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Daidzein: A review of pharmacological effects

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Background: Daidzein is an isoflavone with extensive nutritious value and is mainly extracted from soy plants. It is also called phytoestrogen due to its structural similarity to the human hormone estrogen. However, daidzein is distinct from estrogen due to the specificity of the estrogen receptor (ER) complex. In recent years, the pharmacological properties of daidzein have been extensively investigated and considerable progress has been made. The present review aims to evaluate the pharmacological effects and mechanisms of daidzein as reported in scientific literature.Materials and Methods: Studies were identified as reported in PubMed, Elsevier, Scholar, and Springer over the last ten years and this resulted in the identification of 112 papers.Results: Daidzein is reported to play a significant role in the prevention and treatment of a variety of diseases such as cancer, cardiovascular disease, diabetes, osteoporosis, skin disease, and neurodegenerative disease. This pharmacological activity is attributed to various metabolites including equol and trihydroxy isoflavone.Conclusion: Daidzein appears to play a significant role in the prevention of a variety of diseases and has the potential of being used in a clinical setting. However, further research is needed to understand its molecular mechanisms and safety for use in humans.
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DAIDZEIN: A REVIEW OF PHARMACOLOGICAL EFFECTS
Meng-Yao Suna#, Ying Yeb#, Ling Xiaob, Khalid Rahmanc, Wei Xiad, Hong Zhanga*
#these authors contributed equally to this work
aDepartment of Pharmaceutical Botany, School of Pharmacy, Second Military Medical University, Shanghai
200433, China. bCentral Laboratory, Shanghai Seventh People’s Hospital, Shanghai 200137, China. cSchool
of Pharmacy and Biomolecular Sciences, Faculty of Science, Liverpool John Moores University, Liverpool
L3 3AF, England, UK. dDepartment of Nuclear Medicine, Shanghai Seventh People’s Hospital, Shanghai
200137, China
*Corresponding authors: E-mail: zhanghong@smmu.edu.cn
Abstract
Background: Daidzein is an isoflavone with extensive nutritious value and is mainly extracted from soy plants. It is also called
phytoestrogen due to its structural similarity to the human hormone estrogen. However, daidzein is distinct from estrogen due to the
specificity of the estrogen receptor (ER) complex. In recent years, the pharmacological properties of daidzein have been extensively
investigated and considerable progress has been made. The present review aims to evaluate the pharmacological effects and
mechanisms of daidzein as reported in scientific literature.
Materials and Methods: Studies were identified as reported in PubMed, Elsevier, Scholar, and Springer over the last ten years and
this resulted in the identification of 112 papers.
Results: Daidzein is reported to play a significant role in the prevention and treatment of a variety of diseases such as cancer,
cardiovascular disease, diabetes, osteoporosis, skin disease, and neurodegenerative disease. This pharmacological activity is
attributed to various metabolites including equol and trihydroxy isoflavone.
Conclusion: Daidzein appears to play a significant role in the prevention of a variety of diseases and has the potential of being used
in a clinical setting. However, further research is needed to understand its molecular mechanisms and safety for use in humans.
Key words: Plant, natural product, phytoestrogen, pharmacology
Introduction
Daidzein (4′, 7-dihydroxyisoflavone) whose chemical structure is shown in Figure 1 is a naturally occurring isoflavonic
phytoestrogen belonging to the non-steroidal estrogens (Cassidy, 2003) and is mainly derived from the leguminous plants such as
soybean and mung bean. It is also the major bioactive ingredient in traditional Chinese medicine Gegen (Wang et al., 2003) which is
used frequently in the treatment of fever, acute dysentery, diarrhea, diabetes, cardiac dysfunctions, liver injury etc. (Wong et al.,
2011). The chemical structure of daidzein is similar to mammalian estrogens and it exerts a dual-directional function by
replacing/interfering with estrogen and the estrogen-receptor (ER) complex. Therefore, daidzein exerts protective effects against
some diseases which are linked to the regulation of estrogen such as breast cancer, osteoporosis, diabetes, cardiovascular diseases
(Vitale et al., 2013). It also has a number of other biological activities independent of the ER such as anti-inflammation, anticancer,
inhibition of oxidative damage, protection of skin and the nerves. These beneficial effects are mainly due to regulation of the
immune response (Masilamani et al., 2012), scavenging of oxygen free radicals, inhibition of proliferation and so on. However,
when daidzein is presented in the bound form “daidzin”, it becomes inactive and some metabolites of daidzein also display a similar
pattern.
The safety of phytoestrogens is rather controversial (Humfrey, 1998) as these may exert some negative effects on human health.
In addition, the general absorption of daidzein is poor and many studies have been conducted to improve the bioavailability of
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daidzein. For example, self-micro emulsifying drug delivery system (SMEDDS) was used to formulate and enhance oral absorption
of daidzein (Shen et al., 2010).
This review comprehensively evaluates the pharmacological properties of daidzein based on the summary of previously
reported studies.
Figure 1: Molecular structure of daidzein and its related isoflavones
Pharmacological Effects
Anticancer and anti-Breast Cancer activities
Breast cancer is one of the most common malignant tumors in women which seriously threaten public health. Epidemiological
studies have shown that the incidence of breast cancer in Asian women is lower than Western women due to the higher consumption
of phytoestrogens (Adlercreutz, 2002). Thereby, the use of phytoestrogens may be a valid strategy in the prevention and treatment of
breast cancer, via mechanisms including ER modulation and anti-angiogenesis (Liu et al., 2012a). Due to phytoestrogens being a
significant constituent of daidzein its anticancer activity in breast cancer has attracted wide public attention.
Tumor necrosis factor-α (TNF-α), a type of endogenous cytokine, is able to affect tumorigenesis and dysregulation of TNF-α
production contributes to cancer risk (Locksley et al., 2001; Paul A et al., 2013). Daidzein plays a vital role in the regulation of
mammary tumor cell invasion induced by TNF-α. There are two distinct signaling pathways reported to elucidate the molecular basis
of this, with one being the nuclear factor-kappa B (NF-κB) signaling pathway. In breast cancer cells MDA-MB-231, daidzein
treatment suppressed TNF-α induced NF-κB and AP-1, followed by a reduction in the secretion of uPA from breast cancer cells, thus
inhibiting the migration of breast cancer (Valachovicova et al., 2004). The other pathway is the Hedgehog (Hh) signaling pathway.
Daidzein antagonized these effects via suppressing Gli1 activation and expression, thereby inhibiting migration and invasion of ER
negative MCF10DCIS.com human breast cancer cells. The metabolites of daidzein in vivo exerted stronger activity at the same
concentration. It was found that matrix metalloproteinase (MMP)-2 and MMP-9 also participated in breast cancer invasion. Daidzein
inhibited the activity and expression of MMP-9 induced by TNF-α via Hh/Gli1 signaling pathway (Bao et al., 2014). Another study
on MDA-MB-231 determined its anti-invasive effects partially by reducing expression of MMP-2 (Magee et al., 2014).
Moreover, daidzein displays anti-proliferative effects in breast cancer via cell cycle arrest in the G1 and G2/M phases and via
the induction of apoptosis (Choi and Kim, 2008). The mechanism of apoptosis induced by daidzein is mitochondrial
caspase-dependent pathway. Daidzein increased intracellular reactive oxygen species (ROS) generation which changed
mitochondrial transmembrane potential, leading to the release of cytochrome C. The reduced expression of anti-apoptotic proteins
Bcl-2 and the increased expression of pro-apoptotic proteins Bax enhanced the release of cytochrome C. These factors further
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activated caspase-9 and caspase-7, resulting in eventual cell death (Jin et al., 2010).
