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Concept: Genistein

28

It is well established that aberrant production of inflammatory mediators has been associated with most the toxic manifestations and the genesis of different chronic diseases including cancer. The basic aim of the present study is to investigate the effects of soy isoflavones (SIF) on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced cutaneous inflammatory responses and to explore the underlying molecular mechanisms. We have studied the protective effects of SIF against TPA induced oxidative stress, pro-inflammatory cytokines level, activation of NF-κB, expression of COX-2 and ki-67 in mouse skin. Animals were divided into five groups I-V (n=6). Groups II, III and IV received topical application of TPA at the dose of 10nmol/0.2ml of acetone/animal/day, for 2 days. Animals of the groups III and IV were pre-treated with SIF 1.0μg (D1) and 2.0μg (D2) topically 30min prior to each TPA administration, while groups I and V were given acetone (0.2ml) and SIF (D2), respectively. We have found that SIF pretreatment significantly inhibited TPA induced oxidative stress, proinflammatory cytokines production and activation of NF-κB. SIF also inhibited the expression of COX-2 and ki-67. Histological findings further supported the protective effects of SIF against TPA-induced cutaneous damage. Thus, our results suggest that inhibitory effect of SIF on TPA-induced cutaneous inflammation includes inhibition of proinflammatory cytokines, attenuation of oxidative stress, activation of NF-κB and expression of COX-2.

Concepts: Inflammation, Cytokine, Asthma, Soybean, Isoflavones, Genistein, Topical, Daidzein

28

Soybeans are rich in immuno-modulatory isoflavones such as genistein, daidzein, and glycitein. These isoflavones are well-known antioxidants, chemopreventive and anti-inflammatory agents. Several epidemiological studies suggest that consumption of traditional soy food containing isoflavones is associated with reduced prevalence of chronic health disorders. Isoflavones are considered to be phytoestrogens because of their ability to bind to estrogen receptors. The literature is extensive on the chemistry, bio-availability, and bio-activity of isoflavones. However, their effects on immune response are yet to be fully understood, but are beginning to be appreciated. We review the role of isoflavones in regulation of the immune response and their potential clinical applications in immune-dysfunction. Special emphasis will be made regarding in vivo studies including humans and animal model systems.

Concepts: Immune system, Inflammation, Epidemiology, Soybean, Isoflavones, Genistein, Daidzein, Tofu

27

SCOPE: Daidzein is one of the major soy isoflavones. Following ingestion, daidzein is readily metabolized in the liver and converted into hydroxylated metabolites. One such metabolite is 6,7,4'-trihydroxyisoflavone (6,7,4'-THIF), which has been the focus of recent studies due to its various health benefits, however, its anti-adipogenic activity has not been investigated. Our objective was to determine the effects of 6,7,4'-THIF on adipogenesis in 3T3-L1 preadipocytes and elucidate the mechanisms of action involved. METHODS AND RESULTS: Adipogenesis was stimulated in 3T3-L1 preadipocytes. Both 6,7,4'-THIF and daidzein were treated in the presence and absence of mixture of isobutylmethylxanthine, dexamethasone, and insulin (MDI). We observed that 6,7,4'-THIF, but not daidzein, inhibited MDI-induced adipogenesis significantly at 40 and 80 μM, associated with decreased peroxisome proliferator-activated receptor-γ and C/EBP-α protein expression. 6,7,4'-THIF significantly suppressed MDI-induced lipid accumulation in the early stage of adipogenesis, attributable to a suppression of cell proliferation and the induction of cell cycle arrest. We also determined that 6,7,4'-THIF, but not daidzein, attenuated phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. 6,7,4'-THIF was found to inhibit PI3K activity via direct binding in an ATP-competitive manner. CONCLUSION: Our results suggest that 6,7,4'-THIF suppresses adipogenesis in 3T3-L1 preadipocytes by directly targeting PI3K. Soy isoflavones like 6,7,4'-THIF may have potential for development into novel treatment strategies for chronic obesity.

Concepts: Protein, Signal transduction, Metabolism, Liver, Soybean, Isoflavones, Genistein, Daidzein

25

The objectives of this study are to systematically assess the bioactive substances and overall antioxidant capacities of commercially fermented soy products and to find the relationships between the presence of beneficial components in different types of soybean fermented products. The results show that phenolic profiles increased significantly after fermentation as compared with raw yellow soybeans. Among all the samples, the douchi and fermented black bean sauce had the highest detected antioxidant profiles. Even though the total isoflavone content was reduced in fermented soybean products (794.84 μg/g on average) as compared with raw yellow soybeans (3477.6 μg/g), there was an obvious trend of conversion of the glucoside form in raw soybeans into the aglycone-form isoflavones in the fermented soybean products. The highest daidzein and genistein values were found in the “Yangfan” black bean douchi, i.e. 860.3 μg/g and 1025.9 μg/g, respectively. The amounts of essential amino acids also were improved in most fermented soybean products. The douchi and black bean fermented products are recommended for consumption due to their abundant bioactive substances.

Concepts: Amino acid, Soybean, Isoflavones, Genistein, Daidzein, Glycine, Tempeh, Douchi

8

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.

Concepts: Scientific method, Cancer, Nutrition, Prostate cancer, Soybean, Isoflavones, Genistein, Daidzein

8

Genistein is one of the main soy isoflavones in our daily diet. There were studies proving that high-dietary intake of genistein may relate to the low morbidity and mortality of prostate cancer (PCa) in the Asian population. Since there were few studies of plasma genistein level in the Chinese population, we performed this study to preliminarily evaluate the associations among plasma genistein, epidemiologic factors and PCa in a Chinese population.

