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Daidzein Augments Cholesterol Homeostasis via ApoE to Promote Functional Recovery in Chronic Stroke.The Journal of Neuroscience : the... Nov 2015Stroke is the world's leading cause of physiological disability, but there are currently no available agents that can be delivered early after stroke to enhance...
UNLABELLED
Stroke is the world's leading cause of physiological disability, but there are currently no available agents that can be delivered early after stroke to enhance recovery. Daidzein, a soy isoflavone, is a clinically approved agent that has a neuroprotective effect in vitro, and it promotes axon growth in an animal model of optic nerve crush. The current study investigates the efficacy of daidzein on neuroprotection and functional recovery in a clinically relevant mouse model of stroke recovery. In light of the fact that cholesterols are essential lipid substrates in injury-induced synaptic remodeling, we found that daidzein enhanced the cholesterol homeostasis genetic program, including Lxr and downstream transporters, Apoe, Abca1, and Abcg1 genes in vitro. Daidzein also elevated the cholesterol homeostasis genes in the poststroke brain with Apoe, the highest expressing transporter, but did not affect infarct volume or hemispheric swelling. Despite the absence of neuroprotection, daidzein improved motor/gait function in chronic stroke and elevated synaptophysin expression. However, the daidzein-enhanced functional benefits and synaptophysin expression were abolished in Apoe-knock-out mice, suggesting the importance of daidzein-induced ApoE upregulation in fostering stroke recovery. Dissociation between daidzein-induced functional benefits and the absence of neuroprotection further suggest the presence of nonoverlapping mechanisms underlying recovery processes versus acute pathology. With its known safety in humans, early and chronic use of daidzein aimed at augmenting ApoE may serve as a novel, translatable strategy to promote functional recovery in stroke patients without adverse acute effect.
SIGNIFICANCE STATEMENT
There have been recurring translational failures in treatment strategies for stroke. One underlying issue is the disparity in outcome analysis between animal and clinical studies. The former mainly depends on acute infarct size, whereas long-term functional recovery is an important outcome in patients. In an attempt to identify agents that promote functional recovery, we discovered that an FDA-approved soy isoflavone, daidzein, improved stroke-induced behavioral deficits via enhancing cholesterol homeostasis in chronic stroke, and this occurs without causing adverse effects in the acute phase. With its known safety in humans, the study suggests that the early and chronic use of daidzein serves as a potential strategy to promote functional recovery in stroke patients.
Topics: Animals; Apolipoproteins E; Cell Line, Tumor; Cells, Cultured; Cholesterol; Chronic Disease; Growth Inhibitors; Homeostasis; Humans; Isoflavones; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Recovery of Function; Stroke
PubMed: 26558782
DOI: 10.1523/JNEUROSCI.2890-15.2015 -
Journal of Physiology and Pharmacology... Feb 2013Soy products, commonly used as a protein source in farm animals' diets, contain considerable quantities of non-nutrient constituents such as phytoestrogens. Genistein...
Soy products, commonly used as a protein source in farm animals' diets, contain considerable quantities of non-nutrient constituents such as phytoestrogens. Genistein and daidzein are known to affect the reproductive processes in humans and animals. However, reports concerning phytoestrogens and porcine adrenal steroidogenesis are scarce, and the adrenal mechanism of phytoestrogen action in species other than humans and rodents is poorly recognized. The goal of the present paper was to examine the in vitro effects of genistein and daidzein on the activity of key enzymes for cortisol and corticosterone synthesis in porcine adrenocortical cells harvested during the luteal or follicular phase of the porcine estrous cycle. The cells were treated with genistein or daidzein (10 μM), with or without ACTH (5 nM), in the presence or absence of precursors (1 μM) of cortisol (pregnenolone, P5; progesterone, P4; 17-hydroxyprogesterone, 17OH-P4; or 11-deoxycortisol, 11d-cortisol) or corticosterone: (P5 or P4) synthesis. The supplementation of a medium with P5, P4, 17OH-P4 or 11d-cortisol enabled us to measure the activity of cholesterol side-chain cleavage enzyme (P450scc), 3β-hydroxysteroid dehydrogenase (3β-HSD), 17α-hydroxylase/C17-20 lyase (P450c17) or 21-hydroxylase (P450c21) and 11β-hydroxylase (P45011β), respectively. We demonstrated that in sexually mature, cyclic pigs, regardless of the phase of the estrous cycle, phytoestrogens genistein and daidzein suppressed basal and ACTH-stimulated in vitro secretion of cortisol and corticosterone via progesterone synthesis inhibition. This indicates that phytoestrogens specifically inhibit the 3β-HSD activity in porcine adrenocortical cells. We suggest that genistein and daidzein present in soy products may negatively affect glucocorticoid synthesis of mature gilts by disrupting adrenal steroidogenesis at the 3β-HSD level.
