Identification of phytoestrogens as sirtuin inhibitor against breast cancer: Multitargeted approach.

Despite progress in diagnosis and treatment strategies, breast cancer remains a primary risk to female health as indicated by second most cancer-deaths globally caused by this cancer. High risk mutation is linked to prognosis of breast cancer. Due to high resistance of breast cancer against current therapies, there is necessity of novel treatment strategies. Sirtuins are signaling proteins belonging to histone deacetylase class III family, known to control several cellular processes. Therefore, targeting sirtuins could be one of the approaches to treat breast cancer. Several plants synthesize phytoestrogens which exhibit structural and physiological similarities to estrogens and have been recognized to possess anticancer activity. In our study, we investigated several phytoestrogens for sirtuin inhibition by conducting molecular docking studies, and in-vitro studies against breast cancer cell lines. In molecular docking studies, we identified coumestrol possessing high binding energy with sirtuin proteins 1-3 as compared to other phytoestrogens. The molecular dynamic studies showed stable interaction of ligand and protein with higher affinity at sirtuin proteins 1-3 binding sites. In cell proliferation assay and colony formation assay using breast cancer cell lines (MCF-7 and MDAMB-231) coumestrol caused significant reduction in cell proliferation and number of colonies formed. Further, the flow cytometric analysis showed that coumestrol induces intracellular reactive oxygen species and the western blot analysis revealed reduction in the level of SIRT-1 expression in breast cancer cell lines. In conclusion, in-silico data and in-vitro studies suggest that the phytoestrogen coumestrol has sirtuin inhibitory activity against breast cancer.

Receptor mediated biological activities of phytoestrogens.

Phytoestrogens are plant-derived compounds that have chemical structures and functions similar to estrogen. Phytoestrogens act as ligand-inducible transcription factors involved in cellular growth by binding to estrogen receptors (ERs), specifically ER alpha (ERα) and beta (ERß). Through this mechanism, phytoestrogens have a physiological function similar to that of the female hormone 17ß-estradiol (E2), which can be useful in treating osteoporosis, cardiovascular disease, and cancer. Furthermore, phytoestrogens have been found to elicit various cellular responses depending on their affinity for ERs; in particular, they show a greater affinity with for ERß. This study aimed to comprehensively analyze the mode of action of eight phytoestrogens, namely kaempferol, coumestrol, glycitein, apigenin, daidzein, genistein, equol, and resveratrol, by evaluating their estrogenic activity as ER ligands. Based on the bioluminescence resonance energy transfer (BRET)-based ER dimerization and transactivation assay results, all the phytoestrogens tested were identified as estrogen agonists by mediating ERα and ERß dimerization. The specific binding and functions of ERα and ERß were distinguished by differentiating between their dimerization activity. In addition, this study contributes to advancing our understanding of the overall mechanism of action involving both ERs.

Monitoring of Specific Phytoestrogens by Dedicated Electrochemical Sensors: A Review.

Phytoestrogens are non-steroidal estrogens produced from plants that can bind with the human body's estrogenic receptor site and be used as a substitute for maintaining hormonal balance. They are mainly classified as flavonoids, phenolic acids, lignans, stilbenes, and coumestans; some are resocyclic acids of lactones, which are mycotoxins and not natural phytoestrogen. Phytoestrogens have many beneficial medicinal properties, making them an important part of the daily diet. Electrochemical sensors are widely used analytical tools for analysing various pharmaceuticals, chemicals, pollutants and food items. Electrochemical sensors provide an extensive platform for highly sensitive and rapid analysis. Several reviews have been published on the importance of the biological and medicinal properties of phytoestrogens. However, this review provides an overview of recent work performed through electrochemical measurements with electrochemical sensors and biosensors for all the classes of phytoestrogens done so far since 2019.

Phytoestrogens: Chemistry, potential health benefits, and their medicinal importance.

