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Abstract The stem bark of Erythrina lysistemon, one of the traditionally used 'women remedies', has been assessed for its estrogenic activity. The ethyl-acetate extract of the stem bark of E. [...]

Abstract In most developing countries, 70-80% of the population still resort to traditional medicine for their primary health care. This medicine utilises medicinal plants which are traditionally taken as concoction [...]

Phytoestrogens are naturally occurring plantderived polyphenols with estrogenic potency. They are ubiquitous in diet and therefore, generally consumed. Among Europeans, the diet is rich in multiple putative phytoestrogens including flavonoids, tannins, stilbenoids, and lignans. These compounds have been suggested to provide beneficial effects on multiple menopause-related conditions as well as on development of hormone-dependent cancers, which has increased the interest in products and foods with high phytoestrogen content. However, phytoestrogens may as well have adverse estrogenicity related effects similar to any estrogen. Therefore, the assessment of estrogenic potency of dietary compounds is of critical importance. Due to the complex nature of estrogenicity, no single comprehensive test approach is available. Instead, several in vitro and in vivo assays are applied to evaluate estrogenic potency. In vitro estrogen receptor (ER) binding assays provide information on the ability of the compound to I) interact with ERs, II) bind to estrogen responsive element on promoter of the target gene as ligand-ER complex, and III) interact between the co-activator and ERs in ligand-dependent manner. In addition, transactivation assays in cells screen for ligand-induced ERmediated gene activation. Biochemical in vitro analysis can be used to test for possible effects on protein activities and E-screen assays to measure (anti)proliferative response in estrogen responsive cells. However, for assessment of estrogenicity in organs and tissues, in vivo approaches are essential. In females, the uterotrophic assay is applicable for testing ERa agonistic and antagonistic dietary compounds in immature or adult ovariectomized animals. In addition, mammary gland targeted estrogenicity can be detected as stimulated ductal elongation and altered formation of terminal end buds in immature or peripubertal animals. In males, Hershberger assay in peri-pubertal castrated rats can be used to detect (anti)androgenic/ (anti)estrogenic responses in accessory sex glands and other hormone regulated tissues. In addition to these short-term assays, sub-acute and chronic reproductive toxicity assays as well as two-generation studies can be applied for phytoestrogens to confirm their safety in long-term use. For reliable assessment of estrogenicity of dietary phytoestrogens in vivo, special emphasis should be focused on selection of the basal diet, route and doses of administration, and possible metabolic differences between the species used and humans. In conclusion, further development and standardization of the estrogenicity test methods are needed for better interpretation of both the potential benefits and risks of increasing consumption of phytoestrogens from diets and supplements. [ABSTRACT FROM AUTHOR]

Abstract A dry extract from the roots of rhapontic rhubarb (extract Rheum rhaponticum (L.); ERr) has been commercially available in Germany for over two decades to treat menopausal symptoms. However, the molecular basis of its clinical effectiveness remains obscure. This article reviews the in vitro and in vivo data of its estrogenic actions, particularly those mediated by estrogen receptor-β (ERβ).

Exposure to glyphosate-based herbicides (GBH) and consumption of cafeteria (CAF) diet, which are widespread in Western society, seem to be associated with endometrial hyperplasia (EH). Here, we aimed to evaluate the effects of a subchronic low dose of GBH added to the CAF diet on the rat uterus. Female Wistar rats were fed from postnatal day (PND)21 until PND240 with chow (control) or CAF diet. Since PND140, rats also received GBH (2 mg of glyphosate/kg/day) or water through food, yielding four experimental groups: control, CAF, GBH, and CAF+GBH. On PND240, CAF and CAF+GBH animals showed an increased adiposity index. With respect to the control group, no changes in the serum levels of 17β-estradiol and progesterone were found. However, progesterone levels were higher in the CAF+GBH group than in the CAF and GBH groups. In the uterus, both studied factors alone and in combination induced morphological and molecular changes associated with EH. Furthermore, the addition of GBH provoked an increased thickness of subepithelial stroma in rats fed with the CAF diet. As a consequence of GBH exposure, CAF+GBH rats exhibited an increased density of abnormal gland area, considered preneoplastic lesions, as well as a reduced PTEN and p27 expression, both tumor suppressor molecules that inhibit cell proliferation, with respect to control rats. These results indicate that the addition of GBH exacerbates the CAF effects on uterine lesions and that the PTEN/p27 signaling pathway seems to be involved. Further studies focusing on the interaction between unhealthy diets and environmental chemicals should be encouraged to better understand uterine pathologies.

