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Background: This study investigates the effect of genistein (Gen) on the lipid profiles and expression of low-density lipoprotein receptor (LDLR), liver X receptor α (LXRα) and ATP-binding cassette transporter G1 (ABCG1) in the plasma macrophages of postmenopausal women with hyperlipidemia in China. Methods: This study considered 187 cases, where 160 postmenopausal women had hyperlipidemia. The subjects were divided into placebo group (PG) and experimental group (EG). EG received 60 mg/day of Gen, PG received placebo for 6 months. Body weight, height, waist circumference, body mass index and glucose levels were determined according to standard operating procedures. The triglyceride (TG), total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), apolipoprotein-A1 (Apo-A1) and apolipoprotein-B (Apo-B) levels were detected in the plasma macrophages using ELISA. The protein and mRNA expression levels of LDLR, LXRα and ABCG1 were detected by western blot and real-time PCR techniques, respectively. Results: Compared to the baseline, Gen effectively lowered TG, TC and LDL-C levels, whereas HDL-C levels as well as the protein and mRNA expression levels of LDLR, LXRα and ABCG1 (p < 0.05) were increased. There was a significant difference in the expression of LDLR protein between the two groups (p < 0.05). The mRNA expression levels of LDLR, LXRα and ABCG1 were significantly increased in the EG compared to the PG. Conclusion: Gen effectively modulated the plasma lipid indices. The cholesterol-lowering effects of Gen may be attributed to its regulation on some of the key genes involved in cholesterol homeostasis. [ABSTRACT FROM AUTHOR]

Background: Long term dietary consumption of genistein by Chinese men is associated with decreased PCa metastasis and mortality. Short term treatment of US men with prostate cancer (PCa) with genistein decreases MMP-2 in prostate tissue. MEK4 regulates MMP-2 expression, drives PCa metastasis, and genistein inhibits MEK4, decreases MMP-2 expression and dietary dosing inhibits human PCa metastasis in mice. This study examines short- versus long-term treatment effects of genistein in humans and in vitro. Methods and findings: US men with localized PCa were treated on a phase II trial with genistein (N = 14) versus not (N = 14) for one month prior to radical prostatectomy. Prostate epithelial cells were removed from fresh frozen tissue by laser capture microdissection, and the expression of 12,000 genes profiled. Genistein significantly altered the expression of four genes, three had established links to cancer cell motility and metastasis. Of these three, one was a non-coding transcript, and the other two were BASP1 and HCF2. Genistein increased BASP1 expression in humans, and its engineered over expression and knockdown demonstrated that it suppressed cell invasion in all six human prostate cell lines examined. Genistein decreased HCF2 expression in humans, and it was shown to increase cell invasion in all cell lines examined. The expression of MMP-2, MEK4 and BASP1 was then measured in formalin fixed prostate tissue from N = 38 Chinese men living in China and N = 41 US men living in the US, both cohorts with localized PCa. MMP-2 was 52% higher in Chinese compared to US tissue (P < 0.0001), MEK4 was 48% lower (P < 0.0001), and BASP1 was unaltered. Treatment of PC3 human PCa cells in vitro for up to 8 weeks demonstrated that short term genistein treatment decreased MMP-2, while long term treatment increased it, both changes being significant (P<0.05) compared to untreated control cells. Long term genistein-treated cells retained their responsiveness to genistein’s anti-motility effect. Conclusions: Genistein inhibits pathways in human prostate that drive transformation to a lethal high motility phenotype. Long term treatment induces compensatory changes in biomarkers of efficacy. The current strategy of using such biomarkers after short term intervention as go/no-go determinants in early phase chemoprevention trials should be carefully examined. [ABSTRACT FROM AUTHOR]

