Chronic disease management via modulation of cellular signaling by phytoestrogen Bavachin.

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.

Genistein mitigates nitroglycerine-induced migraine: modulation of nitric oxide-mediated vasodilation and oxidative stress.

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.

Estrogen receptor ß and treatment with a phytoestrogen are associated with inhibition of nuclear translocation of EGFR in the prostate.

Knockout of ERß in the mouse leads to nuclear expression of epidermal growth factor receptor (EGFR) in the prostate. To examine whether ERß plays a similar role in the human prostate, we used four cohorts of men: 1) a Swedish cohort of normal prostates and PCa (prostate cancer) of different Gleason grades; 2) men with benign prostatic hyperplasia (BPH) treated with the 5α-reductase inhibitor, finasteride, and finasteride together with the ERß agonists, soy isoflavones; 3) men with PCa above Gleason grade 4 (GG4), treated with ADT (androgen deprivation therapy) and abiraterone (AA), the blocker of androgen synthesis for different durations; and 4) men with GG4 PCa on ADT or ADT with the AR (androgen receptor) blocker, enzalutamide, for 4 mo to 6 mo. In men with BPH, finasteride treatment induced EGFR nuclear expression, but, when finasteride was combined with isoflavones, EGFR remained on the cell membrane. In GG4 patients, blocking of AR for 4 mo to 6 mo resulted in loss of ERß and PTEN expression and increase in patients with nuclear EGFR from 10 to 40%. In the men with GG4 PCa, blocking of adrenal synthesis of testosterone for 2 mo to 7 mo had the beneficial effect of increasing ERß expression, but, on treatment longer than 8 mo, ERß was lost and EGFR moved to the nucleus. Since nuclear EGFR is a predictor of poor outcome in PCa, addition of ERß agonists together with abiraterone should be considered as a treatment that might sustain expression of ERß and offer some benefit to patients.

Estrogen Receptors: A New Frontier in Alzheimer's Disease Therapy.

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 ß-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.

Molecular mechanisms underlying the potential neuroprotective effects of Trifolium pratense and its phytoestrogen-isoflavones in neurodegenerative disorders.

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.

A review on phytoestrogens: Current status and future direction.

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 ERß, 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.

Phytoestrogen-Based Hormonal Replacement Therapy Could Benefit Women Suffering Late-Onset Asthma.

It has been observed that plasmatic concentrations of estrogens, progesterone, or both correlate with symptoms in asthmatic women. Fluctuations in female sex steroid concentrations during menstrual periods are closely related to asthma symptoms, while menopause induces severe physiological changes that might require hormonal replacement therapy (HRT), that could influence asthma symptoms in these women. Late-onset asthma (LOA) has been categorized as a specific asthmatic phenotype that includes menopausal women and novel research regarding therapeutic alternatives that might provide relief to asthmatic women suffering LOA warrants more thorough and comprehensive analysis. Therefore, the present review proposes phytoestrogens as a promising HRT that might provide these females with relief for both their menopause and asthma symptoms. Besides their well-recognized anti-inflammatory and antioxidant capacities, phytoestrogens activate estrogen receptors and promote mild hormone-like responses that benefit postmenopausal women, particularly asthmatics, constituting therefore a very attractive potential therapy largely due to their low toxicity and scarce side effects.

Multi-Anticancer Activities of Phytoestrogens in Human Osteosarcoma.

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.

Influence of phytoestrogens on endometrial thickness: a systematic review and meta-analysis.

