Estrogens regulate early embryonic development of the olfactory sensory system via estrogen-responsive glia

ABSTRACT Estrogens are well-known to regulate development of sexual dimorphism of the brain; however, their role in embryonic brain development prior to sex-differentiation is unclear. Using estrogen biosensor zebrafish models, we found that estrogen activity in the embryonic brain occurs from early neurogenesis specifically in a type of glia in the olfactory bulb (OB), which we name estrogen-responsive olfactory bulb (EROB) cells. In response to estrogen, EROB cells overlay the outermost layer of the OB and interact tightly with olfactory sensory neurons at the olfactory glomeruli. Inhibiting estrogen activity using an estrogen receptor antagonist, ICI182,780 (ICI), and/or EROB cell ablation impedes olfactory glomerular development, including the topological organisation of olfactory glomeruli and inhibitory synaptogenesis in the OB. Furthermore, activation of estrogen signalling inhibits both intrinsic and olfaction-dependent neuronal activity in the OB, whereas ICI or EROB cell ablation results in the opposite effect on neuronal excitability. Altering the estrogen signalling disrupts olfaction-mediated behaviour in later larval stage. We propose that estrogens act on glia to regulate development of OB circuits, thereby modulating the local excitability in the OB and olfaction-mediated behaviour.

A Correlation Study on In Vitro Physiological Activities of Soybean Cultivars, 19 Individual Isoflavone Derivatives, and Genetic Characteristics

The functionality of soybeans is an important factor in the selection and utilization of excellent soybean cultivars, and isoflavones are representative functional substances in soybeans, which exhibit effects on antioxidants, estrogen activity, and cancer, and prevent cardiovascular diseases. This study analyzed ABTS, DPPH, estrogen, ER (ER) alpha, UCP-1, and NO inhibition activities in 48 types of soybean cultivars, as well as the relationship with 19 isolated types of individual isoflavone derivatives. Statistical analysis was conducted to find individual isoflavone derivatives affecting physiological activities, revealing the high correlation of three types of derivatives: genistein 7-O-(6″-O-acetyl)glucoside (6″-O-acetylgenistin), genistein 7-O-(2″-O-apiosyl)glucoside, and glycitein. Based on these results, 15 types of soybean cultivars were selected (one control type, seven yellow types, six black types, and one green type), which have both high physiological activities and a high content of individual isoflavone derivatives. In addition, these high correlations were further verified through a genome-wide association study (GWAS) to determine the association between activities, substances, and genetic characteristics. This study comprehensively describes the relationship between the specific physiological activities of soybean resources, individual isoflavone derivative substances, and SNPs, which will be utilized for in-depth research, such as selection of excellent soybean resources with specific physiological activities.

Treatment of Benign Prostatic Hyperplasia by Natural Drugs

Benign prostatic hyperplasia (BPH) is one of the most common urinary diseases affecting men, generally after the age of 50. The prevalence of this multifactorial disease increases with age. With aging, the plasma level of testosterone decreases, as well as the testosterone/estrogen ratio, resulting in increased estrogen activity, which may facilitate the hyperplasia of the prostate cells. Another theory focuses on dihydrotestosterone (DHT) and the activity of the enzyme 5α-reductase, which converts testosterone to DHT. In older men, the activity of this enzyme increases, leading to a decreased testosterone/DHT ratio. DHT may promote prostate cell growth, resulting in hyperplasia. Some medicinal plants and their compounds act by modulating this enzyme, and have the above-mentioned targets. This review focuses on herbal drugs that are most widely used in the treatment of BPH, including pumpkin seed, willow herb, tomato, maritime pine bark, Pygeum africanum bark, rye pollen, saw palmetto fruit, and nettle root, highlighting the latest results of preclinical and clinical studies, as well as safety issues. In addition, the pharmaceutical care and other therapeutic options of BPH, including pharmacotherapy and surgical options, are discussed, summarizing and comparing the advantages and disadvantages of each therapy.

