Daidzein

Daidzein is a soy isoflavone, which acts as a PPAR activator.

In Vitro:In 3T3-L1 adipocytes, Daidzein inverses the attenuation of adiponectin gene expression by co-culture, and these effects are inhibited by the PPAR-γ specific inhibitor. Daidzein attenuates the reduction of adiponectin expression in adipocytes, and a PPAR-γ specific inhibitor abrogated this effect. Direct activation of PPAR-α and-γ by Daidzein is confirmed by a luciferase reporter assay. In HEK293T cells, Daidzein significantly increases PPAR-α transcriptional activity in a concentration-dependent manner. Although an obvious dose-dependency is not observed in PPAR-γ transcriptional activity, Daidzein also significantly increases PPAR-γ transcriptional activity over a similar range of concentrations at which Daidzein enhanced PPAR-α transcriptional activity, with a maximum increase at 25 μM[1]. Daidzein is a soy isoflavone, which upregulates the expression of Abcg1, and it promotes axonal outgrowth in cultured hippocampal neurons via estrogen receptor signaling. Daidzein is a major component of soy with structural similarity to estrogen. It exerts an anti-inflammatory effect, lowers lipid levels, and increases mitochondrial biogenesis. As an activator of nuclear receptor peroxisome proliferator-activated receptors (PPARs), Daidzein enhances transcription of PPARs-dependent genes, including liver X receptors (LXRs, Nr1h gene family in mice). Incubation with different concentrations of Daidzein, from 5 to 100 μM, increases APOE transcriptional activity[2].

In Vivo:Treating Apoe KO mice with Daidzein increases Lxr and Abca1 gene expression at 1 month after stroke, showing that the absence of ApoE does not interfere with other cholesterol homeostasis genetic programs. Therefore, the findings suggest that Daidzein-induced ApoE upregulation is a critical component in fostering functional recovery in chronic stroke[2].

References:
[1]. Sakamoto Y1, et al. The Dietary Isoflavone Daidzein Reduces Expression of Pro-Inflammatory Genes through PPARα/γ and JNK Pathways in Adipocyte and Macrophage Co-Cultures. PLoS One. 2016 Feb 22;11(2):e0149676. [2]. Kim E, et al. Daidzein Augments Cholesterol Homeostasis via ApoE to Promote Functional Recovery in Chronic Stroke. J Neurosci. 2015 Nov 11;35(45):15113-26.

Daidzein pretreatment improves survival in mouse model of sepsis.[Pubmed:25908100]

J Surg Res. 2015 Aug;197(2):363-73.

BACKGROUND: The aim of the present study was to assess the effect of seven days Daidzein pretreatment in cecal ligation and puncture (CLP) model of sepsis. METHODS: We assessed the survival benefit of Daidzein and its effect on lung injury in CLP-induced sepsis in mice and determined the bacterial load in peritoneal fluid, blood, and lung homogenates. Tumor necrosis factor alpha (TNF-alpha) and corticosterone levels were measured by enzyme-linked immunosorbent assay; relative mRNA expression was estimated by real-time polymerase chain reaction, and standard biochemical techniques were used to measure nitrite level, myeloperoxidase activity, and vascular permeability. RESULTS: Daidzein pretreatment for seven days at a dose of 1 mg/kg body weight subcutaneously increased the survival time of septic mice. Daidzein decreased the bacterial load in peritoneal fluid, blood, and lungs, reduced the tumor necrosis factor alpha and nitrite level in plasma, and partially suppressed lung injury by reducing vascular permeability and myeloperoxidase activity in septic mice. Further, it restored the relative mRNA expressions of inducible nitric oxide synthase, glucocorticoid receptor alpha, and glucocorticoid receptor beta genes in septic lungs were restored by Daidzein pretreatment. CONCLUSIONS: Daidzein pretreatment for 7 d in sepsis increased the survival time in mice, which may be relate to decrease in bacterial load, anti-inflammatory effect, and protection from lung injury.

Daidzein enhances intramuscular fat deposition and improves meat quality in finishing steers.[Pubmed:25526906]

Exp Biol Med (Maywood). 2015 Sep;240(9):1152-7.