Phytoestrogens (PEs) may harm liver function. However, studies in pregnant women are limited. Our study was conducted in pregnant women to assess the effect of serum PEs on liver function markers. We conducted a cross-sectional study focusing in the first trimester of pregnancy. A total of 352 pregnant women were enrolled in the study. We used generalized linear model (GLM) to explore the associations between each PE and each marker of liver function. We used Quantile g-computation (Qgcomp) and Bayesian kernel machine regression (BKMR) models to explore the associations between mixed exposure to all PEs and liver function markers. The GLM results showed that equol (EQU), daidzein (DAD), genistein (GEN), enterolactone (ENT), and enterodiol (END) were negatively correlated with albumin (ALB). DAD and GEN were associated with elevated alanine aminotransferase (ALT). DAD, GEN, naringin (NAR), and glycitein (GLY) were related to elevated aspartate aminotransferase (AST). Mixed exposure model results showed that the mixture of PEs was associated with reduced ALB. Our results support the existence of associations between PEs and maternal liver function in the first trimester. Emphasizing the detrimental associations between serum PEs and liver function in pregnant women is essential to ensure maternal liver health during pregnancy., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Ormosia hosiei Hemsl. et Wils. is an economical and medicinal plant, increasingly cultivated in China; however, its branches and leaves are often pruned as waste. This is the first study focused on the phytochemical profiles and antioxidant, anti- α -glucosidase, anti-tyrosinase, and anti-neuroinflammatory activities of the branches and leaves of O. hosiei. Herein, thirty-seven characteristic compounds were identified by UPLC-MS/MS and twelve were detected for the first time in O. hosiei. Twenty-seven phenolics were further quantified and significant differences in phenolic compositions between the branches and leaves of O. hosiei were observed. The ethanol extracts exhibited promising antioxidant, anti- α -glucosidase, anti-tyrosinase, and anti-neuroinflammatory effects, and the bioactivities significantly correlated with total phenolic content and twelve individual phenolics. Naringin, genistein, vitexin, vitexin-2- O -rhamnoside, syringaresinol and syringaresinol-4- O - β - D -glucopyranoside can be considered potential quality markers of O. hosiei. Our results provided solid evidence that the branches and leaves of O. hosiei deserve more attention and exploitation, considering the potential to be developed as functional foods or herbal medicines. [Display omitted] • Thirty-seven compounds were identified in O. hosiei by UPLC-MS/MS. • Twenty-seven phenolics in O. hosiei extracts were quantified. • The branches and leaves varied markedly in their phenolic compositions. • Higher phenolic content in O. hosiei extracts results in the higher bioactivities. • Six phenolics can be considered potential quality markers of this herb. [ABSTRACT FROM AUTHOR]

The objective of this work was to investigate the effect of orally administered genistein on the pharmacokinetics of imatinib and N-desmethyl imatinib in rats. Twenty-five healthy male SD (Sprague-Dawley) rats were randomly divided into five groups: A group (control group), B group (multiple dose of 100 mg/kg genistein for consecutive 15 days), C group (multiple dose of 50 mg/kg genistein for consecutive 15 days), D group (a single dose of 100 mg/kg genistein), and E group (a single dose of 50 mg/kg genistein). A single dose of imatinib is administered orally 30 min after administration of genistein (100 mg/kg or 50 mg/kg). The pharmacokinetic parameters of imatinib and N-desmethyl imatinib were calculated by DAS 3.0 software. The multiple dose of 100 mg/kg or 50 mg/kg genistein significantly (P<0.05) decreased the AUC0-t and Cmax of imatinib. AUC0-t and the Cmax of N-desmethyl imatinib were also increased, but without any significant difference. However, the single dose of 100 mg/kg or 50 mg/kg genistein has no effect on the pharmacokinetics of imatinib and N-desmethyl imatinib. Those results indicated that multiple dose of genistein (100 mg/kg or 50 mg/kg) induces the metabolism of imatinib, while single dose of genistein has no effect. [ABSTRACT FROM AUTHOR]

The potential influence of dietary phytoestrogen exposure on human health during different life phases including early childhood is a matter of scientific debate. In order to improve the risk–benefit assessment of exposure to dietary phytoestrogen, reliable and age-stratified exposure data are desirable. For contributing to the database on phytoestrogen exposure, in the present study plant-derived foods from the Chinese market were analysed by LC-MS/MS for their contents of phytoestrogens, including daidzein, genistein, secoisolariciresinol, glycitein and coumestrol. The analytical data showed the presence of phytoestrogens in a concentration range of less than 0.1 to about 50 μg g−1. Dietary intake was assessed on the basis of average food intake data obtained from interviewing 1000 randomly selected people with the help of food frequency questionnaires. Based on the overall population sampled, the average total phytoestrogen intake was estimated at 232 μg kg−1 day−1. Genistein contributed to about 66%, secoisolariciresinol and glycitein to about 10% each, and daidzein to about 7% of the overall intake. Coumestrol was present only in trace amounts. Age-related exposure assessment indicated that pre-pubertal children (aged 0–14 years) were exposed at the highest level with an average total phytoestrogen intake of 621 μg kg−1 day−1. The substantially higher average exposure of children as compared with adults should trigger further research into the potential health effects of early life exposure to phytoestrogen. [ABSTRACT FROM PUBLISHER]

