overexpression of FOXM1 contributes to PCa development. In addition to regulating AR gene transcription and cell cycle-regulatory genes, FOXM1 selectively regulates the gene transcription of KLK2 and PSA, typical androgen responsive genes. Screening the potential FOXM1-binding sites by ChIP-PCR, we found that FOXM1 directly binds to the FHK binding motifs in the PSA promoter/enhancer regions. AI C4-2 cells have more FOXM1 binding sites than androgen dependent LNCaP cells. The depletion of FOXM1 by small molecular inhibitors significantly improves the suppression of PSA gene transcription by the anti-AR agent Cadosax. This is the first report showing that FOXM1 promotes PCa progression by regulating PSA gene transcription, particularly in AI PCa cells. The combination of anti-AR agents and FOXM1 inhibitors has the potential to greatly improve therapy for late-stage PCa patients by suppressing PSA levels.

Classifying chemical mode of action using gene networks and machine learning: a case study with the herbicide linuron.

PubMed

Ornostay, Anna; Cowie, Andrew M; Hindle, Matthew; Baker, Christopher J O; Martyniuk, Christopher J

2013-12-01

The herbicide linuron (LIN) is an endocrine disruptor with an anti-androgenic mode of action. The objectives of this study were to (1) improve knowledge of androgen and anti-androgen signaling in the teleostean ovary and to (2) assess the ability of gene networks and machine learning to classify LIN as an anti-androgen using transcriptomic data. Ovarian explants from vitellogenic fathead minnows (FHMs) were exposed to three concentrations of either 5α-dihydrotestosterone (DHT), flutamide (FLUT), or LIN for 12h. Ovaries exposed to DHT showed a significant increase in 17β-estradiol (E2) production while FLUT and LIN had no effect on E2. To improve understanding of androgen receptor signaling in the ovary, a reciprocal gene expression network was constructed for DHT and FLUT using pathway analysis and these data suggested that steroid metabolism, translation, and DNA replication are processes regulated through AR signaling in the ovary. Sub-network enrichment analysis revealed that FLUT and LIN shared more regulated gene networks in common compared to DHT. Using transcriptomic datasets from different fish species, machine learning algorithms classified LIN successfully with other anti-androgens. This study advances knowledge regarding molecular signaling cascades in the ovary that are responsive to androgens and anti-androgens and provides proof of concept that gene network analysis and machine learning can classify priority chemicals using experimental transcriptomic data collected from different fish species. © 2013.

Epigenetic repression of regulator of G-protein signaling 2 promotes androgen-independent prostate cancer cell growth.

PubMed

Wolff, Dennis W; Xie, Yan; Deng, Caishu; Gatalica, Zoran; Yang, Mingjie; Wang, Bo; Wang, Jincheng; Lin, Ming-Fong; Abel, Peter W; Tu, Yaping

2012-04-01

G-protein-coupled receptor (GPCR)-stimulated androgen-independent activation of androgen receptor (AR) contributes to acquisition of a hormone-refractory phenotype by prostate cancer. We previously reported that regulator of G-protein signaling (RGS) 2, an inhibitor of GPCRs, inhibits androgen-independent AR activation (Cao et al., Oncogene 2006;25:3719-34). Here, we show reduced RGS2 protein expression in human prostate cancer specimens compared to adjacent normal or hyperplastic tissue. Methylation-specific PCR analysis and bisulfite sequencing indicated that methylation of the CpG island in the RGS2 gene promoter correlated with RGS2 downregulation in prostate cancer. In vitro methylation of this promoter suppressed reporter gene expression in transient transfection studies, whereas reversal of this promoter methylation with 5-aza-2'-deoxycytidine (5-Aza-dC) induced RGS2 reexpression in androgen-independent prostate cancer cells and inhibited their growth under androgen-deficient conditions. Interestingly, the inhibitory effect of 5-Aza-dC was significantly reduced by an RGS2-targeted short hairpin RNA, indicating that reexpressed RGS2 contributed to this growth inhibition. Restoration of RGS2 levels by ectopic expression in androgen-independent prostate cancer cells suppressed growth of xenografts in castrated mice. Thus, RGS2 promoter hypermethylation represses its expression and unmasks a latent pathway for AR transactivation in prostate cancer cells. Targeting this reversible process may provide a new strategy for suppressing prostate cancer progression by reestablishing its androgen sensitivity. Copyright © 2011 UICC.

Isoflavones: Anti-Inflammatory Benefit and Possible Caveats

PubMed Central

Yu, Jie; Bi, Xiaojuan; Yu, Bing; Chen, Daiwen

2016-01-01

Inflammation, a biological response of body tissues to harmful stimuli, is also known to be involved in a host of diseases, such as obesity, atherosclerosis, rheumatoid arthritis, and even cancer. Isoflavones are a class of flavonoids that exhibit antioxidant, anticancer, antimicrobial, and anti-inflammatory properties. Increasing evidence has highlighted the potential for isoflavones to prevent the chronic diseases in which inflammation plays a key role, though the underlying mechanisms remain unclear. Recently, some studies have raised concerns about isoflavones induced negative effects like carcinogenesis, thymic involution, and immunosuppression. Therefore, this review aims to summarize the anti-inflammatory effects of isoflavones, unravel the underlying mechanisms, and present the potential health risks. PMID:27294954

Isoflavones: Anti-Inflammatory Benefit and Possible Caveats.

PubMed

Yu, Jie; Bi, Xiaojuan; Yu, Bing; Chen, Daiwen

2016-06-10

Inflammation, a biological response of body tissues to harmful stimuli, is also known to be involved in a host of diseases, such as obesity, atherosclerosis, rheumatoid arthritis, and even cancer. Isoflavones are a class of flavonoids that exhibit antioxidant, anticancer, antimicrobial, and anti-inflammatory properties. Increasing evidence has highlighted the potential for isoflavones to prevent the chronic diseases in which inflammation plays a key role, though the underlying mechanisms remain unclear. Recently, some studies have raised concerns about isoflavones induced negative effects like carcinogenesis, thymic involution, and immunosuppression. Therefore, this review aims to summarize the anti-inflammatory effects of isoflavones, unravel the underlying mechanisms, and present the potential health risks.

Modulating conversion of isoflavone glycosides to aglycones using crude beta-glycosidase extracts from almonds and processed soy.

PubMed

Ahn-Jarvis, J H; Teegarden, M D; Schwartz, S J; Lee, K; Vodovotz, Y

2017-12-15

Food processing alters the physicochemical state of soy which can enhance chemical and enzymatic conversion of isoflavones to their aglycone forms. This study investigated the role of β-glycosidase from processed soy-ingredient mixture (SIM) or almonds, and examined the impact of isoflavone composition in mediating conversion to aglycones. β-Glycosidase activity was quantified using p-nitrophenol-β-d-glucopyranoside and SIM isoflavone extracts. Almond β-glycosidase activity was significantly (p<0.001) reduced after roasting (99% reduction) or steaming (97% reduction) compared to raw almonds. SIM β-glycosidase activity, however, increased, with steaming by 66% (p<0.001) and with roasting by 52% (p=0.022), compared to raw SIM. After incubation with β-glycosidase, percentage of aglycone (total aglycone/total isoflavones) in SIM isoflavone extracts increased significantly in raw (35%), fermented (48%), roasted (88%) and steamed (91%) SIM, compared to their initial (∼5%) compositions. Manipulation of β-glycosidase activity and isoflavone composition can be used to modulate aglycone content in soy food products. Copyright © 2017 Elsevier Ltd. All rights reserved.

Dietary isoflavones and gastric cancer: A brief review of current studies.

PubMed

Golpour, Sahar; Rafie, Nahid; Safavi, Seyyed Morteza; Miraghajani, Maryam

2015-09-01

Although several in vitro and animal studies have suggested that isoflavones might exert inhibitory effects on gastric carcinogenesis, epidemiologic studies have reported inconclusive results in this field. The aim of this brief review was to investigate whether such an association exists among dietary isoflavones and gastric cancer incidence, prevention, and mortality in epidemiologic studies. We conducted a search of PubMed, Google Scholar, Cochrane, Science direct, and Iranian Scientific Databases including Scientific Information Database and IranMedex Database (up to November 2014) using common keywords for studies that focused on dietary isoflavones and gastric cancer risk. A total of nine epidemiologic studies consisting of five case-controls, three prospective cohorts, and one ecologic study were included in this review. An inverse association between dietary isoflavones and gastric cancer was shown in only one case-control and one ecologic study. In summary, whether anticarcinogenic properties of isoflavones are established, research found no substantial correlation in this field. There are insufficient studies to draw any firm conclusions about the relationship between isoflavones intake and the risk of gastric cancer. Hence, further evidence from cohort and trial studies are needed.

Design and Selection of Soy Breads Used for Evaluating Isoflavone Bioavailability in Clinical Trials

PubMed Central

Ahn-Jarvis, Jennifer H.; Riedl, Kenneth M.; Schwartz, Steven J.; Vodovotz, Yael

2013-01-01

To modulate isoflavone aglycone composition within a soy functional food, soy ingredients were processed and evaluated in a soy bread system intended for clinical trials. A soy flour/soy milk mixture (SM) was boiled, fermented, steamed, or roasted prior to dough preparation. The isoflavone compositions of five processed SM and their corresponding breads combined with and without β-glucosidase-rich almonds were examined using HPLC. Isoflavone malonyl-glucosides (>80%) were converted into acetyl and simple glucoside forms (substrates more favorable for β-glucosidase) in steamed and roasted SM. Their corresponding breads had isoflavones predominately as aglycones (∼75%) with soy–almond bread with steamed SM being more consumer acceptable than roasted. Isoflavone composition in soy bread was stable during frozen storage and toasting. A suitable glycoside-rich soy bread (31.6 ± 2.1 mg aglycone equiv/slice) using unprocessed SM and an aglycone-rich soy–almond bread (31.1 ± 1.9 mg aglycone equiv/slice) using steamed SM were developed to evaluate fundamental questions of isoflavone bioavailability in clinical trials. PMID:23451757

Isoflavone-free soy protein prepared by column chromatography reduces plasma cholesterol in rats.

PubMed

Fukui, Kensuke; Tachibana, Nobuhiko; Wanezaki, Satoshi; Tsuzaki, Shinichi; Takamatsu, Kiyoharu; Yamamoto, Takashi; Hashimoto, Yukio; Shimoda, Tadahisa

2002-09-25

To know whether isoflavones are responsible for the hypocholesterolemic effect of soy protein, the effect on plasma cholesterol of isoflavone-free soy protein prepared by column chromatography was examined in rats. Five-week-old male Sprague-Dawley rats were fed cholesterol-enriched AIN-93G diets containing either 20% casein (CAS), 20% soy protein isolate (SPI), 20% isoflavone-free SPI (IF-SPI), 19.7% IF-SPI + 0.3% isoflavone-rich fraction (isoflavone concentrate, IC), or 20% CAS + 0.3% IC for 2 weeks. Plasma total cholesterol concentrations of rats fed SPI and IF-SPI were comparable and were significantly lower than that of rats fed CAS. The addition of IC to the CAS and IF-SPI did not influence plasma cholesterol level. Fecal steroid excretion of the three SPI groups was higher than that of the two CAS groups, whereas the addition of IC showed no effect. Thus, a significant fraction of the cholesterol-lowering effect of SPI in rats can be attributed to the protein content, but the isoflavones and other minor constituents may also play a role.

Isoflavone supplementation and endothelial function in menopausal women.

PubMed

Hale, Georgina; Paul-Labrador, Maura; Dwyer, James H; Merz, C Noel Bairey

2002-06-01

Despite strong observational evidence for a beneficial role of oestrogen in cardiovascular disease, recent trial results suggest that hormone replacement therapy (HRT) may have adverse effects in menopausal women with established coronary heart disease. Isoflavones are oestrogen analogues found in plants with oestrogen-like properties and, because of a favourable side-effect profile, may be ideal alternatives to HRT with respect to cardiovascular benefits. Endothelial function is a marker of cardiovascular health. We aimed to determine the effect of isoflavones on endothelial function using the brachial artery reactivity test. Twenty-nine healthy menopausal women underwent entry and exit brachial artery reactivity testing following randomization to 2 weeks of an oral soy isoflavone concentrate containing 80 mg of soy isoflavones (Archer Daniel Midland Inc., IL, USA) or placebo. At study exit, there was no difference between placebo and isoflavone groups with respect to flow-mediated dilation (%FMD(max)), change (entry to exit) in %FMD(max) or response to nitroglycerine (%TNG). Subgroup analyses assessing lipid and oestrogen effects did not produce any significant results. These results suggest that short-term oral isoflavone supplements do not improve endothelial function in healthy menopausal women.

ERG/AKR1C3/AR Constitutes a Feed-Forward Loop for AR Signaling in Prostate Cancer Cells.

PubMed

Powell, Katelyn; Semaan, Louie; Conley-LaComb, M Katie; Asangani, Irfan; Wu, Yi-Mi; Ginsburg, Kevin B; Williams, Julia; Squire, Jeremy A; Maddipati, Krishna R; Cher, Michael L; Chinni, Sreenivasa R

2015-06-01

Intratumoral androgen synthesis in prostate cancer contributes to the development of castration-resistant prostate cancer (CRPC). Several enzymes responsible for androgen biosynthesis have been shown to be overexpressed in CRPC, thus contributing to CRPC in a castrated environment. The TMPRSS2-ERG transcription factor has been shown to be present in primary prostate cancer tumors as well as CRPC tumors. We hypothesize that TMPRSS2-ERG fusions regulate androgen biosynthetic enzyme (ABE) gene expression and the production of androgens, which contributes to the development of CRPC. We used a panel of assays, including lentivirus transduction, gene expression, chromatin immunoprecipitation and sequencing, liquid chromatography-mass spectrometric quantitation, immunocytochemistry, immunohistochemistry, and bioinformatics analysis of gene microarray databases, to determine ERG regulation of androgen synthesis. We found that ERG regulated the expression of the ABE AKR1C3 in prostate cancer cells via direct binding to the AKR1C3 gene. Knockdown of ERG resulted in reduced AKR1C3 expression, which caused a reduction in both DHT synthesis and PSA expression in VCaP prostate cancer cells treated with 5α-androstanedione (5α-Adione), a DHT precursor metabolite. Immunohistochemical staining revealed that ERG was coexpressed with AKR1C3 in prostate cancer tissue samples. These data suggest that AKR1C3 catalyzes the biochemical reduction of 5α-Adione to DHT in prostate cancer cells, and that ERG regulates this step through upregulation of AKR1C3 expression. Elucidation of ERG regulation of ABEs in CRPC may help to stratify TMPRSS2-ERG fusion-positive prostate cancer patients in the clinic for anti-androgen receptor-driven therapies; and AKR1C3 may serve as a valuable therapeutic target in the treatment of CRPC. ©2015 American Association for Cancer Research.

The phytochemical 3,3'-diindolylmethane decreases expression of AR-controlled DNA damage repair genes through repressive chromatin modifications and is associated with DNA damage in prostate cancer cells.

PubMed

Palomera-Sanchez, Zoraya; Watson, Gregory W; Wong, Carmen P; Beaver, Laura M; Williams, David E; Dashwood, Roderick H; Ho, Emily

2017-09-01

Androgen receptor (AR) is a transcription factor involved in normal prostate physiology and prostate cancer (PCa) development. 3,3'-Diindolylmethane (DIM) is a promising phytochemical agent against PCa that affects AR activity and epigenetic regulators in PCa cells. However, whether DIM suppresses PCa via epigenetic regulation of AR target genes is unknown. We assessed epigenetic regulation of AR target genes in LNCaP PCa cells and showed that DIM treatment led to epigenetic suppression of AR target genes involved in DNA repair (PARP1, MRE11, DNA-PK). Decreased expression of these genes was accompanied by an increase in repressive chromatin marks, loss of AR occupancy and EZH2 recruitment to their regulatory regions. Decreased DNA repair gene expression was associated with an increase in DNA damage (γH2Ax) and up-regulation of genomic repeat elements LINE1 and α-satellite. Our results suggest that DIM suppresses AR-dependent gene transcription through epigenetic modulation, leading to DNA damage and genome instability in PCa cells. Published by Elsevier Inc.

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.

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.

A Somatically Acquired Enhancer of the Androgen Receptor Is a Noncoding Driver in Advanced Prostate Cancer. | Office of Cancer Genomics

Cancer.gov

Increased androgen receptor (AR) activity drives therapeutic resistance in advanced prostate cancer. The most common resistance mechanism is amplification of this locus presumably targeting the AR gene. Here, we identify and characterize a somatically acquired AR enhancer located 650 kb centromeric to the AR. Systematic perturbation of this enhancer using genome editing decreased proliferation by suppressing AR levels. Insertion of an additional copy of this region sufficed to increase proliferation under low androgen conditions and to decrease sensitivity to enzalutamide.

Role of Protein Synthesis Initiation Factors in Dietary Soy Isoflavone-Mediated Effects on Breast Cancer Progression

DTIC Science & Technology

2012-03-01

After 1 week of tumor inoculation, vehicle (10% ethanol, 90% corn oil ), 10 mg/kg body weight (BW) of daidzein, or combined soy isoflavones 10 mg/kg BW...Dietary Soy Isoflavone-Mediated Effects on Breast Cancer Progression. PRINCIPAL INVESTIGATOR: Columba de la Parra Simental CONTRACTING...00935 Role of Protein Synthesis Initiation Factors in Dietary Soy Isoflavone-Mediated Effects on Breast Cancer Progression Columba de la Parra Simental

Genetic Analysis of Seed Isoflavones, Protein, and Oil Contents in Soybean [Glycine max (L.) Merr.

DTIC Science & Technology

2014-09-13

high contents of protein , oil, isoflavones, and other bioactive compounds. However, it is susceptible to many biotic stresses such fungal, bacterial...for protein , oil, and isoflavones contents in three recombinant inbred line (RIL) populations of soybean. We have achieved 100% of the goals. We have...Jun-2011 31-May-2014 Approved for Public Release; Distribution Unlimited Final Report: Genetic Analysis of Seed Isoflavones, Protein , and Oil

Androgens and Hypertension in Men and Women: a Unifying View.

PubMed

Moretti, Costanzo; Lanzolla, Giulia; Moretti, Marta; Gnessi, Lucio; Carmina, Enrico

2017-05-01

This review was designed to revaluate the androgen role on the mechanisms of hypertension and cardiovascular risks in both men and women. Sex steroids are involved in the regulation of blood pressure, but pathophysiological mechanism is not well understood. Androgens have an important effect on metabolism, adipose and endothelial cell function, and cardiovascular risk in both men and women. A focal point in this contest is represented by the possible gender-specific regulation of different tissues and in particular of the adipose cell. Available data confirm that androgen deficiency is linked to increased prevalence of hypertension and cardiovascular diseases. Adipocyte dysfunction seems to be the main involved mechanism. Androgen replacement reduces inflammation state in man, protecting by metabolic syndrome progression. In women, androgen excess has been considered as promoting factor of cardiovascular risk. However, recent data suggest that excessive androgen production has little effect per se in inducing hypertension in young women of reproductive age. Also in postmenopausal women, data on relative androgen excess and hypertension are missing, while adrenal androgen deficiency has been associated to increased mortality. Molecular mechanisms linking androgen dysregulation to hypertension are almost Unknown, but they seem to be related to increased visceral fat, promoting a chronic inflammatory state through different mechanisms. One of these may involve the recruitment and over-activation of NF-kB, a ubiquitous transcription factor also expressed in adipose cells, where it may cause the production of cytokines and other immune factors. The NF-kB signalling pathway may also influence brown adipogenesis leading to the preferential enlargement of visceral adipocytes. Chronic inflammation and adipocyte dysfunction may alter endothelial function leading to hypertension. Both in men and in women, particularly in the post-menopausal period, hypoandrogenism seems to be a major determinant of the increased prevalence of hypertension. The relationship between androgen signalling and NF-kB might explain the pathophysiological mechanism leading to the development of endothelium dysfunction and hypertension.

Why do winners keep winning? Androgen mediation of winner but not loser effects in cichlid fish

PubMed Central

Oliveira, Rui F.; Silva, Ana; Canário, Adelino V.M.

2009-01-01

Animal conflicts are influenced by social experience such that a previous winning experience increases the probability of winning the next agonistic interaction, whereas a previous losing experience has the opposite effect. Since androgens respond to social interactions, increasing in winners and decreasing in losers, we hypothesized that socially induced transient changes in androgen levels could be a causal mediator of winner/loser effects. To test this hypothesis, we staged fights between dyads of size-matched males of the Mozambique tilapia (Oreochromis mossambicus). After the first contest, winners were treated with the anti-androgen cyproterone acetate and losers were supplemented with 11-ketotestosterone. Two hours after the end of the first fight, two contests were staged simultaneously between the winner of the first fight and a naive male and between the loser of first fight and another naive male. The majority (88%) of control winners also won the second interaction, whereas the majority of control losers (87%) lost their second fight, thus confirming the presence of winner/loser effects in this species. As predicted, the success of anti-androgen-treated winners in the second fight decreased significantly to chance levels (44%), but the success of androgenized losers (19%) did not show a significant increase. In summary, the treatment with anti-androgen blocks the winner effect, whereas androgen administration fails to reverse the loser effect, suggesting an involvement of androgens on the winner but not on the loser effect. PMID:19324741

Intracrine Androgens Enhance Decidualization and Modulate Expression of Human Endometrial Receptivity Genes

PubMed Central

Gibson, Douglas A.; Simitsidellis, Ioannis; Cousins, Fiona L.; Critchley, Hilary O. D.; Saunders, Philippa T. K.

2016-01-01

The endometrium is a complex, steroid-dependent tissue that undergoes dynamic cyclical remodelling. Transformation of stromal fibroblasts (ESC) into specialised secretory cells (decidualization) is fundamental to the establishment of a receptive endometrial microenvironment which can support and maintain pregnancy. Androgen receptors (AR) are present in ESC; in other tissues local metabolism of ovarian and adrenal-derived androgens regulate AR-dependent gene expression. We hypothesised that altered expression/activity of androgen biosynthetic enzymes would regulate tissue availability of bioactive androgens and the process of decidualization. Primary human ESC were treated in vitro for 1–8 days with progesterone and cAMP (decidualized) in the presence or absence of the AR antagonist flutamide. Time and treatment-dependent changes in genes essential for a) intra-tissue biosynthesis of androgens (5α-reductase/SRD5A1, aldo-keto reductase family 1 member C3/AKR1C3), b) establishment of endometrial decidualization (IGFBP1, prolactin) and c) endometrial receptivity (SPP1, MAOA, EDNRB) were measured. Decidualization of ESC resulted in significant time-dependent changes in expression of AKR1C3 and SRD5A1 and secretion of T/DHT. Addition of flutamide significantly reduced secretion of IGFBP1 and prolactin and altered the expression of endometrial receptivity markers. Intracrine biosynthesis of endometrial androgens during decidualization may play a key role in endometrial receptivity and offer a novel target for fertility treatment. PMID:26817618

Intracrine Androgens Enhance Decidualization and Modulate Expression of Human Endometrial Receptivity Genes.

PubMed

Gibson, Douglas A; Simitsidellis, Ioannis; Cousins, Fiona L; Critchley, Hilary O D; Saunders, Philippa T K

2016-01-28

The endometrium is a complex, steroid-dependent tissue that undergoes dynamic cyclical remodelling. Transformation of stromal fibroblasts (ESC) into specialised secretory cells (decidualization) is fundamental to the establishment of a receptive endometrial microenvironment which can support and maintain pregnancy. Androgen receptors (AR) are present in ESC; in other tissues local metabolism of ovarian and adrenal-derived androgens regulate AR-dependent gene expression. We hypothesised that altered expression/activity of androgen biosynthetic enzymes would regulate tissue availability of bioactive androgens and the process of decidualization. Primary human ESC were treated in vitro for 1-8 days with progesterone and cAMP (decidualized) in the presence or absence of the AR antagonist flutamide. Time and treatment-dependent changes in genes essential for a) intra-tissue biosynthesis of androgens (5α-reductase/SRD5A1, aldo-keto reductase family 1 member C3/AKR1C3), b) establishment of endometrial decidualization (IGFBP1, prolactin) and c) endometrial receptivity (SPP1, MAOA, EDNRB) were measured. Decidualization of ESC resulted in significant time-dependent changes in expression of AKR1C3 and SRD5A1 and secretion of T/DHT. Addition of flutamide significantly reduced secretion of IGFBP1 and prolactin and altered the expression of endometrial receptivity markers. Intracrine biosynthesis of endometrial androgens during decidualization may play a key role in endometrial receptivity and offer a novel target for fertility treatment.

Regucalcin is an androgen-target gene in the rat prostate modulating cell-cycle and apoptotic pathways.

PubMed

Vaz, Cátia V; Maia, Cláudio J; Marques, Ricardo; Gomes, Inês M; Correia, Sara; Alves, Marco G; Cavaco, José E; Oliveira, Pedro F; Socorro, Sílvia

2014-09-01

Regucalcin (RGN) is a calcium (Ca(2+) )-binding protein underexpressed in prostate adenocarcinoma comparatively to non-neoplastic prostate or benign prostate hyperplasia cases. Moreover, RGN expression is negatively associated with the cellular differentiation of prostate adenocarcinoma, suggesting that loss of RGN may be associated with tumor onset and progression. However, the RGN actions over the control of prostate cell growth have not been investigated. Androgens are implicated in the promotion of prostate cell proliferation, thus we studied the in vivo effect of androgens on RGN expression in rat prostate. The role of RGN modulating cell proliferation and apoptotic pathways in rat prostate was investigated using transgenic animals (Tg-RGN) overexpressing the protein. In vivo stimulation with 5α-dihydrotestosterone (DHT) down-regulated RGN expression in rat prostate. Cell proliferation index and prostate weight were reduced in Tg-RGN, which was concomitant with altered expression of cell-cycle regulators. Tg-RGN presented diminished expression of the oncogene H-ras and increased expression of cell-cycle inhibitor p21. Levels of anti-apoptotic Bcl-2, as well as the Bcl-2/Bax protein ratio were increased in prostates overexpressing RGN. Both caspase-3 expression and enzyme activity were decreased in the prostates of Tg-RGN. Overexpression of RGN resulted in inhibition of cell proliferation and apoptotic pathways, which demonstrated its role maintaining prostate growth balance. Thus, deregulation of RGN expression may be an important event favoring the development of prostate cancer. Moreover, the DHT effect down-regulating RGN expression in rat prostate highlighted for the importance of this protein in prostatic physiology. © 2014 Wiley Periodicals, Inc.

Epidemiologic Studies of Isoflavones & Mammographic Density

PubMed Central

Maskarinec, Gertraud; Verheus, Martijn; Tice, Jeffrey A.

2010-01-01

Isoflavones, phytoestrogens in soy beans with estrogen-like properties, have been examined for their cancer protective effects. Mammographic density is a strong predictor of breast cancer. This review summarizes studies that have examined the association between isoflavones and breast density. Observational investigations in Hawaii and Singapore suggest slightly lower breast density among women of Asian descent with regular soy intake, but two larger studies from Japan and Singapore did not observe a protective effect. The findings from seven randomized trials with primarily Caucasian women indicate that soy or isoflavones do not modify mammographic density. Soy foods and isoflavone supplements within a nutritional range do not appear to modify breast cancer risk as assessed by mammographic density. PMID:22253990

A benzil and isoflavone derivatives from Derris scandens Benth.

PubMed

Mahabusarakam, W; Deachathai, S; Phongpaichit, S; Jansakul, C; Taylor, W C

2004-04-01

A benzil derivative: scandione, 2',2"-dihydroxy-4'-methoxy-4",5"-methylenedioxybenzil and two isoflavones: scandenal, 3'-formyl-4',5-dihydroxy-2",2"-dimethylchromeno-[6,7:5",6"]isoflavone and scanderone, 4',5-dihydroxy-3'-prenyl-2",2"-dimethylchromeno-[7,8:6",5"]isoflavone together with fifteen known compounds were isolated from the stem of D. scandens. Their structures were determined by spectroscopic methods. Radical scavenging, antibacterial and hypertensive activities of some of the compounds were investigated.

Androgen regulation of the human hair follicle: the type I hair keratin hHa7 is a direct target gene in trichocytes.

PubMed

Jave-Suarez, Luis F; Langbein, Lutz; Winter, Hermelita; Praetzel, Silke; Rogers, Michael A; Schweizer, Juergen

2004-03-01

Previous work had shown that most members of the complex human hair keratin family were expressed in terminal scalp hairs. An exception to this rule was the type I hair keratin hHa7, which was only detected in some but not all vellus hairs of the human scalp (Langbein et al, 1999). Here we show that hHa7 exhibits constitutive expression in medullary cells of all types of male and female sexual hairs. Medullated beard, axillary, and pubic hairs arise during puberty from small, unmedullated vellus hairs under the influence of circulating androgens. This suggested an androgen-controlled expression of the hHa7 gene. Further evidence for this assumption was provided by the demonstration of androgen receptor (AR) expression in the nuclei of medullary cells of beard hairs. Moreover, homology search for the semipalindromic androgen receptor-binding element (ARE) consensus sequence GG(A)/(T)ACAnnnTGTTCT in the proximal hHa7 promoter revealed three putative ARE motifs. Electrophoretic mobility shift assays demonstrated the specific binding of AR to all three hHa7 AREs. Their function as AR-responsive elements, either individually or in concert within the hHa7 promoter, could be further confirmed by transfection studies with or without an AR expression vector in PtK2 and prostate PC3-Arwt cells, respectively in the presence or absence of a synthetic androgen. Our study detected hHa7 as the first gene in hair follicle trichocytes whose expression appears to be directly regulated by androgens. As such, hHa7 represents a marker for androgen action on hair follicles and might be a suitable tool for investigations of androgen-dependent hair disorders.

Effects of dietary soy isoflavones on feed intake, growth performance and digestibility in juvenile Japanese flounder ( Paralichthys olivaceus)

NASA Astrophysics Data System (ADS)

Mai, Kangsen; Zhang, Yanjiao; Chen, Wei; Xu, Wei; Ai, Qinghui; Zhang, Wenbing

2012-12-01

An 8-week feeding trial was conducted to investigate the effects of dietary soy isoflavones on feeding intake, growth performance, and digestion of juvenile Japanese flounder ( Paralichthys olivaceus). Four isonitrogenous (49% crude protein) and isoenergetic (20.1 MJ kg-1) diets were formulated to contain four graded levels of soy isoflavones, namely, 0, 1, 4 and 8 g soy isoflavones in 1 kg of diet. Each diet was randomly fed to triplicate tanks of fish (Initial average weight: 2.58 g ± 0.01 g), and each tank was stocked with 35 fish. No significant difference was observed among diets with levels of 0, 1 and 4 g kg-1 soy isoflavones in feed intake, weight gain, feed efficiency ratio (FER), proximate composition of fish whole body and apparent digestibility coefficients (ADC) of nutrients and energy ( P>0.05). However, high dietary soy isoflavones level (8 g kg-1) significantly depressed weight gain, FER, whole-body crude lipid content of fish and ADC of nutrients ( P<0.05). These results indicate that high level of dietary soy isoflavones (above 4 g kg-1) significantly depresses growth responses and FER of Japanese flounder. However, as the content of soy isoflavones in soybean meal is around 1 to 3 g kg-1, the adverse effects might be neglected when soybean products are used as a fish feed ingredient.

Treatment with soy isoflavones during early adulthood improves metabolism in early postnatally overfed rats.

PubMed

Silva, Pamelli; Ribeiro, Tatiane Aparecida; Tófolo, Laize Peron; Prates, Kelly Valério; Francisco, Flávio Andrade; Silveira, Sandra da Silva; Malta, Ananda; Lopes, Denise Alves; Miranda, Rosiane Aparecida; Palma-Rigo, Kesia; Torrezan, Rosana; Mathias, Paulo Cezar de Freitas

2018-01-01

The incidences of obesity and related diseases have reached epidemic proportions, and new therapeutic approaches are needed. Soy isoflavones have been identified as an important dietary factor for preventing and treating metabolic dysfunction. This study examined the effects of high doses of isoflavone on glucose and fat metabolism in a model of programmed obesity and evaluated its effects on the autonomic nervous system. Litters of Wistar rats were standardized at nine pups per dam in normal litters (NL) or reduced to three pups per dam at the third day of life (P3) in small litters (SL) to induce postnatal overfeeding. Gavage with a soy bean isoflavone mixture (1 g/day) diluted in water was started at P60 and continued for 30 days. The control animals received vehicle gavage. At P90, biometric and metabolic parameters as well as direct autonomic nerve activity were measured. Increases in glycaemia and insulinaemia observed in SL rats were reduced by isoflavone treatment, which also caused lower glucose-induced insulin secretion by pancreatic islets. Sympathetic activity in the major splanchnic nerve was increased, while vagus nerve activity was reduced by isoflavone treatment. The dyslipidaemia induced by overfeeding in SL rats was restored by isoflavone treatment. The present study shows that treatment with isoflavone reduces adiposity and improves glucose and lipid metabolism. Collectively, these effects may depend on autonomic changes.

Up-regulating of RASD1 and apoptosis of DU-145 human prostate cancer cells induced by formononetin in vitro.

PubMed

Liu, Xiao-Jia; Li, Yun-Qian; Chen, Qiu-Yue; Xiao, Sheng-Jun; Zeng, Si-En

2014-01-01

Prostate cancer is one of the most prevalent malignant cancers in men. The isoflavone formononetin is a main active component of red clover plants. In the present study, we assessed the effect of formononetin on human prostate cancer DU-145 cells in vitro, and elucidated possible mechanisms. DU-145 cells were treated with different concentrations of formononetin and cell proliferation was assessed by MTT assay, cell apoptosis by Hoechst 33258 and flow cytometry, and protein levels of RASD1, Bcl-2 and Bax by Western blotting. The results showed that formononetin inhibited the proliferation of DU-145 cells in a dose-dependent manner. DU-145 cells treated with different concentrations of formononetin displayed obvious morphological changes of apoptosis under fluorescence microscopy. In addition, formononetin increased the proportion of early apoptotic DU-145 cells, down-regulated the protein levels of Bcl-2 and up-regulated those of RASD1 and Bax. The level of RASD1 reached its maximum at 48 h post-treatment, and rapidly decreased thereafter. Together, we present evidence that formononetin triggered cell apoptosis through the mitochondrial apoptotic pathway by up-regulating RASD1.

ID4 promotes AR expression and blocks tumorigenicity of PC3 prostate cancer cells.

PubMed

Komaragiri, Shravan Kumar; Bostanthirige, Dhanushka H; Morton, Derrick J; Patel, Divya; Joshi, Jugal; Upadhyay, Sunil; Chaudhary, Jaideep

2016-09-09

Deregulation of tumor suppressor genes is associated with tumorigenesis and the development of cancer. In prostate cancer, ID4 is epigenetically silenced and acts as a tumor suppressor. In normal prostate epithelial cells, ID4 collaborates with androgen receptor (AR) and p53 to exert its tumor suppressor activity. Previous studies have shown that ID4 promotes tumor suppressive function of AR whereas loss of ID4 results in tumor promoter activity of AR. Previous study from our lab showed that ectopic ID4 expression in DU145 attenuates proliferation and promotes AR expression suggesting that ID4 dependent AR activity is tumor suppressive. In this study, we examined the effect of ectopic expression of ID4 on highly malignant prostate cancer cell, PC3. Here we show that stable overexpression of ID4 in PC3 cells leads to increased apoptosis and decreased cell proliferation and migration. In addition, in vivo studies showed a decrease in tumor size and volume of ID4 overexpressing PC3 cells, in nude mice. At the molecular level, these changes were associated with increased androgen receptor (AR), p21, and AR dependent FKBP51 expression. At the mechanistic level, ID4 may regulate the expression or function of AR through specific but yet unknown AR co-regulators that may determine the final outcome of AR function. Copyright © 2016 Elsevier Inc. All rights reserved.

Enzalutamide

MedlinePlus

... androgen receptor inhibitors. It works by blocking the effects of androgen (a male reproductive hormone) to stop ... decrease your dose if you experience serious side effects during your treatment. Be sure to talk to ...

Apalutamide

MedlinePlus

... androgen receptor inhibitors. It works by blocking the effects of androgen (a male reproductive hormone) to stop ... decrease your dose if you experience serious side effects during your treatment. Be sure to talk to ...

PTTG1, A novel androgen responsive gene is required for androgen-induced prostate cancer cell growth and invasion

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

Zhang, Zheng; Jin, Bo; Jin, Yaqiong

Androgens (AR) play an important role in initiation and progression of prostate cancer. It has been shown that AR exert their effects mainly through the androgen-activated AR which binds to androgen response elements (AREs) in the regulatory regions of target genes to regulate the transcription of androgen-responsive genes, thus, identification of AR downstream target gene is critical to understand androgen function in prostate cancer. In this study, our results showed that androgen treatment of LNCaP cells induced PTTG1 expression, which was blocked by the androgen receptor antagonist, Casodex. Bioinformatics analysis and experiments using PTTG1 promoter deletion mutants showed that themore » PTTG1 promoter contains a putative androgen response element (ARE), which localizes in the −851 to −836 region of the promoter. Androgen activated androgen receptor (AR) binding to this ARE was confirmed by Chromatin immunoprecipitation (ChIP) assay. Furthermore, Knockdown of PTTG1 expression using short hairpin RNA significantly reduced androgen-induced LNCaP cell growth and invasion. In addition, we showed PTTG1 is highly expressed in metastasis prostate cancer tissue. These results suggest that PTTG1 is a novel downstream target gene of androgen receptor and take part in prostate cancer proliferation and metastasis. - Highlights: • Androgen treatment of LNCaP cells induced PTTG1 expression. • Knockdown of PTTG1 expression significantly reduced androgen-induced LNCaP cell growth and invasion. • PTTG1 is highly expressed in metastasis prostate cancer tissue. • PTTG1 is a novel downstream target gene of androgen receptor.« less

Dietary soy and natto intake and cardiovascular disease mortality in Japanese adults: the Takayama study.

PubMed

Nagata, Chisato; Wada, Keiko; Tamura, Takashi; Konishi, Kie; Goto, Yuko; Koda, Sachi; Kawachi, Toshiyuki; Tsuji, Michiko; Nakamura, Kozue

2017-02-01

Whether soy intake is associated with a decreased risk of cardiovascular disease (CVD) remains unclear. A traditional Japanese soy food, natto, contains a potent fibrinolytic enzyme. However, its relation to CVD has not been studied. We aimed to examine the association of CVD mortality with the intake of natto, soy protein, and soy isoflavones in a population-based cohort study in Japan. The study included 13,355 male and 15,724 female Takayama Study participants aged ≥35 y. At recruitment in 1992, each subject was administered a validated semiquantitative food-frequency questionnaire. Deaths from CVD were ascertained over 16 y. A total of 1678 deaths from CVD including 677 stroke and 308 ischemic heart disease occurred during follow-up. The highest quartile of natto intake compared with the lowest intake was significantly associated with a decreased risk of mortality from total CVD after control for covariates: the HR was 0.75 (95% CI: 0.64, 0.88, P-trend = 0.0004). There were no significant associations between the risk of mortality from total CVD and intakes of total soy protein, total soy isoflavone, and soy protein or soy isoflavone from soy foods other than natto. The highest quartiles of total soy protein and natto intakes were significantly associated with a decreased risk of mortality from total stroke (HR = 0.75, 95% CI: 0.57, 0.99, P-trend = 0.03 and HR = 0.68, 95% CI: 0.52, 0.88, P-trend = 0.0004, respectively). The highest quartile of natto intake was also significantly associated with a decreased risk of mortality from ischemic stroke (HR = 0.67, 95% CI:0.47, 0.95, P-trend = 0.03). Data suggest that natto intake may contribute to the reduction of CVD mortality. © 2017 American Society for Nutrition.

The Interactions between Insulin and Androgens in Progression to Castrate-Resistant Prostate Cancer

PubMed Central

Gunter, Jennifer H.; Lubik, Amy A.; McKenzie, Ian; Pollak, Michael; Nelson, Colleen C.