Interestingly, the effect of daidzein in attenuating breast cancer progression is more effective than tamoxifen (TAM), which is a
clinical drug currently used for the treatment of breast cancer (Liu et al., 2012b). However, some studies have raised concern that
daidzein may not be safe as it may stimulate proliferation of tumor cells (Choi and Kim, 2013), boosting existing breast tumors and
suppressing the pharmaceutical effects of TAM. Therefore, females with breast cancer should be aware of the risks of potential
tumor progression when taking soy products (de Lemos, 2001), as co-administration of TAM with daidzein is reported to produce
tumors of greater size than observed with TAM alone. These findings suggest that simultaneous consumption of
isoflavone with TAM may not be safe (Tonetti et al., 2007) due to its estrogen-like effects; meanwhile, possible detrimental effects of
daidzein in breast cancer patients have also been raised in other studies (Messina and Loprinzi, 2001). In fact, as an estrogen
responsive marker, daidzein had a slight but significant stimulatory effect on MCF-7 tumor progression at the lower concentration
(Ju et al., 2006) but when used at high concentrations, it exhibited anticancer capacity and could play a cooperative role in the
treatment of TAM. Although daidzein has anticancer activity in breast tumor, its application should be applied with caution (Gaete et
al., 2012).
Anti-Prostate Cancer
Epidemiological studies on risk factors of prostate cancer indicate the importance of consumption of soy (Adaramoye et al.,
2015). As the main phytoestrogen of soy, daidzein displayed anti-proliferative properties in three prostate cancer cell lines (LNCaP,
DU 145, PC-3) by the induction of cell cycle arrest at G0/G1 phase and the inhibition of angiogenesis via altering the expression of
cyclin-dependent kinase-related pathway genes. Some of these genes are involved in DNA damage-signaling pathway, and also in
the expression of angiogenesis genes, this can lead to the attenuation of growth factor EGF and IGF thus resulting in tumor growth
inhibition (Rabiau et al., 2010). In androgen-dependent prostate cancer cells and LNCaP cells, the growth of prostate cancer is
androgen dependent. Prostate androgen-regulated transcript-1 gene (PART-1) is a new gene that is responsive to androgens and could
be potentially used as a biomarker of prostate cancer. Daidzein inhibited dihydrotestosterone (DHT)-induced expression of the
PART-1 dose-dependently, implying that daidzein may have anti-androgen activity. Further in vivo studies have focused on the
connection between prostate tumor growth and the inhibition of expression of PART-1 (Yu et al., 2003). Daidzein could induce
apoptosis selectively in tumor cells by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) mediated apoptotic death.
TRAIL is an endogenous anticancer agent, which induces disruption of mitochondrial membrane potential in the LNCaP cells thus
promoting apoptosis (Szliszka and Krol, 2011). Studies in vitro and in vivo have suggested that daidzein can also be used as a radio
sensitizer without inducing metastasis in lymph nodes as with genistein. The mechanism was AR-independent which enhance
radiotherapy and inhibits tumor growth by down-regulating the expression of APE1/Ref-1 alter the activity of NF-κB and HIF-1α
(Singh-Gupta et al., 2011). Overall, daidzein appears to have a role in prevention and treatment of prostate cancer.
Inhibition of Other Cancers
Daidzein was also reported to be beneficial in the treatment of colon cancer in that it produced biphasic effect on human colon
cancer cells at different concentrations. Tumor suppressive effect on LoVo cells was by cell cycle arrest at G0/G1 phase and
caspase-3 dependent apoptosis, which was irrelevant of differentiation (Guo et al., 2004). Using hepatocarcinoma SK-HEP-1 cells as
the cell model, daidzein was reported to inhibit the growth of hepatocarcinoma cells, while having no effect on normal human
hepatocytes. The apoptosis induced by daidzein was related to the regulation of Bcl-2 family via mitochondrial pathway (Park et al.,
2013a). Daidzein still exhibited antitumor effect in a number of murine and human neuroblastoma cell lines by the inhibition of cell
proliferation, cell cycle arrest at G2/M phase, and promotion of cell apoptosis (Lo et al., 2007). Some derivatives of daidzein such as
7, 3′, 4′-THIF a form of daidzein also have anticancer effect which has been demonstrated to play a chemo-preventive role in UVB
induced non-melanoma skin cancer both in vitro and in vivo. The metabolite binds to Cot and MKK4 directly to inhibit the activity
of Cot and MKK4, which further markedly suppresses the expression of UVB-induced cyclooxygenase 2 (COX-2) ultimately,
inhibiting the elongation and the number and volume of tumors. Although daidzein does not have any influence on COX-2
expression, it could be used as a potential chemo-preventive agent in skin cancer due to its biotransformation (Lee et al., 2011a).
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7-(O)-carboxymethyl daidzein conjugated to N-t-Boc-hexylenediamine (cD-tboc) elicits antithyroid cancer and anti-epithelial
ovarian cancer properties by augmenting cell apoptosis (Somjen et al., 2012; Green et al., 2009).
Anti-Cardiovascular Diseases
Cardiovascular diseases(CVD), such as coronary heart disease, atherosclerosis, and hypertension, can be classified as a kind of
estrogen-related disorder (Dubey et al., 2004) since it is prevalent in post-menopause women. Conventional hormone replacement
therapy (HRT) may not be safe since the outcome of clinical trials has reported adverse cardiovascular effects in experimental
studies investigating vascular benefits (Ross et al., 2008). Daidzein is a potential candidate in the treatment of cardiovascular
diseases and it exerts its mechanism by mainly regulating of blood lipid metabolism, endothelial dysfunction attenuation, decreasing
in blood pressure and increasing antioxidant activity.
In a study involving hypercholesteremic subjects, daidzein treatment for 6 months significantly decreased triglyceride (TG)
concentration which is associated with ESR-β RsaI genotype while glucose and other lipids were not affected. In addition, uric acid,
an independent risk factor of CVD, was also down-regulated by daidzein (Qin et al., 2014). In male middle-aged rats which included
two groups, orchidectomized (Orx) and intact (IA), subcutaneous injection of high doses of genistein and daidzein decreased serum
cholesterol levels (Sosić-Jurjević et al., 2007).
Ovariectomy, which produces endothelium dysfunction including attenuation in endothelium-dependent vasorelaxation and
nitric formation increase in oxidative stress and damage to endothelium integrity, can be alleviated by daidzein. It exhibited
estrogen-like effect on endothelium-dependent vasorelaxation and inhibited caveolin-1 leading to an increase in nitric oxide
bioavailability and as a result, daidzein improved endothelium dysfunction (Sharma et al., 2012). Another study in
streptozotocin-induced diabetic rats also demonstrated that chronic supplement with daidzein ameliorated endothelium dysfunction.
It significantly improved the vascular contractile and relaxation response activity endothelium-dependently by NO and
prostaglandin-dependent pathways and it also inhibited lipid peroxidation (Roghani et al., 2013).
Daidzein and its metabolite equol were also reported to play a significant impact on hypertension by controlling vascular
smooth muscle tone via regulating a balance between vasodilator and vasoconstrictor, modulation of humoral systems and renal
function, and this in turn lowers blood pressure. However, the anti-hypertension effect of daidzein has only been demonstrated in
animal models currently, and it still needs further validation in human clinical trials (Martin et al., 2008). The effect of daidzein on
catecholamine synthesis and secretion also contributed to a reduction in the risks of CVD (Yanagihara et al., 2014; Liu et al., 2007).
