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Osteoporosis is a significant concern in bone health, and understanding its pathomechanism is crucial for developing effective prevention and treatment strategies. This article delves into the relationship between estrogen metabolism and bone mineralization, shedding light on how phytoestrogens can influence this intricate process. Estrogen, a hormone primarily associated with reproductive health, plays a pivotal role in maintaining bone density and structure. The article explores the positive effects of estrogen on bone mineralization, highlighting its importance in preventing conditions like osteoporosis. Phytoestrogens, naturally occurring compounds found in certain plant-based foods, are the focal point of the discussion. These compounds have the remarkable ability to mimic estrogen's actions in the body. The article investigates how phytoestrogens can modulate the activity of estrogen, thereby impacting bone health. Furthermore, the article explores the direct effects of phytoestrogens on bone mineralization and structure. By regulating estrogen metabolism, phytoestrogens can contribute to enhanced bone density and reduced risk of osteoporosis. Finally, the article emphasizes the role of plant-based diets as a source of phytoestrogens. By incorporating foods rich in phytoestrogens into one's diet, individuals may potentially bolster their bone health, adding a valuable dimension to the ongoing discourse on osteoporosis prevention. In conclusion, this article offers a comprehensive overview of 137 positions of literature on the intricate interplay between phytoestrogens, estrogen metabolism, and bone health, shedding light on their potential significance in preventing osteoporosis and promoting overall well-being., (Copyright © 2024 American Society for Nutrition. Published by Elsevier Inc. All rights reserved.)

Alzheimer's disease (AD) is a long-term neurodegenerative condition that leads to the deterioration of neurons and synapses in the cerebral cortex, resulting in severe dementia. AD is significantly more prevalent in postmenopausal women, suggesting a neuroprotective role for estrogen. Estrogen is now known to regulate a wide array of physiological functions in the body by interacting with three known estrogen receptors (ERs) and with the β-amyloid precursor protein, a key factor in AD pathogenesis. Recent experimental evidence indicates that new selective ER modulators and phytoestrogens may be promising treatments for AD for their neuroprotective and anti-apoptotic properties. These alternatives may offer fewer side effects compared to traditional hormone therapies, which are associated with risks such as cardiovascular diseases, cancer, and metabolic dysfunctions. This review sheds light on estrogen-based treatments that may help to partially prevent or control the neurodegenerative processes characteristic of AD, paving the way for further investigation in the development of estrogen-based treatments.

The emergence of chronic diseases, particularly cancers, cardiovascular, and bone disorders, presents a formidable challenge, as currently available synthetic drugs often result in significant side effects and incur higher costs. Phytoestrogen Bavachin, present in the Psoralea corylifolia L. plant, represents structural and functional similarity to mammalian estrogen and has recently attracted researchers for its medicinal properties. This review spotlighted the extraction methods, bioavailability and therapeutic interventions of Bavachin against diseases. Bavachin exerted estrogenic properties, demonstrating the ability to bind to estrogen receptors (ERs), mimicking the actions of human estrogen and initiating estrogen-responsive pathways. Bavachin delivered potent therapeutic ventures in abrogating chronic diseases, including cancer, neuronal, bone, cardiovascular, skin, lung, and liver disorders via targeting signaling transductions, managing calcium signaling, immune regulation, inflammation, apoptosis, and oxidative stress. In-silico analysis, including Gene ontology and pathway enrichment analysis, retrieved molecular targets of Bavachin, majorly cytochrome c oxidase (COX), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), Nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3), and ER, hypothesizing Bavachin's cellular mechanism in preventing crucial health ailments. Limitations of Bavachin were also summarized, evidenced by hepatotoxicity at specific dosage levels. In conclusion, Bavachin showed promising therapeutic efficacy in suppressing chronic diseases and can be considered as an adequate replacement for hormone replacement therapy, necessitating further investigations on its effectiveness, safety, and clinical outcomes., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Two factors influencing female reproduction have been repeatedly studied in different animal species and humans, namely, 1. secondary plant compounds, especially phytoestrogens (mainly isoflavones (IFs)), and 2. the physical constitution/metabolic phenotype (e.g., obesity). So far, these research results have only been considered separately. In this study, we investigated the influence on reproduction of both phytochemicals, mainly dietary IFs, and the metabolic phenotype represented by three mouse models considered as three distinct genetic groups (a control group, a mouse model with high metabolic activity, and a mouse line with obese body weight). The IF content in different investigated standard chows with similar macronutrient profiles varied significantly ( p < 0.005), leading to high mean total plasma IF levels of up to 5.8 µmol/L in juvenile and 6.7 µmol/L in adult female mice. Reproductive performance was only slightly affected; only an IF dose-dependent effect on gestation length was observed in all genetic groups, as well as an effect on pregnancy rate in obese mice. Dietary IF exposure, however, caused earlier onset of vaginal opening by 4-10 days in juvenile mice ( p < 0.05), dependent on the genetic group, resulting in a slight acceleration of sexual maturation in the already precocious obese model and to a strong earlier maturation in the otherwise late-maturing sporty model, bred for high treadmill performance. Therefore, our results may help to draw the missing line between the effect of dietary secondary plant constituents, such as IFs, and metabolic phenotype on sexual development.

Peri-menopausal discomfort can have a detrimental effect on the physical health of women due to physiological and behavioral changes. Estrogen and progesterone-based hormone therapy can alleviate menopausal symptoms, but estrogen supplementation may have negative health effects. The effectiveness of hormone replacement therapy using natural compounds for peri-menopausal disorders is still uncertain. Evidence from in vivo experiments indicates that Ferula L. extract in ovariectomized rats leads to better sexual behavior. The effect seems to be linked to the phytoestrogenic properties of ferutinin, the primary bioactive compound in the extract. The purpose of this study was to assess the clinical impact of Ferula communis L. extract (titrated at 20% ferutinin, and given at doses of 100 mg/die for 90 days) on the quality of life of 64 menopausal women. The clinical trial was randomized, double-blind, and placebo controlled. Our data showed that Ferula communis L. extract reduced by 67 + 9% all symptoms associated to postmenopausal discomfort and enhanced significantly sexual behavior. In addition, the supplement led to a significant improvement of BMI and oxidative stress decrease in the women who received it, while also keeping platelet aggregation within normal levels. Overall, these results could point to the potential use of supplementation with Ferula communis L. extract to revert or mitigate menopause dysfunction.

Scope: The decline in estrogen during menopause contributes to a variety of menopausal symptoms, for which hormone replacement therapy (HRT) has been extensively applied. Regarding side effects and limited effectiveness of HRT for specific individuals, there is a growing interest in safe alternatives such as phytoestrogens which are structurally analogous to estrogens. This study aims to investigate the efficacy of yam and gromwell extracts, rich in bioactive compounds, and the synergistic effect of extracts on symptoms induced by estrogen deficiency in ovariectomized (OVX) mice., Methods and Results: OVX mice receive dietary intervention of either yam, gromwell extract, or their mixture for 14 weeks. Sham-operated mice and E2-injected OVX mice serve as positive controls. Following 14 weeks of oral administration, blood, adipose tissue, vagina, uterus, femurs, and tibias are harvested for further investigation. Consequently, yam and gromwell extracts ameliorate menopausal conditions such as weight gain, glucose intolerance, dyslipidemia, and osteoporosis in estrogen-deficient OVX mice. In addition, the mixture of yam and gromwell extracts synergistically aids in the relief of the indications., Conclusion: These results indicate the potential use of yam and gromwell extracts, as well as their mixture, for the development of healthy functional foods to modulate menopausal symptoms., (© 2024 Wiley‐VCH GmbH.)

