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Estrogen receptor and PI3K/Akt signaling pathway involvement in S-(-)equol-induced activation of Nrf2/ARE in endothelial cells.
Zhang, T, Liang, X, Shi, L, Wang, L, Chen, J, Kang, C, Zhu, J, Mi, M
PloS one. 2013;(11):e79075
Abstract
S-(-)equol, a natural product of the isoflavone daidzein, has been reported to offer cytoprotective effects with respect to the cardiovascular system, but how this occurs is unclear. Interestingly, S-(-)equol is produced by the human gut, suggesting a role in physiological processes. We report that treatment of human umbilical vein endothelial cells and EA.hy926 cells with S-(-)equol induces ARE-luciferase reporter gene activity that is dose and time dependent. S-(-)equol (10-250 nM) increases nuclear factor-erythroid 2-related factor 2 (Nrf2) as well as gene products of Nrf2 target genes heme oxygenase-1 (HO-1) and NAD(P)H (nicotinamide-adenine-dinucleotide-phosphate) quinone oxidoreductase 1 (NQO1). Endothelial cells transfected with an HA-Nrf2 expression plasmid had elevated HA-Nrf2, HO-1, and NQO1 in response to S-(-)equol exposure. S-(-)equol treatment affected Nrf2 mRNA only slightly but significantly increased HO-1 and NQO1 mRNA. The pretreatment of cells with specific ER inhibitors or PI3K/Akt (ICI182,780 and LY294002) increased Nrf2, HO-1, and NQO1 protein, impaired nuclear translocation of HA-Nrf2, and decreased ARE-luciferase activity. Identical experiments were conducted with daidzein, which had effects similar to S-(-)equol. In addition, DPN treatment (an ERβ agonist) induced the ARE-luciferase reporter gene, promoting Nrf2 nuclear translocation. Cell pretreatment with an ERβ antagonist (PHTPP) impaired S-(-)equol-induced Nrf2 activation. Pre-incubation of cells followed by co-treatment with S-(-)equol significantly improved cell survival in response to H2O2 or tBHP and reduced apoptotic and TUNEL-positively-stained cells. Notably, the ability of S-(-)equol to protect against H2O2-induced cell apoptosis was attenuated in cells transfected with an siRNA against Nrf2. Thus, beneficial effects of S-(-)equol with respect to cytoprotective antioxidant gene activation may represent a novel strategy to prevent and treat cardiovascular diseases.
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Eviendep® reduces number and size of duodenal polyps in familial adenomatous polyposis patients with ileal pouch-anal anastomosis.
Calabrese, C, Praticò, C, Calafiore, A, Coscia, M, Gentilini, L, Poggioli, G, Gionchetti, P, Campieri, M, Rizzello, F
World journal of gastroenterology. 2013;(34):5671-7
Abstract
AIM: To evaluate if 3 mo oral supplementation with Eviendep® was able to reduce the number of duodenal polyps in familial adenomatous polyposis (FAP) patients with ileal pouch-anal anastomosis (IPAA). METHODS Eleven FAP patients with IPAA and duodenal polyps were enrolled. They underwent upper gastrointestinal (GI) endoscopy at the baseline and after 3 mo of treatment. Each patient received 5 mg Eviendep twice a day, at breakfast and dinner time, for 3 mo. Two endoscopists evaluated in a blinded manner the number and size of duodenal polyps. Upper GI endoscopies with biopsies were performed at the baseline (T0) with the assessment of the Spigelman score. Polyps > 10 mm were removed during endoscopy and at the end of the procedure a new Spigelman score was determined (T1). The procedure was repeated 3 mo after the baseline (T2). Four photograms were examined for each patient, at T1 and T2. The examined area was divided into 3 segments: duodenal bulb, second and third portion duodenum. Biopsy specimens were taken from all polyps > 10 mm and from all suspicious ones, defined by the presence of a central depression, irregular surface, or irregular vascular pattern. Histology was classified according to the updated Vienna criteria. RESULTS At baseline the mean number of duodenal detected polyps was 27.7 and mean sizes were 15.8 mm; the mean Spigelman score was 7.1. After polypectomy the mean number of duodenal detected polyps was 25.7 and mean sizes were 7.6 mm; the mean Spigelman score was 6.4. After 3 mo of Eviendep bid, all patients showed a reduction of number and size of duodenal polyps. The mean number of duodenal polyps was 8 (P = 0.021) and mean size was 4.4 mm; the mean Spigelman score was 6.6. Interrater agreement was measured. Lesions > 1 cm found a very good degree of concordance (kappa 0.851) and a good concordance was as well encountered for smaller lesions (kappa 0.641). CONCLUSION Our study demonstrated that short-term (90 d) supplementation with Eviendep® in FAP patients with IPAA and with recurrent adenomas in the duodenal mucosa, resulted effective in reducing polyps number of 32% and size of 51%.