Phytoestrogens, also known as xenoestrogens, are secondary metabolites derived from plants that have similar structures and biological effects as human estrogens. These compounds do not directly affect biological functions but can act as agonists or antagonists depending on the level of endogenous estrogen in the body. Phytoestrogens may have an epigenetic mechanism of action independent of estrogen receptors. These compounds are found in more than 300 plant species and are synthesized through the phenylpropanoid pathway, with specific enzymes leading to various chemical structures. Phytoestrogens, primarily phenolic compounds, include isoflavonoids, flavonoids, stilbenes, and lignans. Extensive research in animals and humans has demonstrated the protective effects of phytoestrogens on estrogen-dependent diseases. Clinical trials have also shown their potential benefits in conditions such as osteoporosis, Parkinson's disease, and certain types of cancer. This review provides a concise overview of phytoestrogen classification, chemical diversity, and biosynthesis and discusses the potential therapeutic effects of phytoestrogens, as well as their preclinical and clinical development.

Metabolomic study of the estrogenic and anti-osteoporotic potential of Erythrina bidwillii leaf.

Erythrina bidwillii Lindl., Leguminosae, constitutes a valuable crop for horticulture and medicine; however, it is rarely investigated. Menopause is a crucial transitional period in women's health. Women worldwide consider the use of phytoestrogens as a safe hormone replacement therapy to alleviate detrimental menopausal symptoms. Thus, the discovery of novel phytoestrogens is highly demanded. The present study aimed to investigate, for the first time, the metabolomic profile and the estrogenic potential of E. bidwillii Lindl. leaf. Ultra-performance liquid chromatography-electrospray ionization-tandem mass spectrometry and gas chromatography-mass spectrometry metabolite profiling revealed the prevalence of alkaloids, flavonoids, isoflavonoids and fatty acids. Additionally, five erythrinan alkaloids, cristanine A (1), 8-oxoerythraline (2), (+)-erythrinine (3), (+)-erythraline (4) and 8-oxoerythrinine (5), along with the isoflavonoid genistin (6), were isolated. Erythrina bidwillii leaf extract exhibited significant in vivo estrogenic, anti-osteoporotic, anti-hyperlipidemic, hepatoprotective, and nephroprotective activities, utilizing ovariectomized rat model. Moreover, ethyl acetate and hexane fractions possessed significant in vitro estrogeic potential on MCF-7 cell lines. An in silico study of the isolated metabolites revealed that (+)-erythrinine (3) and 8-oxoerythrinine (5) exhibited the highest affinity for ERα and ERß, respectively, modeling them as potential estrogenic lead metabolites. Therefore, E. bidwillii leaf could be employed as promising hormone replacement therapy for postmenopausal women after thorough clinical trials.

Elucidating the estrogen-like effects and biocompatibility of the herbal components in the Qing' E formula.