Derris scandens , which contains isoflavones and prenylated derivatives, has analgesic and anti-inflammatory properties and is an ingredient in traditional Thai medicine for perimenopause and menopause. However, the estrogenic activity of D. scandens has not yet been explored. Therefore, this study aimed to examine the estrogenic activity of the stem extract of D. scandens and its isoflavone derivatives. In this study, we conducted a proliferation assay in MCF-7 cells, and used quantitative reverse transcription polymerase chain reaction to assess gene expression. We found that the relative cell proliferation of the compounds (1 µM) was ranked in the following order as compared to 0.1 nM 17 β -estradiol (100%): genistein (97.84%) > derrisisoflavone A (83.17%) > genistein-7- O -[ α -rhamnopyranosyl-(1 → 6)-glucopyranoside] (69.55%) > 6,8-diprenylgenistein (51.91%) > lupalbigenin (18.72%). Furthermore, cotreatment with 1 µM lupalbigenin and 0.1 nM 17 β -estradiol was performed, which decreased cell proliferation to 80.38%. In vitro results suggest that lupalbigenin has an estrogen-antagonistic effect. At a dose of 1 µM, genistein had the strongest efficacy in increasing the expression of human estrogen receptor β by 4.0-fold compared to the control. Furthermore, genistein-7- O -[ α -rhamnopyranosyl-(1 → 6)]- β -glucopyranoside augmented the gene expression of human estrogen receptor α and human estrogen receptor β by 1.5- and 3.4-fold, respectively. Prenylated derivatives of genistein (derrisisoflavone A, 6,8-diprenylgenistein, and lupalbigenin) significantly suppressed the gene expression of the human androgen receptor. The administration of the crude extract at 10 µg/mL significantly suppressed human androgen receptor (0.6-fold) and transmembrane protease serine 2 (0.1-fold) expression but did not significantly affect human estrogen receptor α and human estrogen receptor β gene expression. This herbal medicine may be safe for estrogen-exposed breast cancer patients., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Endothelial cells express multiple receptors mediating estrogen responses; including the G protein-coupled estrogen receptor (GPER). Past studies on nitric oxide (NO) production elicited by estrogens raised the question whether 17-β-estradiol (E2) and natural phytoestrogens activate equivalent mechanisms. We hypothesized that E2 and phytoestrogens elicit NO production via coupling to distinct intracellular pathways signalling. To this aim, perfusion of E2 and phytoestrogens to the precontracted rat mesentery bed examined vasorelaxation, while fluorescence microscopy on primary endothelial cells cultures quantified single cell NO production determined following 4-amino-5-methylamino-2',7'-difluoroescein diacetate (DAF) incubation. Daidzein (DAI) and genistein (GEN) induced rapid vasodilatation associated to NO production. Multiple estrogen receptor activity was inferred based on the reduction of DAF-NO signals; G-36 (GPER antagonist) reduced 75 % of all estrogen responses, while fulvestrant (selective nuclear receptor antagonist) reduced significantly more the phytoestrogens responses than E2. The joint application of both antagonists abolished the E2 response but not the phytoestrogen-induced DAF-NO signals. Wortmannin or LY-294002 (PI3K inhibitors), reduced by 90% the E2-evoked signal while altering significantly less the DAI-induced response. In contrast, H-89 (PKA inhibitor), elicited a 23% reduction of the E2-induced signal while blocking 80% of the DAI-induced response. Desmethylxestospongin-B (IP3 receptor antagonist), decreased to equal extent the E2 or the DAI-induced signal. Epidermal growth factor (EGF) induced NO production, cell treatment with AG-1478, an EGF receptor kinase inhibitor reduced 90% DAI-induced response while only 53% the E2-induced signals; highlighting GPER induced EGF receptor trans-modulation. Receptor functional selectivity may explain distinct signalling pathways mediated by E2 and phytoestrogens., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Plants from the Fabaceae family are widely distributed around the world, especially in Europe, Asia and North America. They are a rich source of isoflavones, compounds with estrogen-like activity, which are suspected of having a chemopreventive effect against hormone-dependent cancers. Following the PRISMA guidelines, we conducted a systematic review aimed at assessing the impact of Fabaceae plant extracts on hormone-dependent cancer cells and the content of active compounds in plant raw materials. We analyzed the results of 63 articles from in vitro and in vivo studies describing the effect of plant extracts containing isoflavones on cancer cells, along with their anti-inflammatory and antioxidant potential. In the process, we determined the research limitations and future research directions. The collected results indicate the plant species with potentially high contents of phytoestrogens and anti-inflammatory, antioxidant and cytotoxic properties. They point to the potential use of plants in the diet as a source of compounds offering cancer prevention.

Background: Cancer is one of the leading causes of death and a great threat to people around the world. Cancer treatment modalities include surgery, radiotherapy, chemotherapy, radiochemotherapy, hormone therapy, and immunotherapy. The best approach is to use a combination of several types. Among the treatment methods mentioned above, chemotherapy is frequently used, but its activity is hampered by the development of drug resistance and many side effects. In this regard, the use of medicinal plants has been discussed, and in recent decades, the use of isolated phytochemicals came into the focus of interest. By critically evaluating the available evidence and emphasizing the unique perspective offered by this review, we provide insights into the potential of daidzein as a promising therapeutic agent, as well as outline future research directions to optimize its efficacy in clinical settings., Purpose: To summarized the therapeutic potential of daidzein, an isoflavone phytoestrogen in the management of several human diseases with the focuses on the current status and future prospects as a therapeutic agent., Methods: Several search engines, including PubMed, GoogleScholar, and ScienceDirect, were used, with the search terms "daidzein", "daidzein therapeutic potential", or individual effects. The study included all peer-reviewed articles. However, the most recent publications were given priority., Results: Daidzein showed protective effects against malignant diseases such as breast cancer, prostate cancer but also non-malignant diseases such as diabetes, osteoporosis, and cardiovascular diseases. Daidzein activates multiple signaling pathways leading to cell cycle arrest and apoptosis as well as antioxidant and anti-metastatic effects in malignant cells. Moreover, the anticancer effects against different cancer cells were more prominent and discussed in detail., Conclusions: In short, daidzein represents a promising compound for drug development. The comprehensive potential anticancer activities of daidzein through various molecular mechanisms and its therapeutic/clinical status required further detail studies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier GmbH.)

