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Sample records for oestrogen modulates human

  1. Clinically used selective oestrogen receptor modulators increase LDL receptor activity in primary human lymphocytes

    PubMed Central

    Cerrato, F; Fernández-Suárez, M E; Alonso, R; Alonso, M; Vázquez, C; Pastor, O; Mata, P; Lasunción, M A; Gómez-Coronado, D

    2015-01-01

    Background and Purpose Treatment with selective oestrogen receptor modulators (SERMs) reduces low-density lipoprotein (LDL) cholesterol levels. We assessed the effect of tamoxifen, raloxifene and toremifene and their combinations with lovastatin on LDL receptor activity in lymphocytes from normolipidaemic and familial hypercholesterolaemic (FH) subjects, and human HepG2 hepatocytes and MOLT-4 lymphoblasts. Experimental Approach Lymphocytes were isolated from peripheral blood, treated with different compounds, and 1,1′-dioctadecyl-3,3,3,3′-tetramethylindocarbocyanine perchlorate (DiI)-labelled LDL uptake was analysed by flow cytometry. Key Results Tamoxifen, toremifene and raloxifene, in this order, stimulated DiI-LDL uptake by lymphocytes by inhibiting LDL-derived cholesterol trafficking and subsequent down-regulation of LDL receptor expression. Differently to what occurred in HepG2 and MOLT-4 cells, only tamoxifen consistently displayed a potentiating effect with lovastatin in primary lymphocytes. The SERM-mediated increase in LDL receptor activity was not altered by the anti-oestrogen ICI 182 780 nor was it reproduced by 17β-oestradiol. However, the tamoxifen-active metabolite endoxifen was equally effective as tamoxifen. The SERMs produced similar effects on LDL receptor activity in heterozygous FH lymphocytes as in normal lymphocytes, although none of them had a potentiating effect with lovastatin in heterozygous FH lymphocytes. The SERMs had no effect in homozygous FH lymphocytes. Conclusions and Implications Clinically used SERMs up-regulate LDL receptors in primary human lymphocytes. There is a mild enhancement between SERMs and lovastatin of lymphocyte LDLR activity, the potentiation being greater in HepG2 and MOLT-4 cells. The effect of SERMs is independent of oestrogen receptors but is preserved in the tamoxifen-active metabolite endoxifen. This mechanism may contribute to the cholesterol-lowering action of SERMs. PMID:25395200

  2. Tartrazine and sunset yellow are xenoestrogens in a new screening assay to identify modulators of human oestrogen receptor transcriptional activity.

    PubMed

    Axon, Andrew; May, Felicity E B; Gaughan, Luke E; Williams, Faith M; Blain, Peter G; Wright, Matthew C

    2012-08-16

    Primary biliary cirrhosis (PBC) is a cholestatic liver disease of unknown cause that occurs most frequently in post-menopausal women. Since the female sex hormone oestrogen can be cholestatic, we hypothesised that PBC may be triggered in part by chronic exposure to xenoestrogens (which may be more active on a background of low endogenous oestrogen levels seen in post-menopausal women). A reporter gene construct employing a synthetic oestrogen response element predicted to specifically interact with oestrogen receptors (ER) was constructed. Co-transfection of this reporter into an ER null cell line with a variety of nuclear receptor expression constructs indicated that the reporter gene was trans-activated by ERα and ERβ, but not by the androgen, thyroid, progesterone, glucocorticoid or vitamin D receptors. Chemicals linked to PBC were then screened for xenoestrogen activity in the human ERα-positive MCF-7 breast cancer cell line. Using this assay, the coal-derived food and cosmetic colourings--sunset yellow and tartrazine--were identified as novel human ERα activators, activating the human ER with an EC(50%) concentration of 220 and 160 nM, respectively.

  3. Modulation of autoimmune rheumatic diseases by oestrogen and progesterone.

    PubMed

    Hughes, Grant C; Choubey, Divaker

    2014-12-01

    Sexual dimorphism is evident in the risk and expression of several human autoimmune diseases. Differences in disease manifestations observed between sexes are likely to involve immunomodulation by sex steroids, nonhormonal factors encoded by genes on the X and Y chromosomes, and immunological phenomena unique to pregnancy. In systemic lupus erythematosus (SLE), and perhaps other autoantibody-mediated diseases, oestrogen seems to increase the risk of disease in genetically predisposed women by targeting key immune pathways, including the type 1 interferon (IFN) response, differentiation of CD4(+) T helper cells and survival of autoreactive B cells. By contrast, progesterone seems to reduce the risk of SLE by counteracting the effects of oestrogen on some of these same pathways, which suggests that the balance between oestrogen and progesterone can determine disease expression. In this Review we focus on the roles of the sex steroid hormones oestrogen and progesterone in modulating the risk and expression of SLE and rheumatoid arthritis. Intensive research in this area promises to identify novel therapeutic strategies and improve understanding of the immunological requirements and complications of pregnancy, and is expected to define the mechanisms behind sexual dimorphism in autoimmunity, immunity and other aspects of human health--a newly announced directive of the NIH.

  4. Different methylation of oestrogen receptor DNA in human breast carcinomas with and without oestrogen receptor.

    PubMed Central

    Piva, R.; Rimondi, A. P.; Hanau, S.; Maestri, I.; Alvisi, A.; Kumar, V. L.; del Senno, L.

    1990-01-01

    The methylation of the human oestrogen receptor (ER) gene was analysed by restriction enzymes in normal and neoplastic human breast tissues and cell lines. CCGG sequences in regions inside the gene, which are methylated both in normal breast and in tissues that are not the target of the oestrogen, are hypomethylated in 30% of tumours, both ER+ and ER- carcinomas. Moreover, 5' sequences of the gene, which are hypomethylated in normal breast and not in tissues not the target of oestrogen, are methylated to a lower degree in ER+ carcinomas, whereas they are methylated to a greater degree in ER- carcinomas. However, the same region is equally hypomethylated in both ER+ and ER- cancer cell lines. Our results indicate that in breast carcinomas ER DNA methylation is deranged, and in cancer cell lines is different from that observed in primary tumours. Furthermore, the abnormal methylation in the 5' end seems to be related to abnormal expression, namely diffuse hypomethylation in carcinomas with high ER content and hypermethylation in carcinomas without ER. These findings support our previous hypothesis that DNA methylation could be involved in the control of ER gene expression and demonstrate that abnormal ER gene methylation is a typical feature of breast cancers. Images Figure 1 Figure 2 Figure 3 PMID:2155643

  5. Primate-specific oestrogen-responsive long non-coding RNAs regulate proliferation and viability of human breast cancer cells

    PubMed Central

    Lin, Chin-Yo; Dachet, Fabien; Cai, Juan; Ju, Donghong; Goldstone, Amanda; Wood, Emily J.; Liu, Ka; Jia, Hui; Kosir, Mary A.; Thepsuwan, Pattaraporn

    2016-01-01

    Long non-coding RNAs (lncRNAs) are transcripts of a recently discovered class of genes which do not code for proteins. LncRNA genes are approximately as numerous as protein-coding genes in the human genome. However, comparatively little remains known about lncRNA functions. We globally interrogated changes in the lncRNA transcriptome of oestrogen receptor positive human breast cancer cells following treatment with oestrogen, and identified 127 oestrogen-responsive lncRNAs. Consistent with the emerging evidence that most human lncRNA genes lack homologues outside of primates, our evolutionary analysis revealed primate-specific lncRNAs downstream of oestrogen signalling. We demonstrate, using multiple functional assays to probe gain- and loss-of-function phenotypes in two oestrogen receptor positive human breast cancer cell lines, that two primate-specific oestrogen-responsive lncRNAs identified in this study (the oestrogen-repressed lncRNA BC041455, which reduces cell viability, and the oestrogen-induced lncRNA CR593775, which increases cell viability) exert previously unrecognized functions in cell proliferation and growth factor signalling pathways. The results suggest that oestrogen-responsive lncRNAs are capable of altering the proliferation and viability of human breast cancer cells. No effects on cellular phenotypes were associated with control transfections. As heretofore unappreciated components of key signalling pathways in cancers, including the MAP kinase pathway, lncRNAs hence represent a novel mechanism of action for oestrogen effects on cellular proliferation and viability phenotypes. This finding warrants further investigation in basic and translational studies of breast and potentially other types of cancers, has broad relevance to lncRNAs in other nuclear hormone receptor pathways, and should facilitate exploiting and targeting these cell viability modulating lncRNAs in post-genomic therapeutics. PMID:28003470

  6. Immunohistochemical study of oestrogen receptors in 351 human thyroid glands.

    PubMed

    Tavangar, S M; Monajemzadeh, M; Larijani, B; Haghpanah, V

    2007-08-01

    It is well recognised that the pathogenesis of thyroid diseases is complex and different factors such as genetic factors, iodine deficiency, sex, age, radiation therapy in childhood, growth stimulating antibodies, and other epithelial growth factors can influence them. Epidemiological features of thyroid tumours and experimental evidence suggest that female sex hormones may exert effects on the thyroid gland and its neoplasms. This possibility was addressed by investigating the expression of oestrogen receptor protein in 351 thyroid lesions. The tissues from 351 human thyroid glands comprising 130 nodular goitres and 221 neoplastic lesions were used for the present immunohistochemical assessment of oestrogen receptor expression. Incidence of oestrogen receptor positive cases were 24 percent (31/130) for nodular goitres, 22 percent (8/37) for follicular adenomas, 11 percent (2/18) for follicular carcinomas, 31 percent (37/119) for papillary carcinomas, zero percent (0/35) for medullary carcinomas and zero percent (0/12) for undifferentiated carcinomas. The incidence of oestrogen receptor positivity, which is compatible with other studies, is higher in well-differentiated thyroid lesions. The incidence of oestrogen receptor reactivity does not significantly differ between females and males of different age groups and it does not correlate with lymph node status, and vascular and capsular invasions. The relatively high proportion of oestrogen receptor positivity in goitres, follicular adenomas and papillary carcinomas, compared with its reactivity in other thyroid neoplasms, and contrasted against normal thyroid tissue, suggests that the incidence of oestrogen receptor reactivity tends to increase with better differentiation of thyroid lesions. This finding may have clinical relevance.

