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Zhongguo Zhong Yao Za Zhi = Zhongguo... Jun 2023This study aims to improve the solubility and bioavailability of daidzein by preparing the β-cyclodextrin-daidzein/PEG_(20000)/Carbomer_(940) nanocrystals....
This study aims to improve the solubility and bioavailability of daidzein by preparing the β-cyclodextrin-daidzein/PEG_(20000)/Carbomer_(940) nanocrystals. Specifically, the nanocrystals were prepared with daidzein as a model drug, PEG_(20000), Carbomer_(940), and NaOH as a plasticizer, a gelling agent, and a crosslinking agent, respectively. A two-step method was employed to prepare the β-cyclodextrin-daidzein/PEG_(20000)/Carbomer_(940) nanocystals. First, the insoluble drug daidzein was embedded in β-cyclodextrin to form inclusion complexes, which were then encapsulated in the PEG_(20000)/Carbomer_(940) nanocrystals. The optimal mass fraction of NaOH was determined as 0.8% by the drug release rate, redispersability, SEM morphology, encapsulation rate, and drug loading. The inclusion status of daidzein nanocrystals was determined by Fourier transform infrared spectroscopy(FTIR), thermogravimetric analysis(TGA), and X-ray diffraction(XRD) analysis to verify the feasibility of the preparation. The prepared nanocrystals showed the average Zeta potential of(-30.77±0.15)mV and(-37.47±0.64)mV and the particle sizes of(333.60±3.81)nm and(544.60±7.66)nm before and after daidzein loading, respectively. The irregular distribution of nanocrystals before and after daidzein loading was observed under SEM. The redispersability experiment showed high dispersion efficiency of the nanocrystals. The in vitro dissolution rate of nanocrystals in intestinal fluid was significantly faster than that of daidzein, and followed the first-order drug release kinetic model. XRD, FTIR, and TGA were employed to determine the polycrystalline properties, drug loading, and thermal stability of the nanocrystals before and after drug loading. The nanocrystals loaded with daidzein demonstrated obvious antibacterial effect. The nanocrystals had more significant inhibitory effects on Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa than daidzein because of the improved solubility of daidzein. The prepared nanocrystals can significantly increase the dissolution rate and oral bioavailability of the insoluble drug daidzein.
Topics: Sodium Hydroxide; Acrylic Resins; Escherichia coli; Nanoparticles
PubMed: 37381955
DOI: 10.19540/j.cnki.cjcmm.20230329.302 -
Neoplasma 2016Bladder cancer is one of the causes of cancer‑related death and has a high mortality rate. Daidzein, a natural isoflavone compound predominantly extracted from...
Bladder cancer is one of the causes of cancer‑related death and has a high mortality rate. Daidzein, a natural isoflavone compound predominantly extracted from soybeans, has been reported to exhibit several bioactivities, including anti-tumor. However, the effects of daidzein on bladder cancer remains unrevealed. Here we investigated the effects and molecular mechanisms of daidzein on bladder cancer using multiple in vitro cell lines and in vivo xenograft mice studies. Our results showed that daidzein reduced cell viability in a time- and concentration‑dependent manner. Daidzein significantly impaired colony formation, caused G1/S cell cycle arrest and induced apoptosis of the bladder cancer cells. We also verified that daidzein efficiently suppressed RT112 cell xenograft tumor growth in nude mice. Mechanism studies indicated that significant down-regulation of the FGFR3 signaling pathway was responsible for the efficacy of daidzein. The phosphorylation levels of FGFR3, Akt and Erk proteins were suppressed in association with the decreasing of some apoptosis-suppressing molecules under the daidzein treatment. Knockdown of endogenous FGFR3 impaired the activity of daidzein against bladder cancer, which suggested that the effect of daidzein was mainly mediated by FGFR3 pathway. In addition, the function model of daidzein was similar with FGFR3 antagonist PD173074 in RT112 cells. Taken together, the results this study demonstrate that daidzein is capable of inhibiting bladder cancer growth and might be a novel effective chemotherapeutic agent for the application to combat bladder carcinoma.