2012-01-01

An association between the metabolic syndrome and reduced testosterone levels has been identified, and a specific inverse relationship between insulin and testosterone levels suggests that an important metabolic crosstalk exists between these two hormonal axes; however, the mechanisms by which insulin and androgens may be reciprocally regulated are not well described. Androgen-dependant gene pathways regulate the growth and maintenance of both normal and malignant prostate tissue, and androgen-deprivation therapy (ADT) in patients exploits this dependence when used to treat recurrent and metastatic prostate cancer resulting in tumour regression. A major systemic side effect of ADT includes induction of key features of the metabolic syndrome and the consistent feature of hyperinsulinaemia. Recent studies have specifically identified a correlation between elevated insulin and high-grade PCa and more rapid progression to castrate resistant disease. This paper examines the relationship between insulin and androgens in the context of prostate cancer progression. Prostate cancer patients present a promising cohort for the exploration of insulin stabilising agents as adjunct treatments for hormone deprivation or enhancers of chemosensitivity for treatment of advanced prostate cancer. PMID:22548055

[Effect of soy isoflavone on gene expression of leptin and insulin sensibility in insulin-resistant rats].

PubMed

Chen, Shi-wei; Zhang, Li-shi; Zhang, Hong-min; Feng, Xiao-fan; Peng, Xiao-li

2006-04-18

To explore the effects of soy isoflavone (SIF) on gene expression of leptin and insulin sensibility in insulin-resistant (IR) rats induced by high-fat, and to reveal the mechanisms of SIF in ameliorating insulin sensibility. IR rats were randomly divided into four groups based on their insulin-resistant indexes (IRI): one model control group and three SIF groups that were gavaged with water solutions with SIF at doses of 0 mg/kg, 50 mg/kg, 150 mg/kg, and 450 mg/kg, respectively. After one month, fasting glucose, fasting insulin, leptin in serum, and leptin mRNA in the perirenal adipocyte were detected by enzymic method, radioimmunoassay, enzyme linked immunosorbent assay, and real time quantitative RT-PCR, respectively. The model control group was used to compare against the other groups: (1) Insulin and IRI were lower in the 150 mg/kg and 450 mg/kg groups; (2) In the 450 mg/kg group, body weight and leptin mRNA expression were lower, serum leptin content was higher. These results indicate that soy isoflavone might decrease body weight of rats and leptin mRNA, increase serum leptin level, and ameliorate leptin and insulin sensitivities.

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 activity of isoflavones in the cheetah than would be predicted from findings in the domestic cat. However, further investigation is required.

Soy proteins and isoflavones reduce interleukin-6 but not serum lipids in older women: a randomized controlled trial☆,☆☆

PubMed Central

Mangano, Kelsey M.; Hutchins-Wiese, Heather L.; Kenny, Anne M.; Walsh, Stephen J.; Abourizk, Robin H.; Bruno, Richard S.; Lipcius, Rosanne; Fall, Pamela; Kleppinger, Alison; Kenyon-Pesce, Lisa; Prestwood, Karen M.; Kerstetter, Jane E.

2015-01-01

Soy foods contain several components, notably, isoflavones and amino acids, that may improve cardiovascular health. We evaluated the long-term effect of soy protein and/or soy isoflavones supplementation on serum lipids and inflammatory markers using a 1-year randomized, double-blind, placebo-control, clinical trial in 131 healthy ambulatory women older than 60 years. We hypothesized that soy protein, in combination with isoflavones, would have the largest positive effect on coronary heart disease risk factors (serum lipids and inflammatory markers) compared with either intervention alone and that, within groups receiving isoflavones, equol producers would have more positive effects on coronary heart disease risk factors than nonequol producers. After a 1-month baseline period, participants were randomized into 1 of 4 intervention groups: soy protein (18 g/d) and isoflavone tablets (105 mg/d isoflavone aglycone equivalents), soy protein and placebo tablets, control protein and isoflavone tablets, or control protein and placebo tablets. T Tests were used to assess differences between equol and nonequol producers. Ninety-seven women completed the trial. Consumption of protein powder and isoflavone tablets did not differ among groups, and compliance with study powder and tablets was 79% and 90%, respectively. After 1 year, in the entire population, there were either no or little effects on serum lipids and inflammatory markers, regardless of treatment group. Equol producers, when analyzed separately, had significant improvements in total cholesterol/high-density lipoprotein and low-density lipoprotein/high-density lipoprotein ratios (−5.9%, P = .02; −7.2%, P = .04 respectively). Soy protein and isoflavone (either alone or together) did not impact serum lipids or inflammatory markers. Therefore, they should not be considered an effective intervention to prevent cardiovascular disease because of lipid modification in healthy late postmenopausal women lacking the ability to produce equol. PMID:24267042

Significant inverse association of equol-producer status with coronary artery calcification but not dietary isoflavones in healthy Japanese men.

PubMed

Ahuja, Vasudha; Miura, Katsuyuki; Vishnu, Abhishek; Fujiyoshi, Akira; Evans, Rhobert; Zaid, Maryam; Miyagawa, Naoko; Hisamatsu, Takashi; Kadota, Aya; Okamura, Tomonori; Ueshima, Hirotsugu; Sekikawa, Akira

2017-01-01

Equol, a metabolite of the dietary isoflavone daidzein, is produced by the action of gut bacteria in some individuals who are termed as equol-producers. It is proposed to have stronger atheroprotective properties than dietary isoflavones. We examined a cross-sectional association of dietary isoflavones and equol-producer status with coronary artery calcification (CAC), a biomarker of coronary atherosclerosis, among men in Japan. A population-based sample of 272 Japanese men aged 40-49 years recruited from 2004 to 2007 was examined for serum isoflavones, serum equol, CAC and other factors. Equol-producers were classified as individuals having a serum level of equol >83 nm. The presence of CAC was defined as a coronary Ca score ≥10 Agatston units. The associations of dietary isoflavones and equol-producers with CAC were analysed using multiple logistic regression. The median of dietary isoflavones, equol and CAC were 512·7 (interquartile range (IQR) 194·1, 1170·0), 9·1 (IQR 0·10, 33·1) and 0·0 (IQR 0·0, 1·0) nm, respectively. Prevalence of CAC and equol-producers was 9·6 and 16·0 %, respectively. Dietary isoflavones were not significantly associated with CAC. After multivariable adjustment, the OR for the presence of CAC in equol-producers compared with equol non-producers was 0·10 (95 % CI 0·01, 0·90, P<0·04). Equol-producers had significantly lower CAC than equol non-producers, but there was no significant association between dietary isoflavones and CAC, suggesting that equol may be a key factor for atheroprotective properties of isoflavones in Japanese men. This finding must be confirmed in larger studies or clinical trials of equol that is now available as a dietary supplement.

Effects of surfactant and salt species in reverse micellar forward extraction efficiency of isoflavones with enriched protein from soy flour.

PubMed

Zhao, Xiaoyan; Wei, Zhiyi; Du, Fangling; Zhu, Junqing

2010-11-01

Suitability of reverse micelles of anionic surfactant sodium bis(2-ethyl hexyl) sulfosuccinate (AOT) and sodium dodecyl sulfate (SDS), cationic surfactant hexadecyl trimethyl ammonium bromide (CTAB) and nonionic surfactant polyoxyethylene p-t-octylphenol (TritonX-100) in organic solvent isooctane for extraction of soy isoflavone-enriching proteins was investigated. The results showed that the order of combined isoflavone contents was SDS>CTAB>Triton X-100>AOT, while the order of protein recovery was SDS>AOT>TritonX-100>CTAB. As compared with ACN-HCl extraction, the total amount of isoflavones was lower than reverse micellar extraction. Ion strength was one of the important conditions to control extraction of isoflavone-enriching proteins with AOT reversed micelles. For the six salt systems, KNO(3), KCl, MgCl(2), CaCl(2), NaCl, and Na(2)SO(4), extracted fraction of isoflavone-enriching proteins was measured. Salt solutions greatly influenced the extraction efficiency of isoflavones in an order of KNO(3)>MgCl(2)>CaCl(2)>KCl>NaCl>Na(2)SO(4), while protein in an order of MgCl(2)>CaCl(2)>NaCl>KNO(3)>Na(2)SO(4)>KCl.

2-(2-Bromophenyl)-formononetin and 2-heptyl-formononetin are PPARγ partial agonists and reduce lipid accumulation in 3T3-L1 adipocytes.

PubMed

Andersen, Charlotte; Kotowska, Dorota; Tortzen, Christian G; Kristiansen, Karsten; Nielsen, John; Petersen, Rasmus Koefoed

2014-11-01

Isoflavones are bioactive compounds that have been shown to decrease lipid accumulation in vitro. However, the knowledge of the isoflavone formononetin is limited. The aim of the study was to assess the effects of formononetin and its two synthetic analogues, 2-(2-bromophenyl)-formononetin and 2-heptyl-formononetin, on lipid accumulation in 3T3-L1 adipocytes and investigate possible mechanisms. Formononetin and the two analogues were added day 0-8 or day 8-10 of the differentiation period, and lipid accumulation, glycerol release and gene expression were measured. Additionally, competitive peroxisome proliferator-activated receptor (PPAR)-γ binding assay, PPARγ transactivation assay and Western blot for phosphorylated AMP-activated protein kinase (AMPK) were performed. Chronic treatment (day 0-8) with formononetin increased lipid accumulation, whereas the two analogues decreased lipid accumulation partly due to decreased differentiation. The two analogues, but not formononetin, also decreased lipid content in mature adipocytes. 2-Heptyl-formononetin increased glycerol release and lipolytic gene expression and decreased lipogenic gene expression. Formononetin did not bind to or activate PPARγ whereas both analogues bound to the receptor and behaved as PPARγ partial agonists in the transactivation assay. Neither of the compounds affected phosphorylation of AMPK. In conclusion, the analogues of formononetin decreased lipid accumulation possibly in part by acting as PPARγ partial agonists. Copyright © 2014 Elsevier Ltd. All rights reserved.

A new isoflavone glucoside from Pterocarpus santalinus.

PubMed

Krishnaveni, K S; Srinivasa Rao, J V

2000-01-01

A new isoflavone glucoside (1) together with the known santal has been isolated from the heartwood of Pterocarpus santalinus. Based on spectral methods, the structure of the new compound was elucidated as 4',5-dihydroxy 7-O-methyl isoflavone 3'-O-beta-D-glucoside.

Huntingtin interacting protein 1 modulates the transcriptional activity of nuclear hormone receptors.

PubMed

Mills, Ian G; Gaughan, Luke; Robson, Craig; Ross, Theodora; McCracken, Stuart; Kelly, John; Neal, David E

2005-07-18

Internalization of activated receptors regulates signaling, and endocytic adaptor proteins are well-characterized in clathrin-mediated uptake. One of these adaptor proteins, huntingtin interacting protein 1 (HIP1), induces cellular transformation and is overexpressed in some prostate cancers. We have discovered that HIP1 associates with the androgen receptor through a central coiled coil domain and is recruited to DNA response elements upon androgen stimulation. HIP1 is a novel androgen receptor regulator, significantly repressing transcription when knocked down using a silencing RNA approach and activating transcription when overexpressed. We have also identified a functional nuclear localization signal at the COOH terminus of HIP1, which contributes to the nuclear translocation of the protein. In conclusion, we have discovered that HIP1 is a nucleocytoplasmic protein capable of associating with membranes and DNA response elements and regulating transcription.

MEIS1 functions as a potential AR negative regulator

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

Cui, Liang; Department of Urology, Civil Aviation General Hospital/Civil Aviation Medical College of Peking University, Beijing 100123; Li, Mingyang

2014-10-15

The androgen receptor (AR) plays critical roles in human prostate carcinoma progression and transformation. However, the activation of AR is regulated by co-regulators. MEIS1 protein, the homeodomain transcription factor, exhibited a decreased level in poor-prognosis prostate tumors. In this study, we investigated a potential interaction between MEIS1 and AR. We found that overexpression of MEIS1 inhibited the AR transcriptional activity and reduced the expression of AR target gene. A potential protein–protein interaction between AR and MEIS1 was identified by the immunoprecipitation and GST pull-down assays. Furthermore, MEIS1 modulated AR cytoplasm/nucleus translocation and the recruitment to androgen response element in prostatemore » specific antigen (PSA) gene promoter sequences. In addition, MEIS1 promoted the recruitment of NCoR and SMRT in the presence of R1881. Finally, MEIS1 inhibited the proliferation and anchor-independent growth of LNCaP cells. Taken together, our data suggests that MEIS1 functions as a novel AR co-repressor. - Highlights: • A potential interaction was identified between MEIS1 and AR signaling. • Overexpression of MEIS1 reduced the expression of AR target gene. • MEIS1 modulated AR cytoplasm/nucleus translocation. • MEIS1 inhibited the proliferation and anchor-independent growth of LNCaP cells.« less

Effect of the heat shock protein HSP27 on androgen receptor expression and function in prostate cancer cells.

PubMed

Stope, Matthias B; Schubert, Tina; Staar, Doreen; Rönnau, Cindy; Streitbörger, Andreas; Kroeger, Nils; Kubisch, Constanze; Zimmermann, Uwe; Walther, Reinhard; Burchardt, Martin

2012-06-01

Heat shock proteins (HSP) are involved in processes of folding, activation, trafficking and transcriptional activity of most steroid receptors including the androgen receptor (AR). Accumulating evidence links rising heat shock protein 27 (HSP27) levels with the development of castration-resistant prostate cancer. In order to study the functional relationship between HSP27 and the AR, we modulated the expression of the small heat shock protein HSP27 in human prostate cancer (PC) cell lines. HSP27 protein concentrations in LNCaP and PC-3 cells were modulated by over-expression or silencing of HSP27. The effects of HSP27 on AR protein and mRNA levels were monitored by Western blotting and quantitative RT-PCR. Treatment for the AR-positive LNCaP with HSP27-specific siRNA resulted in a down-regulation of AR levels. This down-regulation of protein was paralleled by a decrease in AR mRNA. Most interestingly, over-expression of HSP27 in PC-3 cells led to a significant increase in AR mRNA although the cells were unable to produce functional AR protein. The observation that HSP27 is involved in the regulation of AR mRNA by a yet unknown mechanism highlights the complexity of HSP27-AR signaling network.

Dietary isoflavones and bone mineral density during midlife and the menopausal transition: cross-sectional and longitudinal results from the Study of Women's Health Across the Nation Phytoestrogen Study.

PubMed

Greendale, Gail A; Tseng, Chi-Hong; Han, Weijuan; Huang, Mei-Hua; Leung, Katherine; Crawford, Sybil; Gold, Ellen B; Waetjen, L Elaine; Karlamangla, Arun S

2015-03-01

This study aims to examine cross-sectional and longitudinal relations between dietary intake of isoflavones and bone mineral density (BMD) at the lumbar spine (LS) and femoral neck (FN) in black, white, Chinese, and Japanese women during the menopausal transition. We tested whether tertiles of isoflavone intake were associated with baseline BMD when all women were premenopausal or early perimenopausal. To analyze whether isoflavone intake was associated with longitudinal BMD, we fitted piecewise linear models to repeated measurements of baseline-normalized LS or FN BMD as functions of time before or after the final menstrual period (FMP) date. Multiply adjusted mean FN BMD values of premenopausal Japanese women were monotonically positively related to isoflavone consumption (P for trend = 0.0003). Otherwise, no statistically significant baseline associations were observed. During the period of 1 year before the FMP through 5 years after the FMP, all participants lost LS and FN BMD. Loss was unrelated to isoflavone intake, except for Japanese women during the period of 1 year before the FMP to 2 years after the FMP: higher tertiles of isoflavone intake were associated with greater annual LS BMD loss rates (P for trend = 0.01) and FN loss rates (P for trend = 0.04). In Japanese women, higher isoflavone intake is associated with higher peak FN BMD but also with greater rates of LS and FN BMD loss during the menopausal transition. Results for the other racial/ethnic groups did not support a relation between dietary intake of isoflavones and either peak BMD or BMD loss during the menopausal transition.

Intake of soy foods and soy isoflavones by rural adult women in China.

PubMed

Liu, Zhaoping; Li, Wenxian; Sun, Jing; Liu, Chenghong; Zeng, Qiang; Huang, Jian; Yu, Bo; Huo, Junsheng

2004-01-01

This study evaluated the intake of soy foods and soy isoflavones by rural adult women and potential determinant factors. Soy food consumption and information on age, education and medical history were collected on 1,188 subjects in Gansu Province and Hebei Province, China using a food frequency questionnaire to gather data on food intake over the past year. Weight and height were simultaneously measured. The results showed that 1139 (95.9%) rural women consumed soy foods in the past year. The average intake of soy foods and isoflavones was 38.7 +/- 58.2 (median = 23.5) g/d and 17.7 +/- 26.6 (median= 8.9) mg/d, respectively. Tofu accounted for the most contribution to their intake. The soy isoflavone intake ranged between 0-35 mg/day in 89.2% of subjects. Gansu women had higher intakes of soy foods and isoflavones than Henbei women (P< 0.05). Women aged 41-50 years consumed less soy foods and isoflavones than the 20-30-year olds and 31-40 year olds(P < 0.05). The intake of soy foods (P< 0.01) and isoflavones (P< 0.01) by women who experienced secondary education or above was significantly higher than illiterate women. Women without a medical history had a higher soy isoflavone intake than women with a medical history, but the difference was not statistically significant. These results suggest that the intake of soy isoflavones by Chinese rural adult women was much higher than women in Western countries. The distribution of intake was skewed to the right and varied among women in regard to region, age group and education level.

Influence of dietary isoflavone intake on gastrointestinal symptoms in ulcerative colitis individuals in remission.

PubMed

Głąbska, Dominika; Guzek, Dominika; Grudzińska, Dominika; Lech, Gustaw

2017-08-07

To analyse the association between isoflavone intake and ulcerative colitis motility symptoms in individuals in remission. Cross-sectional study was conducted in a group of ulcerative colitis remission individuals, in sub-groups characterised by various intestinal motility and functioning characteristics (abdominal pain, flatulence, constipations, tenesmus). Total of 56 individuals with ulcerative colitis in remission (19 males and 37 females) were recruited for the study. Assessment of diet was based on self-reported data from each patient's dietary records taken over a period of three typical, random days (2 weekdays and 1 d of the weekend). The daily isoflavone intake (daidzein, genistein, glycitein and total isoflavones) and daily isoflavone intake per 1000 kcal of diet were assessed. No correlations between isoflavone intake levels and number of bowel movements per day were observed both in the case of intake and intake per 1000 kcal of diet. In the group of individuals declaring lack of abdominal pain, the higher intakes of daidzein ( P = 0.0075), daidzein per 1000 kcal of diet ( P = 0.0358) and total isoflavone ( P = 0.0358) were stated, than in the group of individuals declaring abdominal pain. In the group of individuals declaring lack of constipations, the lower intakes of glycitein ( P = 0.0213) and glycitein per 1000 kcal of diet ( P = 0.0213) were stated, than in the group of individuals declaring presence of constipations. No differences were observed in isoflavone intake between groups of ulcerative colitis individuals declaring lack of flatulence and declaring presence of flatulence, as well as between groups declaring lack of tenesmus and declaring presence of tenesmus. The moderate dietary isoflavone intake may be beneficial for individuals with ulcerative colitis in remission, however, before including it into recommendations, further prospective studies are needed.

Influence of dietary isoflavone intake on gastrointestinal symptoms in ulcerative colitis individuals in remission

PubMed Central

Głąbska, Dominika; Guzek, Dominika; Grudzińska, Dominika; Lech, Gustaw

2017-01-01

AIM To analyse the association between isoflavone intake and ulcerative colitis motility symptoms in individuals in remission. METHODS Cross-sectional study was conducted in a group of ulcerative colitis remission individuals, in sub-groups characterised by various intestinal motility and functioning characteristics (abdominal pain, flatulence, constipations, tenesmus). Total of 56 individuals with ulcerative colitis in remission (19 males and 37 females) were recruited for the study. Assessment of diet was based on self-reported data from each patient’s dietary records taken over a period of three typical, random days (2 weekdays and 1 d of the weekend). The daily isoflavone intake (daidzein, genistein, glycitein and total isoflavones) and daily isoflavone intake per 1000 kcal of diet were assessed. RESULTS No correlations between isoflavone intake levels and number of bowel movements per day were observed both in the case of intake and intake per 1000 kcal of diet. In the group of individuals declaring lack of abdominal pain, the higher intakes of daidzein (P = 0.0075), daidzein per 1000 kcal of diet (P = 0.0358) and total isoflavone (P = 0.0358) were stated, than in the group of individuals declaring abdominal pain. In the group of individuals declaring lack of constipations, the lower intakes of glycitein (P = 0.0213) and glycitein per 1000 kcal of diet (P = 0.0213) were stated, than in the group of individuals declaring presence of constipations. No differences were observed in isoflavone intake between groups of ulcerative colitis individuals declaring lack of flatulence and declaring presence of flatulence, as well as between groups declaring lack of tenesmus and declaring presence of tenesmus. CONCLUSION The moderate dietary isoflavone intake may be beneficial for individuals with ulcerative colitis in remission, however, before including it into recommendations, further prospective studies are needed. PMID:28839435

Soya isoflavone-enriched cereal bars affect markers of endothelial function in postmenopausal women.

PubMed

Hallund, J; Bügel, S; Tholstrup, T; Ferrari, M; Talbot, D; Hall, W L; Reimann, M; Williams, C M; Wiinberg, N

2006-06-01

Soya isoflavones are thought to be cardioprotective due to their structural similarity to oestrogen. In order to investigate the effect of soya isoflavones on markers of endothelial function we conducted a randomised, double-blind, placebo-controlled, cross-over study with thirty healthy postmenopausal women. The women consumed cereal bars, with or without soya isoflavones (50 mg/d), for 8 weeks, separated by an 8-week washout period. Systemic arterial compliance (SAC), isobaric arterial compliance (IAC), flow-mediated endothelium-dependent vasodilation (FMD) and nitroglycerine-mediated endothelium-independent vasodilation (NMD) were measured at the beginning of the study and after each intervention period. Blood pressure (BP) and plasma concentrations of nitrite and nitrate (NOx) and endothelin-1 (ET-1) were measured at the beginning and end of each intervention period. NMD was 13.4 (SEM 2.0)% at baseline and 15.5 (SEM 1.1) % after isoflavone treatment compared with 12.4 (SEM 1.0)% after placebo treatment (P=0.03). NOx increased from 27.7 (SEM 2.7) to 31.1 (SEM 3.2) microM after isoflavones treatment compared with 25.4 (SEM 1.5) to 20.4 (SEM 1.1) microM after placebo treatment (P=0.003) and a significant increase in the NOx:ET-1 ratio (P=0.005) was observed after the isoflavone treatment compared with placebo. A significant difference in SAC after the isoflavone and placebo treatment was observed (P=0.04). No significant difference was found in FMD, IAC, BP and ET-1. In conclusion, 8 weeks' consumption of cereals bars enriched with 50 mg soya isoflavones/d increased plasma NOx concentrations and improved endothelium-independent vasodilation in healthy postmenopausal women.

Isoflavones, calcium, vitamin D and inulin improve quality of life, sexual function, body composition and metabolic parameters in menopausal women: result from a prospective, randomized, placebo-controlled, parallel-group study.

PubMed

Vitale, Salvatore Giovanni; Caruso, Salvatore; Rapisarda, Agnese Maria Chiara; Cianci, Stefano; Cianci, Antonio

2018-03-01

Menopause results in metabolic changes that contribute to increase risk of cardiovascular diseases: increase in low density lipoprotein (LDL) and triglycerides and decrease in high density lipoprotein (HDL), weight gain are associated with a correspondent increase in incidence of hypertension and diabetes. The aim of this study was to evaluate the effect of a preparation of isoflavones, calcium vitamin D and inulin in menopausal women. We performed a prospective, randomized, placebo-controlled, parallel-group study. A total of 50 patients were randomized to receive either oral preparations of isoflavones (40 mg), calcium (500 mg) vitamin D (300 UI) and inulin (3 g) or placebo (control group). Pre- and post-treatment assessment of quality of life and sexual function were performed through Menopause-Specific Quality of Life Questionnaire (MENQOL) and Female Sexual Function Index (FSFI); evaluations of anthropometric indicators, body composition through bioelectrical impedance analyser, lumbar spine and proximal femur T-score and lipid profile were performed. After 12 months, a significant reduction in MENQOL vasomotor, physical and sexual domain scores ( p < 0.05) and a significant increase in all FSFI domain scores ( p < 0.05) were observed in treatment group. Laboratory tests showed significant increase in serum levels of HDL ( p < 0.05). No significant changes of lumbar spine and femur neck T-score ( p > 0.05) were found in the same group. According to our data analysis, isoflavones, calcium, vitamin D and inulin may exert favourable effects on menopausal symptoms and signs.

A Novel Dietary Flavonoid Fisetin Inhibits Androgen Receptor Signaling and Tumor Growth in Athymic Nude Mice

PubMed Central

Khan, Naghma; Asim, Mohammad; Afaq, Farrukh; Zaid, Mohammad Abu; Mukhtar, Hasan

2010-01-01

Androgen receptor (AR)–mediated signaling plays an important role in the development and progression of prostate cancer (PCa). Hormonal therapies, mainly with combinations of antiandrogens and androgen deprivation, are the mainstay treatment for advanced disease. However, emergence of androgen resistance largely due to inefficient antihormone action limits their therapeutic usefulness. Here, we report that fisetin, a novel dietary flavonoid, acts as a novel AR ligand by competing with the high-affinity androgen to interact with the ligand binding domain of AR. We show that this physical interaction results in substantial decrease in AR stability and decrease in amino-terminal/carboxyl-terminal (N-C) interaction of AR. This results in blunting of AR-mediated transactivation of target genes including prostate-specific antigen (PSA). In addition, treatment of LNCaP cells with fisetin decreased AR protein levels, in part, by decreasing its promoter activity and by accelerating its degradation. Fisetin also synergized with Casodex in inducing apoptosis in LNCaP cells. Treatment with fisetin in athymic nude mice implanted with AR-positive CWR22Rυ1 human PCa cells resulted in inhibition of tumor growth and reduction in serum PSA levels. These data identify fisetin as an inhibitor of AR signaling axis and suggest that it could be a useful chemopreventive and chemotherapeutic agent to delay progression of PCa. PMID:18922931

Potential rumen, vascular and production benefits of isoflavones in ruminant diets

USDA-ARS?s Scientific Manuscript database

Legumes, such as clovers, are well known for their role in the nitrogen cycle, and as high protein components in ruminant diets. The production of flavonoid secondary metabolites, particularly isoflavones, is another distinguishing feature of legumes. Isoflavones are phytoestrogens, which can inte...

Commercial rodent diets differentially regulate autoimmune glomerulonephritis, epigenetics and microbiota in MRL/lpr mice

PubMed Central

Edwards, Michael R; Dai, Rujuan; Heid, Bettina; Cecere, Thomas E; Khan, Deena; Mu, Qinghui; Cowan, Catharine; Luo, Xin M; Ahmed, S Ansar

2017-01-01

Abstract The course and severity of lupus in spontaneous murine lupus models varies among laboratories, which may be due to variations in diet, housing and/or local environmental conditions. In this study, we investigated the influence of common rodent diets while keeping other factors constant. Female lupus-prone MRL/lpr (MRL/MpJ-Faslpr/J) mice were subjected to the same housing conditions and given one of the three diets: Teklad 7013 containing isoflavone-rich soy and alfalfa, Harlan 2018 isoflavone-rich soy-based diet or Research Diets Inc. D11112226 (RD) purified-ingredients diet containing casein and no phytoestrogens. While the total caloric intake was similar among all three treatment groups, mice fed on the 2018 diet developed higher levels of proteinuria and mice fed on either 7013 or 2018 developed higher levels of glomerular immune complex deposition. Remarkably, mice fed the RD diet had markedly decreased proteinuria with diminished C3, total IgG, IgG1 and IgG3 immune complex deposition, along with reduced CD11b+ cellular infiltration into the glomeruli. The type of diet intake also influenced cytokine production, fecal microbiota (increased Lachnospiraceae in mice fed on 2018), altered microRNAs (miRNAs; higher levels of lupus-associated miR-148a and miR-183 in mice fed on 7013 and/or 2018) and altered DNA methylation. This is the first study to comprehensively compare the cellular, molecular and epigenetic effects of these commercial diets in murine lupus. PMID:28637300

The O-methylated isoflavone, formononetin, inhibits human ovarian cancer cell proliferation by sub G0/G1 cell phase arrest through PI3K/AKT and ERK1/2 inactivation.

PubMed

Park, Sunwoo; Bazer, Fuller W; Lim, Whasun; Song, Gwonhwa

2018-05-15

Formononetin is an isoflavone that is extracted from red clovers or soy. It has anti-oxidant, anti-proliferative, and anti-tumor effects against cells in various diseases. Several cohort studies have indicated that phytoestrogen intake, including formononetin, could reduce the risk of various carcinogenesis. In fact, many case-control studies have indicated the potential value of flavonoids as drug supplements in the treatment of many cancer patients. However, the toxic effects and the anti-cancer mechanism of formononetin in ovarian cancer are unknown. We investigated the toxicological mechanism of formononetin in ES2 and OV90 ovarian cancer cells. Formononetin suppressed cell proliferation through sub G0/G1 phase arrest and increased apoptosis in both cell lines. Furthermore, it induced loss of mitochondrial membrane potential and generation of reactive oxygen species in ES2 and OV90 cells. The formononetin-mediated regulation of cell proliferation and apoptosis involved decreased phosphorylation of ERK1/2, P90RSK, AKT, P70S6K, and S6 proteins, and increased phosphorylation of P38 protein in ES2 and OV90 cells. Co-treatment of formononetin with pharmacological inhibitors (LY294002 or U0126) revealed additional anti-proliferative effects on the two human ovarian cancer cell types. Conclusively, the results indicate the potential value of formononetin as an anti-cancer agent in human ovarian cancer. © 2018 Wiley Periodicals, Inc.

Prostate enlargement in mice due to fetal exposure to low doses of estradiol or diethylstilbestrol and opposite effects at high doses

PubMed Central

Saal, Frederick S. vom; Timms, Barry G.; Montano, Monica M.; Palanza, Paola; Thayer, Kristina A.; Nagel, Susan C.; Dhar, Minati D.; Ganjam, V. K.; Parmigiani, Stefano; Welshons, Wade V.

1997-01-01

On the basis of results of studies using high doses of estrogens, exposure to estrogen during fetal life is known to inhibit prostate development. However, it is recognized in endocrinology that low concentrations of a hormone can stimulate a tissue, while high concentrations can have the opposite effect. We report here that a 50% increase in free-serum estradiol in male mouse fetuses (released by a maternal Silastic estradiol implant) induced a 40% increase in the number of developing prostatic glands during fetal life; subsequently, in adulthood, the number of prostatic androgen receptors per cell was permanently increased by 2-fold, and the prostate was enlarged by 30% (due to hyperplasia) relative to untreated males. However, as the free serum estradiol concentration in male fetuses was increased from 2- to 8-fold, adult prostate weight decreased relative to males exposed to the 50% increase in estradiol. As a model for fetal exposure to man-made estrogens, pregnant mice were fed diethylstilbestrol (DES) from gestation days 11 to 17. Relative to controls, DES doses of 0.02, 0.2, and 2.0 ng per g of body weight per day increased adult prostate weight, whereas a 200-ng-per-g dose decreased adult prostate weight in male offspring. Our findings suggest that a small increase in estrogen may modulate the action of androgen in regulating prostate differentiation, resulting in a permanent increase in prostatic androgen receptors and prostate size. For both estradiol and DES, prostate weight first increased then decreased with dose, resulting in an inverted-U dose-response relationship. PMID:9050904

Rosemary (Rosmarinus officinalis) extract modulates CHOP/GADD153 to promote androgen receptor degradation and decreases xenograft tumor growth.

PubMed

Petiwala, Sakina M; Berhe, Saba; Li, Gongbo; Puthenveetil, Angela G; Rahman, Ozair; Nonn, Larisa; Johnson, Jeremy J

2014-01-01

The Mediterranean diet has long been attributed to preventing or delaying the onset of cardiovascular disease, diabetes and various solid organ cancers. In this particular study, a rosemary extract standardized to carnosic acid was evaluated for its potential in disrupting the endoplasmic reticulum machinery to decrease the viability of prostate cancer cells and promote degradation of the androgen receptor. Two human prostate cancer cell lines, 22Rv1 and LNCaP, and prostate epithelial cells procured from two different patients undergoing radical prostatectomy were treated with standardized rosemary extract and evaluated by flow cytometry, MTT, BrdU, Western blot and fluorescent microscopy. A significant modulation of endoplasmic reticulum stress proteins was observed in cancer cells while normal prostate epithelial cells did not undergo endoplasmic reticulum stress. This biphasic response suggests that standardized rosemary extract may preferentially target cancer cells as opposed to "normal" cells. Furthermore, we observed standardized rosemary extract to decrease androgen receptor expression that appears to be regulated by the expression of CHOP/GADD153. Using a xenograft tumor model we observed standardized rosemary extract when given orally to significantly suppress tumor growth by 46% compared to mice not receiving standardized rosemary extract. In the last several years regulatory governing bodies (e.g. European Union) have approved standardized rosemary extracts as food preservatives. These results are especially significant as it is becoming more likely that individuals will be receiving standardized rosemary extracts that are a part of a natural preservative system in various food preparations. Taken a step further, it is possible that the potential benefits that are often associated with a "Mediterranean Diet" in the future may begin to extend beyond the Mediterranean diet as more of the population is consuming standardized rosemary extracts.

The influence of dietary isoflavone on the uterotrophic response in juvenile rats.

PubMed

Wade, Michael G; Lee, Alice; McMahon, Avril; Cooke, Gerard; Curran, Ivan

2003-11-01

Current in vivo methods to identify and assess reproductive hazards of endocrine disrupting substances are often confounded by the presence of isoflavones (genistein, diadzein, glycitein), strongly hormonally-active substances, in the diet of laboratory rodents. However, studies that have attempted to study the influence of dietary isoflavone on qualitative and quantitative uterotrophic responses have been limited by the few doses of isoflavone tested, stress to the animals due to changing of the diet immediately prior to testing and/or comparing effects of diets of very different composition. The current study examined the effects of isoflavone on uterotrophic response by using immature female rats reared from conception on diets varying only in the amount of isoflavone concentrate (Novasoy) added to a virtually isoflavone-free soya-based diet. The effects of these diets, and a soya-free semipurified diet (AIN 93G) on uterotrophic responses to treatment with a strong (Ethinyl Estradiol, EE) or a weak (bisphenol A, BPA) estrogenic substance were examined. The pups were treated with subcutaneous injections of either EE (1 microg/kg/day), BPA (600 mg/kg/day) or corn oil (vehicle) control for 3 days starting at weaning on post natal day (PND) 21. On the morning of PND 24 pups were sacrificed and uterus weight, epithelium labeling index (Bromo deoxyuridine incorporation), uterine epithelium thickness, and peroxidase activity were determined. Diet did not influence unstimulated uterine weight, epithelial height or peroxidase activity except at the highest isoflavone diet where animals had significantly increases in all three endpoints. Uterine weight, epithelial thickness and peroxidase were all significantly increased by EE or BPA treatment. There was no evidence of diet-induced potentiation or inhibition of the stimulatory actions of either EE or BPA on either uterine weight or epithelial thickness while EE-induced increase in uterine peroxidase activity was increased synergistically by the highest dose of isoflavone. A similar response to the latter effect was seen in BPA treated animals although this response was not significantly different from that of BPA treated rats fed the isoflavone-free soy diet. The rate of endometrial epithelium labeling with BrdU was not altered by any treatment. These results indicate that dietary isoflavone content can directly influence uterine weight and other estrogen-dependent endpoints demonstrating the potential of these to reduce the active range of the uterotrophic assay. However, there is no indication that isoflavones impair or potentiate the stimulatory action of either strong (EE) or weaker (BPA) estrogen agonists on uterine weight or epithelial morphology although the data do suggest the potential for synergy between high isoflavone content and estrogen agonist in inducing uterine peroxidase.

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.

Maternal androgen excess and obesity induce sexually dimorphic anxiety-like behavior in the offspring.

PubMed

Manti, Maria; Fornes, Romina; Qi, Xiaojuan; Folmerz, Elin; Lindén Hirschberg, Angelica; de Castro Barbosa, Thais; Maliqueo, Manuel; Benrick, Anna; Stener-Victorin, Elisabet

2018-03-22

Maternal polycystic ovary syndrome (PCOS), a condition associated with hyperandrogenism, is suggested to increase anxiety-like behavior in the offspring. Because PCOS is closely linked to obesity, we investigated the impact of an adverse hormonal or metabolic maternal environment and offspring obesity on anxiety in the offspring. The obese PCOS phenotype was induced by chronic high-fat-high-sucrose (HFHS) consumption together with prenatal dihydrotestosterone exposure in mouse dams. Anxiety-like behavior was assessed in adult offspring with the elevated-plus maze and open-field tests. The influence of maternal androgens and maternal and offspring diet on genes implicated in anxiety were analyzed in the amygdala and hypothalamus with real-time PCR ( n = 47). Independent of diet, female offspring exposed to maternal androgens were more anxious and displayed up-regulation of adrenoceptor α 1B in the amygdala and up-regulation of hypothalamic corticotropin-releasing hormone ( Crh). By contrast, male offspring exposed to a HFHS maternal diet had increased anxiety-like behavior and showed up-regulation of epigenetic markers in the amygdala and up-regulation of hypothalamic Crh. Overall, there were substantial sex differences in gene expression in the brain. These findings provide novel insight into how maternal androgens and obesity exert sex-specific effects on behavior and gene expression in the offspring of a PCOS mouse model.-Manti, M., Fornes, R., Qi, X., Folmerz, E., Lindén Hirschberg, A., de Castro Barbosa, T., Maliqueo, M., Benrick, A., Stener-Victorin, E. Maternal androgen excess and obesity induce sexually dimorphic anxiety-like behavior in the offspring.

The low dose gamma ionising radiation impact upon cooperativity of androgen-specific proteins.

PubMed

Filchenkov, Gennady N; Popoff, Eugene H; Naumov, Alexander D

2014-01-01

The paper deals with effects of the ionising radiation (γ-IR, 0.5 Gy) upon serum testosterone (T), characteristics of testosterone-binding globulin (TeBG) and androgen receptor (AR) in parallel with observation of androgen (A) responsive enzyme activity - hexokinase (HK). The interdependence or relationships of T-levels with parameters of the proteins that provide androgenic regulation are consequently analyzed in post-IR dynamics. The IR-stress adjustment data reveal expediency of TeBG- and AR-cooperativity measurements for more precise assessments of endocrine A-control at appropriate emergencies. Copyright © 2013 Elsevier Ltd. All rights reserved.

Soy isoflavone supplementation and breast density in postmenopausal women

USDA-ARS?s Scientific Manuscript database

Soy isoflavones may protect against breast cancer. Breast density, a marker for breast cancer risk, increases as a result of hormone replacement therapy. We examined the relation between isoflavone supplementation and breast density using the mammograms from 358 women who participated in the multi-s...

Clinical outcomes of a 2-y soy isoflavone supplementation in menopausal women

USDA-ARS?s Scientific Manuscript database

Soy isoflavones are naturally occurring phytochemicals with weak estrogenic cellular effects. Despite numerous clinical trials of short-term isoflavone supplementation, there is a paucity of data regarding longer-term outcomes and safety. Our aim was to evaluate the clinical outcomes of soy hypocoty...

Red Clover: A ruminant growth promoter you can grow

USDA-ARS?s Scientific Manuscript database

The article summarizes several studies about the benefits of red clover isoflavones for ruminants. Isoflavones are natural chemicals or “natural products” that come from many legumes. Biochanin A is an isoflavone from red clover (Trifolum pratense), a common forage legume. Biochanin A promotes the...

Spatiotemporal dynamics of androgen signaling underlie sexual differentiation and congenital malformations of the urethra and vagina

PubMed Central

Larkins, Christine E.; Enriquez, Ana B.; Cohn, Martin J.

