[Soy isoflavones alleviates calcium overload in rats with cerebral ischemia-reperfusion by inhibiting the Wnt/Ca2+ signaling pathway].

OBJECTIVE: To explore the mechanism by which soybean isoflavone (SI) reduces calcium overload induced by cerebral ischemia-reperfusion (I/R). METHODS: Forty-eight SD rats were randomized into 4 groups to receive sham operation, cerebral middle artery occlusion for 2 h followed by 24 h of reperfusion (I/R model group), or injection of adeno-associated virus carrying Frizzled-2 siRNA or empty viral vector into the lateral cerebral ventricle after modeling.Western blotting was used to examine Frizzled-2 knockdown efficiency and changes in protein expressions in the Wnt/Ca2+ signaling pathway.Calcium levels and pathological changes in the ischemic penumbra (IP) were measured using calcium chromogenic assay and HE staining, respectively.Another 72 SD randomly allocated for sham operation, I/R modeling, or soy isoflavones pretreatment before modeling were examined for regional cerebral blood flow using a Doppler flowmeter, and the cerebral infarct volume was assessed using TTC staining.Pathologies in the IP area were evaluated using HE and Nissl staining, and ROS level, Ca2+ level, cell apoptosis, and intracellular calcium concentration were analyzed using immunofluorescence assay or flow cytometry; the protein expressions of Wnt5a, Frizzled-2, and P-CaMK Ⅱ in the IP were detected with Western blotting and immunohistochemistry. RESULTS: In rats with cerebral I/R, Frizzled-2 knockdown significantly lowered calcium concentration (P < 0.001) and the expression levels of Wnt5a, Frizzled-2, and P-CaMK Ⅱ in the IP area.In soy isoflavones-pretreated rats, calcium concentration, ROS and MDA levels, cell apoptosis rate, cerebral infarct volume, and expression levels of Wnt/Ca2+ signaling pathway-related proteins were all significantly lower while SOD level was higher than those in rats in I/R model group. CONCLUSION: Soy isoflavones can mitigate calcium overload in rats with cerebral I/R by inhibiting the Wnt/Ca2+ signaling pathway.

Association of genetic variants in soy isoflavones metabolism-related genes with decreased lung cancer risk.

BACKGROUND: Soy isoflavones have been reported to exhibit anti-tumor effects. We hypothesize that genetic variants in soy isoflavone metabolism-related genes are associated with the risk of lung cancer. METHODS: A two-stage case-control study design was conducted in this study. The discovery stage included 300 lung cancer cases and 600 healthy controls to evaluate the association of candidate genetic variants with lung cancer risk. The validation stage involved 1200 cases and 1200 controls to validate the associations found. Furthermore, qPCR was performed to assess the mRNA expression levels of different genotypes of the SNP. ELISA was used to explore the association between genotype and soy isoflavone levels, as well as the association between soy isoflavone levels and lung cancer risk. RESULTS: A nonlinear association was observed between plasma soy isoflavone levels and lung cancer risk, with higher soy isoflavone levels associated with lower lung cancer risk (P < 0.001). The two-stage case-control study identified that UGT1A1 rs3755319 A > C was associated with decreased lung cancer risk (Recessive model: adjusted OR = 0.69, 95 %CI = 0.57-0.84, P < 0.001). Moreover, eQTL analysis showed that the expression level of UGT1A1 in the rs3755319 CC genotype was lower than in the AA + AC genotype (P < 0.05). The plasma concentration of soy isoflavones in the rs3755319 CC genotype was higher than in the AA + AC genotype (P = 0.008). CONCLUSIONS: We identified a potentially functional SNP, UGT1A1 rs3755319 A > C, as being associated with decreased lung cancer risk. Further experiments will be needed to explore the mechanisms underlying the observed associations.