Topics: Animals; Apoptosis; Cell Cycle; Cell Line, Tumor; Dose-Response Relationship, Drug; Humans; Isoflavones; Mice; Mice, Nude; Phosphorylation; Receptor, Fibroblast Growth Factor, Type 3; Signal Transduction; Urinary Bladder Neoplasms; Xenograft Model Antitumor Assays
PubMed: 27268915
DOI: 10.4149/neo_2016_405 -
Molecular Immunology Aug 2014Clearance of apoptotic cells, termed "efferocytosis", is the mechanism required to prevent secondary necrosis and release of proinflammatory cytokines. Defective...
Clearance of apoptotic cells, termed "efferocytosis", is the mechanism required to prevent secondary necrosis and release of proinflammatory cytokines. Defective efferocytosis is cumulatively regarded as one of mechanisms in the development of autoimmune and chronic inflammatory diseases. Our previous finding showed that ethanolic extract from Glycine tomentella Hayata (GTH) can enhance mouse macrophage RAW264.7 efferocytosis (clearance of apoptotic cells). We have demonstrated that the major components of GTH are daidzein, catechin, epicatechin and naringin. Here, we explore the potential of each component in modulating efferocytic capability. For this, RAW264.7 cells were cultured with CFDA-stained apoptotic cells and assayed by flow cytometry. We found that daidzein is the main component of GTH, and it can enhance RAW264.7 efferocytosis dose-dependently. Moreover, the enhancive effect of daidzein on macrophage efferocytic capability is accompanied by increased transglutaminase 2 (TG2) at both mRNA and protein levels. TG2 knockdown attenuated daidzein increased macrophage efferocytic capability. After treatment with daidzein, increased phosphorylation was observed in Erk, but not in p38 and JNK. Finally, we report that after daidzein treatment, Rac1 activity was markedly increased and the mitochondrial membrane potential was decreased, which may contribute to efferocytosis. Taken together, these data suggest that enhancement of macrophage efferocytic capability by daidzein treatment was mainly through up-regulation of TG2 expression and Rac1 activity. Daidzein may have the therapeutical potential in the treatment of inflammatory diseases.
Topics: Animals; Cell Line; GTP-Binding Proteins; Humans; Isoflavones; MAP Kinase Signaling System; Membrane Potential, Mitochondrial; Mice; Phagocytosis; Phosphorylation; Protein Glutamine gamma Glutamyltransferase 2; Transglutaminases; Up-Regulation; rac1 GTP-Binding Protein
PubMed: 24859791
DOI: 10.1016/j.molimm.2014.04.006 -
General Physiology and Biophysics Mar 2024Endothelial damage caused by persistent glucose and lipid metabolism disorders is the main reason of diabetic vascular diseases. Daidzein exerts positive effects on...
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.
Topics: Humans; PPAR alpha; PPAR gamma; Endothelial Cells; Glucose; Isoflavones
PubMed: 38477605
DOI: 10.4149/gpb_2023041 -
Molecular Medicine Reports Apr 2018Choriocarcinoma is a malignant gestational trophoblastic disease and relapse or drug resistance occurs in ~25% of gestational trophoblastic tumors. Cell apoptosis serves...