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Reduction in Ki-67 in benign breast tissue of high-risk women with the lignan secoisolariciresinol diglycoside.
Fabian, CJ, Kimler, BF, Zalles, CM, Klemp, JR, Petroff, BK, Khan, QJ, Sharma, P, Setchell, KD, Zhao, X, Phillips, TA, et al
Cancer prevention research (Philadelphia, Pa.). 2010;(10):1342-50
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Abstract
Preclinical and correlative studies suggest reduced breast cancer with higher lignan intake or blood levels. We conducted a pilot study of modulation of risk biomarkers for breast cancer in premenopausal women after administration of the plant lignan secoisolariciresinol given as the diglycoside (SDG). Eligibility criteria included regular menstrual cycles, no oral contraceptives, a >3-fold increase in 5-year risk, and baseline Ki-67 of ≥2% in areas of hyperplasia in breast tissue sampled by random periareolar fine-needle aspiration (RPFNA) during the follicular phase of the menstrual cycle. SDG (50 mg/d) was given for 12 months, followed by repeat RPFNA. The primary end point was change in Ki-67. Secondary end points included change in cytomorphology, mammographic breast density, serum bioavailable estradiol and testosterone insulin-like growth factor-I and IGF-binding protein-3, and plasma lignan levels. Forty-five of 49 eligible women completed the study with excellent compliance (median = 96%) and few serious side effects (4% grade 3). Median plasma enterolactone increased ∼9-fold, and total lignans increased 16-fold. Thirty-six (80%) of the 45 evaluable subjects showed a decrease in Ki-67, from a median of 4% (range, 2-16.8%) to 2% (range, 0-15.2%; P < 0.001, Wilcoxon signed rank test). A decrease from baseline in the proportion of women with atypical cytology (P = 0.035) was also observed. Based on favorable risk biomarker modulation and lack of adverse events, we are initiating a randomized trial of SDG versus placebo in premenopausal women.
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Is there a role for soy isoflavones in the therapeutic approach to polycystic ovary syndrome? Results from a pilot study.
Romualdi, D, Costantini, B, Campagna, G, Lanzone, A, Guido, M
Fertility and sterility. 2008;(5):1826-33
Abstract
OBJECTIVE To evaluate the effect of the soy isoflavone genistein on the metabolic and hormonal disturbances of polycystic ovary syndrome (PCOS), we studied a group of obese, hyperinsulinemic, and dyslipidemic women presenting this syndrome during 6 months of phytoestrogen administration. DESIGN Pilot prospective study. SETTING Operative division of endocrinological gynecology in a university hospital. PATIENT(S): Twelve Caucasian obese, hyperinsulinemic, and dyslipidemic women with PCOS. INTERVENTION(S): Patients received 36 mg/d of genistein for 6 months. Ultrasonographic pelvic exams, hormonal and lipid features, oral glucose tolerance test, and euglycemic hyperinsulinemic clamp were performed at baseline and after 3 and 6 months of treatment. MAIN OUTCOME MEASURE(S): Basal hormonal assays, lipid profile, and glycoinsulinemic assessment. RESULT(S): Phytoestrogens supplementation significantly improved total cholesterol levels, reducing low-density lipoprotein (LDL) cholesterol and resulting in a significant decrease in the LDL-high-density lipoprotein ratio (LDL-HDL). Triglycerides showed a trend toward decrease, whereas no changes were detected in very low-density lipoprotein cholesterol plasma levels. Genistein treatment did not significantly affect anthropometric features, the hormonal milieu, and menstrual cyclicity. No significant changes occurred in glycoinsulinemic metabolism. CONCLUSION(S): The possible advantages derived from the therapeutic use of phytoestrogens in PCOS are limited to improvement of the lipidic assessment.