Abstract: Isoflavones, mainly found in soy, have been shown to inhibit ovarian cancer cell proliferation. We hypothesized that soy consumption and isoflavone intake are related to the risk of ovarian cancer. A case–control study was conducted in southern China to ascertain this hypothesis. Five hundred incident patients with histologically confirmed cancer of the ovary and 500 controls (mean age 59 years) were recruited from four public hospitals in Guangzhou. Information on habitual consumption of soy foods, including soybean, soy milk, fresh tofu, dried tofu, and soybean sprout, was obtained face-to-face from participants through a validated and reliable semi-quantitative food frequency questionnaire. Isoflavone intakes were then estimated using the USDA nutrient database. The ovarian cancer patients reported lower consumption levels of individual and total soy foods (75.3 ± 53.6 g/day) compared to the controls (110.7 ± 88.8 g/day). Logistic regression analyses showed that regular intake of soy foods could reduce the ovarian cancer risk, the adjusted odds ratio being 0.29 (95% confidence interval 0.20 to 0.42) for women who consumed at least 120 g/day relative to those less than 61 g/day. Similarly, isoflavone intakes were inversely associated with the ovarian cancer risk, with significant dose–response relationships (P < 0.001). We concluded that consumption of soy foods is associated with a reduced risk of ovarian cancer in southern Chinese women. [Copyright &y& Elsevier]

To determine the effect of genistein on cytochrome P450 3A (CYP3A) and P-glycoprotein (P-gp) function using the probe substrates midazolam and talinolol, respectively. Eighteen healthy adult male participants were enrolled in a two-phase randomized crossover design. In each phase, the participants received placebo or genistein for 14 days. On the 15th day, midazolam and talinolol were administered and blood samples were obtained. Midazolam and talinolol pharmacokinetic parameter values were calculated and compared before and after genistein administration. Co-administration of genistein decreased the area under the concentration–time curve from 0 to 36 h (AUC 0-36) (143.65 ± 55.40 ng h/mL versus 126.10 ± 40.14 ng h/mL, p < 0.05), and the area under the concentration–time curve from zero to infinity (AUC 0-∞) (209.18 ± 56.61 ng h/mL versus 180.59 ± 43.03 ng h/mL, p < 0.05), and also maximum concentration (Cmax) of midazolam (48.86 ± 20.21 ng/mL versus 36.25 ± 14.35 ng/mL p < 0.05). Similarly, AUC 0-36 (2490.282 ± 668.79 ng h/mL versus 2114.46 ± 861.11 ng h/mL, p < 0.05), AUC 0-∞ (2980.45 ± 921.09 ng h/mL versus 2626.92 ± 1003.78 ng h/mL, p < 0.05) and Cmax of talinolol (326.58 ± 197.67 ng/mL versus 293.42 ± 127.19 ng/mL, p < 0.05) were reduced by genistein co-administration. The oral clearance of midazolam (1.68 ± 0.85 h-1 versus 3.98 ± 0.59 h-1, p < 0.05) and talinolol (3.34 ± 1.24 h-1 versus 3.79 ± 1.55 h-1, p<0.05) were increased by genistien significantly. Administration of genistein can result in a modest induction of CYP3A and possibly P-gp activity in healthy volunteers. [ABSTRACT FROM AUTHOR]

Purpose: This study investigated the effect of 1 g genistein daily for 14 days on caffeine-based metrics of cytochrome P4501A2 (CYP1A2), cytochrome P4502A6 (CYP2A6), N-acetyltransferase 2 (NAT2), and xanthine oxidase (XO). Methods: A single dose of 100 mg caffeine was administered once before and once on the last day of a 14-day treatment regime with 1 g genistein once daily to 18 healthy female volunteers. Urine and blood samples were collected up to 12 and 24 h, respectively, after each caffeine dose. Using high-performance liquid chromatography (HPLC), caffeine and 1,7-dimethylxanthine (17X) were quantified in plasma, whereas 17X, 1,7-dimethylurate (17U), 1-methylxanthine (1X), 1-methylurate (1U), and 5-acetylamino-6-formylamine-3-methyluracil (AFMU) were quantified in urine. Urinary metabolite ratios were calculated to assess enzyme activities and compared between administrations using analysis of variance (ANOVA). Results: Genistein decreased the urinary caffeine metabolite ratio used to assess CYP1A2 activity by 41% [90% confidence interval (CI) 28-51%). The urinary ratio indicating XO activity decreased by 29% (90% CI 24-32%), whereas urinary ratio for CYP2A6 activity increased by 47% (90% CI 29-66%) after 2 weeks of genistein. The NAT2 urinary caffeine metabolite ratio did not change significantly. Conclusions: Two weeks of intake of 1 g genistein daily led to decreases in CYP1A2 and XO activity and an increase in CYP2A6 activity, whereas NAT2 activity did not change in healthy Chinese female volunteers. Pharmacokinetics of other substrates of the enzymes investigated here may be influenced in a similar manner. [ABSTRACT FROM AUTHOR]