Choriocarcinoma is a malignant gestational trophoblastic disease and relapse or drug resistance occurs in ~25% of gestational trophoblastic tumors. Cell apoptosis serves a role in the progression from hydatidiform mole to persistent gestational trophoblastic disease. It has been demonstrated that daidzein [7‑hydroxy‑3‑(4‑hydroxyphenyl)‑4H‑chromen‑4‑one] may induce apoptosis in a number of cancer types via the mitochondrial apoptotic pathway by altering the B‑cell lymphoma (Bcl)‑2/Bcl‑2 associated X, apoptosis regulator (Bax) ratio, and activating the caspase cascade. Daidzein also serves a role in regulation of production of human chorionic gonadotropin in trophoblast cells and inhibition of cell proliferation. However, few reports have been published regarding the effect of daidzein on apoptosis in choriocarcinoma. Therefore, in the present study, JAR and JEG‑3 human gestational choriocarcinoma cells were used to investigate the effect of daidzein on apoptosis of choriocarcinoma cells. Treatment with daidzein for 48 h reduced cell viability in a dose‑dependent manner. The percentages of early and late apoptotic cells also increased following treatment with daidzein in a dose‑dependent manner, with the number of late apoptotic cells increasing more prominently. Furthermore, treatment with daidzein led to apoptosis‑associated alterations in nuclear morphology of JAR and JEG-3 cells. Expression levels of cleaved poly(ADP‑ribose) polymerase, cleaved caspase‑3 and cleaved caspase‑9 increased following treatment with daidzein, whereas the Bcl‑2/Bax ratio decreased in a dose‑dependent manner. In conclusion, the results of the present study demonstrate that daidzein may induce apoptosis of choriocarcinoma cells in a dose‑dependent manner via the mitochondrial apoptotic pathway.
Topics: Apoptosis; Apoptosis Regulatory Proteins; Biomarkers; Cell Line, Tumor; Cell Survival; Choriocarcinoma; Dose-Response Relationship, Drug; Female; Humans; Isoflavones; Mitochondria; Pregnancy; Signal Transduction; Uterine Neoplasms
PubMed: 29436666
DOI: 10.3892/mmr.2018.8604 -
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 -
Toxicological Sciences : An Official... Feb 2002Soy products containing phytoestrogens have received much attention as dietary components to promote better health. Daidzein, an isoflavone and phytoestrogen component...
Soy products containing phytoestrogens have received much attention as dietary components to promote better health. Daidzein, an isoflavone and phytoestrogen component of soy, was investigated for its potential to alter fertility and cause developmental toxicity to the reproductive tract in female rats, for chemoprevention to the mammary gland, and to study its bioavailability. Diets containing 0 mg, 250 mg (low dose), and 1000 mg (high dose) daidzein/kg feed were fed to virgin female rats, starting 2 weeks prior to breeding and continued until the offspring were 50 days postpartum. The serum daidzein concentrations in adult female rats fed the low and high daidzein-containing diets were determined to be 6- and 13-fold higher than serum daidzein concentrations of Asians eating a traditional diet high in soy. Both daidzein doses had no significant effect on fertility, numbers of male and female offspring, and anogenital distances. The high, but not the low, daidzein dose resulted in reduced body weight, a fact that may be explained by reduced feed consumption. Circulating progesterone, but not estrogen, levels were statistically reduced with the high, but not low daidzein-containing diet. Both daidzein doses resulted in slight, but not significant, decreases in ovarian and uterine weights, and mammary gland size. Histomorphological analysis of the reproductive tracts of female offspring 50 days of age exposed perinatally to daidzein did not reveal any pathology in the vaginal, uterine, ovarian, and mammary tissues. Perinatal exposure of female offspring to 250 mg daidzein/kg diet did not alter mammary gland development or ontogeny of chemically induced mammary tumors in rats treated with dimethylbenz(a)anthracene on day 50. With the low dietary daidzein dose, total equol (major metabolite) and daidzein concentrations in the blood of pregnant females, 7-day-old, 21-day-old, and 50-day-old female offspring were 529 and 303 nM, 163 and 982 nM, 1188 and 1359 nM, and 3826 and 630 nM, respectively. With the high daidzein diet, equol and daidzein concentrations in the blood of pregnant females, 7-day-old, 21-day-old, and 50-day-old female offspring were 4462 and 407 nM, 1013 and 3841 nM, 6472 and 3308 nM, and 7228 and 1430 nM, respectively. Eighty-nine to 99% of daidzein and equol were in the conjugated form. In the 21-day-old postconceptus exposed to the low and high daidzein diets, total equol and daidzein blood concentrations were 59 and 34 nM, and 358 and 132 nM, respectively. Virtually all of the daidzein in the milk of 7-day-old rats exposed to the low and high daidzein-containing diet were unconjugated, 2.6 microM and 7.3 microM, respectively. Total milk equol concentrations were 654 nM and 3.8 microM, of which 94% and 44% were unconjugated. In mammary glands of 7-day-old offspring exposed to 250 mg daidzein/kg diet, total daidzein concentrations were 407 nM (98% aglycone). We conclude that supraphysiological concentrations of daidzein administered via the diet did not cause significant toxicity to the female reproductive tract or provide a protective effect against chemically induced mammary cancer.