ETHNOPHARMACOLOGICAL RELEVANCE: The Qing' E Formula (QEF) is a compound preparation that was originally recorded in the 'Prescriptions of the Bureau of Taiping People's Welfare Pharmacy' during the Song Dynasty (10th century CE). It consists of four Chinese medicinal herbs, Eucommiae Cortex (Eucommia ulmoides), Psoraleae Fructus (Psoralea corylifolium), Juglandis Semen (Juglans regia), and Garlic Rhizoma. According to traditional Chinese medicine (TCM), QEF has the ability to tonify the kidney and strengthen muscle and bone. According to the 'kidney governing bone' theory in TCM, QEF is also used to treat the symptoms of climacteric syndrome, especially osteoporosis caused by reduced production of estrogen during the perimenopausal period; however, the therapeutic roles of the individual components of the QEF and their compatibility within the formula has not been investigated. AIM OF THE STUDY: In this study, the compatibility mechanism and estrogen-like action properties of the four herbal components in the QEF was elucidated according to the organizing principle of Chinese medicine formulas using both in vitro and in vivo models. MATERIALS AND METHODS: The estrogen-like effects of QEF and its herbal components were investigated in MCF7 and HEK293 cells as well as ovariectomized (OVX) rats. The estrogen-like effects of the QEF and its components were analyzed in vitro using Cell Counting Kit-8 and Luciferase reporter gene assays. In the in vivo studies, the blood plasma levels of hormones, lipids, neurotransmitters, aromatase, superoxide dismutase (SOD), and malondialdehyde (MDA) were measured through enzyme-linked immunosorbent assays (ELISAs). The histological morphologies of the target organs after exposure to QEF were investigated by HE staining and immunohistochemical methods. The expression levels of estrogen pathway-related proteins and genes in the OVX rats were measured by Western blotting and real time quantitative PCR (RT-qPCR), respectively. RESULTS: The in vitro results showed that the QEF, Eucommia (EC) and Psoralea (PF) promoted the proliferation of MCF-7 cells and upregulated the expression of ERα, ERß and pS2 genes in the MCF-7 cells. Notably, the QEF demonstrated the most active estrogen-like effects compared to the individual ingredients. The in vivo results showed that the QEF, EC, and PF increased the uterine coefficient, upregulated the expression of both ERs (ERα and ERß) in the uterus, and increased blood serum hormone levels. QEF and its individual components ameliorated menopausal-derived lipid metabolism dysfunction, increased neurotransmitter production by stimulating the adrenal glands, enhanced the antioxidant activity in the serum by increasing the concentration of SOD, reversed ovariectomy-derived atrophy in the uterus, and reduced the weight gain associated with estrogen reduction in the OVX rats. The QEF also antagonize the loss of appetite of OVX animals caused by feeding Psoralea alone, which could explain the compatibility mechanism of Qing' E Formula with reducing toxicity and increasing efficiency. CONCLUSIONS: The estrogen-like effects of Eucommia and Psoralea were mainly mediated through activation of ERα and ERß. The phytoestrogen components regulated hormone production and the expression of related proteins and genes, which indicated that these components exhibited estrogen-like therapeutic effects. However, the QEF showed the greatest estrogen-like effects compared to the individual components. Overall, this corroborated the therapeutic prowess of the QEF and clarified the pharmacodynamic interactions between the different components extracts in the QEF.

Preparation of Hop Estrogen-Active Material for Production of Food Supplements.

In recent years, the interest in the health-promoting effects of hop prenylflavonoids, especially its estrogenic effects, has grown. Unfortunately, one of the most potent phytoestrogens identified so far, 8-prenylnaringenin, is only a minor component of hops, so its isolation from hop materials for the production of estrogenically active food supplements has proved to be problematic. The aim of this study was to optimize the conditions (e.g., temperature, the length of the process and the amount of the catalyst) to produce 8-prenylnaringenin-rich material by the magnesium oxide-catalyzed thermal isomerization of desmethylxanthohumol. Under these optimized conditions, the yield of 8-prenylnaringenin was 29 mg per 100 gDW of product, corresponding to a >70% increase in its content relative to the starting material. This process may be applied in the production of functional foods or food supplements rich in 8-prenylnaringenin, which may then be utilized in therapeutic agents to help alleviate the symptoms of menopausal disorders.

The Beneficial Role of Natural Endocrine Disruptors: Phytoestrogens in Alzheimer's Disease.

Alzheimer's disease (AD) is the most common form of dementia with a growing incidence rate primarily among the elderly. It is a neurodegenerative, progressive disorder leading to significant cognitive loss. Despite numerous pieces of research, no cure for halting the disease has been discovered yet. Phytoestrogens are nonestradiol compounds classified as one of the endocrine-disrupting chemicals (EDCs), meaning that they can potentially disrupt hormonal balance and result in developmental and reproductive abnormalities. Importantly, phytoestrogens are structurally, chemically, and functionally akin to estrogens, which undoubtedly has the potential to be detrimental to the organism. What is intriguing, although classified as EDCs, phytoestrogens seem to have a beneficial influence on Alzheimer's disease symptoms and neuropathologies. They have been observed to act as antioxidants, improve visual-spatial memory, lower amyloid-beta production, and increase the growth, survival, and plasticity of brain cells. This review article is aimed at contributing to the collective understanding of the role of phytoestrogens in the prevention and treatment of Alzheimer's disease. Importantly, it underlines the fact that despite being EDCs, phytoestrogens and their use can be beneficial in the prevention of Alzheimer's disease.

