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Climacteric : the Journal of the... Apr 2015To perform a meta-analysis examining the efficacy of phytoestrogens for the relief of menopausal symptoms. (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
To perform a meta-analysis examining the efficacy of phytoestrogens for the relief of menopausal symptoms.
METHODS
Medline, Cochrane, EMBASE, and Google Scholar databases were searched until September 30, 2013 using the following key words: vasomotor symptoms, menopausal symptoms, phytoestrogens, isoflavones, coumestrol, soy, red clover. Inclusion criteria were (1) randomized controlled trial (RCT), (2) perimenopausal or postmenopausal women experiencing menopausal symptoms, (3) intervention with an oral phytoestrogen. Outcome measures included Kupperman index (KI) changes, daily hot flush frequency, and the likelihood of side-effects.
RESULTS
Of 543 potentially relevant studies identified, 15 RCTs meeting the inclusion criteria were included. The mean age of the subjects ranged from 49 to 58.3 and 48 to 60.1 years, respectively, in the placebo and phytoestrogen groups. The number of participants ranged from 30 to 252, and the intervention periods ranged from 3 to 12 months. Meta-analysis of the seven studies that reported KI data indicated no significant treatment effect of phytoestrogen as compared to placebo (pooled mean difference = 6.44, p = 0.110). Meta-analysis of the ten studies that reported hot flush data indicated that phytoestrogens result in a significantly greater reduction in hot flush frequency compared to placebo (pooled mean difference = 0.89, p < 0.005). Meta-analysis of the five studies that reported side-effect data showed no significant difference between the two groups (p = 0.175).
CONCLUSION
Phytoestrogens appear to reduce the frequency of hot flushes in menopausal women, without serious side-effects.
Topics: Female; Hot Flashes; Humans; Isoflavones; Menopause; Middle Aged; Phytoestrogens; Phytotherapy; Placebos; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 25263312
DOI: 10.3109/13697137.2014.966241 -
Biomolecules Feb 2021Coumestrol is a phytoestrogen widely known for its anti-diabetic, anti-oxidant, and anti-inflammatory properties. Thus, it gets a lot of attention as a potential agent...
Coumestrol is a phytoestrogen widely known for its anti-diabetic, anti-oxidant, and anti-inflammatory properties. Thus, it gets a lot of attention as a potential agent in the nutritional therapy of diseases such as obesity and type 2 diabetes. In our study, we evaluated whether coumestrol affects insulin resistance development via the sphingolipid signaling pathway in primary rat hepatocytes. The cells were isolated from the male Wistar rat's liver with the use of collagenase perfusion. Next, we incubated the cells with the presence or absence of palmitic acid and/or coumestrol. Additionally, some groups were incubated with insulin. The sphingolipid concentrations were assessed by HPLC whereas the expression of all the proteins was evaluated by Western blot. Coumestrol markedly reduced the accumulation of sphingolipids, namely, ceramide and sphinganine through noticeable inhibition of the ceramide de novo synthesis pathway in insulin-resistant hepatocytes. Moreover, coumestrol augmented the expression of fatty acid transport proteins, especially FATP5 and FAT/CD36, which also were responsible for excessive sphingolipid accumulation. Furthermore, coumestrol altered the sphingolipid salvage pathway, which was observed as the excessive deposition of the sphingosine-1-phosphate and sphingosine. Our study clearly showed that coumestrol ameliorated hepatic insulin resistance in primary rat hepatocytes. Thus, we believe that our study may contribute to the discovery of novel preventive and therapeutic methods for metabolic disorders.
Topics: Animals; Coumestrol; Fatty Acids; Hepatocytes; Insulin Resistance; Male; Oxidation-Reduction; Rats; Rats, Wistar; Signal Transduction; Sphingolipids
PubMed: 33673122
DOI: 10.3390/biom11020268 -
Reproduction (Cambridge, England) Jul 2023Healthy development of the placenta is dependent on trophoblast cell migration and reduced oxidative stress presence. This article describes how a phytoestrogen found in...