2016-01-01

Disorders of sex development (DSDs) are congenital anomalies that affect sexual differentiation of genitourinary organs and secondary sex characters. A common cause of female genital virilization is congenital adrenal hyperplasia (CAH), in which excess androgen production during development of 46XX females can result in vaginal atresia, masculinization of the urethra, a single urogenital sinus, and clitoral hypertrophy or ambiguous external genitalia. Development of the vagina depends on sexual differentiation of the urogenital sinus ridge, an epithelial thickening that forms where the sex ducts attach to the anterior urethra. In females, the sinus ridge descends posteriorly to allow the vaginal opening to form in the vulva, whereas in males and in females with CAH, androgens inhibit descent of the sinus ridge. The mechanisms that regulate development of the female urethra and vagina are largely unknown. Here we show that the timing and duration of, and the cell population targeted by, androgen signaling determine the position of vaginal attachment to the urethra. Manipulations of androgen signaling in utero reveal a temporal window of development when sinus ridge fate is determined. Cell type-specific genetic deletions of androgen receptor (Ar) identify a subpopulation of mesenchymal cells that regulate sinus ridge morphogenesis. These results reveal a common mechanism that coordinates development of the vagina and feminization of the urethra, which may account for development of a single urogenital sinus in females exposed to excessive androgen during a critical period of prenatal development. PMID:27821748

Spatiotemporal dynamics of androgen signaling underlie sexual differentiation and congenital malformations of the urethra and vagina.

PubMed

Larkins, Christine E; Enriquez, Ana B; Cohn, Martin J

2016-11-22

Disorders of sex development (DSDs) are congenital anomalies that affect sexual differentiation of genitourinary organs and secondary sex characters. A common cause of female genital virilization is congenital adrenal hyperplasia (CAH), in which excess androgen production during development of 46XX females can result in vaginal atresia, masculinization of the urethra, a single urogenital sinus, and clitoral hypertrophy or ambiguous external genitalia. Development of the vagina depends on sexual differentiation of the urogenital sinus ridge, an epithelial thickening that forms where the sex ducts attach to the anterior urethra. In females, the sinus ridge descends posteriorly to allow the vaginal opening to form in the vulva, whereas in males and in females with CAH, androgens inhibit descent of the sinus ridge. The mechanisms that regulate development of the female urethra and vagina are largely unknown. Here we show that the timing and duration of, and the cell population targeted by, androgen signaling determine the position of vaginal attachment to the urethra. Manipulations of androgen signaling in utero reveal a temporal window of development when sinus ridge fate is determined. Cell type-specific genetic deletions of androgen receptor (Ar) identify a subpopulation of mesenchymal cells that regulate sinus ridge morphogenesis. These results reveal a common mechanism that coordinates development of the vagina and feminization of the urethra, which may account for development of a single urogenital sinus in females exposed to excessive androgen during a critical period of prenatal development.

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...

PROSTATE REGULATION: MODELING ENDOGENOUS ...

EPA Pesticide Factsheets

Prostate function is an important indicator of androgen status in toxicological studies making predictive modeling of the relevant pharmacokinetics and pharmacodynamics desirable. Prostate function is an important indicator of androgen status in toxicological studies making predictive modeling of the relevant pharmacokinetics and pharmacodynamics desirable.

Suppression of LIM and SH3 Domain Protein 1 (LASP1) Negatively Regulated by Androgen Receptor Delays Castration Resistant Prostate Cancer Progression.

PubMed

Dejima, Takashi; Imada, Kenjiro; Takeuchi, Ario; Shiota, Masaki; Leong, Jeffrey; Tombe, Tabitha; Tam, Kevin; Fazli, Ladan; Naito, Seiji; Gleave, Martin E; Ong, Christopher J

2017-02-01

LIM and SH3 domain protein 1 (LASP1) has been implicated in several human malignancies and has been shown to predict PSA recurrence in prostate cancer. However, the anti-tumor effect of LASP1 knockdown and the association between LASP1 and the androgen receptor (AR) remains unclear. The aim of this study is to clarify the significance of LASP1 as a target for prostate cancer, and to test the effect of silencing LASP1 in vivo using antisense oligonucleotides (ASO). A tissue microarray (TMA) was performed to characterize the differences in LASP1 expression in prostate cancer treated after hormone deprivation therapy. Flow cytometry was used to analyze cell cycle. We designed LASP1 ASO for knockdown of LASP1 in vivo studies. The expression of LASP1 in TMA was increased after androgen ablation and persisted in castration resistant prostate cancer (CRPC). Also in TMA, compared with LNCaP cell, LASP1 expression is elevated in CRPC cell lines (C4-2 and VehA cells). Interestingly, suppression of AR elevated LASP1 expression conversely, AR activation decreased LASP1 expression. Silencing of LASP1 reduced cell growth through G1 arrest which was accompanied by a decrease of cyclin D1. Forced overexpression of LASP1 promoted cell cycle and induced cell growth which was accompanied by an increase of cyclin D1. Systemic administration of LASP1 ASO with athymic mice significantly inhibited tumor growth in CRPC xenografts. These results indicate that LASP1 is negatively regulated by AR at the transcriptional level and promotes tumor growth through induction of cell cycle, ultimately suggesting that LASP1 may be a potential target in prostate cancer treatment. Prostate 77:309-320, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

The Androgen-Regulated Protease TMPRSS2 Activates aProteolytic Cascade Involving Components of the Tumor Microenvironment and Promotes Prostate Cancer Metastasis

PubMed Central

Lucas, Jared M.; Heinlein, Cynthia; Kim, Tom; Hernandez, Susana A.; Malik, Muzdah S.; True, Lawrence D.; Morrissey, Colm; Corey, Eva; Montgomery, Bruce; Mostaghel, Elahe; Clegg, Nigel; Coleman, Ilsa; Brown, Christopher M.; Schneider, Eric L.; Craik, Charles; Simon, Julian; Bedalov, Tony; Nelson, Peter S.

2014-01-01

TMPRSS2 is an androgen-regulated cell surface serine protease expressed predominantly in prostate epithelium. TMPRSS2 is expressed highly in localized high-grade prostate cancers and in the majority of human prostate cancer metastasis. Through the generation of mouse models with a targeted deletion of Tmprss2, we demonstrate that the activity of this protease regulates cancer cell invasion and metastasis to distant organs. By screening combinatorial peptide libraries we identified a spectrum of TMPRSS2 substrates that include pro-hepatocyte growth factor (HGF). HGF activated by TMPRSS2 promoted c-Met receptor tyrosine kinase signaling, and initiated a pro-invasive EMT phenotype. Chemical library screens identified a potent bioavailable TMPRSS2 inhibitor that suppressed prostate cancer metastasis in vivo. Together, these findings provide a mechanistic link between androgen-regulated signaling programs and prostate cancer metastasis that operate via context-dependent interactions with extracellular constituents of the tumor microenvironment. PMID:25122198

PTEN Regulates Beta-Catenin in Androgen Signaling: Implication in Prostate Cancer Progression

DTIC Science & Technology

2006-03-01

interacts with a single transmembrane LDL receptor-related protein 5/6 (LRP5/6) [14,15]. A number of different secreted proteins, such as secreted...cells [30,33,47,48,51]. Reduction of cellular levels of b-catenin by antisense or shRNA constructs decreases the expression of the PSA gene, a downstream...Zeng, LDL receptor- related proteins 5 and 6 inWnt/beta-catenin signaling: arrows point the way, Development 131 (2004) 1663–1677. [15] J.C. Hsieh

Androgens in pregnancy: roles in parturition

PubMed Central

Makieva, Sofia; Saunders, Philippa T.K.; Norman, Jane E.

2014-01-01

BACKGROUND Understanding the physiology of pregnancy enables effective management of pregnancy complications that could otherwise be life threatening for both mother and fetus. A functional uterus (i) retains the fetus in utero during pregnancy without initiating stretch-induced contractions and (ii) is able to dilate the cervix and contract the myometrium at term to deliver the fetus. The onset of labour is associated with successful cervical remodelling and contraction of myometrium, arising from concomitant activation of uterine immune and endocrine systems. A large body of evidence suggests that actions of local steroid hormones may drive changes occurring in the uterine microenvironment at term. Although there have been a number of studies considering the potential role(s) played by progesterone and estrogen at the time of parturition, the bio-availability and effects of androgens during pregnancy have received less scrutiny. The aim of this review is to highlight potential roles of androgens in the biology of pregnancy and parturition. METHODS A review of published literature was performed to address (i) androgen concentrations, including biosynthesis and clearance, in maternal and fetal compartments throughout gestation, (ii) associations of androgen concentrations with adverse pregnancy outcomes, (iii) the role of androgens in the physiology of cervical remodelling and finally (iv) the role of androgens in the physiology of myometrial function including any impact on contractility. RESULTS Some, but not all, androgens increase throughout gestation in maternal circulation. The effects of this increase are not fully understood; however, evidence suggests that increased androgens might regulate key processes during pregnancy and parturition. For example, androgens are believed to be critical for cervical remodelling at term, in particular cervical ripening, via regulation of cervical collagen fibril organization. Additionally, a number of studies highlight potential roles for androgens in myometrial relaxation via non-genomic, AR-independent pathways critical for the pregnancy reaching term. Understanding of the molecular events leading to myometrial relaxation is an important step towards development of novel targeted tocolytic drugs. CONCLUSIONS The increase in androgen levels throughout gestation is likely to be important for establishment and maintenance of pregnancy and initiation of parturition. Further investigation of the underlying mechanisms of androgen action on cervical remodelling and myometrial contractility is needed. The insights gained may facilitate the development of new therapeutic approaches to manage pregnancy complications such as preterm birth. PMID:24643344

Androgens in pregnancy: roles in parturition.

PubMed

Makieva, Sofia; Saunders, Philippa T K; Norman, Jane E

2014-01-01

Understanding the physiology of pregnancy enables effective management of pregnancy complications that could otherwise be life threatening for both mother and fetus. A functional uterus (i) retains the fetus in utero during pregnancy without initiating stretch-induced contractions and (ii) is able to dilate the cervix and contract the myometrium at term to deliver the fetus. The onset of labour is associated with successful cervical remodelling and contraction of myometrium, arising from concomitant activation of uterine immune and endocrine systems. A large body of evidence suggests that actions of local steroid hormones may drive changes occurring in the uterine microenvironment at term. Although there have been a number of studies considering the potential role(s) played by progesterone and estrogen at the time of parturition, the bio-availability and effects of androgens during pregnancy have received less scrutiny. The aim of this review is to highlight potential roles of androgens in the biology of pregnancy and parturition. A review of published literature was performed to address (i) androgen concentrations, including biosynthesis and clearance, in maternal and fetal compartments throughout gestation, (ii) associations of androgen concentrations with adverse pregnancy outcomes, (iii) the role of androgens in the physiology of cervical remodelling and finally (iv) the role of androgens in the physiology of myometrial function including any impact on contractility. Some, but not all, androgens increase throughout gestation in maternal circulation. The effects of this increase are not fully understood; however, evidence suggests that increased androgens might regulate key processes during pregnancy and parturition. For example, androgens are believed to be critical for cervical remodelling at term, in particular cervical ripening, via regulation of cervical collagen fibril organization. Additionally, a number of studies highlight potential roles for androgens in myometrial relaxation via non-genomic, AR-independent pathways critical for the pregnancy reaching term. Understanding of the molecular events leading to myometrial relaxation is an important step towards development of novel targeted tocolytic drugs. The increase in androgen levels throughout gestation is likely to be important for establishment and maintenance of pregnancy and initiation of parturition. Further investigation of the underlying mechanisms of androgen action on cervical remodelling and myometrial contractility is needed. The insights gained may facilitate the development of new therapeutic approaches to manage pregnancy complications such as preterm birth. © The Author 2014. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.

Androgen receptor regulated microRNA miR-182-5p promotes prostate cancer progression by targeting the ARRDC3/ITGB4 pathway

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

Yao, Jingjing; Xu, Chen; Department of Orthopedics, Changzheng Hospital Affiliated to Second Military Medical University, 415th Feng Yang Road, Shanghai, 200003

Abstracts: MicroRNAs (miRNAs) are important endogenous gene regulators that play key roles in prostate cancer development and metastasis. However, specific miRNA expression patterns in prostate cancer tissues from Chinese patients remain largely unknown. In this study, we compared miRNA expression patterns in 65 pairs of prostate cancer and para-cancer tissues by RNA sequencing and found that miR-182-5p was the most up-regulated miRNA in prostate cancer tissues. The result was validated using realtime PCR in 18 pairs of prostate cancer and para-cancer tissues. In in vitro analysis, it was confirmed that miR-182-5p promotes prostate cancer cell proliferation, invasion and migration and inhibitmore » apoptosis. In addition, the androgen receptor directly regulated the transcription of miR-182-5p, which could target to the 3′UTR of ARRDC3 mRNA and affect the expression of ARRDC3 and its downstream gene ITGB4. For the in vivo experiment, miR-182-5p overexpression also promoted the growth and progression of prostate cancer tumors. In this regard, we suggest that miR-182-5p may be a key androgen receptor-regulated factor that contributes to the development and metastasis of Chinese prostate cancers and may be a potential target for the early diagnosis and therapeutic studies of prostate cancer. -- Highlights: •miR-182-5p is the mostly up-regulated miRNA in Chinese prostate cancer. •miR-182-5p is regulated by androgen receptor. •miR-182-5p promotes prostate cancer progression. •miR-182-5p regulates ARRDC3/ITGB4 pathway.« less

Uncarboxylated Osteocalcin and Gprc6a Axis Produce Intratumoral Androgens in Castration-Resistant Prostate Cancer

DTIC Science & Technology

2016-05-01

multiple pathways, despite castrate levels of testosterone . One such adaptive mechanism is the “intracrine” production of androgens in the primary...despite castrate levels of testosterone . One such adaptive mechanism is the “intracrine” production of androgens in the primary tumor and/or at... testosterone . Thus, just as the skeleton regulates fertility in an endocrine fashion, and it may also promote bone metastasis via an “intracrine” mechanism

New Strategy for Prostate Cancer Prevention Based on Selenium Suppression of Androgen Receptor Signaling

DTIC Science & Technology

2007-10-01

regulates androgen receptor, and finasteride , a 5α-reductase inhibitor, has a synerigistic effect in inhibiting the growth of prostate cancer cells...impact of the selenium and finasteride combination on androgen signaling; 2) Identifying the pro-apoptotic target genes of FOXO1 that are induced by...selenium; 3) studying the potential AR antagonistic effect of finasteride . The last was not proposed in the original application. But we strongly

Quantitative proteomics reveals that peroxidases play key roles in post-flooding recovery in soybean roots.

PubMed

Khan, Mudassar Nawaz; Sakata, Katsumi; Hiraga, Susumu; Komatsu, Setsuko

2014-12-05

Soybean is an important legume crop that exhibits markedly reduced growth and yields under flooding conditions. To unravel the mechanisms involved in recovery after flooding in soybean root, gel-free proteomic analysis was performed. Morphological analysis revealed that growth suppression was more severe with increased flooding duration. Out of a total of 1645 and 1707 identified proteins, 73 and 21 proteins were changed significantly during the recovery stage following 2 and 4 days flooding, respectively. Based on the proteomic, clustering, and in silico protein-protein interaction analyses, six key enzymes were analyzed at the mRNA level. Lipoxygenase 1, which was increased at the protein level during the recovery period, was steadily down-regulated at the mRNA level. The peroxidase superfamily protein continuously increased in abundance during the course of recovery and was up-regulated at the mRNA level. HAD acid phosphatase was decreased at the protein level and down-regulated at the transcript level, while isoflavone reductase and an unknown protein were increased at both the protein and mRNA levels. Consistent with these findings, the enzymatic activity of peroxidase was decreased under flooding stress but increased significantly during the recovery sage. These results suggest that peroxidases might play key roles in post-flooding recovery in soybean roots through the scavenging of toxic radicals.

Various doses of soy isoflavones do not modify mammographic density in postmenopausal women

USDA-ARS?s Scientific Manuscript database

Soy isoflavones have functional similarity to human estrogens and may protect against breast cancer as a result of their antiestrogenic activity or increase risk as a result of their estrogen-like properties. We examined the relation between isoflavone supplementation and mammographic density, a str...

Update of the USDA’s Database for the Isoflavone Content in Selected Foods

USDA-ARS?s Scientific Manuscript database

Isoflavones have weak estrogenic, as well as other, biological properties that may contribute to the reduction of the risk of some chronic diseases. Although evidence for the beneficial role of isoflavones in breast cancer has become conflicted, results of clinical trials for prostate cancer are en...

Effect of soy isoflavone supplementation on nitric oxide metabolism and blood pressure in menopausal women

USDA-ARS?s Scientific Manuscript database

Isoflavones, having chemical structures similar to estrogens, are believed to stimulate nitric oxide production and thus lower blood pressure. The efficacy of soy isoflavone supplementation to stimulate nitric oxide production and lower blood pressure in menopausal women with high normal blood press...

A new acylated isoflavone glucoside from Pterocarpus santalinus.

PubMed

Krishnaveni, K S; Srinivasa Rao, J V

2000-09-01

Phytochemical investigation on the constituents of heartwood of Pterocarpus santalinus resulted in the isolation of a new acylated isoflavone glucoside. The structure of the new compound was elucidated on the basis of spectral studies as 4',5-dihydroxy-7-O-methyl isoflavone 3'-O-D-(3''-E-cinnamoyl)glucoside.

Isoflavone rumen metabolites: A missing link in the benefits of legumes on grazing animal production

USDA-ARS?s Scientific Manuscript database

Clovers are widely used to add protein to ruminant diets. Clovers and other legumes also produce a class of small molecules called isoflavones. Isoflavones have estrogenic properties, which can interfere with reproduction in grazing ruminants, but they also have benefits. We identified potential b...

Interaction of Isoflavones with the BCRP/ABCG2 Drug Transporter

PubMed Central

Bircsak, Kristin M; Aleksunes, Lauren M

2015-01-01

This review will provide a comprehensive overview of the interactions between dietary isoflavones and the ATP-binding cassette (ABC) G2 efflux transporter, which is also named the breast cancer resistance protein (BCRP). Expressed in a variety of organs including the liver, kidneys, intestine, and placenta, BCRP mediates the disposition and excretion of numerous endogenous chemicals and xenobiotics. Isoflavones are a class of naturally-occurring compounds that are found at high concentrations in commonly consumed foods and dietary supplements. A number of isoflavones, including genistein and daidzein and their metabolites, interact with BCRP as substrates, inhibitors, and/or modulators of gene expression. To date, a variety of model systems have been employed to study the ability of isoflavones to serve as substrates and inhibitors of BCRP; these include whole cells, inverted plasma membrane vesicles, in situ organ perfusion, as well as in vivo rodent and sheep models. Evidence suggests that BCRP plays a role in mediating the disposition of isoflavones and in particular, their conjugated forms. Furthermore, as inhibitors, these compounds may aid in reversing multidrug resistance and sensitizing cancer cells to chemotherapeutic drugs. This review will also highlight the consequences of altered BCRP expression and/or function on the pharmacokinetics and toxicity of chemicals following isoflavone exposure. PMID:26179608

Deglycosylation of isoflavones in isoflavone-rich soy germ flour by Aspergillus oryzae KACC 40247.

PubMed

Lee, Seon-Hwa; Seo, Min-Ho; Oh, Deok-Kun

2013-12-11

Aspergillus oryzae KACC 40247 was selected as an efficient daidzein-producing fungus from strains of the genus Aspergillus by using 5% (w/v) soy germ flour (SGF) as an isoflavone-glycoside-rich medium. The culture conditions, including SGF concentration, agitation speed, initial pH, temperature, and time, were optimized as follows: 7% (w/v) SGF, initial pH 6.0, 33 °C, 300 rpm, and 24 h in a 100 mL baffled flask. The determined amount of isoflavone aglycons in SGF using 50% ethyl acetate was the highest among the solvent systems tested and it was 3.7-fold higher than that using 70% methanol. Under the optimized conditions, the content and concentration of daidzein were 134 mg/g of SGF and 9.4 g/L, respectively, with a productivity of 391 ± 2.8 mg/L/h, and those of isoflavone aglycons were 165 mg/g of SGF and 11.5 g/L, respectively, with a productivity of 479 mg/L/h. Optimization of culture conditions increased the content, concentration, and productivity of isoflavone aglycons by 3.1-, 3.0-, and 3.7-fold, respectively. To our knowledge, this is the highest production of isoflavone aglycons reported to date.

Huntingtin interacting protein 1 modulates the transcriptional activity of nuclear hormone receptors

PubMed Central

Mills, Ian G.; Gaughan, Luke; Robson, Craig; Ross, Theodora; McCracken, Stuart; Kelly, John; Neal, David E.

2005-01-01

Internalization of activated receptors regulates signaling, and endocytic adaptor proteins are well-characterized in clathrin-mediated uptake. One of these adaptor proteins, huntingtin interacting protein 1 (HIP1), induces cellular transformation and is overexpressed in some prostate cancers. We have discovered that HIP1 associates with the androgen receptor through a central coiled coil domain and is recruited to DNA response elements upon androgen stimulation. HIP1 is a novel androgen receptor regulator, significantly repressing transcription when knocked down using a silencing RNA approach and activating transcription when overexpressed. We have also identified a functional nuclear localization signal at the COOH terminus of HIP1, which contributes to the nuclear translocation of the protein. In conclusion, we have discovered that HIP1 is a nucleocytoplasmic protein capable of associating with membranes and DNA response elements and regulating transcription. PMID:16027218

Androgen Triggers the Pro-Migratory CXCL12/CXCR4 Axis in AR-Positive Breast Cancer Cell Lines: Underlying Mechanism and Possible Implications for the Use of Aromatase Inhibitors in Breast Cancer.

PubMed

Azariadis, Kalliopi; Kiagiadaki, Fotini; Pelekanou, Vasiliki; Bempi, Vasiliki; Alexakis, Kostas; Kampa, Marilena; Tsapis, Andreas; Castanas, Elias; Notas, George

2017-01-01

Reports regarding the role of androgen in breast cancer (BC) are conflicting. Some studies suggest that androgen could lead to undesirable responses in the presence of certain BC tumor characteristics. We have shown that androgen induces C-X-C motif chemokine 12 (CXCL12) in BC cell lines. Our aim was to identify the mechanisms regulating the phenotypic effects of androgen-induced CXCL12 on Androgen Receptor (AR) positive BC cell lines. We analyzed the expression of CXCL12 and its receptors with qPCR and ELISA and the role of Nuclear Receptor Coactivator 1 (NCOA1) in this effect. AR effects on the CXCL12 promoter was studied via Chromatin-immunoprecipitation. We also analyzed publically available data from The Cancer Genome Atlas to verify AR-CXCL12 interactions and to identify the effect or Aromatase Inhibitors (AI) therapy on CXCL12 expression and disease progression in AR positive cases. CXCL12 induction occurs only in AR-positive BC cell lines, possibly via an Androgen Response Element, upstream of the CXCL12 promoter. The steroid receptor co-regulator NCOA1 is critical for this effect. Androgen only induced the motility of p53-mutant BC cells T47D cells via upregulation of CXCR4 expression while they had no effect on wild-type p53 MCF-7 cells. Loss of CXCR4 expression and depletion of CXCL12 abolished the effect of androgen in T47D cells while inhibition of p53 expression in MCF-7 cells made them responsive to androgen and increased their motility in the presence to androgen. Patients with estrogen receptor positive (ER+)/AR+ BC treated with AIs were at increased risk of disease progression compared to ER+/AR+ non-AI treated and ER+/AR- AI treated cases. AIs may lead to unfavorable responses in some ER/AR positive BC cases, especially in patients with AR+, p53 mutant tumors. © 2017 The Author(s). Published by S. Karger AG, Basel.

Genomic and non-genomic effects of androgens in the cardiovascular system: clinical implications

PubMed Central

Lucas-Herald, Angela K.; Alves-Lopes, Rheure; Montezano, Augusto C.; Ahmed, S. Faisal

2017-01-01

The principle steroidal androgens are testosterone and its metabolite 5α-dihydrotestosterone (DHT), which is converted from testosterone by the enzyme 5α-reductase. Through the classic pathway with androgens crossing the plasma membrane and binding to the androgen receptor (AR) or via mechanisms independent of the ligand-dependent transactivation function of nuclear receptors, testosterone induces genomic and non-genomic effects respectively. AR is widely distributed in several tissues, including vascular endothelial and smooth muscle cells. Androgens are essential for many developmental and physiological processes, especially in male reproductive tissues. It is now clear that androgens have multiple actions besides sex differentiation and sexual maturation and that many physiological systems are influenced by androgens, including regulation of cardiovascular function [nitric oxide (NO) release, Ca2+ mobilization, vascular apoptosis, hypertrophy, calcification, senescence and reactive oxygen species (ROS) generation]. This review focuses on evidence indicating that interplay between genomic and non-genomic actions of testosterone may influence cardiovascular function. PMID:28645930

Tumor suppressor PTEN signaling is up-regulated in mammary epithelial cells by soy isoflavone genistein: Implications for breast cancer protection

USDA-ARS?s Scientific Manuscript database

Breast cancer is the second leading cause of death in the Western hemisphere, affecting one of eight women in their lifetime. In addition to chromosomal and genetic alterations, nutrition is considered a risk determinant for breast cancer. Prevailing evidence suggests a negative correlation between ...

Soy protein diet alters expression of hepatic genes regulating fatty acid and thyroid hormone metabolism in the male rat

USDA-ARS?s Scientific Manuscript database

We determined effects of soy protein (SPI) and the isoflavone genistein (GEN) on mRNA expression of key lipid metabolism and thyroid hormone system genes in young adult, male Sprague-Dawley rats. SPI-fed rats had less retroperitoneal fat and less hepato-steatosis than casein (CAS, control protein)-...

CYP17 inhibitors for prostate cancer therapy

PubMed Central

Vasaitis, Tadas S.; Bruno, Robert D.; Njar, Vincent C. O.

2010-01-01

Prostate cancer (PC) is now the second most prevalent cause of death in men in the USA and Europe. At present, the major treatment options include surgical or medical castration. These strategies cause ablation of the production of testosterone (T), dihydrotestosterone (DHT) and related androgens by the testes. However, because these procedures do not affect adrenal, prostate and other tissues androgen production, they are often combined with androgen receptor antagonists to block their action. Indeed, recent studies have unequivocally established that in castration-resistant prostate cancer (CRPC) many androgen-regulated genes become re-expressed and tissue androgen levels increase despite low serum levels. Clearly, inhibition of the key enzyme which catalyzes the biosynthesis of androgens from pregnane precursors, 17α-hydroxy/17,20-lyase (hereafter referred to as CYP17) could prevent androgen production from all sources. Thus, total ablation of androgen production by potent CYP17 inhibitors may provide effective treatment of prostate cancer patients. This review highlights the role of androgen biosynthesis in the progression of prostate cancer and the impact of CYP17 inhibitors, such as ketoconazole, abiraterone acetate, VN/124-1 (TOK-001) and TAK-700 in the clinic and in clinical development. PMID:21092758

Factors affecting the bioavailability of soy isoflavones in humans after ingestion of physiologically relevant levels from different soy foods.

PubMed

Cassidy, Aedin; Brown, Jonathan E; Hawdon, Anne; Faughnan, Marian S; King, Laurence J; Millward, Joe; Zimmer-Nechemias, Linda; Wolfe, Brian; Setchell, Kenneth D R

2006-01-01

The precise role that isoflavones play in the health-related effects of soy foods, and their potential for adverse effects are controversial. This may be due in part to a lack of basic knowledge regarding their bioavailability and metabolism, particularly as it relates to the soy source. To date, there is little information concerning possible differences in the bioavailability of isoflavones derived from natural soy foods consumed at physiologically relevant intakes and whether age- or gender-related differences influence that bioavailability. In the current study of healthy adults [premenopausal (n = 21) and postmenopausal (n = 17) women and a group of men (n = 21)], we examined the effect of age, gender, and the food matrix on the bioavailability of isoflavones for both the aglycon and glucoside forms that are naturally present in 3 different soy foods, soy milk, textured vegetable protein, and tempeh. The study was designed as a random crossover trial so that all individuals received each of the 3 foods. The dose of isoflavones administered to each individual as a single bolus dose was 0.44 mg/kg body weight. Pharmacokinetic parameters were normalized to mg of each isoflavone ingested per kilogram body weight to account for differences in daidzein and genistein content between the diets. Serum isoflavone concentrations in all individuals and groups increased rapidly after the ingestion of each soy food; as expected, genistein concentrations exceeded daidzein concentrations in serum. In this small study, gender differences in peak concentrations of daidzein were observed, with higher levels attained in women. Consumption of tempeh (mainly isoflavone aglycon) resulted in higher serum peak levels of both daidzein (P < 0.001) and genistein (P < 0.01) and the associated area under the curve (P < 0.001 and P < 0.03, respectively) compared with textured vegetable protein (predominantly isoflavone glucosides). However, soy milk was absorbed faster and peak levels of isoflavones were attained earlier than with the other soy foods. Only 30% of the subjects were equol producers and no differences in equol production with age or gender were observed.

Impact of equol-producing capacity and soy-isoflavone profiles of supplements on bone calcium retention in postmenopausal women: a randomized crossover trial12

PubMed Central

Pawlowski, Jessica W; Martin, Berdine R; McCabe, George P; McCabe, Linda; Jackson, George S; Peacock, Munro; Barnes, Stephen; Weaver, Connie M

2015-01-01

Background: Postmenopausal estrogen depletion is a major contributing factor to bone loss. Soy isoflavones have variable effects on the prevention of postmenopausal bone loss, which is possibly related to the specific isoflavone content or the variable equol-producing capacity of individuals. Objective: We aimed to determine the effects of the content of isoflavones in a soy supplement and the equol-producing ability of the individual on postmenopausal bone calcium retention. Design: The study was a blinded, randomized, crossover intervention trial in 24 postmenopausal women who were prescreened for their ability to convert daidzein to equol. Women were equilibrated with 41Ca before the intervention. Interventions were 5 soy isoflavone oral supplements (2 doses of a genistein-rich soy supplement and 3 doses of mixed isoflavones in various proportions) and a bisphosphonate (risedronate). Each intervention was given sequentially for 50 d followed by a 50-d washout period. The percentage of bone calcium retention was determined from the change in urinary 41Ca:calcium. Results: Interventions that ranged from 52 to 220 mg total isoflavones/d increased bone calcium retention between 3.4% and 7.6% (P < 0.05), which was a moderate effect compared with that of risedronate at 15.3% (95% CI: 7.1%, 22.7%; P = 0.0014). The most-effective soy intervention delivered 105.23 mg total isoflavones/d as genistein, daidzein, and glycitein in their natural ratios and increased bone calcium retention by 7.6% (95% CI: 4.9%, 10.2%; P < 0.0001). Genistein, at 52.85 mg/d, increased bone calcium retention by 3.4% (95% CI: 0.5%, 6.2%; P = 0.029); but there was no benefit at higher amounts (113.52 mg/d). There was no difference (P = 0.5) in bone calcium retention between equol producers and nonproducers. Conclusion: Soy isoflavones, although not as potent as risedronate, are effective bone-preserving agents in postmenopausal women regardless of their equol-producing status, and mixed isoflavones in their natural ratios are more effective than enriched genistein. This trial was registered at clinicaltrials.gov as NCT00244907. PMID:26245807

Specific and non-overlapping functions of testosterone and 11-ketotestosterone in the regulation of professional phagocyte responses in the teleost fish gilthead seabream.

PubMed

Aguila, S; Castillo-Briceño, P; Sánchez, M; Cabas, I; García-Alcázar, A; Meseguer, J; Mulero, V; García-Ayala, A

2013-03-01

Sex hormones, both estrogens and androgens, have a strong impact on immunity in mammals. In fish, the role of androgens in immunity has received little attention and contradictory conclusions have been obtained. However, it is well known that sex steroids are involved in fish growth, osmoregulation and gonad remodelation. In this study, we examine the in vitro effects of testosterone and 11-ketotestosterone, the two main fish androgens, on the professional phagocytes of the teleost fish gilthead seabream (Sparus aurata L.). Although both testosterone and 11-ketotestosterone failed to modulate the respiratory burst of seabream phagocytes, testosterone but not 11-ketotestosterone was able to increase the phagocytic ability of non-activated phagocytes. Curiously, 11-ketotestosterone was more powerful than testosterone at inducing the expression of its own receptor, namely androgen receptor b (ARb), in acidophilic granulocytes (AGs), but none of them affected the basal ARb expression levels in macrophages (MØ). Furthermore, although physiological concentrations of testosterone exerted a pro-inflammatory effect on both AGs and MØs, 11-ketotestosterone showed an anti-inflammatory effect in AGs and a strong pro-inflammatory effect in MØs. Interestingly, both androgens modulated the expression of toll-like receptors in these two immune cell types, suggesting that androgens might regulate the sensitivity of phagocytes to pathogens and damage signals. Testosterone and 11-ketotestosterone have a competitive effect, at least, on the modulation of the expression of some genes. Therefore, our results show for the first time a non-overlapping role for testosterone and 11-ketotestosterone in the regulation of professional phagocyte functions in fish. Copyright © 2012 Elsevier Ltd. All rights reserved.

Soy proteins and isoflavones affect bone mineral density in older women: a randomized controlled trial.

PubMed

Kenny, Anne M; Mangano, Kelsey M; Abourizk, Robin H; Bruno, Richard S; Anamani, Denise E; Kleppinger, Alison; Walsh, Stephen J; Prestwood, Karen M; Kerstetter, Jane E

2009-07-01

Soy foods contain several components (isoflavones and amino acids) that potentially affect bone. Few long-term, large clinical trials of soy as a means of improving bone mineral density (BMD) in late postmenopausal women have been conducted. Our goal was to evaluate the long-term effect of dietary soy protein and/or soy isoflavone consumption on skeletal health in late postmenopausal women. We conducted a randomized, double-blind, placebo-controlled clinical trial in 131 healthy ambulatory women aged >60 y. Ninety-seven women completed the trial. After a 1-mo baseline period, subjects were randomly assigned into 1 of 4 intervention groups: soy protein (18 g) + isoflavone tablets (105 mg isoflavone aglycone equivalents), soy protein + placebo tablets, control protein + isoflavone tablets, and control protein + placebo tablets. Consumption of protein powder and isoflavone pills did not differ between groups, and compliance with the study powder and pills was 80-90%. No significant differences in BMD were observed between groups from baseline to 1 y after the intervention or in BMD change between equol and non-equol producers. However, there were significant negative correlations between total dietary protein (per kg) and markers of bone turnover (P < 0.05). Because soy protein and isoflavones (either alone or together) did not affect BMD, they should not be considered as effective interventions for preserving skeletal health in older women. The negative correlation between dietary protein and bone turnover suggests that increasing protein intakes may suppress skeletal turnover. This trial was registered at ClinicalTrials.gov as NCT00668447.

Growth inhibitory effects of the dual ErbB1/ErbB2 tyrosine kinase inhibitor PKI-166 on human prostate cancer xenografts.

PubMed

Mellinghoff, Ingo K; Tran, Chris; Sawyers, Charles L

2002-09-15

Experiments with human prostate cancer cell lines have shown that forced overexpression of the ErbB2-receptor tyrosine kinase (RTK) promotes androgen-independent growth and increases androgen receptor-transcriptional activity in a ligand-independent fashion. To investigate the relationship between ErbB-RTK signaling and androgen in genetically unmanipulated human prostate cancer, we performed biochemical and biological studies with the dual ErbB1/ErbB2 RTK inhibitor PKI-166 using human prostate cancer xenograft models with isogenic sublines reflecting the transition from androgen-dependent to androgen-independent growth. In the presence of low androgen concentrations, PKI-166 showed profound growth-inhibitory effects on tumor growth, which could be partially reversed by androgen add-back. At physiological androgen concentrations, androgen withdrawal greatly enhanced the ability of PKI-166 to retard tumor growth. The level of extracellular signal-regulated kinase activation correlated with the response to PKI-166 treatment, whereas the expression levels of ErbB1 and ErbB2 did not. These results suggest that ErbB1/ErbB2 RTKs play an important role in the biology of androgen-independent prostate cancer and provide a rationale for clinical evaluation of inhibitors targeted to this pathway.

Postnatal penile growth concurrent with mini-puberty predicts later sex-typed play behavior: Evidence for neurobehavioral effects of the postnatal androgen surge in typically developing boys.

PubMed

Pasterski, Vickie; Acerini, Carlo L; Dunger, David B; Ong, Ken K; Hughes, Ieuan A; Thankamony, Ajay; Hines, Melissa

2015-03-01

The masculinizing effects of prenatal androgens on human neurobehavioral development are well established. Also, the early postnatal surge of androgens in male infants, or mini-puberty, has been well documented and is known to influence physiological development, including penile growth. However, neurobehavioral effects of androgen exposure during mini-puberty are largely unknown. The main aim of the current study was to evaluate possible neurobehavioral consequences of mini-puberty by relating penile growth in the early postnatal period to subsequent behavior. Using multiple linear regression, we demonstrated that penile growth between birth and three months postnatal, concurrent with mini-puberty, significantly predicted increased masculine/decreased feminine behavior assessed using the Pre-school Activities Inventory (PSAI) in 81 healthy boys at 3 to 4years of age. When we controlled for other potential influences on masculine/feminine behavior and/or penile growth, including variance in androgen exposure prenatally and body growth postnally, the predictive value of penile growth in the early postnatal period persisted. More specifically, prenatal androgen exposure, reflected in the measurement of anogenital distance (AGD), and early postnatal androgen exposure, reflected in penile growth from birth to 3months, were significant predictors of increased masculine/decreased feminine behavior, with each accounting for unique variance. Our findings suggest that independent associations of PSAI with AGD at birth and with penile growth during mini-puberty reflect prenatal and early postnatal androgen exposures respectively. Thus, we provide a novel and readily available approach for assessing effects of early androgen exposures, as well as novel evidence that early postnatal aes human neurobehavioral development. Copyright © 2015. Published by Elsevier Inc.

Assessment of Sources and Dietary Intake of Isoflavone in the U.S. Diet

USDA-ARS?s Scientific Manuscript database

Soy products are a major source of dietary isoflavones, with weak estrogenic, and other biological properties that may contribute to the reduction of the risk of some chronic diseases, such as certain cancers, i.e. prostate and melanoma. This presentation will examine sources of isoflavones in the d...

Soy isoflavone supplementation and bone mineral density in menopausal women: a 2-y multicenter clinical trial

USDA-ARS?s Scientific Manuscript database

Isoflavones are naturally occurring plant estrogens that are abundant in soy. Although purported to protect against bone loss, the efficacy of soy isoflavone supplementation in the prevention of osteoporosis in postmenopausal women remains controversial. Our aim was to test the effect of soy isoflav...

Simple, rapid, and environmentally friendly method for the separation of isoflavones using ultra-high performance supercritical fluid chromatography.

PubMed

Wu, Wenjie; Zhang, Yuan; Wu, Hanqiu; Zhou, Weie; Cheng, Yan; Li, Hongna; Zhang, Chuanbin; Li, Lulu; Huang, Ying; Zhang, Feng

2017-07-01

Isoflavones are natural substances that exhibit hormone-like pharmacological activities. The separation of isoflavones remains an analytical challenge because of their similar structures. We show that ultra-high performance supercritical fluid chromatography can be an appropriate tool to achieve the fast separation of 12 common dietary isoflavones. Among the five tested columns the Torus DEA column was found to be the most effective column for the separation of these isoflavones. The impact of individual parameters on the retention time and separation factor was evaluated. These parameters were optimized to develop a simple, rapid, and green method for the separation of the 12 target analytes. It only took 12.91 min using gradient elution with methanol as an organic modifier and formic acid as an additive. These isoflavones were determined with limit of quantitation ranging from 0.10 to 0.50 μg/mL, which was sufficient for reliable determination of various matrixes. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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.

Pseudomonas fluorescens N21.4 metabolites enhance secondary metabolism isoflavones in soybean (Glycine max) calli cultures.