The effect of soy isoflavones given to women in the climacteric period on menopausal symptoms and quality of life: Systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: This systematic review and meta-analysis aimed to examine the effect of soy isoflavones on menopausal symptoms and quality of life in climacteric women. METHOD: The literature search was conducted in PubMed, CINAHL, Scopus, and Science Citation Index (Web of Science) until September 2023. This study is based on the recommendations of the Cochrane guidelines. The data were analysed using the Review Manager computer software (Version 5.4). The methodological quality of the studies was assessed with the RoB-2 tool. RESULTS: This analysis was completed with five studies and 425 climacteric women. According to the results of the analysis, menopausal symptoms (SMD: -0.49, 95 % CI: -1.13 to 0.16, Z = 1.47, p = 0.14), physical component (MD: -1.10, 95 % CI: -4.22 to 2.01, Z = 0.70, p = 0. 49) and mental component (MD: 0.81, 95 % CI: -6.73 to 8.35, Z = 0.21, p = 0.83), but there was a significant difference in depression level (SMD: -0.41, 95 % CI: -0.73 to -0.09, Z = 2.53, p = 0.01). CONCLUSION: According to the results of the analysis, soy isoflavones had no effect on menopausal symptoms (vasomotor, psychosocial, physical, sexual, and urogenital complaints) and quality of life in climacteric women but did reduce the level of depression. There was a high risk of conflict of interest in the included studies. PROSPERO DATABASE: Registration: CRD420234479700.

The Influence of Soy Isoflavones and Soy Isoflavones with Inulin on Kidney Morphology, Fatty Acids, and Associated Parameters in Rats with and without Induced Diabetes Type 2.

Diabetes mellitus resulting from hyperglycemia stands as the primary cause of diabetic kidney disease. Emerging evidence suggests that plasma concentrations of soy isoflavones, substances with well-established antidiabetic properties, rise following supplemental inulin administration. The investigation encompassed 36 male Sprague-Dawley (SD) rats segregated into two cohorts: non-diabetic and diabetic, induced with type 2 diabetes (high-fat diet + two intraperitoneal streptozotocin injections). Each cohort was further divided into three subgroups (n = 6): control, isoflavone-treated, and isoflavone plus inulin-treated rats. Tail blood glucose and ketone levels were gauged. Upon termination, blood samples were drawn directly from the heart for urea, creatinine, and HbA1c/HbF analyses. One kidney per rat underwent histological (H-E) and immunohistochemical assessments (anti-AQP1, anti-AQP2, anti-AVPR2, anti-SLC22A2, anti-ACC-alpha, anti-SREBP-1). The remaining kidney underwent fatty acid methyl ester analysis. Results unveiled notable alterations in water intake, body and kidney mass, kidney morphology, fatty acids, AQP2, AVPR2, AcetylCoA, SREBP-1, blood urea, creatinine, and glucose levels in control rats with induced type 2 diabetes. Isoflavone supplementation exhibited favorable effects on plasma urea, plasma urea/creatinine ratio, glycemia, water intake, and kidney mass, morphology, and function in type 2 diabetic rats. Additional inulin supplementation frequently modulated the action of soy isoflavones.

A Gnotobiotic Mouse Model with Divergent Equol-Producing Phenotypes: Potential for Determining Microbial-Driven Health Impacts of Soy Isoflavone Daidzein.

The implications of soy consumption on human health have been a subject of debate, largely due to the mixed evidence regarding its benefits and potential risks. The variability in responses to soy has been partly attributed to differences in the metabolism of soy isoflavones, compounds with structural similarities to estrogen. Approximately one-third of humans possess gut bacteria capable of converting soy isoflavone daidzein into equol, a metabolite produced exclusively by gut microbiota with significant estrogenic potency. In contrast, lab-raised rodents are efficient equol producers, except for those raised germ-free. This discrepancy raises concerns about the applicability of traditional rodent models to humans. Herein, we designed a gnotobiotic mouse model to differentiate between equol producers and non-producers by introducing synthetic bacterial communities with and without the equol-producing capacity into female and male germ-free mice. These gnotobiotic mice display equol-producing phenotypes consistent with the capacity of the gut microbiota received. Our findings confirm the model's efficacy in mimicking human equol production capacity, offering a promising tool for future studies to explore the relationship between endogenous equol production and health outcomes like cardiometabolic health and fertility. This approach aims to refine dietary guidelines by considering individual microbiome differences.

