Search

The etiology of endometriosis, a gynecological disease characterized by the presence of endometrial glands and stroma outside the uterine cavity, is still unknown. Our research group has recently demonstrated the presence of ectopic endometrium in human female fetuses at different gestational ages. In this manuscript we describe four new cases of fetal endometriosis found among a series of 52 female fetuses analyzed at autopsy. The anatomical localization of this ectopic endometrium, and its histological and immunohistochemical characteristics are depicted. We suggest that endometriosis is caused by dislocation of primitive endometrial tissue outside the uterine cavity during organogenesis. The clinical and pathological implications of these findings are discussed.

Although discovered in 2000, neuroglobin (Ngb) functions are still uncertain. A contribution to the role played by Ngb in neurons could certainly derive from the identification of Ngb endogenous modulators. Here, we evaluate the possibility that Ngb could be regulated by 17β-estradiol (E 2) signaling in both SK-N-BE human neuroblastoma cell line and mouse hippocampal neurons. 1 nM E2 rapidly induced a 300% increase in Ngb levels in both models. The E2 effect was specific, being not induced by testosterone or dihydrotestosterone. The E2-induced Ngb increase requires estrogen receptor (ER) β, but not ERα, as evaluated by the mimetic effect of ERβ-specific agonist DPN and by the blockage of E 2 effect in ERβ-silenced SK-N-BE cells. Furthermore, both rapid (15 min) ERβ-dependent activation of p38/MAPK and transcriptional ERβ activity were required for the estrogenic regulation of Ngb. Finally, E 2 exerted a protective effect against H2O 2-induced neuroblastoma cell death which was completely prevented in Ngb-silenced cells. Overall, these data suggest that Ngb is part of the E 2 signaling mechanism that is activated to exert protective effects against H2O2-induced neurotoxicity. Copyright © 2011 S. Karger AG, Basel.

17-Estradiol (E2) mediates a wide variety of complex biological processes determining the growth and development of reproductive tract as well as nonreproductive tissues of male and female individuals. While E2 effects on the reproductive system, bone, and cardiovascular system are quite well established, less is known about how it affects the physiology of other tissues. Skeletal muscle is a tissue that is expected to be E2 responsive since both isoforms of estrogen receptor (ER- and ER-) are expressed. Significant sex-related differences have been described in skeletal muscle, although the role played by E2 and the mechanisms underlying it remain to be determined. Here, we demonstrate that E2 increases the glucose transporter type 4 translocation at membranes as well as the expression of well-known differentiation markers of myogenesis (i.e., myogenin and myosin heavy chain) in rat myoblast cells (L6). These E2-induced effects require rapid extranuclear signals and the presence of ER-, whereas no contribution of IGF-I receptor has been observed. In particular, ER--dependent Akt activation participates in regulating the first step of myogenic differentiation. Moreover, both receptors mediate the E2-induced activation of p38, which, in turn, affects the expression of myogenin and myosin heavy chain. All together, these data indicate that E2 should be included in the list of skeletal muscle trophic factors.

Cleome arabica L. (Capparidaceae) is a desert plant widely distributed in the North part of Africa whose leaves are used in traditional medicine as a sedative for abdominal and rheumatic pains.The anticancer activity of methanol Cleome arabica leaf extracts (CALE) is investigated in different human cancer cell lines.Five different human cancer cell lines, representative of the most common cancers in Western countries (i.e., breast adenocarcinoma, colon carcinoma, neuroblastoma, hepatoma, cervix carcinoma) were treated with different concentrations of CALE (i.e., 1, 5, 10, 25, 50, 100 and 200 µg/ml). Cell viability and cell cycle were measured by using a hemocytometer chamber and a cytofluorimeter, respectively. Epidermal growth factor (EGF) was used as a positive control. Western blots were performed to evaluate the CALE effects on pathways involved in cell growth regulation and on apoptotic cascade activation.Our results confirm that CALE has a high content of polyphenolic compounds (i.e., 32.21 ± 3.44%), mainly as flavonoids (24.56 ± 4.67%). In all tested cell lines CALE treatment reduces cell number in a dose-dependent manner (ED50 = 175 ± 30 µg/ml). CALE (100 and 200 µg/ml) increases by three-fold the activation of the apoptotic cascade involving caspase-3 activation and the cleavage of its substrate poly(ADP-ribose) polymerase (PARP). Intriguingly, CALE treatment (200 µg/ml) also blocks EGF-induced cell growth by preventing the growth factor-triggered AKT and ERK phosphorylation. As a whole, these data strongly suggest that CALE possesses anticancer effects in all tested cancer cell lines.