An experiment was conducted to determine the effects of soy isoflavone Daidzein on carcass characteristics, fat deposition, meat quality, and blood metabolites in finishing steers. Fourteen crossbred steers were used in a 120-d finishing study. These steers were stratified by weight into groups and randomly allotted by group to one of two dietary treatments: (1) control and (2) Daidzein (500 mg/kg concentrate). The steers were fed a 90% concentrate diet. Supplemental Daidzein did not affect slaughter weight, hot carcass weight, and dressing percentage, but tended to reduce fat proportion (not including intramuscular fat) in carcass and backfat thickness of steers. The carcass bone proportion was greater in steers fed Daidzein diets than those fed control diets. Daidzein supplementation reduced pH at 24 h after slaughtered and moisture content and increased isocitrate dehydrogenase activity, fat content (16.28% and 7.94%), marbling score (5.29 and 3.36), redness (a*), and chroma (C*) values in longissimus muscle relative to control treatment. The concentrations of blood metabolites including glucose, blood urea nitrogen, triglyceride, total cholesterol, non-esterified fatty acid, high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) were all lower in steers fed Daidzein diets than those fed control diets. Current results suggest that supplemental Daidzein can affect lipid metabolism, increase intramuscular fat content and marbling score, and improve meat quality in finishing steers. Daidzein should be a promising feed additive for production of high-quality beef meat.

Daidzein attenuates lipopolysaccharide-induced acute lung injury via toll-like receptor 4/NF-kappaB pathway.[Pubmed:25887269]

Int Immunopharmacol. 2015 Jun;26(2):392-400.

Daidzein, a diphenolic isoflavone from many plants and herbs, has been reported to have anti-inflammatory properties. However, the effects of Daidzein on lipopolysaccharide (LPS)-induced acute lung injury have not been determined. The aim of this study was to detect the effects of Daidzein on LPS-induced acute lung injury and investigate the molecular mechanisms. Daidzein was intraperitoneally injected (2, 4, 8 mg/kg) 30 min after intratracheal instillation of LPS (5 mg/kg) in rats. The results showed that Daidzein treatment remarkably improved the pulmonary histology and decreased the lung wet/dry weight ratios. We also found that Daidzein significantly inhibited LPS-induced increases of macrophages and neutrophils infiltration of lung tissues, as well as markedly attenuated MPO activity. Moreover, Daidzein effectively reduced the inflammatory cytokines release and total protein in bronchoalveolar lavage fluids (BALF). Furthermore, Daidzein significantly inhibited LPS-induced toll-like receptor 4 (TLR4) and myeloid differentiation factor 88 (MyD88) protein up-expressions and NF-kappaB activation in lung tissues. In vitro, Daidzein obviously inhibited the expressions of TLR4 and MyD88 and the activation of NF-kappaB in LPS-stimulated A549 alveolar epithelial cells. In conclusion, these data indicate that the anti-inflammatory effects of Daidzein against LPS-induced ALI may be due to its ability to inhibit TLR4-MyD88-NF-kappaB pathway and Daidzein may be a potential therapeutic agent for LPS-induced ALI.

Daidzein enhances efferocytosis via transglutaminase 2 and augmentation of Rac1 activity.[Pubmed:24859791]

Mol Immunol. 2014 Aug;60(2):135-42.

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.

Daidzein is more efficient than genistein in preventing ovariectomy-induced bone loss in rats.[Pubmed:10867035]

J Nutr. 2000 Jul;130(7):1675-81.