Oral health is a crucial aspect of overall well-being in both humans and nonhuman primates. Understanding the oral pathologies and dental conditions in apes can provide valuable insights into their evolutionary history, dietary habits, and overall health. The present study evaluates dental findings in wild great apes from museum specimens to gain insights into the influence of natural nutrition on dental health. Complete macerated skulls of wild, adult great apes from the collection of the Museum of Natural History, Berlin, Germany, were examined. We analyzed skulls of 53 gorillas (Gorilla gorilla), 63 chimpanzees (Pan troglodytes), and 41 orangutans (Pongo spp.). For each skull, we recorded wear of dental hard tissues (Lussi and Ganss index), carious lesions, and periodontal bone loss. Incisal and occlusal dental hard tissue defects were found in all skulls, as well as considerable external staining. In all species, incisors and canines showed the greatest loss of tissue, followed by molars. The wear of molars decreased from the first to the third molars, premolars showed the least pronounced defects. Some individuals had apical osteolytic defects along with severe dental hard tissue loss with pulp involvement or after dental trauma, respectively (n = 5). Our study did not observe any carious lesions among the examined great ape skulls. However, we did find evidence for localized or generalized periodontal bone loss in a subset of the specimens (n = 3 chimpanzees, n = 7 orangutans). The natural diet and foraging behavior of great apes induces abrasion and attrition of dental hard tissue but does not yield carious lesions. The occurrence of periodontitis in individual apes indicates that the natural circumstances can induce periodontal bone loss even in the wild, despite physiological nutrition., (© 2023 The Authors. American Journal of Primatology published by Wiley Periodicals LLC.)

Background: Despite the high number of synthetic androgenic-anabolic steroids, testosterone is still misused for doping in amateur and professional sports. However, only few studies investigated the dose-response effects of testosterone beyond its physiological concentrations and in over 90 years of research, no saturation dosage has been experimentally described for exogenous testosterone administration., Objectives: We want to elucidate the physiological and pathophysiological effects of supra-physiological testosterone application and close this gap in testosterone dose-response data., Materials and Methods: Male orchiectomized rats were treated with different testosterone doses ranging from 0.1 to 50 mg/kg body weight for 3 weeks. Several physiological endpoints (e.g., body weight, organ and muscle weight, muscle strength, muscle fiber size) were examined during and after the termination of the treatment with an adjusted Hershberger assay, open-field-test, and (immuno-)histologic., Results: The wet weights of androgen responsive organs (penis, prostate, seminal vesicle) showed a significant increase in a dose-dependent manner. Histological evaluation of the prostate showed a significant higher percentage of KI67 positive prostate nuclei in the highest dosage group and an increasing hyperplasia with increasing testosterone administered. A significant anabolic effect was only observed in Levator ani wet weight, and to minor degree for the cardiac muscle. Regarding other skeletal muscles (Musculus soleus and Musculus gastrognemicus), no significant testosterone effects were observed. We showed a significant increasing dosage-response effect for testosterone in androgen responsive organs with saturation at the two highest concentration of 10 and 50 mg/kg body weight., Discussion and Conclusion: The dose-dependent androgenic effects of testosterone were well observable and the anabolic effects on muscle tissue were visible although to a lesser degree, without the support of aerobic exercise and a protein rich diet. Future studies should investigate a combinatorial effect of testosterone and training. Nevertheless, with the chosen range of applied testosterone, we showed a saturation of testosterone effects in prostate, seminal vesicle, penis, and Levator ani., (© 2023 The Authors. Andrology published by Wiley Periodicals LLC on behalf of American Society of Andrology and European Academy of Andrology.)

The elucidation of the metabolic fate of prohibited substances is crucial for the abuse detection. The human hepatocyte cell line HepG2 can be used to study biotransformation. In order to improve this in vitro model system, we compared the HepG2 spheroid generation using three different techniques: a forced floating, a scaffold-free and a scaffold-based method. We characterized the spheroids with regard to the expression levels of the proliferation marker Mki67, the liver-specific marker albumin and biotransformation enzymes. Moreover, the metandienone metabolite pattern was comparatively analysed by high-performance liquid chromatography mass spectrometry. With all three techniques, HepG2 spheroids were generated showing a degree of differentiation. The forced floating method resulted in very large spheroids (1 mm in diameter) showing signs of necrosis in the centre and a very low metandienone conversion rate. The spheroids formed by the two other techniques were comparable in size with 0.5 mm in diameter on average. Among the three different 3D cultivation methods, the HepG2 spheroids formed on Matrigel® as extracellular matrix were the most promising regarding biotransformation studies on anabolic androgenic steroids. Prospectively, HepG2 spheroids are a promising in vitro model system to study multidrug setups, drug-drug interactions and the biotransformation of other substance classes., (© 2023 The Authors. Drug Testing and Analysis published by John Wiley & Sons Ltd.)