Estrogen regulates early embryonic development of the olfactory sensory system via estrogen responsive glia

Estrogen is well-known to regulate development of sexual dimorphisms of the brain, however its role in the brain during early embryonic development prior to sex-differentiation is unclear. Using estrogen biosensor zebrafish models, we found that estrogen activity in the embryonic brain occurs specifically in a type of glia located within the OB, which we name estrogen-responsive olfactory bulb/EROB cells. With estrogen activity, EROB cells extend their ramified projections that overlay the OB outermost layer and tightly interact with olfactory sensory neurons (OSNs) at the olfactory glomeruli. Pharmacologically inhibiting estrogen activity and/or EROB cell ablation impedes olfactory glomerular development, including OSN pathfinding, topological organisation of olfactory glomeruli and inhibitory neurogenesis in the OB. Furthermore, activation of this estrogen/EROB-dependent mechanism decreases the intrinsic neuronal activity primarily in the OB, and this alteration of estrogen signalling disrupts olfaction-mediated behaviour. We propose that estrogen acts on glia to regulate development of functional OB circuits, thereby modulating the local intrinsic excitability in the OB and olfaction-mediated behaviour. Our data also suggest a possibility that the estrogen/EROB cascade may be an important site of action for environmental estrogens causative of neurodevelopmental impairments in animals and humans.

Bisacodyl in Stimulant Laxatives Can Induce Estrogen Agonist/Antagonist Activity in Breast Cancer Cells in Culture

Exposure to xenobiotic estrogens has the potential to induce estrogen activity that may contribute to a range of undesired physiological effects including the stimulation of estrogen responsive tumors. We have previously determined that extracts of OTC medications containing the stimulant laxative bisacodyl induce estrogenic activity in tissue culture bioassays. In this study, we tested the hypothesis that bisacodyl is responsible for the estrogen activity of these extracts and then characterized these effects. Ethanol extracts and dilutions were prepared from OTC medications containing Bisacodyl (1 gm:1 ml). The estrogen agonist and antagonist activity of each extract, as well as bisacodyl and then metabolite DA-bisacodyl was determined using the T47dkbluc estrogen reporter gene and the MCF-7 E3 estrogen responsive proliferation assays. LC-MS analysis was used to determine bisacodyl and DA-bisacodyl concentration in extracts as well as to trace the metabolism of bisacodyl to DA-bisacodyl in the cell culture bioassays. Molecular modeling “docking” simulations of the interactions of bisacodyl and the metabolite DA-bisacodyl with the estrogen receptor (ER) ligand binding domain was performed using MOE from Chemical Computing Group. Bisacodyl and the metabolite DA-bisacodyl induced mixed agonist/antagonist activity in MCF-7 E3 estrogen responsive proliferation assay similar to 4OH-tamoxifen. At the same time, both compounds stimulated only minimal estrogen activity in the T47dkbluc estrogen reporter gene assay. LC-MS analysis determinations identified that almost all bisacodyl was converted to the dihydroxy metabolite DA-bisacodyl in cell culture bioassays. Molecular modeling “docking” simulations determined that while bisacodyl does not fit into the agonist (estradiol) or antagonist (4OH-tamoxifen) conformations of the estrogen receptor ligand binding site, the metabolite DA-bisacodyl may fit into the antagonist induced binding pocket of the ER in a reasonable way. This study characterizes the observed estrogen activity of extracts from OTC medications containing bisacodyl as resulting from the bisacodyl metabolite DA-bisacodyl interacting with the estrogen receptor. Thus, bisacodyl is an OTC medication active ingredient that has potential to induce side effects and or toxicity involving estrogen signalling. The capacity for medications containing bisacodyl or other estrogenic substances to induce estrogen activity in patients is unclear. At the same time, consumers and practitioners should be aware of the potential estrogen activity of bisacodyl containing products.

Estrogen Activity of OTC Topical Medications Containing Parabens Depends on Paraben Type and Concentration

Methylparaben, ethylparaben, and propylparaben are widely used as preservatives in food, cosmetics, and pharmaceutical products. Parabens are also known to bind the estrogen receptor and induce weak estrogen activity in laboratory bioassays. Many OTC topical medications contain one or more parabens as preservative ingredients. In this study, we surveyed the estrogen activity of extracts from OTC topical medications and tested the hypothesis that a combined threshold concentration of particular parabens is required to induce estrogen activity in human breast cancer cell bioassays. Ethanol extracts (1 gm:1 ml) were prepared from OTC topical medications containing parabens (including: Olay Quench Lotion, CeraVe Daily Moisturizing Lotion and Cortizon-10 Lotion). The estrogen agonist and antagonist activity of each extract was determined using the T47dkbluc estrogen reporter gene and the MCF-7 E3 estrogen responsive proliferation assays. The extracts from Olay Quench Lotion and CeraVe Daily Moisturizing Lotion induced estrogen agonist activity in the MCF-7 proliferation assay. The extract from the Cortizon-10 Lotion did not induce significant estrogen activity. The product ingredients of each OTC topical medications tested listed ethyl and propyl parabens while the Olay Quench Lotion also contained the least estrogenic paraben methylparaben. We propose that the estrogenic potential of OTC topical medications can be estimated with LC-MS analysis determination of paraben content and concentration. This study illustrates that measurable estrogen activity from OTC topical medications requires the presence of estrogenic parabens (ethyl and propyl) at total concentrations that exceed a threshold. Thus, estrogen activity depends on the type and concentration of paraben present in the OTC topical products. While the capacity for these OTC topical medications to induce estrogen activity in individuals using the products is unclear, consumers may benefit from more information about the paraben type and concentration present.

