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Introduction: All cosmetic ingredients must be evaluated for their safety to consumers. In the absence of in vivo data, systemic concentrations of ingredients can be predicted using Physiologically based Pharmacokinetic (PBPK) models. However, more examples are needed to demonstrate how they can be validated and applied in Next-Generation Risk Assessments (NGRA) of cosmetic ingredients. We used a bottom-up approach to develop human PBPK models for genistein and daidzein for a read-across NGRA, whereby genistein was the source chemical for the target chemical, daidzein. Methods: An oral rat PBPK model for genistein was built using PK-Sim® and in vitro ADME input data. This formed the basis of the daidzein oral rat PBPK model, for which chemical-specific input parameters were used. Rat PBPK models were then converted to human models using human-specific physiological parameters and human in vitro ADME data. In vitro skin metabolism and penetration data were used to build the dermal module to represent the major route of exposure to cosmetics. Results: The initial oral rat model for genistein was qualified since it predicted values within 2-fold of measured in vivo PK values. This was used to predict plasma concentrations from the in vivo NOAEL for genistein to set test concentrations in bioassays. Intrinsic hepatic clearance and unbound fractions in plasma were identified as sensitive parameters impacting the predicted Cmax values. Sensitivity and uncertainty analyses indicated the developed PBPK models had a moderate level of confidence. An important aspect of the development of the dermal module was the implementation of first-pass metabolism, which was extensive for both chemicals. The final human PBPK model for daidzein was used to convert the in vitro PoD of 33 nM (from an estrogen receptor transactivation assay) to an external dose of 0.2% in a body lotion formulation. Conclusion: PBPK models for genistein and daidzein were developed as a central component of an NGRA read-across case study. This will help to gain regulatory confidence in the use of PBPK models, especially for cosmetic ingredients. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) causes deficits in neurological function, induces pathological changes, and increases oxidative stress. The current investigation aimed to determine Daidzein's neuroprotective potential in experimental TBI. Initially, the HT‐22 cell line exposed to H2O2 underwent in vitro examination, and the results showed that Daidzein had a neuroprotective effect evident from enhanced cell viability and decreased NO generation. Using three different Daidzein doses—1 mg/kg, 5 mg/kg, and 10 mg/kg—in the in vivo experiment, the potential of Daidzein was evaluated against TBI. The neurological severity score (NSS), kondziela's screen test, and elevated plus maze showed improvements after treatment with Daidzein manifested by decreased score, enhanced motor coordination, and anti‐anxiety effects. Additionally, Daidzein improved mechanical allodynia and restored the breakdown of the blood‐brain barrier. The FTIR spectral analysis showed restoration of the biochemical compositional changes. Furthermore, H & E and Toluidine blue staining revealed an improvement in the histopathological alterations. The RT‐qPCR revealed an increase in mRNA expression level of Nrf2, HO‐1, and Bcl‐2 and the downregulation of Keap‐1, Bax and Cleaved caspase‐3 expressions. Thus, exhibiting its antioxidant and antiapoptotic potential. The RT‐qPCR also manifested a decrease in mRNA expression of GFAP and Iba‐1. Further immunohistochemistry results indicated Daidzein's antioxidant and antiapoptotic properties by upregulating Nrf2 and downregulating cleaved caspase‐3. Daidzein also lowered the apoptosis index and improved neuronal survival evidenced by flow cytometric analysis. In addition to this, Daidzein notably increased the antioxidant enzyme levels and decreased the oxidative stress markers. The current study's findings point to the neuroprotective potential of the phytoestrogen Daidzein as it lessened neurological abnormalities, decreased oxidative stress, and lowered proapoptotic protein expression. [ABSTRACT FROM AUTHOR]

Background: Oxidative damage and inflammatory cytokines in osteoarthritis (OA) exacerbate the disease course. Daidzein (DZ) has antioxidant and anti-inflammatory effects. This study evaluated the early histopathological effects of intra-articular daidzein injection on experimentally induced osteoarthritis in rabbit TMJs. Methods: The predictor variable was intra-articular injection of DZ or a saline control. 50 µl of 3 mg/mL MIA solution was injected into the right TMJ of 16 New Zealand rabbits to induce experimental OA. One rabbit was sacrificed after 4 weeks to confirm the formation of the OA model and the OA model was obtained. The remaining 15 rabbits were randomly divided into 2 groups: an experimental group (9 rabbits) and a control group (6 rabbits). On days 1, 7, 14, and 21; 50 µl of saline solution was applied to the right TMJ of the control group and 50 µl daidzein solution (1.8 mg/ml) was applied to the right TMJ to the experimental group. After one week from the date of the last injection, the rabbits were sacrificed, and histopathological and biochemical evaluations were performed. The Shapiro-Wilk test was used to evaluate whether the variables in the study conformed to normal distribution. Mean ± SD (standard deviation) or median (interquartile range (IQR)) was used to show the descriptive statistics of the variables. T-test and Mann Whitney U test were used to compare the control and experimental groups for biochemical changes. The chi-square test was used to show the distribution of histopathological changes variables obtained within the scope of the study based on control and experimental groups. A P-value < 0.05 was considered significant for all evaluations. Results: There were 8 and 6 animate treated with DZ and saline, respectively. There was no statistically significant difference between groups in articular cartilage (p = 0.3), osteochondral junction (p = 0.3), subchondral bone structure (p = 1.0) or chondrocyte appearance (p = 0.4). The experimental group showed significantly lower mean values for Total Oxidant Status (TOS) (p = 0.002) and Oxidative Stress Index (OSI) (p = 0.007). Conclusions: An intra-articular DZ injection appears to show limited reduction of oxidative damage and early OA in the rabbit TMJ. DZ might represent a promising natural compound with beneficial effects in the management of TMJ-OA. [ABSTRACT FROM AUTHOR]

Daidzein (Da), an isoflavone, resembles natural oestrogen in structure and activity. We investigated the effects of dietary Da on the reproductive performance, egg quality, and bone mineralisation of hens in the pre-peak laying period. A total of 432 laying hens (110 days) were randomly allocated to control (CON) or Da-supplemented diet (10, 25, and 50 mg/kg). Each treatment had six replicates of 18 birds/replicate, and the feeding trial lasted 8 weeks. Supplementation of dietary Da significantly improved laying rate, egg weight, egg mass, and feed-to-egg ratio (p

Abstract Background Oxidative damage and inflammatory cytokines in osteoarthritis (OA) exacerbate the disease course. Daidzein (DZ) has antioxidant and anti-inflammatory effects. This study evaluated the early histopathological effects of intra-articular daidzein injection on experimentally induced osteoarthritis in rabbit TMJs. Methods The predictor variable was intra-articular injection of DZ or a saline control. 50 µl of 3 mg/mL MIA solution was injected into the right TMJ of 16 New Zealand rabbits to induce experimental OA. One rabbit was sacrificed after 4 weeks to confirm the formation of the OA model and the OA model was obtained. The remaining 15 rabbits were randomly divided into 2 groups: an experimental group (9 rabbits) and a control group (6 rabbits). On days 1, 7, 14, and 21; 50 µl of saline solution was applied to the right TMJ of the control group and 50 µl daidzein solution (1.8 mg/ml) was applied to the right TMJ to the experimental group. After one week from the date of the last injection, the rabbits were sacrificed, and histopathological and biochemical evaluations were performed. The Shapiro-Wilk test was used to evaluate whether the variables in the study conformed to normal distribution. Mean ± SD (standard deviation) or median (interquartile range (IQR)) was used to show the descriptive statistics of the variables. T-test and Mann Whitney U test were used to compare the control and experimental groups for biochemical changes. The chi-square test was used to show the distribution of histopathological changes variables obtained within the scope of the study based on control and experimental groups. A P-value

Abstract Alzheimer’s disease (AD) is the most common neurodegenerative disease, with symptoms appearing in the cerebral cortex and hippocampus. amyloid β peptide (Aβ) has been shown to deposit in the brain, causing oxidative stress and inflammation, leading to impaired memory and learning. Lactocaseibacillus fermentation can produce deglycosylated isoflavones with high physiological activity, which can scavenge free radicals, enhance total antioxidant capacity and inhibit oxidative inflammatory responses. Therefore, in this study, Lactocaseibacillus paracasei subsp. paracasei NTU101 (NTU101) fermented soybean milk and its extracts were used as test substances, and AD model rats were established by infusion of Aβ40 in the brain for 28 days, and the preventive and ameliorating effects of NTU 101 fermented soymilk were discussed. Effects of soymilk and unfermented soymilk on AD, and explore its effects on AD. Main functional ingredients. The results showed that deglycosylated isoflavones in NTU101 fermented soybean milk improved AD symptoms. Mechanisms of actions include the inhibition of oxidative inflammation; reduction in the expression of risk factors for tau protein and apo E protein production, the deposition of Aβ40 around the hippocampus, and the expression of TLR-2 and RAGE proteins in astrocytes and microglia; and improvement in the memory and learning ability.