Topics: 3-Hydroxysteroid Dehydrogenases; Adrenal Cortex; Adrenocorticotropic Hormone; Animals; Corticosterone; Estrous Cycle; Female; Genistein; Glucocorticoids; Hydrocortisone; Isoflavones; Phytoestrogens; Pregnenolone; Swine
PubMed: 23568977
DOI: No ID Found -
PloS One 2016Obesity-induced inflammation caused by adipocyte-macrophage interactions plays a critical role in developing insulin resistance, and peroxisome proliferator-activated...
Obesity-induced inflammation caused by adipocyte-macrophage interactions plays a critical role in developing insulin resistance, and peroxisome proliferator-activated receptors (PPARs) regulate inflammatory gene expression in these cells. Recently, the soy isoflavone daidzein was reported to act as a PPAR activator. We examined whether daidzein affected adipocyte-macrophage crosstalk via the regulation of PPARs. Co-cultures of 3T3-L1 adipocytes and RAW264 macrophages, or palmitate-stimulated RAW264 macrophages were treated with daidzein in the presence or absence of specific inhibitors for PPARs: GW6471 (a PPARα antagonist), and GW9662 (a PPARγ antagonist). Inflammatory gene expression was then determined. Daidzein significantly decreased chemokine (C-C motif) ligand 2 (Ccl2, known in humans as monocyte chemo-attractant protein 1 (MCP1)) and interleukin 6 (Il6) mRNA levels induced by co-culture. In 3T3-L1 adipocytes, daidzein inversed the attenuation of adiponectin gene expression by co-culture, and these effects were inhibited by the PPAR-γ specific inhibitor. Daidzein also decreased Ccl2 and Il6 mRNA levels in RAW264 macrophages stimulated with palmitate or conditioned medium (CM) from hypertrophied 3T3-L1 adipocytes. This inhibitory effect on Il6 expression was abrogated by a PPAR-α inhibitor. Additionally, we examined the activation of nuclear factor-kappa B (NF-κB) and c-Jun N-terminal kinase (JNK) pathways and found that daidzein significantly inhibited palmitate-induced phosphorylation of JNK. Our data suggest that daidzein regulates pro-inflammatory gene expression by activating PPAR-α and -γ and inhibiting the JNK pathway in adipocyte and macrophage co-cultures. These effects might be favorable in improving adipose inflammation, thus, treatment of daidzein may be a therapeutic strategy for chronic inflammation in obese adipose tissue.
Topics: 3T3-L1 Cells; Adipocytes; Animals; Cell Line, Tumor; Coculture Techniques; Gene Expression Regulation; Humans; Inflammation Mediators; Isoflavones; JNK Mitogen-Activated Protein Kinases; Macrophages; Mice; PPAR alpha; PPAR gamma; Phosphorylation; Signal Transduction
PubMed: 26901838
DOI: 10.1371/journal.pone.0149676 -
Asian Pacific Journal of Cancer... 2013The age-adjusted incidence rate of prostate cancer (PCa) has been reported to be lower among Asians than Western populations. A traditional Japanese meal, high in... (Review)
Review
BACKGROUND
The age-adjusted incidence rate of prostate cancer (PCa) has been reported to be lower among Asians than Western populations. A traditional Japanese meal, high in soybean products or isoflavones, may be associated with a decreased risk of PCa. Equol, which is converted from daidzein by human intestinal flora, is biologically more active than any other isoflavone aglycone.