Quercetin has potentially beneficial effects on disease prevention, including cancer. An intriguing issue regarding the mechanisms of action of quercetin is the ability of this drug to modulate estrogen receptor (ER) activities. In a previous study, we demonstrated that quercetin elicited apoptosis through an ERα-dependent mechanism. However, the contribution of ERβ in quercetin-induced apoptosis remains elusive. Here, we report that quercetin, at nutritionally relevant concentrations, mimicked the 17β-estradiol (E2)-induced apoptotic effect in both ERβ1-transfected HeLa and in ERβ1-containing DLD-1 colon cancer cell lines by inducing the activation of p38. p38 activation is responsible for pro-apoptotic activation of caspase-3 and the cleavage of poly(ADP-ribose) polymerase. Notably, no inactivation or downregulation of the survival kinases (i.e., AKT and ERK1/2) or the antiapoptotic protein Bcl-2 was observed after quercetin stimulation. On the contrary, quercetin acted similarly to E2 by increasing the levels of the oncosuppressor protein PTEN and by impeding ERβ-dependent cyclin D1 promoter activity, which subsequently resulted in the transcription of the estrogen-responsive element remaining unchanged. As a whole, these data indicate that quercetin mimics the E2 effects in the presence of ERβ1, thus maintaining its anti-carcinogenic potential. In addition, the quercetin pro-apoptotic action in the presence of ERα may render it as a dual-sided protective agent against E2-related cancer in the reduction of tumour growth in organs that express ERα and/or ERβ. J. Cell. Physiol. 227: 1891–1898, 2012. © 2011 Wiley Periodicals, Inc.

Sex steroid hormones differently control the major physiological processes in male and female organisms. In particular, their effects on vascular smooth muscle cells (VSMCs) migration are at the root of sex/gender-related differences reported in the cardiovascular system. Several exogenous substances, defined endocrine disruptor chemicals (EDCs), could interfere with these androgen and estrogen effects; however, the sex/gender-related susceptibility of VSMC motility to EDCs is completely unknown. Here, the effect of naturally occurring (naringenin, Nar) and synthetic (bisphenol A, BPA) EDCs on male and female VSMC motility has been evaluated. 17β-estradiol (E2, 0.1 nM-1 µM) induced a dose-dependent inhibition of motility in female-derived VSMC. In contrast, neither dihydrotestosterone (DHT, 0.01-100 nM) nor the common precursor of sex steroid hormones, testosterone (Tes, 0.01-100 nM) modified male-derived VSMC motility. Estrogen receptor (ER) β subtype-dependent activation of p38 was necessary for the E2 effect on cell motility. High BPA concentration prevented E2 effects in female-derived cells being without any effect in male-derived cells. Nar mimicked E2 effects on female-derived cells even in the presence of E2 or BPA. Intriguingly, Nar also inhibited the male-derived VSMC mobility. This latter effect was prevented by ERβ inhibitor, but not by the androgen receptor (AR) inhibitor. As a whole, ERβ-dependent signals in VSMC results more susceptible to the impact of EDCs than AR signals suggesting a possible high and overall susceptibility of female to EDCs. However, several male-derived cells, including VSMC, express ERβ, which could also serve as target of EDC disruption in male organisms.