Dietary Supplementation of Myo-Inositol, Cocoa Polyphenols, and Soy Isoflavones Improves Vasomotor Symptoms and Metabolic Profile in Menopausal Women with Metabolic Syndrome: A Retrospective Clinical Study.

Background and Objectives: Hormonal changes physiologically occurring in menopausal women may increase the risk of developing metabolic and vasomotor disturbances, which contribute to increase the risk of developing other concomitant pathologies, such as metabolic syndrome (MetS). Materials and Methods: Retrospective data from 200 menopausal women with MetS and vasomotor symptoms taking one sachet per day of the dietary supplement INOFOLIC® NRT (Farmares srl, Rome, Italy) were collected. Each sachet consisted of myo-Inositol (2000 mg), cocoa polyphenols (30 mg), and soy isoflavones (80 mg, of which 50 mg is genistin). Patients recorded their symptoms through a medical questionnaire at the beginning of the administration (T0) and after 6 months (T1). Results: We observed an improvement in both the frequency and the severity of hot flushes: increased percentage of 2-3 hot flushes (28 at T0 vs. 65% at T1, p value < 0.001) and decreased percentage of 4-9 hot flushes (54% at T0 vs. 18% at T1, p value < 0.001). Moreover, symptoms of depression improved after supplementation (87% at T0 vs. 56% at T1 of patients reported moderate depression symptoms, p value < 0.001). Regarding metabolic profile, women improved body mass index and waist circumference with a reduction in the percentage of overweight and obesity women (88% at T0 vs. 51% at T1, p value = 0.01; 14% at T0 vs. 9% at T1, p value = 0.04). In addition, the number of women suffering from non-insulin dependent diabetes reduced (26% at T0 vs. 16% at T1, p value = 0.04). Conclusions: These data corroborate previously observed beneficial effects of the oral administration of myo-Inositol, cocoa polyphenols, and soy isoflavones against menopausal symptoms in the study population. Considering the promising results of the present study, further prospective controlled clinical trials are needed to deeply understand and support the efficacy of these natural compounds for the management of menopausal symptoms.

Soy isoflavones induces mitophagy to inhibit the progression of osteosarcoma by blocking the AKT/mTOR signaling pathway.

BACKGROUND: Soy isoflavones (SI) is a natural bioactive substance exhibiting beneficial effects on human health. This study aims to elucidate the therapeutic potential of SI in the treatment of osteosarcoma (OS) and to investigate the underlying mechanisms, particularly focusing on mitophagy. METHODS: The effects of SI on the proliferation, apoptosis, migration, and invasion of U2OS cells were analyzed. Mitophagy was assessed through multiple parameters: mitochondrial autophagosomes, mitochondrial membrane potential, autophagy-related proteins, reactive oxygen species (ROS), and oxygen consumption rate (OCR). Protein levels related to apoptosis, autophagy, and the AKT/mTOR pathway were analyzed using western blot. The therapeutic efficacy of SI was further identified using a mouse tumor xenograft model. Cell apoptosis and proliferation in tumor xenografts were detected by TUNEL staining and immunohistochemistry (IHC), respectively. RESULTS: SI dose-dependently suppressed the viability, colony formation, migration, and invasion of U2OS cells, and enhanced the apoptosis. SI also dose-dependently induced mitophagy in OS cells, evidenced by an increase in autophagosomes and ROS levels, a decrease in mitochondrial membrane potential and OCR, and concomitant changes in autophagy-related proteins. Mdivi-1, an inhibitor of mitophagy, reversed the anti-tumor effects of SI on U2OS cells. In addition, SI blocked the AKT/mTOR pathway in U2OS cells. SC-79, an AKT agonist, reversed the effect of SI on inducing mitophagy. Moreover, SI also promoted cell apoptosis and mitophagy in tumor xenografts in vivo. CONCLUSIONS: SI induces mitophagy in OS cells by blocking the AKT/mTOR pathway, contributing to the inhibition of OS.