IN BRIEF
Healthy development of the placenta is dependent on trophoblast cell migration and reduced oxidative stress presence. This article describes how a phytoestrogen found in spinach and soy causes impaired placental development during pregnancy.
ABSTRACT
Although vegetarianism has grown in popularity, especially among pregnant women, the effects of phytoestrogens in placentation lack understanding. Factors such as cellular oxidative stress and hypoxia and external factors including cigarette smoke, phytoestrogens, and dietary supplements can regulate placental development. The isoflavone phytoestrogen coumestrol was identified in spinach and soy and was found to not cross the fetal-placental barrier. Since coumestrol could be a valuable supplement or potent toxin during pregnancy, we sought to examine its role in trophoblast cell function and placentation in murine pregnancy. After treating trophoblast cells (HTR8/SVneo) with coumestrol and performing an RNA microarray, we determined 3079 genes were significantly changed with the top differentially changed pathways related to the oxidative stress response, cell cycle regulation, cell migration, and angiogenesis. Upon treatment with coumestrol, trophoblast cells exhibited reduced migration and proliferation. Additionally, we observed increased reactive oxygen species accumulation with coumestrol administration. We then examined the role of coumestrol within an in vivo pregnancy by treating wildtype pregnant mice with coumestrol or vehicle from day 0 to 12.5 of gestation. Upon euthanasia, fetal and placental weights were significantly decreased in coumestrol-treated animals with the placenta exhibiting a proportional decrease with no obvious changes in morphology. Therefore, we conclude that coumestrol impairs trophoblast cell migration and proliferation, causes accumulation of reactive oxygen species, and reduces fetal and placental weights in murine pregnancy.
Topics: Pregnancy; Female; Mice; Humans; Animals; Placenta; Coumestrol; Phytoestrogens; Reactive Oxygen Species; Cell Line; Placentation; Trophoblasts; Oxidative Stress
PubMed: 37078791
DOI: 10.1530/REP-23-0017 -
Frontiers in Plant Science 2021Coumestrol is a natural organic compound synthesized in soy leaves and functions as a phytoalexin. The coumestrol levels in plants are reported to increase upon insect...
Coumestrol is a natural organic compound synthesized in soy leaves and functions as a phytoalexin. The coumestrol levels in plants are reported to increase upon insect attack. This study investigates the correlation between coumestrol, senescence, and the effect of phytohormones on the coumestrol levels in soybean leaves. Our analysis involving high-performance liquid chromatography and 2-D gel electrophoresis indicated a significant difference in the biochemical composition of soybean leaves at various young and mature growth stages. Eight chemical compounds were specifically detected in young leaves (V1) only, whereas three different coumestans isotrifoliol, coumestrol, and phaseol were detected only in mature, yellow leaves of the R6 and R7 growth stage. MALDI-TOF-MS analysis was used to identify two proteins 3,9 -dihydroxypterocarpan 6A-monooxygenase (CYP93A1) and isoflavone reductase homolog 2 (IFR2) only in mature leaves, which are key components of the coumestrol biosynthetic pathway. This indicates that senescence in soybean is linked to the accumulation of coumestrol. Following the external application of coumestrol, the detached V1-stage young leaves turned yellow and showed an interesting development of roots at the base of the midrib. Additionally, the application of phytohormones, including SA, methyl jasmonate (MeJA), and ethephon alone and in various combinations induced yellowing within 5 days of the application with a concomitant significant increase in endogenous coumestrol accumulation. This was also accompanied by a significant increase in the expression of genes (Gm08G089500), (Gm16G149300), , and . These results indicate that various coumestans, especially coumestrol, accumulate during leaf maturity, or senescence in soybean.