Several experiments sustain healthful benefits of the flavanone naringenin (Nar) against chronic diseases including its protective effects against estrogen-related cancers. These experiments encourage Nar use in replacing estrogen treatment in post-menopausal women avoiding the serious side effects ascribed to this hormone. However, at the present, scarce data are available on the impact of Nar on E2-regulated cell functions. This study was aimed at determining the impact of Nar on the estrogen receptor (ERα and β)-dependent signals important for 17β-estradiol (E2) effect in muscle cells (rat L6 myoblasts, mouse C2C12 myoblasts, and mouse skeletal muscle satellite cells). Dietary relevant concentration of Nar delays the appearance of skeletal muscle differentiation markers (i.e., GLUT4 translocation, myogenin, and both fetal and slow MHC isoforms) and impairs E2 effects specifically hampering ERα ability to activate AKT. Intriguingly, Nar effects are specific for E2-initiating signals because IGF-I-induced AKT activation, and myoblast differentiation markers were not affected by Nar treatment. Only 7 days after Nar stimulation, early myoblast differentiation markers (i.e., myogenin, and fetal MHC) start to be accumulated in myoblasts. On the other hand, Nar stimulation activates, via ERβ, the phosphorylation of p38/MAPK involved in reducing the reactive oxygen species formation in skeletal muscle cells. As a whole, data reported here strongly sustain that although Nar action mechanisms include the impairment of ERα signals which drive muscle cells to differentiation, the effects triggered by Nar in the presence of ERβ could balance this negative effect avoiding the toxic effects produced by oxidative stress .

The etiology of endometriosis, a gynecological disease characterized by the presence of endometrial glands and stroma outside the uterine cavity, is still unknown. Our research group has recently demonstrated the presence of ectopic endometrium in human female fetuses at different gestational ages. In this manuscript we describe four new cases of fetal endometriosis found among a series of 52 female fetuses analyzed at autopsy. The anatomical localization of this ectopic endometrium, and its histological and immunohistochemical characteristics are depicted. We suggest that endometriosis is caused by dislocation of primitive endometrial tissue outside the uterine cavity during organogenesis. The clinical and pathological implications of these findings are discussed. © 2011 Wiley Periodicals, Inc.

Fruit and vegetable consumption has generally been associated with the prevention or suppression of cancer. However, food could contain a multitude of chemicals (e.g., bisphenol A; BPA) that could synergize or antagonize the effects of diet-derived compounds. Remarkably, food containers (e.g., water and infant bottles) are the largest source of exposure to BPA for human beings. Here, the effects of the coexposure of naringenin (Nar, 1.0 × 10−9 M to 1.0 × 10−4 M) and BPA (1.0 × 10−5 M) in estrogen-dependent breast cancer cell lines expressing (i.e., MCF-7 and T47D) or not expressing (i.e., MDA-MB-231) estrogen receptor α (ERα) are reported. Although both Nar and BPA bind to ERα, they induce opposite effects on breast cancer cell growth. BPA induces cell proliferation, whereas Nar only decreases the number of ERα-positive cells (i.e., MCF-7 and T47D). Notably, even in the presence of BPA, Nar impairs breast cancer cell proliferation by activating caspase-3. The molecular pathways involved require p38 activation, whereas, the BPA-induced AKT activation is completely prevented by the Nar treatment. As a whole, Nar maintains its proapoptotic effects even in the presence of the food contaminant BPA, thus, enlarging the chemopreventive potential of this flavanone. © 2012 IUBMB IUBMB Life, 64(8): 690–696, 2012