  7. Oestrogen Modulates Hypothalamic Control of Energy Homeostasis Through Multiple Mechanisms

    PubMed Central

    Roepke, Troy A.

    2009-01-01

    The control of energy homeostasis in women is correlated with the anorectic effects of oestrogen, which can attenuate body weight gain and reduce food intake in rodent models. This review will investigate the multiple signalling pathways and cellular targets that oestrogen utilises to control energy homeostasis in the hypothalamus. Oestrogen affects all of the hypothalamic nuclei that control energy homeostasis. Oestrogen controls the activity of hypothalamic neurones through gene regulation and neuronal excitability. Oestrogen’s primary cellular pathway is the control of gene transcription through the classical ERs (ERα and ERβ) with ERα having the primary role in energy homeostasis. Oestrogen also controls energy homeostasis through membrane-mediated events via membrane-associated ERs or a novel, putative membrane ER that is coupled to G-proteins. Therefore, oestrogen has at least two receptors with multiple signalling and transcriptional pathways to activate during immediate and long-term anorectic effects. Ultimately, it is the interactions of all the receptor-mediated processes in hypothalamus and other areas of the CNS that will determine the anorectic effects of oestrogen and its control of energy homeostasis. PMID:19076267

  8. Type II oestrogen binding sites in human colorectal carcinoma.

    PubMed Central

    Piantelli, M; Ricci, R; Larocca, L M; Rinelli, A; Capelli, A; Rizzo, S; Scambia, G; Ranelletti, F O

    1990-01-01

    Seven cases of colorectal adenocarcinomas were investigated for the presence of oestrogen receptors and progesterone receptors. The tumours specifically bound oestradiol. This binding almost exclusively resulted from the presence of high numbers of type II oestrogen binding sites. Oestrogen receptors were absent or present at very low concentrations. Immunohistochemical investigation of nuclear oestrogen receptors gave negative results. This indicates that antioestrogen receptor antibodies recognise oestrogen receptors but not type II oestrogen binding sites. The presence of specific type II oestrogen binding sites and progesterone binding offers further evidence for a potential role for these steroids and their receptors in colorectal carcinoma. PMID:2266171

  9. The role of oestrogen in the control of ciliated cells of the human endometrium.

    PubMed

    More, I A; Masterton, R G

    1976-05-01

    The incidence of ciliated cells in the human endometrium was determined. Conditions associated with an excess of oestrogenic activity were characterized by an increased incidence of ciliated cells, whilst oestrogen deficiency was associated with decreased numbers. When endometrium was cultured, addition of oestradiol-17 beta caused an increase in the ciliated cell population.

  10. Antiresorptive drugs beyond bisphosphonates and selective oestrogen receptor modulators for the management of postmenopausal osteoporosis.

    PubMed

    Reginster, J Y; Neuprez, A; Beaudart, C; Lecart, M P; Sarlet, N; Bernard, D; Disteche, S; Bruyere, O

    2014-06-01

    Osteoporotic fractures are a major cause of morbidity in the elderly population. Since postmenopausal osteoporosis is related to an increase in osteoclastic activity at the time of menopause, inhibitors of bone resorption have genuinely been considered an adequate strategy for prevention and treatment of osteoporosis. Bisphosphonates and selective oestrogen receptor modulators are widely prescribed to treat osteoporosis. However, other antiresorptive drugs have been developed for the management of osteoporosis, with the objective of providing a substantial reduction in osteoporotic fractures at all skeletal sites, combined with an acceptable long-term skeletal and systemic safety profile. Denosumab, a human monoclonal antibody to receptor activator for nuclear factor kappa B ligand, has shown efficacy against vertebral, nonvertebral and hip fractures. Its administration every 6 months as a subcutaneous formulation might significantly influence compliance and persistence to therapy. Additional results regarding long-term skeletal safety (i.e. osteonecrosis of the jaw and atypical diaphyseal femoral fracture) are needed. Odanacatib, a selective cathepsin K inhibitor, is a promising new approach to the inhibition of osteoclastic resorption, with the potential to uncouple bone formation from bone resorption. Results regarding its anti-fracture efficacy are expected in the coming months.

  11. From in vivo gene targeting of oestrogen receptors to optimization of their modulation in menopause

    PubMed Central

    Arnal, Jean-François; Lenfant, Françoise; Flouriot, Gilles; Tremollières, Florence; Laurell, Henrik; Fontaine, Coralie; Krust, Andrée; Chambon, Pierre; Gourdy, Pierre

    2012-01-01

    The ancestral status of oestrogen receptor (ER) in the family of the steroid receptors has probably contributed to the pleiotropic actions of oestrogens, and in particular, that of 17β-oestradiol (E2). Indeed, in addition to their well-described role in sexual development and reproduction, they influence most of the physiological processes. The pathophysiological counterpart of these actions includes prevention of osteoporosis, atheroma and type 2 diabetes, and also the promotion of uterus and breast cancer growth. Thus, the major challenge consists in uncoupling some beneficial actions from other deleterious ones, that is, selective ER modulation. Tamoxifen and raloxifene are already used, as they prevent the recurrence of breast cancer and mimic oestrogen action mainly on bone. Both E2 and tamoxifen exhibit a proliferative and, thus, a protumoural action on the endometrium. Activation of ERα and ERβ regulates target gene transcription (genomic action) through two independent activation functions, AF-1 and AF-2, but can also elicit rapid membrane-initiated steroid signals. In the present review, we attempted to summarize recent advances provided by the in vivo molecular ‘dissection’ of ERα, allowing the uncoupling of some of its actions and potentially paving the way to optimized selective ER modulators. PMID:21671899

  12. Hypersensitivity and growth adaptation of oestrogen-deprived MCF-7 human breast cancer cells.

    PubMed

    Darbre, Philippa D

    2014-01-01

    Efficacy of endocrine therapy is compromised when human breast cancer cells circumvent imposed growth inhibition. The model of long-term oestrogen-deprived MCF-7 human breast cancer cells has suggested the mechanism results from hypersensitivity to low levels of residual oestrogen. MCF-7 cells were maintained for up to 30 weeks in phenol-red-free medium and charcoal-stripped serum with 10(-8) M 17β-oestradiol and 10 μg/ml insulin (stock 1), 10(-8) M 17β-oestradiol (stock 2), 10 μg/ml insulin (stock 3) or no addition (stock 4). Loss of growth response to oestrogen was observed only in stock 4 cells. Long-term maintenance with insulin in the absence of oestradiol (stock 3) resulted in raised oestrogen receptor-alpha (ERα) levels (measured by western immunoblotting) and development of hypersensitivity (assayed by oestrogen-responsive reporter gene induction and dose response to oestradiol for proliferation under serum-free conditions), but with no loss of growth response to oestrogen. Hypersensitivity can develop without any growth adaptation and therefore is not a prerequisite for loss of growth response in MCF-7 cells.

  13. Comparative assessment of endocrine modulators with oestrogenic activity: I. Definition of a hygiene-based margin of safety (HBMOS) for xeno-oestrogens against the background of European developments.

    PubMed

    Bolt, H M; Janning, P; Michna, H; Degen, G H

    2001-01-01

    A novel concept - the hygiene-based margin of safety (HBMOS) - is suggested for the assessment of the impact of potential endocrine modulators. It integrates exposure scenarios and potency data for industrial chemicals and naturally occurring dietary compounds with oestrogenic activity. An HBMOS is defined as a quotient of estimated daily intakes weighted by the relative in vivo potencies of these compounds. The Existing Chemicals Programme of the European Union provides Human and Environmental Risk Assessments of Existing Chemicals which include human exposure scenarios. Such exposure scenarios, along with potency estimates for endocrine activities, may provide a basis for a quantitative comparison of the potential endocrine-modulating effects of industrial chemicals with endocrine modulators as natural constituents of human diet. Natural phyto-oestrogens exhibit oestrogenic activity in vitro and in vivo. Important phyto-oestrogens for humans are isoflavones (daidzein, genistein) and lignans, with the highest quantities found in soybeans and flaxseed, respectively. Daily isoflavone exposures calculated for infants on soy-based formulae were in the ranges of 4.5-8 mg/kg body wt.; estimates for adults range up to 1 mg/kg body wt. The Senate Commission on the Evaluation of Food Safety (SKLM) of the Deutsche Forschungsgemeinschaft has also indicated a wide range of dietary exposures. For matters of risk assessment, the SKLM has based recommendations on dietary exposure scenarios, implying a daily intake of phyto-oestrogens in the order of 1 mg/kg body wt. On the basis of information compiled within the Existing Chemicals Programme of the EU, it appears that a daily human exposure to nonylphenol of 2 microg/kg body wt. may be a worst-case assumption, but which is based on valid scenarios. The intake of octylphenol is much lower, due to a different use pattern and applications, and may be neglected. Data from migration studies led to estimations of the daily human

  14. Oestrogen increases S-phase fraction and oestrogen and progesterone receptors in human cervical cancer in vivo.

    PubMed Central

    Bhattacharya, D.; Redkar, A.; Mittra, I.; Sutaria, U.; MacRae, K. D.