Ethnopharmacological Relevance: Siwu decoction (SWD) is widely used in gynecological diseases, such as peripheral menopause syndrome, premature ovarian failure, and menstrual disorder. However, the mechanism of SWD on postmenopausal osteoporosis (PMOP) remains unclear., Aim of the Study: To discover the phytoestrogenic osteoprotective effect of SWD on PMOP., Materials and Methods: The potential mechanism of SWD on PMOP was filtered through network pharmacology research. The potential mechanism was verified in MC3T3-E1 cell lines in vitro. CCK8 assay was conducted to assess cell proliferation and the expressions of ER/PI3K/AKT pathway were analyzed using Western blot. Female F-344 rats were chosen to set up the PMOP model. The osteoprotective effect of SWD in vivo was evaluated using Hematoxylin-eosin staining, TRAP staining, Goldner staining and DXA. The potential mechanism was verified in vivo through Western blot and immunohistochemistry. RT-qPCR was conducted to unveil the expressions of osteogenesis genes., Results: Network pharmacology research showed that ER/PI3K/AKT pathway may be the potential mechanism of SWD on PMOP. SWD promoted the proliferation of osteoblasts and regulated the protein expressions of ER/PI3K/AKT pathway in vitro. SWD improved the morphological structure, bone mineralization and bone mineral density of femurs and suppressed osteoclastogenesis in PMOP rat model via ER/PI3K/AKT pathway in vivo. In addition, SWD regulated the mRNA expressions of osteogenesis-related genes., Conclusions: SWD exerts a phytoestrogenic osteoprotective on PMOP by regulating ER/PI3K/AKT pathway, which marks it as a valuable medicine or supplement of PMOP., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The phytoestrogens daidzein and genistein are ubiquitous in human food. This study aimed to elucidate their anxiety-liked effects, their effects on the reproductive organs, and the molecular mechanism behind any anxiety-liked effects in intact adult male Wistar rats. These phytoestrogens are of interest due to their posited health benefits, particularly for female, but with some effect on males as well. This study comprised two experiments: (1) Male Wistar rats received either a vehicle, daidzein, or genistein (0.25, 0.50, or 1.00 mg/kg) by subcutaneously injection for four weeks. They were then tested for anxiety-liked behaviors. Then, the brain monoamines in anxiolytic rats were determined; (2) The modulation of gamma aminobutyric acid receptors by phytoestrogens was further analyzed by administration of diazepam to phytoestrogen-treated rats before behavioral tests. In the first experiment, the biological parameters measured, including body weight, daily food intake and reproductive organ weights were unaffected by either genistein or daidzein. However, anxiolytic-like effect was observed in the low-dose daidzein (0.25 mg/kg) group. Higher doses of daidzein or genistein of all doses had no effect. Further, the low-dose daidzein did not alter brain monoamine levels. In the second experiment, the anxiolytic-like behavior of daidzein-treated rats receiving diazepam did not differ from that of the rats treated with just diazepam or just daidzein. In conclusion, 4-week exposure to daidzein or genistein had no negative effects on the reproductive organs, body weight, food intake, anxiogenic-like behavior, or monoaminergic and diazepam-modulated GABAergic neurotransmissions of intact male rats. However, beneficial anxiolytic-like effects were apparent after low-dose treatment with daidzein., Competing Interests: Declaration of Competing Interest Authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Osteoporosis is the most common metabolic bone disorder and is associated with a high incidence of fractures. Angiogenesis and adequate blood flow are important during bone repair and maintenance. Estrogens play a key role in bone formation, in the prevention of bone resorption and vasculature maintenance. Hormone replacement therapy (HRT) has been used with great benefits for bone fracture prevention but has been linked to the development of serious important side effects, including cancer and stroke. Phytoestrogens are an attractive alternative to HRT because their chemical structure is similar to estradiol but, they could behave as selective modulators: acting as antagonists of estrogen receptors in the breast and endometrium and as agonists in the vascular endothelium and bone. Hops contain a wide variety of phytoestrogens that have individually been shown to possess estrogenic activity by either blocking or mimicking. In this study we have to evaluate the in vitro effects and mechanisms of action of hops extracts on the osteogenic and adipogenic capacity of bone marrow progenitor cells (BMPCs), and the angiogenic potential of EA.hy926 endothelial cells. We show that hops extracts increase the proliferative capacity of BMPCs and promote their osteogenic differentiation while decreasing their pro-osteoclastogenic capacity; and that these effects are mediated by the MAPK pathway. Additionally, hops extracts prevent the adipogenic differentiation of BMPCs and promote endothelial cell activity, by mechanisms also partially mediated by MAPK., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier B.V. All rights reserved.)

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 (ERβ). Through this mechanism, phytoestrogens have a physiological function similar to that of the female hormone 17β-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 ERβ. 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 ERβ dimerization. The specific binding and functions of ERα and ERβ 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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Migraine is a widespread brain condition described by frequent, recurrent episodes of incapacitating, moderate-to-severe headaches with throbbing pain that are usually one-sided. It is the 2nd most debilitating state lived with disability in terms of years, with a prevalence rate of 15-20%. Significant drops in estrogen levels have been associated with triggering acute migraine attacks in certain cases. Phytoestrogens are plant-derived compounds that resemble estrogen in structure, enabling them to imitate estrogen's functions in the body by attaching to estrogen receptors. Thus, the study was aimed to explore the protective effect of genistein against migraine. Moreover, the role of nitric oxide was also studied in the observed effect of genistein. Nitric oxide (NO) is implicated in migraine pathophysiology due to its role in promoting cerebral vasodilation and modulation of pain perception. Exploring L-NAME, a nitric oxide synthase inhibitor in migraine research helps scientists better understand the role of NO in migraine. Nitroglycerine treatment significantly increased the facial-unilateral head pain and spontaneous pain, as evidenced by the increased number of head scratching and groomings. Nitroglycerine treatment also induced anxiogenic behavior in mice. A significant reduction in the number of entries in the light phase and open arm, respectively. Biochemical analysis indicated a significant increase in inflammatory and oxidative stress in the nitroglycerin group. A significant increase and decrease in brain TBARS and GSH were observed with nitroglycerine treatment, respectively. Moreover, nitroglycerine treatment has uplifted the serum TNF-α level. Genistein (20 mg/kg) significantly mitigated the facial-unilateral head pain, spontaneous pain, photophobia, and anxiety-like behavior induced by nitroglycerine. Biochemical analysis showed that genistein (20 mg/kg) significantly abrogated the nitroglycerine-induced lipid peroxidation and increased serum TNF-α level. Genistein treatment also upregulated the brain GSH level and downregulated the serum TNF-α level. The L-NAME-mediated alleviation of the protective effect of genistein might be attributed to the vasodilatory effect of L-NAME. Conclusively, it can be suggested that genistein might provide relief from migraine pain by inhibiting nitric oxide-mediated vasodilation and oxidative stress., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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., (© 2024 The Authors. Phytotherapy Research published by John Wiley & Sons Ltd.)

Drosophila melanogaster, or the fruit fly, is widely used for modeling numerous human diseases, such as neurodegeneration, tumor development, cachexia, and intestinal dysfunction. It is a suitable model organism for research targeting the physiology and pathophysiology of the intestinal epithelial barrier and has also been used as a model organism for preliminary drug and bioactive nutrient screening. However, the application of D. melanogaster in research on drug bioavailability and pharmacokinetic properties has not yet been well explored. In this study, we applied D. melanogaster to investigate the absorption and excretion of the orally administered phytoestrogens daidzein, glycitein, genistein, and their glycosides. Therefore, we established a quick, noninvasive method to quantify compound retention in D. melanogaster, suitable for the investigation of a broad variety of potentially bioactive substances. We showed that fruit fly sex plays a key role in the metabolization, transportation, and excretion of phytoestrogenic isoflavones. In particular, female fruit flies retained significantly more isoflavones than male fruit flies, which was reflected in the greater metabolic impact of isoflavones on females. Male fruit flies excreted more isoflavones than females did, which was linked to the upregulation of the xenobiotic transporter gene Mdr50. We also demonstrated that micellized isoflavones were more bioavailable than powdered isoflavones, independent of sex, age or the addition of dietary fibers., Competing Interests: Declaration of Competing Interest The authors declare the following competing interests: PM International AG provided support in the form of a salary for the author Markus Iken and the research materials containing isoflavones but did not have any additional role in the study. The authors declare that PM International AG had no role in the design of the study; in the collection, analysis, or interpretation of the data; in the writing of the manuscript; or in the decision to publish the results., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Cancer remains a significant challenge in the field of oncology, with the search for novel and effective treatments ongoing. Calycosin (CA), a phytoestrogen derived from traditional Chinese medicine, has garnered attention as a promising candidate. With its high targeting and low toxicity profile, CA has demonstrated medicinal potential across various diseases, including cancers, inflammation, and cardiovascular disease. Studies have revealed that CA possesses inhibitory effects against a diverse array of cancers. The underlying mechanism of action involves a reduction in tumor cell proliferation, induction of tumor cell apoptosis, and suppression of tumor cell migration and invasion. Furthermore, CA has been shown to enhance the efficacy of certain chemotherapeutic drugs, making it a potential component in treating malignant tumors. Given its high efficacy, low toxicity, and multi-targeting characteristics, CA holds considerable promise as a therapeutic agent for cancer treatment. The objective of this review is to present a synthesis of the current understanding of the antitumor mechanism of CA and its research progress., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Soybean is a source of protein, fibers, and phytochemical isoflavones which are considered to have numerous health benefits for children and adulthood. On the other hand, isoflavones are widely known as phytoestrogens that exert their action via the estrogen signaling pathway. With this regard, isoflavones are also considered as endocrine-disrupting chemicals. Endogenous estrogen plays a crucial role in brain development through binding to estrogen receptors (ERs) or G protein-coupled estrogen receptors 1 (GPER1) and regulates morphogenesis, migration, functional maturation, and intracellular metabolism of neurons and glial cells. Soy isoflavones can also bind to ERs, GPER1, and, furthermore, other receptors to modulate their action. Therefore, soy isoflavone consumption may affect brain development during the pre-and post-natal periods. This review summarizes the current knowledge on the mechanisms of isoflavone action, particularly in the early stages of brain development by introducing representative human, and animal models, and in vitro studies, and discusses their beneficial and adverse impact on neurobehavior. As a conclusion, the soy product consumption during the pre-and post-natal periods under proper range of dose showed beneficial effects in neurobehavior development, including improvement of anxiety, aggression, hyperactive behavior, and cognition, whereas their adverse effect by taking higher doses cannot be excluded. We also present novel research lines to further assess the effect of soy isoflavone administration during brain development.