Abstract: Recently, studies reported that neonatal genistein treatment inhibited breakdown of oocyte nests and increased oocyte survival, resulting in multi-oocyte survival in adult mice. However, whether the inhibition effect in ovarian follicular development exists also in other stages during ovarian development (e.g. adult or climacteric) is unknown. So far, few studies have investigated the effect of genistein in adult or pre-menopausal ovarian follicular development and follicular reserves. We investigated ovarian follicular development in 4-month and 15-month-old rats after 4weeks and 4months treatment with genistein in a dose of 160mg/kgd. Genistein-treated rats obtained a higher percentage of primordial follicles by 4months of age and a greater number of surviving follicles at 15months of age compared to a control group (P<0.05). In addition, vaginal cytology showed that age-dependent cessation of regular estrus was delayed for 2months in the genistein-treated group than control group. These results suggest that genistein alters rat ovarian follicular development and increases the number of surviving follicles, which may prolong ovarian reproductive life. [Copyright &y& Elsevier]

The bioavailability of soybean isoflavones varies widely among individuals due to many factors, including activities of gut microflora. To characterize factors that affect fecal isoflavone disappearance phenotype and isoflavone bioavailability in women, 35 Asian and 33 Caucasian women, 18-43 y of age, provided fecal samples for anaerobic incubation with isoflavones in vitro at two times 5 mo apart (Phases I and II). Diet, physical activity and health history were investigated at these times. A single dose of soymilk powder [1.2 mg (4.57 micromol) total isoflavone/kg body] was given to all subjects with breakfast in phase II. Daidzein and genistein from fecal incubations, urine and fecal samples were measured by reverse-phase HPLC. Three significantly different daidzein and two genistein disappearance phenotypes were identified from fecal isoflavone incubations. More Asians than Caucasians were identified within the high daidzein disappearance phenotype. Caucasians and Asians differed significantly in daily intake of red meat (0.3 +/- 0.1 vs. 1.0 +/- 0.1 servings/d), dairy foods (2.9 +/- 0.2 vs. 1.2 +/- 0.2 servings/d) and insoluble dietary fiber (3.6 +/- 0.3 vs. 1.4 +/- 0.3 g). BMI, maximal oxygen uptake (VO(2 max)) and physical activity level were significantly greater in Caucasians than in Asians. Asian subjects of the low genistein disappearance phenotype had more rapid gut transit time (GTT) and greater isoflavone bioavailability as reflected in urinary genistein excretion than did Asians of the high genistein disappearance phenotype (GTT, 40 +/- 8 vs. 63 +/- 5 h; 11.0 +/- 2.7 vs. 4.0 +/- 1.7% of ingested genistein excreted in urine). Caucasians of both genistein disappearance phenotypes had longer GTT than did Asian subjects (84 +/- 5 vs. 56 +/- 6 h) and resembled Asians of the high genistein disappearance phenotype in genistein bioavailability. Relatively rapid GTT coupled with a low fecal isoflavone disappearance phenotype as occurred in Asian but not Caucasian subjects produced greater genistein bioavailability, as reflected in urinary genistein excretion. [ABSTRACT FROM AUTHOR]

Purpose: Many studies have examined the association of isoflavone intake with type 2 diabetes (T2D), and produced inconsistent results. Few studies, however, explored the association using objective biomarkers (particular for daidzein metabolite-equol) of isoflavones. We aimed to explore the association of urinary equol, daidzein and genistein concentrations with T2D and examine the mediating roles of high-sensitivity C-reactive protein (hsCRP) and retinol binding protein 4 (RBP4)., Methods: This prospective study included 2818 subjects. Urinary concentrations of equol, daidzein and genistein were measured by high-performance liquid chromatography-tandem mass spectrometry. The associations between urinary isoflavones and T2D incidence were evaluated by cox proportional hazards model., Results: After adjustment for covariates, urinary equol except daidzein and genistein was inversely associated with T2D incidence. In comparison with the first tertile, multivariable adjusted hazard ratios (HRs) and 95% confidence intervals (95% CIs) for T2D incidence in the second and third tertile of equol concentration were 0.52 (0.37, 0.73) and 0.72 (0.53, 0.97), respectively. In stratified analyses by sex, the HR (95% CI) of men in the second vs. first tertile of equol was 0.29 (0.14, 0.58). Equivalent estimation in women was 0.67 (0.45, 1.01). Neither women nor men in the third tertile showed significant difference of T2D incidence compared with the first tertile. In path analyses, there was no evidence of mediating effects of hsCRP and RBP4 on the "equol-T2D" relationship., Conclusions: Urinary equol was favorably associated with a decreased T2D incidence in Chinese adults. The equol-T2D relationship might not be mediated by hsCRP and RBP4., Trial Registration: This study has been registered at http://www.clinicaltrials.gov as NCT03179657.