    1997-01-01

    Although cancer of the cervix is traditionally considered not to be responsive to steroid hormones, an in vitro study has reported that the addition of oestrogen increased cellular proliferation in a cervix cancer cell line that was inhibited by progesterone. We investigated whether the reported in vitro effects of oestrogen and progesterone on cellular proliferation can be replicated in locally advanced cervical cancer in vivo and whether these effects, if any, are related to oestrogen and progesterone receptor (ER and PgR) content of the tumour. One hundred post-menopausal patients with locally advanced cervical cancer were systematically allocated by rotation to the four treatment groups: (1) control group receiving no treatment; (2) ethinyl oestradiol 50 micrograms: (3) norethisterone 5 mg: (4) a combination of ethinyl oestradiol and norethisterone. Hormone treatment (five doses) was given orally every 12 h. Tissue biopsies were taken before and 12 h after the last hormone treatment. S-phase fraction (SpF) was measured by flow cytometry, and ER and PgR were measured by enzyme immunoassay. Results were analysed using two-factor analysis of variance, the factors being oestrogen-absent or present- and progesterone-absent or present. The main effects of oestrogen were increases in SpF, ER and PgR, which were statistically significant (P = 0.0056, 0.0009 and 0.01 respectively), indicating that there is much greater change in these three parameters in the presence of oestrogen (mean changes 7.808%, 6.258 fmol mg-1 and 12.716 fmol mg-1 for SpF, ER and PgR respectively) than in its absence (mean change -1.986%,-3.041 fmol mg-1 and 1.736 fmol mg-1 respectively). The progestogen main effect and the oestrogen-progestogen interaction were not significant. The rise in SpF, ER and PgR in the presence of oestrogen had a correlation coefficient with the initial ER values of -0.0565, -0.2863 and -0.1230 respectively, none being statistically significant, suggesting that the

  15. Bisphenol A modulates the metabolic regulator oestrogen-related receptor-α in T-cells.

    PubMed

    Cipelli, Riccardo; Harries, Lorna; Okuda, Katsuhiro; Yoshihara, Shin'ichi; Melzer, David; Galloway, Tamara

    2014-01-01

    Bisphenol A (BPA) is a widely used plastics constituent that has been associated with endocrine, immune and metabolic effects. Evidence for how BPA exerts significant biological effects at chronic low levels of exposure has remained elusive. In adult men, exposure to BPA has been associated with higher expression of two nuclear receptors, oestrogen receptor-β (ERβ) and oestrogen-related-receptor-α (ERRα), in peripheral white blood cells in vivo. In this study, we explore the expression of ESR2 (ERβ) and ESRRA (ERRα) in human leukaemic T-cell lymphoblasts (Jurkat cells) exposed to BPA in vitro. We show that exposure to BPA led to enhanced expression of ESRRA within 6 h of exposure (mean±s.e.m.: 1.43±0.08-fold increase compared with the control, P<0.05). After 72 h, expression of ESRRA remained significantly enhanced at concentrations of BPA ≥1 nM. Oxidative metabolism of BPA by rat liver S9 fractions yields the potent oestrogenic metabolite, 4-methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene (MBP). Exposure of cells to 1-100 nM MBP increased the expression of both ESRRA (significantly induced, P<0.05, at 1, 10, 100 nM) and ESR2 (1.32±0.07-fold increase at 100 nM exposure, P<0.01). ERRα is a major control point for oxidative metabolism in many cell types, including T-cells. Following exposure to both BPA and MBP, we found that cells showed a decrease in cell proliferation rate. Taken together, these results confirm the bioactivity of BPA against putative T-cell targets in vitro at concentrations relevant to general human exposure.

  16. Oestrogens and spermatogenesis

    PubMed Central

    Carreau, Serge; Hess, Rex A.

    2010-01-01

    The role of oestrogens in male reproductive tract physiology has for a long time been a subject of debate. The testis produces significant amounts of oestrogenic hormones, via aromatase, and oestrogen receptors (ERs)α (ESR1) and ERβ (ESR2) are selectively expressed in cells of the testis as well as the epididymal epithelium, depending upon species. This review summarizes the current knowledge concerning the presence and activity of aromatase and ERs in testis and sperm and the potential roles that oestrogens may have in mammalian spermatogenesis. Data show that physiology of the male gonad is in part under the control of a balance of androgens and oestrogens, with aromatase serving as a modulator. PMID:20403867

  17. Transdermal flux predictions for selected selective oestrogen receptor modulators (SERMs): comparison with experimental results.

    PubMed

    Güngör, Sevgi; Delgado-Charro, M Begoña; Masini-Etévé, Valérie; Potts, Russell O; Guy, Richard H

    2013-12-28

    The aim of this work was to evaluate the feasibility of delivering transdermally a series of highly lipophilic compounds (log P ~4-7), comprising several selective oestrogen receptor modulators and a modified testosterone (danazol). The maximum fluxes of the drugs were predicted theoretically using the modified Potts & Guy algorithm (to determine the permeability coefficient (kp) from water) and the calculated aqueous solubilities. The correction provided by Cleek & Bunge took into account the contribution of the viable epidermal barrier to the skin permeation of highly lipophilic compounds. Experimental measurements of drug fluxes from saturated hydroalcoholic solutions were determined in vitro through excised pig skin. Overall, the predicted fluxes were in good general agreement (within a factor of 10) with the experimental results. Most of the experimental fluxes were greater than those predicted theoretically suggesting that the 70:30 v/v ethanol-water vehicle employed may have had a modest skin penetration enhancement effect. This investigation shows that the transdermal fluxes of highly lipophilic compounds can be reasonably predicted from first principles provided that the viable epidermis, underlying the stratum corneum, is included as a potentially important contributor to the skin's overall barrier function. Furthermore, the absolute values of the measured fluxes, when considered in parallel with previous clinical studies, indicate that it might be feasible to topically deliver a therapeutically useful amount of some of the compounds considered to treat cancerous breast tissue.

  18. Oestrogens, via transforming growth factor alpha, modulate basic fibroblast growth factor synthesis in hypothalamic astrocytes: in vitro observations.

    PubMed

    Galbiati, M; Martini, L; Melcangi, R C

    2002-10-01

    The data presented here show that, in cultures of type 1 astrocytes obtained from the hypothalamus of neonatal female rat, 17beta-oestradiol is able to increase both the mRNA and the protein levels of basic fibroblast growth factor (bFGF). In particular, after 24 h of exposure to 17beta-oestradiol (10(-9) and 10(-10) m), an increase of messenger levels of bFGF appears in hypothalamic type 1 astrocytes. Similarly, an induction of bFGF protein is also evident at this time of exposure. The effect on the mRNA and protein levels of bFGF is blocked by the presence in the medium of an antibody raised against the transforming growth factor alpha (TGFalpha) receptor. This observation indicates that, TGFalpha, whose synthesis is modulated by oestrogens in hypothalamic astrocytes and which is able to increase, both the mRNA and the protein levels of bFGF in our experimental model, may act as the mediator of the oestrogenic induction of bFGF. Hypothalamic astrocytes, together with hypothalamic neurones synthesizing and secreting luteinizing hormone-releasing hormone (LHRH), form the LHRH network in conjunction with other neuronal systems. Gonadal steroids in general, and oestrogens in particular, play an important role in the control of the activity of this network. In addition, bFGF and TGFalpha, two growth factors released from astrocytes, are able to influence the activity of LHRH neurones. The present observations suggest that oestrogens may also act on LHRH neurones in an indirect fashion (i.e. by modulating the expression of bFGF and TGFalpha in glial cells).

  19. Sex differences in exercise-induced physiological myocardial hypertrophy are modulated by oestrogen receptor beta.

    PubMed

    Dworatzek, Elke; Mahmoodzadeh, Shokoufeh; Schubert, Carola; Westphal, Christina; Leber, Joachim; Kusch, Angelika; Kararigas, Georgios; Fliegner, Daniela; Moulin, Maryline; Ventura-Clapier, Renée; Gustafsson, Jan-Ake; Davidson, Mercy M; Dragun, Duska; Regitz-Zagrosek, Vera

    2014-06-01

    Oestrogen receptor alpha (ERα) and beta (ERβ) are involved in the regulation of pathological myocardial hypertrophy (MH). We hypothesize that both ER are also involved in physiological MH. Therefore, we investigated the role of ER in exercise-induced physiological MH in loss-of-function models and studied potential mechanisms of action. We performed 1 and 8 weeks of voluntary cage wheel running (VCR) with male and female C57BL/6J wild-type (WT), ERα- and ERβ-deleted mice. In line with other studies, female WT mice ran more than males (P ≤ 0.001). After 8 weeks of VCR, both sexes showed an increase in left ventricular mass (females: P ≤ 0.01 and males: P ≤ 0.05) with more pronounced MH in females (P < 0.05). As previously shown, female ERα-deleted mice run less than female WT mice (P ≤ 0.001). ERβ-deleted mice showed similar running performance as WT mice (females vs. male: P ≤ 0.001), but did not develop MH. Only female WT mice showed an increase in phosphorylation of serine/threonine kinase (AKT), ERK1/2, p38-mitogen-activated protein kinase (MAPK), and ribosomal protein s6, as well as an increase in the expression of key regulators of mitochondrial function and mitochondrial respiratory chain proteins (complexes I, III, and V) after VCR. However, ERβ deletion abolished all observed sex differences. Mitochondrial remodelling occurred in female WT-VCR mice, but not in female ERβ-deleted mice. The sex-specific response of the heart to exercise is modulated by ERβ. The greater increase in physiological MH in females is mediated by induction of AKT signalling, MAPK pathways, protein synthesis, and mitochondrial adaptation via ERβ. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.

  20. Activity of ixabepilone in oestrogen receptor-negative and oestrogen receptor-progesterone receptor-human epidermal growth factor receptor 2-negative metastatic breast cancer.

    PubMed

    Pivot, Xavier B; Li, Rubi K; Thomas, Eva S; Chung, Hyun-Cheol; Fein, Luis E; Chan, Valorie F; Jassem, Jacek; de Mendoza, Fernando Hurtado; Mukhopadyay, Pralay; Roché, Henri H

    2009-11-01

    Oestrogen receptor (ER)-negative breast cancer, including oestrogen receptor-, progesterone receptor- and human epidermal growth factor receptor 2-negative (ER/PR/HER2-negative) breast cancer, is more aggressive than ER-positive disease. A major limitation in the treatment of ER-negative disease subtypes is the inherent insensitivity to hormonal agents (tamoxifen, aromatase inhibitors) that are widely used in the treatment of breast cancer. Thus, therapeutic options for poor prognosis patients with ER-negative breast cancer are limited to a handful of chemotherapeutic agents, and new agents are needed to improve the treatment of this disease. Ixabepilone, a novel epothilone B analogue with low susceptibility to cellular mechanisms that confer resistance to taxanes and other chemotherapeutic agents, has demonstrated potent preclinical antitumour activity in multiple models, including those with primary or acquired drug resistance. This review summarises the results of a prospective subset analysis from a phase III clinical trial evaluating ixabepilone for the treatment of metastatic breast cancer (MBC), in which efficacy and safety were evaluated in patients with ER-negative and ER/PR/HER2-negative disease.

