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Isoflavone pharmacokinetics and metabolism after consumption of a standardized soy and soy-almond bread in men with asymptomatic prostate cancer.
Ahn-Jarvis, JH, Clinton, SK, Grainger, EM, Riedl, KM, Schwartz, SJ, Lee, ML, Cruz-Cano, R, Young, GS, Lesinski, GB, Vodovotz, Y
Cancer prevention research (Philadelphia, Pa.). 2015;(11):1045-54
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Abstract
Epidemiologic associations suggest that populations consuming substantial amounts of dietary soy exhibit a lower risk of prostate cancer. A 20-week randomized, phase II, crossover trial was conducted in 32 men with asymptomatic prostate cancer. The crossover involved 8 weeks each of soy bread (SB) and soy-almond bread (SAB). The primary objective was to investigate isoflavone bioavailability and metabolite profile. Secondary objectives include safety, compliance, and assessment of biomarkers linked to prostate carcinogenesis. Two distinct SBs were formulated to deliver approximately 60 mg aglycone equivalents of isoflavones per day. The isoflavones were present as aglycones (∼78% as aglycones) in the SAB whereas in the standard SB predominantly as glucosides (18% total isoflavones as aglycones). Compliance to SB (97% ± 4%) and SAB (92% ± 18%) was excellent; toxicity was rare and limited to grade 1 gastrointestinal complaints. Pharmacokinetic studies between SB and SAB showed modest differences. Peak serum concentration time (Tmax) was significantly faster with SAB meal compared with SB in some isoflavonoids, and AUC0 to 24 h of dihydrodaidzein and O-desmethylangolensin was significantly greater after an SB meal. An exploratory cluster analysis was used to identify four isoflavone-metabolizing phenotypes. Insulin-like growth factor-binding protein increased significantly by 41% (P = 0.024) with soy intervention. Findings from this study provide the necessary framework to study isoflavone-metabolizing phenotypes as a strategy for identification of individuals that might benefit or show resistance to cancer preventive strategies using dietary soy. A standardized SB used for future large-scale randomized clinical trials to affect human prostate carcinogenesis is feasible.
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Consumption of soy isoflavone enriched bread in men with prostate cancer is associated with reduced proinflammatory cytokines and immunosuppressive cells.
Lesinski, GB, Reville, PK, Mace, TA, Young, GS, Ahn-Jarvis, J, Thomas-Ahner, J, Vodovotz, Y, Ameen, Z, Grainger, E, Riedl, K, et al
Cancer prevention research (Philadelphia, Pa.). 2015;(11):1036-44
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We hypothesized that soy phytochemicals may have immunomodulatory properties that may affect prostate carcinogenesis and progression. A randomized, phase II trial was conducted in 32 patients with prostate cancer with asymptomatic biochemical recurrence but no measurable disease on standard staging studies. Patients were randomized to two slices of soy bread (34 mg isoflavones/slice) or soy bread containing almond powder daily as a source of β-glucosidase. Flow cytometry and bioplex assays were used to measure cytokines or immune cell phenotype in blood at baseline (day 0) and following intervention (day 56). Adequate blood samples were available at enrollment and day 56 and evaluated. Multiple plasma cytokines and chemokines were significantly decreased on day 56 versus baseline. Subgroup analysis indicated reduced TH1 (P = 0.028) and myeloid-derived suppressor cell (MDSC)-associated cytokines (P = 0.035). TH2 and TH17 cytokines were not significantly altered. Phenotypic analysis revealed no change in CD8(+) or CD4(+) T cells but showed increased CD56(+) natural killer (NK) cells (P = 0.038). The percentage of cells with a T regulatory cell phenotype (CD4(+)CD25(+)FoxP3(+)) was significantly decreased after 56 days of soy bread (P = 0.0136). Significantly decreased monocytic (CD33(+)HLADR(neg)CD14(+)) MDSC were observed in patients consuming soy bread (P = 0.0056). These data suggest that soy bread modulates systemic soluble and cellular biomarkers consistent with limiting inflammation and suppression of MDSCs. Additional studies to elucidate impact on the carcinogenic process or as a complement to immune-based therapy are required.
