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Soy Isoflavone Supplementation Increases Long Interspersed Nucleotide Element-1 (LINE-1) Methylation in Head and Neck Squamous Cell Carcinoma.
Rozek, LS, Virani, S, Bellile, EL, Taylor, JMG, Sartor, MA, Zarins, KR, Virani, A, Cote, C, Worden, FP, Mark, MEP, et al
Nutrition and cancer. 2019;(5):772-780
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AIM: Soy isoflavones have been suggested as epigenetic modulating agents with effects that could be important in carcinogenesis. Hypomethylation of LINE-1 has been associated with head and neck squamous cell carcinoma (HNSCC) development from oral premalignant lesions and with poor prognosis. To determine if neoadjuvant soy isoflavone supplementation could modulate LINE-1 methylation in HNSCC, we undertook a clinical trial. METHODS Thirty-nine patients received 2-3 weeks of soy isoflavone supplements (300 mg/day) orally prior to surgery. Methylation of LINE-1, and 6 other genes was measured by pyrosequencing in biopsy, resection, and whole blood (WB) specimens. Changes in methylation were tested using paired t tests and ANOVA. Median follow up was 45 months. RESULTS LINE-1 methylation increased significantly after soy isoflavone (P < 0.005). Amount of change correlated positively with days of isoflavone taken (P = 0.04). Similar changes were not seen in corresponding WB samples. No significant changes in tumor or blood methylation levels were seen in the other candidate genes. CONCLUSION This is the first demonstration of in vivo increases in tissue-specific global methylation associated with soy isoflavone intake in patients with HNSCC. Prior associations of LINE-1 hypomethylation with genetic instability, carcinogenesis, and prognosis suggest that soy isoflavones maybe potential chemopreventive agents in HNSCC.
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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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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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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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Phase II trial of isoflavone in prostate-specific antigen recurrent prostate cancer after previous local therapy.
Pendleton, JM, Tan, WW, Anai, S, Chang, M, Hou, W, Shiverick, KT, Rosser, CJ
BMC cancer. 2008;:132
Abstract
BACKGROUND Data exist that demonstrate isoflavones' potent antiproliferative effects on prostate cancer cells. We evaluated the efficacy of isoflavone in patients with PSA recurrent prostate cancer after prior therapy. We postulated that isoflavone therapy would slow the rate of rise of serum PSA. METHODS Twenty patients with rising PSA after prior local therapy were enrolled in this open-labeled, Phase II, nonrandomized trial (Trial registration # NCT00596895). Patients were treated with soy milk containing 47 mg of isoflavonoid per 8 oz serving three times per day for 12 months. Serum PSA, testosterone, lipids, isoflavone levels (genistein, daidzein, and equol), and quality of life (QOL) were measured at various time points from 0 to 12 months. PSA outcome was evaluated. RESULTS Within the mixed regression model, it was estimated that PSA had increased 56% per year before study entry and only increased 20% per year for the 12-month study period (p = 0.05). Specifically, the slope of PSA after study entry was significantly lower than that before study entry in 6 patients and the slope of PSA after study entry was significantly higher than before study entry in 2 patients. For the remaining 12 patients, the change in slope was statistically insignificant. Nearly two thirds of the patients were noted to have significant levels of free equol in their serum while on therapy. CONCLUSION Dietary intervention with isoflavone supplementation may have biologic activity in men with biochemical recurrent prostate cancer as shown by a decline in the slope of PSA. This study may lend support to the literature that nutritional supplements have biologic activity in prostate cancer and therefore, further studies with these agents in randomized clinical trials should be encouraged.
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Proteomic biomarkers of peripheral blood mononuclear cells obtained from postmenopausal women undergoing an intervention with soy isoflavones.
Fuchs, D, Vafeiadou, K, Hall, WL, Daniel, H, Williams, CM, Schroot, JH, Wenzel, U
The American journal of clinical nutrition. 2007;(5):1369-75
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BACKGROUND The incidence of cardiovascular diseases increases after menopause, and soy consumption is suggested to inhibit disease development. OBJECTIVE The objective was to identify biomarkers of response to a dietary supplementation with an isoflavone extract in postmenopausal women by proteome analysis of peripheral blood mononuclear cells. DESIGN The study with healthy postmenopausal woman was performed in a placebo-controlled sequential design. Peripheral mononuclear blood cells were collected from 10 volunteers after 8 wk of receiving daily 2 placebo cereal bars and after a subsequent 8 wk of intervention with 2 cereal bars each providing 25 mg of isoflavones. The proteome of the cells was visualized after 2-dimensional gel electrophoresis, and peptide mass fingerprinting served to identify proteins that by the intervention displayed altered protein concentrations. RESULTS Twenty-nine proteins were identified that showed significantly altered expression in the mononuclear blood cells under the soy-isoflavone intervention, including a variety of proteins involved in an antiinflammatory response. Heat shock protein 70 or a lymphocyte-specific protein phosphatase and proteins that promote increased fibrinolysis, such as alpha-enolase, were found at increased intensities, whereas those that mediate adhesion, migration, and proliferation of vascular smooth muscle cells, such as galectin-1, were found at reduced intensities after soy extract consumption. CONCLUSION Proteome analysis identified in vivo markers that respond to a dietary intervention with isoflavone-enriched soy extract in postmenopausal women. The nature of the proteins identified suggests that soy isoflavones may increase the antiinflammatory response in blood mononuclear cells that might contribute to the atherosclerosis-preventive activities of a soy-rich diet.