  1. Effects of Tamoxifen and oestrogen on histology and radiographic density in high and low mammographic density human breast tissues maintained in murine tissue engineering chambers.

    PubMed

    Chew, G L; Huo, C W; Huang, D; Blick, T; Hill, P; Cawson, J; Frazer, H; Southey, M C; Hopper, J L; Britt, K; Henderson, M A; Haviv, I; Thompson, E W

    2014-11-01

    Mammographic density (MD) is a strong risk factor for breast cancer. It is altered by exogenous endocrine treatments, including hormone replacement therapy and Tamoxifen. Such agents also modify breast cancer (BC) risk. However, the biomolecular basis of how systemic endocrine therapy modifies MD and MD-associated BC risk is poorly understood. This study aims to determine whether our xenograft biochamber model can be used to study the effectiveness of therapies aimed at modulating MD, by examine the effects of Tamoxifen and oestrogen on histologic and radiographic changes in high and low MD tissues maintained within the biochamber model. High and low MD human tissues were precisely sampled under radiographic guidance from prophylactic mastectomy fresh specimens of high-risk women, then inserted into separate vascularized murine biochambers. The murine hosts were concurrently implanted with Tamoxifen, oestrogen or placebo pellets, and the high and low MD biochamber tissues maintained in the murine host environment for 3 months, before the high and low MD biochamber tissues were harvested for histologic and radiographic analyses. The radiographic density of high MD tissue maintained in murine biochambers was decreased in Tamoxifen-treated mice compared to oestrogen-treated mice (p = 0.02). Tamoxifen treatment of high MD tissue in SCID mice led to a decrease in stromal (p = 0.009), and an increase in adipose (p = 0.023) percent areas, compared to placebo-treated mice. No histologic or radiographic differences were observed in low MD biochamber tissue with any treatment. High MD biochamber tissues maintained in mice implanted with Tamoxifen, oestrogen or placebo pellets had dynamic and measurable histologic compositional and radiographic changes. This further validates the dynamic nature of the MD xenograft model, and suggests the biochamber model may be useful for assessing the underlying molecular pathways of Tamoxifen-reduced MD, and in testing of other

  2. Interactions of ATP, oestradiol, genistein and the anti-oestrogens, faslodex (ICI 182780) and tamoxifen, with the human erythrocyte glucose transporter, GLUT1.

    PubMed Central

    Afzal, Iram; Cunningham, Philip; Naftalin, Richard J

    2002-01-01

    17 beta-Oestradiol (ED when subscript to K) and the phytoestrogen isoflavone genistein (GEN) inhibit glucose transport in human erythrocytes and erythrocyte ghosts. The selective oestrogen receptor modulators or anti-oestrogens, faslodex (ICI 182780) (FAS) and tamoxifen (TAM), competitively antagonize oestradiol inhibition of glucose exit from erythrocytes (K(i(ED/FAS))=2.84+/-0.16 microM and K(i(ED/TAM))=100+/-2 nM). Faslodex has no significant inhibitory effect on glucose exit, but tamoxifen alone inhibits glucose exit (K(i(TAM))=300+/-100 nM). In ghosts, ATP (1-4 mM) competitively antagonizes oestradiol, genistein and cytochalasin B (CB)-dependent inhibitions of glucose exit, (K(i(ATP/ED))=2.5+/-0.23 mM, K(i(ATP/GEN))=0.99+/-0.17 mM and K(i(ATP/CB))=0.76+/-0.08 mM). Tamoxifen and faslodex reverse oestradiol-dependent inhibition of glucose exit with ATP>1 mM (K(i(ED/TAM))=130+/-5 nM and K(i(ED/FAS))=2.7+/-0.9 microM). The cytoplasmic surface of the glucose transporter (GLUT)1 contains four sequences with close homologies to sequences in the ligand-binding domain of human oestrogen receptor beta (hesr-2). One homology is adjacent to the Walker ATP-binding motif II (GLUT1, residues 225-229) in the large cytoplasmic segment linking transmembrane helices 6 and 7; another GLUT (residues 421-423) contains the Walker ATP-binding motif III. Mapping of these regions on to a three-dimensional template of GLUT indicates that a possible oestrogen-binding site lies between His(337), Arg(349) and Glu(249) at the cytoplasmic entrance to the hydrophilic pore spanning GLUT, which have a similar topology to His(475), Glu(305) and Arg(346) in hesr-2 that anchor the head and tail hydroxy groups of oestradiol and genistein, and thus are suitably placed to provide an ATP-sensitive oestrogen binding site that could modulate glucose export. PMID:12133004

  3. Structural basis for androgen specificity and oestrogen synthesis in human aromatase

    SciTech Connect

    Ghosh, Debashis; Griswold, Jennifer; Erman, Mary; Pangborn, Walter

    2009-03-06

    Aromatase cytochrome P450 is the only enzyme in vertebrates known to catalyse the biosynthesis of all oestrogens from androgens. Aromatase inhibitors therefore constitute a frontline therapy for oestrogen-dependent breast cancer. In a three-step process, each step requiring 1 mol of O{sub 2}, 1 mol of NADPH, and coupling with its redox partner cytochrome P450 reductase, aromatase converts androstenedione, testosterone and 16{alpha}-hydroxytestosterone to oestrone, 17{beta}-oestradiol and 17{beta},16{alpha}-oestriol, respectively. The first two steps are C19-methyl hydroxylation steps, and the third involves the aromatization of the steroid A-ring, unique to aromatase. Whereas most P450s are not highly substrate selective, it is the hallmark androgenic specificity that sets aromatase apart. The structure of this enzyme of the endoplasmic reticulum membrane has remained unknown for decades, hindering elucidation of the biochemical mechanism. Here we present the crystal structure of human placental aromatase, the only natural mammalian, full-length P450 and P450 in hormone biosynthetic pathways to be crystallized so far. Unlike the active sites of many microsomal P450s that metabolize drugs and xenobiotics, aromatase has an androgen-specific cleft that binds the androstenedione molecule snugly. Hydrophobic and polar residues exquisitely complement the steroid backbone. The locations of catalytically important residues shed light on the reaction mechanism. The relative juxtaposition of the hydrophobic amino-terminal region and the opening to the catalytic cleft shows why membrane anchoring is necessary for the lipophilic substrates to gain access to the active site. The molecular basis for the enzyme's androgenic specificity and unique catalytic mechanism can be used for developing next-generation aromatase inhibitors.

  4. Structural basis for androgen specificity and oestrogen synthesis in human aromatase.

    PubMed

    Ghosh, Debashis; Griswold, Jennifer; Erman, Mary; Pangborn, Walter

    2009-01-08

    Aromatase cytochrome P450 is the only enzyme in vertebrates known to catalyse the biosynthesis of all oestrogens from androgens. Aromatase inhibitors therefore constitute a frontline therapy for oestrogen-dependent breast cancer. In a three-step process, each step requiring 1 mol of O(2), 1 mol of NADPH, and coupling with its redox partner cytochrome P450 reductase, aromatase converts androstenedione, testosterone and 16alpha-hydroxytestosterone to oestrone, 17beta-oestradiol and 17beta,16alpha-oestriol, respectively. The first two steps are C19-methyl hydroxylation steps, and the third involves the aromatization of the steroid A-ring, unique to aromatase. Whereas most P450s are not highly substrate selective, it is the hallmark androgenic specificity that sets aromatase apart. The structure of this enzyme of the endoplasmic reticulum membrane has remained unknown for decades, hindering elucidation of the biochemical mechanism. Here we present the crystal structure of human placental aromatase, the only natural mammalian, full-length P450 and P450 in hormone biosynthetic pathways to be crystallized so far. Unlike the active sites of many microsomal P450s that metabolize drugs and xenobiotics, aromatase has an androgen-specific cleft that binds the androstenedione molecule snugly. Hydrophobic and polar residues exquisitely complement the steroid backbone. The locations of catalytically important residues shed light on the reaction mechanism. The relative juxtaposition of the hydrophobic amino-terminal region and the opening to the catalytic cleft shows why membrane anchoring is necessary for the lipophilic substrates to gain access to the active site. The molecular basis for the enzyme's androgenic specificity and unique catalytic mechanism can be used for developing next-generation aromatase inhibitors.

  5. Structural basis for androgen specificity and oestrogen synthesis in human aromatase

    PubMed Central

    Ghosh, Debashis; Griswold, Jennifer; Erman, Mary; Pangborn, Walter

    2009-01-01

    Aromatase cytochrome P450 is the only enzyme in vertebrates known to catalyse the biosynthesis of all oestrogens from androgens1–3. Aromatase inhibitors therefore constitute a front-line therapy for oestrogen-dependent breast cancer3,4. In a three-step process, each step requiring 1 mol of O2, 1 mol of NADPH, and coupling with its redox partner cytochrome P450 reductase, aromatase converts androstenedione, testosterone and 16α-hydroxytestosterone to oestrone, 17β-oestradiol and 17β,16α-oestriol, respectively1–3. The first two steps are C19-methyl hydroxylation steps, and the third involves the aromatization of the steroid A-ring, unique to aromatase. Whereas most P450s are not highly substrate selective, it is the hallmark androgenic specificity that sets aromatase apart. The structure of this enzyme of the endoplasmic reticulum membrane has remained unknown for decades, hindering elucidation of the biochemical mechanism. Here we present the crystal structure of human placental aromatase, the only natural mammalian, full-length P450 and P450 in hormone biosynthetic pathways to be crystallized so far. Unlike the active sites of many microsomal P450s that metabolize drugs and xenobiotics, aromatase has an androgen-specific cleft that binds the androstenedione molecule snugly. Hydrophobic and polar residues exquisitely complement the steroid backbone. The locations of catalytically important residues shed light on the reaction mechanism. The relative juxtaposition of the hydrophobic amino-terminal region and the opening to the catalytic cleft shows why membrane anchoring is necessary for the lipophilic substrates to gain access to the active site. The molecular basis for the enzyme’s androgenic specificity and unique catalytic mechanism can be used for developing next-generation aromatase inhibitors. PMID:19129847