Pretreatment with daidzein in a rat ischemia/reperfusion model markedly reduced myocardial injury induced by ischemia
reperfusion, such as improved myocardial contractile dysfunction, inhibition of myocardial apoptosis, and decreased myocardial
infarct size. These beneficial effects could be largely due to the activation of NF-κB, which regulated expression of inflammatory
cytokine by its antioxidant activity (Kimet al., 2009). However, the protective effect of daidzein on CVD is different because the
ability is different for people to produce equol from daidzein which plays an important role in decreasing arterial stiffness and
anti-atherosclerotic effects (Gil-Izquierdo et al., 2012).
In general, daidzein exhibits protective action on CVD risk factors although the mechanisms are not clearly defined. It has the
potential to be an alternative agent for the therapy of CVD, especially in post-menopause CVD women (Gencel et al., 2012).
However, the absorption and bioavailability of daidzein is poor when given in oral administration, but daidzein-loaded solid lipid
nanoparticles (SLNs), a new type of daidzein, exerts a better effect on cardiovascular system and it has the potential to be used in
the treatment of cardio-cerebrovascular diseases in the future(Gao et al., 2008).
Anti-Osteoporosis
Osteoporosis is a disease characterized by increased bone loss and fracture risks (Body, 2011). It is also common in menopausal
women due to estrogen deficiency. Pretreatment with estrogen may prevent osteoporosis by affecting osteoclast formation and
activation through promoting TGF-mediated apoptosis, which is produced by osteoblasts (Hughes et al., 1996). Estrogen could also
directly induce osteoclast apoptosis by binding to ERα in osteoclast and then altering the expression of FasL (Novack, 2007).
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Although HRT is effective in the treatment of osteoporosis, its potential negative effects such as breast cancer cannot be ignored
(Lewis, 2009).
As a phytoestrogen, daidzein displays estrogen-like effects. Moreover, equol, a metabolite of daidzein, showed stronger
estrogenic activity than other isoflavones. Therefore, daidzein is unique compared to other isoflavones and has the potential to treat
osteoporosis (Setchell et al., 2002). Daidzein can also inhibit bone reabsorption. A study on cultured osteoblasts from long bones of
young female piglets showed that the low concentration of daidzein (1 nM) promoted differentiation of osteoblast via ERβ pathway,
increased ALP activity and mineralization. Furthermore ERβ was evidenced by increase in the secretion of osteoprotegerin (OPG)
and RANK ligand (RANK-L) which are involved in osteoclastogenesis and runx2/Cbfa1, thus daidzein plays a vital role in
osteoblast differentiation and function (De Wilde et al., 2004). Moreover, daidzein inhibited differentiation and activation of
osteoclast largely by activating caspase 3 to induce osteoclast progenitor apoptosis. The expression of osteoclastogenesis inhibitory
factor (OCIF) in osteoblast-like cells downregulated secretion of some factors such as OPG, also associated with the inhibition of
osteoclast differentiation. The mechanism was by ERS, mainly by ERβ pathway in porcine bone marrow cells (Rassi et al., 2002). In
addition, daidzein exhibited bone protection and bone resorption inhibition indirectly by stimulating secretion of calcitonine, which
is a kind of hormone produced by Thyroid C cells, inhibiting the activity of osteoclasts and inducing osteoblast-line cell proliferation.
This study was conducted in ovariectomized (Ovx) male rats and it provided a feasible way in the treatment of male osteoporosis
(Filipović et al., 2010). In vivo model using parietal bone defects from New Zealand white rabbits has demonstrated the effect of
daidzein on bone formation in collagen matrix. There were 602% more new bone formation in collagen matrix with daidzein when
compared to the control, suggesting that daidzein stimulated new bone formation and it could be applied to bone grafting (Wong and
Rabie, 2009).
Mathey et al. (2007) pointed out that daidzein treatement together with equol improved not only total femoral BMD but also
bone strength in Ovx rat. Thus, the addition of fructooligosaccharides (FOS) or live microbial to promote intestinal bacterial
metabolism of daidzein could markedly enhance the protection action of daidzein on bone. Combination of daidzein with high dose
of Ca also augmented the protective effect on bone mass and biomechanical strength, although their mechanisms were different
(Fonseca and Ward, 2004). When daidzein was used in combination with kiwifruit, the effect on reducing bone loss caused by
estrogen deficiency was little while exerting no effect on the production of equol (Tousen et al., 2014).
However, some side effects of daidzein such as low bioavailability, unfavorable metabolism and uterine estrogenicity have
limited its clinical application. Recently, a number of daidzein analogs were found to exert protective impact on osteoporosis by
promoting of differentiation in bone marrow-derived mesenchymal stem cells (BMSCs) and adipose-derived stromal stem cells
(ASC) ER-independently. For example, isoformonetin, a methoxy daidzein, prevented osteoblasts from apoptosis and controlled
bone loss (Strong et al., 2014; Srivastava et al., 2013).
Anti-Diabetic Activity
In recent years, due to an increase in living standards, diabetes has become a worldwide epidemic disease. International
Diabetes Federation (IDF) report a persistent growth in diabetes incidence and it is projected that by the year 2030, there will be 439
million diabetics in the world. Moreover, about 90% of diabetic patients diagnosed had type II diabetes (Getek et al., 2014).
Undoubtedly, finding an effective method to treat diabetes is urgent.
Soy phytoestrogen plays an important role in Type 2 diabetes. Daidzein is one of the most bioactive components exerting
anti-diabetic activity in soy phytoestrogen (Jayagopal et al., 2002). Both in vitro and in vivo experiments have proved
anti-hyperglycemic effect of daidzein. In Type 2 diabetic cell model, L6 myotubes, daidzein stimulated glucose uptake through
promoting AMPK phosphorylation to increase glucose transporter 4 translocation to PM of muscle cells, which in turn led to glucose
homeostasis insulin-independently. In vivo studies used KK-Ay mice and db/db mice as Type II diabetic animal model. It has been
observed that daidzein controlled increased blood glucose levels to exhibit its anti-hyperglycemia effect (Cheong et al., 2014).
Another study in C57BL/KsJ-db/db mice found that the anti-diabetic effect of daidzein in type 2 diabetes was also associated with
liver glucose and lipid metabolism by modulating related enzyme activities. Genistein and daidzein treatment regulated blood
metabolism by significantly lowering the ratio of glucose-6-phosphatase (G6Pase)/GK and phosphoenolpyruvate carboxykinase
(PEPCK) in the liver of db/db mice while had no effect on the levels of plasma insulin and C-peptide, but increased the ratio of
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insulin/glucagon. Insulin resistance is related to hepatic lipid accumulation, genistein and daidzein dramatically lowered the plasma
FFA level to decrease β-oxidation via carnitine palmitoyltransferase (CPT-1) in type 2 diabetic mice. As a result, it improved the
metabolism of liver lipid, and then controlled blood glucose concentration (Ae Park et al., 2006). To conclude, daidzein prevented
against Type II diabetes and has the potential to be developed as a potent anti-diabetic phytochemical medical agent.
Daidzein could also play a beneficial role in regulation of fasting blood glucose level in type I diabetes which is also known as
insulin dependent diabetes (IDDM). Insulin deficiency is the main pathogenetic mechanism responsible for type I diabetes. Daidzein
treatment induced survival of pancreatic β-cells and insulin secretion while having no effect on glucagon in non-obese diabetic
(NOD) mice, an animal model of human type 1diabetes. The regulation of hepatic glucose and lipid metabolism by altering a series
of related enzyme activity has also been demonstrated, the mechanism of which is similar to the type II diabetes, such as reducing
activities of G6Pase, PEPCK, fatty acid beta-oxidation and CPT and increasing activities of malic enzyme and G6PD (Choi et al.,
2008). The molecular basis of daidzein regulating glucose and lipid metabolism is activation of peroxisome proliferator-activated
receptors(PPAR) and further regulation of PPAR-α-mediated and PPAR-γ-mediated gene expression involved in glucose and lipid
metabolism (Mezei et al., 2003). Daidzein also suppressed up-regulation of postprandial blood glucose levels by inhibiting the
activity of carbohydrate digestive enzymes, α-glucosidase and α-amylase (Park et al., 2013b).