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Effects of short-term fructooligosaccharide intake on equol production in Japanese postmenopausal women consuming soy isoflavone supplements: a pilot study.
Tousen, Y, Uehara, M, Abe, F, Kimira, Y, Ishimi, Y
Nutrition journal. 2013;:127
Abstract
BACKGROUND Recent studies suggest that some of the clinical effectiveness of soy or daidzein, which is a type of isoflavone, may be attributed to a person's ability to produce equol from daidzein. Equol, which is a metabolite of one of the major soybean isoflavones called daidzein, is produced in the gastrointestinal tract by certain intestinal microbiota where present. Habitual dietary patterns may alter the intestinal bacterial profile, and influence the metabolism of isoflavones and the production of equol. Fructooligosaccharides (FOS) have a prebiotic activity as well as being a dietary fibre. The purpose of the present study was to determine whether FOS supplementation increases equol production in equol producers and stimulates equol production in equol non-producers in Japanese postmenopausal women. METHODS A soy challenge was used to assess equol-producer status prior to the start of the study in healthy postmenopausal Japanese women. The study involved 4 separate groups in randomised crossover design. First, subjects were classified as equol producers (n = 25) or non-producers (n = 18), and then they were randomly assigned to the FOS or control group. All subjects received a daily dose of 37 mg isoflavone conjugates in the capsule (21 mg aglycone form) and either FOS (5 g/day) or sucrose as control, in a randomised crossover study design. Equol -production was assessed by testing the serum and urine before and after the 2-week supplementation period. RESULTS The analyses were conducted on 34 subjects completed the study, 21 (61.8%) were classified as equol producers, and 13 (38.2%) as non-producers. Significant differences were observed in the interaction effect of time × equol state after 1 week of intervention (p = 0.006). However there were no effects after 2 weeks of intervention (p = 0.516). Finally, in both equol producers and non-producers, FOS supplementation did not affect the serum equol concentration or the urinary equol to daidzein concentration ratios. CONCLUSIONS We have reported that FOS intervention (5 g/day for 2 weeks) does not significantly modulate the capacity of intestinal microbiota to produce equol in postmenopausal Japanese women, in either equol producers or non-producers in this pilot study. Further larger investigations that explore the roles of specific intestinal microbiota in equol production will enable the establishment of dietary conditions that are required to enhance equol production.
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Soy isoflavone supplementation for breast cancer risk reduction: a randomized phase II trial.
Khan, SA, Chatterton, RT, Michel, N, Bryk, M, Lee, O, Ivancic, D, Heinz, R, Zalles, CM, Helenowski, IB, Jovanovic, BD, et al
Cancer prevention research (Philadelphia, Pa.). 2012;(2):309-19
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Abstract
Soy isoflavone consumption may protect against breast cancer development. We conducted a phase IIB trial of soy isoflavone supplementation to examine its effect on breast epithelial proliferation and other biomarkers in the healthy high-risk breast. One hundred and twenty-six consented women underwent a random fine-needle aspiration (rFNA); those with 4,000 or more epithelial cells were randomized to a double-blind 6-month intervention of mixed soy isoflavones (PTIG-2535) or placebo, followed by repeat rFNA. Cells were examined for Ki-67 labeling index and atypia. Expression of 28 genes related to proliferation, apoptosis, and estrogenic effect was measured using quantitative reverse transcriptase PCR. Hormone and protein levels were measured in nipple aspirate fluid (NAF). All statistical tests were two-sided. Ninety-eight women were evaluable for Ki-67 labeling index. In 49 treated women, the median Ki-67 labeling index was 1.18 at entry and 1.12 post intervention, whereas in 49 placebo subjects, it was 0.97 and 0.92 (P for between-group change: 0.32). Menopausal stratification yielded similar results between groups, but within premenopausal soy-treated women, Ki-67 labeling index increased from 1.71 to 2.18 (P = 0.04). We saw no treatment effect on cytologic atypia or NAF parameters. There were significant increases in the expression of 14 of 28 genes within the soy, but not the control group, without significant between-group differences. Plasma genistein values showed excellent compliance. A 6-month intervention of mixed soy isoflavones in healthy, high-risk adult Western women did not reduce breast epithelial proliferation, suggesting a lack of efficacy for breast cancer prevention and a possible adverse effect in premenopausal women.