  6. High level expression of differentially localized BAG-1 isoforms in some oestrogen receptor-positive human breast cancers

    PubMed Central

    Brimmell, M; Burns, J S; Munson, P; McDonald, L; O’Hare, M J; Lakhani, S R; Packham, G

    1999-01-01

    Sensitivity to oestrogens and apoptosis are critical determinants of the development and progression of breast cancer and reflect closely linked pathways in breast epithelial cells. For example, induction of BCL-2 oncoprotein expression by oestrogen contributes to suppression of apoptosis and BCL-2 and oestrogen receptor (ER) are frequently co-expressed in tumours. BAG-1/HAP is a multifunctional protein which complexes with BCL-2 and steroid hormone receptors (including the ER), and can suppress apoptosis and influence steroid hormone-dependent transcription. Therefore, analysis of expression of BAG-1 in human breast cancer is of considerable interest. BAG-1 was readily detected by immunostaining in normal breast epithelial cells and most ER-positive tumours, but was undetectable or weakly expressed in ER-negative tumours. BAG-1 positive cells showed a predominantly cytoplasmic or cytoplasmic plus nuclear distribution of staining. A correlation between ER and BAG-1 was also evident in breast cancer derived cell lines, as all lines examined with functional ER expression also expressed high levels of BAG-1. In addition to the prototypical 36 kDa BAG-1 isoform, breast cancer cells expressed higher molecular weight isoforms and, in contrast to BCL-2, BAG-1 expression was independent of oestrogens. BAG-1 isoforms were differentially localized to the nucleus or cytoplasm and this was also independent of oestrogens. These results demonstrate a close association between BAG-1 and functional ER expression and suggest BAG-1 may be useful as a therapeutic target or prognostic marker in breast cancer. © 1999 Cancer Research Campaign PMID:10576663

  7. Proliferative effect of whey from cows' milk varying in phyto-oestrogens in human breast and prostate cancer cells.

    PubMed

    Nielsen, Tina S; Höjer, Annika; Gustavsson, Anne-Maj; Hansen-Møller, Jens; Purup, Stig

    2012-05-01

    Intake of dietary phyto-oestrogens has received a great deal of attention owing to their potential influence on hormone-sensitive cancers such as breast and prostate cancer. Cows' milk contains phyto-oestrogens and the content varies according to the composition of the feed and the type and amount of legumes used. In this study we evaluated the proliferative effect of milk (whey) with different phyto-oestrogen content in human breast (MCF-7) and prostate cancer cells (PC-3). Milk was obtained from cows fed either a birdsfoot trefoil-timothy silage based ration (B1) or two different red clover silage based diets (R1 and R2) resulting in total phyto-oestrogen contents of 403, 1659 and 1434 ng/ml for the B1, R1 and R2 diets, respectively. Whey was produced from the milk and added to cell culture medium in concentrations up to 10% for MCF-7 cells and 5% for PC-3 cells. Cell proliferation was measured fluorometrically after 7 d for MCF-7 cells and 5 d for PC-3 cells. There was no significant difference in the proliferative effect of whey from the different dietary treatments at any of the whey concentrations tested. An anti-proliferative effect (P<0·01) of 5 and 10% whey was seen when tested in the presence of 10 pM oestradiol in the medium. This effect was independent of dietary treatment of cows. Whey induced a significant (P<0·01) proliferative response in PC-3 cells independent of dietary treatment. Purified equol in concentrations similar to equol concentrations in milk decreased PC-3 cell proliferation, and therefore the stimulatory effect of whey in PC-3 cells is believed to be mediated by other bioactives than equol. In conclusion, our results suggest that using whey in these proliferation assays, it was not possible to discriminate between milk with high or low levels of phyto-oestrogens.

  8. Effect of aluminium on migration of oestrogen unresponsive MDA-MB-231 human breast cancer cells in culture.

    PubMed

    Bakir, Ayse; Darbre, Philippa D

    2015-11-01

    Aluminium (Al) has been measured in human breast tissue, and may be a contributory factor in breast cancer development. At the 10th Keele meeting, we reported that long-term exposure to Al could increase migratory properties of oestrogen-responsive MCF-7 human breast cancer cells suggesting a role for Al in the metastatic process. We now report that long-term exposure (20-25 weeks) to Al chloride or Al chlorohydrate at 10(-4) M or 10(-5) M concentrations can also increase the migration of oestrogen unresponsive MDA-MB-231 human breast cancer cells as measured using time-lapse microscopy and xCELLigence technology. In parallel, Al exposure was found to give rise to increased secretion of active matrix metalloproteinase MMP9 as measured by zymography, and increased intracellular levels of activated MMP14 as measured by western immunoblotting. These results demonstrate that Al can increase migration of human breast cancer cells irrespective of their oestrogen responsiveness, and implicate alterations to MMPs as a potential mechanism worthy of further study. Copyright © 2015 Elsevier Inc. All rights reserved.

  9. Effect of sulphation on the oestrogen agonist activity of the phytoestrogens genistein and daidzein in MCF-7 human breast cancer cells.

    PubMed

    Pugazhendhi, D; Watson, K A; Mills, S; Botting, N; Pope, G S; Darbre, P D

    2008-06-01

    The phytoestrogens genistein, daidzein and the daidzein metabolite equol have been shown previously to possess oestrogen agonist activity. However, following consumption of soya diets, they are found in the body not only as aglycones but also as metabolites conjugated at their 4'- and 7-hydroxyl groups with sulphate. This paper describes the effects of monosulphation on the oestrogen agonist properties of these three phytoestrogens in MCF-7 human breast cancer cells in terms of their relative ability to compete with [(3)H]oestradiol for binding to oestrogen receptor (ER), to induce a stably transfected oestrogen-responsive reporter gene (ERE-CAT) and to stimulate cell growth. In no case did sulphation abolish activity. The 4'-sulphation of genistein reduced oestrogen agonist activity to a small extent in whole-cell assays but increased the relative binding affinity to ER. The 7-sulphation of genistein, and also of equol, reduced oestrogen agonist activity substantially in all assays. By contrast, the position of monosulphation of daidzein acted in an opposing manner on oestrogen agonist activity. Sulphation at the 4'-position of daidzein resulted in a modest reduction in oestrogen agonist activity but sulphation of daidzein at the 7-position resulted in an increase in oestrogen agonist activity. Molecular modelling and docking studies suggested that the inverse effects of sulphation could be explained by the binding of daidzein into the ligand-binding domain of the ER in the opposite orientation compared with genistein and equol. This is the first report of sulphation enhancing activity of an isoflavone and inverse effects of sulphation between individual phytoestrogens.

  10. Oestrogen status in relation to the early training responses in human thumb adductor muscles.

    PubMed

    Onambele, G N L; Bruce, S A; Woledge, R C

    2006-09-01

    The aims of this study were to identify the mechanisms for the early response to training in women of different oestrogen status and to determine whether any oestrogen and exercise effects on these would be additive. We monitored training (ten 5-s contractions per day for 12 weeks)-induced changes in the size, strength, voluntary activation capacity and index of crossbridge force state (i.e. rapid stretch to isometric torque ratio), in the thumb adductor muscles of postmenopausal [eight who had never used, and 14 who were using, hormone replacement therapy (HRT)] and seven premenopausal eumenorrhoeic women. The contralateral untrained muscle was used as a control. There was a significant effect of oestrogen status on the magnitude of training-induced strength increment, with the non-HRT postmenopausal group exhibiting the greatest benefits (28 +/- 6%, P = 0.024) from training. There were no significant or commensurate changes in either cross-sectional area or voluntary activation capacity. The index of crossbridge force state improved most in the no-HRT group (19 +/- 7%, P < 0.05). Presence, rather than absence of oestrogen, is associated with relatively higher muscle function which limits the potential for any further training-induced increments in muscle performance, as would be expected if the muscle strengthening actions of training and oestrogen share a common, partially saturable physiological pathway. The mechanism that is involved in the early training-induced strength increment in the three differing oestrogen groups cannot be due to increased size or recruitment. It would appear instead that increased motor unit firing frequency is involved.

  11. Phyto-oestrogens and breast cancer chemoprevention

    PubMed Central

    Limer, Jane L; Speirs, Valerie

    2004-01-01

    Phytoestrogens are polyphenol compounds of plant origin that exhibit a structural similarity to the mammalian steroid hormone 17β-oestradiol. In Asian nations the staple consumption of phyto-oestrogen-rich foodstuffs correlates with a reduced incidence of breast cancer. Human dietary intervention trials have noted a direct relationship between phyto-oestrogen ingestion and a favourable hormonal profile associated with decreased breast cancer risk. However, these studies failed to ascertain the precise effect of dietary phyto-oestrogens on the proliferation of mammary tissue. Epidemiological and rodent studies crucially suggest that breast cancer chemoprevention by dietary phyto-oestrogen compounds is dependent on ingestion before puberty, when the mammary gland is relatively immature. Phyto-oestrogen supplements are commercially marketed for use by postmenopausal women as natural and safe alternatives to hormone replacement therapy. Of current concern is the effect of phyto-oestrogen compounds on the growth of pre-existing breast tumours. Data are contradictory, with cell culture studies reporting both the oestrogenic stimulation of oestrogen receptor-positive breast cancer cell lines and the antagonism of tamoxifen activity at physiological phyto-oestrogen concentrations. Conversely, phyto-oestrogen ingestion by rodents is associated with the development of less aggressive breast tumours with reduced metastatic potential. Despite the present ambiguity, current data do suggest a potential benefit from use of phyto-oestrogens in breast cancer chemoprevention and therapy. These aspects are discussed. PMID:15084232

  12. Relationship between oestrogen-receptor content and histological grade in human primary breast tumours.

    PubMed Central

    Maynard, P. V.; Davies, C. J.; Blamey, R. W.; Elston, C. W.; Johnson, J.; Griffiths, K.