PubMed: 34899782
DOI: 10.3389/fpls.2021.756308 -
Molecules (Basel, Switzerland) May 2022Coumestrol (3,9-dihydroxy-6-benzofuran [3,2-c] chromenone) as a phytoestrogen and polyphenolic compound is a member of the Coumestans family and is quite common in...
Coumestrol (3,9-dihydroxy-6-benzofuran [3,2-c] chromenone) as a phytoestrogen and polyphenolic compound is a member of the Coumestans family and is quite common in plants. In this study, antiglaucoma, antidiabetic, anticholinergic, and antioxidant effects of Coumestrol were evaluated and compared with standards. To determine the antioxidant activity of coumestrol, several methods-namely N,N-dimethyl-p-phenylenediamine dihydrochloride radical (DMPD)-scavenging activity, 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulphonate) radical (ABTS)-scavenging activity, 1,1-diphenyl-2-picrylhydrazyl radical (DPPH)-scavenging activity, potassium ferric cyanide reduction ability, and cupric ion (Cu)-reducing activity-were performed. Butylated hydroxyanisole (BHA), Trolox, α-Tocopherol, and butylated hydroxytoluene (BHT) were used as the reference antioxidants for comparison. Coumestrol scavenged the DPPH radical with an IC value of 25.95 μg/mL (r: 0.9005) while BHA, BHT, Trolox, and α-Tocopherol demonstrated IC values of 10.10, 25.95, 7.059, and 11.31 μg/mL, respectively. When these results evaluated, Coumestrol had similar DPPH-scavenging effect to BHT and lower better than Trolox, BHA and α-tocopherol. In addition, the inhibition effects of Coumestrol were tested against the metabolic enzymes acetylcholinesterase (AChE), butyrylcholinesterase (BChE), carbonic anhydrase II (CA II), and α-glycosidase, which are associated with some global diseases such as Alzheimer's disease (AD), glaucoma, and diabetes. Coumestrol exhibited K values of 10.25 ± 1.94, 5.99 ± 1.79, 25.41 ± 1.10, and 30.56 ± 3.36 nM towards these enzymes, respectively.
Topics: Acetylcholinesterase; Antioxidants; Butylated Hydroxyanisole; Butylated Hydroxytoluene; Butyrylcholinesterase; Carbonic Anhydrases; Coumestrol; Free Radical Scavengers; Glycoside Hydrolases; alpha-Tocopherol
PubMed: 35630566
DOI: 10.3390/molecules27103091 -
Biochimica Et Biophysica Acta Sep 2016Two nuclear receptors, the pregnane X receptor (PXR) and the constitutive androstane receptor (CAR), participate in the xenobiotic detoxification system by regulating... (Review)
Review
Two nuclear receptors, the pregnane X receptor (PXR) and the constitutive androstane receptor (CAR), participate in the xenobiotic detoxification system by regulating the expression of drug-metabolizing enzymes and transporters in order to degrade and excrete foreign chemicals or endogenous metabolites. This review aims to expand the perceived relevance of PXR and CAR beyond their established role as master xenosensors to disease-oriented areas, emphasizing their modulation by small molecules. Structural studies of these receptors have provided much-needed insight into the nature of their binding promiscuity and the important elements that lead to ligand binding. Reports of species- and isoform-selective activation highlight the need for further scrutiny when extrapolating from animal data to humans, as animal models are at the forefront of early drug discovery. This article is part of a Special Issue entitled: Xenobiotic nuclear receptors: New Tricks for An Old Dog, edited by Dr. Wen Xie.