PubMed

Algar, Elena; Gutierrez-Mañero, Francisco Javier; Bonilla, Alfonso; Lucas, Jose Antonio; Radzki, Wojtek; Ramos-Solano, Beatriz

2012-11-07

Phytopharmaceuticals are plant secondary metabolites that are strongly inducible and especially sensitive to biotic changes. Plant cell cultures are a good alternative to obtain secondary metabolites, in case effective stimulation can be achieved. In this study, metabolic elicitors from two rhizobacteria able to enhance isoflavone content in soybean seedlings were tested on three different soybean calli cell lines. Results show that metabolic elicitors from Chryseobacterium balustinum Aur9 were not effective. However, there are at least two different metabolic elicitors from Pseudomonas fluorescens N21.4, one under 10 kDa and another over 10 kDa, that trigger isoflavone metabolism in the three cell lines with different isoflavone content. Elicitors from N21.4 achieved total isoflavone increases up to 29.7% (0.205 mg/g), 64.5% (0.487 mg/g), and 23.4% (0.726 mg/g) in the low-, intermediate-, and high-yield lines, respectively. Therefore, these elicitors have a great potential to enhance isoflavone production in cell cultures for development of functional ingredients.

Comprehensive evaluation of the role of soy and isoflavone supplementation in humans and animals over the past two decades.

PubMed

Xiao, Yunqi; Zhang, Shan; Tong, Haibing; Shi, Shourong

2018-03-01

Soy and soy-based foods are considered healthy, particularly in many Asia-Pacific countries, where soy products have long been consumed. Soy and soy-related products have been found to help prevent the occurrence of cardiovascular diseases and certain types of cancer, such as breast and prostate cancer. These products can also have antioxidative effects that alleviate hot flashes during menopause and bone loss. These biological and therapeutic functions are primarily due to the isoflavones derived from soy, whose structure is similar to the structure of 17-β-oestradiol. Despite the many health benefits for humans and animals, the application of isoflavones remains controversial because of their anti-oestrogenic properties. We focused on general information regarding isoflavones, as well as their structure, function, and application. We summarized evidence showing that dietary or supplemental isoflavones exert protective effects on the health of humans and animals. Based on the literature, we conclude that soy foods and isoflavones may be effective and safe; however, more high-quality trials are needed to fully substantiate their potential use. Copyright © 2017 John Wiley & Sons, Ltd.

Evaluation of the isoflavone and total phenolic contents of kefir-fermented soymilk storage and after the in vitro digestive system simulation.

PubMed

da Silva Fernandes, Meg; Sanches Lima, Fernando; Rodrigues, Daniele; Handa, Cintia; Guelfi, Marcela; Garcia, Sandra; Ida, Elza Iouko

2017-08-15

This study aimed to evaluate the isoflavone and total phenolic contents in kefir-fermented soymilk storage and after the in vitro digestive system simulation (DSS). Soymilk was fermented with kefir culture (0.02UC/L) at 25°C for 15h and stored at 4°C for 4days. After the fermentation and storage, the isoflavone and total phenolic contents were quantified by high performance liquid chromatography and spectrophotometry, respectively. The cell viability of lactic acid bacteria and yeast was evaluated. Fermentation promoted an increase of approximately 3log CFU/g cycles of the microorganisms and the storage process did not alter the aglycone isoflavones and total phenolic contents. The content of aglycone isoflavones increased 2-fold, and the total phenolic content increased 9-fold. Therefore, kefir-fermented soymilk is a good source of aglycone isoflavones and phenolics, since the content of these substances was increased significantly after the in vitro digestive system simulation of the product. Copyright © 2017 Elsevier Ltd. All rights reserved.

Androgens and the male reproductive tract: an overview of classical roles and current perspectives.

PubMed

Patrão, Marilia T C C; Silva, Erick J R; Avellar, Maria Christina W

2009-11-01

Androgens are steroid hormones that play key roles in the development and maintenance of male phenotype and reproductive function. These hormones also affect the function of several non-reproductive organs, such as bone and skeletal muscle. Endogenous androgens exert most of their effects by genomic mechanisms, which involve hormone binding to the androgen receptor (AR), a ligand-activated transcription factor, resulting in the modulation of gene expression. AR-induced non-genomic mechanisms have also been reported. A large number of steroidal and non-steroidal AR-ligands have been developed for therapeutic use, including the treatment of male hypogonadism (AR agonists) and prostate diseases (AR antagonists), among other pathological conditions. Here, the AR gene and protein structure, mechanism of action and AR gene homologous regulation were reviewed. The AR expression pattern, its in vivo regulation and physiological relevance in the developing and adult testis and epididymis, which are sites of sperm production and maturation, respectively, were also presented.

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 diet can contribute to the health of postmenopausal women. © 2014 American Society for Nutrition.

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

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.

Bacterial communities and metabolic activity of faecal cultures from equol producer and non-producer menopausal women under treatment with soy isoflavones.

PubMed

Guadamuro, Lucía; Dohrmann, Anja B; Tebbe, Christoph C; Mayo, Baltasar; Delgado, Susana

2017-04-17

Isoflavones are polyphenols with estrogenic activity found mainly in soy and soy-derived products that need to be metabolised in the intestine by the gut bacteria to be fully active. There is little knowledge about isoflavone bioconversion and equol production in the human intestine. In this work, we developed an in vitro anaerobic culture model based on faecal slurries to assess the impact of isoflavone supplementation on the overall intestinal bacterial composition changes and associated metabolic transformations. In the faecal anaerobic batch cultures of this study bioconversion of isoflavones into equol was possible, suggesting the presence of viable equol-producing bacterial taxa within the faeces of menopausal women with an equol producer phenotype. The application of high-throughput DNA sequencing of 16S rRNA gene amplicons revealed the composition of the faecal cultures to be modified by the addition of isoflavones, with enrichment of some bacterial gut members associated with the metabolism of phenolics and/or equol production, such as Collinsella, Faecalibacterium and members of the Clostridium clusters IV and XIVa. In addition, the concentration of short-chain fatty acids (SCFAs) detected in the isoflavone-containing faecal cultures was higher in those inoculated with faecal slurries from equol-producing women. This study constitutes the first step in the development of a faecal culturing system with isoflavones that would further allow the selection and isolation of intestinal bacterial types able to metabolize these compounds and produce equol in vitro. Although limited by the low number of faecal cultures analysed and the inter-individual bacterial diversity, the in vitro results obtained in this work tend to indicate that soy isoflavones might provide an alternative energy source for the increase of equol-producing taxa and enhancement of SCFAs production. SCFAs and equol are both considered pivotal bacterial metabolites in the triggering of intestinal health-related beneficial effects.

Long-term soy isoflavone supplementation and cognition in women: a randomized, controlled trial.

PubMed

Henderson, V W; St John, J A; Hodis, H N; Kono, N; McCleary, C A; Franke, A A; Mack, W J

2012-06-05

To determine the cognitive effects of long-term dietary soy isoflavones in a daily dose comparable to that of traditional Asian diets. In the double-blind Women's Isoflavone Soy Health trial, healthy postmenopausal women were randomly allocated to receive daily 25 g of isoflavone-rich soy protein (91 mg of aglycone weight of isoflavones: 52 mg of genistein, 36 mg of daidzein, and 3 mg glycitein) or milk protein-matched placebo. The primary cognitive endpoint compared between groups at 2.5 years was change from baseline on global cognition, a composite of the weighted sum of 14 neuropsychological test score changes. Secondary outcomes compared changes in cognitive factors and individual tests. A total of 350 healthy postmenopausal women aged 45-92 years enrolled in this trial; 313 women with baseline and endpoint cognitive test data were included in intention-to-treat analyses. Adherence in both groups was nearly 90%. There was no significant between-group difference on change from baseline in global cognition (mean standardized improvement of 0.42 in the isoflavone group and 0.31 in the placebo group; mean standardized difference 0.11, 95% confidence interval [CI] -0.13 to 0.35). Secondary analyses indicated greater improvement on a visual memory factor in the isoflavone group (mean standardized difference 0.33, 95% CI 0.06-0.60) but no significant between-group differences on 3 other cognitive factors or individual test scores, and no significant difference within a subgroup of younger postmenopausal women. For healthy postmenopausal women, long-term dietary soy isoflavone supplementation in a dose comparable to that of traditional Asian diets has no effect on global cognition but may improve visual memory. This study provides Class I evidence that long-term dietary supplementation with isoflavone-rich soy protein does not improve global cognition of healthy postmenopausal women.

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.

Effect of a soy isoflavone supplement on lung function and clinical outcomes in patients with poorly controlled asthma: a randomized clinical trial.

PubMed

Smith, Lewis J; Kalhan, Ravi; Wise, Robert A; Sugar, Elizabeth A; Lima, John J; Irvin, Charles G; Dozor, Allen J; Holbrook, Janet T

2015-05-26

Soy isoflavone supplements are used to treat several chronic diseases, although the data supporting their use are limited. Some data suggest that supplementation with soy isoflavone may be an effective treatment for patients with poor asthma control. To determine whether a soy isoflavone supplement improves asthma control in adolescent and adult patients with poorly controlled disease. Multicenter, randomized, double-blind, placebo-controlled trial conducted between May 2010 and August 2012 at 19 adult and pediatric pulmonary and allergy centers in the American Lung Association Asthma Clinical Research Centers network. Three hundred eighty-six adults and children aged 12 years or older with symptomatic asthma while taking a controller medicine and low dietary soy intake were randomized, and 345 (89%) completed spirometry at week 24. Participants were randomly assigned to receive soy isoflavone supplement containing 100 mg of total isoflavones (n=193) or matching placebo (n=193) in 2 divided doses administered daily for 24 weeks. The primary outcome measure was change in forced expiratory volume in the first second (FEV1) at 24 weeks. Secondary outcome measures were symptoms, episodes of poor asthma control, Asthma Control Test score (range, 5-25; higher scores indicate better control), and systemic and airway biomarkers of inflammation. Mean changes in prebronchodilator FEV1 over 24 weeks were 0.03 L (95% CI, -0.01 to 0.08 L) in the placebo group and 0.01 L (95% CI, -0.07 to 0.07 L) in the soy isoflavone group, which were not significantly different (P = .36). Mean changes in symptom scores on the Asthma Control Test (placebo, 1.98 [95% CI, 1.42-2.54] vs soy isoflavones, 2.20 [95% CI, 1.53-2.87]; positive values indicate a reduction in symptoms), number of episodes of poor asthma control (placebo, 3.3 [95% CI, 2.7-4.1] vs soy isoflavones, 3.0 [95% CI, 2.4-3.7]), and changes in exhaled nitric oxide (placebo, -3.48 ppb [95% CI, -5.99 to -0.97 ppb] vs soy isoflavones, 1.39 ppb [95% CI, -1.73 to 4.51 ppb]) did not significantly improve more with the soy isoflavone supplement than with placebo. Mean plasma genistein level increased from 4.87 ng/mL to 37.67 ng/mL (P < .001) in participants receiving the supplement. Among adults and children aged 12 years or older with poorly controlled asthma while taking a controller medication, use of a soy isoflavone supplement, compared with placebo, did not result in improved lung function or clinical outcomes. These findings suggest that this supplement should not be used for patients with poorly controlled asthma. clinicaltrials.gov Identifier: NCT01052116.

Effects of Adult Female Rat Androgenization on Brain Morphology and Metabolomic Profile.

PubMed

Perez-Laso, Carmen; Cerdan, Sebastián; Junque, Carme; Gómez, Ángel; Ortega, Esperanza; Mora, Mireia; Avendaño, Carlos; Gómez-Gil, Esther; Del Cerro, María Cruz Rodríguez; Guillamon, Antonio

2017-07-06

Androgenization in adult natal women, as in transsexual men (TM), affects brain cortical thickness and the volume of subcortical structures. In order to understand the mechanism underlying these changes we have developed an adult female rat model of androgenization. Magnetic resonance imaging and spectroscopy were used to monitor brain volume changes, white matter microstructure and ex vivo metabolic profiles over 32 days in androgenized and control subjects. Supraphysiological doses of testosterone prevents aging decrease of fractional anisotropy values, decreased general cortical volume and the relative concentrations of glutamine (Gln) and myo-Inositol (mI). An increase in the N-acetylaspartate (NAA)/mI ratio was detected d. Since mI and Gln are astrocyte markers and osmolytes, we suspect that the anabolic effects of testosterone change astrocyte osmolarity so as to extrude Mi and Gln from these cells in order to maintain osmotic homeostasis. This mechanism could explain the brain changes observed in TM and other individuals receiving androgenic anabolic steroids. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Isoflavones, calcium, vitamin D and inulin improve quality of life, sexual function, body composition and metabolic parameters in menopausal women: result from a prospective, randomized, placebo-controlled, parallel-group study

PubMed Central

Caruso, Salvatore; Rapisarda, Agnese Maria Chiara; Cianci, Stefano; Cianci, Antonio

2018-01-01

Introduction Menopause results in metabolic changes that contribute to increase risk of cardiovascular diseases: increase in low density lipoprotein (LDL) and triglycerides and decrease in high density lipoprotein (HDL), weight gain are associated with a correspondent increase in incidence of hypertension and diabetes. The aim of this study was to evaluate the effect of a preparation of isoflavones, calcium vitamin D and inulin in menopausal women. Material and methods We performed a prospective, randomized, placebo-controlled, parallel-group study. A total of 50 patients were randomized to receive either oral preparations of isoflavones (40 mg), calcium (500 mg) vitamin D (300 UI) and inulin (3 g) or placebo (control group). Pre- and post-treatment assessment of quality of life and sexual function were performed through Menopause-Specific Quality of Life Questionnaire (MENQOL) and Female Sexual Function Index (FSFI); evaluations of anthropometric indicators, body composition through bioelectrical impedance analyser, lumbar spine and proximal femur T-score and lipid profile were performed. Results After 12 months, a significant reduction in MENQOL vasomotor, physical and sexual domain scores (p < 0.05) and a significant increase in all FSFI domain scores (p < 0.05) were observed in treatment group. Laboratory tests showed significant increase in serum levels of HDL (p < 0.05). No significant changes of lumbar spine and femur neck T-score (p > 0.05) were found in the same group. Conclusions According to our data analysis, isoflavones, calcium, vitamin D and inulin may exert favourable effects on menopausal symptoms and signs. PMID:29725283

Growth performance, carcass characteristics and bioavailability of isoflavones in pigs fed soy bean based diets.

PubMed

Kuhn, Gerda; Hennig, U; Kalbe, Claudia; Rehfeldt, Charlotte; Ren, M Q; Moors, S; Degen, Gisela H

2004-08-01

A growth trial with 38 weaners (castrated male pigs) was designed to compare the growth performance and carcass quality of pigs fed diets containing either soy bean meal or soy protein concentrate in a pair-feeding design. Soy bean meal (SBM) and soy protein concentrate (SPC) differed in isoflavone (daidzein plus genistein) content (782 microg/g in SBM and 125 microg/g in SPC, respectively). During the experiment, all pigs were fed four-phases-diets characterized by decreasing protein concentrations with increasing age (weaner I, weaner II, grower, finisher diets). Rations of control and experimental groups were isoenergetic, isonitrogenous, and isoaminogen. The weanling pigs with an initial live weight of 8.4 +/- 1.1 kg were allotted to flat deck boxes. During the growing/finishing period (days 70-170 of age), the pigs were housed in single boxes. Both, the weaning and the grower/finishing performances (daily body weight gain, feed intake, feed conversion ratio) were similar in both groups. No differences were found between the groups in carcass composition (percentages of cuts, tissues, and protein/fat), and meat quality of pigs. Moreover, the IGF-1R mRNA expression in longissimus muscle was not influenced by the kind of soy product. However, circulating levels of isoflavones were clearly different between pigs fed SBM (genistein 239 +/- 44; daidzein 162 +/- 42; equol 12 +/- 4 ng/ml plasma) and animals fed SPC (genistein 22 +/- 9 and daidzein 8 +/- 3, and equol 10 +/- 3 ng/ml plasma). The results confirm the expected differences in the bioavailability of soy isoflavones, yet, there were no significant differences in performance of pigs fed either soy bean meal or soy protein concentrate.

Increased probiotic yogurt or resistant starch intake does not affect isoflavone bioavailability in subjects consuming a high soy diet.

PubMed

Larkin, Theresa A; Price, William E; Astheimer, Lee B

2007-10-01

Probiotics and prebiotics that affect gut microflora balance and its associated enzyme activity may contribute to interindividual variation in isoflavone absorption after soy intake, possibly enhancing isoflavone bioavailability. This study examined the effects of the consumption of bioactive yogurt (a probiotic) or resistant starch (a known prebiotic) in combination with high soy intake on soy isoflavone bioavailability. Using a crossover design, chronic soy consumption was compared with soy plus probiotic yogurt or resistant starch in older male and postmenopausal females (n = 31). Isoflavone bioavailability was assessed at the beginning and end of each 5-wk dietary period by sampling plasma and urine after a standardized soy meal. Chronic soy intake did not significantly affect plasma or urinary isoflavones after the soy meal and there were no significant effects of probiotic or resistant starch treatment. However, there were trends for increased circulating plasma daidzein and genistein after the probiotic treatment and for increased plasma daidzein and genistein 24 h after soy intake with resistant starch treatment. Neither treatment induced or increased equol production, although there was a trend for increased plasma equol in "equol-positive" subjects (n = 12) after probiotic treatment. The weak or absence of effects of probiotic yogurt or resistant starch supplement to a chronic soy diet suggests that gut microflora were not modified in a manner that significantly affected isoflavone bioavailability or metabolism.

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.

Changes in amount and intracellular distribution of androgen receptor in human foreskin as a function of age.

PubMed Central

Roehrborn, C G; Lange, J L; George, F W; Wilson, J D

1987-01-01

To provide insight into the factors that control growth of the penis we measured the amount and intracellular distribution of specific high affinity androgen receptor in foreskins obtained at circumcision from 49 males varying in age from newborn to 59 yr. Total (cytosolic plus nuclear extract) androgen receptor decreased from approximately 40 fmol/g tissue weight in newborn foreskins to approximately 25 fmol/g by 1 yr of age. The amount of receptor rose in childhood to approximately 180 fmol/g in the late teenage years and fell thereafter to approximately 20-40 fmol/g in men older than 40 yr. The amount of receptor in the nuclear fraction increased at the time of puberty and subsequently decreased in parallel with the decline in total receptor level. These changes in androgen-receptor amount are similar when expressed per milligram DNA or per milligram protein. Images PMID:3491838

Effect of gamma irradiation on microbial load, physicochemical and sensory characteristics of soybeans (Glycine max L. Merrill)

NASA Astrophysics Data System (ADS)

Yun, Juan; Li, Xihong; Fan, Xuetong; Tang, Yao; Xiao, Yao; Wan, Sen

2012-08-01

Gamma irradiation is highly effective in inactivating microorganisms in various foods and offers a safe alternative method of food decontamination. In the present study, soybeans (Glycine max L. Merrill) were treated with 0, 1.0, 3.0, 5.0 and 10.0 KGy of gamma irradiation. Microbial populations on soybeans, isoflavone, tocopherol contents, raffinose family oligosaccharides, color and sensory properties were evaluated as a function of irradiation dose. The results indicated that gamma irradiation reduced aerobic bacterial and fungal load. Irradiation at the doses applied did not cause any significant change (p>0.05) in the contents of isoflavone of soybeans, but decreased tocopherol contents. The content of key flatulence-producing raffinose family oligosaccharides in irradiated soybeans (10.0 kGy) decreased by 82.1% compared to the control. Sensory analysis showed that the odor of the soybeans was organoleptically acceptable at doses up to 5.0 kGy and no significant differences were observed between irradiated and nonirradiated samples in flavor, texture and color after irradiation.

Quantitative trait loci for seed isoflavones contents in 'MD96-5722' by 'Spencer' recombinant inbred lines of soybean

USDA-ARS?s Scientific Manuscript database

Isoflavones from soybeans (Glycine max L. Merr.) have significant impact on human health in reducing the risk of several major diseases. Breeding soybean for high isoflavones content in the seed is possible through marker assisted selection (MAS), which can be based on quantitative trait loci (QTL)....

Intermittent androgen suppression in the LuCaP 23.12 prostate cancer xenograft model.

PubMed

Buhler, K R; Santucci, R A; Royai, R A; Whitney, S C; Vessella, R L; Lange, P H; Ellis, W J

2000-04-01

Intermittent androgen suppression (IAS) has been proposed as a method of delaying the onset of androgen-independent growth in prostate cancer. While several pilot studies have demonstrated the feasibility of such a treatment, no study to date has defined the effect of IAS on survival. We developed an IAS protocol for mice bearing the LuCaP 23.12 human prostate cancer xenograft, with each cycle consisting of 1 week of androgen replacement with a testosterone pellet followed by 3 weeks of androgen withdrawal. Mice that responded to castration with a 40% or greater decrease in serum prostate-specific antigen (PSA) were randomized to treatment with either continuous androgen suppression (CAS) or IAS. Serum PSA, tumor volume, and overall survival were monitored. A total of 75 mice met the randomization criteria. There was no significant difference of survival between animals treated with CAS or IAS (185 vs. 239 days, P = 0.1835). Serum PSA showed evidence of cycling with hormonal manipulation. No cycling was noted in tumor volume. IAS is not associated with a decrease in survival compared to CAS, yet in patients may offer quality-of-life improvements. Further studies of IAS in the setting of Institutional Review Board (IRB) approved clinical trials should be encouraged. Prostate 43:63-70, 2000. Published 2000 Wiley-Liss, Inc.

Role of Stromal Paracrine Signals in Proliferative Diseases of the Aging Human Prostate

PubMed Central

Takahashi, Sanai; Sugimura, Yoshiki

2018-01-01

Androgens are essential for the development, differentiation, growth, and function of the prostate through epithelial–stromal interactions. However, androgen concentrations in the hypertrophic human prostate decrease significantly with age, suggesting an inverse correlation between androgen levels and proliferative diseases of the aging prostate. In elderly males, age- and/or androgen-related stromal remodeling is spontaneously induced, i.e., increased fibroblast and myofibroblast numbers, but decreased smooth muscle cell numbers in the prostatic stroma. These fibroblasts produce not only growth factors, cytokines, and extracellular matrix proteins, but also microRNAs as stromal paracrine signals that stimulate prostate epithelial cell proliferation. Surgical or chemical castration is the standard systemic therapy for patients with advanced prostate cancer. Androgen deprivation therapy induces temporary remission, but the majority of patients eventually progress to castration-resistant prostate cancer, which is associated with a high mortality rate. Androgen deprivation therapy-induced stromal remodeling may be involved in the development and progression of castration-resistant prostate cancer. In the tumor microenvironment, activated fibroblasts stimulating prostate cancer cell proliferation are called carcinoma-associated fibroblasts. In this review, we summarize the role of stromal paracrine signals in proliferative diseases of the aging human prostate and discuss the potential clinical applications of carcinoma-associated fibroblast-derived exosomal microRNAs as promising biomarkers. PMID:29614830

Influence of androgen deprivation therapy on choline PET/CT in recurrent prostate cancer.

PubMed

Dost, Rutger J; Glaudemans, Andor W J M; Breeuwsma, Anthonius J; de Jong, Igle J

2013-07-01

Recurrent prostate cancer is usually treated by combining radiotherapy and androgen deprivation therapy. To stage the cancer, choline positron emission tomography (PET)/CT can be performed. It is generally thought that androgen deprivation therapy does not influence choline PET/CT. In this article we focus on the molecular backgrounds of choline and androgens, and the results of preclinical and clinical studies performed using PET/CT. Using PubMed, we looked for the relevant articles about androgen deprivation therapy and choline PET/CT. During ADT, a tendency of decreased uptake of choline in prostate cancer was observed, in particular in hormone-naïve patients. We conclude that in order to prevent false-negative choline PET/CT scans androgen deprivation should be withheld prior to scanning, especially in hormone-naïve patients.

Urinary isoflavone excretion as a compliance measure in a soy intervention among young girls: a pilot study

PubMed Central

Maskarinec, G; Oshiro, C; Morimoto, Y; Hebshi, S; Novotny, R; Franke, AA

2006-01-01

Objective To investigate the compliance of young girls with a soy intervention. Design An 8-week dietary intervention and urine sample collection. Setting Free-living girls. Subjects A convenience sample of 8-to 14-y-old girls (20 started and 17 finished the study) recruited through flyers distributed to staff members and previous study participants. Intervention The girls consumed one daily serving of soymilk, soy nuts, or tofu, completed 3-day food records, kept daily soy intake logs, and collected weekly urine samples. Main outcome measures Compliance with the intervention was evaluated by daily soy intake logs, 3-day food records analyzed by the center’s Food Composition and Food Groups Servings Databases, and weekly urinary isoflavone excretion using high-pressure liquid chromatography. The statistical analysis included paired t-tests, analysis of variance, and Spearman’s rank-order correlation coefficients. Results Daily soy intake logs indicated a mean intake of 6.28 servings out of a maximum of 7.0 servings per week. The food records revealed a six-fold increase in isoflavone intake during the study period (P < 0.01) which was confirmed by an increase in urinary isoflavone excretion of similar magnitude (23.3–142.1 nmol/mg creatinine, P = 0.02). Conclusions This study demonstrated the ability of young girls to consume one daily soy serving and the usefulness of urinary isoflavones as a primary compliance measure. The high urinary isoflavone excretion levels detected in girls as compared to adult women suggest less intestinal degradation and/or greater absorption of isoflavones in nonadult populations. This finding requires further investigations into the pharmacokinetics of isoflavones. PMID:15523482

Beneficial effect of soy isoflavones on bone mineral content was modified by years since menopause, body weight, and calcium intake: a double-blind, randomized, controlled trial.

PubMed

Chen, Yu-Ming; Ho, Suzanne C; Lam, Silvia S H; Ho, Susan S S; Woo, Jean L F

2004-01-01

Many studies have shown that soy isoflavones have an effect in preventing estrogen-related bone loss, but no data reported whether such an effect could be influenced by other important factors affecting bone loss. This study examines whether the associations between isoflavone supplementation and rates of change in bone mineral content (BMC) could be modified by years since menopause (YSM), body weight (BW), and dietary calcium intake in postmenopausal Chinese women aged 48 to 62 years. A group of 203 eligible women were randomly assigned to three treatment groups: placebo (daily dose of 0 mg isoflavones + 500 mg calcium, n = 67), mid-dose (40 mg isoflavones + 500 mg calcium, n = 68); and high-dose (80 mg isoflavones + 500 mg calcium, n = 68). Bone mineral density (BMD) and BMC at the whole body, spine, and hip were measured by dual-energy x-ray absorptiometry at baseline and posttreatment after 1 year. YSM, BW, and dietary calcium intake stratified analyses were performed to evaluate whether the associations between isoflavones supplementation and BMC change rates were varied with these factors. Both univariate and multivariate analyses observed significant favorable effect of isoflavone supplementation on rates of change in BMC at the total hip and trochanter among later postmenopausal women (> 4 y), in women with lower BW (< or =median, 55.5 kg), or among women with lower level of calcium intake (< or =median, 1095 mg/d). The independent effect of soy on the maintenance of hip BMC is more marked in women in later menopause or those with lower BW or calcium intake.

Effect of soy isoflavone protein and soy lecithin on endothelial function in healthy postmenopausal women.

PubMed

Evans, Marian; Njike, Valentine Yanchou; Hoxley, Martha; Pearson, Meghan; Katz, David L

2007-01-01

To assess the effects of soy isoflavone protein concentrate and soy lecithin on endothelial function, measured as flow-mediated dilation (FMD) of the brachial artery in healthy postmenopausal women. This was a randomized, double-blind, placebo-controlled crossover trial with 25 participants (mean age, 61 years; body mass index, 25.46 kg/m2). The women underwent endothelial function testing at baseline and after 4 weeks of randomly assigned treatment with intervening 4-week washout periods. Treatment assignments included soy isoflavone protein (25 g/day) and soy lecithin (20 g/day), soy isoflavone protein (25 g/day) and placebo lecithin, placebo protein and soy lecithin (20 g/day), and double placebo. FMD and serum lipid levels were assessed at baseline and the end of each 4-week treatment phase. Twenty-two women completed the trial. No statistically significant (P > 0.05) difference was seen in FMD between treatment groups. A trend was suggested with FMD highest after treatment with soy protein plus lecithin (7.50 +/- 9.85), followed by soy protein (5.51 +/- 10.11), soy lecithin (5.35 +/- 6.13), and lowest after placebo (4.53 +/- 7.84). Soy isoflavone protein and soy lecithin significantly increased the high-density lipoprotein/low-density lipoprotein ratio (soy isoflavone protein plus soy lecithin, 0.64 +/- 0.19, P < 0.0001; soy isoflavone protein plus placebo lecithin, 0.58 +/- 0.17, P = 0.0058; placebo protein plus soy lecithin, 0.65 +/- 0.18, P < 0.0001) relative to the baseline value (0.49 +/- 0.15). In this sample of healthy postmenopausal women, soy isoflavone protein and soy lecithin significantly improved the lipid profile. A favorable influence on endothelial function could not be confirmed.

The clinical importance of the metabolite equol-a clue to the effectiveness of soy and its isoflavones.

PubMed

Setchell, Kenneth D R; Brown, Nadine M; Lydeking-Olsen, Eva

2002-12-01

Equol [7-hydroxy-3-(4'-hydroxyphenyl)-chroman] is a nonsteroidal estrogen of the isoflavone class. It is exclusively a product of intestinal bacterial metabolism of dietary isoflavones and it possesses estrogenic activity, having affinity for both estrogen receptors, ERalpha and ERbeta. Equol is superior to all other isoflavones in its antioxidant activity. It is the end product of the biotransformation of the phytoestrogen daidzein, one of the two main isoflavones found in abundance in soybeans and most soy foods. Once formed, it is relatively stable; however, equol is not produced in all healthy adults in response to dietary challenge with soy or daidzein. Several recent dietary intervention studies examining the health effects of soy isoflavones allude to the potential importance of equol by establishing that maximal clinical responses to soy protein diets are observed in people who are good "equol-producers." It is now apparent that there are two distinct subpopulations of people and that "bacterio-typing" individuals for their ability to make equol may hold the clue to the effectiveness of soy protein diets in the treatment or prevention of hormone-dependent conditions. In reviewing the history of equol, its biological properties, factors influencing its formation and clinical data, we propose a new paradigm. The clinical effectiveness of soy protein in cardiovascular, bone and menopausal health may be a function of the ability to biotransform soy isoflavones to the more potent estrogenic isoflavone, equol. The failure to distinguish those subjects who are "equol-producers" from "nonequol producers" in previous clinical studies could plausibly explain the variance in reported data on the health benefits of soy.

Expression of a hyperactive androgen receptor leads to androgen-independent growth of prostate cancer cells.

PubMed

Hsieh, Chen-Lin; Cai, Changmeng; Giwa, Ahmed; Bivins, Aaronica; Chen, Shao-Yong; Sabry, Dina; Govardhan, Kumara; Shemshedini, Lirim

2008-07-01

Cellular changes that affect the androgen receptor (AR) can cause prostate cancer to transition from androgen dependent to androgen independent, which is usually lethal. One common change in prostate tumors is overexpression of the AR, which has been shown to lead to androgen-independent growth of prostate cancer cells. This led us to hypothesize that expression of a hyperactive AR would be sufficient for androgen-independent growth of prostate cancer cells. To test this hypothesis, stable lune cancer prostate (LNCaP) cell lines were generated, which express a virion phosphoprotein (VP)16-AR hybrid protein that contains full-length AR fused to the strong viral transcriptional activation domain VP16. This fusion protein elicited as much as a 20-fold stronger transcriptional activity than the natural AR. Stable expression of VP16-AR in LNCaP cells yielded androgen-independent cell proliferation, while under the same growth conditions the parental LNCaP cells exhibited only androgen-dependent growth. These results show that expression of a hyperactive AR is sufficient for androgen-independent growth of prostate cancer cells. To study the molecular basis of this enhanced growth, we measured the expression of soluble guanylyl cyclase-alpha1 (sGCalpha1), a subunit of the sGC, an androgen-regulated gene that has been shown to be involved in prostate cancer cell growth. Interestingly, the expression of sGCalpha1 is androgen independent in VP16-AR-expressing cells, in contrast to its androgen-induced expression in control LNCaP cells. RNA(I)-dependent inhibition of sGCalpha1 expression resulted in significantly reduced proliferation of VP16-AR cells, implicating an important role for sGCalpha1 in the androgen-independent growth of these cells.

Androgens Up-regulate Transcription of the Notch Inhibitor Numb in C2C12 Myoblasts via Wnt/β-Catenin Signaling to T Cell Factor Elements in the Numb Promoter*

PubMed Central

Liu, Xin-Hua; Wu, Yong; Yao, Shen; Levine, Alice C.; Kirschenbaum, Alexander; Collier, Lauren; Bauman, William A.; Cardozo, Christopher P.

2013-01-01

Androgen signaling via the androgen receptor is a key pathway that contributes to development, cell fate decisions, and differentiation, including that of myogenic progenitors. Androgens and synthetic steroids have well established anabolic actions on skeletal muscle. Wnt and Notch signaling pathways are also essential to myogenic cell fate decisions during development and tissue repair. However, the interactions among these pathways are largely unknown. Androgenic regulation of Wnt signaling has been reported. Nandrolone, an anabolic steroid, has been shown to inhibit Notch signaling and up-regulate Numb, a Notch inhibitor. To elucidate the mechanisms of interaction between nandrolone and Wnt/Notch signaling, we investigated the effects of nandrolone on Numb expression and Wnt signaling and determined the roles of Wnt signaling in nandrolone-induced Numb expression in C2C12 myoblasts. Nandrolone increased Numb mRNA and protein levels and T cell factor (Tcf) transcriptional activity via inhibition of glycogen synthase kinase 3β. Up-regulation of Numb expression by nandrolone was blocked by the Wnt inhibitors, sFRP1 and DKK1, whereas Wnt3a increased Numb mRNA and protein expression. In addition, we observed that the proximal promoter of the Numb gene had functional Tcf binding elements to which β-catenin was recruited in a manner enhanced by both nandrolone and Wnt3a. Moreover, site-directed mutagenesis indicated that the Tcf binding sites in the Numb promoter are required for the nandrolone-induced Numb transcriptional activation in this cell line. These results reveal a novel molecular mechanism underlying up-regulation of Numb transcription with a critical role for increased canonical Wnt signaling. In addition, the data identify Numb as a novel target gene of the Wnt signaling pathway by which Wnts would be able to inhibit Notch signaling. PMID:23649620

Regulators of Androgen Action Resource: a one-stop shop for the comprehensive study of androgen receptor action.

PubMed

DePriest, Adam D; Fiandalo, Michael V; Schlanger, Simon; Heemers, Frederike; Mohler, James L; Liu, Song; Heemers, Hannelore V

2016-01-01

Androgen receptor (AR) is a ligand-activated transcription factor that is the main target for treatment of non-organ-confined prostate cancer (CaP). Failure of life-prolonging AR-targeting androgen deprivation therapy is due to flexibility in steroidogenic pathways that control intracrine androgen levels and variability in the AR transcriptional output. Androgen biosynthesis enzymes, androgen transporters and AR-associated coregulators are attractive novel CaP treatment targets. These proteins, however, are characterized by multiple transcript variants and isoforms, are subject to genomic alterations, and are differentially expressed among CaPs. Determining their therapeutic potential requires evaluation of extensive, diverse datasets that are dispersed over multiple databases, websites and literature reports. Mining and integrating these datasets are cumbersome, time-consuming tasks and provide only snapshots of relevant information. To overcome this impediment to effective, efficient study of AR and potential drug targets, we developed the Regulators of Androgen Action Resource (RAAR), a non-redundant, curated and user-friendly searchable web interface. RAAR centralizes information on gene function, clinical relevance, and resources for 55 genes that encode proteins involved in biosynthesis, metabolism and transport of androgens and for 274 AR-associated coregulator genes. Data in RAAR are organized in two levels: (i) Information pertaining to production of androgens is contained in a 'pre-receptor level' database, and coregulator gene information is provided in a 'post-receptor level' database, and (ii) an 'other resources' database contains links to additional databases that are complementary to and useful to pursue further the information provided in RAAR. For each of its 329 entries, RAAR provides access to more than 20 well-curated publicly available databases, and thus, access to thousands of data points. Hyperlinks provide direct access to gene-specific entries in the respective database(s). RAAR is a novel, freely available resource that provides fast, reliable and easy access to integrated information that is needed to develop alternative CaP therapies. Database URL: http://www.lerner.ccf.org/cancerbio/heemers/RAAR/search/. © The Author(s) 2016. Published by Oxford University Press.

Testosterone regulates the autophagic clearance of androgen binding protein in rat Sertoli cells

PubMed Central

Ma, Yi; Yang, Hao-Zheng; Xu, Long-Mei; Huang, Yi-Ran; Dai, Hui-Li; Kang, Xiao-Nan

2015-01-01

Dysregulation of androgen-binding protein (ABP) is associated with a number of endocrine and andrology diseases. However, the ABP metabolism in Sertoli cells is largely unknown. We report that autophagy degrades ABP in rat Sertoli cells, and the autophagic clearance of ABP is regulated by testosterone, which prolongs the ABP biological half-life by inhibiting autophagy. Further studies identified that the autophagic clearance of ABP might be selectively regulated by testosterone, independent of stress (hypoxia)-induced autophagic degradation. These data demonstrate that testosterone up-regulates ABP expression at least partially by suppressing the autophagic degradation. We report a novel finding with respect to the mechanisms by which ABP is cleared, and by which the process is regulated in Sertoli cells. PMID:25745956

ID4 promotes AR expression and blocks tumorigenicity of PC3 prostate cancer cells

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

Komaragiri, Shravan Kumar; Bostanthirige, Dhanushka H.; Morton, Derrick J.

Deregulation of tumor suppressor genes is associated with tumorigenesis and the development of cancer. In prostate cancer, ID4 is epigenetically silenced and acts as a tumor suppressor. In normal prostate epithelial cells, ID4 collaborates with androgen receptor (AR) and p53 to exert its tumor suppressor activity. Previous studies have shown that ID4 promotes tumor suppressive function of AR whereas loss of ID4 results in tumor promoter activity of AR. Previous study from our lab showed that ectopic ID4 expression in DU145 attenuates proliferation and promotes AR expression suggesting that ID4 dependent AR activity is tumor suppressive. In this study, wemore » examined the effect of ectopic expression of ID4 on highly malignant prostate cancer cell, PC3. Here we show that stable overexpression of ID4 in PC3 cells leads to increased apoptosis and decreased cell proliferation and migration. In addition, in vivo studies showed a decrease in tumor size and volume of ID4 overexpressing PC3 cells, in nude mice. At the molecular level, these changes were associated with increased androgen receptor (AR), p21, and AR dependent FKBP51 expression. At the mechanistic level, ID4 may regulate the expression or function of AR through specific but yet unknown AR co-regulators that may determine the final outcome of AR function. - Highlights: • ID4 expression induces AR expression in PC3 cells, which generally lack AR. • ID4 expression increased apoptosis and decreased cell proliferation and invasion. • Overexpression of ID4 reduces tumor growth of subcutaneous xenografts in vivo. • ID4 induces p21 and FKBP51 expression- co-factors of AR tumor suppressor activity.« less

Defining the Construct of Synthetic Androgen Intoxication: An Application of General Brain Arousal.

PubMed

Hildebrandt, Tom; Heywood, Ashley; Wesley, Daniel; Schulz, Kurt

2018-01-01

Synthetic androgens (i. e., anabolic-androgenic steroids) are the primary component to the majority of problematic appearance and performance enhancing drug (APED) use. Despite evidence that these substances are associated with increased risk for aggression, violence, body image disturbances, and polypharmacy and can develop a pattern of chronic use consistent with drug dependence, there are no formal definitions of androgen intoxication. Consequently, the purpose of this paper is to establish a testable theory of androgen intoxication. We present evidence and theorize that synthetic androgen intoxication can be defined by a pattern of poor self-regulation characterized by increased propensity for a range of behaviors (e.g., aggression, sex, drug seeking, exercise, etc.) via androgen mediated effects on general brain arousal. This theory posits that androgens reduce threshold for emotional reactivity, motor response, and alertness to sensory stimuli and disrupt inhibitory control over the behaviors associated with synthetic androgen use. These changes result from alteration to basic neurocircuitry that amplifies limbic activation and reduces top-down cortical control. The implications for this definition are to inform APED specific hypotheses about the behavioral and psychological effects of APED use and provide a basis for establishing clinical, legal, and public health guidelines to address the use and misuse of these substances.