MATERIALS AND METHODS
We reviewed not only recent epidemiological studies on association of isoflavones with PCa risk, but also recent research on human intestinal bacteria responsible for converting daidzein into equol. Studies were systematically searched from the database published within the last 5 years of from 2008-2012.
RESULTS
Five out of 6 articles showed significant association of isoflavones with a decreased risk of PCa, and two of them consistently showed that equol-producers carry a significantly reduced risk of PCa. Furthermore, 5 human intestinal bacteria that can convert daidzein into equol were identified in the last 5 years.
CONCLUSIONS
If equol can reduce risk of PCa, a possible strategy for reducing the risk of PCa may be to increase the proportion of equol-producers by changing the intestinal flora to carrying an equol-producing bacterium with dietary alteration or probiotic technology.
Topics: Bacteria; Equol; Feces; Food; Gastrointestinal Tract; Humans; Isoflavones; Male; Metabolome; Prostatic Neoplasms
PubMed: 23534704
DOI: 10.7314/apjcp.2013.14.1.1 -
Molecules (Basel, Switzerland) Jan 2017Daidzein, which is scarce in nature, has gained significant attention due to its superior biological activity and bioavailability compared with daidzin. So far, it has...
Daidzein, which is scarce in nature, has gained significant attention due to its superior biological activity and bioavailability compared with daidzin. So far, it has been widely used in the medicine and health care products industries. The enzymatic approach for the preparation of daidzein has prevailed, benefitted by its high efficiency and eco-friendly nature. Our present research aimed at providing a preparation method of daidzein by enzymatic hydrolysis of daidzin in a new "green" reaction medium-deep eutectic solvents (DESs). Herein, the DESs were screened via evaluating enzyme activity, enzyme stability and the substrate solubility, and the DES (ChCl/EG 2:1, 30 vol %) was believed to be the most appropriate co-solvent to improve the bioconversion efficiency. Based on the yield of daidzein, response surface methodology (RSM) was employed to model and optimize the reaction parameters. Under these optimum process conditions, the maximum yield of 97.53% was achieved and the purity of daidzein crude product reached more than 70%, which is more efficient than conversions in DESs-free buffer. Importantly, it has been shown that DESs medium could be reused for six batches of the process with a final conversion of above 50%. The results indicated that this procedure could be considered a mild, environmentally friendly, highly efficient approach to the economical production of daidzein, with a simple operation process and without any harmful reagents being involved.
Topics: Enzymes; Glycosides; Hydrolysis; Intestinal Absorption; Isoflavones; Glycine max
PubMed: 28117755
DOI: 10.3390/molecules22010186 -
Heliyon Nov 2019The present study involves the contribution of cocrystallization towards the modification of the biopharmaceutical parameters of poorly watersoluble plant-originated...
The present study involves the contribution of cocrystallization towards the modification of the biopharmaceutical parameters of poorly watersoluble plant-originated isoflavone, daidzein (DAID). The cocrystals were prepared with GRAS status coformers i.e., isonicotinamide, theobromine and cytosine using mechanochemical grinding and characterized by various analytical techniques (DSC, FT-IR, PXRD and solid-state NMR). Crystal structures were obtained from PXRD data using BIOVIA Materials Studio software and compared in terms of supramolecular motifs. An additional qualitative and quantitative insight into interactions between both components of the cocrystal illustrated the presence of OH⋯N and OH⋯O=C heterosynthons and revealed a stabilizing role of hydrogen bonding. The cocrystals were further evaluated for their solubility, intrinsic dissolution and in vivo profile. Solubility and dissolution studies of pure daidzein and its cocrystals, namely daidzein-isonicotinamide (DIS), daidzein-cytosine (DCYT) and daidzein-theobromine (DTB) exhibited an almost 2-fold improvement. Evaluation of maximum concentration (Cmax) of cocrystals reveals that the DIS cocrystal shows the highest Cmax of 1848.7 ng/ml followed by DCYT cocrystal (1614.9 ng/ml) and DTB cocrystal (1326.0 ng/ml) in comparison to DAID which has a Cmax 870.5 ng/ml. Each of these cocrystals showed significant enhancement in and activities in comparison to daidzein. Thus, this report suggests cocrystallization as a viable approach to resolve the solubility and bioavailability issues that circumvent the use of a therapeutically potential isoflavone, daidzein.