Due to estrogen deficiency, postmenopausal women may suffer from an imbalance in bone metabolism that leads to bone fractures. Isoflavones, a type of phytoestrogen, have been suggested to improve bone metabolism and increase bone mass. Therefore, isoflavones are increasingly recognized as a promising natural alternative to hormone replacement therapy for postmenopausal women who face a heightened risk of osteoporosis and are susceptible to bone fractures., Purpose: This study aimed to evaluate the efficacy of isoflavone interventions on bone mineral density (BMD) in postmenopausal women by means of systematic review and meta-analysis., Methods: The electronic database searches were performed on PubMed, Embase, Scopus, and Cochrane Library databases, covering literature up to April 20, 2023. A random-effects model was used to obtain the main effect estimates, with a mean difference (MD) and its 95% confidence interval (CI) as the effect size summary. The risk of bias assessment was conducted using the Risk of Bias 2 (RoB2) tool., Results: A total of 63 randomized controlled trials comparing isoflavone interventions (n = 4,754) and placebo (n = 4,272) were included. The results indicated that isoflavone interventions significantly improved BMD at the lumbar spine (MD = 0.0175 g/cm 2 ; 95% CI, 0.0088 to 0.0263, P < 0.0001), femoral neck (MD = 0.0172 g/cm 2 ; 95% CI, 0.0046 to 0.0298, P = 0.0073), and distal radius (MD = 0.0138 g/cm 2 ; 95% CI, 0.0077 to 0.0198, P < 0.0001) in postmenopausal women. Subgroup analysis showed that the isoflavone intervention was effective for improving BMD when the duration was ≥ 12 months and when the intervention contained genistein of at least 50 mg/day., Conclusion: This systematic review and meta-analysis suggests that isoflavone interventions, especially those containing genistein of at least 50 mg/day, can effectively enhance BMD in postmenopausal women., (© 2023. International Osteoporosis Foundation and Bone Health and Osteoporosis Foundation.)

The estrous cycle is known to modify food, fluid, and electrolyte intake behaviors and energy homeostasis in various species, in part through fluctuations in estrogen levels. Simultaneously, commonly commercially available rodent dietary formulations greatly vary in soy protein content, and thereby the delivery of biologically active phytoestrogens. To explore the interactions among the estrous cycle, sodium, fluid, and caloric seeking behaviors, and energy homeostasis, young adult C57BL/6J female mice were maintained on a soy protein-free 2920x diet and provided water, or a choice between water and 0.15 mol/L NaCl drink solution. Comprehensive metabolic phenotyping was performed using a multiplexed Promethion (Sable Systems International) system, and estrous stages were determined via daily vaginal cytology. When provided food and water, estrous cycling had no major modulatory effects on intake behaviors or energy balance. When provided a saline solution drink choice, significant modulatory effects of the transition from diestrus to proestrus were observed upon fluid intake patterning, locomotion, and total energy expenditure. Access to saline increased total daily sodium consumption and aspects of energy expenditure, but these effects were not modified by the estrous stage. Collectively, these results indicate that when supplied a phytoestrogen-free diet, the estrous cycle has minor modulatory effects on ingestive behaviors and energy balance in C57BL/6J mice that are sensitive to sodium supply. NEW & NOTEWORTHY When provided a phytoestrogen-free diet, the estrous cycle had very little effect on food and water intake, physical activity, or energy expenditure in C57BL/6J mice. In contrast, when provided an NaCl drink in addition to food and water, the estrous cycle was associated with changes in intake behaviors and energy expenditure. These findings highlight the complex interactions among estrous cycling, dietary formulation, and nutrient presentation upon ingestive behaviors and energy homeostasis in mice.

Background: Phytoestrogens have been praised for their beneficial health effects, whereas synthetic xenoestrogens have been connected to ailments., Aims: To ascertain whether the toxicities of natural and synthetic estrogens differ, we examined the potent phytoestrogen 8-prenylnaringenin (8-PN), the common synthetic xenoestrogen tartrazine, and the physiological estrogen 17β-estradiol (E2)., Methods: These three compounds were tested for cytotoxicity, cell proliferation and genotoxicity in human HepG2 and rat H4IIE hepatoma cells., Results: All three estrogens elicited cytotoxicity at high concentrations in both cell lines. They also inhibited cell proliferation, with E2 being the most effective. They all tended to increase micronuclei formation., Conclusion: Natural estrogens were no less toxic than a synthetic one.

Estrogen receptors (ERs) are transcription factors with two subtypes: estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ), which are essential for the maintenance of human health and play a regulatory role in common diseases such as breast cancer, osteoporosis, neurodegenerative disorders, liver injuries and lung cancers. A number of phytochemicals extracted from various fruits and vegetables have been demonstrated to exhibit estrogenic effects and are termed phytoestrogens. As modulators of ERs, phytoestrogens can be involved in the prevention and treatment of multiple diseases as complementary or alternative therapeutic agents and have a variety of health benefits for humans. This article reviews the health benefits of phytoestrogens in clinical and epidemiologic studies for several diseases and also provides a detailed description of the molecular mechanisms of their action. A brief comparison of the advantages and disadvantages of natural phytochemicals compared to synthetic drugs is also presented. The role of phytoestrogens in the treatment of diseases and human health requires further research to fully realize their therapeutic potential.

Phytoestrogens are non-steroidal plant compounds, which bind to α and β estrogen receptors, thereby causing specific effects. The best-known group of phytoestrogens are flavonoids, including isoflavonoids-genistein and daidzein. They play a role in the metabolism of bone tissue, improving its density and preventing bone loss, which contributes to reducing the risk of fractures. Vitamin D is found in the form of cholecalciferol (vitamin D3) and ergocalciferol (vitamin D2) and is traditionally recognized as a regulator of bone metabolism. The aim of this review was to evaluate the synergistic effect of isoflavonoids and vitamin D on bone mineral density (BMD). The MEDLINE (PubMed), Scopus and Cochrane databases were searched independently by two authors. The search strategy included controlled vocabulary and keywords. Reference publications did not provide consistent data regarding the synergistic effect of isoflavonoids on BMD. Some studies demonstrated a positive synergistic effect of these compounds, whereas in others, the authors did not observe any significant differences. Therefore, further research on the synergism of isoflavonoids and vitamin D may contribute to a significant progress in the prevention and treatment of osteoporosis.