The objective of this systematic review was to evaluate the influence of the use of phytoestrogens on variations in endometrial thickness in postmenopausal women. Randomized controlled trials were searched in the following electronic databases until March 2020: MEDLINE, Embase, Cochrane Library, Web of Science and LILACS. We used the terms 'phytoestrogens' and 'endometrium' or 'endometrial hyperplasia' to search for relevant trials. The data were analyzed using RevMan 5.3 software. A total of 10 studies involving 1476 patients were included. The difference in endometrial thickness was evaluated in 10 studies, with a total of 805 participants in the phytoestrogen group and 761 in the control group. Such a difference was not significant between groups after 3 months (standardized mean difference [SMD] 0.00, 95% confidence interval [CI] - 0.37 to 0.37; I2 = 63%), 6 months (SMD -0.30, 95% CI -0.79 to 0.19; I2 = 70%), 12 months (SMD -0.02, 95% CI 0.22 to -0.18; I2 = 0%) and 24 months (SMD -0.09, 95% CI -0.25, 0.08; I2 = 0%) of use. Our meta-analysis shows no changes in endometrial thickness in women using phytoestrogens. Evidence is still uncertain owing to the presence of heterogeneity among the studies currently available, whose reported outcomes cover a period between 3 and 6 months.

Targeting Breast Cancer Stem Cells Using Naturally Occurring Phytoestrogens.

Breast cancer therapies have made significant strides in improving survival for patients over the past decades. However, recurrence and drug resistance continue to challenge long-term recurrence-free and overall survival rates. Mounting evidence supports the cancer stem cell model in which the existence of a small population of breast cancer stem cells (BCSCs) within the tumor enables these cells to evade conventional therapies and repopulate the tumor, giving rise to more aggressive, recurrent tumors. Thus, successful breast cancer therapy would need to target these BCSCs, as well the tumor bulk cells. Since the Women's Health Initiative study reported an increased risk of breast cancer with the use of conventional hormone replacement therapy in postmenopausal women, many have turned their attention to phytoestrogens as a natural alternative. Phytoestrogens are plant compounds that share structural similarities with human estrogens and can bind to the estrogen receptors to alter the endocrine responses. Recent studies have found that phytoestrogens can also target BCSCs and have the potential to complement conventional therapy eradicating BCSCs. This review summarized the latest findings of different phytoestrogens and their effect on BCSCs, along with their mechanisms of action, including selective estrogen receptor binding and inhibition of molecular pathways used by BCSCs. The latest results of phytoestrogens in clinical trials are also discussed to further evaluate the use of phytoestrogen in the treatment and prevention of breast cancer.

Naringenin and Phytoestrogen 8-Prenylnaringenin Protect against Islet Dysfunction and Inhibit Apoptotic Signaling in Insulin-Deficient Diabetic Mice.

It has been shown that citrus flavanone naringenin and its prenyl derivative 8-prenylnaringenin (8-PN) possess various pharmacological activities in in vitro and in vivo models. Interestingly, it has been proposed that prenylation can enhance biological potentials, including the estrogen-like activities of flavonoids. The objective of this study was to investigate the anti-diabetic potential and molecular mechanism of 8-PN in streptozotocin (STZ)-induced insulin-deficient diabetic mice in comparison with naringenin reported to exhibit hypoglycemic effects. The oral administration of naringenin and 8-PN ameliorated impaired glucose homeostasis and islet dysfunction induced by STZ treatment. These protective effects were associated with the suppression of pancreatic ß-cell apoptosis and inflammatory responses in mice. Moreover, both naringenin and 8-PN normalized STZ-induced insulin-signaling defects in skeletal muscles and apoptotic protein expression in the liver. Importantly, 8-PN increased the protein expression levels of estrogen receptor-α (ERα) in the pancreas and liver and of fibroblast growth factor 21 in the liver, suggesting that 8-PN could act as an ERα agonist in the regulation of glucose homeostasis. This study provides novel insights into the mechanisms underlying preventive effects of naringenin and 8-PN on the impairment of glucose homeostasis in insulin-deficient diabetic mice.

Roles of Phytoestrogen in the Pathophysiology of Intracranial Aneurysm.