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The prenylflavonoid isoxanthohumol from hops (Humulus lupulus L.) is activated into the potent phytoestrogen 8-prenylnaringenin in vitro and in the human intestine.
Possemiers, S, Bolca, S, Grootaert, C, Heyerick, A, Decroos, K, Dhooge, W, De Keukeleire, D, Rabot, S, Verstraete, W, Van de Wiele, T
The Journal of nutrition. 2006;(7):1862-7
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Hops, an essential beer ingredient, are a source of prenylflavonoids, including 8-prenylnaringenin (8-PN), one of the most potent phytoestrogens. Because 8-PN concentrations in beers are generally low, its health effects after moderate beer consumption were considered negligible. However, human intestinal microbiota may activate up to 4 mg/L isoxanthohumol (IX) in beer into 8-PN. Depending on interindividual differences in the intestinal transformation potential, this conversion could easily increase the 8-PN exposure 10-fold upon beer consumption. Here, we present a further investigation of the process both in vitro and in vivo. In vitro experiments with the dynamic SHIME model showed that hop prenylflavonoids pass unaltered through the stomach and small intestine and that activation of IX into 8-PN (up to 80% conversion) occurs only in the distal colon. In vitro incubations of 51 fecal samples from female volunteers with IX enabled us to separate the fecal microbiota into high (8 of 51), moderate (11 of 51) and slow (32 of 51) 8-PN producers, clearly illustrating an interindividual variability. Three women, selected from the respective groups, received a daily dose of 5.59 mg IX for 4 d. Intestinal IX activation and urinary 8-PN excretion were correlated (R(2) = 0.6417, P < 0.01). These data show that intestinal conversion of IX upon moderate beer consumption can lead to 8-PN exposure values that might fall within the range of human biological activity.
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Method of defining equol-producer status and its frequency among vegetarians.
Setchell, KD, Cole, SJ
The Journal of nutrition. 2006;(8):2188-93
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7-Hydroxy-3-(4'-hydroxyphenyl)-chroman (S-equol) is a specific end-metabolite formed in the biotransformation of the dietary soy isoflavones daidzin and daidzein by intestinal bacteria. The frequency of equol production varies among individuals and populations, and it is suggested that the efficacy of soy foods differs depending on the ability of an individual to produce equol. To develop a standardized approach to define equol-producer status that can be universally adopted to differentiate these 2 distinct populations, we measured isoflavones in serum and urine collected from a cohort of 41 healthy adults, comprising 29 vegetarians and 12 nonvegetarians, after consuming 2 x 250 mL/d soy milk on 3 consecutive days. Serum and urinary daidzein and S-equol concentrations were analyzed by MS. Serum S-equol and daidzein concentrations ranged from 10.3-139 nmol/L (2.5-33.6 microg/L) and 16-1401 nmol/L (4.0-356 microg/L), respectively, whereas in urine the corresponding concentrations ranged from 16-12,574 nmol/L (4-3043 microg/L) and 539-26,834 nmol/L (137-6816 microg/L), respectively. The log10-transformed urinary S-equol:daidzein ratio provided a clearer distinction of equol-producer status than the absolute serum or urinary S-equol concentrations because it is independent of isoflavone intake and minimizes interindividual variation in isoflavone pharmacokinetics or differences in analytical methodologies. A threshold value for the log10-transformed urinary S-equol:daidzein ratio of -1.75 provided a demarcation to define equol-producer status. The frequency of equol producers in the vegetarians was 59%, similar to the reported frequency in Japanese adults consuming soy, and much higher than for nonvegetarian adults (25%), suggesting that dietary components other than soy influence S-equol synthesis by intestinal bacteria.