Genistein is a natural compound belonging to flavonoids, having antioxidant, anti-inflammatory, and anti-neoplastic properties. Genistein is considered a phytoestrogen. As such, genistein can bind estrogen receptors (ERα and ERβ), although with a lower affinity than that of estradiol. Despite considerable work, the effects of genistein are not well established yet. This review aims to clarify the role of genistein on female and male reproductive functions in mammals. In females, at a high dose, genistein diminishes the ovarian activity regulating several pathway molecules, such as topoisomerase isoform I and II, protein tyrosine kinases (v-src, Mek-4, ABL, PKC, Syk, EGFR, FGFR), ABC, CFTR, Glut1, Glut4, 5α-reductase, PPAR-γ, mitogen-activated protein kinase A, protein histidine kinase, and recently circulating RNA-miRNA. The effect of genistein on pregnancy is still controversial. In males, genistein exerts an estrogenic effect by inducing testosterone biosynthesis. The interaction of genistein with both natural and synthetic endocrine disruptors has a negative effect on testis function. The positive effect of genistein on sperm quality is still in debate. In conclusion, genistein has a potentially beneficial effect on the mechanisms regulating the reproduction of females and males. However, this is dependent on the dose, the species, the route, and the time of administration.

Genistein, a commonly occurring isoflavone, has recently gained popularity owing to its ever-expanding spectrum of pharmacological benefits. In addition to health benefits such as improved bone health and reduced postmenopausal complications owing to its phytoestrogen properties, it has been widely evaluated for its anti-cancer potential. Several studies have established the potential for its usage in the management of breast, lung, and prostate cancers, and its usage has significantly evolved from early applications in traditional systems of medicine. This review offers an insight into its current status of usage, the chemistry, and pharmacokinetics of the molecule, an exploration of its apoptotic mechanisms in cancer management, and opportunities for synergism to improve therapeutic outcomes. In addition to this, the authors have presented an overview of recent clinical trials, to offer an understanding of contemporary studies and explore prospects for a greater number of focused trials, moving forward. Advancements in the application of nanotechnology as a strategy to improve safety and efficacy have also been highlighted, with a brief discussion of results from safety and toxicology studies., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Phytoestrogens are xenoestrogens found in plants with a myriad of health benefits. However, various studies reported the genotoxic effects of these substances. Thus, we reviewed in vitro and in vivo studies published in PubMed, Scopus, and Web of Science to evaluate the genotoxic and the genoprotective potential of phytoestrogens. Only studies written in English and intended to study commercially available phytoestrogens were included. The screening was performed manually. Moreover, the underlying mechanism of action of phytoestrogens was described. Around half of those studies (43%) reported genoprotective results. However, several studies revealed positive results for genotoxicity with specific model organisms and with dose/concentration dependence. The assessment of the selected articles showed substantial differences in the used concentrations and a biphasic response was recorded in some phytoestrogens. As far as we know, this is the first study to assess the genotoxic and genoprotective effects of phytoestrogens systematically.

Icariin, a flavonoid glycoside derived from Epimedium brevicornum Maxim, exerts bone protective effects via estrogen receptors (ERs). This study aimed to investigate the role of ER-α66, ER-α36, and GPER in bone metabolism in osteoblasts following treatment with icariin. Human osteoblastic MG-63 cells and osteoblast-specific ER-α66 knockout mice were employed. The ERs crosstalk in the estrogenic action of icariin was evaluated in ER-α66-negative human embryonic kidney HEK293 cells. Icariin, like E2, regulated ER-α36 and GPER protein expression in osteoblasts by downregulating them and upregulating ER-α66. ER-α36 and GPER suppressed the actions of icariin and E2 in bone metabolism. However, the in vivo administration of E2 (2 mg/kg/day) or icariin (300 mg/kg/day) restored bone conditions in KO osteoblasts. ER-α36 and GPER expression increased significantly and rapidly activated and translocated in KO osteoblasts after treatment with E2 or icariin. ER-α36 overexpression in KO osteoblasts further promoted the OPG/RANKL ratio induced by E2 or icariin treatment. This study showed icariin and E2 elicit rapid estrogenic responses in bone through recruiting ER-α66, ER-α36, and GPER. Notably, in osteoblasts lacking ER-α66, ER-α36, and GPER mediate the estrogenic effects of icariin and E2, while in intact osteoblasts, ER-α36 and GPER act as negative regulators of ER-α66., (© 2023 John Wiley & Sons Ltd.)

Phytoestrogens are plant-derived bioactive compounds with estrogen-like properties. Their potential health benefits, especially in cancer prevention and treatment, have been a subject of considerable research in the past decade. Phytoestrogens exert their effects, at least in part, through interactions with estrogen receptors (ERs), mimicking or inhibiting the actions of natural estrogens. Recently, there has been growing interest in exploring the impact of phytoestrogens on osteosarcoma (OS), a type of bone malignancy that primarily affects children and young adults and is currently presenting limited treatment options. Considering the critical role of the estrogen/ERs axis in bone development and growth, the modulation of ERs has emerged as a highly promising approach in the treatment of OS. This review provides an extensive overview of current literature on the effects of phytoestrogens on human OS models. It delves into the multiple mechanisms through which these molecules regulate the cell cycle, apoptosis, and key pathways implicated in the growth and progression of OS, including ER signaling. Moreover, potential interactions between phytoestrogens and conventional chemotherapy agents commonly used in OS treatment will be examined. Understanding the impact of these compounds in OS holds great promise for developing novel therapeutic approaches that can augment current OS treatment modalities.

Isoflavenes have received the greatest research attention among the many groups of phytoestrogens. In this study, various isoflavene-based Mannich bases were selected for their theoretical studies. The purpose of this research was to discover the binding potential of all the designated Mannich bases acting as inhibitors against cancerous proteins EGFR, cMet, hTrkA, and HER2 (PDB codes: 5GTY, 3RHK, 6PL2, and 7JXH, respectively). For their virtual screening, DFT calculations and molecular docking studies were undertaken using in silico software. Docking studies predicted that ligands 5 and 15 exhibited the highest docking score by forming hydrogen bonds within the active pocket of protein 6PL2, ligands 1 and 15 both with protein 3RHK, and 7JXH, 12, and 17 with protein 5GTY. Rendering to the trends in polarizability and dipole moment, the energy gap values (0.2175 eV, 0.2106 eV) for the firm conformers of Mannich bases (1 and 4) replicate the increase in bioactivity and chemical reactivity. The energy gap values (0.2214 eV and 0.2172 eV) of benzoxazine-substituted isoflavene-based Mannich bases (9 and 10) reflect the increase in chemical potential due to the most stable conformational arrangements. The energy gap values (0.2188 eV and 0.2181 eV) of isoflavenes with tertiary amine-based Mannich bases (14 and 17) reflect the increase in chemical reactivity and bioactivity due to the most stable conformational arrangements. ADME was also employed to explore the pharmacokinetic properties of targeted moieties. This study revealed that these ligands have a strong potential to be used as drugs for cancer treatment.