We investigated the ability of genistein and Daidzein, two soybean isoflavones, compared with that of 17 alpha-ethinylestradiol, to prevent bone loss in ovariectomized rats, a model for postmenopausal osteoporosis. Female Wistar rats (n = 65; 12 mo old) were either sham-operated (SH; n = 13) or ovariectomized (OVX; n = 52). On d 0, OVX rats were randomly assigned to groups as follows: 13 received genistein [G; 10 mcg/(g body weight. d)], 13 were treated with Daidzein [D; 10 mcg/(g body weight. d)], 13 received 17 alpha-ethinylestradiol [E(2); 30 mcg/kg body weight. d)] and 13 were untreated (OVX). Compounds were mixed with a soy protein-free powdered semipurified diet and given orally for 3 mo. On d 90, the bone mineral density (BMD) in lumbar vertebrae, femur and its metaphyseal and diaphyseal zones (rich in cancellous and cortical bone, respectively) was lower in OVX than in SH (P < 0.01). In D or E(2), the four BMD were not different from SH, whereas in G, only the diaphyseal BMD was not different from SH. Image analysis performed in the distal femur metaphysis revealed that the cancellous bone area was lower in OVX than in SH (P < 0.01). Only the area in D was not different from that in SH. Finally, the bone turnover, which was higher in OVX than in SH (P < 0.005 and P < 0.05 for plasma osteocalcin concentration and urinary deoxypyridinoline excretion, respectively), was not different in G, D or E(2) compared with SH. Therefore, consumption of 17 alpha-ethinylestradiol or Daidzein was more efficient than genistein in preventing ovariectomy-induced bone loss in rats.

Daidzein exhibits anti-fibrotic effect by reducing the expressions of Proteinase activated receptor 2 and TGFbeta1/smad mediated inflammation and apoptosis in Bleomycin-induced experimental pulmonary fibrosis.[Pubmed:24769130]

Biochimie. 2014 Aug;103:23-36.

Pulmonary fibrosis (PF) is a progressive lethal disorder. In this study, the effect of Daidzein, a soyisoflavone against Bleomycin (BLM) induced PF in rats was elucidated. A single intratracheal instillation of BLM (3 U/kg.bw) was administered in rats to induce PF. Daidzein (0.2 mg/kg) was administered subcutaneously, twice a week for a period of 28 days. Daidzein restored the histological alteration and aberrant collagen deposition, suppressed the mast cells, and reduced the expressions of Cyclooxygenase 2 (COX2) and Nuclear factor kappa B (Nf-kB) in lung tissue of BLM-induced rats. Treatment with Daidzein reduced the expression of Matrix metalloproteinase 2 (MMP-2) and increased the expression of Tissue inhibitor of matrixmetalloproteinases 1 (TIMP 1). Recently, Proteinase activated receptor 2 (PAR2) has been reported to play a major role in the progression of PF. Confocal microscopic and immunoblot analysis revealed that BLM injured rat lungs exhibited increased expression of PAR2 that was reduced upon treatment with Daidzein. During BLM induction, Transforming growth factor beta (TGFbeta1) was found to be up-regulated along with p-smad2/3, a mediator of TGFbeta signaling. Further, Daidzein regulated the apoptosis by modulating the expressions of Bcl-2, Bax and caspase 3. This study provides evidence on the anti-fibrotic role of Daidzein in BLM-induced experimental fibrosis.

Developmental effects of dietary phytoestrogens in Sprague-Dawley rats and interactions of genistein and daidzein with rat estrogen receptors alpha and beta in vitro.[Pubmed:10543025]

Toxicol Sci. 1999 Oct;51(2):236-44.