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Bioavailability of isoflavone phytoestrogens in postmenopausal women consuming soya milk fermented with probiotic bifidobacteria.
Tsangalis, D, Wilcox, G, Shah, NP, Stojanovska, L
The British journal of nutrition. 2005;(6):867-77
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We investigated the effects of consuming an isoflavone aglycone-enriched soya milk containing viable bifidobacteria on urinary isoflavone excretion and percentage recovery. Sixteen postmenopausal women were randomly divided into two groups to consume either fermented or non-fermented soya milk. Each group participated in a double-blind, crossover study with three 14 d supplementation periods, separated by a 14 d washout. Subjects ingested three daily dosages of isoflavone via the soya milk and collected four 24 h pooled urine specimens per supplementation period. Soya milks were prepared with soya protein isolate and soya germ, followed by fermentation with bifidobacteria. Isoflavone levels were quantified using HPLC. Non-fermented soya milks at 20, 40 and 80 mg isoflavone/200 ml contained 10 %, 9 % and 7 % aglycone, respectively, with their fermented counterparts containing 69 %, 57 % and 36 % aglycone (P<0.001). A trend to a greater percentage urinary recovery of daidzein and glycitein was observed among women consuming fermented soya milk at a dosage of 40 mg isoflavone (P=0.13). A distinct linear dose response for the fermented soya milk group (R2=0.9993) compared with the non-fermented group (R2=0.8865) suggested less interindividual variation in isoflavone absorption. However, total urinary isoflavone excretion was similar for both groups (P>0.05), with urinary isoflavone recovery at approximately 31 %. Increasing the isoflavone dosage correlated positively with its urinary excretion, but urinary percentage recovery of isoflavone was inversely related to dosage level. Hence, a modest dosage ranging from 20 to 30 mg/d may provide the most bioavailable source of isoflavone, regardless of whether it is via an aglycone-rich fermented soya milk or a glucoside-rich soya milk.
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Assessment of soy phytoestrogens' effects on bone turnover indicators in menopausal women with osteopenia in Iran: a before and after clinical trial.
Roudsari, AH, Tahbaz, F, Hossein-Nezhad, A, Arjmandi, B, Larijani, B, Kimiagar, SM
Nutrition journal. 2005;:30
Abstract
BACKGROUND Osteoporosis is the gradual declining in bone mass with age, leading to increased bone fragility and fractures. Fractures in hip and spine are known to be the most important complication of the disease which leads in the annual mortality rate of 20% and serious morbidity rate of 50%. Menopause is one of the most common risk factors of osteoporosis. After menopause, sex hormone deficiency is associated with increased remodeling rate and negative bone balance, leading to accelerated bone loss and micro-architectural defects, resulting into increased bone fragility. Compounds with estrogen-like biological activity similar to "Isoflavones" present in plants especially soy, may reduce bone loss in postmenopausal women as they are similar in structure to estrogens. This research, therefore, was carried out to study the effects of Iranian soy protein on biochemical indicators of bone metabolism in osteopenic menopausal women. MATERIALS AND METHODS This clinical trial of before-after type was carried out on 15 women 45-64 years of age. Subjects were given 35 g soy protein per day for 12 weeks. Blood and urine sampling, anthropometric measurement and 48-h-dietary recalls were carried out at zero, 6 and 12 weeks. Food consumption data were analyzed using Food Proccessor Software. For the study of bone metabolism indicators and changes in anthropometric data as well as dietary intake, and repeated analyses were employed. RESULTS Comparison of weight, BMI, physical activity, energy intake and other intervening nutrients did not reveal any significant changes during different stages of the study. Soy protein consumption resulted in a significant reduction in the urinary deoxypyridinoline and increasing of total alkaline phosphatase (p < 0.05), although the alterations in osteocalcin, c-telopeptide, IGFBP3 and type I collagen telopeptide were not significant. CONCLUSION In view of beneficial effect of soy protein on bone metabolism indicators, inclusion of this relatively inexpensive food in the daily diet of menopausal women, will probably delay bone resorption, thereby preventing osteoporosis.