Background and Purpose: The incidences of intracranial aneurysm and aneurysmal subarachnoid hemorrhage are high in postmenopausal women. Although population-based studies suggest that hormone replacement therapy is beneficial for postmenopausal women with intracranial aneurysms, estrogen replacement may no longer be recommended for the prevention of chronic diseases given its association with adverse outcomes, such as cancer and ischemic stroke. The isoflavone daidzein and its intestinal metabolite equol are bioactive phytoestrogens and potent agonists of estrogen receptors. Given their estrogenic properties, we investigated whether the isoflavones daidzein and equol are protective against the formation and rupture of intracranial aneurysms in a mouse model of the postmenopausal state. Methods: We induced intracranial aneurysms in ovariectomized adult female mice using a combination of induced systemic hypertension and a single injection of elastase into the cerebrospinal fluid. We fed the mice with an isoflavone-free diet with/without daidzein supplementation, or in a combination of intraperitoneal equol, or oral vancomycin treatment. We also used estrogen receptor beta knockout mice. Results: Both dietary daidzein and supplementation with its metabolite, equol, were protective against aneurysm formation in ovariectomized mice. The protective effects of daidzein and equol required estrogen receptor-ß. The disruption of the intestinal microbial conversion of daidzein to equol abolished daidzein's protective effect against aneurysm formation. Mice treated with equol had lower inflammatory cytokines in the cerebral arteries, suggesting that phytoestrogens modulate inflammatory processes important to intracranial aneurysm pathogenesis. Conclusions: Our study establishes that both dietary daidzein and its metabolite, equol, protect against aneurysm formation in ovariectomized female mice through the activation of estrogen receptor-ß and subsequent suppression of inflammation. Dietary daidzein's protective effect required the intestinal conversion to equol. Our results indicate the potential therapeutic value of dietary daidzein and its metabolite, equol, for the prevention of the formation of intracranial aneurysms and related subarachnoid hemorrhage.

Genistein attenuates cognitive deficits and neuroapoptosis in hippocampus induced by ketamine exposure in neonatal rats.

Ketamine is a frequently used anesthetic in pediatric patients that can cause cognitive impairment. Genistein, a bioactive component of soy products, has been shown to suppress neuronal death through regulating the expression of apoptosis related genes. In this study, we hypothesized that genistein could alleviate ketamine-induced cognitive impairment by ameliorating hippocampal neuronal loss and tested this hypothesis in rats. Neonatal rats were treated with ketamine and genistein. Hippocampal tissue was harvested for histological and biochemical analysis to determine neuronal apoptosis and proteins involved in the apoptotic pathways. Behavioral assays including contextual fear conditioning test and Morris water maze test were performed to assess cognitive functions, including learning and memory. We found that in fear conditioning test, genistein restored freezing time in ketamine treated rats in a dose dependent manner. Similarly, genistein attenuated impaired learning and memory in Morris water maze test in rats treated with ketamine. Additionally, ketamine-induced neuronal apoptosis in rat hippocampus was attenuated by genistein treatment. Finally, we found that genistein partially restored proteins associated with apoptosis, including Bax, Bcl-2, cleaved caspase 3, and phosphorylated GSK-3ß and Akt. Genistein suppresses hippocampal neuronal loss and cognitive disruption induced by ketamine in rats.

The effects of phytoestrogens on postmenopausal health.

Phytoestrogens are a group of non-steroidal polyphenolic plant-based substances, commonly used for the treatment of menopause-related conditions. They have both genomic and non-genomic effects, displaying weak affinity for estrogen receptors (ER) and preferentially binding to ER-B over ER-A. However, evidence for the benefits of phytoestrogen consumption has been limited. We conducted a review of recent literature, focusing on systematic reviews and meta-analyses reporting on postreproductive health effects of phytoestrogens. While many trials concerning dietary and supplementary phytoestrogens have been conducted, evidence of clinical efficacy is heterogeneous and inconclusive. There appears to be reduction in the vasomotor symptoms of menopause with phytoestrogen intake; however, it is likely small and slow in onset. Phytoestrogens also appear to improve bone mineral density and markers of cardiovascular risk; however, there is inadequate research regarding long-term outcomes. There appear to be no harmful effects of phytoestrogens on breast, endometrial cancer or colorectal cancer and phytoestrogens intake may in fact be protective. Research regarding the effect of phytoestrogens on cognition is mixed, with most studies reporting no significant association. Overall, individual variations in the metabolism of phytoestrogens and age-related genomic effects may account for the considerable variability in the measured effects of phytoestrogens.