Background: Sarcopenic obesity, which is associated with a poorer prognosis than that of sarcopenia alone, may be positively affected by soy isoflavones, known inhibitors of muscle atrophy. Herein, we hypothesize that these compounds may prevent sarcopenic obesity by upregulating the gut metabolites with anti-inflammatory effects. Methods: To explore the effects of soy isoflavones on sarcopenic obesity and its mechanisms, we employed both in vivo and in vitro experiments. Mice were fed a high-fat, high-sucrose diet with or without soy isoflavone supplementation. Additionally, the mouse C2C12 myotube cells were treated with palmitic acid and daidzein in vitro. Results: The isoflavone considerably reduced muscle atrophy and the expression of the muscle atrophy genes in the treated group compared to the control group (Fbxo32, p = 0.0012; Trim63, p < 0.0001; Foxo1, p < 0.0001; Tnfa, p = 0.1343). Elevated levels of daidzein were found in the muscles and feces of the experimental group compared to the control group (feces, p = 0.0122; muscle, p = 0.0020). The real-time PCR results demonstrated that the daidzein decreased the expression of the palmitate-induced inflammation and muscle atrophy genes in the C2C12 myotube cells (Tnfa, p = 0.0201; Il6, p = 0.0008; Fbxo32, p < 0.0001; Hdac4, p = 0.0002; Trim63, p = 0.0114; Foxo1, p < 0.0001). Additionally, it reduced the palmitate-induced protein expression related to the muscle atrophy in the C2C12 myotube cells (Foxo1, p = 0.0078; MuRF1, p = 0.0119). Conclusions: The daidzein suppressed inflammatory cytokine- and muscle atrophy-related gene expression in the C2C12 myotubes, thereby inhibiting muscle atrophy. [ABSTRACT FROM AUTHOR]

Cervical cancer is a leading cause of gynecological malignancies and cancer-related deaths among women worldwide. This study investigates the anti-cancer activity of Thua Nao, a Thai fermented soybean, against HeLa cervical carcinoma cells, and explores its underlying mechanisms. Our findings reveal that the ethyl acetate fraction of Thua Nao (TN-EA) exhibits strong anti-cancer potential against HeLa cells. High-performance liquid chromatography (HPLC) analysis identified genistein and daidzein as the major isoflavones in TN-EA responsible for its anti-cancer activity. TN-EA and genistein reduced cell proliferation and induced G2/M phase arrest, while daidzein induced G1 arrest. These responses were associated with the downregulation of cell cycle regulators, including Cyclin B1, cycle 25C (Cdc25C), and phosphorylated cyclin-dependent kinase 1 (CDK-1), and the upregulation of the cell cycle inhibitor p21. Moreover, TN-EA and its active isoflavones promoted apoptosis in HeLa cells through the intrinsic pathway, evidenced by increased levels of cleaved Poly (ADP-ribose) polymerase (PARP) and caspase-3, loss of mitochondrial membrane potential, and the downregulation of anti-apoptotic proteins B-cell leukemia/lymphoma 2 (Bcl-2), B-cell lymphoma-extra-large (Bcl-xL), cellular inhibitor of apoptosis proteins 1 (cIAP), and survivin. Additionally, TN-EA and its active isoflavones effectively reduced cell invasion and migration by downregulating extracellular matrix degradation enzymes, including Membrane type 1-matrix metalloproteinase (MT1-MMP), urokinase-type plasminogen activator (uPA), and urokinase-type plasminogen activator receptor (uPAR), and reduced the levels of the mesenchymal marker N-cadherin. At the molecular level, TN-EA suppressed STAT3 activation via the regulation of JNK and Erk1/2 signaling pathways, leading to reduced proliferation and invasion of HeLa cells. [ABSTRACT FROM AUTHOR]

Neuropathy is the most common disorder comprising peripheral nerve damage in diabetic patients. Prolonged hyperglycaemia and oxidative stress cause metabolic imbalance and are the key reasons for the development of diabetic neuropathy. Daidzein, a soy isoflavone possesses potent anti-hyperglycaemic and antioxidant activity. The present study aims to check the protective effect of Daidzein in diabetic neuropathy in rats. The experimental animal model involved induction of diabetes in rats by intraperitoneal injection of streptozotocin (55 mg/kg). Following confirmation of diabetes, the diabetic rats were subjected to oral treatment with varying doses of Daidzein (25, 50, and 100 mg/kg) and pregabalin (30 mg/kg) for a duration of 4 weeks, initiated 6 weeks after diabetes induction. Results indicated that Daidzein treatment led to a significant reduction in plasma glucose levels and an improvement in body weight among diabetic animals. Moreover, Daidzein demonstrated a positive impact on sensory functions, as evidenced by the effect on tail withdrawal and response latency. Mechanical hyperalgesia and allodynia, common symptoms of diabetic neuropathy, were also significantly reduced with both Daidzein and pregabalin treatment. Notably, nerve conduction velocities exhibited improvement following the administration of Daidzein and pregabalin. Further investigation into the molecular mechanisms revealed that Daidzein treatment resulted in a notable enhancement of antioxidant enzyme levels and a reduction in the overexpression of NOX-4 in the sciatic nerve. This suggests that Daidzein's therapeutic effect is associated with the inhibition of oxidative stress via NOX-4. In summary, the findings of study suggests that, Daidzein treatment significantly attenuated diabetic neuropathy by inhibiting oxidative stress via NOX-4 inhibition. [ABSTRACT FROM AUTHOR]

Background and Purpose: Parkinson's disease (PD) is a prevalent neurodegenerative movement disorder characterized by motor dysfunction. Environmental factors, especially manganese (Mn), contribute significantly to PD. Existing therapies are focused on motor coordination, whereas nonmotor features such as neuropsychiatric symptoms are often neglected. Daidzein (DZ), a phytoestrogen, has piqued interest due to its antioxidant, anti‐inflammatory, and anxiolytic properties. Therefore, we anticipate that DZ might be an effective drug to alleviate the nonmotor symptoms of Mn‐induced Parkinsonism. Experimental Approach: Naïve zebrafish were exposed to 2 mM of Mn for 21 days and intervened with DZ. Nonmotor symptoms such as anxiety, social behaviour, and olfactory function were assessed. Acetylcholinesterase (AChE) activity and antioxidant enzyme status were measured from brain tissue through biochemical assays. Dopamine levels and histology were performed to elucidate neuroprotective mechanism of DZ. Key Results: DZ exhibited anxiolytic effects in a novel environment and also improved intra and inter fish social behaviour. DZ improved the olfactory function and response to amino acid stimuli in Mn‐induced Parkinsonism. DZ reduced brain oxidative stress and AChE activity and prevented neuronal damage. DZ increased DA level in the brain, collectively contributing to neuroprotection. Conclusion and Implications: DZ demonstrated a promising effect on alleviating nonmotor symptoms such as anxiety and olfactory dysfunction, through the mitigation of cellular damage. These findings underscore the therapeutic potential of DZ in addressing nonmotor neurotoxicity induced by heavy metals, particularly in the context of Mn‐induced Parkinsonism. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the most common neurodegenerative disease, with symptoms appearing in the cerebral cortex and hippocampus. amyloid β peptide (Aβ) has been shown to deposit in the brain, causing oxidative stress and inflammation, leading to impaired memory and learning. Lactocaseibacillus fermentation can produce deglycosylated isoflavones with high physiological activity, which can scavenge free radicals, enhance total antioxidant capacity and inhibit oxidative inflammatory responses. Therefore, in this study, Lactocaseibacillus paracasei subsp. paracasei NTU101 (NTU101) fermented soybean milk and its extracts were used as test substances, and AD model rats were established by infusion of Aβ40 in the brain for 28 days, and the preventive and ameliorating effects of NTU 101 fermented soymilk were discussed. Effects of soymilk and unfermented soymilk on AD, and explore its effects on AD. Main functional ingredients. The results showed that deglycosylated isoflavones in NTU101 fermented soybean milk improved AD symptoms. Mechanisms of actions include the inhibition of oxidative inflammation; reduction in the expression of risk factors for tau protein and apo E protein production, the deposition of Aβ40 around the hippocampus, and the expression of TLR-2 and RAGE proteins in astrocytes and microglia; and improvement in the memory and learning ability. Key points: Lactocaseibacillus-fermented soybean milk improved memory and learning abilityof AD rat Deglycosylated isoflavones (genistein and daidzein) were the functional compounds Deglycosylated isoflavones repress Aβ40 deposition by inhibiting TLR 2 and RAGE [ABSTRACT FROM AUTHOR]