    1978-01-01

    A series of 300 patients presenting consecutively with primary operable breast cancer has been studied. A significant correlation was found between oestrogen-receptor (ER) content and histological grade: the better-differentiated tumours rarely lacked receptor. This correlation was significant only in women defined as post-menopausal. Data on early recurrence of disease indicate a worse prognosis for women in whom primary tumours are ER-. PMID:743491

  13. Steroid sulphatase and oestrogen sulphotransferase in human non-small-cell lung carcinoma

    PubMed Central

    Iida, S; Kakinuma, H; Miki, Y; Abe, K; Sakurai, M; Suzuki, S; Niikawa, H; Akahira, J; Suzuki, T; Sasano, H

    2013-01-01

    Background: Steroid sulphatase (STS) is one of the steroid-metabolising enzymes involved in desulphating inactive steroid sulphates and oestrogen sulphotransferase (EST) sulphates active oestrogen. The roles of both STS and EST have not been examined in oestrogen-dependent non-small-cell lung cancer (NSCLC). Methods: We evaluated the immunoreactivity of STS and EST in NSCLC cases using immunohistochemistry. The function of STS and EST was further demonstrated using NSCLC cell lines. Results: The immunoreactivity of STS and EST was detected in 49.5% and 27.8% of NSCLC cases, respectively. The immunoreactivity of STS was significantly higher in female adenocarcinoma cases. The STS-positive NSCLCs were also significantly correlated in an inversed manner with tumour size and cell proliferation and tended to be associated with better clinical outcome. However, the immunoreactivity of EST was significantly correlated with intracellular oestradiol concentration. Results of in vitro analysis demonstrated that oestrone sulphate (E1-S) induced and pregnenolone sulphate (Preg-S) inhibited the proliferation in STS-expressing cell lines. The inhibition by Preg-S was reversed by a specific progesterone receptor blocker. Simultaneous addition of E1-S and Preg-S significantly suppressed the proliferation. Conclusion: In NSCLC patients, STS is considered a good prognostic factor. Results of our present study also indicated the benefits of potential progesterone therapy for NSCLC patients. PMID:23531699

  14. Topical oestrogen keratinises the human foreskin and may help prevent HIV infection.

    PubMed

    Pask, Andrew J; McInnes, Kerry J; Webb, David R; Short, Roger V

    2008-06-04

    With the growing incidence of HIV, there is a desperate need to develop simple, cheap and effective new ways of preventing HIV infection. Male circumcision reduces the risk of infection by about 60%, probably because of the removal of the Langerhans cells which are abundant in the inner foreskin and are the primary route by which HIV enters the penis. Langerhans cells form a vital part of the body's natural defence against HIV and only cause infection when they are exposed to high levels of HIV virions. Rather than removing this natural defence mechanism by circumcision, it may be better to enhance it by thickening the layer of keratin overlying the Langerhans cells, thereby reducing the viral load to which they are exposed. We have investigated the ability of topically administered oestrogen to induce keratinization of the epithelium of the inner foreskin. Histochemically, the whole of the foreskin is richly supplied with oestrogen receptors. The epithelium of the inner foreskin, like the vagina, responds within 24 hours to the topical administration of oestriol by keratinization, and the response persists for at least 5 days after the cessation of the treatment. Oestriol, a cheap, readily available natural oestrogen metabolite, rapidly keratinizes the inner foreskin, the site of HIV entry into the penis. This thickening of the overlying protective layer of keratin should reduce the exposure of the underlying Langerhans cells to HIV virions. This simple treatment could become an adjunct or alternative to surgical circumcision for reducing the incidence of HIV infection in men.

  15. Oestrogen exposure and breast cancer risk

    PubMed Central

    Travis, Ruth C; Key, Timothy J

    2003-01-01

    Epidemiological and experimental evidence implicates oestrogens in the aetiology of breast cancer. Most established risk factors for breast cancer in humans probably act through hormone-related pathways, and increased concentrations of circulating oestrogens have been found to be strongly associated with increased risk for breast cancer in postmenopausal women. This article explores the evidence for the hypothesis that oestrogen exposure is a major determinant of risk for breast cancer. We review recent data on oestrogens and breast cancer risk, consider oestrogen-related risk factors and examine possible mechanisms that might account for the effects of oestrogen. Finally, we discuss how these advances might influence strategies for reducing the incidence of breast cancer. PMID:12927032

  16. Selective oestrogen receptor modulators lasofoxifene and bazedoxifene inhibit joint inflammation and osteoporosis in ovariectomised mice with collagen-induced arthritis.

    PubMed

    Andersson, Annica; Bernardi, Angelina I; Stubelius, Alexandra; Nurkkala-Karlsson, Merja; Ohlsson, Claes; Carlsten, Hans; Islander, Ulrika

    2016-03-01

    RA predominantly affects post-menopausal women and is strongly associated with development of generalised osteoporosis. To find treatments that target both joint manifestations and osteoporosis in RA is desirable. The third generation of selective oestrogen receptor modulators (SERMs) [lasofoxifene (LAS) and bazedoxifene (BZA)] are new treatment options for post-menopausal osteoporosis. The aim of this study was to investigate the effects of LAS and BZA on arthritic disease and inflammation-associated bone loss using CIA in mice. Female DBA/1 mice were ovariectomised and subjected to CIA as a model of post-menopausal RA. Mice received treatment with LAS, BZA, 17β-estradiol (E2) as reference or vehicle. Arthritis development was assessed and BMD was determined by peripheral quantitative CT of the femurs. Serologic markers of inflammation and cartilage destruction were analysed. Immune cells in lymph nodes were studied by flow cytometry. LAS and BZA reduced the clinical severity of arthritis as well as the grade of histologic synovitis and erosions on cartilage and bone. Moreover, SERMs protected against generalised bone loss in CIA by increasing trabecular BMD. Both SERMs decreased serum marker of cartilage destruction and LAS reduced serum IL-6 levels. SERMs did not alter Th17 cells in lymph nodes as E2 did. The anti-osteoporotic drugs LAS and BZA were found to be potent inhibitors of joint inflammation and bone destruction in experimental arthritis. This study provides new important knowledge regarding the treatment regimen of post-menopausal women with RA who suffer from increased risk for osteoporosis. © The Author 2015. Published by Oxford University Press on behalf of the British Society for Rheumatology.

  17. Inverse antagonist activities of parabens on human oestrogen-related receptor γ (ERRγ): In vitro and in silico studies

    SciTech Connect

    Zhang, Zhaobin; Sun, Libei; Hu, Ying; Jiao, Jian; Hu, Jianying

    2013-07-01

    Parabens are p-hydroxybenzoic acid esters that have been used extensively as preservatives in foods, cosmetics, drugs and toiletries. These intact esters are commonly detected in human breast cancer tissues and other human samples, thus arousing concern about the involvement of parabens in human breast cancer. In this study, an in vitro nuclear receptor coactivator recruiting assay was developed and used to evaluate the binding activities of parabens, salicylates and benzoates via antagonist competitive binding on the human oestrogen-related receptor γ (ERRγ), which is known as both a diagnostic biomarker and a treatment target of breast cancer. The results showed that all of the test parabens (methyl-, ethyl-, propyl-, butyl- and benzylparaben) possessed clear inverse antagonist activities on ERRγ, with a lowest observed effect level (LOEL) of 10{sup −7} M and the 50% relative effective concentrations (REC50) varying from 3.09 × 10{sup −7} to 5.88 × 10{sup −7} M, whereas the salicylates possessed much lower activities and the benzoates showed no obvious activity. In silico molecular docking analyses showed that parabens fitted well into the active site of ERRγ, with hydrogen bonds forming between the p-hydroxyl group of parabens and the Glu275/Arg316 of ERRγ. As the paraben levels reported in breast cancer tissues are commonly higher than the LOELs observed in this study, parabens may play some role via ERRγ in the carcinogenesis of human breast cancer. In addition, parabens may have significant effects on breast cancer patients who are taking tamoxifen, as ERRγ is regarded as a treatment target for tamoxifen. - Highlights: • An oestrogen-related receptor γ coactivator recruiting assay was developed. • Strong binding activities of parabens with oestrogen-related receptor γ were found. • The paraben levels reported in breast cancer tissues were higher than their LOELs. • Parabens may play some role via ERRγ in the carcinogenesis of human

  18. Synergic hypocholesterolaemic effect of n-3 PUFA and oestrogen by modulation of hepatic cholesterol metabolism in female rats.

    PubMed

    Oh, Yuna; Jin, Youri; Park, Yongsoon

    2015-12-14

    n-3 PUFA such as EPA and DHA as well as oestrogen have been reported to decrease blood levels of cholesterol, but their underlying mechanism is unclear. The purpose of this study was to determine the effects of the combination of n-3 PUFA supplementation and oestrogen injection on hepatic cholesterol metabolism. Rats were fed a modified AIN-93G diet with 0, 1 or 2 % n-3 PUFA (EPA+DHA) relative to the total energy intake for 12 weeks. Rats were surgically ovariectomised at week 8, and, after 1-week recovery, rats were injected with 17β-oestradiol-3-benzoate (E2) or maize oil for the last 3 weeks. Supplementation with n-3 PUFA and E2 injection significantly increased the ratio of the hepatic expression of phosphorylated AMP activated protein kinase (p-AMPK):AMP activated protein kinase (AMPK) and decreased sterol regulatory element-binding protein-2, 3-hydroxy-3-methylglutaryl coenzyme A reductase and proprotein convertase subtilisin/kexin type 9. Supplementation with n-3 PUFA increased hepatic expression of cholesterol 7α-hydroxylase (CYP7A1), sterol 12α-hydroxylase (CYP8B1) and sterol 27-hydroxylase (CYP27A1); however, E2 injection decreased CYP7A1 and CYP8B1 but not CYP27A1. Additionally, E2 injection increased hepatic expression of oestrogen receptor-α and β. In conclusion, n-3 PUFA supplementation and E2 injection had synergic hypocholesterolaemic effects by down-regulating hepatic cholesterol synthesis (n-3 PUFA and oestrogen) and up-regulating bile acid synthesis (n-3 PUFA) in ovariectomised rats.