Taking daidzein and hemin together might decrease the expression of caveolin, inhibiting RAAS system and enhancing the
level of renal nitric oxide in the wistar rat mode (Katyal et al., 2013). Comprehensive factors have to be taken into consideration as
combined therapy in diabetes may protect kidney and related systems such as renin-angiotensin system (RAS).
Anti-Aging Activity
Daidzein has a role in the cosmetic industry due to its ability to prevent skin aging and photo-damaging. Skin aging is primarily
associated with collagen reduction in the dermis, type I and type III collagens are the main component of extracellular matrix (ECM)
which is vitally important in maintenance of the dermis structure.
Transforming growth factor (TGF-β) mediated by smad is involved in the regulation of ECM (Choi et al., 2007). It has been
demonstrated in vitro and in vivo that daidzein promoted collagen deposition by stimulating collagen synthesis via up-regulating the
expression of type I pro-collagen and inhibiting collagen degradation via down-regulating the levels of MMP1 (matrix
metalloproteinase1), and MMP2. This collagen metabolic regulation was mediated by TGF-β/smad signal pathway,
phosphorylated-smad2, smad3 and TGF-β was significantly higher in the daidzein-treated cells when compared to the control (Zhao
et al., 2015). Exposure to solar UV radiation for a long time, in particular UVB radiation, accelerates skin aging due to induced
production of oxygen free radicals in a study of pig skin model which is similar to the human skin. The photo-protection effect of
daidzein was demonstrated by evaluating colorimeter-measured erythema and photo-damaged cell numbers after solar-simulated
ultraviolet (ssuv) irradiation (Lin et al., 2008). It was widely believed that daidzein exhibited photo-protection due to its antioxidant
activity by clearing free radical of keratinocytes induced by UV radiation (Huang et al., 2008a). However, another study found the
primary mechanism related to ERβ. S-equol is a gut metabolite of daidzein which prevents skin from natural or photo-aging via
activating ERβ directly. The selective activation of ERβ increased levels of the antioxidant enzymes which protected skin from
harmful oxygen-free radical injury and reduced levels of snail which modulated proliferation and migration of keratinocyte, resulting
in an increase in the expression of type I and type III collagens (Jackson et al., 2011). Retinoid a vitamin A derivative has been used
to treat skin-aging and it enhances collagen accumulation in the dermis, however retinoid-induced skin irritation can lead to
epidermal hyperplasia. Co-treatment with daidzein inhibited these side effects of retinoid (Varanl et al., 2004). Daidzein could bind
to RAR and RARγ directly to increase the activity of RAR and RARγ, further exerting photo-protective effects. Moreover, it
inhibited the activity of matrix metalloproteinase-9 (Oh et al., 2013). Hyaluronic acid (HA) was another major ingredient present in
the epidermis and dermis, maintaining hydration and inhibiting elasticity loss, which can prevent skin from aging. HA exhibits
age-dependent loss similar to that observed with collagen. Both in vitro and in vivo studies demonstrated that daidzein stimulated the
production of cutaneous HA (Miyazaki et al., 2002). Bifidobasterium-fermented (BE) soy milk extract mainly containing genistein
and daidzein enhanced HA production and improved the elasticity and viscoelasticity of mouse skin, while non-fermented (SME)
soy milk extract did not exert the stimulative effect of daidzein on HAproduction (Miyazaki et al., 2003).
Based on the ability of daidzein to protect the skin, the ability of percutaneous absorption of daidzein to achieve stable
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treatment concentration was studied. The results indicate that daidzein showed higher skin deposition in a non-ionized form than in
an ionized form. Although aglycone mixture and PEG400 can improve skin permeation, the ability of daidzein absorption by the
transdermal route was very weak (Minghetti et al., 2006), however, repeated transdermal application of daidzein could improve its
concentration in plasma (Vänttinen and Moravcova, 2001).
Antioxidant Activity
Daidzein is a natural antioxidant and there are two mechanisms mediating its antioxidant activity. First, in liposomal
membranes, daidzein inhibited lipid oxidation by clearing radical directly and impeded the migration of radicals by changing the
fluidity of membrane via binding to it (Liang et al., 2008). Secondly, daidzein exerted antioxidant effect indirectly via improving the
activity of anti-oxidative enzymes (AOE) which including catalase, glutathione peroxidase (GPx) and superoxide dismutase (SOD)
(CuZn-and Mn-SOD) (Kampkötter et al., 2008a). The effect of daidzein on modulating the expression level of AOE in a study of rat
hepatoma H4IIE cells reached the maximum at the concentration of 300 micromol/L. Transfection experiments suggested that
daidzein can up-regulate the expression of catalase mRNA via activating catalase promoter region directly. However, the oxidative
stress induced by H2O2 was not affected by daidzein through this mechanism and daidzein itself exhibited a weak antioxidant
capacity (Röhrdanz et al., 2002). Furthermore, it was demonstrated that daidzein significantly enhanced the activity of catalase and
the expression of catalase gene by acting on the proximal part of the catalase promoter (Kampkötter et al., 2008b). In general,
changes in AOE system are more important than daidzein itself in exerting antioxidant activity.
Daidzein was reported to be beneficial to animal health due to its antioxidant activity. In streptozotocin-induced diabetic rats,
daidzein down-regulated the increased concentration of MDA, a product of lipid peroxidation and stimulated the inhibited activity of
SOD to attenuate the oxidative stress including the prevention of vascular dysfunction (Roghani et al., 2013). The administration of
flutamide resulted in androgen (AE) deficiency which lowered the levels of endogenous AOE in Wistar rats. Daidzein exerted
protective effect by restoring the levels of AOE and AE to normal in a dose dependent manner (Lateef et al., 2012). It was observed
in vitro that some metabolites of daidzein such as O-DMA and equol generally exhibited stronger antioxidant potential by increasing
the activity and expression of catalase and SOD compared to daidzein alone (Choi and Kim, 2014). 3′-OH-daidzein and
6-OH-daidzein, another two metabolites of daidzein were also more effective than daidzein (Liang et al., 2008). Thereby, these
antioxidant metabolites might contribute to the antioxidant properties of dietary isoflavonone. In addition, gamma irradiation on
soybean will significantly improve concentration of genistin and daidzein and the antioxidant activity at dose up to 10 kGy (Popović
et al., 2013).
Anti-Inflammatory Activity
Failure to clear apoptotic cells in time can lead to the initiation of inflammatory diseases. Efferocytosis is defined as clearance
of apoptotic cells and daidzein augmented efferocytosis capability of macrophage cell RAW264.7 by up-regulating the
expressionofTG2 which is needed for effective engulfment during efferocytosis. The increased TG2 stimulated phosphorylation of
Erk to activate Rac1 and the down-regulation of mitochondrial membrane potential eventually enhances efferocytosis (Yen and Yang,
2014).
Daidzein could also inhibit activation of NF-κB which is a type of transcription factor, closely related to inflammation by
regulating the transcriptional activation of array of target genes including pro-inflammatory mediators, such as iNOS, COX-2,
various cytokines, chemokines, and adhesion molecules. It can be activated by many stimuli such as TNF-α (Pahl, 1999).