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Serum IGF-1 concentrations change with soy and seaweed supplements in healthy postmenopausal American women.
Teas, J, Irhimeh, MR, Druker, S, Hurley, TG, Hébert, JR, Savarese, TM, Kurzer, MS
Nutrition and cancer. 2011;(5):743-8
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Insulin-like growth factor 1 (IGF-1) is an anabolic hormone important for growth and development. However, high-circulating serum concentrations in adults are associated with increased risk of postmenopausal breast cancer. Nutritional status and specific foods influence serum IGF-1 concentrations. Breast cancer incidence is typically low in Asian countries where soy is commonly consumed. Paradoxically, soy supplement trials in American women have reported significant increases in IGF-1. Seaweed also is consumed regularly in Asian countries where breast cancer risk is low. We investigated the possibility that seaweed could modify soy-associated increases in IGF-1 in American women. Thirty healthy postmenopausal women (mean age 58 yr) participated in this 14-wk double-blinded, randomized, placebo-controlled crossover clinical trial. Participants consumed 5 g/day placebo or seaweed (Alaria esculenta) in capsules for 7 wk. During the 7th wk, a high-soy protein isolate powder was added (2 mg/kg body weight aglycone equivalent isoflavones). Overnight fasting blood samples were collected after each intervention period. Soy significantly increased serum IGF-1 concentrations compared to the placebo (21.2 nmol/L for soy vs. 16.9 nmol/L for placebo; P = 0.0001). The combination of seaweed and soy significantly reduced this increase by about 40% (21.2 nmol/L for soy alone vs. 19.4 nmol/L; P = 0.01). Concurrent seaweed and soy consumption may be important in modifying the effect of soy on IGF-1 serum concentrations.
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A mechanism of benefit of soy genistein in asthma: inhibition of eosinophil p38-dependent leukotriene synthesis.
Kalhan, R, Smith, LJ, Nlend, MC, Nair, A, Hixon, JL, Sporn, PH
Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology. 2008;(1):103-12
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BACKGROUND Dietary intake of the soy isoflavone genistein is associated with reduced severity of asthma, but the mechanisms responsible for this effect are unknown. OBJECTIVE To determine whether genistein blocks eosinophil leukotriene C(4) (LTC(4)) synthesis and to evaluate the mechanism of this effect, and to assess the impact of a 4-week period of soy isoflavone dietary supplementation on indices of eosinophilic inflammation in asthma patients. METHODS Human peripheral blood eosinophils were stimulated in the absence and presence of genistein, and LTC(4) synthesis was measured. 5-lipoxygenase (5-LO) nuclear membrane translocation was assessed by confocal immunofluorescence microscopy. Mitogen-activated protein (MAP) kinase activation was determined by immunoblot. Human subjects with mild-to-moderate persistent asthma and minimal or no soy intake were given a soy isoflavone supplement (100 mg/day) for 4 weeks. The fraction of exhaled nitric oxide (FE(NO)) and ex vivo eosinophil LTC(4) production were assessed before and after the soy isoflavone treatment period. RESULTS Genistein inhibited eosinophil LTC(4) synthesis (IC(50) 80 nm), blocked phosphorylation of p38 MAP kinase and its downstream target MAPKAP-2, and reduced translocation of 5-LO to the nuclear membrane. In patients with asthma, following 4 weeks of dietary soy isoflavone supplementation, ex vivo eosinophil LTC(4) synthesis decreased by 33% (N=11, P=0.02) and FE(NO) decreased by 18% (N=13, P=0.03). CONCLUSION At physiologically relevant concentrations, genistein inhibits eosinophil LTC(4) synthesis in vitro, probably by blocking p38- and MAPKAP-2-dependent activation of 5-LO. In asthma patients, dietary soy isoflavone supplementation reduces eosinophil LTC(4) synthesis and eosinophilic airway inflammation. These results support a potential role for soy isoflavones in the treatment of asthma.