PubMed: 31763466
DOI: 10.1016/j.heliyon.2019.e02669 -
Nutrients May 2023Soy isoflavones belong to the group of phytoestrogens and are associated with beneficial health effects but are also discussed to have adverse effects. Isoflavones are...
BACKGROUND
Soy isoflavones belong to the group of phytoestrogens and are associated with beneficial health effects but are also discussed to have adverse effects. Isoflavones are intensively metabolized by the gut microbiota leading to metabolites with altered estrogenic potency. The population is classified into different isoflavone metabotypes based on individual metabolite profiles. So far, this classification was based on the capacity to metabolize daidzein and did not reflect genistein metabolism. We investigated the microbial metabolite profile of isoflavones considering daidzein and genistein.
METHODS
Isoflavones and metabolites were quantified in the urine of postmenopausal women receiving a soy isoflavone extract for 12 weeks. Based on these data, women were clustered in different isoflavone metabotypes. Further, the estrogenic potency of these metabotypes was estimated.
RESULTS
Based on the excreted urinary amounts of isoflavones and metabolites, the metabolite profiles could be calculated, resulting in 5 metabotypes applying a hierarchical cluster analysis. The metabotypes differed in part strongly regarding their metabolite profile and their estimated estrogenic potency.
Topics: Humans; Female; Genistein; Postmenopause; Isoflavones; Phytoestrogens; Glycine max
PubMed: 37242235
DOI: 10.3390/nu15102352 -
The FEBS Journal Feb 2006Genistein and daidzein, the major isoflavones present in soybeans, possess a wide spectrum of physiological and pharmacological functions. The binding of genistein to...
Genistein and daidzein, the major isoflavones present in soybeans, possess a wide spectrum of physiological and pharmacological functions. The binding of genistein to human serum albumin (HSA) has been investigated by equilibrium dialysis, fluorescence measurements, CD and molecular visualization. One mole of genistein is bound per mole of HSA with a binding constant of 1.5 +/- 0.2 x 10(5) m(-1). Binding of genistein to HSA precludes the attachment of daidzein. The ability of HSA to bind genistein is found to be lost when the tryptophan residue of albumin is modified with N-bromosuccinimide. At 27 degrees C (pH 7.4), van't Hoff's enthalpy, entropy and free energy changes that accompany the binding are found to be -13.16 kcal x mol(-1), -21 cal x mol(-1) K(-1) and -6.86 kcal x mol(-1), respectively. Temperature and ionic strength dependence and competitive binding measurements of genistein with HSA in the presence of fatty acids and 8-anilino-1-naphthalene sulfonic acid have suggested the involvement of both hydrophobic and ionic interactions in the genistein-HSA binding. Binding measurements of genistein with BSA and HSA, and those in the presence of warfarin and 2,3,5-tri-iodobenzoic acid and Förster energy transfer measurements have been used for deducing the binding pocket on HSA. Fluorescence anisotropy measurements of daidzein bound and then displaced with warfarin, 2,3,5-tri-iodobenzoic acid or diazepam confirm the binding of daidzein and genistein to subdomain IIA of HSA. The ability of HSA to form ternery complexes with other neutral molecules such as warfarin, which also binds within the subdomain IIA pocket, increases our understanding of the binding dynamics of exogenous drugs to HSA.