Investigating the Role of 17ß-Estradiol on the Serotonergic System, Targeting Soy Isoflavones as a Strategy to Reduce Menopausal Depression: A Mechanistic Review.

Low serotonin is one factor implicated in the development of depression. 17ß-estradiol (E2) has been shown to modulate gene expression regulating the neurotransmission of serotonin. Sex hormone levels fluctuate dramatically during the menopausal transition, coinciding with a 14-fold increased risk of depression. This review aimed to examine the effect of soy isoflavones to support decreased and variable E2 levels before and after menopause, linked to an investigation of the pathophysiological mechanisms underlying the protective influence of E2 on the serotonin pathway. The overall aim of this review is to assess the potential of soy isoflavones to reduce depression in middle-aged women. A systematic literature search was performed in three stages. 1,421 papers were screened for relevance to the research aims and objectives. 63 papers were selected based on pre-defined inclusion/exclusion criteria (13 reviews, 24 mechanistic and 26 intervention studies) and critically appraised. Available research supported the hypotheses that E2 increases serotonin synthesis and availability through stimulation of tryptophan hydroxylase-2 (TPH-2) and decreased degradation by monoamine oxidase-A (MAO-A). There was less scientific agreement on the effects of E2 on serotonin transporter (SERT) and serotonin receptors 1 A and 2 A. Studies varied widely on the effectiveness of soy isoflavones in reducing depressive symptoms in (peri)menopausal women. Animal and human studies acknowledge women's increased risk of depression linked to fluctuating E2 rather than absolute levels. However, mechanisms linking E2 variability with depression remain an underrepresented area of research. Study limitations and heterogeneity may contribute to varying results for soy isoflavones and some effects of E2 on the serotonin pathway.

17ß-estradiol increases serotonin synthesis and availability through its effects on tryptophan hydroxylase-2, monoamine oxidase-A, serotonin transporter and serotonin receptors 1A and 2A.Soy isoflavones may ameliorate depressive symptoms around the menopausal transition by replicating the effect of 17ß-estradiol on serotonin.Combining research on the mechanistic pathway of soy isoflavones with the effectiveness of outcomes can enhance clinical decision-making.

Safety Assessment and Hepatic-Renal Protection of Cajanus cajan (L.) Millsp. Root and Its Soy Isoflavone Contents.

Cajanus cajan (L.) Millsp., also known as pigeon pea, has roots that have exhibited much pharmacological potential. The present study was conducted to assess the safe dose of the ethanolic extract of C. cajan roots (EECR95) and to analyze the main soy isoflavones contents. In vitro, we investigated the mutagenicity and cytotoxic effect of EECR95 on Salmonella typhimurium-TA98 and TA100 (by Ames tests) and RAW 264.7, L-929, and HGF-1 cell lines (by MTT tests) for 24 h of incubation. We found no mutagenic or cytotoxic effects of EECR95. After administration of 0.2 or 1.0 g/kg bw of EECR95 to both male and female Wistar rats for 90 days, there were no significant adverse effects on the behaviors (body weight, water intake, and food intake), organ/tissue weights, or immunohistochemical staining, and the urine and hematological examinations of the rats were within normal ranges. EECR95 potentially decreases renal function markers in serum (serum uric acid, BUN, CRE, and GLU) or liver function markers (cholesterol, triglyceride, and glutamic-pyruvate-transaminase (GPT)). We also found that EECR95 contained five soy isoflavones (genistein, biochanin A, daidzein, genistin, and cajanol), which may be related to its hepatorenal protection. Based on the high dose (1.0 g/kg bw) of EECR95, a safe daily intake of EECR95 for human adults is estimated to be 972 mg/60 kg person/day.

The improving effect of soybean isoflavones on ovarian function in older laying hens.