TNF-α-treated murine lung MLE-12 epithelial cells were the cell models to elucidate the underlying anti-inflammatory mechanism
of daidzein. Daidzein markedly decreased the level of TNF-α-induced protein poly-adenosine diphosphate-ribosylation (PARylation)
by binding to PARP-1 directly, resulting in the suppression of the transcription of pro-inflammatory genes such as NF-κB, which
further inhibited the expression of chemokine Cxcl2 (Li and Pan, 2014). Daidzein was effective in the treatment of periodontal
inflammation which was induced by lipopolysaccharide (LPS) from Prevotella intermedia, a pathogen. In P. intermedia LPS-treated
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RAW264.7 cells, daidzein significantly inhibited the production of NO and IL-6 through NF-κB signal pathway via suppressing
degradation of IκB-α and iNOS activation to alter the function of NF-κB, and STAT1 plays a cooperative role with NF-κB in this
process via suppressing STAT1 phosphorylation. These reduced secretion of inflammatory factors from macrophage contributed to
anti-inflammatory effect of daidzein in the periodontium (Choi et al., 2012).
As for obesity-related adipose inflammation, daidzein was reported to activate PPARγ directly to promote differentiation of
adipocytes and regulate expression of adipokine. Mainly, it up-regulated the expression of adiponectin and further decreased the
expression of pro-inflammatory factor TNF-α and MCP-1 which plays an important role in suppressing macrophage infiltration in
adipose tissue. Moreover, daidzein inhibited hypertrophy in adipocyte size and it is apparent that daidzein can improve
obesity-related inflammation which is related to insulin resistance (Sakamoto et al., 2014). In addition, daidzein is still used in the
treatment of inflammatory damage of the skin caused by UVB or 12-O-tetradecanoylphorbol-13-acetate (TPA). Keratinocytes and
fibroblasts were used to investigate UVB induced cutaneous inflammation, and the result indicated that daidzein suppressed
macrophage infiltration to the dermis and epidermis induced by UVB, further decreasing the production of ROS, the expression of
pro-inflammatory mediators such as iNOS and COX-2 and the pro-inflammatory factors such as TNF-α via inhibiting the
mitogen-activated protein kinase (MAPK) signaling pathway (Lee et al., 2014).Besides, daidzein suppressed TPA-induced skin
inflammation by reducing the activation of NF-κB, and the expression of IL-6,TNF-αand COX-2 (Khan et al., 2012). Consequently,
daidzein has the potential to improve therapy in inflammatory diseases in the future.
Neuroprotective Activity
Daidzein has also been evaluated for its protective effect against neurodegenerative diseases. Stroke morbidity rate is high in
the world, and currently there is no suitable drug for its treatment. It is well known that stroke is associated with brain injury which
can result in lasting damage to the body. Rats were used to demonstrate the neuroprotective effect of daidzein after stroke. The
results indicated that when treated with daidzein, rats expressed fewer deep slips in the skilled ladder rung walking task compared to
rats treated with no daidzein, suggesting that daidzein was effective in neuroprotection and function recovery after stroke, although
the mechanism is not clearly defined (Stout et al., 2013). There were three possible hypotheses reported to explain this
neuroprotective effect of daidzein. Firstly, daidzein binds to ERβ and G-protein-coupled receptor 30 (GPR30) directly to inhibit
neuron cell apoptosis by mitochondrial caspase-dependent pathway (Kajta et al., 2013). Secondly, daidzein induces the transcription
of arginase 1 (Arg1), further stimulating the survival and regeneration of neuron in central nervous system (CNS) by inhibiting MAG
cAMP independently (Ma et al., 2010). Thirdly, daidzein activates PPARγ by regulating nuclear translocation from cytoplasm to
inhibit neural cells death and promote axon cells maturation. Moreover, the activation of PPARγ is not related to ligand binding of
daizein (Hurtado et al., 2012). In addition, Yang et al. (2012) showed that daidzein may induce phosphorylation of Src kinase, further
activating Src-protein kinase C delta (PKCδ)-ERK signal pathway to promote axon growth of rat dorsal root ganglion (DRG)
neurons. In cerebellar granule cells, daidzein could reduce oxidative damage of mitochondria by down-regulation of the ROS levels,
and thus subsequent inhibition of apoptosis (Atlante et al., 2010).
It is well known that hippocampus is mainly responsible for learning and memory. Scopolamine induced memory damage in
male rats can be ameliorated by daidzein through ER and some behavioral tests have demonstrated this (Kim et al., 2010). Axon
formation and extension was stimulated with daidzein treatment in hippocampus neuron. Daidzein activated ERβ in the membrane,
further promoting phosphorylation of PKCα in growth-associated protein GAP-43. Eventually, the growth of axon in hippocampus
neuron led further to the modulation of learning and memory ability (Wang et al., 2008). When exposed to a very high-fat diet,
animals would suffer from high fat diet-induced energy metabolism imbalance which resulted in apoptosis and gliosis in the adult
hippocampus. Pretreatment with daidzein enhanced cell proliferation, while inhibited apoptosis and gliosis by down regulating the
expression of ERα, caspase3, GFAP and IBA1, in the hippocampus (Rivera et al., 2013).
In vitro, daidzein inhibited aggregation of Aβ and in the used pheochromocytoma PC12 neuronal cellular model, treatment with
daidzein, Aβ-induced cytotoxicity was also inhibited. Moreover, the co-treatment in the cultures with baicalein further enhanced this
effect. Therefore, daidzein may play a significant role in the treatment of Alzheimer's disease in the future (Choi et al., 2013).
Other Activities
Sun et al., Afr J Tradit Complement Altern Med. (2016) 13(3):117-132
125
In addition to the described pharmaceutical activities, daidzein exhibits other beneficial effects. Menopausal women are at
higher risk of multiple problems like heart disease and bone loss which was mentioned earlier due to estrogen deficiency. The
incidence of hot flashes is also high in that about 75% of postmenopausal women experience this leading to a reduction in their
quality of life. Ricciotti HA found isoflavone supplement which is rich in daidzein significantly ameliorated hot flashes in a study of
twenty-four postmenopausal women (Ricciotti et al., 2005). Daidzein was also effective in pulmonary fibrosis induced bybleomycin
in rats, inflammation and alveolar epithelial cell apoptosis was mainly responsible for pulmonary fibrosis. Daidzein reversed this
effect by decreasing the level of proteinase activated receptor 2 and TGF-β (Soumyakrishnan et al., 2014). In addition, daidzein can
inhibit the over-secretion of mucin from airway epithelial cells which would cause respiratory diseases (Lee et al., 2011b). In OVX
rats, daidzein was reported to stimulate cadmium excretion to avoid the damage of heavy metal accumulation on renal function (Om
& Shim, 2007). It was reported that daidzein treatment in male Balb/cJ mice alleviated anxiety, increased locomotor activity and
decreased their social behavior including aggression and sexual behavior, the mechanism may be related to ER (Zeng et al., 2010).
Daidzein supplementation to the mother also affected social behavior of female offspring. Daidzein reduced the expression of ERα in
the brain, resulting in behavioral masculinization in adult female mice while it had no effect on anxiety (Yu et al., 2010).
Conclusion
Daidzein as a plant extract has been extensively investigated recently. In this paper, pharmacological effects of daidzein have
been reported and these include anticancer, anti-cardiovascular diseases, anti-osteoporosis, anti-diabetes, anti-inflammation,
antioxidant, anti-aging activity, neuroprotective activity and some other activities as presented in Figure 2. Over the years,
conventional HRT has been used to ameliorate menopause symptoms clinically but unfortunately various complications such as
breast cancer have limited its clinical usage. Daidzein was discovered to have a structure similar to estrogen and to be selective to the
ER. Currently it is being widely used in the treatment of some diseases and there is hope for further development in its clinical
application. However, the mechanisms of action remain uncertain and its poor bioavailability limits its application, and some
possible side effects of daidzein have been reported. Besides promotion of tumor growth mentioned earlier, daidzein can cause
erectile dysfunction due to down-regulation of androgen and alternation of penile cavernosal structures (Pan et al., 2007; Huang et
al., 2008a). Thus, the details of the mechanisms involved need to be further clarified to reduce the side effects.