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The effect of the phytoestrogen genistein and hormone replacement therapy on homocysteine and C-reactive protein level in postmenopausal women.
D'Anna, R, Baviera, G, Corrado, F, Cancellieri, F, Crisafulli, A, Squadrito, F
Acta obstetricia et gynecologica Scandinavica. 2005;(5):474-7
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BACKGROUND The aim of the study was to evaluate the effect, in postmenopausal women, of the phytoestrogen genistein and hormone replacement therapy (HRT) on circulating two independent factors of cardiovascular risk: homocysteine and C-reactive protein (CRP). METHODS Ninety healthy postmenopausal women, from 50 to 60 years of age, were randomly assigned to receive genistein (n = 30; 54 mg/die) or continuous combined estrogen/progestin therapy (17-beta-estradiol 1 mg plus norethisterone acetate 0.5 mg) or placebo. Plasma homocysteine and serum CRP were measured at baseline and after 6 months of treatment. RESULTS In the genistein group, plasma homocysteine and serum CRP showed no statistically significant difference from baseline (homocysteine: 11.36 +/- 0.39 micromol/l; CRP: 1.73 +/- 0.31 mg/l) to 6 months treatment (homocysteine: 10.72 +/- 0.46 micromol/l; CRP: 2.13 +/- 0.45 mg/l), without any significant difference versus the placebo group (homocysteine: 11.25 +/- 0.43 micromol/l; CRP: 1.74 +/- 0.22 mg/l). In the HRT group there was a slight, but not significant reduction, of plasma homocysteine mean value from baseline (11.21 +/- 0.44 micromol/l) to 6 months treatment (10.45 +/- 0.38 micromol/l); whereas CRP mean value at the end of treatment (3.30 +/- 0.55 mg/l) was significantly higher from baseline (1.61 +/- 0.25 mg/l) (P < 0.01). However, after 6 months, no significant difference existed with the other two groups. CONCLUSIONS The phytoestrogen genistein, after 6 months treatment, does not modify the independent cardiovascular risk linked to circulating homocysteine or CRP level. Our experience confirms critical increase of CRP serum level after HRT treatment, but not plasma homocysteine significant variation.
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Phytoestrogens may improve the pregnancy rate in in vitro fertilization-embryo transfer cycles: a prospective, controlled, randomized trial.
Unfer, V, Casini, ML, Gerli, S, Costabile, L, Mignosa, M, Di Renzo, GC
Fertility and sterility. 2004;(6):1509-13
Abstract
OBJECTIVE To compare the effectiveness of i.m. P and i.m. P plus oral phytoestrogens for luteal phase support in patients undergoing IVF-ET cycles. DESIGN Prospective, controlled, randomized trial. SETTING University Hospital, Perugia, Italy. PATIENT(S): Two hundred thirteen infertile patients undergoing IVF-ET were included in the study. The inclusion criteria were use of a GnRH agonist for pituitary down-regulation and age <40 years. The total number of cycles performed was 274. INTERVENTION(S): Patients were assigned to receive either i.m. P (50 mg daily) plus placebo or P (50 mg daily) plus phytoestrogen supplementation (1,500 mg daily) for luteal phase support starting from the evening of oocyte retrieval until either a serum pregnancy test result was negative or embryonic heartbeat was sonographically confirmed. MAIN OUTCOME MEASURE(S): The outcomes of IVF-ET were evaluated in both study groups in terms of implantation rate, biochemical pregnancy rate (PR), clinical PR, spontaneous abortion rate, and ongoing pregnancy/delivered rate. RESULT(S): Statistically significant higher values for implantation rate, clinical PR, and ongoing pregnancy/delivered rate were recorded in the patients who received P plus phytoestrogens for luteal phase support in comparison with patients receiving P and placebo. CONCLUSION(S): Although the results of this study encourage the use of phytoestrogens for luteal phase support in patients undergoing IVF-ET program, more studies are necessary to support the hypothesis that phytoestrogens have a beneficial effect in IVF cycles.