Estrogenic isoflavones, such as genistein and Daidzein, are present in virtually all natural-ingredient rodent diets that use soy as a source of protein. Since these compounds are endocrine-active, it is important to determine whether the amounts present in rodent diets are sufficient to affect sexual development. The present study consisted of in vitro and in vivo parts. In the in vitro portion, human hepatoma cells were transfected with either rat estrogen receptor (ER) alpha or beta plus an estrogen-responsive luciferase reporter gene. Genistein and Daidzein were complete agonists at both ERs, genistein being more potent than Daidzein, and both compounds were more potent at ER beta than ER alpha. In combined studies with estradiol, genistein exerted additive effects with estradiol in vitro. In the in vivo portion of the study, groups of six pregnant Sprague-Dawley females were fed one of the following four diets, and the pups were maintained on the same diets until puberty: (1) a natural-ingredient, open-formula rodent diet (NIH-07) containing 16 mg genistein and 14 mg Daidzein per 100 g of feed; (2) a soy- and alfalfa-free diet (SAFD) in which casein and corn oil were substituted for soy and alfalfa meal and soy oil, respectively, that contained no detectable isoflavones; (3) SAFD containing 0.02% genistein (GE.02); or (4) SAFD containing 0.1% genistein (GE.1). In the GE.1 group, effects of dietary genistein included a decreased rate of body-weight gain, a markedly increased (2.3-fold) uterine/body weight (U/BW) ratio on postnatal day (pnd) 21, a significant acceleration of puberty among females, and a marginal decrease in the ventral prostate weight on postnatal day (pnd) 56. However, developmental differences among the groups fed SAFD, GE.02, or NIH-07 were small and suggested minimal effects of phytoestrogens at normal dietary levels. In particular, on pnd 21, the U/BW ratio of the GE.02 and NIH-07 groups did not differ significantly from that of the SAFD group. Only one statistically significant difference was detected between groups fed SAFD and NIH-07: the anogenital distance (AGD) of female neonates on pnd 1 whose dams were fed NIH-07 was 12% larger than that of neonates whose dams were fed SAFD. The results suggest that normal amounts of phytoestrogens in natural-ingredient rodent diets may affect one developmental parameter, the female AGD, and that higher doses can affect several other parameters in both males and females. Based on these findings, we do not suggest replacing soy- and alfalfa-based rodent diets with phytoestrogen-free diets in most developmental toxicology studies. However, phytoestrogen-free diets are recommended for endocrine toxicology studies at low doses, to determine whether interactive effects may occur between dietary phytoestrogens and man-made chemicals.

Daidzein inhibits insulin- or insulin-like growth factor-1-mediated signaling in cell cycle progression of Swiss 3T3 cells.[Pubmed:8130274]

Biochim Biophys Acta. 1994 Mar 10;1221(1):29-35.

An isoflavone compound, Daidzein, inhibits the cell proliferation of Swiss 3T3 cells. Analysis of entry in S phase of Swiss 3T3 cells reveals that Daidzein blocked cell cycle G1 phase progression 4.6 h after stimulation by bombesin plus insulin. After removal of Daidzein, insulin or insulin-like growth factors (IGFs) reinitiate cell cycle progression of Daidzein-blocked cells without further addition of bombesin. The order in the mitogenic action of insulin or IGFs is as follows: IGF-1 (5 ng/ml) >> IGF-2 (0.5 microgram/ml) congruent to insulin (1 microgram/ml). Studies in vivo of protein kinase activation by mitogenic stimulation reveal that the treatment with Daidzein decreased the activation of a MAP2 phosphorylating protein kinase (MAP2 kinase). In vitro kinase assays showed that Daidzein inhibits casein kinase II activity, but does not inhibit MAP2 kinase activity. Activation of casein kinase II by polylysine augments the activity of MAP2 kinase in digitonin-permeabilized 3T3 cells. These results suggest that Daidzein blocked G1 phase cell cycle progression of Swiss 3T3 by inhibiting the activity of casein kinase II which is required for the commitment of mitogenic signal by insulin or IGF-1 in G1 phase.

Differentiation of promyelocytic leukemia cells HL-60 induced by daidzein in vitro and in vivo.[Pubmed:8352524]

Anticancer Res. 1993 Jul-Aug;13(4):1049-54.

We have screened more than one thousand synthetic and natural chemicals to explore differentiation inducers and found that Daidzein has potent differentiation-inducing activity for human leukemia HL-60 cells, both in vitro and in vivo. In vitro study showed that Daidzein at concentrations exceeding 10 micrograms/ml caused inhibition of HL-60 cells; and it induced differentiation of the cells into granulocytic lineage as judged by NBT reduction activity, phagocytic ability and morphological characteristics. Flow cytometry study indicated that Daidzein arrested HL-60 cells in the G1 phase. The growth of HL-60 cells in the subrenal capsules of mice and in diffusion chambers implanted into the peritoneal cavities of mice was inhibited by 50 mg/kg Daidzein. HL-60 cells treated with Daidzein in vivo also exhibited characteristic morphological changes of matured cells. Moreover, the colony forming efficiency of HL-60 cells in diffusion chambers in mice was markedly inhibited by the administration of Daidzein.