Topics: Animals; Body Weight; Breast; Dose-Response Relationship, Drug; Eating; Estradiol; Estrogens, Non-Steroidal; Female; Genitalia, Female; Isoflavones; Male; Mammary Neoplasms, Experimental; Organ Size; Pregnancy; Prenatal Exposure Delayed Effects; Progesterone; Rats; Rats, Sprague-Dawley; Reproduction
PubMed: 11812927
DOI: 10.1093/toxsci/65.2.228 -
European Journal of Drug Metabolism and... Mar 2022Daidzein has several biological effects such as antioxidation, anti-inflammation, chemoprevention, and anticancer effects. The aim of this study was to evaluate the...
BACKGROUND AND OBJECTIVES
Daidzein has several biological effects such as antioxidation, anti-inflammation, chemoprevention, and anticancer effects. The aim of this study was to evaluate the impact of nano-formulations (nanoemulsion-NE and nanosuspension-NS) prepared to increase the oral bioavailability of daidzein, a poorly water-soluble isoflavone, on the pharmacokinetic parameters of daidzein in rats.
METHODS
A high-performance liquid chromatography-ultraviolet (HPLC-UV) method was successfully developed for daidzein analysis in rat plasma. The pharmacokinetics studies of the nano-sized formulations, compared to coarse daidzein suspension, were carried out in the rats by a single oral dose at 10 mg/kg (n = 6/group). Area under the plasma concentration-time curve from time zero to extrapolation to time infinity (AUC, maximum plasma concentration (C), time to reach maximum plasma concentration (t), and elimination half life (t) values for coarse daidzein suspension, daidzein-NS, and daidzein-NE were estimated by a non-compartmental analysis.
RESULTS
The AUC values of daidzein-NE and daidzein-NS were approximately 2.62 and 2.65 times higher than that of coarse daidzein suspension, respectively (p < 0.05). Relative bioavailability (F) (%) values of daidzein following oral administration of nanosuspension or nanoemulsion formulations were about 265.6% and 262.3%, respectively.
CONCLUSION
It revealed that nanoscale size is an important factor to overcome any dissolution rate barriers to oral bioavailability of the low water-soluble compound. Nanoemulsion and nanosuspension formulations are beneficial dosage forms to increase the oral bioavailability of Biopharmaceutical Classification System (BCS) Class II and Class IV compounds.
Topics: Administration, Oral; Animals; Area Under Curve; Biological Availability; Drug Compounding; Isoflavones; Rats
PubMed: 35018554
DOI: 10.1007/s13318-021-00746-5 -
Neurochemistry International Jul 2012Phytoestrogens are a group of plant-derived compounds that include mainly isoflavones like daidzein. Phytoestrogens prevent neuronal damage and improve outcome in...