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Soy isoflavone intake and estrogen excretion patterns in young women: effect of probiotic administration.
Cohen, LA, Crespin, JS, Wolper, C, Zang, EA, Pittman, B, Zhao, Z, Holt, PR
In vivo (Athens, Greece). 2007;(3):507-12
Abstract
BACKGROUND Soy isoflavones may lower breast cancer risk through altered hepatic estrogen metabolism, leading to increased urinary excretion ratios of 2-hydroxyestrone (20HE1) to 16a-hydroxyestrone (16alphaOHE1). MATERIALS AND METHODS Urinary excretion of 20HE1/16alphaOHE1 was measured in 36 healthy, pre-menstrual women before and after ingestion of a soy-protein formula containing 120 mg of isoflavone daily for one month. Since isoflavone absorption and metabolism depends on intestinal bacteria, effects of co-administration of Lactobacillus GG (2 x 10(12)) on estrogen ratios and isoflavone excretion were studied. Urinary isoflavone excretion measurements assessed compliance. RESULTS Soy isoflavone ingestion induced quantitative differences in urinary excretion of estrogen metabolites and isoflavones but failed to alter 20HE1/16alphaOHE1 ratios. Co-administration of Lactobacillus GG with soy reduced excretion of total and individual isoflavones by 40% (p=0.08), without altering 2OHE1/16alphaOHE1 ratios. CONCLUSION Isoflavone-rich soy protein administration alone, or with probiotic supplement, did not alter urinary excretion of estrogen metabolites in premenopausal women. However, adding concentrated probiotics may alter isoflavone bioavailability.
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Blood lipid and oxidative stress responses to soy protein with isoflavones and phytic acid in postmenopausal women.
Engelman, HM, Alekel, DL, Hanson, LN, Kanthasamy, AG, Reddy, MB
The American journal of clinical nutrition. 2005;(3):590-6
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BACKGROUND Postmenopausal women are at risk of cardiovascular disease (CVD) as a result of unfavorable blood lipid profiles and increased oxidative stress. Soy protein consumption may help protect against these risk factors. OBJECTIVE Our objective was to ascertain the effect of the soy protein components isoflavones and phytate on CVD risk in postmenopausal women. DESIGN In a double-blind 6-wk study, 55 postmenopausal women were randomly assigned to 1 of 4 treatments with soy protein (40 g/d) isolate (SPI): low phytate/low isoflavone (LP/LI); normal phytate/low isoflavone (NP/LI); low phytate/normal isoflavone (LP/NI); or normal phytate/normal isoflavone (NP/NI). Blood lipids (total, LDL, and HDL cholesterol and triacylglycerol) and oxidative stress indexes (protein carbonyls, oxidized LDLs, and 8-iso-prostaglandin-F(2alpha)) were measured at baseline and 6 wk. RESULTS The oxidative stress indexes were not significantly affected by either phytate or isoflavones. Phytate treatment had a minimal but nonsignificant effect in reducing protein carbonyls and 8-iso-prostaglandin-F(2alpha); the reductions were 6-8% and 4-6% in the NP/LI and NP/NI groups and 1-4% and 3-4% in the LP/LI and LP/NI groups, respectively. Similarly, circulating lipids were not significantly affected by either phytate or isoflavones. The decline in total (6%-7% compared with 2%-4%) and LDL (10%-11% compared with 3%-7%) cholesterol did not differ significantly between the normal- and low-isoflavone groups, respectively. CONCLUSION In postmenopausal women, neither phytate nor isoflavones in SPI have a significant effect of reducing oxidative damage or favorably altering blood lipids.
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The effect of soy consumption on the urinary 2:16-hydroxyestrone ratio in postmenopausal women depends on equol production status but is not influenced by probiotic consumption.