The human gut is a host for trillions of microorganisms, divided into more than 3,000 heterogeneous species that is called the gut microbiota. The gut microbiota composition can be altered by many different endogenous and exogenous factors, especially diet and nutrition. A diet rich in phytoestrogens, a variable group of chemical compounds similar to 17-β-estradiol (E2), the essential female steroid sex hormone is potent to change the composition of gut microbiota. However, the metabolism of phytoestrogens also highly depends on the action of enzymes produced by gut microbiota. Novel studies have shown that phytoestrogens could play an important role in the treatment of different types of cancers, such as breast cancer in women, due to their potential to decrease estrogen levels. This review aims to summarize recent findings about the lively dialogue between phytoestrogens and gut microbiota and to address their possible future application, especially in treating patients with diagnosed breast cancer. A potential therapeutic approach for the prevention and improving outcomes in breast cancer patients could be based on targeted probiotic supplementation with the use of soy phytoestrogens. A positive effect of probiotics on the outcome and survival of patients with breast cancer has been established. However, more in vivo scientific studies are needed to pave the way for the use of probiotics and phytoestrogens in the clinical practice of breast cancer treatment., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Phytoestrogens are plant secondary metabolite that is structurally and functionally similar to mammalian estrogens, which have been shown to have various health benefits in humans. Isoflavones, coumestans, and lignans are the three major bioactive classes of phytoestrogens. It has a complicated mechanism of action involving an interaction with the nuclear estrogen receptor isoforms ERα and ERβ, with estrogen agonist and estrogen antagonist effects. Depending on their concentration and bioavailability in various plant sources, phytoestrogens can act as estrogen agonist or antagonists. Menopausal vasomotor symptoms, breast cancer, cardiovascular disease, prostate cancer, menopausal symptoms, and osteoporosis/bone health have all been studied using phytoestrogens as an additional standard hormone supplemental remedy. The botanical sources, techniques of identification, classification, side effects, clinical implications, pharmacological and therapeutic effects of their proposed mode of action, safety issues, and future directions for phytoestrogens have all been highlighted in this review., (© 2023 John Wiley & Sons Ltd.)

Rutin has been reported as a potential anti-cancer agent for several decades. This study evaluated the effects of rutin on the proliferation, metastasis, and angiogenesis of MDA-MB-231 and MCF-7 breast cancer cell lines. Increasing concentrations of rutin significantly stimulated the proliferation of MDA-MB-231 and MCF-7 cells compared to controls. Wound scratch assay demonstrated that rutin had an inducing effect on the migration of the cells. In MDA-MB-231 and MCF-7 cells, rutin upregulated MKI67, VIM, CDH2, FN1, and VEGFA and downregulated CDH1 and THBS1 genes. It also increased N-cadherin and VEGFA and decreased E-cadherin and thrombospondin 1 protein expression. Our data indicated that rutin could stimulate proliferation, migration, and pro-angiogenic activity in two different breast cancer cell lines. This phytoestrogen induced invasion and migration of both cell lines by a mechanism involving the EMT process. This suggests that rutin may act as a breast-cancer-promoting phytoestrogen.

Ethnopharmacological Relevance: Dementias including Alzheimer disease (AD) are three times higher in menopausal women than in men. Phytoestrogens, a group of plant-derived compounds are known to alleviate menopausal complaints including dementia. Millettia griffoniana Baill is a phytoestrogen-rich plant used to treat menopausal complaints and dementia., Aim: Evaluating the estrogenic and neuroprotective potential of Millettia griffoniana on ovariectomized (OVX) rats., Materials and Methods: The in vitro safety of M. griffoniana ethanolic extract was assayed by MTT in human mammary epithelial (HMEC) and mouse neuronal (HT-22) cells and its lethal dose 50 (LD 50 ) was estimated following OECD 423 guidelines. For estrogenicity, in vitro the well known E-screen assay on MCF-7 cells was performed and in vivo four groups of OVX rats were treated either with 75, 150 and 300 mg/kg M. griffoniana extract doses or estradiol (1 mg/kg BW) for three days; and changes in uterine and vagina were analyzed. Then, for neuroprotective effect, Alzheimer-type dementia induction was achieved by scopolamine (1.5 mg/kg B.W., i.p.) injection four days/week and M. griffoniana extract as well as piracetam (standard) were administered daily for 2 weeks to evaluate the extract's neuroprotective potential. The endpoints were the assessment of learning and working memory, oxidative stress state (SOD, CAT, and MDA) in brain, acetylcholine esterase (AChE) activity and the histopathological changes in hippocampus., Results: No toxic effect was observed when incubating mammary (HMEC) and neuronal (HT-22) cells with M. griffoniana ethanol extract for 24 h and its LD 50 was found >2000 mg/kg. The extract also exhibited both in vitro and in vivo estrogenic activities, displayed by a significant (p < 0.01) increment in MCF-7 cells population in vitro and an increase in the epithelium height of the vagina and the wet weight of the uterus mainly with the 150 mg/kg BW extract dose compared to untreated OVX rats. The extract also reversed scopolamine-induced memory impairment in rat by improving learning, working and reference memory. This was associated with an increment in CAT and SOD expression, alongside a decrement in MDA content and AChE activity in hippocampus. Further, the extract reduced neuronal cell loss in hippocampal structures (CA1, CA3 and dentate gyrus). High Performance Liquid Chromatography coupled with Mass Spectrometry (HPLC-MS) spectra, revealed the presence of numerous phytoestrogens in M. griffoniana extract., Conclusion: M. griffoniana ethanolic extract has estrogenic, anticholinesterase and antioxidant activities that could account for its anti-amnesic effects. These findings therefore sheds light on why this plant is commonly used in the therapy of menopausal complaints and dementia., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: The fruit of Kadsura coccinea (Lem.) A. C. Smith is an ethnomedicine used to treat abnormal menstruation, menopausal syndrome, and female infertility among the Dong Nationality in China., Aim of the Study: Our study aimed to identify the volatile oil profiles of the K. coccinea fruit and elucidate their estrogenic activity., Materials and Methods: The peel volatile oil (PeO), pulp volatile oil (PuO), and seed volatile oil (SeO) of K. coccinea were extracted using hydrodistillation and qualitatively analyzed using gas chromatography-mass spectrometry (GC-MS). Estrogenic activity was evaluated in vitro using cell assay and in vivo using immature female rats. Serum 17β-Estradiol (E2) and follicle-stimulating hormone (FSH) levels were detected using ELISA., Results: In total, 46 PeO, 27 PuO, and 42 SeO components representing 89.96%, 90.19%, and 97% of the total composition, respectively, were identified. The compounds with the highest content in PeO, PuO, and SeO were β-caryophyllene, γ-amorphene, and n-hexadecanoic acid, respectively. PeO induced proliferation of MCF-7 cells with an EC 50 of 7.40 μg/mL. Subcutaneous administration of 10 mg/kg PeO significantly increased the weight of the uteri in immature female rats, with no effect on serum E2 and FSH levels. PeO acted as an agonist of ERα and ERβ. PuO and SeO showed no estrogenic activity., Conclusion: The chemical compositions of PeO, PuO, and SeO of K. coccinea are different. PeO is the main effective fraction for estrogenic activities, providing a new source of phytoestrogen for the treatment of menopausal symptoms., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Genistein (GEN) is a non-steroidal phytoestrogen that belongs to the isoflavone class. It is abundantly found in soy. Soy and its products are used as food components in many countries including India. The present review is focused to address roles of GEN in brain functions in the context of learning and memory as a function of aging and neurological disorders. Memory decline is one of the most disabling features observed during normal aging and age-associated neurodegenerative disorders namely Alzheimer's disease (AD) and Parkinson's disease (PD), etc. Anatomical, physiological, biochemical and molecular changes in the brain with advancement of age and pathological conditions lead to decline of cognitive functions. GEN is chemically comparable to estradiol and binds to estrogen receptors (ERs). GEN acts through ERs and mimics estrogen action. After binding to ERs, GEN regulates a plethora of brain functions including learning and memory; however detailed study still remains elusive. Due to the neuroprotective, anti-oxidative and anti-inflammatory properties, GEN is used to restore or improve memory functions in different animal models and humans. The present review may be helpful to understand roles of GEN in learning and memory during aging and neurological disorders, its direction of research and therapeutic perspectives., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