Some bio-transformations in the body or synthetic analogues of daidzein maybe more effective on health or/and less toxic,
such as isoformonetin and 7, 3′, 4′-THIF. Although some bioactive analogues of daidzein have been identified for their benefits on
human health, many other potential metabolites remain unknown. Therefore, it is necessary to find novel effective substances based
on the structure of daidzein. In addition, it is also crucial to enhance the absorption and bioavailability of daidzein, which may be
realized via the appropriate way of administration or drug modification according to its physicochemical properties and
pharmacokinetic parameters. Further studies are needed before daidzein can be widely promoted for use in clinical settings.
Sun et al., Afr J Tradit Complement Altern Med. (2016) 13(3):117-132
126
Figure 2: The pharmacological effects of daidzein
Acknowledgment
This work was supported by funds from Scientific and Technologic Innovation Action of Shanghai Municipal Science and
Technology Commission (15401971800 and 15401902700), Shanghai Municipal Health and Family Planning Commission
(ZY3-JSFC-2-2010, 20134090, 20134173 and ZYXK2012010), Pudong New Area Health and Family Planning Commission
(PWZz2013-02 and PWRd2013-03), and Key Disciplines Group Construction Project of Pudong Health Bureau of Shanghai
(PWZxq2014-12).
Conflict of Interest: The authors have declared that there is no conflict of interest.
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... Finally, various other compounds were tentatively identified within the extracts. The most abundant were the isoflavones daidzein [148], genistein [149] and glycitein [150] for which antioxidant, anticancer and antimicrobial properties have been reported. ...
... Finally, various other compounds were tentatively identified within the extracts. The most abundant were the isoflavones daidzein [148], genistein [149] and glycitein [150] that have antioxidant, anticancer and antimicrobial properties and several more metabolites with antibiotic properties, such as 21-demethyl-leptomycin A [165], that could explain the differences observed between the antimicrobial activity and the production levels of phocoenamicins in some of the extracts. The wide and diverse metabolic profile of these strains highlighted their metabolic potential and the need for further investigation. ...
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Historically, natural products (NPs) have played a major role in the discovery of antibiotics. They offer special characteristics in comparison with synthetic compounds, which carry both advantages and challenges for the drug discovery process. Over the past few years, new technological and scientific advances have reinforced the field of NP discovery and the discovery of new antibiotics, contributing to the fight against Antimicrobial Resistance (AMR). The marine environment bears a treasure chest of bioactive compounds and marine actinomycetes have proven to be one of the most prolific producers. The spirotetronate class of polyketides, with more than 100 bioactive compounds described to date, has recently grown with the discovery of phocoenamicins, marine actinomycete derived compounds that possess different antibiotic activities and three compounds have initially been discovered, phocoenamicin, phocoenamicin B and C. Exploring the MEDINA’s strain collection for possible new phocoenamicins producers, 27 actinomycete strains were identified, including 3 marine-derived and 24 terrestrial strains, and their taxonomic identification by 16S rDNA sequencing showed that they all belong to the Micromonospora genus, suggesting that the biosynthesis of the phocoenamicins is restrained within this genus. Despite the close taxonomic relationship of the strains, the producers identified were isolated from very diverse ecosystems and a wide geographical distribution. Using a One Strain Many Compounds (OSMAC) approach, these 27 strains were cultivated in 10 different media each, resulting in 270 fermentations, whose crude extracts were analyzed by LC-HRMS and tested against a panel of pathogens showing activity against methicillin-resistant Staphylococcus aureus (MRSA), Mycobacterium tuberculosis H37Ra and Mycobacterium bovis, revealing a rich antimicrobial potential within the 27 strains. Metabolomics analysis showed that all 27 strains produced the three known phocoenamicins, in at least one of the culture media and the analysis of the production of these phocoenamicins determined the most suitable culture media. The influence of the different cultivation parameters in the chemical profile obtained was studied and only variations in the culture medium could explain the chemical variation and determine a significant change in the metabolic profile of the different Micromonospora strains. The combination of the LC-UV-HRMS analysis, metabolomic profiling and molecular networking allowed the putative dereplication of the main compounds produced by the 27 strains in the different culture conditions, which were divided into three main groups, spirotetronates, siderophores and various other compounds. The spirotetronate maklamicin, structurally related to phocoenamicins, was also tentatively identified to be produced by all 27 strains and its coexistence with the phocoenamicins in the extracts confirmed the obvious common biosynthetic origin of both families of compounds. Moreover, the analyses tentatively revealed the presence of several structurally related compounds not disclosed before and thus candidates for isolation and discovery of new bioactive compounds. This wide and chemically diverse metabolic profile of these strains highlighted the need for further research. Combining these analyses proved to be a rapid and efficient way to prioritize strains. Although previous statements in the literature about phocoenamicins production only in unique marine environments were not confirmed, the marine-derived Micromonospora species were identified as the best producers of phocoenamicins in terms of both the abundance in their extracts of some of the major members, as well as the variety of molecular structures produced. Exploring the growth of Micromonospora and the production of phocoenamicins, suggested the best growing conditions for the production of the three compounds. As a result, cultures of the three marine-derived Micromonospora strains (CA-214671, CA-214658 and CA-218877) were scaled up (3 and 5 L fermentations) and optimal chromatographic conditions for the purification of the phocoenamicins were established, leading to the isolation and structural elucidation of seven compounds, including two new phocoenamicins, phocoenamicins D and E, together with the known phocoenamicin, phocoenamicins B and C, as well as maklamicin and the new analog 29-deoxymaklamicin, reported for the first time as a natural product, and for which the name maklamicin B has been proposed. The two families of compounds shared multiple structural features, as well as common structural variations that were highlighted. Interestingly, one of the new phocoenamicins described bore the side chain of maklamicin, unique so far in this compound, indicating common structural features conserved within the two families. All the compounds isolated were tested against a panel of bacterial human pathogens, including methicillin-resistant S. aureus (MRSA), M. tuberculosis H37Ra, Enterococcus faecium, Enterococcus faecalis and Neisseria gonorrhoeae. Similarly to other related spirotetronates, most of the compounds showed some antibacterial activity against Gram-positive bacteria and the antibacterial assays revealed some structure-activity relationships. Overall, the most active compounds were maklamicin B and maklamicin, followed by phocoenamicin and phocoenamicin B, being some of these activities reported for the first time. The compounds demonstrated weak or no cytotoxicity against the human liver adenocarcinoma cell line (Hep G2). Finally, the toxicity of the three major compounds obtained, namely phocoenamicin, phocoenamicin B and maklamicin, was evaluated against zebrafish eleuthero embryos and no toxicity was displayed up to the highest concentration tested (25 μM). Maklamicin B resulted to be the most interesting compound, combining strong antimicrobial activity against MRSA, M. tuberculosis and E. faecium and no cytotoxicity. The new analogues isolated highlighted the wide range of structural diversities of the spirotetronates and the possible structure-activity relationships recorded here, along with others reported before within the spirotetronate class, can be used as pieces in a puzzle to unveil the biosynthetic potential of these compounds.
... After 30 min of incubation in the dark and at room temperature, the reduction of the DPPH• free radical was measured by reading the absorbance at 515 nm. The result was expressed as EC 50 (the concentration needed for the extract to sequester 50% of the radical). ...