Defining the Construct of Synthetic Androgen Intoxication: An Application of General Brain Arousal

PubMed Central

Hildebrandt, Tom; Heywood, Ashley; Wesley, Daniel; Schulz, Kurt

2018-01-01

Synthetic androgens (i. e., anabolic-androgenic steroids) are the primary component to the majority of problematic appearance and performance enhancing drug (APED) use. Despite evidence that these substances are associated with increased risk for aggression, violence, body image disturbances, and polypharmacy and can develop a pattern of chronic use consistent with drug dependence, there are no formal definitions of androgen intoxication. Consequently, the purpose of this paper is to establish a testable theory of androgen intoxication. We present evidence and theorize that synthetic androgen intoxication can be defined by a pattern of poor self-regulation characterized by increased propensity for a range of behaviors (e.g., aggression, sex, drug seeking, exercise, etc.) via androgen mediated effects on general brain arousal. This theory posits that androgens reduce threshold for emotional reactivity, motor response, and alertness to sensory stimuli and disrupt inhibitory control over the behaviors associated with synthetic androgen use. These changes result from alteration to basic neurocircuitry that amplifies limbic activation and reduces top-down cortical control. The implications for this definition are to inform APED specific hypotheses about the behavioral and psychological effects of APED use and provide a basis for establishing clinical, legal, and public health guidelines to address the use and misuse of these substances. PMID:29651261

Androgen actions on endothelium functions and cardiovascular diseases

PubMed Central

Cai, Jing-Jing; Wen, Juan; Jiang, Wei-Hong; Lin, Jian; Hong, Yuan; Zhu, Yuan-Shan

2016-01-01

The roles of androgens on cardiovascular physiology and pathophysiology are controversial as both beneficial and detrimental effects have been reported. Although the reasons for this discrepancy are unclear, multiple factors such as genetic and epigenetic variation, sex-specificity, hormone interactions, drug preparation and route of administration may contribute. Recently, growing evidence suggests that androgens exhibit beneficial effects on cardiovascular function though the mechanism remains to be elucidated. Endothelial cells (ECs) which line the interior surface of blood vessels are distributed throughout the circulatory system, and play a crucial role in cardiovascular function. Endothelial progenitor cells (EPCs) are considered an indispensable element for the reconstitution and maintenance of an intact endothelial layer. Endothelial dysfunction is regarded as an initiating step in development of atherosclerosis and cardiovascular diseases. The modulation of endothelial functions by androgens through either genomic or nongenomic signal pathways is one possible mechanism by which androgens act on the cardiovascular system. Obtaining insight into the mechanisms by which androgens affect EC and EPC functions will allow us to determine whether androgens possess beneficial effects on the cardiovascular system. This in turn may be critical in the prevention and therapy of cardiovascular diseases. This article seeks to review recent progress in androgen regulation of endothelial function, the sex-specificity of androgen actions, and its clinical applications in the cardiovascular system. PMID:27168746

Androgen responsiveness of the new human endometrial cancer cell line MFE-296.

PubMed

Hackenberg, R; Beck, S; Filmer, A; Hushmand Nia, A; Kunzmann, R; Koch, M; Slater, E P; Schulz, K D

1994-04-01

MFE-296 endometrial cancer cells express androgen receptors in vitro. These cells, which are tumorigenic in nude mice, are derived from a moderately differentiated human endometrial adenocarcinoma. They express vimentin and the cytokeratins 7, 8, 18, and 19. Karyotyping revealed near-tetraploidy for most of the cells. No marker chromosomes were observed. DNA analyses confirmed the genetic identity of the cell line and the patient from whom the cell line was derived. Proliferation of MFE-296 cells was inhibited by the progestin R5020 and the androgen dihydrotestosterone (DHT). The inhibition of proliferation by DHT was antagonized by the antiandrogen Casodex, demonstrating the involvement of the androgen receptor. Androgen binding was determined at 22,000 binding sites per cell using a whole-cell assay (KD = 0.05 nM) and 30 fmol/mg protein with the dextran charcoal method; 7 fmol/mg protein of progesterone receptors were found, whereas estrogen receptors were below 5 fmol/mg protein. The androgen receptor was functionally intact, as demonstrated by transfection experiments with a reporter-gene construct, containing an androgen-responsive element. In MFE-296 cells the content of the androgen receptor was up-regulated by its own ligand.

Action mechanism and signal pathways of Psidium guajava L. aqueous extract in killing prostate cancer LNCaP cells.

PubMed

Chen, Kuan-Chou; Peng, Chiung-Chi; Chiu, Wen-Ta; Cheng, Yu-Ting; Huang, Guan-Ta; Hsieh, Chiu-Lan; Peng, Robert Y

2010-01-01

Aqueous extract of Psidium guajava L. budding leaves (PE) has been shown to possess anti-prostate cancer activity in a cell line model. We examined whether its bioactivity could be conserved either in the presence or the absence of synthetic androgen R1881. In both cases, PE was shown to inhibit LNCaP cell proliferation and down-regulate expressions of androgen receptor (AR) and prostate specific antigen (PSA). The cytotoxicity of PE was shown by enhanced LDH release in LNCaP cells. The flow cytometry analysis revealed cell cycle arrests at G(0)/G(1) phase with huge amount of apoptotic LNCaP cells after treatment with PE for 48 h in a dose-responsive manner, which was also confirmed by TUNEL assay. From the results of decreased Bcl-2/Bax ratio, inactivation of phosphor-Akt, activation of phosphor-p38, phospho-Erk1/phospho-Erk2, the molecular action mechanism of PE to induce apoptosis in LNCaP cells was elucidated. Compatible with the in vitro study findings, treatment with PE (1.5 mg/mouse/day) significantly diminished both the PSA serum levels and tumor size in a xenograft mouse tumor model. Conclusively, PE is a promising anti-androgen-sensative prostate cancer agent.

Adipose Estrogen and Increased Breast Cancer Risk in Obesity: Regulation by Leptin and Insulin

DTIC Science & Technology

2007-09-07

enzyme aromatase which catalyses the biosynthesis of estrogen from androgen and also 17-beta- hydroxysteroid dehydrogenase (17- beta HSD) important for...biosynthesis of estrogen from androgen and also 17-β- hydroxysteroid dehydrogenase (17-βHSD) important for the conversion of estrone to estradiol. In

Beyond hormones: a novel hypothesis for the biological basis of male sexual orientation.

PubMed

Bocklandt, S; Hamer, D H

2003-01-01

For the past several decades, research on the development of human sexual orientation has focused on the role of pre- or peri-natal androgen levels on brain development. However, there is no evidence that physiologically occurring variations in androgen exposure influence differences in sexual orientation. In this review, we discuss an alternative hypothesis involving genomic imprinting in the regulation of sex specific expression of genes regulating sexually dimorphic traits, including sexual orientation. A possible experiment to test this hypothesis is discussed.

The Soy Isoflavones to Reduce Bone Loss (SIRBL) Study: Three Year Effects on pQCT Bone Mineral Density and Strength Measures in Postmenopausal Women

USDA-ARS?s Scientific Manuscript database

Soy isoflavones exert inconsistent bone density preserving effects, but the bone strength preserving effects in humans are unknown. Our double-blind randomized controlled trial examined 2 soy isoflavone doses (80 or 120 mg/d) vs placebo tablets on volumetric bone mineral density (vBMD) and strength ...

Nutritional aspects of second generation soy foods.

PubMed

Alezandro, Marcela Roquim; Granato, Daniel; Lajolo, Franco Maria; Genovese, Maria Inés

2011-05-25

Samples of 15 second generation soy-based products (n = 3), commercially available, were analyzed for their protein and isoflavone contents and in vitro antioxidant activity, by means of the Folin-Ciocalteu reducing ability, DPPH radical scavenging capacity, and oxygen radical absorbance capacity. Isoflavone identification and quantification were performed by high-performance liquid chromatography. Products containing soy and/or soy-based ingredients represent important sources of protein in addition to the low fat amounts. However, a large variation in isoflavone content and in vitro antioxidant capacity was observed. The isoflavone content varied from 2.4 to 18.1 mg/100 g (FW), and soy kibe and soy sausage presented the highest amounts. Chocolate had the highest antioxidant capacity, but this fact was probably associated with the addition of cocoa liquor, a well-known source of polyphenolics. This study showed that the soy-based foods do not present a significant content of isoflavones when compared with the grain, and their in vitro antioxidant capacity is not related with these compounds but rather to the presence of other phenolics and synthetic antioxidants, such as sodium erythorbate. However, they may represent alternative sources and provide soy protein, isoflavones, and vegetable fat for those who are not ready to eat traditional soy foods.

Development of techniques for the analysis of isoflavones in soy foods and nutraceuticals.

PubMed

Dentith, Susan; Lockwood, Brian

2008-05-01

For over 20 years, soy isoflavones have been investigated for their ability to prevent a wide range of cancers and cardiovascular problems, and numerous other disease states. This research is underpinned by the ability of researchers to analyse isoflavones in various forms in a range of raw materials and biological fluids. This review summarizes the techniques recently used in their analysis. The speed of high performance liquid chromatography analysis has been improved, allowing analysis of more samples, and increasing the sensitivity of detection techniques allows quantification of isoflavones down to nanomoles per litre levels in biological fluids. The combination of high-performance liquid chromatography with immunoassay has allowed identification and estimation of low-level soy isoflavones. The use of soy isoflavone supplements has shown an increase in their circulating levels in plasma and urine, aiding investigation of their biological effects. The significance of the metabolite equol has spurned research into new areas, and recently the specific enantiomers have been studied. High-performance liquid chromatography, capillary electrophoresis and gas chromatography are widely used with a range of detection systems. Increasingly, immunoassay is being used because of its high sensitivity and low cost.

A Comparative Analysis of the Photo-Protective Effects of Soy Isoflavones in Their Aglycone and Glucoside Forms

PubMed Central

Iovine, Barbara; Iannella, Maria Luigia; Gasparri, Franco; Giannini, Valentina; Monfrecola, Giuseppe; Bevilacqua, Maria Assunta

2012-01-01

Isoflavones exist in nature predominantly as glucosides such as daidzin or genistin and are rarely found in their corresponding aglycone forms daidzein and genistein. The metabolism and absorption of isoflavones ingested with food is well documented, but little is known about their use as topical photo-protective agents. The aim of this study was to investigate in a comparative analysis the photo-protective effects of isoflavones in both their aglycone and glucoside forms. In human skin fibroblasts irradiated with 60 mJ/cm2 ultraviolet B (UVB), we measured the expression levels of COX-2 and Gadd45, which are involved in inflammation and DNA repair, respectively. We also determined the cellular response to UVB-induced DNA damage using the comet assay. Our findings suggest that both the isoflavone glucosides at a specific concentration and combination with an aglycone mixture exerted an anti-inflammatory and photo-protective effect that prevented 41% and 71% of UVB-induced DNA damage, respectively. The advantages of using either isoflavone glucosides or an aglycone mixture in applications in the field of dermatology will depend on their properties and their different potential uses. PMID:23211668

Hypertensive crisis associated with high dose soy isoflavone supplementation in a post-menopausal woman: a case report [ISRCTN98074661

PubMed Central

Hutchins, Andrea M; McIver, Imogene E; Johnston, Carol S

2005-01-01

Background Isoflavones are gaining popularity as alternatives to hormone replacement therapy. However, few guidelines exist to inform the public as to an appropriate dose. This case involves a postmenopausal woman who experienced a hypertensive crisis while consuming a high-dose isoflavone supplement as part of a research protocol. Case Presentation The participant was part of a placebo-controlled crossover trial to investigate the potential synergism of the antioxidant activity of soy isoflavones and vitamin C. Upon entry into the study, this healthy, well-nourished, normotensive postmenopausal woman (51 years old), consumed the first of four randomly assigned treatments (500 mg vitamin C plus 5 mg/kg body weight soy isoflavones). During this treatment, the participant's systolic blood pressure spiked to a recorded 226/117 mmHg, necessitating medical intervention and discontinuation of study participation. Two plausible mechanisms for this hypertensive crisis are discussed. Conclusion Due to the availability and increasing popularity of soy supplements, practitioners should be aware of the potential side effects associated with their use. Practitioners counseling clients who are consuming soy isoflavone supplements should advise them that elevated blood pressure may be a potential side-effect to consider and monitor. PMID:15975148

Androgen receptor: structure, role in prostate cancer and drug discovery

PubMed Central

Tan, MH Eileen; Li, Jun; Xu, H Eric; Melcher, Karsten; Yong, Eu-leong

2015-01-01

Androgens and androgen receptors (AR) play a pivotal role in expression of the male phenotype. Several diseases, such as androgen insensitivity syndrome (AIS) and prostate cancer, are associated with alterations in AR functions. Indeed, androgen blockade by drugs that prevent the production of androgens and/or block the action of the AR inhibits prostate cancer growth. However, resistance to these drugs often occurs after 2–3 years as the patients develop castration-resistant prostate cancer (CRPC). In CRPC, a functional AR remains a key regulator. Early studies focused on the functional domains of the AR and its crucial role in the pathology. The elucidation of the structures of the AR DNA binding domain (DBD) and ligand binding domain (LBD) provides a new framework for understanding the functions of this receptor and leads to the development of rational drug design for the treatment of prostate cancer. An overview of androgen receptor structure and activity, its actions in prostate cancer, and how structural information and high-throughput screening have been or can be used for drug discovery are provided herein. PMID:24909511

Genomic and non-genomic effects of androgens in the cardiovascular system: clinical implications.

PubMed

Lucas-Herald, Angela K; Alves-Lopes, Rheure; Montezano, Augusto C; Ahmed, S Faisal; Touyz, Rhian M

2017-07-01

The principle steroidal androgens are testosterone and its metabolite 5α-dihydrotestosterone (DHT), which is converted from testosterone by the enzyme 5α-reductase. Through the classic pathway with androgens crossing the plasma membrane and binding to the androgen receptor (AR) or via mechanisms independent of the ligand-dependent transactivation function of nuclear receptors, testosterone induces genomic and non-genomic effects respectively. AR is widely distributed in several tissues, including vascular endothelial and smooth muscle cells. Androgens are essential for many developmental and physiological processes, especially in male reproductive tissues. It is now clear that androgens have multiple actions besides sex differentiation and sexual maturation and that many physiological systems are influenced by androgens, including regulation of cardiovascular function [nitric oxide (NO) release, Ca 2+ mobilization, vascular apoptosis, hypertrophy, calcification, senescence and reactive oxygen species (ROS) generation]. This review focuses on evidence indicating that interplay between genomic and non-genomic actions of testosterone may influence cardiovascular function. © 2017 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society.

Hormone Treatment and Muscle Anabolism during Aging: Androgens

PubMed Central

Dillon, E. Lichar; Durham, William J.; Urban, Randall J.; Sheffield-Moore, Melinda

2010-01-01

Aging is associated with a gradual decline in circulating testosterone concentrations and decreased musculature in men. While testosterone administration is often considered when symptoms of hypogonadism are presented, the long-term effects of androgen use on muscle physiology are not yet fully understood. The definition of hypogonadism in men remains obscure but is generally indicated by total testosterone concentrations less than a threshold value of 300-500 ng/dL. Androgen replacement therapy is generally safe in men and women with low endogenous testosterone concentrations. The development of selective androgen receptor modulators (SARMs) may provide additional options in treatment of hypogonadism while lowering the potential of side effects often associated with long-term androgen use. Androgen administration, either alone or in combination with other treatments, can be successful in improving muscle mass by increasing protein anabolism and reducing protein catabolism in men and women. Further research is necessary to optimize the anabolic and anticatabolic properties of androgens for treatment and prevention of muscle loss in men and women. PMID:20452103

Tetragonia tetragonioides (Pall.) Kuntze Regulates Androgen Production in a Letrozole-Induced Polycystic Ovary Syndrome Model.

PubMed

Pyun, Bo-Jeong; Yang, Hyun; Sohn, Eunjin; Yu, Song Yi; Lee, Dongoh; Jung, Dong Ho; Ko, Byoung Seob; Lee, Hye Won

2018-05-14

Tetragonia tetragonioides (Pall.) Kuntze (TTK) is a medicinal plant traditionally used to treat various diseases such as diabetic, inflammatory, and female-related disorders. Polycystic ovary syndrome (PCOS) is a common endocrinological disorder in women of reproductive age, and hyperandrogenism is a prominent feature of PCOS resulting in anovulation and infertility. In this study, we investigated the effects of a TTK extract on androgen generation and regulation of steroidogenic enzymes in vitro and in vivo. Human adrenocortical NCI-H295R cells were used to assess the effects of TTK extract on production of dehydroepiandrosterone and testosterone, as well as the protein expression of steroidogenic enzymes. Further, a letrozole-induced PCOS rat model was used in vivo to assess whether dietary administration of TTK extract restores normal hormones and reduces PCOS symptoms. TTK extract significantly inhibited forskolin (FOR)-induced androgen production in NCI-H295R cells and serum luteinizing hormone, testosterone, and follicular cysts, but not estradiol, were reduced in letrozole-induced PCOS rats orally administered the TTK extract. In addition, TTK extract inhibits androgen biosynthesis through the ERK-CREB signaling pathway, which regulates CYP17A1 or HSD3B2 expression. TTK extract could be utilized for the prevention and treatment of hyperandrogenism and other types of PCOS.

Effect of a Soy Isoflavone Supplement on Lung Function and Clinical Outcomes in Patients With Poorly Controlled Asthma

PubMed Central

Smith, Lewis J.; Kalhan, Ravi; Wise, Robert A.; Sugar, Elizabeth A.; Lima, John J.; Irvin, Charles G.; Dozor, Allen J.; Holbrook, Janet T.

2017-01-01

IMPORTANCE Soy isoflavone supplements are used to treat several chronic diseases, although the data supporting their use are limited. Some data suggest that supplementation with soy isoflavone may be an effective treatment for patients with poor asthma control. OBJECTIVE To determine whether a soy isoflavone supplement improves asthma control in adolescent and adult patients with poorly controlled disease. DESIGN, SETTING, AND PARTICIPANTS Multicenter, randomized, double-blind, placebo-controlled trial conducted between May 2010 and August 2012 at 19 adult and pediatric pulmonary and allergy centers in the American Lung Association Asthma Clinical Research Centers network. Three hundred eighty-six adults and children aged 12 years or older with symptomatic asthma while taking a controller medicine and low dietary soy intake were randomized, and 345 (89%) completed spirometry at week 24. INTERVENTIONS Participants were randomly assigned to receive soy isoflavone supplement containing 100 mg of total isoflavones (n=193) or matching placebo (n=193) in 2 divided doses administered daily for 24 weeks. MAIN OUTCOMES AND MEASURES The primary outcome measure was change in forced expiratory volume in the first second (FEV1) at 24 weeks. Secondary outcome measures were symptoms, episodes of poor asthma control, Asthma Control Test score (range, 5–25; higher scores indicate better control), and systemic and airway biomarkers of inflammation. RESULTS Mean changes in prebronchodilator FEV1 over 24 weeks were 0.03 L (95% CI, −0.01 to 0.08 L) in the placebo group and 0.01 L (95% CI, −0.07 to 0.07 L) in the soy isoflavone group, which were not significantly different (P = .36). Mean changes in symptom scores on the Asthma Control Test (placebo, 1.98 [95% CI, 1.42–2.54] vs soy isoflavones, 2.20 [95% CI, 1.53–2.87]; positive values indicate a reduction in symptoms), number of episodes of poor asthma control (placebo, 3.3 [95% CI, 2.7–4.1] vs soy isoflavones, 3.0 [95% CI, 2.4–3.7]), and changes in exhaled nitric oxide (placebo, −3.48 ppb [95% CI, −5.99 to −0.97 ppb] vs soy isoflavones, 1.39 ppb [95% CI, −1.73 to 4.51 ppb]) did not significantly improve more with the soy isoflavone supplement than with placebo. Mean plasma genistein level increased from 4.87 ng/mL to 37.67 ng/mL (P < .001) in participants receiving the supplement. CONCLUSIONS AND RELEVANCE Among adults and children aged 12 years or older with poorly controlled asthma while taking a controller medication, use of a soy isoflavone supplement, compared with placebo, did not result in improved lung function or clinical outcomes. These findings suggest that this supplement should not be used for patients with poorly controlled asthma. PMID:26010632

Sex steroids and human behavior: prenatal androgen exposure and sex-typical play behavior in children.

PubMed

Hines, Melissa

2003-12-01

Gonadal hormones, particularly androgens, direct certain aspects of brain development and exert permanent influences on sex-typical behavior in nonhuman mammals. Androgens also influence human behavioral development, with the most convincing evidence coming from studies of sex-typical play. Girls exposed to unusually high levels of androgens prenatally, because they have the genetic disorder, congenital adrenal hyperplasia (CAH), show increased preferences for toys and activities usually preferred by boys, and for male playmates, and decreased preferences for toys and activities usually preferred by girls. Normal variability in androgen prenatally also has been related to subsequent sex-typed play behavior in girls, and nonhuman primates have been observed to show sex-typed preferences for human toys. These findings suggest that androgen during early development influences childhood play behavior in humans at least in part by altering brain development.

A novel class of pyranocoumarin anti-androgen receptor signaling compounds.

PubMed

Guo, Junming; Jiang, Cheng; Wang, Zhe; Lee, Hyo-Jeong; Hu, Hongbo; Malewicz, Barbara; Lee, Hyo-Jung; Lee, Jae-Ho; Baek, Nam-In; Jeong, Jin-Hyun; Kim, Dae-Keun; Kang, Kyung-Sun; Kim, Sung-Hoon; Lu, Junxuan

2007-03-01

Androgen and the androgen receptor (AR)-mediated signaling are crucial for prostate cancer development. Novel agents that can inhibit AR signaling in ligand-dependent and ligand-independent manners are desirable for the chemoprevention of prostate carcinogenesis and for the treatment of advanced prostate cancer. We have shown recently that the pyranocoumarin compound decursin from the herb Angelica gigas possesses potent anti-AR activities distinct from the anti-androgen bicalutamide. Here, we compared the anti-AR activities and the cell cycle arrest and apoptotic effects of decursin and two natural analogues in the androgen-dependent LNCaP human prostate cancer cell culture model to identify structure-activity relationships and mechanisms. Decursin and its isomer decursinol angelate decreased prostate-specific antigen expression with IC(50) of approximately 1 mumol/L. Both inhibited the androgen-stimulated AR nuclear translocation and transactivation, decreased AR protein abundance through proteasomal degradation, and induced G(0/1) arrest and morphologic differentiation. They also induced caspase-mediated apoptosis and reactive oxygen species at higher concentrations. Furthermore, they lacked the agonist activity of bicalutamide in the absence of androgen and were more potent than bicalutamide for suppressing androgen-stimulated cell growth. Decursinol, which does not contain a side chain, lacked the reactive oxygen species induction and apoptotic activities and exerted paradoxically an inhibitory and a stimulatory effect on AR signaling and cell growth. In conclusion, decursin and decursinol angelate are members of a novel class of nonsteroidal compounds that exert a long-lasting inhibition of both ligand-dependent and ligand-independent AR signaling. The side chain is critical for sustaining the anti-AR activities and the growth arrest and apoptotic effects.

Additive effects due to biochar and endophyte application enable soybean to enhance nutrient uptake and modulate nutritional parameters* #

PubMed Central

Waqas, Muhammad; Kim, Yoon-Ha; Khan, Abdul Latif; Shahzad, Raheem; Asaf, Sajjad; Hamayun, Muhammad; Kang, Sang-Mo; Khan, Muhammad Aaqil; Lee, In-Jung

2017-01-01

We studied the effects of hardwood-derived biochar (BC) and the phytohormone-producing endophyte Galactomyces geotrichum WLL1 in soybean (Glycine max (L.) Merr.) with respect to basic, macro-and micronutrient uptakes and assimilations, and their subsequent effects on the regulation of functional amino acids, isoflavones, fatty acid composition, total sugar contents, total phenolic contents, and 1,1-diphenyl-2-picrylhydrazyl (DPPH)-scavenging activity. The assimilation of basic nutrients such as nitrogen was up-regulated, leaving carbon, oxygen, and hydrogen unaffected in BC+G. geotrichum-treated soybean plants. In comparison, the uptakes of macro-and micronutrients fluctuated in the individual or co-application of BC and G. geotrichum in soybean plant organs and rhizospheric substrate. Moreover, the same attribute was recorded for the regulation of functional amino acids, isoflavones, fatty acid composition, total sugar contents, total phenolic contents, and DPPH-scavenging activity. Collectively, these results showed that BC+G. geotrichum-treated soybean yielded better results than did the plants treated with individual applications. It was concluded that BC is an additional nutriment source and that the G. geotrichum acts as a plant biostimulating source and the effects of both are additive towards plant growth promotion. Strategies involving the incorporation of BC and endophytic symbiosis may help achieve eco-friendly agricultural production, thus reducing the excessive use of chemical agents. PMID:28124840

Formononetin, an isoflavone, activates AMP-activated protein kinase/β-catenin signalling to inhibit adipogenesis and rescues C57BL/6 mice from high-fat diet-induced obesity and bone loss.

PubMed

Gautam, Jyoti; Khedgikar, Vikram; Kushwaha, Priyanka; Choudhary, Dharmendra; Nagar, Geet Kumar; Dev, Kapil; Dixit, Preety; Singh, Divya; Maurya, Rakesh; Trivedi, Ritu

2017-03-01

Balance between adipocyte and osteoblast differentiation is the key link of disease progression in obesity and osteoporosis. We have previously reported that formononetin (FNT), an isoflavone extracted from Butea monosperma, stimulates osteoblast formation and protects against postmenopausal bone loss. The inverse relationship between osteoblasts and adipocytes prompted us to analyse the effect of FNT on adipogenesis and in vivo bone loss, triggered by high-fat diet (HFD)-induced obesity. The anti-obesity effect and mechanism of action of FNT was determined in 3T3-L1 cells and HFD-induced obese male mice. Our findings show that FNT suppresses the adipogenic differentiation of 3T3-L1 fibroblasts, through down-regulation of key adipogenic markers such as PPARγ, CCAAT/enhancer-binding protein alpha (C/EBPα) and sterol regulatory element-binding protein (SREBP) and inhibits intracellular TAG accumulation. Increased intracellular reactive oxygen species levels and AMP-activated protein kinase (AMPK) activation accompanied by stabilisation of β-catenin were attributed to the anti-adipogenic action of FNT. In vivo, 12 weeks of FNT treatment inhibited the development of obesity in mice by attenuating HFD-induced body weight gain and visceral fat accumulation. The anti-obesity effect of FNT results from increased energy expenditure. FNT also protects against HFD-induced dyslipidaemia and rescues deterioration of trabecular bone volume by increasing bone formation and decreasing bone resorbtion caused by HFD. FNT's rescuing action against obesity-induced osteoporosis commenced at the level of progenitors, as bone marrow progenitor cells, obtained from the HFD mice group supplemented with FNT, showed increased osteogenic and decreased adipogenic potentials. Our findings suggest that FNT inhibits adipogenesis through AMPK/β-catenin signal transduction pathways and protects against HFD-induced obesity and bone loss.

Chronic Exposure to Anabolic Androgenic Steroids Alters Neuronal Function in the Mammalian Forebrain via Androgen Receptor- and Estrogen Receptor-Mediated Mechanisms

PubMed Central

Penatti, Carlos A A; Porter, Donna M; Henderson, Leslie P

2009-01-01

Anabolic androgenic steroids (AAS) can promote detrimental effects on social behaviors for which γ-aminobutyric acid type A (GABAA) receptor-mediated circuits in the forebrain play a critical role. While all AAS bind to androgen receptors (AR), they may also be aromatized to estrogens and thus potentially impart effects via estrogen receptors (ER). Chronic exposure of wild type male mice to a combination of chemically distinct AAS increased action potential (AP) frequency, selective GABAA receptor subunit mRNAs, and GABAergic synaptic current decay in the medial preoptic area (mPOA). Experiments performed with pharmacological agents and in AR-deficient Tfm mutant mice suggest that the AAS-dependent enhancement of GABAergic transmission in wild type mice is AR-mediated. In AR-deficient mice, the AAS elicited dramatically different effects, decreasing AP frequency, sIPSC amplitude and frequency and the expression of selective GABAA receptor subunit mRNAs. Surprisingly, in the absence of AR signaling, the data indicate that the AAS do not act as ER agonists, but rather suggest a novel in vivo action in which the AAS inhibit aromatase and impair endogenous ER signaling. These results show that the AAS have the capacity to alter neuronal function in the forebrain via multiple steroid signaling mechanisms and suggest that effects of these steroids in the brain will depend not only on the balance of AR- vs. ER-mediated regulation for different target genes, but also on the ability of these drugs to alter steroid metabolism and thus the endogenous steroid milieu. PMID:19812324

Association between Soy Isoflavone Intake and Breast Cancer Risk for Pre- and Post-Menopausal Women: A Meta-Analysis of Epidemiological Studies

PubMed Central

Zheng, Yi; Wei, Shiqing; Li, Ye; Guo, Tong; Yin, Ping

2014-01-01

Background Conclusions drawn from meta-analyses on the association between soy isoflavone intake and breast cancer risk for pre- and post-menopausal women are not fully consistent. These meta-analyses did not explore the influence of different study designs on the pooled results on the basis of distinguishing between pre- and post-menopausal women. Methodology and Principal Findings We performed a meta-analysis of 35 studies which reported results of association between soy isoflavone intake and breast cancer risk for pre- and/or post-menopausal women, calculated pooled odds ratios and their 95% confidence intervals of pre- and post-menopausal women respectively, and further explored soy isoflavone-breast cancer association on the basis of considering different study regions and designs. Summary results suggested that soy isoflavone intake has a protective effect against breast cancer for both pre- and post-menopausal women. However, they are influenced by study design and region. Pooled ORs of studies carried out in Asian countries suggested that soy isoflavone’s protective effect exist in both pre- and post-menopausal women (OR = 0.59, 95%CI: 0.48–0.69 for premenopausal women; OR = 0.59, 95%CI: 0.44–0.74 for postmenopausal women). However, there are some differences between the results pooled from different study designs for women in Asian countries (test for consistency, P = 0.04). Pooled OR of studies on postmenopausal women in Western countries suggested that soy isoflavone intake has a marginally significant protective effect (OR = 0.92; 95%CI: 0.83∼1.00), but further analyses stratifying by study design found no statistically significant association. Conclusions We meta-analyzed more and newer research results, and separated women according to menopausal status to explore soy isoflavone-breast cancer association. We founded that soy isoflavone intake could lower the risk of breast cancer for both pre- and post-menopausal women in Asian countries. However, for women in Western countries, pre- or post-menopausal, there is no evidence to suggest an association between intake of soy isoflavone and breast cancer. PMID:24586662

Serum/glucocorticoid-regulated kinase 1 expression in primary human prostate cancers.

PubMed

Szmulewitz, Russell Z; Chung, Elizabeth; Al-Ahmadie, Hikmat; Daniel, Silver; Kocherginsky, Masha; Razmaria, Aria; Zagaja, Gregory P; Brendler, Charles B; Stadler, Walter M; Conzen, Suzanne D

2012-02-01

Serum/glucocorticoid-regulated kinase 1 (SGK1), a known target of the androgen receptor (AR) and glucocorticoid receptor (GR), is reported to enhance cell survival. This study sought to better define the role of SGK1 and GR in prostate cancer. Immunohistochemistry was performed for AR, GR, and SGK1 on primary prostate cancers (n = 138) and 18 prostate cancers from patients treated with androgen deprivation therapy. Relative staining intensity was compared utilizing a Fisher's exact test. Univariate analyses were performed using log-rank and chi-squared tests to evaluate prostate cancer recurrence with respect to SGK1 expression. SGK1 expression was strong (3+) in 79% of untreated cancers versus 44% in androgen-deprived cancers (P = 0.003). Conversely, GR expression was present in a higher proportion of androgen-deprived versus untreated cancers (78% vs. 38%, P = 0.002). High-grade cancers were nearly twice as likely to have relatively low (0 to 2+) SGK1 staining compared to low-grade cancers (13.8% vs. 26.5%, P = 0.08). Low SGK1 expression in untreated tumors was associated with increased risk of cancer recurrence (adjusted log-rank test P = 0.077), 5-year progression-free survival 47.8% versus 72.6% (P = 0.034). SGK1 expression is high in most untreated prostate cancers and declines with androgen deprivation. However, these data suggest that relatively low expression of SGK1 is associated with higher tumor grade and increased cancer recurrence, and is a potential indicator of aberrant AR signaling in these tumors. GR expression increased with androgen deprivation, potentially providing a mechanism for the maintenance of androgen pathway signaling in these tumors. Further study of the AR/GR/SGK1 network in castration resistance. Copyright © 2011 Wiley Periodicals, Inc.

Premature adrenarche: etiology, clinical findings, and consequences.

PubMed

Voutilainen, Raimo; Jääskeläinen, Jarmo

2015-01-01

Adrenarche means the morphological and functional change of the adrenal cortex leading to increasing production of adrenal androgen precursors (AAPs) in mid childhood, typically at around 5-8 years of age in humans. The AAPs dehydroepiandrosterone (DHEA) and its sulfate conjugate (DHEAS) are the best serum markers of adrenal androgen (AA) secretion and adrenarche. Normal ACTH secretion and action are needed for adrenarche, but additional inherent and exogenous factors regulate AA secretion. Inter-individual variation in the timing of adrenarche and serum concentrations of DHEA(S) in adolescence and adulthood are remarkable. Premature adrenarche (PA) is defined as the appearance of clinical signs of androgen action (pubic/axillary hair, adult type body odor, oily skin or hair, comedones, acne, accelerated statural growth) before the age of 8 years in girls or 9 years in boys associated with AAP concentrations high for the prepubertal chronological age. To accept the diagnosis of PA, central puberty, adrenocortical and gonadal sex hormone secreting tumors, congenital adrenal hyperplasia, and exogenous source of androgens need to be excluded. The individually variable peripheral conversion of circulating AAPs to biologically more active androgens (testosterone, dihydrotestosterone) and the androgen receptor activity in the target tissues are as important as the circulating AAP concentrations as determinants of androgen action. PA has gained much attention during the last decades, as it has been associated with small birth size, the metabolic and polycystic ovarian syndrome (PCOS), and thus with an increased risk for type 2 diabetes and cardiovascular diseases in later life. The aim of this review is to describe the known hormonal changes and their possible regulators in on-time and premature adrenarche, and the clinical features and possible later health problems associating with PA. Copyright © 2014 Elsevier Ltd. All rights reserved.

Sox2 Is an Androgen Receptor-Repressed Gene That Promotes Castration-Resistant Prostate Cancer

PubMed Central

Kregel, Steven; Kiriluk, Kyle J.; Rosen, Alex M.; Cai, Yi; Reyes, Edwin E.; Otto, Kristen B.; Tom, Westin; Paner, Gladell P.; Szmulewitz, Russell Z.; Vander Griend, Donald J.

2013-01-01

Despite advances in detection and therapy, castration-resistant prostate cancer continues to be a major clinical problem. The aberrant activity of stem cell pathways, and their regulation by the Androgen Receptor (AR), has the potential to provide insight into novel mechanisms and pathways to prevent and treat advanced, castrate-resistant prostate cancers. To this end, we investigated the role of the embryonic stem cell regulator Sox2 [SRY (sex determining region Y)-box 2] in normal and malignant prostate epithelial cells. In the normal prostate, Sox2 is expressed in a portion of basal epithelial cells. Prostate tumors were either Sox2-positive or Sox2-negative, with the percentage of Sox2-positive tumors increasing with Gleason Score and metastases. In the castration-resistant prostate cancer cell line CWR-R1, endogenous expression of Sox2 was repressed by AR signaling, and AR chromatin-IP shows that AR binds the enhancer element within the Sox2 promoter. Likewise, in normal prostate epithelial cells and human embryonic stem cells, increased AR signaling also decreases Sox2 expression. Resistance to the anti-androgen MDV3100 results in a marked increase in Sox2 expression within three prostate cancer cell lines, and in the castration-sensitive LAPC-4 prostate cancer cell line ectopic expression of Sox2 was sufficient to promote castration-resistant tumor formation. Loss of Sox2 expression in the castration-resistant CWR-R1 prostate cancer cell line inhibited cell growth. Up-regulation of Sox2 was not associated with increased CD133 expression but was associated with increased FGF5 (Fibroblast Growth Factor 5) expression. These data propose a model of elevated Sox2 expression due to loss of AR-mediated repression during castration, and consequent castration-resistance via mechanisms not involving induction of canonical embryonic stem cell pathways. PMID:23326489

Neuroprotective effects of formononetin against NMDA-induced apoptosis in cortical neurons.

PubMed

Tian, Zhen; Liu, Shui-Bing; Wang, Yu-Cai; Li, Xiao-Qiang; Zheng, Lian-He; Zhao, Ming-Gao

2013-12-01

Formononetin (FMNT) is an isoflavone found in many herbs including Trifolium pratense L., Spatholobus suberectus Dunn., and Astragalus mongholicus Bunge. The purpose of this study is to investigate pharmacological properties of FMNT on neurotoxicity induced by N-methyl-D-asparate (NMDA) in primary-cultured cortical neurons. The cell viability was significantly decreased after exposure to NMDA (200 μM) for 40 min. Pretreatment of FMNT (10 μM) for 12 h significantly attenuated the cell loss induced by NMDA exposure. Flow cytometry analysis revealed that treatment of FMNT attenuated the number of apoptotic cells, especially the early phase apoptotic cells, induced by NMDA exposure. Western blot analysis showed that FMNT regulated the expression of apoptosis-related proteins by increasing the levels of Bcl-2 and pro-caspase-3 and decreasing the levels of Bax and caspase-3. These findings demonstrate that FMNT is capable of protecting neurons from NMDA-evoked excitotoxic injury and has a potential perspective to the clinical treatment for neurodegenerative disorders in central nervous system. Copyright © 2013 John Wiley & Sons, Ltd.

Differential requirements of androgen receptor in luminal progenitors during prostate regeneration and tumor initiation

PubMed Central

Chua, Chee Wai; Epsi, Nusrat J; Leung, Eva Y; Xuan, Shouhong; Lei, Ming; Li, Bo I; Bergren, Sarah K; Hibshoosh, Hanina; Mitrofanova, Antonina

2018-01-01

Master regulatory genes of tissue specification play key roles in stem/progenitor cells and are often important in cancer. In the prostate, androgen receptor (AR) is a master regulator essential for development and tumorigenesis, but its specific functions in prostate stem/progenitor cells have not been elucidated. We have investigated AR function in CARNs (CAstration-Resistant Nkx3.1-expressing cells), a luminal stem/progenitor cell that functions in prostate regeneration. Using genetically--engineered mouse models and novel prostate epithelial cell lines, we find that progenitor properties of CARNs are largely unaffected by AR deletion, apart from decreased proliferation in vivo. Furthermore, AR loss suppresses tumor formation after deletion of the Pten tumor suppressor in CARNs; however, combined Pten deletion and activation of oncogenic Kras in AR-deleted CARNs result in tumors with focal neuroendocrine differentiation. Our findings show that AR modulates specific progenitor properties of CARNs, including their ability to serve as a cell of origin for prostate cancer. PMID:29334357

Inhibition of androgen receptor and β-catenin activity in prostate cancer

PubMed Central

Lee, Eugine; Madar, Aviv; David, Gregory; Garabedian, Michael J.; DasGupta, Ramanuj; Logan, Susan K.