Topics: Animals; Camptothecin; Constitutive Androstane Receptor; Coumestrol; Energy Metabolism; Gene Expression Regulation; Humans; Inactivation, Metabolic; Ketoconazole; Liver; Metformin; Pregnane X Receptor; Protein Binding; Receptors, Cytoplasmic and Nuclear; Receptors, Steroid; Signal Transduction; Small Molecule Libraries; Species Specificity; Substrate Specificity
PubMed: 26921498
DOI: 10.1016/j.bbagrm.2016.02.013 -
Nutrients Sep 2022leaves contain a variety of phytoestrogens, including flavonoids, isoflavonoids, and coumestan derivatives. In this study, we aimed to identify the active ingredients...
leaves contain a variety of phytoestrogens, including flavonoids, isoflavonoids, and coumestan derivatives. In this study, we aimed to identify the active ingredients of leaves and to elucidate their function in monoamine oxidase (MAO) activation and Aβ self-aggregation using in vitro and in silico approaches. To the best of our knowledge, this is the first study to elucidate coumestrol as a selective and competitive MAO-A inhibitor. We identified that coumestrol, a coumestan-derivative, exhibited a selective inhibitory effect against MAO-A (IC = 1.99 ± 0.68 µM), a key target protein for depression. In a kinetics analysis with 0.5 µg MAO-A, 40-160 µM substrate, and 25 °C reaction conditions, coumestrol acts as a competitive MAO-A inhibitor with an inhibition constant of 1.32 µM. During an in silico molecular docking analysis, coumestrol formed hydrogen bonds with FAD and pi-pi bonds with hydrophobic residues at the active site of the enzyme. Moreover, based on thioflavin-T-based fluorometric assays, we elucidated that coumestrol effectively prevented self-aggregation of amyloid beta (Aβ), which induces an inflammatory response in the central nervous system (CNS) and is a major cause of Alzheimer's disease (AD). Therefore, coumestrol could be used as a CNS drug to prevent diseases such as depression and AD by the inhibition of MAO-A and Aβ self-aggregation.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Coumestrol; Flavin-Adenine Dinucleotide; Flavonoids; Humans; Molecular Docking Simulation; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Phytoestrogens; Structure-Activity Relationship
PubMed: 36145197
DOI: 10.3390/nu14183822 -
Archives of Biochemistry and Biophysics May 2023The propensity of breast cancer to preferentially metastasize to the skeleton is well known. Once established in bone metastatic breast cancers have a poor prognosis due...
Genistein and coumestrol reduce MCF-7 breast cancer cell viability and inhibit markers of preferential metastasis, bone matrix attachment and tumor-induced osteoclastogenesis.
The propensity of breast cancer to preferentially metastasize to the skeleton is well known. Once established in bone metastatic breast cancers have a poor prognosis due to their ability to promote extensive bone loss which augments tumor burden. Unfortunately, current anti-resorptive therapies for skeletal metastasis are typically prescribed after secondary tumors have formed and are palliative in nature. One group of compounds with the potential to reduce both tumor burden and osteolysis are phytoestrogens (PE), but the mechanisms mediating a beneficial effect are unclear. Therefore, the current study examined the effect of genistein and coumestrol alone or in combination on breast cancer cell number, expression of mediators of preferential skeletal metastasis, bone matrix attachment and tumor-induced osteoclast formation. Results showed that genistein and coumestrol significantly reduced viable cell number in an estrogen receptor dependent manner (p < 0.05), whereas combinations of PE had no effect. In addition, genistein and coumestrol significantly reduced expression of genes driving epithelial to mesenchymal transition (snail), bone attachment (CXCR4 and integrin αV) and osteolysis (PTHrP and TNF-α). In keeping with this genistein and coumestrol significantly suppressed attachment of breast cancer cells to bone matrix and inhibited tumor and RANKL-induced osteoclast formation. Our data suggests that phytoestrogens not only decrease breast cancer cell viability but also antagonize essential tumor bone interactions that establish and drive the progression of skeletal metastasis.
Topics: Humans; Female; Genistein; Coumestrol; Phytoestrogens; Breast Neoplasms; MCF-7 Cells; Osteogenesis; Osteolysis; Epithelial-Mesenchymal Transition; Cell Survival; Bone Matrix; Bone Neoplasms
PubMed: 36967033
DOI: 10.1016/j.abb.2023.109583 -
The Journal of Nutritional Biochemistry Feb 2020Coumestrol is a dietary phytoestrogen with estrogen-mimicking characteristics. This study investigated the molecular mechanisms of antiobesity effects of coumestrol. Two...