Aims: Enhancing crop yields is a contemporary challenge of the modern world, and selenium (Se) has been shown to improve plant health against various abiotic stressors. This study aimed to evaluate the influence of Se on the biosynthesis of photosynthetic pigments, nitrogen metabolism, antioxidant metabolism, flavonoid synthesis and nodulation of cowpea plants. Methods: We carried out a soil experiment with five Se application rates (0, 7.5, 15, 30, and 45 µg kg−1) and a hydroponics experiment with four Se concentrations (0, 5, 10, and 15 µmol L−1). Results: Both experiments revealed hormetic-like responses of cowpea plants to Se, at both molecular and whole-plant levels. Se dose-dependently increased the synthesis of chlorophylls, carotenoids and pheophytin as well as the efficiency of enzymatic antioxidant metabolism by decreasing MDA levels and increasing CAT and APX activity. Selenium also enhanced nitrate reductase activity, resulting in greater biosynthesis of amino acids and proteins in the leaves. However, the dose responses were not identical in the two experiments. Hormetic-like biphasic responses were uniquely revealed for daidzein, genistein, and kaempferol in the hydroponics experiment. Selenium also enhanced the number of nodules in roots, which generated increases in the production of ureides and greater production of shoot dry weight in both experiments. Low rates of Se stimulated the translocation of allantoic acid from nodules to leaves. Conclusions: This study adds new insights regarding Se effect on antioxidant and nitrogen metabolism, photosynthetic pigments and nodulation, which can increase cowpea yield. [ABSTRACT FROM AUTHOR]

To overcome the poor solubility, permeability, and bioavailability of the plant isoflavone daidzein (DAI), a novel salt of DAI with anhydrous piperazine (PIP) was obtained based on cocrystallization strategy. The new salt DAI-PIP was characterized by powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), Fourier-transform infrared (FT-IR) spectroscopy, and optical microscopy. The results showed that the maximum apparent solubility (Smax) of DAI-PIP increased by 7.27-fold and 1000-fold compared to DAI in pH 6.8 buffer and water, respectively. The peak apparent permeability coefficient (Papp) of DAI-PIP in the Caco-2 cell model was 30.57 ± 1.08 × 10-6 cm/s, which was 34.08% higher than that of DAI. Additionally, compared to DAI, the maximum plasma concentration (Cmax) value of DAI-PIP in beagle dogs was approximately 4.3 times higher, and the area under the concentration-time curve (AUC0-24) was approximately 2.4 times higher. This study provides a new strategy to enhance the dissolution performance and bioavailability of flavonoid drugs, laying a foundation for expanding their clinical applications. [ABSTRACT FROM AUTHOR]

Continuing research is being conducted on novel preventive and therapeutic drugs for cardiovascular diseases (CVDs). Daidzein has shown potential beneficial effects regarding various CVDs and risk factors. However, data in this regard are inconsistent, and there is an urge to accumulate. Therefore, we reviewed the effects of daidzein and daidzin on CVDs. We conducted a search through Scopus, PubMed, Google Scholar, and Web of Science from inception up to October 2023 to find studies with the primary intention of assessing the impacts of daidzein and daidzin on cardiovascular disease in various in vitro, animal, and clinical settings. In vitro and animal studies showed that daidzein and daidzin are effective in terms of reducing inflammation, oxidative stress, hyperlipidemia, myocardial infarction, thromboembolism, hypertension, and aneurysms. However, clinical studies only confirmed a relatively small portion of the previous findings of the in vitro and animal investigations, including anti‐hyperlipidemic effects. In conclusion, in vitro and animal studies have reported potential therapeutic effects for daidzein and daidzin regarding CVDs. However, most of the clinical studies were unable to exhibit the same results. Hence, further clinical studies are required to determine the outcomes of administering daidzein and its derivatives for an extended period and in various doses. [ABSTRACT FROM AUTHOR]

Pueraria candollei var. mirifica produces and accumulates various phytoestrogen compounds in its tuberous roots, including daidzein and genistein. Plant cell culture methods have been established to alleviate the problems associated with producing valuable phytochemicals from natural or field-cultivated plants, and hairy root culture is one of the most promising methods for the in vitro production of plant secondary metabolites. Thus, this study aimed to produce daidzein and genistein from hairy root cultures of P. candollei var. mirifica. The influences of cultivation parameters, including the culture medium, light conditions, sugar content in the culture medium, incubation temperature, and agitation speed, on biomass and daidzein and genistein production in hairy root cultures of this medicinal plant were investigated. The results revealed that the optimal cultivation conditions for biomass and bioactive compound production were Murashige & Skoog (MS) medium, a sucrose concentration of 30 g/L, a 16/8 h light/dark photoperiod, an incubation temperature of 26 °C, and an agitation speed of 90 rpm. The highest biomass and daidzein and genistein contents achieved in this study were 17.76 g/L, 6.85 mg/g DW, and 0.96 mg/g DW, respectively. Interestingly, the daidzein and genistein contents obtained from hairy roots were approximately 45.7- and 12.0-fold greater than those obtained from normal roots, respectively, suggesting that hairy root culture is a suitable method for the sustainable production of phytoestrogen, daidzein, and genistein from this medicinal plant. [ABSTRACT FROM AUTHOR]

The role of estrogens in prostate cancer (PCa) is shrouded in mystery, with its actions going from angelic to devilish. The findings by Huggins and Hodges establishing PCa as a hormone-sensitive cancer have provided the basis for using estrogens in therapy. However, despite the clinical efficacy in suppressing tumor growth and the panoply of experimental evidence describing its anticarcinogenic effects, estrogens were abolished from PCa treatment because of the adverse secondary effects. Notwithstanding, research work over the years has continued investigating the effects of estrogens, reporting their pros and cons in prostate carcinogenesis. In contrast with the beneficial therapeutic effects, many reports have implicated estrogens in the disruption of prostate cell fate and tissue homeostasis. On the other hand, epidemiological data demonstrating the lower incidence of PCa in Eastern countries associated with a higher consumption of phytoestrogens support the beneficial role of estrogens in counteracting cancer development. Many studies have investigated the effects of phytoestrogens and the underlying mechanisms of action, which may contribute to developing safe estrogen-based anti-PCa therapies. This review compiles the existing data on the anti- and protumorigenic actions of estrogens and summarizes the anticancer effects of several phytoestrogens, highlighting their promising features in PCa treatment. [ABSTRACT FROM AUTHOR]