Neurodegenerative disorders are heterogeneous, debilitating, and incurable groups of brain disorders that have common features including progressive degeneration of the structure and function of the nervous system. Phytoestogenic-isoflavones have been identified as active compounds that can modulate different molecular signaling pathways related to the nervous system. The main aim is to shed the light on the molecular mechanisms followed by phytoestrogen-isoflavones profound in the Trifolium pratense and discuss the latest pharmacological findings in the treatment of neurodegenerative disorders. Data were collected using different databases. The search terms used included "Phytoestrogens," "Isoflavones," "neurodegenerative disorders," "Neuronal plasticity," etc., and combinations of these keywords. As a result, this review article mainly demonstrates the potential neuroprotective properties of phystoestrogen-isoflavones present in the Trifolium pratense (Red clover), particularly in neurodegenerative disorders. Phytochemical studies have shown that Trifolium pratense mainly includes more than 30 isoflavone compounds. Among them, phytoestrogen-isoflavones, such as biochanin A, daidzein, formononetin, genistein (Gen), etc.,are characterized by potent neuroprotective properties against different neurodegenerative disorders. There are preclinical and clinical scientific evidence on their mechanisms of action involve molecular interaction with estrogenic receptors, anti-inflammatory, anti-oxidative, antiapoptotic, autophagic inducing, and so on. phytoestrogen-isoflavones are the major bioactive components in the Trifolium pratense that exhibit therapeutic efficacy in the case of neurodegenerative disorders. This review provides detailed molecular mechanisms targeted by phytoestrogen-isoflavones and experimental key findings for the clinical use of prescriptions containing Trifolium pratense-derived isoflavones for the treatment of neurodegenerative disorders., (© 2023 John Wiley & Sons Ltd.)

The calyxes of Hibiscus sabdariffa present multiple pharmacological effects primarily attributed to their high anthocyanin content; however, little is known about their phytoestrogenic effect. Ovarian hypofunction (OH) is a process characterized by the rapid detention of the production of ovarian hormones, which compromises reproductive and cognitive functions. Hormone replacement therapy (HRT) efficiently compensates for OH; nevertheless, questions have been raised on its secondary effects and safety. One of the alternatives to tackling OH involves using phytoestrogens such as anthocyanins for their structural similarity to natural estrogens. In a Wistar rat model of ovariectomy (OVX), we recently reported the beneficial properties of an anthocyanin-rich extract prepared from the calyces of H. sabdariffa (HSE) in hindering the adverse effects of OH on memory performance and highlighted a possible phytoestrogenic impact through the modulation of estrogen receptor (ER) expression. We now report that HSE and estradiol differentially affected the expression of ERα and ERβ. ERα was more sensitive to HSE; meanwhile, estradiol preferentially modulated ERβ. Thus, our study leads to further research on using H. sabdariffa as a nutrition-based alternative to HRT., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The main task of targeted therapy is the selective destruction of cancer cells without affecting normal ones. For these purposes, small molecules and antibodies are used that target specific receptors and proteins or block signaling pathways in tumor cells. The natural phytoestrogens daidzein (Dz) and genistein (Gn) possess binding capacity to estrogen receptors (ER). Methionine γ-lyase (MGL) is promising in two strategies of antitumor therapy: for the elimination of l-methionine, which is necessary for the proliferation of tumor cells, and for the production of cytotoxic dialkyl thiosulfinates in situ. For delivery of MGL-loaded nanocapsules (nanoreactors) to the surface of cancer cells a technique for Dz or Gn incorporation into the shell of polyionic vesicles (PICsomes) was developed. The nanoreactors were characterized by dynamic light scattering and transmission electron microscopy. The enzyme retained its catalytic efficiency inside the decorated PICsomes. The binding of Dz/Gn-nanoreactors to the surface of ER + MCF7 breast adenocarcinoma cells was demonstrated. For the first time an influence of enzyme-loaded PICsomes and their individual components on embryos development was evaluated. The high rate of blastocysts formation (>80%) was observed for all tested components and nanoreactors themselves. A strong inhibitory effect on the early embryonic development of MGL-loaded PICsomes in the presence of S-alkyl-l-cysteine sulfoxide substrates was showed. This proves that the substrates can freely penetrate through the polymer shell of the polyionic vesicle and are cleaved by MGL to form cytotoxic thiosulfinates. The data obtained for phytoestrogens decorated PICsomes may be applied in enzyme therapy of malignant tumors., Competing Interests: Declaration of competing interest The authors declare no competing financial interest., (Copyright © 2023 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.)

Ethnopharmacological Relevance: Selaginella moellendorffii (SM) has been applied as an ethnic drug to treat conditions such as osteoporosis, idiopathic thrombocytopenic purpura, and chronic inflammation. It is known to be rich in flavonoids, including apigenin glycosides and unique elements of bioflavonoids., Aim of the Study: To investigate estrogen-like constituents of SM and the possible mechanism., Materials and Methods: We identified the main components in liquid chromatography and liquid chromatography-mass spectrometry. The estrogenic effects were examined using a recombinant yeast screening assay, an E-screen cell proliferation assay, and an in vivo uterotrophic assay., Results: Flavonoid glycosides extract, some flavonoid glycosides, and apigenin showed estrogen agonistic activity in the yeast screening assay. They also induced cell proliferation in estrogen receptor-positive (ER+) cells but not in estrogen receptor-negative (ER-) cells. Consistently, the protein expression of ERα, phosphorylation protein kinase B (p-AKT), phosphatidylinositol 3 kinase (PI3K), phosphorylation mammalian target of rapamycin (p-mTOR), phosphorylation 38,000-Da protein (p-P38), and phosphorylation extracellular-regulated kinase 1/2 (p-ERK1/2) elevated following treatment with flavonoid glycoside extract (P < 0.01 or P < 0.05). These effects could be blocked by ER antagonist or ERα antagonist but not be blocked by ERβ antagonist. In vivo assay, flavonoid glycoside extract could significantly increase body weight, serum estradiol level, uterine wet weight, alter uterine morphology, and promote ERα protein expression (P < 0.01 or P < 0.05)., Conclusions: ERα induction via mitogen-activated protein kinases (MAPK) and PI3K/Akt/mTOR pathways might be the possible mechanism underlying the phytoestrogen effect of SM, and the flavonoid glycosides might be the critical estrogenic constituents., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

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., Competing Interests: Declaration of competing interest The authors report no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

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.

Calcium-selective oncochannel TRPV6 is the major driver of cell proliferation in human cancers. While significant effort has been invested in the development of synthetic TRPV6 inhibitors, natural channel blockers have been largely neglected. Here we report the structure of human TRPV6 in complex with the plant-derived phytoestrogen genistein, extracted from Styphnolobium japonicum, that was shown to inhibit cell invasion and metastasis in cancer clinical trials. Despite the pharmacological value, the molecular mechanism of TRPV6 inhibition by genistein has remained enigmatic. We use cryo-EM combined with electrophysiology, calcium imaging, mutagenesis, and molecular dynamics simulations to show that genistein binds in the intracellular half of the TRPV6 pore and acts as an ion channel blocker and gating modifier. Genistein binding to the open channel causes pore closure and a two-fold symmetrical conformational rearrangement in the S4-S5 and S6-TRP helix regions. The unprecedented mechanism of TRPV6 inhibition by genistein uncovers new possibilities in structure-based drug design., (© 2023. The Author(s).)

Soybean is the most economically important legume globally, providing a major source of plant protein for millions of people; it offers a high-quality, cost-competitive and versatile base-protein ingredient for plant-based meat alternatives. The health benefits of soybean and its constituents have largely been attributed to the actions of phytoestrogens, which are present at high levels. Additionally, consumption of soy-based foods may also modulate gastrointestinal (GI) health, in particular colorectal cancer risk, via effects on the composition and metabolic activity of the GI microbiome. The aim of this narrative review was to critically evaluate the emerging evidence from clinical trials, observational studies and animal trials relating to the effects of consuming soybeans, soy-based products and the key constituents of soybeans (isoflavones, soy proteins and oligosaccharides) on measures of GI health. Our review suggests that there are consistent favourable changes in measures of GI health for some soy foods, such as fermented rather than unfermented soy milk, and for those individuals with a microbiome that can metabolise equol. However, as consumption of foods containing soy protein isolates and textured soy proteins increases, further clinical evidence is needed to understand whether these foods elicit similar or additional functional effects on GI health.