... Naringenin has antioxidant, and anti-inflammatory activity and acts in different types of effects on sex hormone metabolism. 48 For Şöhretoğlu and Renda 49 and Sun et al., 50 it has already been well elucidated that daidzein mimics the actions of estrogen improving the cardiovascular system, acts as an anticancer, anti-osteoporosis, antidiabetic, antioxidant, anti-inflammatory, and neuroprotective agent. Formononetin, on the other hand, has immuno-enhancing, antiangiogenesis, antitumor, and hepatoprotective actions. ...
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In this paper, we report the characterization of Brazilian red propolis from two origins. The commercial value of this product is due to its composition and bioactivity, which depend on geographical factors. Total and individual phenolic, antioxidant, and medium infrared spectroscopic (MIR) characterization of 72 red propolis samples from two origins (Bahia (BA) and Rio Grande do Norte (RN), Brazil) were performed. Samples from RN showed higher concentrations of biomarkers. The BA samples showed higher antioxidant capacity despite having lower concentrations of the red propolis biomarker molecules when compared to the RN samples. The MIRS showed differences regarding the origin. The principal component analysis confirmed the differences, generating well-defined groups. Linear discriminant analysis or discriminant analysis and and partial least squares discriminant analysis showed excellent model performance. The models with MIRS data from raw propolis have a high correct classification rate and require no sample preparation. These findings can affect red propolis production, boosting sustainable extractivism, and changing the reality of small communities.
... Daidzein (DZN: 7-(β-D-glucopyranosyloxy)−4hydroxyisoflavone) is an isoflavone derived from soy plants. Scientific reports suggest that DZN has many important biological activities, including anticancer, cardioprotective, antidiabetes, anti-osteoporosis, skin protective, hepatoprotective (Kim et al., 2009), nephroprotective (Wu et al., 2018), and neuroprotective activity, such as anxiolytic, anti-epileptic, and memory-enhancing activity (Kazmi et al., 2020;Kim et al., 2010;Sun et al., 2016;Zeng et al., 2010). Substances have anxiolytic effects and have antidepressant effects in animals. ...
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Daidzin (DZN: 7-(β-D-Glucopyranosyloxy)-4-hydroxyisoflavone) is a soy plant-derived isoflavone. It has diverse biological activities, including nephroprotective effects. To date, its anxiolytic, memory-enhancing, and antiepileptic properties have been discovered. However, its antidepressant activity has not yet been investigated.This study aimed to investigate DZN’s antidepressant activity through animal and in silico studies. Male Swiss albino mice were randomly divided into nine groups consisting of control (vehicle), DZN 5, 10, and 20mg/kg, diazepam (GABAA agonist), flumazenil (GABAA antagonist), and a combination of DZN-10 with diazepam and/or flumazenil. Additionally, in silico studies were also performed to understand the possible molecular mechanisms behind this neurological activity. Findings suggest that DZN dose-dependently and significantly (p < 0.05) enhanced immobility time (IMT) in animals. DZN-10 also increased diazepam’s effects significantly (p < 0.05), possibly by raising its IMT values. However, DZN significantly (p < 0.05) declined flumazenil’s effect in their combination. In silico findings suggest that DZN has a strong binding affinity against GABAA receptor subtypes. We suppose DZN exerts its antidepressant effect, possibly by interacting with GABAA receptors. It exerts a synergistic effect with the GABA agonist drug diazepam. Further studies are required to determine the exact molecular mechanism behind this neurological activity.
... Daidzin (DZN: 7-(β-d-Glucopyranosyloxy)− 4′-hydroxyisoflavone or 7-O-glucoside of daidzein) (Fig. 1) is a naturally occurring isoflavone that belongs to the Fabaceae family [27]. It is mostly obtained from legume plants like soybeans and mung beans [28]. Additionally, it is the main bioactive component in traditional Chinese medicine [29]. ...
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Epilepsy is a neurological disorder characterized by recurrent seizures, affecting approximately 50 million people globally. Daidzin (DZN), a naturally occurring isoflavone, has shown various pharmacological effects, including neuroprotective activities in animals. This study investigated the anticonvulsant effects of DZN with possible mechanisms of action using behavioral studies using experimental animals and in silico approaches. For this, a pentylenetetrazole (PTZ, 80 mg/kg, i.p.)-induced seizure model was applied in young broiler chicks. Treatment groups included DZN (5, 10, 20 mg/kg, p.o.), carbamazepine (CAR: 80 mg/kg, p.o.), and diazepam (DZP: 5 mg/kg, p.o.) alone and in combinations. After PTZ administration, convulsion onset, frequency, duration, and mortality rates were recorded. We also performed an in vitro study to check GABAergic activity of DZN and DZP. Additionally, molecular docking studies were performed against the GABAA receptor and voltage-gated sodium channel, along with pharmacokinetics and toxicity assessments of the test compound and the reference drugs. Results showed that DZN dose-dependently increased convulsion onset and significantly reduced convulsion frequency and duration compared to the control group (p < 0.05). The combination of DZN- 20 with CAR- 80 and DZP- 5 significantly enhanced convulsion onset and protection rates while reducing convulsion frequency and durations compared to their individual treatment groups. Both DZP and DZN also showed a concentration-dependent GABA activity inhibition capacity. DZN showed the highest binding affinities with GABAA receptor (− 7.8 kcal/mol) and voltage-gated sodium channel (− 9.1 kcal/mol) than the standard drugs. It also supported acceptable pharmacokinetic and toxicity profiles in in silico studies. Taken together, DZN exerted and enhanced the anticonvulsant effects of CAR and DZP, possibly through GABAA receptor and voltage-gated sodium channel interaction pathways.
... Cumulative literature reports demonstrate that DZN has diverse biological activities, including anticancer, cardioprotective, antidiabetes, anti-osteoporosis, skin protective, hepatoprotective (Kim et al., 2009), nephroprotective (Wu et al., 2018), and so on. A number of scienti c studies suggest that DZN has some neurological activities (Sun et al., 2016); these include anxiolytic (Zeng et al., 2010), memory-enhancing (Kim et al., 2010), and antiepileptic effects (Kazmi et al., 2020) in experimental animals. However, its sedative and hypnotic effects are yet to be discovered. ...
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The soy isoflavone daidzein (DZN) has been considered a hopeful bioactive compound having diverse biological activities, including neuroprotective effects, such as anxiolytic, memory-enhancing, and antiepileptic effects, in experimental animals. However, its sedative and hypnotic effects are yet to be discovered. This study aimed to evaluate its sedative/hypnotic effect on Swiss mice. Additionally, in silico studies were also performed to see the possible molecular mechanisms behind the tested neurological effect. For this, male Swiss albino mice were treated with DZN (5, 10, or 20 mg/kg) with or without the standard GABAergic medication diazepam and/or flumazenil and checked for the onset and duration of sleeping time using thiopental sodium-induced as well as diazepam-induced sleeping tests. A molecular docking study was also performed to check its interaction capacity with the α1 and β2 subunits of the GABA A receptor. Findings suggest that DZN dose-dependently and significantly reduced the latency while increasing the duration of sleep in animals. It significantly (p < 0.05) reduced latency and increased sleep duration with the standard combinations DZP-2 and DZP-2 + FLU-0.05, suggesting its possible synergistic effects with these co-treatments. Further, molecular docking studies demonstrate that DZN has a strong binding affinity of − 7.2 kcal/mol, which is closer to the standard ligand DZP (–8.3 kcal/mol) against the GABA A receptor. Molecular dynamic simulations indicated the stability and similar binding locations for DZP and DZN with 6X3X. In conclusion, DZN showed sedative effects on Swiss mice, possibly through the GABA A receptor interaction pathway.