In the present study, 17 flavonoids, including 9 prenylated isoflavones, 4 isoflavones, 3 flavanones and 1 flavone, were isolated from the twigs and leaves of Erythrina variegata. By NMR spectroscopic means and comparision with the data in the leteratures, their structures were elucidated to be euchrenone b10 (1), senegalensin (2), erythrinin C (3), scandenone (4), osajin (5), alpinum isoflavone (6), isoerysenegalensein E (7), erysenegalensein E (8), diprenylgenistein (9), abyssinone V (10), abyssinone V 4'-methyl ether (11), 4',7-dihydroxyflavanone (12), 3',5,7-trihydroxy-4'-methoxyisoflavone (13), 2',4',5,7-tetrahydroxyisoflavone (14), genistein (15), daidzein (16), and apigenin (17). Except for compounds 1, 4-7, and 9-10, other compounds were isolated from E. variegata for the first time. [ABSTRACT FROM AUTHOR]

Introduction: We performed an exposure-based Next Generation Risk Assessment case read-across study using New Approach Methodologies (NAMs) to determine the highest safe concentration of daidzein in a body lotion, based on its similarities with its structural analogue, genistein. Two assumptions were: (1) daidzein is a new chemical and its dietary intake omitted; (2) only in vitro data were used for daidzein, while in vitro and legacy in vivo data for genistein were considered. Methods: The 10-step tiered approach evaluating systemic toxicity included toxicokinetics NAMs: PBPK models and in vitro biokinetics measurements in cells used for toxicogenomics and toxicodynamic NAMs: pharmacology profiling (i.e., interaction with molecular targets), toxicogenomics and EATS assays (endocrine disruption endpoints). Whole body rat and human PBPK models were used to convert external doses of genistein to plasma concentrations and in vitro Points of Departure (PoD) to external doses. The PBPK human dermal module was refined using in vitro human skin metabolism and penetration data. Results: The most relevant endpoint for daidzein was from the ERa assay (Lowest Observed Effective Concentration was 100 ± 0.0 nM), which was converted to an in vitro PoD of 33 nM. After application of a safety factor of 3.3 for intra-individual variability, the safe concentration of daidzein was estimated to be 10 nM. This was extrapolated to an external dose of 0.5 µg/cm2 for a body lotion and face cream, equating to a concentration of 0.1%. Discussion: When in vitro PoD of 33 nM for daidzein was converted to an external oral dose in rats, the value correlated with the in vivo NOAEL. This increased confidence that the rat oral PBPK model provided accurate estimates of internal and external exposure and that the in vitro PoD was relevant in the safety assessment of both chemicals. When plasma concentrations estimated from applications of 0.1% and 0.02% daidzein were used to calculate bioactivity exposure ratios, values were >1, indicating a good margin between exposure and concentrations causing adverse effects. In conclusion, this case study highlights the use of NAMs in a 10-step tiered workflow to conclude that the highest safe concentration of daidzein in a body lotion is 0.1%. [ABSTRACT FROM AUTHOR]

We treated dry black bean dreg fermentation products with radio-frequency (RF) waves. With RF treatment (RF output power of 3 kW and electrode gap of 12 cm), a sample was dried within 1 h, which would take 10 h to dry via hot-air drying at 60 °C (sample weight reduction from 100 to 28.2 g). RF treatment thus accelerated fermented black bean dreg drying approximately 10-fold. The fermented black bean dregs were dried for 60 min at a fixed RF output power of 3 kW with different electrode gaps (12, 16, and 20 cm). Samples treated with electrode gaps of 12 and 16 cm were completely dried. When the fermented black bean dregs were dried for 60 min with an RF output power of 3 kW with a 16 cm electrode gap, their water activity decreased from 0.98 to 0.65. Colorimetric analysis showed that the sample color darkened significantly (ΔE = 5.73 ± 2.71), whereas its solubility (28.8 ± 0.1%) and antioxidant capacity (EC50 = 51.7 ± 0.7 mg/mL) increased. In addition, deglycosylated isoflavone daidzein content significantly increased, whereas that of the glycosylated isoflavone genistin decreased. These results reveal that RF application can efficiently dry fermented black bean dregs. [ABSTRACT FROM AUTHOR]

Lung cancer is the most common cause of cancer-related mortality, chemo-resistance, and toxicity limit treatment. The focus is on innovative combined phytotherapy to improve treatment outcomes. Our aim was to investigate the potential effects of daidzein nanosuspension (DZ-NS) and its combination with cisplatin (CIS) on A549 non-small lung cancer cells. Cytotoxicity was investigated using MTT and Chou-Talalay methods. Oxidative, apoptotic, and inflammatory markers were analyzed by ELISA and qRT-PCR. The IC50 value for DZ-NS was 25.23 µM for 24 h and was lower than pure DZ (IC50 = 835 µM for pure DZ). DZ-NS (at IC50x2 and IC50 values) showed synergistic cytotoxicity with CIS. The cells treated with DZ-NS had low TOS and OSI levels. However, DZ-NS failed to regulate Cas3 and TGF-β1 activation in A549 cells. MMP-9 gene expression was significantly suppressed in DZ-NS-treated cells, especially in combination therapy. DZ represents a potential combination option for the treatment of lung cancer, and its poor toxicokinetic properties limit its clinical use. To overcome these limitations, the effects of the nanosuspension formulation were tested. DZ-NS showed a cytotoxic effect on A549 cells and optimized the therapeutic effect of CIS. This in vitro synergistic effect was mediated by suppression of MMP-9 and not by oxidative stress or Cas3-activated apoptosis. This study provides the basis for an in vivo and clinical trial of DZ-NS with concurrent chemotherapy. [ABSTRACT FROM AUTHOR]

Abstract A natural product is a compound or substance originating from a living organism and found in nature. Daidzein belongs to the class of bioflavonoids, which are plant‐derived compounds with various biological activities. Predominantly exists in soybeans and several legumes in either glycoside or aglycone forms. Its primary chemical constituents include metabolites like equol and trihydroxy isoflavone, generated through the influence of intestinal bacteria. Daidzein has exhibited pharmacological impacts on different ailments, including cardiovascular disease, cancer, diabetes, skin disorders, osteoporosis, and neurodegenerative disorders. Daidzein's mechanisms of action involve interactions with estrogen receptors, as well as its antioxidant and anti‐inflammatory properties, along with its ability to regulate apoptosis and the cell cycle. In efforts to enhance its solubility, stability, bioavailability, and targeting, daidzein has been innovatively formulated into novel dosage forms, including nanoparticles, liposomes, microemulsions, and nanosuspensions. As a promising nutraceutical, daidzein presents multiple health benefits and holds potential for various clinical applications. Additional investigation is required to comprehend the molecular mechanisms of this phenomenon and assess its safety. The purpose of this review is to provide a short description of the therapeutic properties, chemical composition, traditional use, toxicology profile, new insights on the dosage form, and future prospects of daidzein.

IntroductionAll cosmetic ingredients must be evaluated for their safety to consumers. In the absence of in vivo data, systemic concentrations of ingredients can be predicted using Physiologically based Pharmacokinetic (PBPK) models. However, more examples are needed to demonstrate how they can be validated and applied in Next-Generation Risk Assessments (NGRA) of cosmetic ingredients. We used a bottom-up approach to develop human PBPK models for genistein and daidzein for a read-across NGRA, whereby genistein was the source chemical for the target chemical, daidzein.MethodsAn oral rat PBPK model for genistein was built using PK-Sim® and in vitro ADME input data. This formed the basis of the daidzein oral rat PBPK model, for which chemical-specific input parameters were used. Rat PBPK models were then converted to human models using human-specific physiological parameters and human in vitro ADME data. In vitro skin metabolism and penetration data were used to build the dermal module to represent the major route of exposure to cosmetics.ResultsThe initial oral rat model for genistein was qualified since it predicted values within 2-fold of measured in vivo PK values. This was used to predict plasma concentrations from the in vivo NOAEL for genistein to set test concentrations in bioassays. Intrinsic hepatic clearance and unbound fractions in plasma were identified as sensitive parameters impacting the predicted Cmax values. Sensitivity and uncertainty analyses indicated the developed PBPK models had a moderate level of confidence. An important aspect of the development of the dermal module was the implementation of first-pass metabolism, which was extensive for both chemicals. The final human PBPK model for daidzein was used to convert the in vitro PoD of 33 nM (from an estrogen receptor transactivation assay) to an external dose of 0.2% in a body lotion formulation.ConclusionPBPK models for genistein and daidzein were developed as a central component of an NGRA read-across case study. This will help to gain regulatory confidence in the use of PBPK models, especially for cosmetic ingredients.