Background Fertile women may be encouraged to use contraception during clinical trials to avoid potential drug effects on fetuses. However, hormonal contraception interferes with pharmacokinetics and pharmacodynamics and modifies internal milieus. Macrophages depend on the milieu to which they are exposed. Therefore, we assessed whether macrophage function would be affected by the use of combined oral contraceptives (OCs) and if this influence depended on the androgenic or non-androgenic properties of progestin. Methods Healthy adult women were enrolled and stratified into two groups: women who did not use OCs (Fs) and women treated with OCs (FOCs). FOCs were further stratified as a function of androgenic (FOCA+) and non-androgenic (FOCA-) properties of progestins. Routine hematological, biochemical, inflammatory and endothelial dysfunction parameters were measured. Monocyte-derived macrophages (MDMs) were evaluated for the expression and activity of estrogen receptors and androgen receptors, and release of tumor necrosis factor α (TNFα) was measured from unstimulated and lipopolysaccharide-stimulated cells. Results As is already known, the use of OCs changed numerous parameters: the number of lymphocytes, iron levels, total iron-binding capacity of transferrin, triglycerides, high-density lipoprotein, total cholesterol, and C-reactive protein increased, while prothrombin time and alkaline phosphatase decreased. Hormonal levels also varied: cortisol was higher in FOCs, while luteinizing hormone, follicle-stimulating hormone, and testosterone were lower in FOCs. Asymmetric dimethylarginine, an index of endothelial function, was lower in FOC than in Fs, as were cysteine and bilirubin. The androgenic properties of progestins affected the activity of OCs: in particular, white blood cell count, hemoglobin, high-density lipoprotein and calcium were higher in FOCA- than in FOCA+, whereas percentage oxygen saturation and γ-glutamyl transpeptidase were lower in FOCA- than in FOCA+. Importantly, FOCs had a lower global DNA methylation, indicating that OC may have epigenetic effects on gene expression. OC did not modify the expression of androgen receptor but increased estrogen receptor α expression, more considerably in FOCA+, and decreased estrogen receptor β, more considerably in FOCA-. Importantly, the activation state of estrogen receptor β in FOCs was decreased, while estrogen receptor α was not active in either Fs or FOCs. Unstimulated MDMs obtained from FOCs showed higher release of TNFα in comparison with Fs. After lipopolysaccharide stimulation, the release of TNFα was significantly higher in Fs than in FOCs. Conclusions OC use induced many changes in hematological and plasmatic markers, modifying hormonal levels, endothelial function, inflammation index and some redox state parameters, producing a perturbation of the internal milieu that impacted macrophagic function. In fact, different levels of estrogen receptor expression and release of TNFα were observed in macrophages derived from OC users. Some of the above activities were linked to the androgenic properties of progestin. Even though it is not known whether these effects are reversible, the results indicate that to avoid potential skewing of results only a single type of OC should be used during a single clinical trial.

Several substances present in the environment, now classified as endocrine disruptors (EDs), strongly interfere with both androgen and oestrogen actions in reproductive tissues. However, nowadays it is well recognized that these sex steroid hormones are more than regulators of gonadal functions. In fact, they, in synergy with genes, are responsible of sex-related differences in anatomical, physiological, and behavioral traits which characterize males and females of many vertebrate species, including humans. Thus, even if EDs are present in minute amount (part for trillion) in environment, their effects in male and female physiology could be greater than before expected also prejudicing the sex-steroid hormone-induced integrated physiological responses in women and men. In addition, differences in male and female susceptibility to EDs could be present even if scarce information on this aspect is still available. Here we have reviewed the state of the art on the sex-related susceptibility to EDs underlying the mechanism at the root of these effects.

Nutrition exerts a life-long impact on human health, and the interaction between nutrition and health has been known for centuries. The recent literature has suggested that nutrition could differently influence the health of male and female individuals. Until the last decade of the 20th century, research on women has been neglected, and the results obtained in men have been directly translated to women in both the medicine and nutrition fields. Consequently, most modern guidelines are based on studies predominantly conducted on men. However, there are many sex–gender differences that are the result of multifactorial inputs, including gene repertoires, sex steroid hormones, and environmental factors (e.g., food components). The effects of these different inputs in male and female physiology will be different in different periods of ontogenetic development as well as during pregnancy and the ovarian cycle in females, which are also age dependent. As a result, different strategies have evolved to maintain male and female body homeostasis, which, in turn, implies that there are important differences in the bioavailability, metabolism, distribution, and elimination of foods and beverages in males and females. This article will review some of these differences underlying the impact of food components on the risk of developing diseases from a sex–gender perspective.

Bisphenol A (BPA), a prototype of endocrine disruptors, mimics 17β-estradiol (E2)-induced proliferation in several cancer cells by binding to estrogen receptor α (ERα). However, scarce and conflicting data are available concerning the effect of BPA on estrogen receptor β (ERβ)-mediated functions. Here, the detailed analysis of the effect of BPA, alone or in combination with E2, on ERβ-mediated cellular functions is reported in ERβ-expressing colon cancer cell line. BPA binds to ERβ without activating any receptor activities. On the other hand, BPA inhibits E2-induced genomic activity of ERβ as well as ERβ extra-nuclear activities (i.e., ERβ:p38 association and p38 activation). As a consequence, BPA impairs the E2-induced activation of the apoptotic cascade which is at the root of the protective role played by the hormone against colon cancer growth. Thus, women may be considered a highly susceptible population with an increased risk of colon cancers after BPA exposures. © 2010 IUBMB IUBMB Life, 62(9): 684–687, 2010

Sexual dimorphism, detectable in vascular smooth muscle cells freshly isolated from aorta of male and female rats, is associated with a different susceptibility to radiation-induced apoptosis. In this work we investigated the mechanism underlying this difference and discovered that, in comparison with cells from male rats, cells from female rats show adhesion-associated resistance to apoptosis, the so called anoikis resistance. This is apparently due to a more adhering phenotype, characterized by a well organized actin microfilament cytoskeleton and to an increased phosphorylated focal adhesion kinase, and, more importantly, to a higher propensity to undergo survival by autophagy.