Effects of Pueraria candollei var mirifica (Airy Shaw and Suvat.) Niyomdham on Ovariectomy-Induced Cognitive Impairment and Oxidative Stress in the Mouse Brain.

The effects of the phytoestrogen-enriched plant Pueraria mirifica (PM) extract on ovari-ectomy (OVX)-induced cognitive impairment and hippocampal oxidative stress in mice were investigated. Daily treatment with PM and 17ß-estradiol (E2) significantly elevated cognitive behavior as evaluated by using the Y maze test, the novel object recognition test (NORT), and the Morris water maze test (MWM), attenuated atrophic changes in the uterus and decreased serum 17ß-estradiol levels. The treatments significantly ameliorated ovariectomy-induced oxidative stress in the hippocampus and serum by a decrease in malondialdehyde (MDA), an enhancement of superoxide dismutase, and catalase activity, including significantly down-regulated expression of IL-1ß, IL-6 and TNF-α proinflammatory cytokines, while up-regulating expression of PI3K. The present results suggest that PM extract suppresses oxidative brain damage and dysfunctions in the hippocampal antioxidant system, including the neuroinflammatory system in OVX animals, thereby preventing OVX-induced cognitive impairment. The present results indicate that PM exerts beneficial effects on cognitive deficits for which menopause/ovariectomy have been implicated as risk factors.

Botanicals in Postmenopausal Osteoporosis.

Osteoporosis is a systemic bone disease characterized by reduced bone mass and the deterioration of bone microarchitecture leading to bone fragility and an increased risk of fractures. Conventional anti-osteoporotic pharmaceutics are effective in the treatment and prophylaxis of osteoporosis, however they are associated with various side effects that push many women into seeking botanicals as an alternative therapy. Traditional folk medicine is a rich source of bioactive compounds waiting for discovery and investigation that might be used in those patients, and therefore botanicals have recently received increasing attention. The aim of this review of literature is to present the comprehensive information about plant-derived compounds that might be used to maintain bone health in perimenopausal and postmenopausal females.

The Potential Effects of Phytoestrogens: The Role in Neuroprotection.

Phytoestrogens are naturally occurring non-steroidal phenolic plant compounds. Their structure is similar to 17-ß-estradiol, the main female sex hormone. This review offers a concise summary of the current literature on several potential health benefits of phytoestrogens, mainly their neuroprotective effect. Phytoestrogens lower the risk of menopausal symptoms and osteoporosis, as well as cardiovascular disease. They also reduce the risk of brain disease. The effects of phytoestrogens and their derivatives on cancer are mainly due to the inhibition of estrogen synthesis and metabolism, leading to antiangiogenic, antimetastatic, and epigenetic effects. The brain controls the secretion of estrogen (hypothalamus-pituitary-gonads axis). However, it has not been unequivocally established whether estrogen therapy has a neuroprotective effect on brain function. The neuroprotective effects of phytoestrogens seem to be related to both their antioxidant properties and interaction with the estrogen receptor. The possible effects of phytoestrogens on the thyroid cause some concern; nevertheless, generally, no serious side effects have been reported, and these compounds can be recommended as health-promoting food components or supplements.

Utilization of Isoflavones in Soybeans for Women with Menopausal Syndrome: An Overview.