A new series of daidzein‐based short peptidomimetic compounds were developed. In this study, we incorporated an alkyl chain with different chain lengths as hydrophobic groups, various amino acids and their respective guanidinium salts as hydrophilic groups. The most potent compound 9 a showed excellent antibacterial activity with minimum inhibitory concentration (MIC) of 8 μM against S. aureus and 32 μM against Escherichia coli. Furthermore, 9 a inhibited more than 65 % S. aureus biofilm formation at sub‐MIC, it also disrupted 69 % pre‐established S. aureus at 64 μM. The cytoplasmic membrane permeability study of 9 a revealed that the depolarization of membrane could be the possible mechanism of action. However, 9 a exhibited moderate toxicity against human erythrocytes. [ABSTRACT FROM AUTHOR]

Background: The inflammasome is a cytosolic multiprotein complex associated with multiple autoimmune diseases. Phytochemical compounds in soy (Glycine max) foods, such as isoflavones, have been reported for their anti-inflammatory properties. Aim: the anti-inflammatory activity of DZ (daidzein) and EQ (equol) were investigated in an ex vivo model of LPS-stimulated murine peritoneal macrophages and by molecular docking correlation. Methods: Cells were pre-treated with DZ (25, 50, and 100 µM) or EQ (5, 10, and 25 µM), followed by LPS stimulation. The levels of PGE2, NO, TNF-α, IL-6, and IL-1β were analyzed by ELISA, whereas the expressions of COX-2, iNOS, NLRP3, ASC, caspase 1, and IL-18 were measured by Western blotting. Also, the potential for transcriptional modulation by targeting NF-κB, COX-2, iNOS, NLRP3, ASC, and caspase 1 was investigated by molecular docking. Results: The anti-inflammatory responses observed may be due to the modulation of NF-κB due to the binding of DZ or EQ, which is translated into decreased TNF-α, COX-2, iNOS, NLRP3, and ASC levels. Conclusion: This study establishes that DZ and EQ inhibit LPS-induced inflammatory responses in peritoneal murine macrophages via down-regulation of NO and PGE2 generation, as well as the inhibition of the canonical inflammasome pathway, regulating NLRP3, and consequently decreasing IL-1β and IL-18 activation. [ABSTRACT FROM AUTHOR]

Tofu, one of soy food products widely consumed in Indonesia, has been reported as a source of natural protein. It is important to evaluate the contents of genistein and daidzein to provide information according to the nutrient information on soy food products. A reversed-phase high performance liquid chromatography (RP-HPLC) was developed in this study in order to analyze genistein and daidzein content in tofu samples simultaneously. Employing a Box-Behnken design (BBD) for designing the experiment, the response surface methodology (RSM) was then applied to optimize chromatographic conditions including methanol composition, flowrate, and column temperature. Separation response such as retention time, resolution, and tailing factor were evaluated to build an optimization model followed by analyzing the desirability. It was found that the model predicted a composite desirability of 0.9778 can be obtained by applying the methanol composition of 60%, flowrate of 0.80 mL.min-1, and column temperature of 50°C. The optimized HPLC conditions met the acceptance criteria for retention time and area deviations, resolution, tailing factor, and theoretical plates number. [ABSTRACT FROM AUTHOR]

Gastric cancer is considered a class 1 carcinogen that is closely linked to infection with Helicobacter pylori (H. pylori), which affects over 1 million people each year. However, the major challenge to fight against H. pylori and its associated gastric cancer due to drug resistance. This research gap had led our research team to investigate a potential drug candidate targeting the Helicobacter pylori‐carcinogenic TNF‐alpha‐inducing protein. In this study, a total of 45 daidzein derivatives were investigated and the best 10 molecules were comprehensively investigated using in silico approaches for drug development, namely pass prediction, quantum calculations, molecular docking, molecular dynamics simulations, Lipinski rule evaluation, and prediction of pharmacokinetics. The molecular docking study was performed to evaluate the binding affinity between the target protein and the ligands. In addition, the stability of ligand–protein complexes was investigated by molecular dynamics simulations. Various parameters were analysed, including root‐mean‐square deviation (RMSD), root‐mean‐square fluctuation (RMSF), radius of gyration (Rg), hydrogen bond analysis, principal component analysis (PCA) and dynamic cross‐correlation matrix (DCCM). The results has confirmed that the ligand–protein complex CID: 129661094 (07) and 129664277 (08) formed stable interactions with the target protein. It was also found that CID: 129661094 (07) has greater hydrogen bond occupancy and stability, while the ligand–protein complex CID 129664277 (08) has greater conformational flexibility. Principal component analysis revealed that the ligand–protein complex CID: 129661094 (07) is more compact and stable. Hydrogen bond analysis revealed favourable interactions with the reported amino acid residues. Overall, this study suggests that daidzein derivatives in particular show promise as potential inhibitors of H. pylori. [ABSTRACT FROM AUTHOR]

It is well known that daidzein has various significant medicinal values and health benefits, such as anti-oxidant, anti-inflammatory, anti-cancer, anti-diabetic, cholesterol lowering, neuroprotective, cardioprotective and so on. To our disappointment, poor solubility, low permeability and inferior bioavailability seriously limit its clinical application and market development. To optimize the solubility, permeability and bioavailability of daidzein, the cocrystal of daidzein and piperazine was prepared through a scientific and reasonable design, which was thoroughly characterized by single-crystal X-ray diffraction, powder X-ray diffraction, Fourier transform infrared spectroscopy, differential scanning calorimetry and thermogravimetric analysis. Combining single-crystal X-ray diffraction analysis with theoretical calculation, detailed structural information on the cocrystal was clarified and validated. In addition, a series of evaluations on the pharmacogenetic properties of the cocrystal were investigated. The results indicated that the cocrystal of daidzein and piperazine possessed the favorable stability, increased solubility, improved permeability and optimized bioavailability of daidzein. Compared with the parent drug, the formation of cocrystal, respectively, resulted in 3.9-, 3.1-, 4.9- and 60.8-fold enhancement in the solubility in four different media, 4.8-fold elevation in the permeability and 3.2-fold in the bioavailability of daidzein. Targeting the pharmaceutical defects of daidzein, the surprising elevation in the solubility, permeability and bioavailability of daidzein was realized by a clever cocrystal strategy, which not only devoted assistance to the market development and clinical application of daidzein but also paved a new path to address the drug-forming defects of insoluble drugs. [ABSTRACT FROM AUTHOR]

Encapsulating antioxidant-rich plant extracts, such as those found in red clover, within microcapsules helps protect them from degradation, thus improving stability, shelf life, and effectiveness. This study aimed to develop a microencapsulation delivery system using chitosan and alginate for microcapsules that dissolve in both the stomach and intestines, with the use of natural and synthetic emulsifiers. The microcapsules were formed using the extrusion method and employing alginate or chitosan as shell-forming material. In this study, all selected emulsifiers formed Pickering (β-CD) and traditional (white mustard extract, polysorbate 80) stable emulsions. Alginate-based emulsions resulted in microemulsions, while chitosan-based emulsions formed macroemulsions, distinguishable by oil droplet size. Although chitosan formulations with higher red clover extract (C1) concentrations showed potential, they exhibited slightly reduced firmness compared to other formulations (C2). Additionally, both alginate and chitosan formulations containing β-CD released bioactive compounds more effectively. The combined use of alginate and chitosan microcapsules in a single pill offers an innovative way to ensure dual solubility in both stomach and intestinal environments, increasing versatility for biomedical and pharmaceutical applications. [ABSTRACT FROM AUTHOR]