2013-01-01

Androgen receptor (AR) is the major therapeutic target in aggressive prostate cancer. However, targeting AR alone can result in drug resistance and disease recurrence. Therefore, simultaneous targeting of multiple pathways could in principle be an effective approach to treating prostate cancer. Here we provide proof-of-concept that a small-molecule inhibitor of nuclear β-catenin activity (called C3) can inhibit both the AR and β-catenin–signaling pathways that are often misregulated in prostate cancer. Treatment with C3 ablated prostate cancer cell growth by disruption of both β-catenin/T-cell factor and β-catenin/AR protein interaction, reflecting the fact that T-cell factor and AR have overlapping binding sites on β-catenin. Given that AR interacts with, and is transcriptionally regulated by β-catenin, C3 treatment also resulted in decreased occupancy of β-catenin on the AR promoter and diminished AR and AR/β-catenin target gene expression. Interestingly, C3 treatment resulted in decreased AR binding to target genes accompanied by decreased recruitment of an AR and β-catenin cofactor, coactivator-associated arginine methyltransferase 1 (CARM1), providing insight into the unrecognized function of β-catenin in prostate cancer. Importantly, C3 inhibited tumor growth in an in vivo xenograft model and blocked renewal of bicalutamide-resistant sphere-forming cells, indicating the therapeutic potential of this approach. PMID:24019458

Testofen, a specialised Trigonella foenum-graecum seed extract reduces age-related symptoms of androgen decrease, increases testosterone levels and improves sexual function in healthy aging males in a double-blind randomised clinical study.

PubMed

Rao, Amanda; Steels, Elizabeth; Inder, Warrick J; Abraham, Suzanne; Vitetta, Luis

2016-06-01

This study examined the effect of Testofen, a specialised Trigonella foenum-graecum seed extract on the symptoms of possible androgen deficiency, sexual function and serum androgen concentrations in healthy aging males. This was a double-blind, randomised, placebo-controlled trial involving 120 healthy men aged between 43 and 70 years of age. The active treatment was standardised Trigonella foenum-graecum seed extract at a dose of 600 mg/day for 12 weeks. The primary outcome measure was the change in the Aging Male Symptom questionnaire (AMS), a measure of possible androgen deficiency symptoms; secondary outcome measures were sexual function and serum testosterone. There was a significant decrease in AMS score over time and between the active and placebo groups. Sexual function improved, including number of morning erections and frequency of sexual activity. Both total serum testosterone and free testosterone increased compared to placebo after 12 weeks of active treatment. Trigonella foenum-graecum seed extract is a safe and effective treatment for reducing symptoms of possible androgen deficiency, improves sexual function and increases serum testosterone in healthy middle-aged and older men.

Aromatization of androgens is important for skeletal maintenance of aged male rats.

PubMed

Vanderschueren, D; Van Herck, E; De Coster, R; Bouillon, R

1996-09-01

A nonsteroidal aromatase inhibitor vorozole (VOR) was administered to aged (12 months old) male Wistar rats and its effect was compared with the effect of androgen deficiency. The rats were either sham-operated (SHAM) or orchidectomized (ORCH) and treated with or without VOR. Thus, four experimental groups were created (SHAM, ORCH, SHAM + VOR, ORCH + VOR). The follow-up period was 4 months. At the end of the experimental period, bone mineral density (BMD) of the first four lumbar vertebrae and right femur was measured ex vivo with dual-energy X-ray absorptiometry, bone formation was evaluated by serum osteocalcin, and bone resorption by urinary excretion of (deoxy)pyridinoline. Orchidectomy increased bone resorption 2- to 3-fold whereas bone formation was only slightly increased. Treatment of intact male rats with VOR also increased bone resorption (+30% increase) whereas bone formation was not increased in this SHAM + VOR group. Their BMD was 7% lower in the femur (P < 0.01) and 6% lower in the lumbar vertebrae (P < 0.01) compared with the SHAM group that had not received VOR. Moreover, this decrease of bone mineral density was not significantly different from the expected decrease of bone density observed in the ORCH groups (6-10%). This was also reflected by a decrease of calcium content of the first four lumbar vertebrae of 15% (P < 0.001) in the SHAM + VOR group and 9-14% (P < 0.05) in the ORCH groups compared with the SHAM group, respectively. These data therefore suggest that inhibition of aromatization of androgens into estrogens increases bone resorption and bone loss similar to that observed after complete removal of androgens. Aromatization of androgens into estrogens may therefore, at least partly, explain the effects of androgens on skeletal maintenance.

Telomerase as an Androgen Receptor-Regulated Target in Selenium Chemoprevention of Prostate Cancer

DTIC Science & Technology

2011-04-01

CONTRACTING ORGANIZATION : Tulane University New Orleans, LA 70112...Mail: liushuangbear@hotmail.com 5f. WORK UNIT NUMBER 7. PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) 8. PERFORMING ORGANIZATION REPORT...combination of both agents in patients with HNSCC. Methylseleninic Acid Enhances Anti-Androgen Efficacy Liu et al. ______________Page 2016 The

Identifying Environmental Chemicals as Agonists of the Androgen Receptor by Applying a Quantitative High-throughput Screening Platform

EPA Science Inventory

Background: The androgen receptor (AR, NR3C4) is a nuclear receptor whose main function is acting as a transcription factor regulating gene expression for male sexual development and maintaining accessory sexual organ function. It is also a necessary component of female fertility...

A PHARMACOKINETIC-PHARMACODYNAMIC MODEL FOR GENE-REGULATED PROSTATE MAINTENANCE: COMPARING THE EFFECTS OF CASTRATION WITH ANTIANDROGEN EXPOSURE IN THE RAT

EPA Science Inventory

Antiandrogens affect prostate maintenance in two ways. Androgen antagonists, such as the fungicide vinclozolin, act as competitive ligands for the androgen receptor (AR). Enzyme inhibitors, such as the therapeutic drug Finasteride, inhibit the enzyme 5 -reductase (5 R) from metab...

Next-generation steroidogenesis inhibitors, dutasteride and abiraterone, attenuate but still do not eliminate androgen biosynthesis in 22RV1 cells in vitro.

PubMed

Pham, Steven; Deb, Subrata; Ming, Dong Sheng; Adomat, Hans; Hosseini-Beheshti, Elham; Zoubeidi, Amina; Gleave, Martin; Guns, Emma S Tomlinson

2014-10-01

Castration resistant prostate cancer (CRPC) is often lethal and inevitably develops after androgen ablation therapy. However, in the majority of cases it remains androgen dependent. CRPC tumors have the ability to synthesize their own androgens from cholesterol by engaging in de novo steroidogenesis. We investigated the potential of 22RV1 prostate cancer cells to convert the supplemented steroid precursors within this pathway under the effects of current clinical steroidogenesis inhibitors such as abiraterone and dutasteride, either alone or in combination. Under steroid starved conditions, enzymes responsible for de novo steroidogenesis were upregulated. Testosterone and dihydrotestosterone (DHT) were formed by using both dehydroepiandrosterone (DHEA) and progesterone as substrates. Formation of testosterone and DHT was higher following incubation with DHEA compared to progesterone. Progesterone decreased the mRNA expression of enzymes responsible for steroidogenesis. Abiraterone treatment decreased testosterone production but increased several precursor steroids in both classical and backdoor pathways in the presence of progesterone. In contrast, the DHT levels were elevated following treatment with abiraterone when progesterone was absent. Dutasteride decreased the formation of testosterone, DHT and precursor steroids in the backdoor pathway but increased steroid precursors in the classical steroidogenesis pathway. The combination of abiraterone and dutasteride decreased testosterone and DHT in the presence of progesterone but increased DHT in the absence of progesterone. Abiraterone inhibited androgen receptor (AR) activation but not to the same extent as MDV3100. However, abiraterone and dutasteride treatment, either alone or in combination, were more effective in decreasing prostate specific antigen secretion into the media than MDV3100. Thus, while interventions with these drugs alone or in combination fail to completely inhibit steroidogenesis in the 22RV1 cells, the combined inhibition of androgen production and blockade of AR can exceed the effect of MDV3100. Further characterization of bypass mechanisms that may develop as a response to these inhibitors is necessary to achieve optimal suppression of testosterone and DHT synthesis as a part of therapeutic regimens for the treatment of CRPC. Copyright © 2014 Elsevier Ltd. All rights reserved.

Soy infant formula: is it that bad?

PubMed

Vandenplas, Yvan; De Greef, Elisabeth; Devreker, Thierry; Hauser, Bruno

2011-02-01

The objective of this study is to review the indications of soy infant formula (SIF). Structured review of publications is made available through standard search engines (Pubmed,…). The medical indications for SIF are limited to galactosaemia and hereditary lactase deficiency. In the treatment of cow's milk allergy, SIF is used for economic reasons, as extensive hydrolysates are expensive. SIF is dissuaded mainly because of its phytooestrogen content. Isoflavone serum levels are much higher in SIF-fed infants than in breastfed or cow milk formula-fed infants. Administration of pure isoflavones to animals causes decreased fertility, but clinically relevant adverse effects of SIF in infants are not reported.   Soy infant formula remains an option for feeding of term born infants if breastfeeding is not possible and if standard infant formula is not tolerated. © 2010 The Author(s)/Acta Paediatrica © 2010 Foundation Acta Paediatrica.

Pituitary Androgen Receptor Signalling Regulates Prolactin but Not Gonadotrophins in the Male Mouse

PubMed Central

O’Hara, Laura; Curley, Michael; Tedim Ferreira, Maria; Cruickshanks, Lyndsey; Milne, Laura; Smith, Lee B.

2015-01-01

Production of the androgen testosterone is controlled by a negative feedback loop within the hypothalamic-pituitary-gonadal (HPG) axis. Stimulation of testicular Leydig cells by pituitary luteinising hormone (LH) is under the control of hypothalamic gonadotrophin releasing hormone (GnRH), while suppression of LH secretion by the pituitary is controlled by circulating testosterone. Exactly how androgens exert their feedback control of gonadotrophin secretion (and whether this is at the level of the pituitary), as well as the role of AR in other pituitary cell types remains unclear. To investigate these questions, we exploited a transgenic mouse line (Foxg1Cre/+; ARfl/y) which lacks androgen receptor in the pituitary gland. Both circulating testosterone and gonadotrophins are unchanged in adulthood, demonstrating that AR signalling is dispensable in the male mouse pituitary for testosterone-dependent regulation of LH secretion. In contrast, Foxg1Cre/+; ARfl/y males have a significant increase in circulating prolactin, suggesting that, rather than controlling gonadotrophins, AR-signalling in the pituitary acts to suppress aberrant prolactin production in males. PMID:25799562

A hypothetical pathogenesis model for androgenic alopecia: clarifying the dihydrotestosterone paradox and rate-limiting recovery factors.

PubMed

English, Robert S

2018-02-01

Androgenic alopecia, also known as pattern hair loss, is a chronic progressive condition that affects 80% of men and 50% of women throughout a lifetime. But despite its prevalence and extensive study, a coherent pathology model describing androgenic alopecia's precursors, biological step-processes, and physiological responses does not yet exist. While consensus is that androgenic alopecia is genetic and androgen-mediated by dihydrotestosterone, questions remain regarding dihydrotestosterone's exact role in androgenic alopecia onset. What causes dihydrotestosterone to increase in androgenic alopecia-prone tissues? By which mechanisms does dihydrotestosterone miniaturize androgenic alopecia-prone hair follicles? Why is dihydrotestosterone also associated with hair growth in secondary body and facial hair? Why does castration (which decreases androgen production by 95%) stop pattern hair loss, but not fully reverse it? Is there a relationship between dihydrotestosterone and tissue remodeling observed alongside androgenic alopecia onset? We review evidence supporting and challenging dihydrotestosterone's causal relationship with androgenic alopecia, then propose an evidence-based pathogenesis model that attempts to answer the above questions, account for additionally-suspected androgenic alopecia mediators, identify rate-limiting recovery factors, and elucidate better treatment targets. The hypothesis argues that: (1) chronic scalp tension transmitted from the galea aponeurotica induces an inflammatory response in androgenic alopecia-prone tissues; (2) dihydrotestosterone increases in androgenic alopecia-prone tissues as part of this inflammatory response; and (3) dihydrotestosterone does not directly miniaturize hair follicles. Rather, dihydrotestosterone is a co-mediator of tissue dermal sheath thickening, perifollicular fibrosis, and calcification - three chronic, progressive conditions concomitant with androgenic alopecia progression. These conditions remodel androgenic alopecia-prone tissues - restricting follicle growth space, oxygen, and nutrient supply - leading to the slow, persistent hair follicle miniaturization characterized in androgenic alopecia. If true, this hypothetical model explains the mechanisms by which dihydrotestosterone miniaturizes androgenic alopecia-prone hair follicles, describes a rationale for androgenic alopecia progression and patterning, makes sense of dihydrotestosterone's paradoxical role in hair loss and hair growth, and identifies targets to further improve androgenic alopecia recovery rates: fibrosis, calcification, and chronic scalp tension. Copyright © 2017 The Author. Published by Elsevier Ltd.. All rights reserved.

Liquid chromatography with absorbance detection and with isotope-dilution mass spectrometry for determination of isoflavones in soy standard reference materials.

PubMed

Phillips, Melissa M; Bedner, Mary; Reitz, Manuela; Burdette, Carolyn Q; Nelson, Michael A; Yen, James H; Sander, Lane C; Rimmer, Catherine A

2017-02-01

Two independent analytical approaches, based on liquid chromatography with absorbance detection and liquid chromatography with mass spectrometric detection, have been developed for determination of isoflavones in soy materials. These two methods yield comparable results for a variety of soy-based foods and dietary supplements. Four Standard Reference Materials (SRMs) have been produced by the National Institute of Standards and Technology to assist the food and dietary supplement community in method validation and have been assigned values for isoflavone content using both methods. These SRMs include SRM 3234 Soy Flour, SRM 3236 Soy Protein Isolate, SRM 3237 Soy Protein Concentrate, and SRM 3238 Soy-Containing Solid Oral Dosage Form. A fifth material, SRM 3235 Soy Milk, was evaluated using the methods and found to be inhomogeneous for isoflavones and unsuitable for value assignment. Graphical Abstract Separation of six isoflavone aglycones and glycosides found in Standard Reference Material (SRM) 3236 Soy Protein Isolate.

Impact of Food Matrix on Isoflavone Metabolism and Cardiovascular Biomarkers in Adults with Hypercholesterolemia

PubMed Central

Ahn-Jarvis, Jennifer; Clinton, Steven K.; Riedl, Kenneth M.; Vodovotz, Yael; Schwartz, Steven J.

2012-01-01

The role of food matrix and gender on soy isoflavone metabolism and biomarkers of activity were examined in twenty free-living adults (34.7±11.5 yrs old) with hypercholesterolemia (221.9 ±18.7mg/dL). In a randomized crossover design study, participants consumed soy-bread (3 wk) or soy-beverage (3 wk) containing 20 g soy protein with 99 and 93 mg isoflavones aglycone equivalents per day, respectively. During soy bread intervention, women had significantly greater microbial metabolite excretion (P=0.05) of isoflavonoids than men. In men, isoflavone metabolite excretion was not discernibly different between the two matrices. Significant reductions (P ≤ 0.05) in triglycerides (24.8%), LDL cholesterol (6.0%), apolipoprotein A-I (12.3%), and lipid oxidative stress capacity (25.5%), were observed after soy food intervention. Our findings suggest that the food matrix significantly impacts soy isoflavone metabolism, particularly microbial metabolites in women. PMID:22739802

Regulation of prostate cancer by hormone-responsive G protein-coupled receptors.

PubMed

Wang, Wei; Chen, Zhao-Xia; Guo, Dong-Yu; Tao, Ya-Xiong

2018-06-15

Regulation of prostate cancer by androgen and androgen receptor (AR), and blockade of AR signaling by AR antagonists and steroidogenic enzyme inhibitors have been extensively studied. G protein-coupled receptors (GPCRs) are a family of membrane receptors that regulate almost all physiological processes. Nearly 40% of FDA-approved drugs in the market target GPCRs. A variety of GPCRs that mediate reproductive function have been demonstrated to be involved in the regulation of prostate cancer. These GPCRs include gonadotropin-releasing hormone receptor, luteinizing hormone receptor, follicle-stimulating hormone receptor, relaxin receptor, ghrelin receptor, and kisspeptin receptor. We highlight here GPCR regulation of prostate cancer by these GPCRs. Further therapeutic approaches targeting these GPCRs for the treatment of prostate cancer are summarized. Copyright © 2018. Published by Elsevier Inc.

Evaluation of new natural deep eutectic solvents for the extraction of isoflavones from soy products.

PubMed

Bajkacz, Sylwia; Adamek, Jakub

2017-06-01

Natural deep eutectic solvents (NADESs) are considered to be new, safe solvents in green chemistry that can be widely used in many chemical processes such as extraction or synthesis. In this study, a simple extraction method based on NADES was used for the isolation of isoflavones (daidzin, genistin, genistein, daidzein) from soy products. Seventeen different NADES systems each including two or three components were tested. Multivariate data analysis revealed that NADES based on a 30% solution of choline chloride: citric acid (molar ratio of 1:1) are the most effective systems for the extraction of isoflavones from soy products. After extraction, the analytes were detected and quantified using ultra-high performance liquid chromatography with ultraviolet detection (UHPLC-UV). The proposed NADES extraction procedure achieved enrichment factors up to 598 for isoflavones and the recoveries of the analytes were in the range 64.7-99.2%. The developed NADES extraction procedure and UHPLC-UV determination method was successfully applied for the analysis of isoflavones in soy-containing food samples. The obtained results indicated that new natural deep eutectic solvents could be an alternative to traditional solvents for the extraction of isoflavones and can be used as sustainable and safe extraction media for another applications. Copyright © 2017 Elsevier B.V. All rights reserved.

Population versus hospital controls in the assessment of dietary intake of isoflavone for case-control studies on cancers in China.

PubMed

Li, Lin; Zhang, Min; Holman, C D'Arcy J

2013-01-01

To assess dietary isoflavone intake between population and hospital outpatient controls and examine if cancer risks estimated for isoflavone using hospital outpatient controls would be different from those using population controls. Three parallel case-control studies on leukemia, breast, and colorectal cancers in China in 2009-2010 were conducted, using population and hospital outpatient controls to separately match 560 incident cases at a 1:1 ratio. A validated food frequency questionnaire was administered by face-to-face interview. Conditional logistic regression analysis was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). The 2 control groups had closely similar distributions of dietary isoflavone intake. Risk estimates for breast cancers were adjusted ORs (95% CI) of 0.39 (0.23-0.66) and 0.31 (0.18-0.55) for daidzein, 0.35 (0.20-0.61) and 0.28 (0.16-0.52) for genistein, 0.66 (0.41-1.08) and 0.53 (0.32-0.88) for glycitein, and 0.53 (0.33-0.85) and 0.43 (0.26-0.71) for total isoflavone using hospital outpatient and population controls respectively. The study found that hospital outpatient controls were comparable to population controls in measured dietary intake of isoflavone in the Chinese hospital setting.

Bioavailability of soy isoflavones through placental/lactational transfer and soy food

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

Doerge, Daniel R., E-mail: daniel.doerge@fda.hhs.gov

2011-07-15

Isoflavones are non-nutritive components of soy responsible for estrogenic responses observed in vitro and in experimental animals. Possible beneficial effects (e.g., reduction of serum lipids, increased bone mineral density, relief of hot flashes and other menopausal symptoms, mammary and prostate cancer chemoprevention) in humans have been attributed to consumption of isoflavones but evidence for potential adverse effects (e.g., stimulation of estrogen-dependent mammary tumors and aberrant perinatal development) has also been reported in experimental animal models. Bioavailability from appropriate food matrices and exposure during different life stages are both critical determinants of isoflavone effects. For these reasons, it is important tomore » compare isoflavone bioavailability in adults to that in fetal and neonatal animals for a more complete understanding of potential susceptibility issues. Studies of the major soy isoflavone genistein were conducted in pregnant and lactating Sprague-Dawley rats to quantify placental and lactational transfer to plasma and brain to understand better biological effects observed in multigenerational studies. In addition, studies were conducted with genistein in adult Balb/c mice to define absolute bioavailability from both gavage and soy protein isolate (SPI)-containing food. The information derived from these studies makes it possible to predict internal exposures of children to genistein from soy infant formula, which is manufactured using SPI.« less

Synergistic killing effect of chloroquine and androgen deprivation in LNCaP cells

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

Kaini, Ramesh R.; Hu, Chien-An A., E-mail: AHu@salud.unm.edu

2012-08-24

Highlights: Black-Right-Pointing-Pointer Chloroquine synergistically killed LNCaP cells during androgen deprivation treatment. Black-Right-Pointing-Pointer Chloroquine inhibited the function of autolysosomes and decreases the cytosolic ATP. Black-Right-Pointing-Pointer Chloroquine induced nuclear and DNA fragmentation in androgen deprived LNCaP. Black-Right-Pointing-Pointer Chloroquine may be an useful adjuvant in hormone ablation therapy in PCa patients. -- Abstract: Modulation of autophagy is a new paradigm in cancer therapeutics. Recently a novel function of chloroquine (CLQ) in inhibiting degradation of autophagic vesicles has been revealed, which raises the question whether CLQ can be used as an adjuvant in targeting autophagic pro-survival mechanism in prostate cancer (PCa). We previously showedmore » that autophagy played a protective role during hormone ablation therapy, in part, by consuming lipid droplets in PCa cells. In addition, blocking autophagy by genetic and pharmacological means in the presence of androgen deprivation caused cell death in PCa cells. To further investigate the importance of autophagy in PCa survival and dissect the role of CLQ in PCa death, we treated hormone responsive LNCaP cells with CLQ in combination with androgen deprivation. We observed that CLQ synergistically killed LNCaP cells during androgen deprivation in a dose- and time-dependent manner. We further confirmed that CLQ inhibited the maturation of autophagic vesicles and decreased the cytosolic ATP. Moreover, CLQ induced nuclear condensation and DNA fragmentation, a hallmark of apoptosis, in androgen deprived LNCaP cells. Taken together, our finding suggests that CLQ may be an useful adjuvant in hormone ablation therapy to improve the therapeutic efficacy.« less

Oligomeric proanthocyanidin complexes (OPC) exert anti-proliferative and pro-apoptotic effects on prostate cancer cells.

PubMed

Neuwirt, Hannes; Arias, Mercedes Cedeno; Puhr, Martin; Hobisch, Alfred; Culig, Zoran

2008-11-01

Oligomeric proanthocyanidin complexes (OPC) are extracted from grape seeds or maritime pine bark and have been used for enhancement of capillary stability and lymphatic drainage. Since a role for OPC in cancer prevention was postulated, we asked whether they have an effect on prostate cancer cells. Cell proliferation was determined by (3)H-thymidine assay and cell cycle status was analyzed on a flow cytometer. Expression of regulators of proliferation and apoptosis was determined by Western blot. We found that androgen-responsive cells LNCaP are more sensitive to OPC in terms of inhibition of proliferation in comparison to androgen receptor-negative PC3 or DU145 cells. Treatment with OPC resulted in a decrease in the percentage of LNCaP cells in the S phase and an increase in the percentage of cells in sub G1 phase. The anti-proliferative and pro-apoptotic effect of OPC in the LNCaP cell line was associated with down-regulation of expression of the androgen receptor. Interestingly, similar regulatory effects of OPC, such as inhibition of expression of cyclin-dependent kinases and cyclins and stimulation of tumor suppressors p21 and p27, were seen in LNCaP and PC3 cells. Favorable changes in the Bcl-2/Bax ratio were observed in LNCaP and PC3 cells after the treatment with OPC. OPC caused an increase of phosphorylated mitogen-activated protein kinase p44 and p42, thus suggesting induction of cellular differentiation. We conclude that OPC is a candidate that fulfills criteria for chemopreventive strategies in prostate cancer that might be established in following in vivo studies. (c) 2008 Wiley-Liss, Inc.

Isoflavones in soy flour diet have different effects on whole-genome expression patterns than purified isoflavone mix in human MCF-7 breast tumors in ovariectomized athymic nude mice.

PubMed

Liu, Yunxian; Hilakivi-Clarke, Leena; Zhang, Yukun; Wang, Xiao; Pan, Yuan-Xiang; Xuan, Jianhua; Fleck, Stefanie C; Doerge, Daniel R; Helferich, William G

2015-08-01

Soy flour diet (MS) prevented isoflavones from stimulating MCF-7 tumor growth in athymic nude mice, indicating that other bioactive compounds in soy can negate the estrogenic properties of isoflavones. The underlying signal transduction pathways to explain the protective effects of soy flour consumption were studied here. Ovariectomized athymic nude mice inoculated with MCF-7 human breast cancer cells were fed either Soy flour diet (MS) or purified isoflavone mix diet (MI), both with equivalent amounts of genistein. Positive controls received estradiol pellets and negative controls received sham pellets. GeneChip Human Genome U133 Plus 2.0 Array platform was used to evaluate gene expressions, and results were analyzed using bioinformatics approaches. Tumors in MS-fed mice exhibited higher expression of tumor growth suppressing genes ATP2A3 and BLNK and lower expression of oncogene MYC. Tumors in MI-fed mice expressed a higher level of oncogene MYB and a lower level of MHC-I and MHC-II, allowing tumor cells to escape immunosurveillance. MS-induced gene expression alterations were predictive of prolonged survival among estrogen-receptor-positive breast cancer patients, whilst MI-induced gene changes were predictive of shortened survival. Our findings suggest that dietary soy flour affects gene expression differently than purified isoflavones, which may explain why soy foods prevent isoflavones-induced stimulation of MCF-7 tumor growth in athymic nude mice. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

The isoflavone content of two new alfalfa-derived products for instant beverage preparation.

PubMed

Soto-Zarazúa, M Guadalupe; Rodrigues, Francisca; Pimentel, Filipa B; Bah, M M; Oliveira, M Beatriz P P

2016-01-01

The frequent use of plant-based products to promote health leads to the search for scientific information related to efficacy and safety of those products for human consumption. Two alfalfa-derived products (ADP), freeze-dried juice (FDJ) and dehydrated powder (DP), from alfalfa harvested in Mexico, are being developed as new possible nutraceuticals. To the best of our knowledge, any study reports the real composition of such products used to prepare instant beverages in what concerns isoflavone contents. Seven isoflavones (glycitein, formononetin, biochanin A, daidzein, genistein, daidzin and genistin) were assessed by HPLC-DAD analysis as well as its variation in five different batches of these products. Different solvents were tested in order to choose the best one to extract isoflavones. The results showed the presence of daidzein, genistein, genistin and daidzin in most samples while glycitein, formononetin and biochanin A were not detected. Significant differences between isoflavone contents were found with different solvent systems. Water was the best option to extract daidzein (0.40-1.08 mg per unit and 1.30-4.90 mg per unit for DP and FDJ, respectively) whereas the water-methanol-formic acid mixture was efficient to extract genistein (0.19-0.43 mg per unit and 0.15-0.72 mg per unit for DP and FDJ, respectively). In all cases, the total isoflavone content was higher in freeze-dried juices than in dehydrated powders. Genistein and daidzein were the more abundant isoflavones quantified. Further physiological and nutritional studies are needed to complete the validation of effectiveness and safety of these products.

Different effects of isoflavones on vascular function in premenopausal and postmenopausal smokers and nonsmokers: NYMPH study.

PubMed

Hoshida, Shiro; Miki, Takashi; Nakagawa, Takafumi; Shinoda, Yukinori; Inoshiro, Nobuaki; Terada, Katsuhiko; Adachi, Takayoshi

2011-11-01

Isoflavone intake has been associated with a reduction in the risk of cardiovascular disease in postmenopausal women. The aim of the present study was to determine if the effects of isoflavones on vascular function differ between premenopausal and postmenopausal women and between women who smoke and those who do not. Women smokers and nonsmokers who consumed 50 mg of isoflavone/day as black soybean tea for a period of 2 months (n = 55, mean age 39) were enrolled in the present study. We examined endothelial function, which was assessed by the percent change in flow-mediated dilation (%FMD) and arterial wall stiffness using the cardio-ankle vascular index (CAVI), as well as by biochemical parameters of the blood. Neither premenopausal (p = 0.697) nor postmenopausal (p = 0.389) smokers experienced an increase in %FMD after daily consumption of isoflavones. However, both premenopausal (p = 0.004) and postmenopausal (p = 0.019) nonsmokers exhibited a marked elevation in %FMD. By contrast, isoflavone intake effectively reduced CAVI among both premenopausal smokers (p = 0.027) and nonsmokers (p = 0.013), but had no effect on CAVI among postmenopausal smokers (p = 0.169) or nonsmokers (p = 0.128). The women smokers and nonsmokers did not differ in age or %FMD at the time of enrollment in the study. Thus, isoflavones have different effects on vascular endothelial function and arterial wall stiffness in premenopausal and postmenopausal smokers and nonsmokers.

Androgens and endometrium: New insights and new targets.

PubMed

Simitsidellis, Ioannis; Saunders, Philippa T K; Gibson, Douglas A

2018-04-15

Androgens are synthesised in both the ovary and adrenals in women and play an important role in the regulation of female fertility, as well as in the aetiology of disorders such as polycystic ovarian syndrome, endometriosis and endometrial cancer. The endometrium is an androgen target tissue and the impact of AR-mediated effects has been studied using human endometrial tissue samples and rodent models. In this review we highlight recent evidence that endometrial androgen biosynthesis and intracrine action is important in preparation of a tissue microenvironment that can support implantation and establishment of pregnancy. The impact of androgens on endometrial cell proliferation, in repair of the endometrial wound at the time of menstruation and in endometrial disorders is discussed. Future directions for research focused on AR function as a therapeutic target are considered. Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.

Effects of Isoflavone-Enriched Feed on the Rumen Microbiota in Dairy Cows

PubMed Central

Kasparovska, Jitka; Pecinkova, Martina; Dadakova, Katerina; Krizova, Ludmila; Hadrova, Sylvie; Lexa, Matej; Lochman, Jan; Kasparovsky, Tomas

2016-01-01

In this study, we compared the effects of two diets containing different isoflavone concentrations on the isoflavone transfer from feed into milk and on the rumen microbiota in lactating dairy cows. The on-farm experiment was conducted on twelve lactating Czech Fleckvieh x Holstein cows divided into two groups, each with similar mean milk yield. Twice daily, cows were individually fed a diet based on maize silage, meadow hay and supplemental mixture. Control group (CTRL) received the basal diet while the experimental group (EXP) received the basal diet supplemented with 40% soybean isoflavone extract. The average daily isoflavone intake in the EXP group (16 g/day) was twice as high as that in the CTRL group (8.4 g/day, P<0.001). Total isoflavone concentrations in milk from the CTRL and EXP groups were 96.89 and 276.07 μg/L, respectively (P<0.001). Equol concentrations in milk increased from 77.78 μg/L in the CTRL group to 186.30 μg/L in the EXP group (P<0.001). The V3-4 region of bacterial 16S rRNA genes was used for metagenomic analysis of the rumen microbiome. The experimental cows exhibited fewer OTUs at a distance level of 0.03 compared to control cows (P<0.05) and reduced microbial richness compared to control cows based on the calculated Inverse Simpson and Shannon indices. Non-metric multidimensional scaling analysis showed that the major contributor to separation between the experimental and control groups were changes in the representation of bacteria belonging to the phyla Bacteroidetes, Proteobacteria, Firmicutes, and Planctomycetes. Surprisingly, a statistically significant positive correlation was found only between isoflavones and the phyla Burkholderiales (r = 0.65, P<0.05) and unclassified Betaproteobacteria (r = 0.58, P<0.05). Previous mouse and human studies of isoflavone effects on the composition of gastrointestinal microbial populations generally report similar findings. PMID:27124615

Androgens affect muscle, motor neuron, and survival in a mouse model of SOD1-related amyotrophic lateral sclerosis.

PubMed

Aggarwal, Tanya; Polanco, Maria J; Scaramuzzino, Chiara; Rocchi, Anna; Milioto, Carmelo; Emionite, Laura; Ognio, Emanuela; Sambataro, Fabio; Galbiati, Mariarita; Poletti, Angelo; Pennuto, Maria

2014-08-01

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by selective loss of upper and lower motor neurons and skeletal muscle atrophy. Epidemiologic and experimental evidence suggest the involvement of androgens in ALS pathogenesis, but the mechanism through which androgens modify the ALS phenotype is unknown. Here, we show that androgen ablation by surgical castration extends survival and disease duration of a transgenic mouse model of ALS expressing mutant human SOD1 (hSOD1-G93A). Furthermore, long-term treatment of orchiectomized hSOD1-G93A mice with nandrolone decanoate (ND), an anabolic androgenic steroid, worsened disease manifestations. ND treatment induced muscle fiber hypertrophy but caused motor neuron death. ND negatively affected survival, thereby dissociating skeletal muscle pathology from life span in this ALS mouse model. Interestingly, orchiectomy decreased androgen receptor levels in the spinal cord and muscle, whereas ND treatment had the opposite effect. Notably, stimulation with ND promoted the recruitment of endogenous androgen receptor into biochemical complexes that were insoluble in sodium dodecyl sulfate, a finding consistent with protein aggregation. Overall, our results shed light on the role of androgens as modifiers of ALS pathogenesis via dysregulation of androgen receptor homeostasis. Copyright © 2014 Elsevier Inc. All rights reserved.

Inhibition of progression of androgen-dependent prostate LNCaP tumors to androgen independence in SCID mice by oral caffeine and voluntary exercise.

PubMed

Zheng, Xi; Cui, Xiao-Xing; Huang, Mou-Tuan; Liu, Yue; Wagner, George C; Lin, Yong; Shih, Weichung Joe; Lee, Mao-Jung; Yang, Chung S; Conney, Allan H

2012-01-01

The effect of oral caffeine or voluntary running wheel exercise (RW) alone or in combination on the progression of human androgen-dependent LNCaP prostate tumors to androgen independence in male severe combined immunodeficiency mice was determined. The mice were injected subcutaneously with LNCaP cells, and when the tumors reached a moderate size, the mice were surgically castrated and treated with caffeine (0.40 mg/ml drinking water) or RW alone or in combination for 42 days. We found that caffeine administration or RW inhibited the progression and growth of androgen-dependent LNCaP tumors to androgen independence, and a combination of the 2 regimens was more effective than the individual regimens alone. The ratios of the percent mitotic cells/caspase-3 positive cells in tumors from the caffeine-treated, RW-treated, or combination-treated mice were decreased by 34%, 38%, and 52%, respectively. Caffeine treatment increased the percentage of mitotic tumor cells undergoing apoptosis (lethal mitosis) whereas RW inhibited the increase in interleukin-6 that occurred during the progression of LNCaP tumors from androgen dependence to androgen independence. Our results indicate that oral administration of caffeine in combination with voluntary exercise may be an effective strategy for the prevention of prostate cancer progression from androgen dependence to androgen independence.

The physiological and pharmacological basis for the ergogenic effects of androgens in elite sports.

PubMed

Choong, Karen; Lakshman, Kishore M; Bhasin, Shalender

2008-05-01

Androgen doping in power sports is undeniably rampant worldwide. There is strong evidence that androgen administration in men increases skeletal muscle mass, maximal voluntary strength and muscle power. However, we do not have good experimental evidence to support the presumption that androgen administration improves physical function or athletic performance. Androgens do not increase specific force or whole body endurance measures. The anabolic effects of testosterone on the skeletal muscle are mediated through androgen receptor signaling. Testosterone promotes myogenic differentiation of multipotent mesenchymal stem cells and inhibits their differentiation into the adipogenic lineage. Testosterone binding to androgen receptor induces a conformational change in androgen receptor protein, causing it to associate with beta-catenin and TCF-4 and activate downstream Wnt target genes thus promoting myogenic differentiation. The adverse effects of androgens among athletes and recreational bodybuilders are under reported and include acne, deleterious changes in the cardiovascular risk factors, including a marked decrease in plasma high-density lipoproteins (HDL) cholesterol level, suppression of spermatogenesis resulting in infertility, increase in liver enzymes, hepatic neoplasms, mood and behavioral disturbances, and long term suppression of the endogenous hypothalamic-pituitary-gonadal axis. Androgens are often used in combination with other drugs which may have serious adverse events of their own. In spite of effective methods for detecting androgen doping, the policies for screening of athletes are highly variable in different countries and organizations and even existing policies are not uniformly enforced. 2008, Asian Journal of Andrology, SIMM and SJTU. All rights reserved.

Lepidium meyenii (Maca) does not exert direct androgenic activities.

PubMed

Bogani, P; Simonini, F; Iriti, M; Rossoni, M; Faoro, F; Poletti, A; Visioli, F

2006-04-06

Maca is the edible root of the Peruvian plant Lepidum meyenii, traditionally employed for its purported aphrodisiac and fertility-enhancing properties. This study aimed at testing the hypothesis that Maca contains testosterone-like compounds, able to bind the human androgen receptor and promote transcription pathways regulated by steroid hormone signaling. Maca extracts (obtained with different solvents: methanol, ethanol, hexane and chloroform) are not able to regulate GRE (glucocorticoid response element) activation. Further experiments are needed to assess which compound, of the several Maca's components, is responsible of the observed in vivo effects.

Effect of soy-based breakfast cereal on blood lipids and oxidized low-density lipoprotein.

PubMed

Jenkins, D J; Kendall, C W; Vidgen, E; Vuksan, V; Jackson, C J; Augustin, L S; Lee, B; Garsetti, M; Agarwal, S; Rao, A V; Cagampang, G B; Fulgoni, V

2000-11-01

Consumption of soy protein may reduce the risk of cardiovascular disease both through reduction in serum lipids and by the antioxidant properties of protein-associated soy isoflavones. However, the effect that processing required for the manufacture of breakfast cereals may have on the lipid lowering and antioxidant activities of soy has not been studied. We have therefore assessed the health benefits of soy incorporation into breakfast cereals. Twenty-five hyperlipidemic men and women took soy (providing 36 g/d soy protein and 168 mg/d isoflavones) and control breakfast cereals, each for 3 weeks in a randomized crossover study with a 2-week washout period between treatments. Fasting blood samples were obtained pretreatment and at weeks 2 and 3 of each treatment. No significant difference was seen in serum lipids between treatments at week 3 apart from a 3.8% +/- 1.5% higher apolipoprotein A-1 level on control versus soy (P = .021). However, oxidized low-density lipoprotein (LDL) was reduced on the test compared with the control both as total dienes in LDL and as the ratio of conjugated dienes to cholesterol in the LDL fraction by 9.2% +/- 4.3% (P = .042) and 8.7% +/- 4.2% (P = .050), respectively. High isoflavone intakes in soy breakfast cereals may decrease the risk of cardiovascular disease by reducing oxidized LDL, while having no significant effect on the absolute concentration of LDL cholesterol.

Effect of dihydrotestosterone on the expression of mucin 1 and the activity of Wnt signaling in mouse corneal epithelial cells.

PubMed

Qin, Li; Pei, Cheng; Kang, Qian-Yan; Liu, Zhao; Li, Li

2016-01-01

To explore the effects of the androgen dihydrotestosterone on the expression of mucin 1 (MUC1) and the activity of Wnt signaling in mouse corneal epithelial cells. Primary mouse corneal epithelial cells were isolated from the corneas of BALB/c mice. Quantitative real-time polymerase chain reaction, immunofluorescence and Western blot analysis were used to quantify the differential expression of selected genes. The androgen receptor was silenced by transfecting cells with androgen receptor shRNAs. TOP-Flash and FOP-flash reporter plasmids were used to measure β-catenin-driven transcription. Dihydrotestosterone treatment increased MUC1 expression and activated the Wnt signaling pathway and led to the translocation of β-catenin and upregulation of the Wnt downstream target gene TATA box binding protein and urokinase plasminogen activator. These effects were prevented by downregulating the androgen receptor. Androgens may protect against dry eye by regulating the expression of MUC1 which is stimulated by the activation of Wnt signaling via the androgen receptor. An understanding of the mechanisms associated with androgen-mediated protection against dry eye is an important step in developing new therapies for this disease.

Hypercholesterolemia in Male Power Lifters Using Anabolic-Androgenic Steroids.

ERIC Educational Resources Information Center

Cohen, Jonathan C.; And Others

1988-01-01

Measurement of serum cholesterol concentrations in male power lifters who used anabolic-androgenic steroids for eight weeks, three years, or eight years indicated that mean serum cholesterol levels increased with drug use, but decreased promptly to near pre-steroid levels after steroid use ended. (Author/CB)

Virilization caused by an ectopic adrenal tumor located behind the iliopsoas muscle.