Emerging evidence suggests an association between estrogen levels and reduced egg-laying performance as the layer became old. Since soy isoflavones (SF) have estrogen-mimic effects, whether it can enhance production performance and ovarian function of older layers is still not known. A total of 160 Lohmann pink layers (66-wk-old) were used in a 2 × 2 factorial design, which included 2 egg-laying levels [low (76.89 ± 1.65%; LOW) and normal (84.96 ± 1.01%; NOR)] and 2 different dietary groups [0 mg/kg SF, 20 mg/kg SF] were used. The results showed the NOR group had higher egg-laying rate, egg mass, and feed efficiency during the all phases (P(laying) < 0.05). The unqualified egg rate was lower in NOR group (9-12 wk, 1-12 wk) (P(laying) < 0.05). Dietary supplementation with SF increased the egg-laying rate and feed efficiency (5-8 wk, 9-12 wk, 1-12 wk), increased egg mass (9-12 wk, 1-12 wk) (P(SF) < 0.05). The NOR layers presented higher eggshell quality (redness, yellowness, brightness, eggshell ratio) at 12 wk (P(laying) < 0.05). Eggshell quality was found to be improved by SF (eggshell strength and eggshell thickness), egg albumen quality (higher albumen height and Haugh unit) at 12 wk (P(SF) < 0.05). Supplementing with SF led to an increase in eggshell strength in LOW group (P(laying*SF) < 0.05). The higher serum lever of glucose (GLU) and lower serum lever of follicle stimulating hormone (FSH) were in NOR group (P(laying) < 0.05). Supplementing SF in diets increased serum of estradiol (E2) and insulin-like growth factors-1 (IGF-1), decreased serum of FSH (P(SF) < 0.05). The NOR layers presented lower estrogen receptor α (ERα), estrogen receptor ß (ERß), B lymphoma 2 associated X protein (Bax), cytochrome c (Cytc), interleukin 6 (IL-6), caspase3, caspase9, IKKα, P50, and P65 expression in the ovary (P(laying) < 0.05). Dietary SF supplementation decreased the anti-Müllerian hormone receptor (AMHR), Bax, caspase3, caspase9, Cytc, IL-6, IKKα, P50, P65 expression in the ovary (P(SF) < 0.05). These findings indicated that layers with NOR group had higher production performance, egg quality, and ovarian function, while dietary supplementation with SF improved production performance and ovarian function by reducing inflammation and apoptosis-related genes expression in ovary.

In ovo injection of soy isoflavones on hatching performance and intestinal development of newly hatched chicks.

This study aimed to evaluate the effects of in ovo injection of soy isoflavones (ISF) on hatchability, body weight, antioxidant status and intestinal development of newly hatched broiler chicks. One hundred and eighty fertile eggs were divided as follows: the control group, 3 mg/egg ISF (low dose) and 6 mg/egg ISF (high dose) on the 18th day of incubation. The results demonstrated that in ovo inclusion of 6 mg of ISF significantly increased hatchability and hatch weight. Both doses of ISF inclusion elevated the serum glutathione peroxidase and slightly decreased malondialdehyde compared to the control group. The high dose of ISF brings higher villus height and a higher villus/crypt ratio in chicks. Moreover, the mRNA levels of tumour necrosis factor- α and interferon-gamma in the spleen were significantly decreased. The ISF treatments showed an improvement in intestinal enzyme expression levels of sucrose isomaltase and mucin 2  as well as tight junction protein (TJ) mRNA expression of claudin-1 at high doses of ISF (p < 0.05) when compared with the other groups. Furthermore, the mRNA level of IGF-1 was increased in the high doses of ISF compared to the control. Overall, these findings indicate that in ovo administration of ISF on the 18th day of incubation enhances hatchability, antioxidant status and intestinal morphometrics in hatched chicks and modulates the expression of proinflammatory cytokines, TJs and insulin-like growth factor. In addition, the sustainability of antioxidants and other positive effects of ISF may increase chick viability and growth performance.

Effects of Phytochemicals from Fermented Food Sources in Alzheimer's Disease In Vivo Experimental Models: A Systematic Review.