Topics: Anilino Naphthalenesulfonates; Animals; Binding Sites; Binding, Competitive; Bromosuccinimide; Cattle; Fatty Acids; Fluorescence Polarization; Genistein; Humans; Isoflavones; Molecular Structure; Protein Binding; Protein Conformation; Protein Structure, Secondary; Protein Structure, Tertiary; Serum Albumin; Serum Albumin, Bovine; Spectrometry, Fluorescence; Structure-Activity Relationship; Triiodobenzoic Acids; Warfarin
PubMed: 16420470
DOI: 10.1111/j.1742-4658.2005.05071.x -
Journal of Diabetes Investigation May 2023Equol, which is produced by enteric bacteria from soybean isoflavones, has a chemical structure similar to estrogen. Both in vivo and in vitro studies have shown the...
AIMS/INTRODUCTION
Equol, which is produced by enteric bacteria from soybean isoflavones, has a chemical structure similar to estrogen. Both in vivo and in vitro studies have shown the beneficial metabolic effects of equol. However, its effects on type 2 diabetes remain unclear. We investigated the association between the equol producers/non-producers and type 2 diabetes.
MATERIALS AND METHODS
The participants included 147 patients with type diabetes mellitus aged 70-89 years, and 147 age- and sex-matched controls. To ascertain the equol producers or non-producers, we used the comparative logarithm between the urinary equol and daidzein concentrations (cut-off value -1.75).
RESULTS
The urinary equol concentration was significantly lower in the diabetes group compared with the non-diabetes group (P = 0.01). A significant difference in the proportion of equol producers was observed among all participants (38.8% in the diabetes group and 53.1% in the non-diabetes group; P = 0.01). The proportion of equol producers among women was significantly lower in the diabetes group (31.4%) than in the non-diabetes group (52.8%; P < 0.01). Additionally, the frequency of dyslipidemia in female equol producers was significantly lower than that in female non-equol producers (P < 0.01). Among men, no such differences were observed. We found a significant positive correlation between the urinary equol and daidzein concentrations among equol producers (r = 0.55, P < 0.01).
CONCLUSIONS
Our study findings showed that postmenopausal women had a low proportion of equol producers with diabetes and dyslipidemia.
Topics: Aged; Female; Humans; Male; Diabetes Mellitus, Type 2; East Asian People; Equol; Isoflavones; Aged, 80 and over; Gastrointestinal Microbiome; Glycine max; Phytoestrogens; Sex Factors; Postmenopause; Dyslipidemias
PubMed: 36852538
DOI: 10.1111/jdi.13995 -
The British Journal of Nutrition May 2003There has been much recent interest in the cardiovascular benefits of dietary isoflavones. The aim of the present in vitro studies was to investigate potential... (Comparative Study)
Comparative Study
There has been much recent interest in the cardiovascular benefits of dietary isoflavones. The aim of the present in vitro studies was to investigate potential anti-thrombogenic and anti-atherogenic effects of the isoflavones genistein and daidzein in platelets, macrophages and endothelial cells. Pre-treatment with either isoflavone inhibited collagen-induced platelet aggregation in a dose-dependent manner. In a macrophage cell line (RAW 264.7) activated with interferon gamma plus lipopolysaccharide, both isoflavones were found to inhibit NO production and tumour necrosis factor alpha (TNF-alpha) secretion dose-dependently, but they did not affect mRNA levels for inducible nitric oxide synthase and cyclo-oxygenase-2. Both isoflavones also dose-dependently decreased monocyte chemoattractant protein-1 secretion induced by TNF-alpha in human umbilical vein endothelial cells. Compared with daidzein, genistein exerted greater inhibitory effects for all parameters studied. The present data contributes to our knowledge on the molecular mechanisms by which isoflavones may protect against coronary artery disease. Further studies are required to determine whether the effects of isoflavones observed in the current in vitro studies are relevant to the aetiology of coronary artery disease in vivo.
Topics: Analysis of Variance; Animals; Arteriosclerosis; Cell Line; Cells, Cultured; Chemokine CCL2; Cyclooxygenase 2; Dose-Response Relationship, Drug; Endothelium, Vascular; Genistein; Humans; Isoenzymes; Isoflavones; Macrophage Activation; Macrophages; Membrane Proteins; Mice; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Platelet Aggregation; Prostaglandin-Endoperoxide Synthases; Tumor Necrosis Factor-alpha
PubMed: 12720581
DOI: 10.1079/BJN2003820