The flavonol quercetin, especially abundant in apple, wine, and onions, is reported to have anti-proliferative effects in many cancer cell lines. Antioxidant or pro-oxidant activities and kinase inhibition have been proposed as molecular mechanisms for these effects. In addition, an estrogenic activity has been observed but, at the present, it is poorly understood whether this latter activity plays a role in the quercetin-induced anti-proliferative effects. Here, we studied the molecular mechanisms of quercetin committed to the generation of an apoptotic cascade in cancer cells devoid or containing transfected estrogen receptor alpha (ERalpha; i.e., human cervix epitheloid carcinoma HeLa cells). Although none of tested quercetin concentrations increase reactive oxygen species (ROS) generation in HeLa cells, quercetin stimulation prevents the H(2)O(2)-induced ROS production both in the presence and in the absence of ERalpha. However, this flavonoid induces the activation of p38/MAPK, leading to the pro-apoptotic caspase-3 activation and to the poly(ADP-ribose) polymerase cleavage only in the presence of ERalpha. Notably, no down-regulation of survival kinases (i.e., AKT and ERK) was reported. Taken together, these findings suggest that quercetin results in HeLa cell death through an ERalpha-dependent mechanism involving caspase- and p38 kinase activation. These findings indicate new potential chemopreventive actions of flavonoids on cancer growth.

Naringenin (Nar) is a component of fruits and vegetables associated with healthful benefits, such as in osteoporosis, cancer, and cardiovascular diseases. These protective effects have been linked with Nar antiestrogenic as well as estrogenic activities. Previous studies indicate that Nar impaired estrogen receptor (ER) alpha signaling by interfering with ERalpha-mediated activation of ERK and phosphoinositide 3-kinase signaling pathways in the absence of effects at the transcriptional level. The present studies evaluated the hypothesis that these Nar antagonistic effects occur at the level of the plasma membrane. Our results indicate that Nar induces ERalpha depalmitoylation faster than 17beta-estradiol, which results in receptor rapid dissociation from caveolin-1. Furthermore, Nar impedes ERalpha to bind adaptor (modulator of nongenomic actions of the ER) and signaling (c-Src) proteins involved in the activation of the mitogenic signaling cascades (i.e. ERK and phosphoinositide 3-kinase). On the other hand, Nar induces the ER-dependent, but palmitoylation-independent, activation of p38 kinase, which in turn is responsible for Nar-mediated antiproliferative effects in cancer cells. Altogether, these data highlight new ER-dependent mechanisms on the root of antiproliferative and antiestrogenic effects of Nar. Moreover, the different modulation of ERalpha palmitoylation exerted by different ligands represents a pivotal mechanism that drives cancer cell to proliferation or apoptosis.

Adipose tissue has recently been described as one of the major endocrine gland that plays a role in energy homeostasis, lipid metabolism, immune response, and reproduction. An excess of white adipose tissue, caused by a complex interaction between genetic, hormonal, behavioral, and environmental factors, results in obesity: a heterogeneous disorder that predisposes humans to a variety of diseases. Among several hormones, estrogens promote, maintain, and control the typical distribution of body fat and adipose tissue metabolism through still unknown mechanisms. These steroids are known to regulate fat mass, adipose deposition and differentiation, and adipocyte metabolism. Moreover, estrogen deficiency results in increases in adipose tissue, preferentially in visceral fat, which would link obesity to the susceptibility of related disorders. In this review the role of estrogens in adipose tissue differentiation and in the protection against the onset of obesity will be discussed with particular attention being drawn to the underlying molecular mechanisms mediated by estrogen receptor isoforms ERalpha and ERbeta.