  19. Modulation of nociceptive threshold by combined hormonal contraceptives in women with oestrogen-withdrawal migraine attacks: a pilot study.

    PubMed

    De Icco, Roberto; Cucinella, Laura; De Paoli, Irene; Martella, Silvia; Sances, Grazia; Bitetto, Vito; Sandrini, Giorgio; Nappi, Giuseppe; Tassorelli, Cristina; Nappi, Rossella E

    2016-12-01

    Menstrually-related headache and headaches associated with oestrogen withdrawal are common conditions, whose pathophysiology has not been completely elucidated. In this study we evaluated the influence of combined hormonal contraceptives (CHC) on pain threshold in women presenting migraine attacks during hormone-free interval. Eleven women with migraine attacks recurring exclusively during the oestrogen-withdrawal period were studied with the nociceptive flexion reflex, a neurophysiological assessment of the pain control systems, during the third week of active treatment and during the hormone-free interval. During the hormone-free interval, nociceptive withdrawal reflex threshold was significantly lower (12.8 ± 8.0 mA) as compared to the third week of hormonal treatment (15.6 ± 6.6 mA) (p = 0.02). No change was observed in the pain perceived and in the temporal summation. Oestrogen withdrawal may mediate an increased sensitivity to somatosensory stimuli in women with migraine attacks recurring during the hormone-free interval.

  20. A role for the androgen metabolite, 5alpha-androstane-3beta,17beta-diol, in modulating oestrogen receptor beta-mediated regulation of hormonal stress reactivity.

    PubMed

    Handa, R J; Weiser, M J; Zuloaga, D G

    2009-03-01

    Activation of the hypothalamic-pituitary-adrenal (HPA) axis is a basic response of animals to environmental perturbations that threaten homeostasis. These responses are regulated by neurones in the paraventricular nucleus of the hypothalamus (PVN) that synthesise and secrete corticotrophin-releasing hormone (CRH). Other PVN neuropeptides, such as arginine vasopressin and oxytocin, can also modulate activity of CRH neurones in the PVN and enhance CRH secretagogue activity of the anterior pituitary gland. In rodents, sex differences in HPA reactivity are well established; females exhibit a more robust activation of the HPA axis after stress than do males. These sex differences primarily result from opposing actions of sex steroids, testosterone and oestrogen, on HPA function. Ostreogen enhances stress activated adrenocorticotrophic hormone (ACTH) and corticosterone (CORT) secretion, whereas testosterone decreases the gain of the HPA axis and inhibits ACTH and CORT responses to stress. Data show that androgens can act directly on PVN neurones in the male rat through a novel pathway involving oestrogen receptor (ER)beta, whereas oestrogen acts predominantly through ERalpha. Thus, we examined the hypothesis that, in males, testosterone suppresses HPA function via an androgen metabolite that binds ERbeta. Clues to the neurobiological mechanisms underlying such a novel action can be gleaned from studies showing extensive colocalisation of ERbeta in oxytocin-containing cells of the PVN. Hence, in this review, we address the possibility that testosterone inhibits HPA reactivity by metabolising to 5alpha-androstane-3beta,17beta-diol, a compound that binds ERbeta and regulates oxytocin containing neurones of the PVN. These findings suggest a re-evaluation of studies examining pathways for androgen receptor signalling.

  1. The peripubertal male rat assay as an alternative to the Hershberger castrated male rat assay for the detection of anti-androgens, oestrogens and metabolic modulators.

    PubMed

    Ashby, J; Lefevre, P A

    2000-01-01

    A range of chemicals with various levels of activity as actual or potential endocrine disrupters have been evaluated for activity in the peripubertal male rat assay. The chemicals studied included anti-androgens (vinclozolin), cyproterone acetate, flutamide, 2, 2-bis(4-chlorophenyl)-1,1-dichloroethylene (DDE), metabolic modulators (anastrazole, finasteride, ketoconazole) and oestrogens (butyl benzyl phthalate (BBP), methoxychlor, bisphenol A (BPA), diethylstilboestrol (DES)), the suspected anti-androgen dibutyl phthalate (DBP) and the non-oestrogen fenitrothion. Dosing extended over postnatal days (pnd) 22-35, 36-50, 36-55 and 22-35, with recovery to pnd 55 or 22-55. The endpoints studied were changes in the weights of testes, epididymides, seminal vesicles and prostate. Changes in body weight and the weights of the liver and kidney were also monitored. In some experiments changes in the day of prepuce separation (PPS) were also determined. Only BBP and BPA were inactive in all the assays conducted. Changes in the weight of reproductive tissues provided a sensitive indicator of activity for the remaining chemicals with the exception of DDE, for which higher dose levels could have been used. However, none of the curtailed periods of exposure were able to detect all of the agents. Diethyl stilboestrol, and to a lesser extent DBP and DDE, delayed PPS when exposure occurred over the period pnd 22-55. A complex dependence of the day of PPS on the period of exposure and the body weight of the test animals was observed, and caution is recommended when assessing this endpoint in the presence of reductions in body weight. It is concluded that reproductive tissue weight changes in the peripubertal male have shown sensitivity to a range of biochemical modulators, oestrogens and anti-androgens, and that as such the assay warrants further evaluation. Measurement of delays in PPS may be of value in cases of large delays, but delays of 1-2 days will be difficult to interpret with

  2. Relevance of the selective oestrogen receptor modulators tamoxifen, toremifene and clomiphene in doping field: endogenous steroids urinary profile after multiple oral doses.

    PubMed

    Mazzarino, Monica; Braganò, Maria Cristina; de la Torre, Xavier; Molaioni, Francesco; Botrè, Francesco

    2011-11-01

    The present study was performed to investigate the influence of the intake of selective oestrogen receptor modulators on the urinary endogenous steroids profile. For this purpose the circadian variability of luteinizing hormone, follicle-stimulating hormone, testosterone, 5α-androstan-3α,17β-diol, 5β-androstan-3α,17β-diol, epitestosterone, 4-androstenedione, androsterone and etiocholanolone were measured on eight subjects (four males and four females) by gas chromatography-mass spectrometry and chemiluminescent immunometric assay techniques before and after oral administration of multiple doses of either tamoxifen (80 mg for 2 days) or toremifene (120 mg for 2 days) or clomiphene (100 mg for 2 days). The individual baseline variability of the steroids studied was set up by collecting the urine samples every 3 h, for 3 days prior to the treatment; whereas the evaluation of the effects of the oral administration of multiple doses of selective oestrogen receptor modulators on the steroid urinary profile was assessed by collecting urine samples every three hours for at least five days from the first administration. The results of our measurements showed that, only in male subjects, the relative urinary concentrations of testosterone, epitestosterone and 4-androstenedione were significantly altered generally after the second day of drug administration. While no significant effects were recorded in both sexes on the luteinizing hormone, follicle-stimulating hormone, androsterone, etiocholanolone, 5α-androstan-3α,17β-diol and 5β-androstan-3α,17β-diol urinary levels and on testosterone/epitestosterone, 5α-androstan-3α,17β-diol/5β-androstan-3α,17β-diol and androsterone/etiocholanolone ratios. Copyright © 2011 Elsevier Inc. All rights reserved.

  3. In vivo oestrogenic modulation of Egr1 and Pitx1 gene expression in female rat pituitary gland.

    PubMed

    Gajewska, Alina; Herman, Andrzej P; Wolińska-Witort, Ewa; Kochman, Kazimierz; Zwierzchowski, Lech

    2014-12-01

    EGR1 and PITX1 are transcription factors required for gonadotroph cell Lhb promoter activation. To determine changes in Egr1 and Pitx1 mRNA levels in central and peripheral pituitary stimulations, an in vivo model based on i.c.v. pulsatile (1 pulse/0.5 h over 2 h) GnRH agonist (1.5 nM buserelin) or antagonist (2 nM antide) microinjections was used. The microinjections were given to ovariectomised and 17β-oestradiol (E2) (3×20 μg), ERA (ESR1) agonist propyl pyrazole triol (PPT) (3×0.5 mg), ERB (ESR2) agonist diarylpropionitrile (DPN) (3×0.5 mg) s.c. pre-treated rats 30 min after last pulse anterior pituitaries were excised. Relative mRNA expression was determined by quantitative RT-PCR (qRT-PCR). Results revealed a gene-specific response for GnRH and/or oestrogenic stimulations in vivo. Buserelin pulses enhanced Egr1 expression by 66% in ovariectomised rats, whereas the oestradiol-supplemented+i.c.v. NaCl-microinjected group showed a 50% increase in Egr1 mRNA expression. The oestrogenic signal was transmitted via ERA (ESR1) and ERB (ESR2) activation as administration of PPT and DPN resulted in 97 and 62%, respectively, elevation in Egr1 mRNA expression. A synergistic action of GnRH agonist and 17β-oestradiol (E2) stimulation of the Egr1 gene transcription in vivo were found. GnRHR activity did not affect Pitx1 mRNA expression; regardless of NaCl, buserelin or antide i.c.v. pulses, s.c. oestrogenic supplementation (with E2, PPT or DPN) consistently decreased (by -46, -48 and -41% respectively) the Pitx1 mRNA in the anterior pituitary gland. Orchestrated Egr1 and Pitx1 activities depending on specific central and peripheral regulatory inputs could be responsible for physiologically variable Lhb gene promoter activation in vivo. © 2014 Society for Endocrinology.

  4. Inverse antagonist activities of parabens on human oestrogen-related receptor γ (ERRγ): in vitro and in silico studies.