... It is reported to play a significant role in the prevention and treatment of a variety of diseases, such as cancer, cardiovascular disease, diabetes, and neurodegenerative disease. 38 Research showed that daidzein also suppressed increases in blood glucose levels and urinary glucose excretion in KK-Ay mice. 39 Puerarin is an isoflavonoid extracted from Pueraria lobata roots and has been used for various medicinal purposes. ...
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The complex network approach is an effective method to analyze the global properties of complex biological systems, which can be used to explore the interactions between multiple compounds and protein targets of drug. Radix Pueraria has a long history of efficacy in different diseases, containing a variety of compounds that can produce multiple therapeutic effects via multiple targets. To explore the interrelationship between compounds of Radix Pueraria, protein targets, and pathways, the present investigation used the complex network approach to construct the compound-protein target-pathway network of Radix Pueraria. The analysis of the statistical and topological characteristics shows that the network has small-world and scale-free characteristics. The diameter of the network is 7, indicating that the information exchange between two nodes could quickly spread to the whole network. With the rank of degree value and integrated centrality as identification indicators, by taking the threshold of integrated centrality as 0.70, a total of nine key hub nodes containing three active compounds, two protein targets, and four biological pathways were identified: genistein, daidzein, puerarin, MAPK3, MAPK1, hsa01100, hsa05200, hsa05417, and hsa05207. The network analysis suggests these key hub nodes should play an important role in the pharmacological action of Radix Pueraria. The results of this study provide useful information and knowledge for further exploring the pharmacological mechanism of Radix Pueraria in the course of disease treatment.
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Macrotyloma uniflorum is known for being a rich source of protein, fat, fiber, carbohydrates, vitamins, and micronutrients. Since ancient times, it has been used as a pulse and traditional remedy in the Himalayan Mountains for curing kidney and bladder stones, bronchitis, asthma, piles, leukoderma, and heart diseases. Horse gram contains bioactive compounds such as phenolic acids, flavonoids, and tannins, which contribute to its health advantages. These bioactive compounds demonstrated antioxidant, antidiabetic, anti‐inflammatory, anticarcinogenic, antimicrobial, antidiarrheal, and neuroprotective effects. These horse gram products are now considered superfoods and are widely utilized in worldwide cuisines. Horse gram and its crude extracts or fractions have been shown to exhibit a wide range of in vivo and in vitro pharmacological and nutraceutical properties. However, there is currently a scarcity of structure‐activity investigations of isolated compounds and mechanistic research on this species. This review demonstrates that horse gram, despite its traditional usage by diverse cultures, has a profusion of bioactive chemicals with a wide range of biological effects that might be employed as biopharmaceuticals and adopted by nutraceutical industries. This study focuses on the thorough phytochemistry, folk medicinal applications, and pharmacological properties of this versatile legume plant. Furthermore, we discussed the value of plants as a source of functional foods and nutraceuticals.
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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.
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Soybean may be a promising ingredient for regulating UVB-induced inflammatory damage to the skin. We investigated the anti-inflammatory effects of diets supplemented with fermented soybean on UVB-induced skin photodamage and the effectiveness of soybean (S) and fermented soybean (FS) dietary supplementation. To investigate the effects of two major isoflavones-daidzein and genistein-from FS, we used co-cultures with keratinocytes and fibroblasts. Genistein treatment strongly inhibited the production of IL-6 and MAPK signaling. Forty hairless male mice divided into four groups were fed with a control diet (Group N: normal, Group C; +UVB) or diets with 2.5% S+UVB or 2.5% FS+UVB (Group S, Group FS) for 8 weeks. Macrophage infiltration to the dermis was reduced more in Groups S and FS than in Group C. The expression levels of iNOS and COX-2 were significantly decreased in Group FS (by 7.7% ± 0.4% and 21.2% ± 0.3%, respectively [p < 0.05]).
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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 (3U/kg.bw) was administered in rats to induce PF. Daidzein (0.2mg/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 expressions of Matrix metalloproteinase 2 (MMP-2) and increased the expressions 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 (TGFβ1) was found to be up-regulated along with psmad2/3, a mediator of TGFβ 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.
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In breast cancer, the cytokine tumor necrosis factor-α (TNF-α) induces cell invasion, although the molecular basis of it have not been clearly elucidated. In this study, we investigated the role of daidzein in regulating TNF-α induced cell invasion and the underlying molecular mechanisms. Daidzein inhibited TNF-α induced cellular migration and invasion in estrogen receptor (ER) negative MCF10DCIS.com human breast cancer cells. TNF-α activated Hedgehog (Hh) signaling by enhancing Gli1 nuclear translocation and transcriptional activity, which resulted in increased invasiveness; these effects were blocked by daidzein and the Hh signaling inhibitors, cyclopamine and vismodegib. Moreover, these compounds suppressed TNF-α induced matrix metalloproteinase (MMP)-9 mRNA expression and activity. Taken together, mammary tumor cell invasiveness was stimulated by TNF-α induced activation of Hh signaling; these effects were abrogated by daidzein, which suppressed Gli1 activation, thereby inhibiting migration and invasion.
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Background/Objectives The objective of this study was to investigate the effects of daidzein on collagen metabolism and its underlying mechanism in cultured skin fibroblast and nude mouse skin.Methods Skin fibroblasts were exposed to different concentrations of daidzein (0.5–50 μg/mL) for 24 h or 48 h, respectively. Female nude mice were treated topically with 200 μg/mL daidzein once a day for 6 weeks. Cell viability and cell cycle were determined by MTT and flow cytometer. The transcriptional activity of collagen type I was evaluated and the expression of procollagen, matrix metalloproteinase-1 (MMP1) and MMP2 were measured by real-time polymerase chain reaction. A Western blot analysis was applied to detect the levels of phosphorylated-Smad2 and Smad3.ResultsIn the daidzein-treated cells the expression of type I procollagen increased markedly while the expressions of MMP1, and MMP2 was significantly inhibited. Additionally, the mouse skin showed more collagen deposition after daidzein treatment. The levels of transforming growth factor (TGF)-β, phosphorylated-smad2 and smad3 were also higher in the daidzein treated skin fibroblasts than in the controls.Conclusions The results showed that daidzein treatment can increase skin collagen synthesis and inhibit collagen degradation in vitro and in vivo. It seems that TGF-β/smad signalling pathways play an important role in daidzein-induced collagen accumulation.
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Daidzein shows estrogenic, antioxidant and antiandrogenic properties as well as cell cycle regulatory activity. However, the antihyperglycemic effect of daidzein remains to be elucidated. In this study, we investigated the in vitro effect of daidzein on glucose uptake, AMPK phosphorylation and GLUT4 translocation on plasma membrane in L6 myotubes and its in vivo antihyperglycmic effect in obese-diabetic model db/db mice. Daidzein was found to promote glucose uptake, AMPK phosphorylation and GLUT4 translocation by Western blotting analyses in L6 myotubes under a condition of insulin absence. Promotion by daidzein of glucose uptake as well as GLUT4 translocation to plasma membrane by immunocytochemistry was also demonstrated in L6 myoblasts transfected with a GLUT4 cDNA-coding vector. Daidzein (0.1% in the diet) suppressed the rises in the fasting blood glucose, serum total cholesterol levels and homeostasis model assessment index of db/db mice. In addition, daidzein supplementation markedly improved the AMPK phosphorylation in gastrocnemius muscle of db/db mice. Daidzein also suppressed increases in blood glucose levels and urinary glucose excretion in KK-Ay mice, another Type 2 diabetic animal model. These in vitro and in vivo findings suggest that daidzein is preventive for Type 2 diabetes and an antidiabetic phytochemical.