Nettleton, JA, Greany, KA, Thomas, W, Wangen, KE, Adlercreutz, H, Kurzer, MS
The Journal of nutrition. 2005;(3):603-8
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Some epidemiologic studies reported an association between a low ratio of urinary 2-hydroxyestrogens (2-hydroxyestradiol + 2-hydroxyestrone) to 16alpha-hydroxyestrone (2:16OHE(1)) and increased breast cancer risk. Some studies show that soy consumption increases this ratio, and it is suggested that this effect may reduce breast cancer risk. We hypothesized that consumption of probiotic bacteria would alter fecal bacteria and enzymes involved in soy isoflavone metabolism, thereby increasing isoflavone bioavailability and enhancing the beneficial effects of soy on estrogen metabolism. Breast cancer survivors (n = 20) and controls (n = 20) were given 4 treatments for 6 wk each, separated by 2-wk washout periods, in a randomized, crossover design: soy protein (26.6 +/- 4.5 g protein/d containing 44.4 +/- 7.5 mg isoflavones/d); soy protein + probiotics (10(9) colony-forming units Lactobacillus acidophilus DDS(R)+1 & Bifidobacterium longum, 15-30 mg fructooligosaccharide/d); milk protein (26.6 +/- 4.5 g protein/d); and milk protein + probiotics. Survivors tended to have a lower baseline urine 2:16OHE(1) ratio than controls (P = 0.10). In the group as a whole, soy consumption tended to increase urinary 2-hydroxyestrogens (P = 0.07) and 16alpha-hydroxyestrone (P = 0.11) but had no effect on the urinary 2:16OHE(1) ratio. When subjects were divided into groups by plasma concentrations and urinary levels of the daidzein metabolite equol, soy increased urinary 2-hydroxyestrogens (P = 0.01) and the 2:16OHE(1) ratio (P = 0.04) only in subjects with high plasma equol concentrations. None of these results were influenced by probiotic consumption. These results are consistent with studies that found lower urine 2:16OHE(1) ratios in women with breast cancer and suggest that soy consumption increases this ratio only in women who are equol producers.
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Randomized controlled trial of the effects of soy protein containing isoflavones on vascular function in postmenopausal women.
Kreijkamp-Kaspers, S, Kok, L, Bots, ML, Grobbee, DE, Lampe, JW, van der Schouw, YT
The American journal of clinical nutrition. 2005;(1):189-95
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BACKGROUND The incidence of cardiovascular disease increases after menopause, possibly because of the decline in estrogen. Soy protein, a rich source of estrogen-like isoflavones, is hypothesized to improve vascular function. OBJECTIVE The objective of this study was to investigate whether supplementation with soy protein, a rich source of estrogen-like isoflavones, improves vascular function. DESIGN We performed a 12-mo double-blind randomized trial to compare the effects of soy protein containing 99 mg isoflavones/d (aglycone weights) with those of milk protein (placebo) on blood pressure and endothelial function in 202 postmenopausal women aged 60-75 y. RESULTS Changes in endothelial function during the intervention were not significantly different between the soy and the placebo groups. After the intervention, systolic blood pressure increased in the soy group significantly more than it did in the placebo group; the difference in change was 4.3 mm Hg (95% CI: 0.3, 8.4 mm Hg; P = 0.04) for systolic blood pressure, but only 2.0 mm Hg (95% CI: -0.74, 4.71 mm Hg; P = 0.15) for diastolic blood pressure. In the soy group only, systolic and diastolic blood pressure decreased and endothelial function improved in the equol producers, whereas systolic and diastolic blood pressure increased and endothelial function deteriorated in the equol nonproducers. CONCLUSIONS The results of this trial do not support the hypothesis that soy protein containing isoflavones have beneficial effects on vascular function in older postmenopausal women. Whether certain subgroups of women (eg, equol producers) do benefit from the intervention remains to be elucidated.
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The effects of phytoestrogen isoflavones on bone density in women: a double-blind, randomized, placebo-controlled trial.
Atkinson, C, Compston, JE, Day, NE, Dowsett, M, Bingham, SA
The American journal of clinical nutrition. 2004;(2):326-33
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BACKGROUND Isoflavone phytoestrogen therapy has been proposed as a natural alternative to hormone replacement therapy (HRT). HRT has a beneficial effect on bone, but few trials in humans have investigated the effects of isoflavones on bone. OBJECTIVE The objective of the study was to determine the effect on bone density of a red clover-derived isoflavone supplement that provided a daily dose of 26 mg biochanin A, 16 mg formononetin, 1 mg genistein, and 0.5 mg daidzein for 1 y. Effects on biochemical markers of bone turnover and body composition were also studied. DESIGN Women aged 49-65 y (n = 205) were enrolled in a double-blind, randomized, placebo-controlled trial; 177 completed the trial. Bone density, body composition, bone turnover markers, and diet were measured at baseline and after 12 mo. RESULTS Loss of lumbar spine bone mineral content and bone mineral density was significantly (P = 0.04 and P = 0.03, respectively) lower in the women taking the isoflavone supplement than in those taking the placebo. There were no significant treatment effects on hip bone mineral content or bone mineral density, markers of bone resorption, or body composition, but bone formation markers were significantly increased (P = 0.04 and P = 0.01 for bone-specific alkaline phosphatase and N-propeptide of collagen type I, respectively) in the intervention group compared with placebo in postmenopausal women. Interactions between treatment group and menopausal status with respect to changes in other outcomes were not significant. CONCLUSION These data suggest that, through attenuation of bone loss, isoflavones have a potentially protective effect on the lumbar spine in women.