Based on their nutrient composition, soybeans and related foods have been considered to be nutritious and healthy for humans. Particularly, the biological activity and subsequent benefits of soy products may be associated with the presence of isoflavone in soybeans. As an alternative treatment for menopause-related symptoms, isoflavone has gained much popularity for postmenopausal women who have concerns related to undergoing hormone replacement therapy. However, current research has still not reached a consensus on the effects of isoflavone on humans. This overview is a summary of the current literature about the processing of soybeans and isoflavone types (daidzein, genistein, and S-equol) and supplements and their extraction and analysis as well as information about the utilization of isoflavones in soybeans. The processes of preparation (cleaning, drying, crushing and dehulling) and extraction of soybeans are implemented to produce refined soy oil, soy lecithin, free fatty acids, glycerol and soybean meal. The remaining components consist of inorganic constituents (minerals) and the minor components of biologically interesting small molecules. Regarding the preventive effects on diseases or cancers, a higher intake of isoflavones is associated with a moderately lower risk of developing coronary heart disease. It may also reduce the risks of breast and colorectal cancer as well as the incidence of breast cancer recurrence. Consumption of isoflavones or soy foods is associated with reduced risks of endometrial and bladder cancer. Regarding the therapeutic effects on menopausal syndrome or other diseases, isoflavones have been found to alleviate vasomotor syndromes even after considering placebo effects, reduce bone loss in the spine and ameliorate hypertension and in vitro glycemic control. They may also alleviate depressive symptoms during pregnancy. On the other hand, isoflavones have not shown definitive effects regarding improving cognition and urogenital symptoms. Because of lacking standardization in the study designs, such as the ingredients and doses of isoflavones and the durations and outcomes of trials, it currently remains difficult to draw overall conclusions for all aspects of isoflavones. These limitations warrant further investigations of isoflavone use for women's health.

The Biological Effects of Forsythia Leaves Containing the Cyclic AMP Phosphodiesterase 4 Inhibitor Phillyrin.

Forsythia fruit (Forsythia suspensa Vahl (Oleaceae)) is a common component of Kampo medicines for treating the common cold, influenza, and allergies. The main polyphenolic compounds in the leaves of F. suspensa are pinoresinol ß-d-glucoside, phillyrin and forsythiaside, and their levels are higher in the leaves of the plant than in the fruit. It is known that polyphenolic compounds stimulate lipid catabolism in the liver and suppress dyslipidemia, thereby attenuating diet-induced obesity and polyphenolic anti-oxidants might attenuate obesity in animals consuming high-fat diets. Recently, phillyrin was reported as a novel cyclic AMP phosphodiesterase 4 (PDE4) inhibitor derived from forsythia fruit. It was expected that the leaves of F. suspensa might display anti-obesity effects and serve as a health food material. In this review, we summarized our studies on the biological effects of forsythia leaves containing phillyrin and other polyphenolic compounds, particularly against obesity, atopic dermatitis, and influenza A virus infection, and its potential as a phytoestrogen.

Auto-hydrolysis of red clover as "green" approach to (iso)flavonoid enriched products.

Optimal parameters for the auto-hydrolysis of (iso)flavone glycosides to aglycones in ground Trifolium pratense L. plant material were established as a "green" method for the production of a reproducible red clover extract (RCE). The process utilized 72-h fermentation in DI water at 25 and 37 °C. The aglycones obtained at 25 °C, as determined by UHPLC-UV and quantitative 1H NMR (qHNMR), increased significantly in the auto-hydrolyzed (ARCE) (6.2-6.7% w/w biochanin A 1, 6.1-9.9% formononetin 2) vs a control ethanol (ERCE) extract (0.24% 1, 0.26% 2). After macerating ARCE with 1:1 (v/v) diethyl ether/hexanes (ARCE-d/h), 1 and 2 increased to 13.1-16.7% and 14.9-18.4% w, respectively, through depletion of fatty components. The final extracts showed chemical profiles similar to that of a previous clinical RCE. Biological standardization revealed that the enriched ARCE-d/h extracts produced the strongest estrogenic activity in ERα positive endometrial cells (Ishikawa cells), followed by the precursor ARCE. The glycoside-rich ERCE showed no estrogenic activity. The estrogenicity of ARCE-d/h was similar to that of the clinical RCE. The lower potency of the ARCE compared to the prior clinical RCE indicated that substantial amounts of fatty acids/matter likely reduce the estrogenicity of crude hydrolyzed preparations. The in vitro dynamic residual complexity of the conversion of biochanin A to genistein was evaluated by LC-MS-MS. The outcomes help advance translational research with red clover and other (iso)flavone-rich botanicals by inspiring the preparation of (iso)flavone aglycone-enriched extracts for the exploration of new in vitro and ex vivo bioactivities that are unachievable with genuine, glycoside-containing extracts.