Making functional and nutritionally balanced date bars is of innovative concern. The current study intends to create a novel high-fiber and nutritious Khalas date-based bar (KDBB). The proximate composition, mineral contents, sugar profile, amino and fatty acids profile, volatiles and phytochemicals, antioxidant activity, and an in vitro digestion of protein and carbohydrates for bar formula containing 50% Khalas dates (KD) were investigated. Results indicated that protein, fat, ash, fiber, available carbohydrates, and vitamin C were 9.34, 4.93, 2.05, 8.01, 54.04 g 100 g-1 , and 16.67 mg, respectively. Potassium, magnesium, phosphorus, and calcium were present in abundance. Sucrose had the highest sugar concentration at 246.35 mg g-1. Total phenolic content (TPC) was 547.19 mg gallic acid equivalent 100 g-1 , giving 719.39 and 815.98 µmol of Trolox equivalent (TE) 100 g-1 for 2,2-diphenylpicrylhy-drazyl radical scavenging activity (DPPH-RSA) and 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS)-RSA, respectively. Total carotenoids, flavonoids, and flavonols were 327.19 mg 100 g-1 , 998.25 mg quercetin equivalent 100 g-1 , and 749.57 mg QE 100 g-1 , respectively. The highest discovered phenolics, flavonoids, and isoflavone were pyrocatechol (10249.73 μg g-1), catechin (193.50 μg g-1), and daidzein (18.77 μg g-1), respectively. Lysine was the highest among the essential amino acids. Saturated and unsaturated fatty acids were 43.73% and 56.27%, respectively. The omega-6 fatty acid, cis -8,11,14-eicosatrienoic, was predominant with a 31.08% valuation. The gas chromatography–mass spectrometry analysis identified 17 compounds, with a predominant presence of 9,12-octadecadienoyl chloride (38.13 g 100 g-1). The glycemic index (GI) of KDBB was 39.97, which was lower than KD's score (54.12). In conclusion, prepared KDBB could present a good idea for consuming dates and the based products with high fiber content and lower GI. Scaling up such products could be helpful to health-conscious individuals. [ABSTRACT FROM AUTHOR]

With its estrogenic activity, (S)-equol plays an important role in maintaining host health and preventing estrogen-related diseases. Exclusive production occurs through the transformation of soy isoflavones by intestinal bacteria, but the reasons for variations in (S)-equol production among different individuals and species remain unclear. Here, fecal samples from humans, pigs, chickens, mice, and rats were used as research objects. The concentrations of (S)-equol, along with the genetic homology and evolutionary relationships of (S)-equol production-related genes [daidzein reductase (DZNR), daidzein racemase (DDRC), dihydrodaidzein reductase (DHDR), tetrahydrodaidzein reductase (THDR)], were analyzed. Additionally, in vitro functional verification of the newly identified DDRC gene was conducted. It was found that approximately 40% of human samples contained (S)-equol, whereas 100% of samples from other species contained (S)-equol. However, there were significant variations in (S)-equol content among the different species: rats > pigs > chickens > mice > humans. The distributions of the four genes displayed species-specific patterns. High detection rates across various species were exhibited by DHDR, THDR, and DDRC. In contrast, substantial variations in detection rates among different species and individuals were observed with respect to DZNR. It appears that various types of DZNR may be associated with different concentrations of (S)-equol, which potentially correspond to the regulatory role during (S)-equol synthesis. This enhances our understanding of individual variations in (S)-equol production and their connection with functional genes in vitro. Moreover, the newly identified DDRC exhibits higher potential for (S)-equol synthesis compared to the known DDRC, providing valuable resources for advancing in vitro (S)-equol production. IMPORTANCE (S)-equol ((S)-EQ) plays a crucial role in maintaining human health, along with its known capacity to prevent and treat various diseases, including cardiovascular diseases, metabolic syndromes, osteoporosis, diabetes, brain-related diseases, high blood pressure, hyperlipidemia, obesity, and inflammation. However, factors affect ing individual variations in (S)-EQ production and the underlying regulatory mechanisms remain elusive. This study examines the association between functional genes and (S)-EQ production, highlighting a potential correlation between the DZNR gene and (S)-EQ content. Various types of DZNR may be linked to the regulation of (S)-EQ synthesis. Furthermore, the identification of a new DDRC gene offers promising prospects for enhancing in vitro (S)-EQ production. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Soybean is a pulse which has considerable nutritional value due to its high protein, fibers and polyunsaturated fatty acid (PUFA) contents. It also contains phytoestrogenic compounds that definitely hinder its recommendation for general consumption. Contrary to ancient times, when soybeans were boiled, modern commercial soy foods can contain up to 150 mg/100g of estrogenic isoflavones. Interestingly, current estimations of isoflavone intake in the literature do not distinguish between the origins of soy food, i.e., whether it is homemade or commercial. As a result, the isoflavone exposure in Asian countries may well be overestimated. This study aims to demonstrate, based on step-by-step monitoring of isoflavones, that traditional and domestic treatments, leveraging isoflavones water-solubility, can indeed significantly reduce their content in soy foods. Indeed, when compared to commercial foods, the isoflavone content was found to be 20, 2.6, 4.5 and 9.8 times lower in "homemade" soy juice, tofu, tempeh and miso, respectively. Additionally, water soaking was found to reduce the isoflavones levels in soy-textured proteins by more than 70%. Hence, this simple process has the potential to help drastically reduce overall xenoestrogens exposure. This study could serve as a basis for establishing the isoflavones Reference Dose and issuing food safety guidelines. [ABSTRACT FROM AUTHOR]

Introduction: Daidzein, a secondary metabolite found in Soybean (Glycine max L.) and Pueraria lobata (Willd.), plays a pivotal role in various therapeutic applications, including its potential as an anticancer agent, particularly in estrogen-dependent breast cancer, along with anti-allergic, anti-inflammatory, cardiovascular, antidiabetic, antioxidative, and neurogenerative effects. Daidzein's ability to traverse the blood-brain barrier enhances cognition, reduces aggression, and promotes locomotor activity. Its structural resemblance to estrogens positions it as a potential remedy for menopausal osteoporosis. Methodology: The methodology for the comprehensive review on Daidzein entailed a literature search utilising keywords such as ''Daidzein'' and various therapeutic activities, including “Antioxidant,” “Anti-inflammatory,” “Anticancer,” “Antiviral,” “Antiobesity,” “Antidiabetic,” “Nephrotoxicity,” “Cardiovascular,” “Neuroprotective,” “Osteoporosis,” “Menopausal Symptoms,” “Aging,” “Cognitive Activities”. Academic databases such as PubMed, Google Scholar, Scopus, and Web of Science were employed for the search, considering articles published within the last 20 years to capture recent research while encompassing significant historical studies. Results: The results provide insights into the diverse effects of daidzein across various health domains, including its antioxidant, anti-inflammatory, anticancer, antiviral, antiobesity, antidiabetic, nephrotoxicity, cardiovascular, neuroprotective, osteoporosis, menopausal symptoms, ageing, and cognitive activities. Discussion: : The discussion section critically analyses the collective evidence gathered from the studies. It explores the mechanisms underlying daidzein's therapeutic effects and discusses the implications of these findings for both Traditional Chinese Medicine and modern healthcare practices. However, challenges related to its low bioavailability and toxicity necessitate further research, providing a foundation for future studies on daidzein's potential applications.