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Short-term soybean intake and its effect on steroid sex hormones and cognitive abilities.
Ostatníková, D, Celec, P, Hodosy, J, Hampl, R, Putz, Z, Kúdela, M
Fertility and sterility. 2007;(6):1632-6
Abstract
OBJECTIVE To observe the effects of short-term soybean consumption on cognitive spatial abilities and changes in sex endocrine net in both genders. DESIGN Short-term prospective intervention study. SETTING Academic medical center. PATIENT(S): Fifty-four healthy females and 32 healthy males (18 - 25 y of age). INTERVENTION(S): Volunteers were asked to eat 2 g/kg per day of soybeans during 1 week. Saliva and plasma samples were taken, and psychometric tests were performed on the 1st (before soybean intake), 7th (after soybean intake), and 14th days (after washout period) of the study. MAIN OUTCOME MEASURE(S): Salivary T and plasma E(2) were measured. Mental rotation (MR) and spatial visualization (SV) tests were performed on the days of sampling. RESULT(S): Soybean intake did not change salivary T and plasma E(2) levels in men. During the washout period, both parameters have shown a tendency to rise. The effect of soybean intake on hormonal parameters in men was, however, dependent on the basal T levels. In women, salivary T as well as plasma E(2) levels showed a tendency toward a decline after soybean intake (the decrease in E(2) was statistically significant) and to increase back toward basal levels during the washout period. Both males and females statistically significantly improved in MR and SV after soybean intake. During the washout period, both genders further improved their results in MR but not in SV. CONCLUSION(S): Short-term soybean consumption alters the concentrations of salivary T and plasma E(2) in both men and women. Spatial abilities appear to be improved by short-term soybean intake, but the exact mechanisms require further study.
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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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Influence of 10 wk of soy consumption on plasma concentrations and excretion of isoflavonoids and on gut microflora metabolism in healthy adults.
Wiseman, H, Casey, K, Bowey, EA, Duffy, R, Davies, M, Rowland, IR, Lloyd, AS, Murray, A, Thompson, R, Clarke, DB
The American journal of clinical nutrition. 2004;(3):692-9
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BACKGROUND 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. OBJECTIVE 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. DESIGN 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. RESULTS 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. CONCLUSIONS 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.
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Gastrointestinal absorption and plasma kinetics of soy Delta(5)-phytosterols and phytostanols in humans.
Ostlund, RE, McGill, JB, Zeng, CM, Covey, DF, Stearns, J, Stenson, WF, Spilburg, CA
American journal of physiology. Endocrinology and metabolism. 2002;(4):E911-6
Abstract
Our objective was to measure the systemic absorption of lecithin-emulsified Delta(5)-phytosterols and phytostanols during test meals by use of dual stable isotopic tracers. Ten healthy subjects underwent two single-meal absorption tests in random order 2 wk apart, one with intravenous dideuterated Delta(5)-phytosterols and oral pentadeuterated Delta(5)-phytosterols and the other with the corresponding labeled stanols. The oral-to-intravenous tracer ratio in plasma, a reflection of absorption, was measured by a sensitive negative ion mass spectroscopic technique and became constant after 2 days. Absorption from 600 mg of Delta(5)-soy sterols given with a standard test breakfast was 0.512 +/- 0.038% for sitosterol and 1.89 +/- 0.27% for campesterol. The absorption from 600 mg of soy stanols was 0.0441 +/- 0.004% for sitostanol and 0.155 +/- 0.017% for campestanol. Reduction of the double bond at position 5 decreased absorption by 90%. Plasma t(1/2) for stanols was significantly shorter than that for Delta(5)-sterols. We conclude that the efficiency of phytosterol absorption is lower than what was reported previously and is critically dependent on the structure of both sterol nucleus and side chain.