Exploring the Biological Activity and Mechanism of Xenoestrogens and Phytoestrogens in Cancers: Emerging Methods and Concepts.

Xenoestrogens and phytoestrogens are referred to as "foreign estrogens" that are produced outside of the human body and have been shown to exert estrogen-like activity. Xenoestrogens are synthetic industrial chemicals, whereas phytoestrogens are chemicals present in the plant. Considering that these environmental estrogen mimics potentially promote hormone-related cancers, an understanding of how they interact with estrogenic pathways in human cells is crucial to resolve their possible impacts in cancer. Here, we conducted an extensive literature evaluation on the origins of these chemicals, emerging research techniques, updated molecular mechanisms, and ongoing clinical studies of estrogen mimics in human cancers. In this review, we describe new applications of patient-derived xenograft (PDX) models and single-cell RNA sequencing (scRNA-seq) techniques in shaping the current knowledge. At the molecular and cellular levels, we provide comprehensive and up-to-date insights into the mechanism of xenoestrogens and phytoestrogens in modulating the hallmarks of cancer. At the systemic level, we bring the emerging concept of window of susceptibility (WOS) into focus. WOS is the critical timing during the female lifespan that includes the prenatal, pubertal, pregnancy, and menopausal transition periods, during which the mammary glands are more sensitive to environmental exposures. Lastly, we reviewed 18 clinical trials on the application of phytoestrogens in the prevention or treatment of different cancers, conducted from 2002 to the present, and provide evidence-based perspectives on the clinical applications of phytoestrogens in cancers. Further research with carefully thought-through concepts and advanced methods on environmental estrogens will help to improve understanding for the identification of environmental influences, as well as provide novel mechanisms to guide the development of prevention and therapeutic approaches for human cancers.

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.

Assessment of consumer awareness on the consumption of phytoestrogens in diet and their supplementation - survey studies.

INTRODUCTION: Phytoestrogens are plant-derived compounds with structural similarity to 17-ß-estradiol. They are considered safer substitutes for synthetic drugs, especially in the treatment of menopause related symptoms. They are delivered to the body with diet or as dietary supplements. AIM OF THE STUDY: The aim of the study was to assess consumer awareness of taking phytoestrogens with diet and supplements, as well as the benefits and risks of such supplementation. MATERIALS AND METHODS: An original survey form was created for the purpose of the study, 133 questionnaires were completed online, and 100 were distributed to random respondents in the Silesian Voivodship. The vast majority of the respondents (84.5%) was represented by women. The study group was diverse in terms of age, education and place of residence. RESULTS: Most of the respondents (67.4%) encountered the concept of phytoestrogens. Common plants as: flax, sunflower, pumpkin, European olive and hops were indicated as phytoestrogen main sources. A small group of respondents (6%) was convinced of the effectiveness of phytoestrogens and indicated their specific health-promoting activities, 49.4% said that not every therapy with their use would improve health and 42.9% declared lack of knowledge in this area. According to the survey outcomes, 16.7% of respondents unambiguously confirmed beneficial effect of phytoestrogens on menopause symptoms. Half of the respondents had no opinion whether phytoestrogens could be an effective replacement for synthetic drugs based therapies. CONCLUSIONS: Incomplete knowledge of society regarding the use of phytoestrogens indicates the need for raising awareness of patients/consumers in this area by medical staff and dietitians. Phytoestrogens, when taken responsibly, can have many benefits for human health.

The Role of Diet in Osteoporotic Fracture Healing: a Systematic Review.