Tamoxifen (TAM) is a selective estrogen receptor modulator (SERM) that is used in the treatment of breast cancer, yet with the risk of developing uterine cancer. A perfect SERM would act as an estrogen activator on bones, the cardiovascular system, and the central nervous system while providing neutral or estrogen blocking effects on the breast and the uterus. Herein, we report on the design, synthesis, and evaluation of new rigid and flexible TAM analogues. Mainly, a chloro substituent is introduced at the para position of the TAM ring C blocking the CYP2D6 hydroxylation site. Most compounds showed estrogenic activity higher than TAM using the yeast estrogen screen assays, indicating the determinant role of the chloro substituent upon functional activity. Despite being estrogenic, compound 2B showed potent antiproliferative activity in the NCI 60 cell lines with mean GI 50 = 3.67 μM, GI 50 = 1.05 μM on MCF-7 cell lines, and GI 50 = 1.30 μM on MDA-MB-231. The estrogenic activity of compound 2B was further confirmed by stimulating alkaline phosphatase in Ishikawa cells, and it showed no increase in relative uterine wet weight in ovariectomized rats. Compound 2F showed EC 90 = 0.31 μg/mL and SI 90 = 60 against Ebola virus; this is 200-fold more potent than the positive control favipiravir. This is the first time to report estrogenic triphenylethylenes as anti-EBOV agents. The anti-EBOV activity reported is a function of the substitution pattern of the scaffold rather than the functional activity. Moreover, compound 3D showed excellent PO pharmacokinetic properties in mice. In conclusion, for this class of TAM-like compounds, the blockage of the p -position of ring C is decisive for the functional activity; meanwhile, the triarylethylene substitution pattern is detrimental for the antiviral activity., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

Herbivorous animals that regularly consume tannin-rich food are known to secrete certain tannin-binding salivary proteins (TBSPs), especially proline-rich proteins and histidine-rich proteins, as an effective measure to counteract the antinutritive effects of dietary tannins. Due to their high binding capacity, TBSPs complex with tannins in the oral cavity, and thereby protect dietary proteins and digestive enzymes. Although the natural diet of great apes (Hominidae) is biased toward ripe fruits, analyses of food plants revealed that their natural diet contains considerable amounts of tannins, which is raising the question of possible counter-measures to cope with dietary tannins. In our study, we investigated the salivary amino acid profiles of zoo-housed Pan paniscus, Pan troglodytes, Gorilla gorilla, and Pongo abelii, and compared their results with corresponding data from Homo sapiens. Individual saliva samples of 42 apes and 17 humans were collected and quantitated by amino acid analysis, using cation-exchange chromatography with postcolumn derivatization, following acid hydrolysis. We found species-specific differences in the salivary amino acid profiles with average total salivary protein concentration ranging from 308.8 mg/dL in Po. abelii to 1165.6 mg/dL in G. gorilla. Total salivary protein was consistently higher in ape than in human saliva samples (174 mg/dL). All apes had on average also higher relative proline levels than humans did. Histidine levels had the highest concentration in the samples from Po. abelii followed by P. paniscus. In all ape species, the high salivary concentrations of proline and histidine are considered to be indicative of high concentrations of TBSPs in hominids. Given that the species differences in salivary composition obtained in this study correspond with overall patterns of secondary compound content in the diet of wild populations, we assume that salivary composition is resilient to acute and long-lasting changes in diet composition in general and tannin content in particular., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

In anti-doping science, the knowledge of drug metabolism is a prerequisite to identify analytical targets for the detection of misused prohibited substances. As the most obvious way to study xenobiotic metabolism, the administration to human volunteers, faces ethical concerns, there is a need for model systems. In the present study, we investigated whether Oryzias latipes (medaka) embryos might be an alternative, non-animal test model to study human-like metabolism. In the present study, we exposed medaka embryos at the morula stage to the anabolic steroid metandienone (10 µM or 50 µM) for a period of 2 or 8 days. According to the fish embryo toxicity test (OECD test), we assessed the developmental status of the embryos. We further investigated metandienone metabolites by high-performance liquid chromatography- and gas chromatography-mass spectrometry. Medaka embryos produced three mono-hydroxylated and one reduced metabolite known from human biotransformation. Developmental malformations were observed for the exposition to 50 µM metandienone, while a significant elevation of the heart beat was also present in those individuals exposed to the lower dose for 8 days. The present study demonstrates that the medaka embryo represents a promising model to study human-like metabolism. Moreover, the judgement of developmental parameters of the fish embryos enables for the simultaneous assessment of toxicity., (© 2022. The Author(s).)

Hops (Humulus lupulus) is used as an alternative to hormone replacement therapy due to the phytoestrogen, 8-prenylnaringenin (8-PN). To examine the potential risks/benefits of hops extract and its compounds (8-PN and 6-prenylnaringenin, 6-PN), we aimed to evaluate the estrogen receptor α (ERα) and aryl hydrocarbon receptor (AHR) signaling pathways in human endometrial cancer cells. Hops extract, 8-PN and 6-PN showed estrogenic activity. Hops extract and 6-PN activated both ERα and AHR pathways. 6-PN increased the expression of the tumor suppressor gene (AHRR), and that of genes involved in the estrogen metabolism (CYP1A1, CYP1B1). Although 6-PN might activate the detoxification and genotoxic pathways of estrogen metabolism, hops extract as a whole only modulated the genotoxic pathway by an up-regulation of CYP1B1 mRNA expression. These data demonstrate the relevant role of 6-PN contained in the hops extract as potential modulator of estrogen metabolism due to its ERα and AHR agonist activity., (Copyright © 2021 Elsevier B.V. All rights reserved.)