Phytoestrogens are a group of plant-derived compounds that include mainly isoflavones like daidzein. Phytoestrogens prevent neuronal damage and improve outcome in experimental stroke; however, the mechanisms of this neuroprotective action have not been fully elucidated. In this context, it has been postulated that phytoestrogens might activate the peroxisome proliferator-activated receptor-γ (PPARγ), which exerts neuroprotective effects in several settings. The aim of this study was to determine whether the phytoestrogen daidzein elicits beneficial actions in neuronal cells by mechanisms involving activation of PPARγ. Our results show that daidzein (0.05-5 μM) decreases cell death induced by exposure to oxygen-glucose deprivation (OGD) from rat cortical neurons and that improves synaptic function, in terms of increased synaptic vesicle recycling at nerve terminals, being both effects inhibited by the PPARγ antagonist T0070907 (1 μM). In addition, this phytoestrogen activated PPARγ in neuronal cultures, as shown by an increase in PPARγ transcriptional activity. Interestingly, these effects were not due to binding to the receptor ligand site, as shown by a TR-FRET PPARγ competitive binding assay. Conversely, daidzein increased PPARγ nuclear protein levels and decreased cytosolic ones, suggesting nuclear translocation. We have used the receptor antagonist (RE) fulvestrant to study the neuroprotective participation of daidzein via estrogen receptor and at least in our model, we have discarded this pathway. These results demonstrate that the phytoestrogen daidzein has cytoprotective properties in neurons, which are due to an increase in PPARγ activity not mediated by direct binding to the receptor ligand-binding domain but likely due to post-translational modifications affecting its subcellular location and not depending to the RE and it is not additive with the agonist rosiglitazone.
Topics: Animals; Benzamides; Cells, Cultured; Glucose; Isoflavones; Ligands; Neurons; Neuroprotective Agents; Oxygen; PPAR gamma; Pyridines; Rats
PubMed: 22521773
DOI: 10.1016/j.neuint.2012.04.007 -
Food and Chemical Toxicology : An... Oct 2013Daidzein, which belongs to the group of isoflavones from soybeans, has been extensively researched prostate, cervix, brain, breast, and colon cancer cell lines. However,...
Daidzein, which belongs to the group of isoflavones from soybeans, has been extensively researched prostate, cervix, brain, breast, and colon cancer cell lines. However, daidzein has not been thoroughly investigated in human hepatic cancer cells; therefore, we investigated whether it inhibits hepatic cancer cell growth. Decreased cell proliferation was measured in daidzein-treated hepatic cancer cells (SK-HEP-1) upon real-time cell electronic sensing analysis however, it was not affected on normal human hepatocytes (Chang). Daidzein-induced apoptosis was demonstrated by comet and TUNEL assay. Moreover, we conducted two-dimensional electrophoresis to study the mechanism of daidzein-induced apoptosis in daidzein-treated SK-HEP-1 cells. Expression of peroxiredoxin-3 (Prdx-3), which modulates redox homeostasis of cells, was increased in protein analysis. Additionally, we measured the levels of reactive oxygen species and it was decreased in daidzein-treated SKHEP-1 cells. Daidzein-induced apoptosis in SK-HEP-1 cells was also associated with the up-regulation of Bak and down-regulation of Bcl-2 and Bcl-xL proteins. Moreover, daidzein treatment increased in the release of mitochondrial cytochrome c and activation of APAF-1, caspase 9 and caspase 3. Overall, these result indicate that daidzein is a potent inducer of apoptosis in hepatic cancer cells via mitochondrial pathway.
Topics: Apoptosis; Apoptosis Regulatory Proteins; Apoptotic Protease-Activating Factor 1; Caspase 3; Caspase 9; Cell Line, Tumor; Cell Proliferation; Comet Assay; Cytochromes c; Down-Regulation; Humans; In Situ Nick-End Labeling; Isoflavones; Liver Neoplasms; Mitochondria; Peroxiredoxin III; Reactive Oxygen Species; Signal Transduction; Up-Regulation; bcl-2 Homologous Antagonist-Killer Protein; bcl-X Protein
PubMed: 23959101
DOI: 10.1016/j.fct.2013.08.022