Concepts: Cancer, Metastasis, Obesity, Prostate cancer, Soybean, Isoflavones, Genistein, Daidzein

8

Soy isoflavones (SIF) are present in the systemic circulation as conjugated forms of which the estrogenic potency is not yet clear. The present study provides evidence that the major SIF glucuronide metabolites in blood, genistein-7-O-glucuronide (GG) and daidzein-7-O-glucuronide (DG), only become estrogenic after deconjugation. The estrogenic potencies of genistein (Ge), daidzein (Da), GG and DG were determined using stably transfected U2OS-ERα, U2OS-ERβ reporter gene cells and proliferation was tested in T47D-ERβ cells mimicking the ERα/ERβ ratio of healthy breast cells and inT47D breast cancer cells. In all assays applied, the estrogenic potency of the aglycones was significantly higher than that of their corresponding glucuronides. UPLC analysis revealed that in U2OS and T47D cells, 0.2-1.6% of the glucuronides were deconjugated to their corresponding aglycones.The resulting aglycone concentrations can account for the estrogenicityobserved upon glucuronide exposure. Interestingly, under similar experimental conditions, rat breast tissue S9 fraction was about 30 times more potent in deconjugating these glucuronides than human breast tissue S9 fraction. Our study confirms that SIF glucuronides are not estrogenic as such, and that the small% of deconjugation in the cell is enough to explain the slight bioactivity observed for the SIF-glucuronides. Species differences in deconjugation capacity should be taken into account when basing risk-benefit assessment of these SIF for the human population on animal data.

Concepts: Breast cancer, Estrogen, Soybean, Isoflavones, Genistein, Breast, Glycoside, Daidzein

5

Pueraria lobata roots accumulate a rich source of isoflavonoid glycosides, including 7-O- and 4'-O-mono-glucosides, and 4',7-O-diglucosides, which have numerous human health benefits. Although, isoflavonoid 7-O-glucosyltranferases (7-O-UGTs) have been well-characterized at molecular levels in legume plants, genes, or enzymes that are required for isoflavonoid 4'-O- and 4',7-O-glucosylation have not been identified in P. lobata to date. Especially for the 4',7-O-di-glucosylations, the genetic control for this tailing process has never been elucidated from any plant species. Through transcriptome mining, we describe here the identification and characterization of a novel UGT (designated PlUGT2) governing the isoflavonoid 4',7-O-di-glucosylations in P. lobata. Biochemical roles of PlUGT2 were assessed by in vitro assays with PlUGT2 protein produced in Escherichia coli and analyzed for its qualitative substrate specificity. PlUGT2 was active with various (iso)flavonoid acceptors, catalyzing consecutive glucosylation activities at their O-4' and O-7 positions. PlUGT2 was most active with genistein, a general isoflavone in legume plants. Real-time PCR analysis showed that PlUGT2 is preferentially transcribed in roots relative to other organs of P. lobata, which is coincident with the accumulation pattern of 4'-O-glucosides and 4',7-O-diglucosides in P. lobata. The identification of PlUGT2 would help to decipher the P. lobata isoflavonoid glucosylations in vivo and may provide a useful enzyme catalyst for an efficient biotransformation of isoflavones or other natural products for food or pharmacological purposes.

Concepts: Protein, Genetics, Polymerase chain reaction, Molecular biology, Enzyme, Plant, Escherichia coli, Genistein

5

There is much speculation with regard to the potential cardioprotective benefits of equol, a microbial-derived metabolite of the isoflavone daidzein, which is produced in the large intestine after soy intake in 30% of Western populations. Although cross-sectional and retrospective data support favorable associations between the equol producer (EP) phenotype and cardiometabolic health, few studies have prospectively recruited EPs to confirm this association.

Concepts: Randomized controlled trial, Intestine, Small intestine, Soybean, Isoflavones, Genistein, Producer, Daidzein

1

Menopausal estrogen loss leads to an increased bone loss. Soy isoflavones can act as selective estrogen receptor modulators, their role in bone turnover is unclear. The primary outcome was assessing changes in plasma bone turnover markers. The secondary outcomes were assessing changes in cardiovascular risk markers including insulin resistance, blood pressure and lipid profile. We performed a double blind randomised parallel study where 200 women within 2 years after the onset of their menopause were randomised to 15 g soy protein with 66mg isoflavone (SPI) or 15 g soy protein alone (SP), daily for 6 months. There was a significant reduction in type I collagen crosslinked Beta C-telopeptide (βCTX) (bone-resorption marker) with SPI supplementation (0.40 ± 0.17 vs. 0.15 ± 0.09µg/L; p < 0.01) compared to SP supplementation (0.35 ± 0.12 vs. 0.35 ± 0.13µg/L; p = 0.92) after 6 months. There was also a significant reduction in type I procollagen-N-propeptide (P1NP) (bone-formation marker) with SPI supplementation (50.5 ± 25.0 vs. 34.3 ± 17.6µg/L; p < 0.01), more marked between 3 and 6 month. Following SPI there was a significant reduction in fasting glucose, fasting insulin, insulin resistance and systolic blood pressure whereas no significant changes in these parameters was observed with SP. There were no significant changes in fasting lipid profile and diastolic blood pressure with either preparation. There was a significant increase in TSH and reduction in free thyroxine (p < 0.01) with SPI supplementation though free tri-iodothyronine was unchanged. In conclusion, soy protein with isoflavones may confer a beneficial effect on bone health, analogous to the mode of action of anti-resorptive agents albeit to a less magnitude. There was a significant improvement of cardiovascular risk markers, but a significant increase in TSH and reduction in free thyroxine after SPI supplementation indicating a detrimental effect on thyroid function. This article is protected by copyright. All rights reserved.

Concepts: Osteoporosis, Blood, Hormone, Blood pressure, Menopause, Estrogen, Soybean, Genistein