PubMed

Mavroudis, Konstantinos; Aloumanis, Kyriakos; Papapetrou, Peter D; Voros, Dionisios; Spanos, Iraklis

2007-06-01

Virilization due to androgen-secreting neoplasms in women is a result of androgen overproduction from benign or malignant tumors that are found in the ovaries or rarely in the adrenal glands. Virilizing tumors that arise from ectopic adrenal tissue are extremely rare. We describe a very rare case of an ectopic androgen-producing adrenal tumor. Case report study. Endocrinology outpatient department of university-affiliated teaching hospital. A 45-year-old woman with symptoms of virilization of abrupt onset and rapid progression, with high serum androgen hormone levels and normal glucocorticoid secretion. Basal hormonal levels, stimulation and suppression tests, imaging techniques, and selective venous sampling. Localization and surgical removal of the source of androgen production. An ectopic mass was detected behind the left iliopsoas muscle. The patient was operated on and an oblong-shaped lesion, weighing 6 g, was removed. Histologically, the tissue was identified to be of adrenal origin. Postoperatively the androgen levels decreased to normal levels. This case illustrates difficulties in detecting and localizing the rare contingence of an ectopic adrenocortical androgen-secreting tumor.

Cardiac Nitric Oxide Synthases and Na⁺/K⁺-ATPase in the Rat Model of Polycystic Ovary Syndrome Induced by Dihydrotestosterone.

PubMed

Tepavčević, S; Milutinović, D V; Macut, D; Stanišić, J; Nikolić, M; Božić-Antić, I; Rodaljević, S; Bjekić-Macut, J; Matić, G; Korićanac, G

2015-05-01

Nitric oxide synthases (NOSs) and Na(+)/K(+)-ATPase are enzymes essential for regular functioning of the heart. Since both enzymes are under insulin and androgen regulation and since insulin action and androgen level were disturbed in polycystic ovary syndrome (PCOS), we hypothesized that cardiac nitric oxide (NO) production and sodium/potassium transport would be deteriorated in PCOS. To test our hypothesis we introduced animal model of PCOS based on dihydrotestosterone (DHT) treatment of female Wistar rats and analyzed protein expression, phosphorylation or subcellular localization of endothelial NOS (eNOS), inducible NOS (iNOS) and alpha subunits of Na(+)/K(+)-ATPase in the heart. Obtained results indicate that DHT treatment significantly decreased cardiac eNOS protein level and activating phosphorylation at serine 1,177, while inhibitory phosphorylation at threonine 495 was increased. In contrast to expression of eNOS, iNOS protein level in the heart of DHT-treated rats was significantly elevated. Furthermore, cardiac protein level of alpha 1 subunit of the ATPase, as well as its plasma membrane content, were decreased in rats with PCOS. In line with this, alpha 2 subunit protein level in fraction of plasma membranes was also significantly below control level. In conclusion, DHT treatment impaired effectiveness of NOSs and Na(+)/K(+)-ATPase in the female rat heart. Regarding the importance of NO production and sodium/potassium transport in the cardiac contraction and blood flow regulation, it implicates strong consequences of PCOS for heart functioning. © Georg Thieme Verlag KG Stuttgart · New York.

KDM1A triggers androgen-induced miRNA transcription via H3K4me2 demethylation and DNA oxidation.

PubMed

Yang, Shu; Zhang, Jiyuan; Zhang, Yalong; Wan, Xuechao; Zhang, Congzhe; Huang, Xiaohui; Huang, Wenhua; Pu, Honglei; Pei, Chaohan; Wu, Hai; Huang, Yan; Huang, Shengdong; Li, Yao

2015-06-15

Androgen receptor (AR) is a ligand dependent transcription factor that regulates the transcription of target genes. AR activity is closely involved in the maintenance and progression of prostate cancer. After the binding with androgen, AR moves into nucleus and binds to DNA sequence containing androgen response elements (ARE). Flavin-dependent monoamine oxidase KDM1A is necessary for AR driven transcription while the mechanism remains unclear. The association between androgen-dependent transcription and oxidation was tested through pharmaceutical inhibitions and siRNA knockdown of DNA oxidation repair components in prostate cancer cells. The recruitment of involved proteins and the histone methylation dynamics on ARE region was explored by chromatin immunoprecipitation (ChIP). Oxidation inhibition reduced AR dependent expression of KLK3, TMPRSS2, hsa-miR-125b2, and hsa-miR-133b. And such reduction could be restored by H2 O2 treatment. KDM1A recruitment and H3K4me2 demethylation on ARE regions, which produce H2 O2 , are associated with AR targets transcription. AR targets transcription and coupled oxidation recruit 8-oxoguanine-DNA glycosylase (OGG1) and the nuclease APEX1 to ARE regions. Such recruitment depends on KDM1A, and is necessary for AR targets transcription. Our work underlined the importance of histone demethylation and DNA oxidation/repairing machinery in androgen-dependent transcription. The present finds have implications for research into new druggable targets for prostate cancer relying on the cascade of AR activity regulation. © 2015 Wiley Periodicals, Inc.

Androgen responses to reproductive competition of males pursuing either fixed or plastic alternative reproductive tactics.

PubMed

von Kuerthy, Corinna; Ros, Albert F H; Taborsky, Michael

2016-11-15

Alternative reproductive tactics (ARTs), which can be plastic or fixed for life, may be characterized by distinct hormonal profiles. The relative plasticity hypothesis predicts flexible androgen regulation for adult males pursuing plastic tactics, but a less flexible regulation for males using a fixed tactic throughout life. Furthermore, androgen profiles may respond to changes in the social environment, as predicted by the social reciprocity models of hormone/behaviour interactions. The cichlid fish Lamprologus callipterus provides a rare opportunity to study the roles of androgens for male ARTs within a single species, because fixed and plastic ARTs coexist. We experimentally exposed males to competitors pursuing either the same or different tactics to test predictions of the relative plasticity and the social reciprocity models. Androgen profiles of different male types partly comply with predictions derived from the relative plasticity hypothesis: males of the plastic bourgeois/sneaker male trajectory showed different 11-ketotestosterone (11-KT) levels when pursuing either bourgeois or parasitic sneaker male behaviours. Surprisingly, males pursuing the fixed dwarf male tactic showed the highest free and conjugated 11-KT and testosterone (T) levels. Our experimental social challenges significantly affected the free 11-KT levels of bourgeois males, but the androgen responses did not differ between challenges involving different types of competitors. Furthermore, the free T-responses of the bourgeois males correlated with their aggressive behaviour exhibited against competitors. Our results provide new insights into the endocrine responsiveness of fixed and plastic ARTs, confirming and refuting some predictions of both the relative plasticity and the social reciprocity models. © 2016. Published by The Company of Biologists Ltd.

Alterations in ubiquitin ligase Siah-2 and its corepressor N-CoR after P-MAPA immunotherapy and anti-androgen therapy: new therapeutic opportunities for non-muscle invasive bladder cancer

PubMed Central

Garcia, Patrick Vianna; Apolinário, Letícia Montanholi; Böckelmann, Petra Karla; Nunes, Iseu da Silva; Duran, Nelson; Fávaro, Wagner José

2015-01-01

The present study describes the role of the ubiquitin ligase Siah-2 and corepressor N-CoR in controlling androgen receptor (AR) and estrogen receptors (ERα and ERβ) signaling in an appropriate animal model (Fischer 344 female rats) of non-muscle invasive bladder cancer (NMIBC), especially under conditions of anti-androgen therapy with flutamide. Furthermore, this study describes the mechanisms of a promising therapeutic alternative for NMIBC based on Protein aggregate magnesium-ammonium phospholinoleate-palmitoleate anhydride (P-MAPA) intravesical immunotherapy combined with flutamide, involving the interaction among steroid hormone receptors, their regulators and Toll-like receptors (TLRs). Our results demonstrated that increased Siah-2 and AR protein levels and decreased N-CoR, cytochrome P450 (CYP450) and estrogen receptors levels played a critical role in the urothelial carcinogenesis, probably leading to escape of urothelial cancer cells from immune system attack. P-MAPA immunotherapy led to distinct activation of innate immune system TLRs 2 and 4-mediated, resulting in increase of interferon signaling pathway, which was more effective in recovering the immunosuppressive tumor immune microenvironment and in recovering the bladder histology features than BCG (Bacillus Calmette-Guerin) treatments. The AR blockade therapy was important in the modulating of downstream molecules of TLR2 and TLR4 signaling pathway, decreasing the inflammatory cytokines signaling and enhancing the interferon signaling pathway when associated with P-MAPA. Taken together, the data obtained suggest that interferon signaling pathway activation and targeting AR and Siah-2 signals by P-MAPA intravesical immunotherapy alone and/ or in combination with AR blockade may provide novel therapeutic approaches for NMIBC. PMID:26191134

Alterations in ubiquitin ligase Siah-2 and its corepressor N-CoR after P-MAPA immunotherapy and anti-androgen therapy: new therapeutic opportunities for non-muscle invasive bladder cancer.

PubMed

Garcia, Patrick Vianna; Apolinário, Letícia Montanholi; Böckelmann, Petra Karla; da Silva Nunes, Iseu; Duran, Nelson; Fávaro, Wagner José

2015-01-01

The present study describes the role of the ubiquitin ligase Siah-2 and corepressor N-CoR in controlling androgen receptor (AR) and estrogen receptors (ERα and ERβ) signaling in an appropriate animal model (Fischer 344 female rats) of non-muscle invasive bladder cancer (NMIBC), especially under conditions of anti-androgen therapy with flutamide. Furthermore, this study describes the mechanisms of a promising therapeutic alternative for NMIBC based on Protein aggregate magnesium-ammonium phospholinoleate-palmitoleate anhydride (P-MAPA) intravesical immunotherapy combined with flutamide, involving the interaction among steroid hormone receptors, their regulators and Toll-like receptors (TLRs). Our results demonstrated that increased Siah-2 and AR protein levels and decreased N-CoR, cytochrome P450 (CYP450) and estrogen receptors levels played a critical role in the urothelial carcinogenesis, probably leading to escape of urothelial cancer cells from immune system attack. P-MAPA immunotherapy led to distinct activation of innate immune system TLRs 2 and 4-mediated, resulting in increase of interferon signaling pathway, which was more effective in recovering the immunosuppressive tumor immune microenvironment and in recovering the bladder histology features than BCG (Bacillus Calmette-Guerin) treatments. The AR blockade therapy was important in the modulating of downstream molecules of TLR2 and TLR4 signaling pathway, decreasing the inflammatory cytokines signaling and enhancing the interferon signaling pathway when associated with P-MAPA. Taken together, the data obtained suggest that interferon signaling pathway activation and targeting AR and Siah-2 signals by P-MAPA intravesical immunotherapy alone and/ or in combination with AR blockade may provide novel therapeutic approaches for NMIBC.

Developmental programming: gestational testosterone treatment alters fetal ovarian gene expression.

PubMed

Luense, Lacey J; Veiga-Lopez, Almudena; Padmanabhan, Vasantha; Christenson, Lane K

2011-12-01

Prenatal testosterone (T) treatment leads to polycystic ovarian morphology, enhanced follicular recruitment/depletion, and increased estradiol secretion. This study addresses whether expression of key ovarian genes and microRNA are altered by prenatal T excess and whether changes are mediated by androgenic or estrogenic actions of T. Pregnant Suffolk ewes were treated with T or T plus the androgen receptor antagonist, flutamide (T+F) from d 30 to 90 of gestation. Expression of steroidogenic enzymes, steroid/gonadotropin receptors, and key ovarian regulators were measured by RT-PCR using RNA obtained from fetal ovaries collected on d 65 [n = 4, 5, and 5 for T, T+F, and control groups, respectively] and d 90 (n = 5, 7, 4) of gestation. Additionally, fetal d 90 RNA were hybridized to multispecies microRNA microarrays. Prenatal T decreased (P < 0.05) Cyp11a1 expression (3.7-fold) in d 90 ovaries and increased Cyp19 (3.9-fold) and 5α-reductase (1.8-fold) expression in d 65 ovaries. Flutamide prevented the T-induced decrease in Cyp11a1 mRNA at d 90 but not the Cyp19 and 5α-reductase increase in d 65 ovaries. Cotreatment with T+F increased Cyp11a1 (3.0-fold) expression in d 65 ovaries, relative to control and T-treated ovaries. Prenatal T altered fetal ovarian microRNA expression, including miR-497 and miR-15b, members of the same family that have been implicated in insulin signaling. These studies demonstrate that maternal T treatment alters fetal ovarian steroidogenic gene and microRNA expression and implicate direct actions of estrogens in addition to androgens in the reprogramming of ovarian developmental trajectory leading up to adult reproductive pathologies.

Regulation of androgen receptor transactivity and mTOR-S6 kinase pathway by Rheb in prostate cancer cell proliferation.

PubMed

Kobayashi, Takashi; Shimizu, Yosuke; Terada, Naoki; Yamasaki, Toshinari; Nakamura, Eijiro; Toda, Yoshinobu; Nishiyama, Hiroyuki; Kamoto, Toshiyuki; Ogawa, Osamu; Inoue, Takahiro

2010-06-01

Ras homolog-enriched in brain (Rheb), a small GTP-binding protein, is associated with prostate carcinogenesis through activating mammalian target of rapamycin (mTOR) signaling pathway. This study aimed to elucidate whether Rheb promotes proliferation of prostate cancer cells and can act as a potent therapeutic target in prostate cancer. Prostate cancer cell lines and human prostatic tissues were examined for the expression of Rheb. The effects of forced expression or knockdown of Rheb on cell proliferation were also examined. Semi-quantitative and quantitative RT-PCR were performed to evaluate mRNA expression. Western blotting was used to examine protein expression. Cell count and WST-1 assay were used to measure cell proliferation. Fluorescence-activated cell sorting was used to assess the cell cycle. Rheb mRNA and protein expression was higher in more aggressive, androgen-independent prostate cancer cell lines PC3, DU145, and C4-2, compared with the less aggressive LNCaP. Rheb expression was higher in cancer tissues than in benign prostatic epithelia. Forced expression of Rheb in LNCaP cells accelerated proliferation without enhancing androgen receptor transactivity. Attenuation of Rheb expression or treatment with the mTOR inhibitor rapamycin decreased proliferation of PC3 and DU145 cells, with a decrease in the activated form of p70S6 kinase, one of the main targets of mTOR. Rheb potentiates proliferation of prostate cancer cells and inhibition of Rheb or mTOR can lead to suppressed proliferation of aggressive prostate cancer cell lines in vitro. Rheb and the mTOR pathway are therefore probable targets for suppressing prostate cancer.

Transcriptional role of androgen receptor in the expression of long non-coding RNA Sox2OT in neurogenesis

PubMed Central

Tosetti, Valentina; Sassone, Jenny; Ferri, Anna L. M.; Taiana, Michela; Bedini, Gloria; Nava, Sara; Brenna, Greta; Di Resta, Chiara; Pareyson, Davide; Di Giulio, Anna Maria; Carelli, Stephana

2017-01-01

The complex architecture of adult brain derives from tightly regulated migration and differentiation of precursor cells generated during embryonic neurogenesis. Changes at transcriptional level of genes that regulate migration and differentiation may lead to neurodevelopmental disorders. Androgen receptor (AR) is a transcription factor that is already expressed during early embryonic days. However, AR role in the regulation of gene expression at early embryonic stage is yet to be determinate. Long non-coding RNA (lncRNA) Sox2 overlapping transcript (Sox2OT) plays a crucial role in gene expression control during development but its transcriptional regulation is still to be clearly defined. Here, using Bicalutamide in order to pharmacologically inactivated AR, we investigated whether AR participates in the regulation of the transcription of the lncRNASox2OTat early embryonic stage. We identified a new DNA binding region upstream of Sox2 locus containing three androgen response elements (ARE), and found that AR binds such a sequence in embryonic neural stem cells and in mouse embryonic brain. Our data suggest that through this binding, AR can promote the RNA polymerase II dependent transcription of Sox2OT. Our findings also suggest that AR participates in embryonic neurogenesis through transcriptional control of the long non-coding RNA Sox2OT. PMID:28704421

Transcriptional role of androgen receptor in the expression of long non-coding RNA Sox2OT in neurogenesis.

PubMed

Tosetti, Valentina; Sassone, Jenny; Ferri, Anna L M; Taiana, Michela; Bedini, Gloria; Nava, Sara; Brenna, Greta; Di Resta, Chiara; Pareyson, Davide; Di Giulio, Anna Maria; Carelli, Stephana; Parati, Eugenio A; Gorio, Alfredo

2017-01-01

The complex architecture of adult brain derives from tightly regulated migration and differentiation of precursor cells generated during embryonic neurogenesis. Changes at transcriptional level of genes that regulate migration and differentiation may lead to neurodevelopmental disorders. Androgen receptor (AR) is a transcription factor that is already expressed during early embryonic days. However, AR role in the regulation of gene expression at early embryonic stage is yet to be determinate. Long non-coding RNA (lncRNA) Sox2 overlapping transcript (Sox2OT) plays a crucial role in gene expression control during development but its transcriptional regulation is still to be clearly defined. Here, using Bicalutamide in order to pharmacologically inactivated AR, we investigated whether AR participates in the regulation of the transcription of the lncRNASox2OTat early embryonic stage. We identified a new DNA binding region upstream of Sox2 locus containing three androgen response elements (ARE), and found that AR binds such a sequence in embryonic neural stem cells and in mouse embryonic brain. Our data suggest that through this binding, AR can promote the RNA polymerase II dependent transcription of Sox2OT. Our findings also suggest that AR participates in embryonic neurogenesis through transcriptional control of the long non-coding RNA Sox2OT.

Coregulation of srGAP1 by Wnt and Androgen Receptor Signaling: A New Target for Treatment of CRPC

DTIC Science & Technology

2015-10-01

Specific Aim 1: Test the... Specific Aim2: Test the hypothesis that down regulating srGAP1 in CRPC cells change phenotypic...direct interaction between AR and β-catenin seemed to elicit a specific expression of a set of target genes in low androgen conditions in CRPC.

Up-regulation of miR-146a contributes to the inhibition of invasion of pancreatic cancer cells

PubMed Central

Li, Yiwei; VandenBoom, Timothy G.; Wang, Zhiwei; Kong, Dejuan; Ali, Shadan; Philip, Philip A.; Sarkar, Fazlul H.

2009-01-01

Pancreatic cancer (PC) is an aggressive malignancy with high mortality and is believed to be in part due to its highly invasive and metastatic behavior, which is associated with over-expression of EGFR and activation of NF-κB. Emerging evidence also suggest critical roles of microRNAs (miRNAs) in the regulation of various pathobiological processes including metastasis in PC and in other human malignancies. In the present study, we found lower expression of miR-146a in PC cells compared to normal human pancreatic duct epithelial (HPDE) cells. Interestingly, re-expression of miR-146a inhibited the invasive capacity of Colo357 and Panc-1 PC cells with concomitant down-regulation of EGFR and IRAK-1. Mechanistic studies including miR-146a re-expression, anti-miR-146 transfection, and EGFR knock-down experiment showed that there was a crosstalk between EGFR, MTA-2, IRAK-1, IκBα and NF-κB. Most importantly, we found that the treatment of PC cells with “natural agents” [3,3′-diinodolylmethane (DIM) or isoflavone] led to an increase in the expression of miR-146a and consequently down-regulated the expression of EGFR, MTA-2, IRAK-1 and NF-κB, resulting in the inhibition of invasion of Colo357 and Panc-1 cells. These results provide experimental evidence in support of the role of DIM and isoflavone as potential non-toxic agents as regulators of miRNA, which could be useful for the inhibition of cancer cell invasion and metastasis, and further suggesting that these agents could be important for designing novel targeted strategy for the treatment of PC. PMID:25242818

Androgen-induced programs for prostate epithelial growth and invasion arise in embryogenesis and are reactivated in cancer

PubMed Central

Schaeffer, EM; Marchionni, L; Huang, Z; Simons, B; Blackman, A; Yu, W; Parmigiani, G; Berman, DM

2008-01-01

Cancer cells differentiate along specific lineages that largely determine their clinical and biologic behavior. Distinct cancer phenotypes from different cells and organs likely result from unique gene expression repertoires established in the embryo and maintained after malignant transformation. We used comprehensive gene expression analysis to examine this concept in the prostate, an organ with a tractable developmental program and a high propensity for cancer. We focused on gene expression in the murine prostate rudiment at three time points during the first 48 h of exposure to androgen, which initiates proliferation and invasion of prostate epithelial buds into surrounding urogenital sinus mesenchyme. Here, we show that androgen exposure regulates genes previously implicated in prostate carcinogenesis comprising pathways for the phosphatase and tensin homolog (PTEN), fibroblast growth factor (FGF)/mitogen-activated protein kinase (MAPK), and Wnt signaling along with cellular programs regulating such ‘hallmarks’ of cancer as angiogenesis, apoptosis, migration and proliferation. We found statistically significant evidence for novel androgeninduced gene regulation events that establish and/or maintain prostate cell fate. These include modulation of gene expression through microRNAs, expression of specific transcription factors, and regulation of their predicted targets. By querying public gene expression databases from other tissues, we found that rather than generally characterizing androgen exposure or epithelial budding, the early prostate development program more closely resembles the program for human prostate cancer. Most importantly, early androgen-regulated genes and functional themes associated with prostate development were highly enriched in contrasts between increasingly lethal forms of prostate cancer, confirming a ‘reactivation’ of embryonic pathways for proliferation and invasion in prostate cancer progression. Among the genes with the most significant links to the development and cancer, we highlight coordinate induction of the transcription factor Sox9 and suppression of the proapoptotic phospholipid-binding protein Annexin A1 that link early prostate development to early prostate carcinogenesis. These results credential early prostate development as a reliable and valid model system for the investigation of genes and pathways that drive prostate cancer. PMID:18794802

Androgen and AR contribute to breast cancer development and metastasis: an insight of mechanisms.

PubMed

Feng, J; Li, L; Zhang, N; Liu, J; Zhang, L; Gao, H; Wang, G; Li, Y; Zhang, Y; Li, X; Liu, D; Lu, J; Huang, B

2017-05-18

The role of androgen and androgen receptor (AR) in breast carcinogenesis has long been a disputed issue. This report provides a mechanistic insight into how androgen and AR contributes to invasion and metastasis of breast cancer. We find that dihydrotestosterone (DHT) is able to induce the epithelial-to-mesenchymal transition in breast cancer cells in an AR-dependent/estrogen receptor-independent manner. This process is dependent on the demethylation activity of lysine-specific demethylase 1A (LSD1) by epigenetically regulating the target genes E-cadherin and vimentin. In vivo, DHT promotes metastasis in a nude mouse model, and AR and LSD1 are indispensable in this process. We establish that higher expression of nucleus AR to cytoplasm AR associated with worse prognostic outcomes in breast cancer patient samples. This study maps an 'androgen-AR/LSD1-target genes' pathway in breast carcinogenesis, implicating the importance of hormonal balance in women, and the potential clinical significance of serum androgen and AR in prediction of breast cancer and selection of breast cancer therapy.

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 food and isoflavone intake and colorectal cancer risk: the Fukuoka Colorectal Cancer Study.

PubMed

Budhathoki, Sanjeev; Joshi, Amit Man; Ohnaka, Keizo; Yin, Guang; Toyomura, Kengo; Kono, Suminori; Mibu, Ryuichi; Tanaka, Masao; Kakeji, Yoshihiro; Maehara, Yoshihiko; Okamura, Takeshi; Ikejiri, Koji; Futami, Kitaroh; Maekawa, Takafumi; Yasunami, Yohichi; Takenaka, Kenji; Ichimiya, Hitoshi; Terasaka, Reiji

2011-02-01

It has been suggested that soy food and isoflavone intake may be protective against the risk of colorectal cancer. However, epidemiologic evidence remains sparse and inconsistent. We addressed this issue in the Fukuoka Colorectal Cancer Study. The study subjects were the 816 incident cases of histologically confirmed colorectal cancer and 815 community controls. Intakes of soy foods and isoflavones were assessed by in-person interview using a computer-assisted dietary method. Logistic regression analysis was applied to estimate odds ratio (OR) and 95% confidence interval (CI) of colorectal cancer with adjustment for dietary intakes of calcium and n-3 polyunsaturated fatty acids as well as for body mass index, physical activity, alcohol use, and other lifestyle factors. Energy-adjusted intakes of soy foods (dry weight) and isoflavones were inversely associated with colorectal cancer risk in men and postmenopausal women, but not in premenopausal women. The multivariate-adjusted OR for the highest versus lowest quintile was 0.65 (95% CI 0.41-1.03, p for trend = 0.03) for soy foods and 0.68 (95% CI 0.42-1.10, p for trend = 0.051) for isoflavones in men. The corresponding values for postmenopausal women were 0.60 (95% CI 0.29-1.25, p for trend = 0.053) and 0.68 (95% CI 0.33-1.40, p for trend = 0.049). The site-specific analysis showed inverse associations of soy foods (p for trend = 0.007) and isoflavones (p for trend = 0.02) with rectal cancer in men. The findings add to epidemiologic evidence for protective effects of soy foods and isoflavones in colorectal carcinogenesis.

Isoflavone Malonyltransferases GmIMaT1 and GmIMaT3 Differently Modify Isoflavone Glucosides in Soybean (Glycine max) under Various Stresses

PubMed Central

Ahmad, Muhammad Z.; Li, Penghui; Wang, Junjie; Rehman, Naveed Ur; Zhao, Jian

2017-01-01

Malonylated isoflavones are the major forms of isoflavonoids in soybean plants, the genes responsible for their biosyntheses are not well understood, nor their physiological functions. Here we report a new benzylalcohol O-acetyltransferase, anthocyanin O-hydroxycinnamoyltransferase, anthranilate N-hydroxycinnamoyl/benzoyltransferase, deacetylvindoline 4-O-acetyltransferase (BAHD) family isoflavone glucoside malonyltransferase GmIMaT1, and GmIMaT3, which is allelic to the previously characterized GmMT7 and GmIF7MaT. Biochemical studies showed that recombinant GmIMaT1 and GmIMaT3 enzymes used malonyl-CoA and several isoflavone 7-O-glucosides as substrates. The Km values of GmIMaT1 for glycitin, genistin, and daidzin were 13.11, 23.04, and 36.28 μM, respectively, while these of GmIMaT3 were 12.94, 26.67, and 30.12 μM, respectively. Transgenic hairy roots overexpressing both GmIMaTs had increased levels of malonyldaidzin and malonylgenistin, and contents of daidzin and glycitin increased only in GmIMaT1-overexpression lines. The increased daidzein and genistein contents were detected only in GmIMaT3-overexpression lines. Knockdown of GmIMaT1 and GmIMaT3 reduced malonyldaidzin and malonylgenistin contents, and affected other isoflavonoids differently. GmIMaT1 is primarily localized to the endoplasmic reticulum while GmIMaT3 is primarily in the cytosol. By examining their transcript changes corresponding to the altered isoflavone metabolic profiles under various environmental and hormonal stresses, we probed the possible functions of GmIMaTs. Two GmIMaTs displayed distinct tissue expression patterns and respond differently to various factors in modifying isoflavone 7-O-glucosides under various stresses. PMID:28559900

Daidzein and genistein content of fruits and nuts.

PubMed

Liggins, J; Bluck, L J; Runswick, S; Atkinson, C; Coward, W A; Bingham, S A

2000-06-01

Dietary phytoestrogens such as the isoflavones daidzein and genistein are thought to protect against chronic diseases that are common in Western societies, such as cancer, osteoporosis, and ischemic heart disease. In addition, there are concerns regarding the deleterious effects of hormone-like compounds, especially with respect to the development of infants. However, there is little information regarding the phytoestrogen content of foods, and therefore epidemiologic investigations of phytoestrogens are limited. As part of a study quantifying the consumption of phytoestrogens, the objective of this work was to assess the daidzein and genistein content of fruits and nuts commonly eaten in Europe. Eighty different fruits and nuts were sampled, prepared for eating, and freeze-dried. Daidzein and genistein were extracted from the dried foods, and the two isoflavones were quantified after hydrolytic removal of any conjugated carbohydrate. Completeness of extraction and any procedural losses of the isoflavones were accounted for using synthetic daidzin (7-O-glucosyl-4'-hydroxyisoflavone) and genistin (7-O-glucosyl-4'5-dihydroxyisoflavone) as internal standards. Of the 80 foods assayed, 43 contained no detectable daidzein or genistein, at a limit of quantification of 1 microg/kg dry weight of food. Nine foods contained more than 100 microg of the two isoflavones combined per kilogram wet weight, and 28 contained less than this amount. Currants and raisins were the richest sources of the isoflavones, containing 2,250 microg and 1,840 microg of the two isoflavones combined per kilogram of wet weight of food. Although fruits and nuts are not as rich in isoflavone phytoestrogens as are soy and other legumes, this is the first documentation of levels of daidzein and genistein occurring in these foods.

Effect of oral isoflavone supplementation on vascular endothelial function in postmenopausal women: a meta-analysis of randomized placebo-controlled trials.

PubMed

Li, Shao-Hua; Liu, Xu-Xia; Bai, Yong-Yi; Wang, Xiao-Jian; Sun, Kai; Chen, Jing-Zhou; Hui, Ru-Tai

2010-02-01

The effect of isoflavone on endothelial function in postmenopausal women is controversial. The objective of this study was to evaluate the effect of oral isoflavone supplementation on endothelial function, as measured by flow-mediated dilation (FMD), in postmenopausal women. A meta-analysis of randomized placebo-controlled trials was conducted to evaluate the effect of oral isoflavone supplementation on endothelial function in postmenopausal women. Trials were searched in PubMed, Embase, the Cochrane Library database, and reviews and reference lists of relevant articles. Summary estimates of weighted mean differences (WMDs) and 95% CIs were obtained by using random-effects models. Meta-regression and subgroup analyses were performed to identify the source of heterogeneity. A total of 9 trials were reviewed in the present meta-analysis. Overall, the results of the 9 trials showed that isoflavone significantly increased FMD (WMD: 1.75%; 95% CI: 0.83%, 2.67%; P = 0.0002). Meta-regression analysis indicated that the age-adjusted baseline FMD was inversely related to effect size. Subgroup analysis showed that oral supplementation of isoflavone had no influence on FMD if the age-adjusted baseline FMD was > or = 5.2% (4 trials; WMD: 0.24%; 95% CI: -0.94%, 1.42%; P = 0.69). This improvement seemed to be significant when the age-adjusted baseline FMD levels were <5.2% (5 trials; WMD: 2.22%; 95% CI: 1.15%, 3.30%; P < 0.0001), although significant heterogeneity was still detected in this low-baseline-FMD subgroup. Oral isoflavone supplementation does not improve endothelial function in postmenopausal women with high baseline FMD levels but leads to significant improvement in women with low baseline FMD levels.

Antagonism of Human Formyl Peptide Receptor 1 (FPR1) by Chromones and Related Isoflavones

PubMed Central

Schepetkin, Igor A.; Kirpotina, Liliya N.; Khlebnikov, Andrei I.; Cheng, Ni; Ye, Richard D.; Quinn, Mark T.

2014-01-01

Formyl peptide receptors (FPRs) are G protein-coupled receptors (GPCRs) expressed on a variety of cell types. Because FPRs play an important role in the regulation of inflammatory reactions implicated in disease pathogenesis, FPR antagonists may represent novel therapeutics for modulating innate immunity. Previously, 4H-chromones were reported to be potent and competitive FPR1 antagonists. In the present studies, 96 additional chromone analogs, including related synthetic and natural isoflavones were evaluated for FPR1 antagonist activity. We identified a number of novel competitive FPR1 antagonists that inhibited fMLF-induced intracellular Ca2+ mobilization in FPR1-HL60 cells and effectively competed with WKYMVm-FITC for binding to FPR1 in FPR1-HL60 and FPR1-RBL cells. Compound 10 (6-hexyl-2-methyl-3-(1-methyl-1H-benzimidazol-2-yl)-4-oxo-4H-chromen-7-yl acetate) was found to be the most potent FPR1-specific antagonist, with binding affinity Ki~100 nM. These chromones inhibited Ca2+ flux and chemotaxis in human neutrophils with nanomolar-micromolar IC50 values. In addition, the most potent novel FPR1 antagonists inhibited fMLF-induced phosphorylation of extracellular signal-regulated kinases (ERK1/2) in FPR1-RBL cells. These antagonists were specific for FPR1 and did not inhibit WKYMVM/WKYMVm-induced intracellular Ca2+ mobilization in FPR2-HL60 cells, FPR3-HL60 cells, RBL cells transfected with murine Fpr1, or interleukin 8-induced Ca2+ flux in human neutrophils and RBL cells transfected with CXC chemokine receptor 1 (CXCR1). Moreover, pharmacophore modeling showed that the active chromones had a significantly higher degree of similarity with the pharmacophore template as compared to inactive analogs. Thus, the chromone/isoflavone scaffold represents a relevant backbone for development of novel FPR1 antagonists. PMID:25450672

Probiotic Beverage with Soy Isoflavone Consumption for Breast Cancer Prevention: A Case-control Study

PubMed Central

Toi, Masakazu; Hirota, Saya; Tomotaki, Ai; Sato, Nobuaki; Hozumi, Yasuo; Anan, Keisei; Nagashima, Takeshi; Tokuda, Yutaka; Masuda, Norikazu; Ohsumi, Shozo; Ohno, Shinji; Takahashi, Masato; Hayashi, Hironori; Yamamoto, Seiichiro; Ohashi, Yasuo

2013-01-01

The purpose of this study is to evaluate how beverages containing Lactobacillus casei Shirota (BLS) and soy isoflavone consumption since adolescence affected the incidence of breast cancer. In a population-based case-control study, three hundred and six cases with breast cancer and 662 controls aged 40 to 55 were matched for age and residential area and included in the analyses. Diet, lifestyle and other breast cancer risk factors were investigated using the self-administered questionnaire and interview. Odds ratios (ORs) of BLS and soy isoflavone consumption for breast cancer incidence were independently and jointly estimated using a conditional logistic regression. The ORs of BLS consumption (≥ four times a week against < four times a week) was 0.65 and statistically significant (p = 0.048). The analysis of association between soy consumption and breast cancer incidence showed the more the isoflavone consumption is, the lower the odds of breast cancer becomes. Adjusted ORs for breast cancer in the second, the third and the fourth quartiles of soy consumption against the first quartile were 0.76, 0.53 and 0.48, respectively (trend test, p = 0.0002). The BLS-isoflavone interaction was not statistically significant; however, a biological interaction was suggested. Regular consumption of BLS and isoflavones since adolescence was inversely associated with the incidence of breast cancer in Japanese women. PMID:23966890

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

Producing chicken eggs containing isoflavone as functional food due to feeding effect of soy sauce by-product

NASA Astrophysics Data System (ADS)

Mahfudz, L. D.; Sarjana, T. A.; Muryani, R.; Suthama, N.

2018-01-01

The present study was aimed to verify the impact of feeding soy sauce by-product in producing isoflavone-enriched chicken eggs as functional food. Experiment used 200 laying hens of 80-week old with average body weight of 1,932.75±189.50 g. Experimental diets were formulated using yellow corn, rice bran, soybean meal, fish meal, meat bone meal, poultry meal, premix, CaCO3, and soy sauce by-product (SSBP). A completely randomized design with 4 treatments and 5 replication (10 birds each), was assigned in this experiment. Inclusion levels of SSBP were the treatments, namely, none (T0), 10 (T1), 12.5 (T2), and 15.0% (T3). Parameters observed were colour, index, and weight of egg yolk, and isoflavone content. Analysis of variance was applied and continued to Duncan test at 5% probability. Results indicated that yolk colour index and weight were not affected by the treatments, but isoflavone content was significantly (P<0.05) increased by feeding SSBP. Egg yolk isoflavone in T2 (0.41 mg/g) and T3 (0.47 mg/g) were higher than those in T0 (0.31 mg/g) and T1 (0.35 mg/g). In conclusion, dietary inclusion of soy sauce by-product at higher level (12.5 and 15.0%) can produce isoflavone-enriched eggs as functional food.

Intratumoral conversion of adrenal androgen precursors drives androgen receptor-activated cell growth in prostate cancer more potently than de novo steroidogenesis.

PubMed

Kumagai, Jinpei; Hofland, Johannes; Erkens-Schulze, Sigrun; Dits, Natasja F J; Steenbergen, Jacobie; Jenster, Guido; Homma, Yukio; de Jong, Frank H; van Weerden, Wytske M

2013-11-01

Despite an initial response to hormonal therapy, patients with advanced prostate cancer (PC) almost always progress to castration-resistant disease (CRPC). Although serum testosterone (T) is reduced by androgen deprivation therapy, intratumoral T levels in CRPC are comparable to those in prostate tissue of eugonadal men. These levels could originate from intratumoral conversion of adrenal androgens and/or from de novo steroid synthesis. However, the relative contribution of de novo steroidogenesis to AR-driven cell growth is unknown. The relative contribution of androgen biosynthetic pathways to activate androgen receptor (AR)-regulated cell growth and expression of PSA, FKBP5, and TMPRSS2 was studied at physiologically relevant levels of adrenal androgen precursors and intermediates of de novo androgen biosynthesis in human prostate cancer cell lines, PC346C, VCaP, and LNCaP. In PC346C and VCaP, responses to pregnenolone and progesterone were absent or minimal, while large effects of adrenal androgen precursors were found. VCaP CRPC clones overexpressing CYP17A1 did not acquire an increased ability to use pregnenolone or progesterone to activate AR. In contrast, all precursors stimulated growth and gene expression in LNCaP cells, presumably resulting from the mutated AR in these cells. Our data indicate that at physiological levels of T precursors PC cells can generally convert adrenal androgens, while de novo steroidogenesis is not generally possible in PC cells and is not able to support AR transactivation and PC growth. © 2013 Wiley Periodicals, Inc.

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

miR-146a Suppresses Invasion of Pancreatic Cancer Cells

PubMed Central

Li, Yiwei; VandenBoom, Timothy G.; Wang, Zhiwei; Kong, Dejuan; Ali, Shadan; Philip, Philip A.; Sarkar, Fazlul H.

2010-01-01

The aggressive course of pancreatic cancer is believed to reflect its unusually invasive and metastatic nature, which is associated with epidermal growth factor receptor (EGFR) overexpression and NF-κB activation. MicroRNAs (miRNA) have been implicated in the regulation of various pathobiological processes in cancer, including metastasis in pancreatic cancer and in other human malignancies. In this study, we report lower expression of miR-146a in pancreatic cancer cells compared with normal human pancreatic duct epithelial cells. Reexpression of miR-146a inhibited the invasive capacity of pancreatic cancer cells with concomitant downregulation of EGFR and the NF-κB regulatory kinase interleukin 1 receptor–associated kinase 1 (IRAK-1). Cellular mechanism studies revealed crosstalk between EGFR, IRAK-1, IκBα, NF-κB, and MTA-2, a transcription factor that regulates metastasis. Treatment of pancreatic cancer cells with the natural products 3,3′-diinodolylmethane (DIM) or isoflavone, which increased miR-146a expression, caused a downregulation of EGFR, MTA-2, IRAK-1, and NF-κB, resulting in an inhibition of pancreatic cancer cell invasion. Our findings reveal DIM and isoflavone as nontoxic activators of a miRNA that can block pancreatic cancer cell invasion and metastasis, offering starting points to design novel anticancer agents. PMID:20124483

Reciprocal feedback regulation of PI3K and androgen receptor signaling in PTEN-deficient prostate cancer

PubMed Central

Carver, Brett S; Chapinski, Caren; Wongvipat, John; Hieronymus, Haley; Chen, Yu; Chandarlapaty, Sarat; Arora, Vivek K; Le, Carl; Koutcher, Jason; Scher, Howard; Scardino, Peter T; Rosen, Neal; Sawyers, Charles L

2011-01-01

Summary Prostate cancer is characterized by its dependence on androgen receptor and frequent activation of PI3K signaling. We find that AR transcriptional output is decreased in human and murine tumors with PTEN deletion and that PI3K pathway inhibition activates AR signaling by relieving feedback inhibition of HER kinases. Similarly, AR inhibition activates AKT signaling by reducing levels of the AKT phosphatase PHLPP. Thus, these two oncogenic pathways cross-regulate each other by reciprocal feedback. Inhibition of one activates the other, thereby maintaining tumor cell survival. However, combined pharmacologic inhibition of PI3K and AR signaling caused near complete prostate cancer regressions in a Pten-deficient murine prostate cancer model and in human prostate cancer xenografts, indicating that both pathways coordinately support survival. Significance The two most frequently activated signaling pathways in prostate cancer are driven by AR and PI3K. Inhibitors of the PI3K pathway are in early clinical trials and AR inhibitors confer clinical responses in most patients. However, these inhibitors rarely induce tumor regression in preclinical models. Here we show that these pathways regulate each other by reciprocal negative feedback, such that inhibition of one activates the other. Therefore, tumor cells can adapt and survive when either single pathway is inhibited pharmacologically. Our demonstration of profound tumor regressions with combined pathway inhibition in preclinical prostate tumor models provides rationale for combination therapy in patients. PMID:21575859

Comparison between testosterone oenanthate-induced azoospermia and oligozoospermia in a male contraceptive study. IV. Suppression of endogenous testicular and adrenal androgens.