Structure-Activity Relationship of Phytoestrogen Analogs as ERα/ß Agonists with Neuroprotective Activities.

A set of isoflavononid and flavonoid analogs was prepared and evaluated for estrogen receptor α (ERα) and ERß transactivation and anti-neuroinflammatory activities. Structure-activity relationship (SAR) study of naturally occurring phytoestrogens, their metabolites, and related isoflavone analogs revealed the importance of the C-ring of isoflavonoids for ER activity and selectivity. Docking study suggested putative binding modes of daidzein 2 and dehydroequol 8 in the active site of ERα and ERß, and provided an understanding of the promising activity and selectivity of dehydroequol 8. Among the tested compounds, equol 7 and dehydroequol 8 were the most potent ERα/ß agonists with ERß selectivity and neuroprotective activity. This study provides knowledge on the SAR of isoflavonoids for further development of potent and selective ER agonists with neuroprotective potential.

Rheum rhaponticum Root Extract Improves Vasomotor Menopausal Symptoms and Estrogen-Regulated Targets in Ovariectomized Rat Model.

Ovarian insufficiency and ovariectomy are characterized by deregulated heat loss mechanisms. Unlike hormone therapy, ERr 731 (a standardized botanical extract of Siberian rhubarb Rheum rhaponticum L. high in rhaponticin) acts like a selective estrogen receptor modulator for ERß receptors and may offer a higher degree of safety while maintaining the desired efficacy profile. In this study, we examined the relationship between oral administration of ERr 731 and the underlying components of skin vasomotion responses in an ovariectomized (OVX) rat model. ERr 731 dose-dependently reduced tail skin temperature (Tskin) values by an average of 1 °C. The rapid onset of this effect was observed in 1 and 3 mg/kg/day ERr 731 groups as early as day 2 of administration, and remained in place for the duration of the treatment (2 weeks). Substituting ERr 731 after E2 withdrawal helped maintain body temperature similarly to E2 alone, suggesting the usefulness of ERr 731 for replacing existing hormonal therapy in humans. ERr 731 also acted as a highly selective agonist for ERß in the hypothalamus of OVX rats, as well as in ERα/ß cell-based reporter assays. These data validate the OVX/Tskin rat model as a suitable screening platform to evaluate botanical and pharmaceutical treatments of menopause, while providing further evidence for the efficacy of ERr 731 towards alleviating vasomotor menopausal symptoms and improving wellbeing during the menopausal transition.

Ferutinin: A phytoestrogen from ferula and its anticancer, antioxidant, and toxicity properties.

This study was performed to evaluate the antioxidant, anticancer, and toxicity properties of ferutinin, a phytoestrogen derived from Ferula species. The human Michigan Cancer Foundation-7 (MCF-7) breast cancer cell line and normal human fibroblast (HDF) were cultured and treated with different ferutinin concentrations. The cell viability was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and cell death-defining tests (a comparative real-time polymerase chain reaction [for Bax and Bcl-2 genes], flow cytometry, and acridine orange/propidium iodide cell staining). Moreover, 15 white male balb/c mice were divided into three groups of five (one untreated control group and two groups), which received different doses of ferutinin-supplemented water (500 and 1000 µg/kg mice weight) to check the mice liver and kidney pathomorphological alterations and to determine the antioxidant enzymes' expression profile (superoxide dismutase [SOD], catalase [CAT], and glutathione peroxidase) in the mentioned tissues. Finally, the liver lipid peroxidation of mice was analyzed. The results of MTT and cell death-defining tests indicate the significant reduction in cell viability and induction of apoptotic death in MCF-7 cells (enhanced sub-G1 peaks, Bax overexpression, Bcl-2 downregulation, and increased apoptotic cells). The antioxidant enzymes (SOD and CAT) in the mice liver and kidney cells were found to be upregulated (p < .05) in response to the increasing doses of ferutinin. Besides, the lipid peroxidation of the liver tissue of mice was significantly reduced. According to the results, we suggest that ferutinin has the potential to be served as a selective anticancer compound for breast cancer treatment.