The socioeconomic burden of Alzheimer's Disease (AD) stems from its characteristic multifactorial etiology and, implicitly, the difficulties associated with its treatment. With the increase in life expectancy and health awareness, nutraceuticals and functional foods are filling in the gaps left by the limitation of classical medical treatment in chronic conditions associated with lifestyle factors, such as neurological disorders. Processes, such as fermentation that enhance food phytochemical content are garnering increased attention due to their functional and health-related properties. This systematic review aims to provide an overview of the evidence of phytochemicals from fermented food sources inducing therapeutic outcomes and cognitive benefits from in vivo experimental models of Alzheimer's Disease. The present systematic review was conducted in accordance with PRISMA guidelines. Searches were performed in the following databases: MEDLINE, Embase, Cochrane, Scopus, Google Scholar, and Science Citation Index Expanded (Web of Science) by two independent reviewers. Titles and abstracts yielded by the search were screened for eligibility against the inclusion criteria. The search strategy yielded 1899 titles, encompassing studies from 1948 to 2022. After the removal of duplicates, and screening of titles, abstracts, and full texts, thirty three studies obtained from the original search strategy and seven studies from references satisfied the inclusion criteria and were included in the present systematic review. Several studies have emphasized the potential of fermentation to yield small-molecule phytochemicals that are not present in raw products. When these phytochemicals are combined, their collective strength has demonstrated the ability to exceed the antioxidant, anti-inflammatory, and neuroprotective benefits of individual phytochemicals when given in their pure form. Among the various fermented foods that have been studied, soy isoflavones obtained through fermentation have shown the most substantial evidence of altering phytochemical content and improving outcomes in animal models of AD. While promising in initial results, other fermented foods and traditional medicines require more detailed research in order to establish their effectiveness and proper utilization. As is, many of the experimental designs lacked phytochemical analysis of the used fermented product or comparison with the non-fermented counterpart. This, coupled with proper reporting in animal studies, will significantly raise the quality of performed studies as well as the weight of obtained results.

The Role of Choline, Soy Isoflavones, and Probiotics as Adjuvant Treatments in the Prevention and Management of NAFLD in Postmenopausal Women.

Nonalcoholic fatty liver disease (NAFLD) is a prevalent condition among postmenopausal women that can lead to severe liver dysfunction and increased mortality. In recent years, research has focused on identifying potential lifestyle dietary interventions that may prevent or treat NAFLD in this population. Due to the complex and multifactorial nature of NAFLD in postmenopausal women, the disease can present as different subtypes, with varying levels of clinical presentation and variable treatment responses. By recognizing the significant heterogeneity of NAFLD in postmenopausal women, it may be possible to identify specific subsets of individuals who may benefit from targeted nutritional interventions. The purpose of this review was to examine the current evidence supporting the role of three specific nutritional factors-choline, soy isoflavones, and probiotics-as potential nutritional adjuvants in the prevention and treatment of NAFLD in postmenopausal women. There is promising evidence supporting the potential benefits of these nutritional factors for NAFLD prevention and treatment, particularly in postmenopausal women, and further research is warranted to confirm their effectiveness in alleviating hepatic steatosis in this population.

The fortification of encapsulated soy isoflavones and texture modification of soy milk by α-lactalbumin nanotubes.

Nanocarriers can improve the dispersibility of hydrophobic bioactive compounds and potentially improve the texture of liquid food formulations. Here, nanotubes (NTs) with a high aspect ratio formed by self-assembly of peptides partially hydrolyzed from α-lactalbumin (α-lac) were used to deliver soy isoflavones (IFs) and modify soy milk texture. IFs encapsulated by nanotube (NT/IFs) via hydrophobic interactions, which had improved dispersibility, with a maximum loading efficiency of 4%. The rheological characterization showed that the nanotubes enhanced the viscoelastic property and long term-stability of soy milk. About 80% of the NT/IFs in soy milk survived simulated in in vitro gastric digestion promoting the release of IFs in the intestinal phase. Overall, this work demonstrated that α-lac nanotubes may be a multi-functional carrier system for hydrophobic compounds providing beneficial changes to functional food texture.

Enrichment of soy isoflavone extracts through macroporous resin for characterization of toxicity and estrogenic activities.