PubMed

Anderson, R A; Wallace, A M; Kicman, A T; Wu, F C

1997-08-01

Administration of supraphysiological doses of testosterone to normal men causes inhibition of spermatogenesis, but while most become azoospermic, 30-55% maintain a low rate of spermatogenesis. We have investigated whether there are differences in endogenous androgen production, of testicular and adrenal origin, which may be related to the degree of suppression of spermatogenesis. Thirty-three healthy Caucasian men were given weekly i.m. injections of 200 mg testosterone oenanthate (TE), 18 became azoospermic, while 15 remained oligozoospermic. Urinary excretion of epitestosterone, a specific testicular product, was reduced to <10% of pretreatment values, with no differences between the groups. Similar results were obtained for other markers of testicular steroidogenesis. Urinary and plasma adrenal androgens were also reduced during TE treatment: a statistically significant decrease in both (P < 0.001 and P < 0.05 respectively) was seen in the azoospermic but not oligozoospermic responders. These results suggest that testicular steroidogenesis is decreased to <10% by the administration of supraphysiological doses of exogenous testosterone. Differences in the degree of ongoing steroidogenesis in the testis do not appear to account for incomplete suppression of spermatogenesis, thus differences in androgen metabolism may underlie this heterogeneous response. A small but significant reduction in secretion of adrenal androgens was also detectable, the relevance of which is unclear.

Roles of leptin, adiponectin and resistin in the transcriptional regulation of steroidogenic genes contributing to decreased Leydig cells function in obesity.

PubMed

Roumaud, Pauline; Martin, Luc J

2015-10-01

The increase in obesity rate is a major public health issue associated with increased pathological conditions such as type 2 diabetes or cardiovascular diseases. Obesity also contributes to decreased testosterone levels in men. Indeed, the adipose tissue is an endocrine organ which produces hormones such as leptin, adiponectin and resistin. Obesity results in pathological accumulations of leptin and resistin, whereas adiponectin plasma levels are markedly reduced, all having a negative impact on testosterone synthesis. This review focuses on current knowledge related to transcriptional regulation of Leydig cells' steroidogenesis by leptin, adiponectin and resistin. We show that there are crosstalks between the regulatory mechanisms of these hormones and androgen production which may result in a dramatic negative influence on testosterone plasma levels. Indeed leptin, adiponectin and resistin can impact expression of different steroidogenic genes such as Star, Cyp11a1 or Sf1. Further investigations will be required to better define the implications of adipose derived hormones on regulation of steroidogenic genes expression within Leydig cells under physiological as well as pathological conditions.

Antiandrogenic mechanisms of pesticides in human LNCaP prostate and H295R adrenocortical carcinoma cells.

PubMed

Robitaille, Christina N; Rivest, Patricia; Sanderson, J Thomas

2015-01-01

Several pesticides suspected or known to have endocrine disrupting effects were screened for pro- or antiandrogenic properties by determining their effects on proliferation, prostatic-specific antigen (PSA) secretion and androgen receptor (AR) expression, and AR phosphorylation in androgen-dependent LNCaP human prostate cancer cells, as well as on the expression and catalytic activity of the enzyme CYP17 in H295R human adrenocortical carcinoma cells, an in vitro model of steroidogenesis. Effects on SRD5A gene expression were determined in both cell lines. Benomyl, vinclozolin, and prochloraz, but not atrazine, concentration dependently (1-30 μM) decreased dihydrotestosterone (DHT)-stimulated proliferation of LNCaP cells. All pesticides except atrazine decreased DHT-stimulated PSA secretion, AR nuclear accumulation, and AR phosphorylation on serines 81 and 213 in LNCaP cells. Benomyl and prochloraz, but not vinclozolin or atrazine, decreased levels of CYP17 gene and protein expression, as well as catalytic activity in H295R cells. In the case of prochloraz, some of these effects corresponded with cytotoxicity. H295R cells expressed AR protein and SRD5A1, but not SRD5A2 transcripts. SRD5A1 gene expression in H295R cells was increased by 10 nM DHT, whereas in LNCaP cells significant induction was observed by 0.1 nM DHT. AR protein expression in H295R cells was not increased by DHT. Vinclozolin decreased DHT-induced SRD5A1 gene expression in LNCaP, but not H295R cells, indicating a functional difference of AR between the cell lines. In conclusion, pesticides may exert antiandrogenic effects through several mechanisms that are cell type-specific, including AR antagonism and down-regulation or catalytic inhibition of androgen biosynthetic enzymes, such as CYP17 and SRD5A1. © The Author 2014. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Prepubertal Development of Gonadotropin-Releasing Hormone Neuron Activity Is Altered by Sex, Age, and Prenatal Androgen Exposure.

PubMed

Dulka, Eden A; Moenter, Suzanne M

2017-11-01

Gonadotropin-releasing hormone (GnRH) neurons regulate reproduction though pulsatile hormone release. Disruption of GnRH release as measured via luteinizing hormone (LH) pulses occurs in polycystic ovary syndrome (PCOS), and in young hyperandrogenemic girls. In adult prenatally androgenized (PNA) mice, which exhibit many aspects of PCOS, increased LH is associated with increased GnRH neuron action potential firing. How GnRH neuron activity develops over the prepubertal period and whether this is altered by sex or prenatal androgen treatment are unknown. We hypothesized GnRH neurons are active before puberty and that this activity is sexually differentiated and altered by PNA. Dams were injected with dihydrotestosterone (DHT) on days 16 to 18 post copulation to generate PNA mice. Action potential firing of GFP-identified GnRH neurons in brain slices from 1-, 2-, 3-, and 4-week-old and adult mice was monitored. GnRH neurons were active at all ages tested. In control females, activity increased with age through 3 weeks, then decreased to adult levels. In contrast, activity did not change in PNA females and was reduced at 3 weeks. Activity was higher in control females than males from 2 to 3 weeks. PNA did not affect GnRH neuron firing rate in males at any age. Short-term action potential patterns were also affected by age and PNA treatment. GnRH neurons are thus typically more active during the prepubertal period than adulthood, and PNA reduces prepubertal activity in females. Prepubertal activity may play a role in establishing sexually differentiated neuronal networks upstream of GnRH neurons; androgen-induced changes during this time may contribute to the adult PNA, and possibly PCOS, phenotype. Copyright © 2017 Endocrine Society.

Formononetin inhibits human bladder cancer cell proliferation and invasiveness via regulation of miR-21 and PTEN.

PubMed

Wu, Yiying; Zhang, Xing; Li, Zhengzhao; Yan, Haibiao; Qin, Jian; Li, Tianyu

2017-03-22

The isoflavone formononetin is the main active component of Astragalus membranaceus and possesses anti-tumorigenic properties. However, the role of formononetin in human bladder cancer (BCa) has not been fully elucidated. The aim of the present study was to investigate the anti-tumor effects of formononetin on BCa cells and its potential molecular mechanism. T24 cells were treated with different concentrations of formononetin, and then the cell proliferation was assessed by MTT assay, cell apoptosis by Hoechst 33258 stain assay, cell invasiveness by transwell invasion assay, microRNA-21 (miR-21) expression by real-time PCR and the protein level of phosphatase and tensin homolog (PTEN) and phosphorylated homolog of Akt (p-Akt) by western blotting. The results showed that formononetin significantly inhibited the proliferation of T24 cells in a time- and dose-dependent manner. T24 cells treated with formononetin displayed obvious morphological changes of apoptosis and lower invasiveness. In addition, miR-21 expression was significantly decreased in formononetin-treated T24 cells, followed by increase of PTEN, and down-regulation of p-Akt. Collectively, these results suggest that formononetin exerts an anti-carcinogenic effect on BCa in vitro, which might be due to miR-21-mediated regulation of the PTEN/Akt pathway.

Isoflavones enhance pharmacokinetic exposure of active lovastatin acid via the upregulation of carboxylesterase in high-fat diet mice after oral administration of Xuezhikang capsules.

PubMed

Feng, Dong; Ge, Chun; Tan, Zhao-Yi; Sun, Jian-Guo; Xie, Yuan; Yao, Lan; Yan, Cai-Xia; Aa, Ji-Ye; Wang, Guang-Ji

2018-06-19

Xuezhikang capsule (XZK) is a traditional Chinese medicine that contains lovastatin (Lv) for hyperlipidemia treatment, although it has fewer side effects than Lv. However, the pharmacokinetic mechanisms contributing to its distinct efficacy and low side effects are unclear. Mice were fed a high-fat diet (HFD) for 6 weeks to induce hyperlipidemia. We first conducted the pharmacokinetic studies in HFD mice following oral administration of Lv (10 mg/kg, i.g.) and found that HFD remarkably decreased the active form of Lv (the lovastatin acid, LvA) exposure in the circulation system, especially in the targeting organ liver, with a declined conversion from Lv to LvA, whereas the Lv (responsible for myotoxicity) exposure in muscle markedly increased. Then we compared the pharmacokinetic profiles of Lv in HFD mice after the oral administration of XZK (1200 mg/kg, i.g.) or an equivalent dose of Lv (10 mg/kg, i.g.). A higher exposure of LvA and lower exposure of Lv were observed after XZK administration, suggesting a pharmacokinetic interaction of some ingredients in XZK. Further studies revealed that HFD promoted the inflammation and inhibited carboxylesterase (CES) activities in the intestine and the liver, thus contributing to the lower transformation of Lv into LvA. In contrast, XZK inhibited the inflammation and upregulated CES in the intestine and the liver. Finally, we evaluated the effects of monacolins and phytosterols, the fractional extracts of isoflavones, on inflammatory LS174T or HepG2 cells, which showed that isoflavones inhibited inflammation, upregulated CES, and markedly enhanced the conversion of Lv into LvA. For the first time, we provide evidence that isoflavones and Lv in XZK act in concert to enhance the efficacy and reduce the side effects of Lv.

P52 Activation and Enzalutamide Therapy in Prostate Cancer

DTIC Science & Technology

2017-10-01

c-Myc:hnRNPA1 pathway regulates expression of androgen receptor splice variants and enzalutamide sensitivity in prostate cancer . Castration resistant... prostate cancer (CRPC) remains dependent on androgen receptor (AR) signaling. Alternative splicing of the AR to generate constitutively active... receptor splice variants and enzalutamide sensitivity in prostate cancer . • We discovered that quercetin, a naturally occurring polyphenolic compound

Negative regulation of parathyroid hormone-related protein expression by steroid hormones

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

Kajitani, Takashi; Tamamori-Adachi, Mimi; Okinaga, Hiroko

Highlights: {yields} Steroid hormones repress expression of PTHrP in the cell lines where the corresponding nuclear receptors are expressed. {yields} Nuclear receptors are required for suppression of PTHrP expression by steroid hormones, except for androgen receptor. {yields} Androgen-induced suppression of PTHrP expression appears to be mediated by estrogen receptor. -- Abstract: Elevated parathyroid hormone-related protein (PTHrP) is responsible for humoral hypercalcemia of malignancy (HHM), which is of clinical significance in treatment of terminal patients with malignancies. Steroid hormones were known to cause suppression of PTHrP expression. However, detailed studies linking multiple steroid hormones to PTHrP expression are lacking. Here wemore » studied PTHrP expression in response to steroid hormones in four cell lines with excessive PTHrP production. Our study established that steroid hormones negatively regulate PTHrP expression. Vitamin D receptor, estrogen receptor {alpha}, glucocorticoid receptor, and progesterone receptor, were required for repression of PTHrP expression by the cognate ligands. A notable exception was the androgen receptor, which was dispensable for suppression of PTHrP expression in androgen-treated cells. We propose a pathway(s) involving nuclear receptors to suppress PTHrP expression.« less

High SPDEF May Identify Patients Who Will Have a Prolonged Response to Androgen Deprivation Therapy

PubMed Central

Haller, Andrew C.; Tan, Wei; Payne-Ondracek, Rochelle; Underwood, Willie; Tian, Lili; Morrison, Carl; Li, Fengzhi

2015-01-01

Background Due to the indolent nature of prostate cancer, new prognostic measures are needed to identify patients with life threatening disease. SAM pointed domain-containing Ets transcription factor (SPDEF) has been associated with good prognosis and demonstrates an intimate relationship with the androgen receptor (AR), however its role in prostate cancer progression remains unclear. Methods A tissue microarray constructed from cores of 713 consecutive radical prostatectomy specimens were immunohistochemically stained for SPDEF and correlated with progression free and metastatic free survival. In vitro studies assessed growth rate, migration, and sensitivity to bicalutamide to explore mechanisms behind the tissue microarray observations. Results Patients with high SPDEF demonstrate longer metastases free survival after receiving the standard of care (HR = 9.80, P = 0.006). SPDEF expression corresponded with bicalutamide growth inhibition and apoptosis induction in all cell lines studied. In addition, a feed-forward loop of AR-SPEF expression regulation is observed. Conclusions SPDEF may be clinically useful to identify patients who will have extended benefits from androgen deprivation therapy. In vitro observations suggest SPDEF mediates initial sensitivity to androgen deprivation therapy through both AR regulation and downstream events. PMID:24375440

Amino acid substitutions in the hormone-binding domain of the human androgen receptor alter the stability of the hormone receptor complex.

PubMed Central

Marcelli, M; Zoppi, S; Wilson, C M; Griffin, J E; McPhaul, M J

1994-01-01

We have investigated the basis of androgen resistance in seven unrelated individuals with complete testicular feminization or Reifenstein syndrome caused by single amino acid substitutions in the hormone-binding domain of the androgen receptor. Monolayer-binding assays of cultured genital skin fibroblasts demonstrated absent ligand binding, qualitative abnormalities of androgen binding, or a decreased amount of qualitatively normal receptor. The consequences of these mutations were examined by introducing the mutations by site-directed mutagenesis into the androgen receptor cDNA sequence and expressing the mutant cDNAs in mammalian cells. The effects of the amino acid substitutions on the binding of different androgens and on the capacity of the ligand-bound receptors to activate a reporter gene were investigated. Substantial differences were found in the responses of the mutant androgen receptors to incubation with testosterone, 5 alpha-dihydrotestosterone, and mibolerone. In several instances, increased doses of hormone or increased frequency of hormone addition to the incubation medium resulted in normal or near normal activation of a reporter gene by cells expressing the mutant androgen receptors. These studies suggest that the stability of the hormone receptor complex is a major determinant of receptor function in vivo. Images PMID:7929841

Minor pyrano-isoflavones from Eriosema kraussianum: activity-, structure-, and chemical reaction studies.

PubMed

Drewes, Siegfried E; Horn, Marion M; Khan, Fatima; Munro, Orde Q; Dhlamini, Jabu T B; Rakuambo, Christopher; Meyer, J J Marion

2004-07-01

The isolation and identification of two minor pyrano-isoflavones from Eriosema kraussianum is described. New studies on the original pyrano-isoflavones shows that: (i) kraussianone 2 (a major compound in the plant) can be cyclised under acid conditions, (ii) kraussianones 3 and 5 cause contraction (not relaxation as anticipated) of corpus cavernosum tissue and (iii) the structures proposed previously for 4 and 5 are confirmed by the data obtained from an X-ray study of 5.

Synthesis of isoflavones by room-temperature nickel-catalyzed cross-couplings of 3-iodo(bromo)chromones with arylzincs.

PubMed

Zhang, Zunting; Qiao, Jinfeng; Wang, Ding; Han, Ling; Ding, Ru

2014-05-01

A new concise, facile method for synthesis of isoflavones was accomplished in moderate to good yields for 3-iodochromones or 3-bromochromones and arylzinc bromides via Negishi cross-coupling reaction catalyzed by NiCl(2)/PPh(3) or NiCl(2)(PPh(3))(2) at room temperature. The Isoflavone core was synthesized in four steps in good yield, starting from commercially available 2-hydroxyacetophenone and aromatic bromide. Three steps of the procedure were carried out at room temperature.

Sertoli cell androgen receptor expression regulates temporal fetal and adult Leydig cell differentiation, function, and population size.

PubMed

Hazra, Rasmani; Jimenez, Mark; Desai, Reena; Handelsman, David J; Allan, Charles M

2013-09-01

We recently created a mouse model displaying precocious Sertoli cell (SC) and spermatogenic development induced by SC-specific transgenic androgen receptor expression (TgSCAR). Here we reveal that TgSCAR regulates the development, function, and absolute number of Leydig cells (LCs). Total fetal and adult type LC numbers were reduced in postnatal and adult TgSCAR vs control testes, despite normal circulating LH levels. Normal LC to SC ratios found in TgSCAR testes indicate that SC androgen receptor (SCAR)-mediated activity confers a quorum-dependent relationship between total SC and LC numbers. TgSCAR enhanced LC differentiation, shown by elevated ratios of advanced to immature LC types, and reduced LC proliferation in postnatal TgSCAR vs control testes. Postnatal TgSCAR testes displayed up-regulated expression of coupled ligand-receptor transcripts (Amh-Amhr2, Dhh-Ptch1, Pdgfa-Pdgfra) for potential SCAR-stimulated paracrine pathways, which may coordinate LC differentiation. Neonatal TgSCAR testes displayed normal T and dihydrotestosterone levels despite differential changes to steroidogenic gene expression, with down-regulated Star, Cyp11a1, and Cyp17a1 expression contrasting with up-regulated Hsd3b1, Hsd17b3, and Srd5a1 expression. TgSCAR males also displayed elevated postnatal and normal adult serum testosterone levels, despite reduced LC numbers. Enhanced adult-type LC steroidogenic output was revealed by increased pubertal testicular T, dihydrotestosterone, 3α-diol and 3β-diol levels per LC and up-regulated steroidogenic gene (Nr5a1, Lhr, Cyp11a1, Cyp17a1, Hsd3b6, Srd5a1) expression in pubertal or adult TgSCAR vs control males, suggesting regulatory mechanisms maintain androgen levels independently of absolute LC numbers. Our unique gain-of-function TgSCAR model has revealed that SCAR activity controls temporal LC differentiation, steroidogenic function, and population size.

Dietary phenethyl isothiocyanate inhibition of androgen-responsive LNCaP prostate cancer cell tumor growth correlates with decreased angiogenesis

USDA-ARS?s Scientific Manuscript database

Phenethyl isothiocyanate (PEITC), found in certain cruciferous vegetables, has antitumor activity in several cancer models, including prostate cancer. In our xenograft model, dietary administration of PEITC (100-150 mg/kg/d) inhibited androgen-responsive LNCaP human prostate cancer cell tumor growth...

The androgen receptor controls expression of the cancer-associated sTn antigen and cell adhesion through induction of ST6GalNAc1 in prostate cancer

PubMed Central

Munkley, Jennifer; Oltean, Sebastian; Vodák, Daniel; Wilson, Brian T.; Livermore, Karen E.; Zhou, Yan; Star, Eleanor; Floros, Vasileios I.; Johannessen, Bjarne; Knight, Bridget; McCullagh, Paul; McGrath, John; Crundwell, Malcolm; Skotheim, Rolf I.; Robson, Craig N.; Leung, Hing Y.; Harries, Lorna W.; Rajan, Prabhakar; Mills, Ian G.; Elliott, David J.

2015-01-01

Patterns of glycosylation are important in cancer, but the molecular mechanisms that drive changes are often poorly understood. The androgen receptor drives prostate cancer (PCa) development and progression to lethal metastatic castration-resistant disease. Here we used RNA-Seq coupled with bioinformatic analyses of androgen-receptor (AR) binding sites and clinical PCa expression array data to identify ST6GalNAc1 as a direct and rapidly activated target gene of the AR in PCa cells. ST6GalNAc1 encodes a sialytransferase that catalyses formation of the cancer-associated sialyl-Tn antigen (sTn), which we find is also induced by androgen exposure. Androgens induce expression of a novel splice variant of the ST6GalNAc1 protein in PCa cells. This splice variant encodes a shorter protein isoform that is still fully functional as a sialyltransferase and able to induce expression of the sTn-antigen. Surprisingly, given its high expression in tumours, stable expression of ST6GalNAc1 in PCa cells reduced formation of stable tumours in mice, reduced cell adhesion and induced a switch towards a more mesenchymal-like cell phenotype in vitro. ST6GalNAc1 has a dynamic expression pattern in clinical datasets, being significantly up-regulated in primary prostate carcinoma but relatively down-regulated in established metastatic tissue. ST6GalNAc1 is frequently upregulated concurrently with another important glycosylation enzyme GCNT1 previously associated with prostate cancer progression and implicated in Sialyl Lewis X antigen synthesis. Together our data establishes an androgen-dependent mechanism for sTn antigen expression in PCa, and are consistent with a general role for the androgen receptor in driving important coordinate changes to the glycoproteome during PCa progression. PMID:26452038

Primary Xenografts of Human Prostate Tissue as a Model to Study Angiogenesis Induced by Reactive Stroma

PubMed Central

Montecinos, Viviana P.; Godoy, Alejandro; Hinklin, Jennifer; Vethanayagam, R. Robert; Smith, Gary J.

2012-01-01

Characterization of the mechanism(s) of androgen-driven human angiogenesis could have significant implications for modeling new forms of anti-angiogenic therapies for CaP and for developing targeted adjuvant therapies to improve efficacy of androgen-deprivation therapy. However, models of angiogenesis by human endothelial cells localized within an intact human prostate tissue architecture are until now extremely limited. This report characterizes the burst of angiogenesis by endogenous human blood vessels in primary xenografts of fresh surgical specimens of benign prostate or prostate cancer (CaP) tissue that occurs between Days 6–14 after transplantation into SCID mice pre-implanted with testosterone pellets. The wave of human angiogenesis was preceded by androgen-mediated up-regulation of VEGF-A expression in the stromal compartment. The neo-vessel network anastomosed to the host mouse vascular system between Days 6–10 post-transplantation, the angiogenic response ceased by Day 15, and by Day 30 the vasculature had matured and stabilized, as indicated by a lack of leakage of serum components into the interstitial tissue space and by association of nascent endothelial cells with mural cells/pericytes. The angiogenic wave was concurrent with the appearance of a reactive stroma phenotype, as determined by staining for α-SMA, Vimentin, Tenascin, Calponin, Desmin and Masson's trichrome, but the reactive stroma phenotype appeared to be largely independent of androgen availability. Transplantation-induced angiogenesis by endogenous human endothelial cells present in primary xenografts of benign and malignant human prostate tissue was preceded by induction of androgen-driven expression of VEGF by the prostate stroma, and was concurrent with and the appearance of a reactive stroma phenotype. Androgen-modulated expression of VEGF-A appeared to be a causal regulator of angiogenesis, and possibly of stromal activation, in human prostate xenografts. PMID:22303438

Commentary on "integrative genomic analyses reveal an androgen-driven somatic alteration landscape in early-onset prostate cancer." Weischenfeldt J, Simon R, Feuerbach L, Schlangen K, Weichenhan D, Minner S, Wuttig D, Warnatz HJ, Stehr H, Rausch T, Jäger N, Gu L, Bogatyrova O, Stütz AM, Claus R, Eils J, Eils R, Gerhäuser C, Huang PH, Hutter B, Kabbe R, Lawerenz C, Radomski S, Bartholomae CC, Fälth M, Gade S, Schmidt M, Amschler N, Haß T, Galal R, Gjoni J, Kuner R, Baer C, Masser S, von Kalle C, Zichner T, Benes V, Raeder B, Mader M, Amstislavskiy V, Avci M, Lehrach H, Parkhomchuk D, Sultan M, Burkhardt L, Graefen M, Huland H, Kluth M, Krohn A, Sirma H, Stumm L, Steurer S, Grupp K, Sültmann H, Sauter G, Plass C, Brors B, Yaspo ML, Korbel JO, Schlomm T, Genome Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.: Cancer Cell 2013;23(2):159-70.

PubMed

Olumi, Aria F

2014-02-01

Early-onset prostate cancer (EO-PCA) represents the earliest clinical manifestation of prostate cancer. To compare the genomic alteration landscapes of EO-PCA with "classical" (elderly-onset) PCA, we performed deep sequencing-based genomics analyses in 11 tumors diagnosed at young age, and pursued comparative assessments with seven elderly-onset PCA genomes. Remarkable age-related differences in structural rearrangement (SR) formation became evident, suggesting distinct disease pathomechanisms. Whereas EO-PCAs harbored a prevalence of balanced SRs, with a specific abundance of androgen-regulated ETS gene fusions including TMPRSS2:ERG, elderly-onset PCAs displayed primarily non-androgen-associated SRs. Data from a validation cohort of>10,000 patients showed age-dependent androgen receptor levels and a prevalence of SRs affecting androgen-regulated genes, further substantiating the activity of a characteristic "androgen-type" pathomechanism in EO-PCA. Copyright © 2014 Elsevier Inc. All rights reserved.

[Effect of minoxidil on hair growth in androgenic alopecia in women].

PubMed

Brzezińska-Wcisło, Ligia

2002-09-01

The aim of the study was to carry out clinical and trichological examination (trichogram and assessment of hair loss) before and after treatment in 17 women aged 41-50 years with androgenic alopecia. Minoxidil (Loxon) was topically applied twice a day massaging the solution into the scalp over 6-12 months. It was revealed on the ground of clinical and trichological examination that the medication containing 2% solution of minoxidil externally applied on the scalp with androgenic alopecia over a few months caused normalization of hair root condition and decrease of hair loss in some patients of the observed group. The drug has a stimulating influence on hair growth and should be administered as an adjuvant therapy in androgenic alopecia in women.

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.

Seasonal variation of red clover (Trifolium pratense L., Fabaceae) isoflavones and estrogenic activity

PubMed Central

Booth, Nancy L.; Overk, Cassia R.; Yao, Ping; Totura, Steve; Deng, Yunfan; Hedayat, A. S.; Bolton, Judy L.; Pauli, Guido F.; Farnsworth, Norman R.

2007-01-01

Red clover (Trifolium pratense L., Fabaceae) dietary supplements are currently used to treat menopausal symptoms because of their high content of the mildly estrogenic isoflavones daidzein, genistein, formononetin and biochanin A. These compounds are estrogenic in vitro and in vivo, but little information exists on the best time to harvest red clover fields to maximize content of the isoflavones and thus make an optimal product. Samples of cultivated red clover aboveground parts and flower heads were collected in parallel over one growing season in northeastern Illinois. Generally, autohydrolytic extracts of aboveground parts contained more isoflavones and had more estrogenic activity in Ishikawa endometrial cells, compared with extracts of flower heads. Daidzein and genistein content peaked around June to July, while formononetin and biochanin A content peaked in early September. Flower head and total aboveground parts extracts exhibited differential estrogenic activity in an Ishikawa (endometrial) cell-based alkaline phosphatase (AP) induction assay, whereas nondifferential activity was observed for most extracts tested in an MCF-7 (breast) cell proliferation assay when tested at the same final concentrations. Ishikawa assay results could be mapped onto the extracts’ content of individual isoflavones, but MCF-7 results did not show such a pattern. These results suggest that significant metabolism of isoflavones may occur in MCF-7 cells, but not in Ishikawa cells, and therefore caution is advised in the choice of bioassay used for the biological standardization of botanical dietary supplements. PMID:16478248

Comparison of the Pharmacological Effects of a Novel Selective Androgen Receptor Modulator, the 5α-Reductase Inhibitor Finasteride, and the Antiandrogen Hydroxyflutamide in Intact Rats: New Approach for Benign Prostate Hyperplasia

PubMed Central

Gao, Wenqing; Kearbey, Jeffrey D.; Nair, Vipin A.; Chung, Kiwon; Parlow, A. F.; Miller, Duane D.; Dalton, James T.

2007-01-01

Tissue-selective androgen receptor modulators (SARMs) demonstrate tissue selectivity in both castrated and intact male rats, behaving as partial agonists in androgenic tissues (i.e. prostate and seminal vesicle), but full agonists in anabolic tissues (i.e. levator ani muscle). The partial agonist activity of SARMs (compounds S-1 and S-4) in the prostate of intact rats suggested that SARM could be used for androgen suppression in the treatment of benign prostate hyperplasia (BPH). This study was designed to explore the mechanisms of action of SARM and to characterize the tissue selectivity of S-1 in intact male rats compared with that of hydroxyflutamide (antiandrogen) and finasteride (5α-reductase inhibitor), two major drugs used for androgen suppression treatment of BPH. In intact male rats, S-1 (5, 10, and 25 mg/kg) selectively decreased the prostate weight with similar efficacy to finasteride (5 mg/kg), without affecting the levator ani muscle or increasing the plasma levels of testosterone, LH, and FSH. Hydroxyflutamide (0.5, 1, 5, 10, and 25 mg/kg), however, decreased both the prostate and levator ani muscle weights without any selectivity and increased plasma hormone levels in a dose-dependent manner. Furthermore, S-1 and S-4 showed very weak inhibitory effects toward transiently expressed type I and II human 5α-reductase (Ki, >20 µM) during in vitro assays. Therefore, although S-1 and finasteride showed very similar suppressive effects in the prostate of intact male rats, they decreased prostate size via different mechanisms of action. S-1 simply worked as androgen receptor partial agonist, whereas finasteride inhibited prostatic 5α-reductase. These studies indicate that SARMs may demonstrate clinical utility as single agent or combination therapy for BPH. PMID:15308613

Antiandrogens act as selective androgen receptor modulators at the proteome level in prostate cancer cells.

PubMed

Brooke, Greg N; Gamble, Simon C; Hough, Michael A; Begum, Shajna; Dart, D Alwyn; Odontiadis, Michael; Powell, Sue M; Fioretti, Flavia M; Bryan, Rosie A; Waxman, Jonathan; Wait, Robin; Bevan, Charlotte L

2015-05-01

Current therapies for prostate cancer include antiandrogens, inhibitory ligands of the androgen receptor, which repress androgen-stimulated growth. These include the selective androgen receptor modulators cyproterone acetate and hydroxyflutamide and the complete antagonist bicalutamide. Their activity is partly dictated by the presence of androgen receptor mutations, which are commonly detected in patients who relapse while receiving antiandrogens, i.e. in castrate-resistant prostate cancer. To characterize the early proteomic response to these antiandrogens we used the LNCaP prostate cancer cell line, which harbors the androgen receptor mutation most commonly detected in castrate-resistant tumors (T877A), analyzing alterations in the proteome, and comparing these to the effect of these therapeutics upon androgen receptor activity and cell proliferation. The majority are regulated post-transcriptionally, possibly via nongenomic androgen receptor signaling. Differences detected between the exposure groups demonstrate subtle changes in the biological response to each specific ligand, suggesting a spectrum of agonistic and antagonistic effects dependent on the ligand used. Analysis of the crystal structures of the AR in the presence of cyproterone acetate, hydroxyflutamide, and DHT identified important differences in the orientation of key residues located in the AF-2 and BF-3 protein interaction surfaces. This further implies that although there is commonality in the growth responses between androgens and those antiandrogens that stimulate growth in the presence of a mutation, there may also be influential differences in the growth pathways stimulated by the different ligands. This therefore has implications for prostate cancer treatment because tumors may respond differently dependent upon which mutation is present and which ligand is activating growth, also for the design of selective androgen receptor modulators, which aim to elicit differential proteomic responses dependent upon cellular context. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Antiandrogens Act as Selective Androgen Receptor Modulators at the Proteome Level in Prostate Cancer Cells*

PubMed Central

Brooke, Greg N.; Gamble, Simon C.; Hough, Michael A.; Begum, Shajna; Dart, D. Alwyn; Odontiadis, Michael; Powell, Sue M.; Fioretti, Flavia M.; Bryan, Rosie A.; Waxman, Jonathan; Wait, Robin; Bevan, Charlotte L.

2015-01-01

Current therapies for prostate cancer include antiandrogens, inhibitory ligands of the androgen receptor, which repress androgen-stimulated growth. These include the selective androgen receptor modulators cyproterone acetate and hydroxyflutamide and the complete antagonist bicalutamide. Their activity is partly dictated by the presence of androgen receptor mutations, which are commonly detected in patients who relapse while receiving antiandrogens, i.e. in castrate-resistant prostate cancer. To characterize the early proteomic response to these antiandrogens we used the LNCaP prostate cancer cell line, which harbors the androgen receptor mutation most commonly detected in castrate-resistant tumors (T877A), analyzing alterations in the proteome, and comparing these to the effect of these therapeutics upon androgen receptor activity and cell proliferation. The majority are regulated post-transcriptionally, possibly via nongenomic androgen receptor signaling. Differences detected between the exposure groups demonstrate subtle changes in the biological response to each specific ligand, suggesting a spectrum of agonistic and antagonistic effects dependent on the ligand used. Analysis of the crystal structures of the AR in the presence of cyproterone acetate, hydroxyflutamide, and DHT identified important differences in the orientation of key residues located in the AF-2 and BF-3 protein interaction surfaces. This further implies that although there is commonality in the growth responses between androgens and those antiandrogens that stimulate growth in the presence of a mutation, there may also be influential differences in the growth pathways stimulated by the different ligands. This therefore has implications for prostate cancer treatment because tumors may respond differently dependent upon which mutation is present and which ligand is activating growth, also for the design of selective androgen receptor modulators, which aim to elicit differential proteomic responses dependent upon cellular context. PMID:25693800

Anabolic androgen use in the management of hereditary angioedema: Not so cheap after all.

PubMed

Tse, Kevin Y; Zuraw, Bruce L; Chen, Qiaoling; Christiansen, Sandra C

2017-04-01

Hereditary angioedema due to C1 inhibitor deficiency (HAE) is a rare, life-threatening disease that imposes a significant burden on affected patients. 17α-alkylated androgens (anabolic androgens) decrease attack frequency and severity but carry the risk of potentially serious dose-related adverse effects. Despite the emergence of targeted therapies for HAE, continued anabolic androgen use has been driven in part by their low cost. To examine the hidden cost of anabolic androgen use related to the risk of developing non-HAE comorbidities. Patients with HAE were identified in the Southern California Kaiser Permanente database using clinical and laboratory findings compatible with HAE. These patients were stratified into anabolic androgen exposed and nonexposed groups. Matched controls were selected from the Kaiser database who did not have HAE or anabolic androgen exposure. Using multivariate analysis, we determined the number of non-HAE comorbidities linked to anabolic androgen use. We next determined the association between dosing and increasing exposure to anabolic androgens and the likelihood of having various comorbidities. Patients with HAE exposed to anabolic androgens had a 28% increase (P = .04) in non-HAE comorbidities when compared with their matched (nonexposed) controls. With each gram per month increase in exposure, a 12% increase in non-HAE comorbidities is observed (P < .01). The most commonly occurring non-HAE comorbidities were psychiatric, muscle cramps, obesity, and hyperlipidemia. Our data suggest that long-term anabolic androgen use enhances the risk of developing comorbid health conditions, thus amplifying the cost of care. Our report provides additional support for the preferred use of newer, targeted therapies for the management of HAE. Copyright © 2017 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Expression of the androgen receptor in the testes and the concentrations of gonadotropins and sex steroid hormones in male turkeys (Meleagris gallopavo) during growth and development.

PubMed

Kiezun, J; Leska, A; Kaminska, B; Jankowski, J; Dusza, L

2015-04-01

Androgens, including testosterone (T) and androstenedione (A4), are essential for puberty, fertility and sexual functions. The biological activity of those hormones is mediated via the androgen receptor (AR). The regulation of androgen action in birds is poorly understood. Therefore, the present study analysed mRNA and protein expression of AR in the testes, plasma concentrations of the luteinizing hormone (LH), follicle-stimulating hormone (FSH), T, A4 and oestradiol (E2), as well as the levels of T, A4 and E2 in testicular homogenates of male turkeys (Meleagris gallopavo) at the age of 4, 8, 12, 16, 20, 24 and 28weeks. Plasma concentrations of LH and FSH, as well as plasma and testicular levels of T and A4 began to increase at 20weeks of age. The lowest plasma levels of E2 were noted at 20weeks relative to other growth stages. The 20th week of life seems to be the key phase in the development of the reproductive system of turkeys. The AR protein was found in the nuclei of testicular cells in all examined growth stages. Higher expression of AR protein in the testes beginning at 20weeks of age was accompanied by high plasma concentrations of LH and high plasma and testicular levels of androgens. This relationship seems to be necessary to regulate male sexual function. Copyright © 2014 Elsevier Inc. All rights reserved.

Adrenal hyperandrogenism is induced by fetal androgen excess in a rhesus monkey model of polycystic ovary syndrome.

PubMed

Zhou, Rao; Bird, Ian M; Dumesic, Daniel A; Abbott, David H

2005-12-01

Adrenal androgen excess is found in approximately 25-60% of women with polycystic ovary syndrome (PCOS), but the mechanisms underlying PCOS-related adrenal androgen excess are unclear. The objective of this study was to determine whether adrenal androgen excess is manifest in a nonhuman primate model for PCOS. Six prenatally androgenized (PA) and six control female rhesus monkeys of similar age, body weight, and body mass index were studied during d 2-6 of two menstrual cycles or anovulatory 30-d periods. Predexamethasone adrenal steroid levels were assessed in the first cycle (cycle 1). In a subsequent cycle (cycle 2), occurring one to three cycles after cycle 1, adrenal steroids were determined 14.5-16.0 h after an i.m. injection of 0.5 mg/kg dexamethasone (postdexamethasone levels) and after an i.v. injection of 50 microg ACTH-(1-39). Both before and after dexamethasone, serum levels of dehydroepiandrosterone (DHEA) in PA females exceeded those in controls. After ACTH injection, PA females exhibited higher circulating levels of DHEA, androstenedione, and corticosterone but comparable levels of 17alpha-hydroxyprogesterone, cortisol, the sulfoconjugate of DHEA, and testosterone compared with controls. Enhanced basal and ACTH-stimulated adrenal androgen levels in PA female monkeys may reflect up-regulation of 17,20 lyase activity in the adrenal zona reticularis, causing adrenal androgen excess comparable with that found in PCOS women with adrenal androgen excess. These findings open the possibility that PCOS adrenal hyperandrogenism may have its origins in fetal androgen excess reprogramming of adrenocortical function.

Systematic Identification of Genes Required for Expression of Androgen Receptor Splice Variants

DTIC Science & Technology

2016-08-01

engineering tool has been developed from bacterial Clustered Regularly Interspaced Short Palindromic Repeats ( CRISPR )/ CRISPR ‐Associated System (Cas...regulation of AR splice variant through CRISPR /Cas screening system. 15. SUBJECT TERMS CRISPR /Cas, Androgen receptor, castration resistance, biomarker 16...control (non-targeting) gRNAs available from Addgene (http://www.addgene.org/ CRISPR /libraries/). Generation of AR3 reporter: We used molecular cloning

Indole-3-carbinol and 3’, 3’-diindolylmethane modulate androgen effect up-regulation on C-C chemokine ligand 2 and monocyte attraction to prostate cancer cells

USDA-ARS?s Scientific Manuscript database

Inflammation has a role in prostate tumorigenesis. Recruitment of inflammatory monocytes to the tumor site is mediated by C-C chemokine ligand 2 (CCL2) through binding to its receptor CCR2. We hypothesized that androgen could modulate CCL2 expression in hormone-responsive prostate cancer cells, and ...