Phytotherapy in endometriosis: an up-to-date review

Endometriosis is a benign gynecological disease which symptoms can provide a severe impact on patient’s quality of life with subsequent impact on psychological well-being. Different therapeutic strategies are available to treat this disease, such as surgery, hormonal therapies, and nonsteroidal anti-inflammatory drugs. Nevertheless, the efficacy of conventional medical treatments is limited or intermittent in most of the patients due to the associated side effects. Therefore, a woman with endometriosis often search for additional and alternative options, and phytotherapy might be a promising alternative and complementary strategy. Different medicinal plants, multicomponent herbal preparations, and phytochemicals were investigated for pharmacological proprieties in endometriosis therapy. In most of the cases, the effect on endometriosis was related to phenolic compounds, such as flavonoids and phenolic acids reporting anti-inflammatory, proapoptotic, antioxidant, and immunomodulatory functions. Moreover, some phytochemicals have been related to a strong phytoestrogenic effect modulating the estrogen activity. Although promising, available evidence is based on in vitro and animal models of endometriosis with a limited number of well-performed clinical studies. There are almost none randomized control trials in this area. Therefore, properly constructed clinical trials are mandatory to achieve more conclusive results about the promising role of phytotherapy in the management of endometriosis.

Flavonoids as Phytoestrogenic Components of Hops and Beer

The value of hops (Humulus lupulus L.) in beer production has been undisputed for centuries. Hops is rich in humulones and lupulones which gives the characteristic aroma and bitter taste, and preserves this golden drink against growing bacteria and molds. Besides α- and β-acids, the lupulin glands of hop cones excrete prenylated flavonoids, which exhibit a broad spectrum of biological activities and therefore has therapeutic potential in humans. Recently, interest in hops was raised due to hop prenylated flavanones which show extraordinary estrogen activities. The strongest known phytoestrogen so far is 8-prenylnaringenin (8-PN), which along with 6-prenylanaringenin (6-PN), 6,8-diprenylnaringenin (6,8-DPN) and 8-geranylnaringenin (8-GN) are fundamental for the potent estrogen activity of hops. This review provides insight into the unusual hop phytoestrogens and shows numerous health benefits associated with their wide spectrum of biological activities including estrogenic, anticancer, neuropreventive, antinflamatory, and antimicrobial properties, which were intensively studied, and potential applications of these compounds such as, as an alternative to hormone replacement therapy (HRT).

Pharmacogenetic score predicts overall survival, progression-free survival and platinum sensitivity in ovarian cancer

Aim: To define the impact of polymorphisms in genes involved in platinum-taxane and estrogen activity in the outcome of platinum-based treated ovarian cancer patients (OCP). Patients & Methods: Two hundred and thirty OCP were analyzed for 124 germ-line polymorphisms to generate a prognostic score for overall survival (OS), progression-free survival (PFS) and platinum-free interval (PFI). Results: ABCG2 rs3219191D>I, UGT1A rs10929302G>A and UGT1A rs2741045T>C polymorphisms were significantly associated with all three parameters (OS, PFS and PFI) and were used to generate a score. Patients in high-risk group had a poorer OS (hazard ratio [HR]: 1.8; 95% CI: 1.3–2.7; p = 0.0019), PFS (HR: 2.0; 95% CI: 1.4–2.9; p < 0.0001) and PFI (HR: 1.9; 95% CI: 1.4–2.8; p = 0.0002) compared with those in low-risk group. Conclusion: The prognostic-score including polymorphisms involved in drug and estrogen pathways stratifies OCP according to OS, PFS and PFI.