While endocrine therapy is considered as an effective way to treat breast cancer, it still faces many challenges, such as drug resistance and individual discrepancy. Therefore, novel preventive and therapeutic modalities are still in great demand to decrease the incidence and mortality rate of breast cancer. Numerous studies suggested that G protein-coupled estrogen receptor (GPER), a membrane estrogen receptor, is a potential target for breast cancer prevention and treatment. It was also shown that not only endogenous estrogens can activate GPERs, but many phytoestrogens can also function as selective estrogen receptor modulators (SERMs) to interact GPERs. In this review, we discussed the possible mechanisms of GPERs pathways and shed a light of developing novel phytoestrogens based dietary supplements against breast cancers., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Masson SAS.)

In Brief: Dietary phytoestrogens disrupt a specific stage of ram spermatogenesis, causing subtle decreases in sperm quality by affecting the expression of pathways involved in the structural integrity of the spermatozoa. This paper demonstrates for the first time that ram reproduction is compromised by oestrogenic pasture, whilst also providing a longitudinal model for the impact of phytoestrogens on male fertility., Abstract: Compounds with oestrogen-like actions are now common in both the Western diet. The long-term impacts and underlying mechanisms by which oestrogenic compounds alter male reproduction, however, are unclear. To investigate this, we used a longitudinal sheep model examining the impact of oestrogenic pasture consumption on semen quality and production, testicular size, sexual behaviour and the seminal plasma proteome of Merino rams (n = 20), over a full spermatogenic cycle and in the subsequent breeding season. Throughout the study period, sexual behaviour, sperm production and motility were similar between the exposed and non-exposed rams (P > 0.05). However, between 5 and 8 weeks of exposure to dietary phytoestrogens, rams produced a higher percentage of spermatozoa with a specific malformation of the sperm midpiece and reduced DNA integrity, compared to non-exposed rams (P < 0.001). Investigation into the seminal plasma proteome revealed 93 differentially expressed proteins between phytoestrogen-exposed and control rams (P < 0.05). Exposure to phytoestrogens increased the expression of proteins involved in cellular structure development, actin cytoskeleton reorganisation, regulation of cell function and decreased expression in those related to catabolic processes. The greatest fold changes were in proteins involved in the assembly of the sperm flagella, removal of cytoplasm, spermatid development and maintenance of DNA integrity. After returning to non-oestrogenic pasture, no differences in any measure were observed between treatment groups during the subsequent breeding season. We conclude that dietary phytoestrogens can transiently disrupt specific stages of ram spermatogenesis, causing subtle decreases in sperm quality by affecting the expression of pathways involved in the structural integrity of the spermatozoa.

Phytoestrogens play pivotal roles in controlling not only the endocrine system but also inflammatory metabolic disorders. However, the effects of dietary phytoestrogens on allergic diseases and underlying mechanisms remain unclear. In this study, we revealed the unique metabolic conversion of phytoestrogen to exert anti-allergic properties, using an ovalbumin-induced allergic rhinitis mouse model. We found that dietary secoisolariciresinol diglucoside (SDG), a phytoestrogen abundantly present in flaxseed, alleviated allergic rhinitis by the microbial conversion to enterodiol (ED). We also found that ED circulated mainly in the glucuronide form (EDGlu) in blood, and deconjugation of EDGlu to ED aglycone occurred in the nasal passage; this activity was enhanced after the induction of allergic rhinitis, which was mediated by β-glucuronidase. We further found that IgE-mediated degranulation was inhibited by ED aglycone, but not by EDGlu, in a G protein-coupled receptor 30 (GPR30)-dependent manner. These results provide new insights into the anti-allergic properties of phytoestrogens and their metabolism in vivo for the development of novel therapeutic strategies against allergic rhinitis., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Backgroud: Estrogen deficiency is the leading cause of postmenopausal osteoporosis(PMOP) and phytoestrogens soy isoflavones (SI) have been shown to improve PMOP. Equol (Eq), an in vivo metabolite of phytoestrogens soy isoflavones (SI), has a more stable structure and stronger biological activity than its parent compound and has the greatest estrogenic activity. However, there are few studies on the therapeutic effect of Eq on PMOP., Purpose: To explore the therapeutic effect and mechanisms of Eq on POMP., Methods: Osteoblast-like cells ROS1728 were cultured with different doses of Eq, estradiol (E2), separately. The effect of Eq on the proliferation, apoptosis, cell cycle of osteoblasts were detected by CCK-8 and flow cytometry, and the expression of OPG/RANK/RANKL signaling pathway of osteoblasts was detected by Quantitative real-time PCR (qRT-PCR) and Western blot (WB), and RNA silencing technology were carried out to explore the receptors through which Eq plays a role. Then PMOP rat model was established and treated by Eq or E2 to further verification of the effect and mechanism of Eq on PMOP., Result: Eq promoted the proliferation and inhibited the apoptosis of osteoblasts and increased the proportion of osteoblasts in the S phase and G2/M phase in a dose-dependent manner. Mechanistically, Eq treatment upregulated the expression of OPG and OPG/RANKL ratio in osteoblasts and this regulatory effect was mainly mediated through the ERβ receptor. Furthermore, in vivo study, Eq improved microstructure and BMD of the femur of PMOP rat model, which imitated the osteoprotective effect of E2. Moreover, the Eq or E2 treatment increased serum levels of Ca, 1,25(OH)2D3, bone Gla-protein(BGP), and Type I procollagen (PC1), and reduced serum levels of phosphorus (P), parathyroid hormone(PTH), pyridinol (PYD), tartrate-resistant acid phosphatase (TRAP) and urinary level of deoxypyridinoline (DPD) in the treatment OVX group compared with the untreated OVX group. Meanwhile, Eq or E2 markedly induced the mRNA and protein expression of OPG and OPG/RANKL ratio., Conclusion: Eq can combine with ERβ and exert a protective effect on PMOP by upregulating OPG/RANKL pathway., Competing Interests: Declarations of interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Radiation for medical use is a well-established therapeutic method with an excellent prognosis rate for various cancer treatments. Unfortunately, a high dose of radiation therapy comes with its own share of side effects, causing radiation-induced non-specific cellular toxicity; consequently, a large percentage of treated patients suffer from chronic effects during the treatment and even after the post-treatment. Accumulating data evidenced that radiation exposure to the brain can alter the diverse cognitive-related signaling and cause progressive neurodegeneration in patients because of elevated oxidative stress, neuroinflammation, and loss of neurogenesis. Epidemiological studies suggested the beneficial effect of hormonal therapy using estrogen in slowing down the progression of various neuropathologies. Despite its primary function as a sex hormone, estrogen is also renowned for its neuroprotective activity and could manage radiation-induced side effects as it regulates many hallmarks of neurodegenerations. Thus, treatment with estrogen and estrogen-like molecules or modulators, including phytoestrogens, might be a potential approach capable of neuroprotection in radiation-induced brain degeneration. This review summarized the molecular mechanisms of radiation effects and estrogen signaling in the manifestation of neurodegeneration and highlighted the current evidence on the phytoestrogen mediated protective effect against radiationinduced brain injury. This existing knowledge points towards a new area to expand to identify the possible alternative therapy that can be taken with radiation therapy as adjuvants to improve patients' quality of life with compromised cognitive function., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)