Soy isoflavone extracts are widely researched for their distinctive potential in contributing to various functional foods. The research work focuses on testing the toxicity of purified soy isoflavone extracts in mice models. With an agreement of the animal ethics, acute toxicity is firstly used to screen the effects of test compounds in mice for therapeutic purposes. Moreover, tests were conducted on BALB/c for estrogen in vivo and MCF7 for in vitro, screening active protection of liver cells, lipid peroxidation and scavenging free radicals 2,2-diphenyl-1-picrylhydrazyl (DPPH). Genistin and daidzin were found to be the two major compounds accounting for 47% and 35% of total purified soy isoflavones. The acute toxicity test results exhibited no effect against physiological accretion of BALB/c after 7-day administration with the given dose of 10 g/kgBW. Moreover, modified E-screen assay on MCF7 cells proved that the estrogen of isoflavone extracts induces cell proliferation by 15% compared with other non-steroid culture techniques. Therefore, this research contributes to helping researchers apply soy isoflavones in functional food, to alleviate the difficulties in menopausal symptoms for women in the future. Supplementary Information: The online version contains supplementary material available at 10.1007/s13197-022-05491-4.

Validation of ELISAs for Isoflavones and Enterolactone for Phytoestrogen Intake Assessment in the French Population.

Phytoestrogens are dietary compounds with low estrogenic activity. The two main categories in the French diet are isoflavones from pulses and enterolignans metabolized by the gut flora from various lignans found in fruits, vegetables, grains, and beverages. Isoflavones and lignans have different effects on human physiology and can antagonize each other. Comprehensive lists of phytoestrogen sources were constructed based on measurements and literature data. The 24 h and 48 h dietary recalls were proposed to the volunteers of the ISOLED cohort (NCT03421184). Urine and plasma samples from these volunteers were assayed for genistein, daidzein, equol, and enterolactone. A dietary score was constructed considering the pharmacokinetic characteristics of these compounds. Correlation analyses were applied to fluid concentrations associated with dietary scores. Pearson correlations reached 0.921 (p < 0.001) for urineIF, 0.900 (p < 0.001) for plasmaIF, 0.764 (p < 0.001) for urineENL, and 0.723 (p < 0.001) for plasmaENL. ELISAs associated with careful intake assessments proved to be good tools for phytoestrogens' exposure estimation.

A Randomized Controlled Trial of Soy Isoflavone Intake on Mammographic Density among Malaysian Women.

Soy intake is associated with lower breast cancer risk in observational studies concerning Asian women, however, no randomized controlled trials (RCT) have been conducted among Asian women living in Asia. This three-armed RCT assessed the effects of one-year soy isoflavone (ISF) intervention on mammographic density (MD) change among healthy peri- and postmenopausal Malaysian women. This study was registered at ClinicalTrials.gov (NCT03686098). Participants were randomized into the 100 mg/day ISF Supplement, 50 mg/day ISF Diet, or control arm, and assessed for change in absolute and relative dense area from digital mammograms conducted at enrolment and after 12 months, compared over time across study arms using Kruskal-Wallis tests. Out of 118 women enrolled, 91 women completed the intervention, while 27 women (23%) were lost in follow up. The ISF supplement arm participants observed a larger decline in dense area (−1.3 cm2), compared to the ISF diet (−0.5 cm2) and control arm (−0.8 cm2), though it was not statistically significant (p = 0.48). Notably, among women enrolled within 5 years of menopause; dense area declined by 6 cm2 in the ISF supplement arm, compared to <1.0 cm2 in the control arm (p = 0.13). This RCT demonstrates a possible causal association between soy ISF intake and MD, a biomarker of breast cancer risk, among Asian women around the time of menopause, but these findings require confirmation in a larger trial.

Effect of soy isoflavones on C-reactive protein in chronic inflammatory disorders.