The influence of phytoestrogens on different physiological and pathological processes: An overview.

Functional foods have nutritional properties and organic functions, which are beneficial to health. Certain types of functional food components are so-called phytoestrogens, non-steroidal compounds derived from the metabolism of precursors contained in plants, which originate secondary metabotypes known to induce biological responses and by mimicry or modulating the action of endogenous estrogen. These molecules are involved in several physiological and pathological processes related to reproduction, bone remodeling, skin, cardiovascular, nervous, immune systems, and metabolism. This review aimed to present an overview of phytoestrogens regarding their chemical structure, actions, and effects in the organism given several pathologies. Several studies have demonstrated beneficial phytoestrogen actions, such as lipid profile improvement, cognitive function, menopause, oxidative stress, among others. Phytoestrogens effects are not completely elucidated, being necessary future research to understand the exact action mechanisms, whether they are via estrogen receptor or whether other hidden mechanisms produce these effects. Thus, this review makes a general approach to the phytoestrogen actions, beneficial effects, risk and limitations. However, the complexities of biological effects after ingestion of phytoestrogens and the differences in their metabolism and bioavailability indicate that interpretation of either risk or benefits needs to be made with caution.

Engagement of phytoestrogens in breast cancer suppression: Structural classification and mechanistic approach.

Cancer is the world's devastating disease, and breast cancer is the most common reason for the death of women worldwide. Many synthetic drugs and medications are provided with their beneficial actions, but all of these have side effects and resistance problems. Natural remedies are coming forward to overcome the disadvantages of synthetic drugs. Among the natural categories, phytoestrogens having a structural similarity of mammalian oestradiol proves its benefit with various mechanisms not only in the treatment of breast cancer but even to prevent the occurrence of postmenopausal symptoms. Phytoestrogens are plant-derived compounds that were utilized in ancient medications and traditional knowledge for its sex hormone properties. Phytoestrogens exert pleiotropic effects on cellular signalling and show effects on estrogen-dependent diseases. However, because of activation/inhibition of steroid hormonal receptor ER-α or ER-ß, these compounds induce or inhibit steroid hormonal (estrogen) action and, therefore, have the potential to disrupt hormone (estrogen) signalling pathway. In this review, we have discussed and summarize the effect of certain phytoestrogens and their possible mechanisms that can substantiate advantageous benefits for the treatment of post-menopausal symptoms as well as for breast cancer.

Ferula L. Plant Extracts and Dose-Dependent Activity of Natural Sesquiterpene Ferutinin: From Antioxidant Potential to Cytotoxic Effects.

The employment studies of natural extracts in the prevention and treatment of several diseases highlighted the role of different species of genus Ferula L., belonging to the Apiaceae family, dicotyledonous plants present in many temperate zones of our planet. Ferula communis L. is the main source of sesquiterpene ferutinin, a bioactive compound studied both in vitro and in vivo, because of different effects, such as phytoestrogenic, antioxidant, anti-inflammatory, but also antiproliferative and cytotoxic activity, performed in a dose-dependent and cell-dependent way. The present review will focus on the molecular mechanisms involved in the different activities of Ferutinin, starting from its antioxidant potential at low doses until its ionophoric property and the subsequent mitochondrial dysfunction induced through administration of high doses, which represent the key point of its anticancer action. Furthermore, we will summarize the data acquired from some experimental studies on different cell types and on several diseases. The results obtained showed an important antioxidant and phytoestrogenic regulation with lack of typical side effects related to estrogenic therapy. The preferential cell death induction for tumor cell lines suggests that ferutinin may have anti-neoplastic properties, and may be used as an antiproliferative and cytotoxic agent in an estrogen dependent and independent manner. Nevertheless, more data are needed to clearly understand the effect of ferutinin in animals before using it as a phytoestrogen or anticancer drug.