Coumestrol is a dietary phytoestrogen with estrogen-mimicking characteristics. This study investigated the molecular mechanisms of antiobesity effects of coumestrol. Two weeks of coumestrol treatment reduced body weight and improved glucose tolerance of high-fat diet (HFD)-fed mice. Notably, coumestrol treatment reduced adiposity but expanded brown adipose tissue mass. In addition, coumestrol treatment induced up-regulation of brown adipocyte markers and lipolytic gene expression in adipose tissue. Mechanistically, coumestrol induced an increase in mitochondrial contents of brown adipose tissue, which was associated with up-regulation of adenosine monophosphate-activated protein kinase and sirtuin 1. In vitro knockdown of estrogen receptor 1 inhibited the effect of coumestrol on brown adipogenic marker expression, increase in mitochondrial contents and oxygen consumption rate in brown adipocytes. Furthermore, lineage tracing of platelet-derived growth factor receptor A-positive (PDGFRA+) adipocyte progenitors confirmed increased levels of de novo brown adipogenesis from PDGFRA+ cells by coumestrol treatment. In conclusion, our results indicate that coumestrol has antiobesity effects through the expansion and activation of brown adipose tissue metabolism.
Topics: Adipocytes, Beige; Adipogenesis; Adipose Tissue, Brown; Adipose Tissue, White; Adiposity; Animals; Body Weight; Coumestrol; Diet, High-Fat; Glucose Tolerance Test; Lipolysis; Male; Mice; Mice, Inbred C57BL; Obesity; Phytoestrogens
PubMed: 31812908
DOI: 10.1016/j.jnutbio.2019.108300 -
Frontiers in Plant Science 2022Coumestrol (CMS) derivatives are unique compounds, which function as phytoalexins; they are derived from soybean roots, following abiotic and biotic stresses. As a...
Coumestrol (CMS) derivatives are unique compounds, which function as phytoalexins; they are derived from soybean roots, following abiotic and biotic stresses. As a phytoalexin, CMS forms a defense system that enables plants to maintain their viability. However, it is still challenging to achieve the mass production of phytoalexins, which exhibit pharmacological values, plant breeding. Here, the synthesis of CMS derivatives from the seedling, plant, and adventitious root (AR) of were investigated under artificial light, as well as a chemical elicitor treatment. In the presence of constant light, as well as under treatment with methyl jasmonate, the CMS monoglucoside (coumestrin; CMSN) and malonyl CMSN (M-CMSN) contents of the AR culture (4 weeks) increased drastically. The two CMS derivatives, CMSN and M-CMSN, were obtained as a mixture of isomers, which were identified nuclear magnetic resonance analysis. These derivatives were also observed in a soybean plant that was grown on artificial soil (AS; 5 weeks) and a Petri dish (9 days) although in considerably lesser quantities than those observed in the AR culture. Compared with the two other media (AS and the Petri dish), the AR culture achieved the superior synthesis of CMSN and M-CMSN within a relatively short cultivation period (<1 month) in laboratory-scale (3 L) and pilot-scale (1,000 L) bioreactors. The isoflavone content of AR under the constant light conditions was three-fold that under dark conditions. Significant quantities of malonyl daidzin and malonyl genistin were produced in the root of AS and the seedling of Petri dish, respectively. Flavonol glycosides were not produced in the AR culture under the dark and light conditions, as well as in AS under the dark condition. However, significant contents of kaempferol glycosides were produced in the leaves of AS and seedling of Petri dish, following the light treatment. Thus, we proposed that the established soybean AR-cultivation approach represented a better method for biosynthesizing phytoalexins, such as the CMS derivatives, as plant-derived functional materials.
PubMed: 35800610
DOI: 10.3389/fpls.2022.923163