Neuropathy is the most common disorder comprising peripheral nerve damage in diabetic patients. Prolonged hyperglycaemia and oxidative stress cause metabolic imbalance and are the key reasons for the development of diabetic neuropathy. Daidzein, a soy isoflavone possesses potent anti-hyperglycaemic and antioxidant activity. The present study aims to check the protective effect of Daidzein in diabetic neuropathy in rats. The experimental animal model involved induction of diabetes in rats by intraperitoneal injection of streptozotocin (55 mg/kg). Following confirmation of diabetes, the diabetic rats were subjected to oral treatment with varying doses of Daidzein (25, 50, and 100 mg/kg) and pregabalin (30 mg/kg) for a duration of 4 weeks, initiated 6 weeks after diabetes induction. Results indicated that Daidzein treatment led to a significant reduction in plasma glucose levels and an improvement in body weight among diabetic animals. Moreover, Daidzein demonstrated a positive impact on sensory functions, as evidenced by the effect on tail withdrawal and response latency. Mechanical hyperalgesia and allodynia, common symptoms of diabetic neuropathy, were also significantly reduced with both Daidzein and pregabalin treatment. Notably, nerve conduction velocities exhibited improvement following the administration of Daidzein and pregabalin. Further investigation into the molecular mechanisms revealed that Daidzein treatment resulted in a notable enhancement of antioxidant enzyme levels and a reduction in the overexpression of NOX-4 in the sciatic nerve. This suggests that Daidzein’s therapeutic effect is associated with the inhibition of oxidative stress via NOX-4. In summary, the findings of study suggests that, Daidzein treatment significantly attenuated diabetic neuropathy by inhibiting oxidative stress via NOX-4 inhibition.

Soybean is a source of protein, fibers, and phytochemical isoflavones which are considered to have numerous health benefits for children and adulthood. On the other hand, isoflavones are widely known as phytoestrogens that exert their action via the estrogen signaling pathway. With this regard, isoflavones are also considered as endocrine-disrupting chemicals. Endogenous estrogen plays a crucial role in brain development through binding to estrogen receptors (ERs) or G protein-coupled estrogen receptors 1 (GPER1) and regulates morphogenesis, migration, functional maturation, and intracellular metabolism of neurons and glial cells. Soy isoflavones can also bind to ERs, GPER1, and, furthermore, other receptors to modulate their action. Therefore, soy isoflavone consumption may affect brain development during the pre-and post-natal periods. This review summarizes the current knowledge on the mechanisms of isoflavone action, particularly in the early stages of brain development by introducing representative human, and animal models, and in vitro studies, and discusses their beneficial and adverse impact on neurobehavior. As a conclusion, the soy product consumption during the pre-and post-natal periods under proper range of dose showed beneficial effects in neurobehavior development, including improvement of anxiety, aggression, hyperactive behavior, and cognition, whereas their adverse effect by taking higher doses cannot be excluded. We also present novel research lines to further assess the effect of soy isoflavone administration during brain development.

The chemopreventive and chemotherapeutic properties of soy and soy‐derived compounds, especially isoflavones, have been extensively studied in recent years. However, in contrast to their anticancer effects, such as cell growth inhibition, cell cycle arrest and apoptosis induction, isoflavones have also been found to promote the growth of cancer cells. Therefore, the aim of this comprehensive review article is to present the current state of knowledge regarding the molecular mechanisms by which soy‐derived isoflavones target multiple cellular signalling pathways in cancer cells. Our findings indicate that soy‐derived isoflavones act as, among other things, potent modulators of HOX transcript antisense RNA (HOTAIR)/SWI/SNF‐related matrix‐associated actin‐dependent regulator of chromatin subfamily B member 1 (SMARCB1), vascular endothelial growth factor (VEGF)/C–X–C motif chemokine ligand 12 (CXCL12)/C–X–C motif chemokine receptor type 4 (CXCR4), 17‐β‐oestradiol (E2)/oestrogen receptor‐α (ERα)/neuroglobin (NGB) and sonic hedgehog signalling pathways, epigenetic modulatory agents (i.a. miR‐155, miR‐34a and miR‐10a‐5p) and cancer stem cells and epithelial‐to‐mesenchymal transition inhibitors. The paper also discusses the latest epidemiological studies and clinical trials and provides an insight into recent extensive research on the chemo‐preventive and therapeutic potential of soy‐derived isoflavones. [ABSTRACT FROM AUTHOR]

Endothelial damage caused by persistent glucose and lipid metabolism disorders is the main reason of diabetic vascular diseases. Daidzein exerts positive effects on vascular dysfunction. Peroxisome proliferator-activated receptors (PPARs) regulate critically glucose and lipid metabolism. However, the interaction of daidzein to PPARs is still insufficiently explored. In this study, the cell proliferation was detected by EdU. The intrinsic activity and binding affinity of daidzein for human PPARs (hPPARs) were estimated by transactivation reporter gene test and HPLC-UV method, respectively. Daidzein significantly reversed high glucose (HG, at 30 mmol/l)-induced injury in HUVECs, which was inhibited by both PPARα and PPARγ antagonist, but no PPARβ antagonist. Daidzein selectively activated hPPARα and hPPARγ1, but weakly hPPARβ. Additionally, daidzein also bound to both hPPARα and hPPARγ1. The findings suggested that daidzein may be a PPARα and PPARγ dual-agonist. The amelioration of daidzein on HUVECs from hyperglycemia may be mediated by the activation of PPARα and PPARγ receptors. [ABSTRACT FROM AUTHOR]

In this study, we aimed to detect daidzein secreted in the soybean rhizosphere using an indirect competitive immunochromatographic assay. A specific anti-daidzein monoclonal antibody was obtained through the establishment of a hybridoma. The antibody exhibited a detection limit of 5 ppb daidzein and showed strong cross-reactivity with daidzein, as determined by an indirect competitive method using a surface plasmon resonance sensor. Through the findings, a unique binding pattern differing from those of genistein and other saponins was observed. Enhanced sensitivity with the ability to detect daidzein concentrations as low as 10 nM (2.5 ng/mL) was achieved using immunochromatographic test strips with modified gold nanoparticles. [ABSTRACT FROM AUTHOR]

Objective We aimed to (i) investigate the protective effect of active components of water extract of huangqi (milkvetch root) on high glucose (25 mmol/L) induced injury of human umbilical vein endothelial cells (HUVEC) and (ii) elucidate the underlying mechanism. Methods Male SD rats were continuously fed with water extract [20 g/(kg·d)] for 7 d, and blood samples were colleeted 1, 2 and 4 h after the last gavage, combined with supernatant, and performed ultra-performance liquid chromatography (UPLC-MS) analysis to screen the active components of the extract in rats. Cells were divided into normal group, model group, different active components groups treated with different concentrations, and the concerted application of active components group. Cell viability was measured by Cell Counting Kit-8 to explore the optimal concentration of the effective components of milkvetch root. Oxidative damage was measured by reactive oxygen species (ROS). The enzyme-linked immunosorbent assay measured the contents of superoxide dismutase (SOD), catalase (CAT) and malondialdehyde (MDA); the protein expression level of nuclear factor E2 related factor (Nrf 2) and heme oxygenase 1 (HO-1) by Western blotting. Results Formononetin, daidzein, and calycosin are the active components of milkvetch root water extract.Compared with the normal group, the cell viability of the model group was increased (P<0.05). Compared with the model group, cell viability was decreased in each concentration(26, 13, 6.5 μmol/L) of formononetin group (P<0.05), a high dose of daidzein (0.11 μmol/L) could reduce cell viability (P<0.05). Compared with the normal group, the ROS levels in the model group were increased(P<0.05); compared with the model group, the ROS levels in the formononetin high and medium concentrations(26, 13 μmol/L) groups, different concentrations of daidzein (0.11, 0.06, 0.03 μmol/L), the calycosin high concentration group (7.00 μmol/L) were decreased (P<0.05). The combined active components inhibitive rate was higher than the single active components, and highest in the high concentration group. Compared with the normal group, Nrf2 and HO-1 protein expressions were decreased in the model group (P<0.05); compared with the model group, Nrf2 and HO-1 proteins were increased in the group with high concentration of concerted application group (P<0.05). Compared with the normal group, SOD, CAT were decreased (P<0.05), MDA increased (P<0.05) in the model group; compared with the model group, SOD, CAT in the high concentration concerted application group were increased (P<0.05), MDA was significantly decreased (P<0.05). Conclusion The active components of milkvetch root water extract, formononetin, daidzein, calycosin can protect HUVEC from high glucose-induced injury. The mechanism may be related to the regulation of Nrf2, HO-1, SOD, CAT, and MDA expression and their antioxidant effects. [ABSTRACT FROM AUTHOR]