PURPOSE OF REVIEW: Summarize the in vivo evidences on the association between nutrition and osteoporosis fracture healing. RECENT FINDINGS: Osteoporotic fractures constitute a considerable public health burden. The healing capacity of fractures is influenced by local factors related to the fracture and by general factors (e.g., age, sex, osteoporosis, muscular mass, smoking, alcohol, drugs, and diet). The systematic review was conducted according to PRISMA statement. From the literature search on PubMed and Web of Science, from January 2016 to October 2019, twelve studies were selected and resulted highly variable in samples, exposure, methods, outcomes, and outcome assessment. Eleven studies were conducted on laboratory animals. Only one study aimed to investigate the impact of nutritional status on fracture healing in osteoporotic patients. In this review, the role of calcium/vitamin D supplementation remained controversial, while sialoglycoprotein supplementation, phytoestrogen-rich herb extract, flavonoids, and phosphorylated peptides showed a positive effect on osteoporotic fracture healing.

Beneficial effects of estrogens in obstructive sleep apnea hypopnea syndrome.

Epidemiological studies showing the higher frequency of obstructive sleep apnea hypopnea syndrome in men, polycystic ovary syndrome (PCOS), and in post-menopausal women suggest the beneficial role of estrogen. These findings are well supported by the pre-clinical studies (ten research studies described in this review) showing that estrogen and phytoestrogens attenuate the deleterious effects of chronic intermittent hypoxia (obstructive apnea in animals) on the genioglossal muscles and on other organs (co-morbidities) in ovariectomized rodents. Moreover, clinical studies (four research studies described in this review) have also shown the beneficial role of estrogen therapy on the parameters of obstructive apnea in post-menopausal women. The beneficial effects of estrogen and phytoestrogens on obstructive sleep apnea and its co morbidities have been attributed to increase in thioredoxin, Nrf-2, activation of p38 MAP kinases, inhibition of vagal C fibers, and attenuation of HIF-1α. It is possible that estrogen-mediated activation of p38 MAP kinase may inhibit HIF-1α to attenuate lung inflammation, which may inhibit the activation of vagal C fibers to attenuate bronchoconstriction and prevent obstruction during sleep. Moreover, estrogen-mediated increase in thioredoxin and Nrf-2 may also contribute in increasing antioxidant defense and attenuating inflammation.

Cuprizone-induced demyelination in the mouse hippocampus is alleviated by phytoestrogen genistein.

One of the major female sex hormones, estrogen, can influence a variety of mental states. Individuals with multiple sclerosis (MS) often suffer from mental health issues, which are correlated with the pathology of gray matter. In this study, we aimed to elucidate the validity of phytoestrogen genistein (GEN) for treating the gray matter lesions in MS using the mouse model of cuprizone (CPZ)-induced demyelination. First, we confirmed that 5-week 0.2% CPZ intoxication induced demyelination in the hippocampus, and that myelination was successfully recovered by GEN. Loss of mature oligodendrocytes following CPZ intoxication was counteracted by GEN. Neither CPZ nor GEN affected the densities of oligodendrocyte precursor cells and astrocytes. CPZ-induced activation and proliferation of microglia were not inhibited by GEN. Upregulation of gene expression of the pro-inflammatory cytokine, interleukin-1ß, in sorted microglia by CPZ was not inhibited by GEN either. However, the expression levels of genes related to phagocytosis, such as cluster of differentiation 68 and lysosomal-associated membrane protein 1, in sorted microglia were elevated by CPZ but lowered by GEN. Notably, physical contact of microglia with myelin was increased by CPZ but decreased by GEN. The expression levels of myelin-related genes, such as myelin basic protein and myelin oligodendrocyte glycoprotein, in the whole hippocampal tissue were decreased by CPZ but recovered by GEN. These results show that GEN may act on mature oligodendrocytes in the hippocampus by promoting their survival and myelin formation, and suggest the therapeutic potential of phytoestrogens for treating MS patients suffering from mental health issues.