New evidence suggests that soy products might reduce chronic systemic inflammation. Therefore, we aimed to summarize the effect of soy isoflavones on serum concentration of C-reactive protein (CRP) among participants with chronic inflammatory disorders by conducting this study. Cochrane Library, Scopus, ISI Web of Science, clinicaltrials.gov, and PubMed were searched to identify randomized clinical trials (RCTs) published up to December 2020. The effect size was calculated by the mean change from baseline in concentrations of CRP and its standard deviation for both intervention and comparison groups. DerSimonian and Laird random-effects model was used when the heterogeneity test was statistically significant. In total, thirteen RCTs involving 1213 participants and ten RCTs involving 1052 participants were eligible for our systematic review and meta-analysis respectively. Study duration ranged from 4 to 96 weeks and soy isoflavones dose varied from 33 to 132 mg/day. Overall effect size indicated a non-significant effect on serum concentration of CRP following soy isoflavones intake (weighted mean differences (WMD)=-0.15 mg/L, 95% confidence interval (CI): -0.54, 0.23; p=0.430). Subgroup analysis revealed that soy isoflavones significantly reduced serum concentration of CRP in studies among participants with age >57 years and baseline CRP levels >3.75 mg/L. The present study proposed that soy isoflavones could not significantly reduce serum CRP levels. It seems more RCTs on participants with age more than 57 years and higher levels of CRP is necessary.

Modulation of monepantel secretion into milk by soy isoflavones.

Monepantel (MNP), a novel anthelmintic drug from amino-acetonitrile derivatives, is a substrate for breast cancer resistance protein (BCRP). BCRP-mediated milk secretion of drugs can be altered by isoflavones. In this study, we aimed to show how soy isoflavones and BCRP inhibitors genistein (GEN) and daidzein (DAI) can modulate the secretion of MNP into milk. Moreover, we observed that the expression of BCRP in the lactating mammary gland of sheep was significantly higher than in non-lactating sheep using Western blot analysis. These properties of MNP and MNPSO2 (monepantel sulfone, the major active metabolite of MNP), identified as a BCRP substrate in determining the interaction with BCRP, were examined by vesicular transport (VT) inhibition assays. In pharmacokinetic studies, we demonstrated the transport of MNP into milk in three experimental groups: G1 fed standard forage; G2 fed soy-enriched forage; G3 fed standard forage paired with orally administered exogenous GEN and DAI. The concentrations of MNP and MNPSO2 were analyzed by high-performance liquid chromatography. Compared to the control group (3.27 ± 1.13 vs. 5.46 ± 2.23), the AUC (0-840 h) milk/plasma ratio decreased by 40% in the soy-enriched diet group. The concentrations of GEN and DAI were determined using liquid chromatography coupled with tandem mass spectrometry in soy. A VT inhibition assay was conducted to determine the IC50 values for MNP and MNPSO2 as BCRP inhibitors. This study showed that milk excretion of a BCRP substrate, such as monepantel, can be diminished by the presence of isoflavones in the diet.

Can soy isoflavones in combination with soy protein change serum concentration of adiponectin and resistin? A systematic review and meta-analysis on randomized clinical trials.

Some studies proposed the anti-inflammatory effect of soy protein and soy isoflavones by changing the serum adiponectin and resistin levels. The purpose of this research was to determine the impact of soy isoflavones and soy protein on blood adiponectin and resistin levels in adults. Scopus, PubMed, Cochrane Library, ISI Web of Science, and ClinicalTrials.gov databases were searched until April 2022. The effect size was computed by the mean changes from the beginning for intervention and comparison groups and their standard deviation. In the case of significant heterogeneity, DerSimonian and Laird random-effects model was used. Six and five clinical trials were selected for the systematic review and meta-analysis, respectively. The overall estimate indicated that soy isoflavones in combination with soy protein did not significantly change serum adiponectin level (weighted mean differences (WMD) = 0.36 µg/ml; 95% confidence interval (CI): -0.26, 0.99; p = .25), but significantly increased serum resistin level (WMD = 0.64 ng/ml, 95% CI: 0.25, 1.04; p = .001). In combination with soy protein, soy isoflavones nonsignificantly increased serum adiponectin levels, but significantly increased resistin levels. New intervention studies with a high dose of soy isoflavones and soy protein in different parts of the world and an updated meta-analysis are needed to confirm the results of our study.