Polyphenolic compounds constitute a diverse group of natural components commonly occurring in various plant species, known for their potential to exert both beneficial and detrimental effects. Additionally, these polyphenols have also been implicated as endocrine-disrupting (ED) chemicals, raising concerns about their widespread use in the cosmetics industry. In this comprehensive review, we focus on the body of literature pertaining to the estrogenic properties of ED chemicals, with a particular emphasis on the interaction of isoflavones with estrogen receptors. Within this review, we aim to elucidate the multifaceted roles and effects of polyphenols on the skin, exploring their potential benefits as well as their capacity to act as ED agents. By delving into this intricate subject matter, we intend to provoke thoughtful consideration, effectively opening a Pandora's box of questions for the reader to ponder. Ultimately, we invite the reader to contemplate whether polyphenols should be regarded as friends or foes in the realm of skincare and endocrine disruption. [ABSTRACT FROM AUTHOR]

Adequate calcium intake is crucial for the prevention and treatment of bone-related issues. Developing a nutritional source of readily bioavailable calcium is particularly significant for individuals deficient in this essential element and at risk of developing osteoporosis. This research aimed to evaluate the impact of tempeh (T), daidzein (D), and Lactobacillus acidophilus (LA) within a simulated intestinal environment consisting of Caco-2 epithelial and Saos-2 cells, focusing on their implications for bone mineralization mechanisms. In the initial phase, calcium bioaccessibility from calcium citrate (CaCt), LA, D, the daidzein combination D–CaCt–LA (D1:1:1), and the tempeh combination T–CaCt–LA (T1:1:1) was assessed through digestion simulation. The calcium content of both untreated and digested samples was determined using atomic absorption spectrometry (AAS). In the subsequent stage, the digested samples were used to induce intestinal absorption in differentiated enterocyte-like Caco-2 cells. The permeable fractions were then evaluated in a culture of osteoblast-like Saos-2 cells. Preliminary cellular experiments employed the MTT assay to assess cytotoxicity. The results indicated that the analyzed products did not influence the deposition of extracellular calcium in Saos-2 cells cultured without mineralization stimulators. The combined formulations of permeable fractions of digested CaCt, LA, D, and T demonstrated the capacity to enhance the proliferation of Saos-2 cells. In Saos-2 cells, D, D1:1:1, and LA showed no discernible impact on intracellular calcium accumulation, whereas T and T1:1:1 reduced the calcium deposits. Additionally, mRNA transcripts and alkaline phosphatase (ALP) activity levels in Saos-2 cells cultured without mineralization induction were unaffected by the analyzed products. An examination of the products revealed no discernible effect on ALP activity or mRNA expression during Saos-2 cell differentiation. Our findings suggest that tempeh, daidzein, and L. acidophilus did not positively impact cellular calcium deposition in Saos-2 cells. However, tempeh, daidzein and its combination, and L. acidophilus might enhance the process of osteogenic differentiation in Saos-2 cells. Nevertheless, this study did not identify any synergistic impact on calcium deposition and the process of osteogenic differentiation in Saos-2 cells of isoflavones and probiotics. [ABSTRACT FROM AUTHOR]

[Objectives]The phytoestrogen daidzein(DZ)was used to act on adolescent mice to investigate its effects on mammary development by increasing 1, 7-β-estradiol(E2)level and upregulating estrogen receptor β(ERβ)expression, providing a basis for DZ and other phytoestrogens in animal production and clinical application. [Methods]Forty-eight 2-week-old female C57BL/6 mices randomly divided into 3 groups:control group, intraperitoneal injection of sterile PBS; DZ group, intraperitoneal injection of DZ(100 mg·kg-1·d-1); positive control group, intraperitoneal injection of E2(0.2 mg·kg-1·d-1). On the 21 and 28 day, 8 mices from each group were randomly selected and their blood was collected, the content of E2 in the blood was measured on the basis of group. After death, the mammary glands were immediately isolated and weighed to measure the index of mammary glands and detect the content of E2 in mammary tissues. The expression of proliferating cell nuclear antigen(PCNA)protein was detected by immunohistochemistry. Cell cycle-related protein and estrogen receptor β(ERβ)protein expression levels were analyzed by Western blot. [Results]Compared with the control group, DZ treatment significantly increased the body weight and daily feed intake of mice on the 21 and 28 day, increased E2 levels in blood and breast tissues of mice on the 21 day, but not significantly(P>0.05)and significantly increased them on the 28 day(P<0.05). Similarly, E2 treatment also significantly increased the content of E2 in blood. DZ treatment had little effect on the mammary index of mice on the 21 day, but significantly increased the index on the 28 day(P<0.05); E2 treatment had the same trend(P<0.05). HE staining showed that DZ and E2 treatments significantly increased the numbers of ducts and PCNA positive cells in breast tissues of mice on the 21 and 28 day(P<0.01). Western blot results showed that DZ and E2 treatments up-regulated the protein expressions of cyclinD1, cyclinB1 and ERβ in breast tissues of mice, and specially significantly up-regulated the protein expressions of cyclinD1, cyclinB1 and ERβ on the 28 day(P<0.05). [Conclutions]Phytoestrogen DZ could promote the development of mammary gland of adolescent mice, and promote the proliferation and division of mammary cells, which might be related to the increase of endogenous E2 level and ERβ receptor. [ABSTRACT FROM AUTHOR]

Depression is one of the most prevalent severe CNS disorders, which negatively affects social lives, the ability to work, and the health of people. As per the World Health Organisation (WHO), it is a psychological disorder that is estimated to be a leading disease by 2030. Clinically, various medicines have been formulated to treat depression but they are having a setback due to their side effects, slow action, or poor bioavailability. Nowadays, flavonoids are regarded as an essential component in a variety of nutraceutical, pharmaceutical and medicinal. Isoflavones are a distinctive and important subclass of flavonoids that are generally obtained from soybean, chickpeas, and red clover. The molecules of this class have been extensively explored in various CNS disorders including depression and anxiety. Isoflavones such as genistein, daidzein, biochanin-A, formononetin, and glycitein have been reported to exert an anti-depressant effect through the modulation of different mediators. Fatty acid amide hydrolase (FAAH) mediated depletion of anandamide and hypothalamic-pituitary-adrenal (HPA) axis-mediated modulation of brain-derived neurotrophic factor (BDNF), monoamine oxidase (MAO) mediated depletion of biogenic amines and inflammatory signaling are the important underlying pathways leading to depression. Upregulation in the levels of BDNF, anandamide, antioxidants and monoamines, along with inhibition of MAO, FAAH, HPA axis, and inflammatory stress are the major modulations produced by different isoflavones in the observed anti-depressant effect. Therefore, the present review has been designed to explore the mechanistic interplay of various mediators involved in mediating the anti-depressant action of different isoflavones. [ABSTRACT FROM AUTHOR]

In this study, a deep eutectic solvent (DES) extraction combined with a magnetic bead ligand affinity analytical method was developed and used for α‐glucosidase inhibitor identification from Pueraria lobata. Several critical parameters affecting the analysis performance, including the type of DES, molar ratio, water amount, pH, salt concentration, and volume of DES, were investigated. The selected analytical sample preparation conditions were as follows. The composition of DES is choline chloride‐1,4‐butanediol (1:3), the water content is 40%, pH is 7.0 and the volume of extraction solution is 2 mL. The obtained sample extraction solution was analyzed directly using α‐glucosidase immobilized magnetic beads (GMBs). Three α‐glucosidase inhibitors in Pueraria lobata, including puerarin, daidzin, and daidzein, were identified. Luteolin was used as a positive control to evaluate the method's selectivity. Results showed it could selectively bond to the GMBs in the DES. As the affinity analysis was performed directly in a DES, the solution‐removing process could be avoided. The intra‐day and inter‐day precisions of the method are 5.21% and 6.38%, respectively. The solvent amount was 1/50–1/2000 of that used in traditional methods. [ABSTRACT FROM AUTHOR]