    PubMed

    Zhang, Zhaobin; Sun, Libei; Hu, Ying; Jiao, Jian; Hu, Jianying

    2013-07-01

    Parabens are p-hydroxybenzoic acid esters that have been used extensively as preservatives in foods, cosmetics, drugs and toiletries. These intact esters are commonly detected in human breast cancer tissues and other human samples, thus arousing concern about the involvement of parabens in human breast cancer. In this study, an in vitro nuclear receptor coactivator recruiting assay was developed and used to evaluate the binding activities of parabens, salicylates and benzoates via antagonist competitive binding on the human oestrogen-related receptor γ (ERRγ), which is known as both a diagnostic biomarker and a treatment target of breast cancer. The results showed that all of the test parabens (methyl-, ethyl-, propyl-, butyl- and benzylparaben) possessed clear inverse antagonist activities on ERRγ, with a lowest observed effect level (LOEL) of 10(-7)M and the 50% relative effective concentrations (REC50) varying from 3.09×10(-7) to 5.88×10(-7)M, whereas the salicylates possessed much lower activities and the benzoates showed no obvious activity. In silico molecular docking analyses showed that parabens fitted well into the active site of ERRγ, with hydrogen bonds forming between the p-hydroxyl group of parabens and the Glu275/Arg316 of ERRγ. As the paraben levels reported in breast cancer tissues are commonly higher than the LOELs observed in this study, parabens may play some role via ERRγ in the carcinogenesis of human breast cancer. In addition, parabens may have significant effects on breast cancer patients who are taking tamoxifen, as ERRγ is regarded as a treatment target for tamoxifen. Copyright © 2013 Elsevier Inc. All rights reserved.

  5. Steroid hormone receptor gene expression in human breast cancer cells: inverse relationship between oestrogen and glucocorticoid receptor messenger RNA levels.

    PubMed

    Hall, R E; Lee, C S; Alexander, I E; Shine, J; Clarke, C L; Sutherland, R L

    1990-12-15

    The relative expression in human breast cancer cells of messenger ribonucleic acids (mRNA) encoding different steroid hormone receptors is unknown. Accordingly, mRNA levels in total RNA extracted from 13 human breast cancer cell lines were measured by Northern analysis employing complementary DNA probes for the human oestrogen (ER), progesterone (PR), androgen (AR), vitamin D3 (VDR) and glucocorticoid receptors (GR). The 7 ER+ lines expressed a single 6.4 kilobases (kb) ER mRNA. Interestingly, low concentrations of ER mRNA were detected in the ER- cell lines, MDA-MB-330 and BT 20. PR mRNA, predominantly a 13.5 kb species, was expressed in the 6 lines known to be ER+, PR+ by radioligand binding; however, one ER+ cell line, MDA-MB-134, failed to express PR mRNA. A 10.5 kb AR mRNA was expressed at significantly higher levels in ER+ than ER- cell lines. All cell lines expressed a single 4.6 kb mRNA for VDR and a single 7.4 kb mRNA for GR. ER and PR mRNA levels were positively correlated (p = 0.011) and each was positively correlated with androgen receptor (AR) mRNA levels (p less than or equal to 0.009). ER, PR and AR mRNAs were negatively associated with GR levels (p less than or equal to 0.012), while ER and AR mRNA levels were negatively correlated with mRNA for the epidermal growth factor receptor. In contrast, levels of VDR mRNA were unrelated to the concentration of any other steroid receptor mRNA. Our data demonstrate the coordinate expression of ER, PR and AR genes, and an inverse relationship between sex steroid hormone receptor and GR gene expression in human breast cancer cell lines.

  6. The oestrogen receptor alpha-regulated lncRNA NEAT1 is a critical modulator of prostate cancer

    PubMed Central

    Chakravarty, Dimple; Sboner, Andrea; Nair, Sujit S.; Giannopoulou, Eugenia; Li, Ruohan; Hennig, Sven; Mosquera, Juan Miguel; Pauwels, Jonathan; Park, Kyung; Kossai, Myriam; MacDonald, Theresa Y.; Fontugne, Jacqueline; Erho, Nicholas; Vergara, Ismael A.; Ghadessi, Mercedeh; Davicioni, Elai; Jenkins, Robert B.; Palanisamy, Nallasivam; Chen, Zhengming; Nakagawa, Shinichi; Hirose, Tetsuro; Bander, Neil H.; Beltran, Himisha; Fox, Archa H.; Elemento, Olivier; Rubin, Mark A.

    2014-01-01

    The androgen receptor (AR) plays a central role in establishing an oncogenic cascade that drives prostate cancer progression. Some prostate cancers escape androgen dependence and are often associated with an aggressive phenotype. The oestrogen receptor alpha (ERα) is expressed in prostate cancers, independent of AR status. However, the role of ERα remains elusive. Using a combination of chromatin immunoprecipitation (ChIP) and RNA-sequencing data, we identified an ERα-specific non-coding transcriptome signature. Among putatively ERα-regulated intergenic long non-coding RNAs (lncRNAs), we identified nuclear enriched abundant transcript 1 (NEAT1) as the most significantly overexpressed lncRNA in prostate cancer. Analysis of two large clinical cohorts also revealed that NEAT1 expression is associated with prostate cancer progression. Prostate cancer cells expressing high levels of NEAT1 were recalcitrant to androgen or AR antagonists. Finally, we provide evidence that NEAT1 drives oncogenic growth by altering the epigenetic landscape of target gene promoters to favour transcription. PMID:25415230

  7. Human Development Student Modules.

    ERIC Educational Resources Information Center

    South Carolina State Dept. of Education, Columbia. Office of Vocational Education.

    This set of 61 student learning modules deals with various topics pertaining to human development. The modules, which are designed for use in performance-based vocational education programs, each contain the following components: an introduction for the student, a performance objective, a variety of learning activities, content information, a…

  8. Human Development Student Modules.

    ERIC Educational Resources Information Center

    South Carolina State Dept. of Education, Columbia. Office of Vocational Education.

    This set of 61 student learning modules deals with various topics pertaining to human development. The modules, which are designed for use in performance-based vocational education programs, each contain the following components: an introduction for the student, a performance objective, a variety of learning activities, content information, a…

  9. Exercise-induced changes in tumour LDH-B and MCT1 expression are modulated by oestrogen-related receptor alpha in breast cancer-bearing BALB/c mice.

    PubMed

    Aveseh, Malihe; Nikooie, Rohollah; Aminaie, Mohsen

    2015-06-15

    Monocarboxylate transporters (MCTs) and lactate dehydrogenase A (LDH-A) play important roles in sustaining the glycolytic phenotype seen in cancer. Endurance training improves aerobic capacity; however, whether endurance training alters the metabolic phenotype of a solid tumour, from the perspective of lactate metabolism, is yet to be proven. This study showed that endurance training decreases expression of the MCT1 basigin (CD147) and LDH-A , and also increases LDH-B expression in solid tumours and attenuates tumour lactate metabolism. Similar results for MCT1 and LDH-B were found with inhibition of the oestrogen-related receptor alpha (ERRα). The training effects were not additive to the ERRα effects on MCT1 and LDH-B expression in the tumour, which indicated that exercise-induced alterations in MCT1 and LDH-B expression were modulated by ERRα. These results suggest that endurance training could be a useful tool in cancer therapy, especially in basal-like and luminal-like breast carcinomas. Several factors, including overexpression of lactate dehydrogenase (LDH) and monocarboxylate transporters (MCTs), promote an aerobic lactate production that allows some cancer cells to sustain higher proliferation rates in hostile environments outside the cell. To elucidate the effect of endurance training on the metabolic phenotype of solid tumours, we focused on the tumour expression of LDH-A, LDH-B, MCT1, MCT4, oestrogen-related receptor alpha (ERRα) and LDH isozymes in control (C), trained (T), control+XCT790 (CX) and trained+XCT790 (TX) mice. First, we found that the metabolically altered tumours from the trained animals exhibited lower values for lactate concentration than the control group. The decreased lactate concentration was associated with a shift in the tumour LDH isozyme profile towards LDH-1. These exercise-induced changes were also associated with decreases in the expression of the tumour MCT1, ERRα and CD147 in the trained animals. Secondly, the

  10. Genistein modulates the effects of parathyroid hormone in human osteoblastic SaOS-2 cells.

    PubMed

    Chen, Wen-Fang; Wong, Man-Sau

    2006-06-01

    Genistein and parathyroid hormone (PTH) are anabolic agents that stimulate bone formation through their direct actions in osteoblastic cells. In the present study, we aimed to determine whether genistein modulates the actions of PTH in human osteoblastic SaOS-2 cells in an oestrogen-depleted condition. The present results showed that genistein (10(-8) to 10(-6) m) induced alkaline phosphatase (ALP) activity and osteoprotegrin (OPG) expression in SaOS-2 cells in a dose-dependent manner. These effects could be completely abolished by co-treatment with oestrogen antagonist ICI 182780 (7alpha-[9-[(4,4,5,5,5-pentafluoropentyl)sulfonyl]nonyl]-estra-1,3,5(10)-triene-3,17beta-diol). Genistein (at 1 microM) could stimulate the mRNA expression of receptor activator of NF-kappaB ligand (RANKL). As OPG and RANKL are known to modulate osteoclastogenesis, the ability of genistein to modulate OPG and RANKL expression in SaOS-2 cells suggested that it might modulate osteoclastogenesis through its direct actions on osteoblastic cells. PTH (at 10 nM) stimulated ALP activity, induced RANKL mRNA expression and suppressed OPG mRNA expression in SaOS-2 cells, confirming its bi-directional effects on osteoblastic cells. Pre-treatment of SaOS-2 cells with genistein and oestrogen not only enhanced PTH-induced ALP activity, but also attenuated PTH up regulation of RANKL mRNA expression and PTH down regulation of OPG mRNA expression. Taken together, the present study provides the first evidence that genistein could modulate the actions of PTH in human osteoblastic SaOS-2 cells in an oestrogen-depleted condition.

  11. Oestrogen, ocular function and low-level vision: a review.

    PubMed

    Hutchinson, Claire V; Walker, James A; Davidson, Colin

    2014-11-01

    Over the past 10 years, a literature has emerged concerning the sex steroid hormone oestrogen and its role in human vision. Herein, we review evidence that oestrogen (oestradiol) levels may significantly affect ocular function and low-level vision, particularly in older females. In doing so, we have examined a number of vision-related disorders including dry eye, cataract, increased intraocular pressure, glaucoma, age-related macular degeneration and Leber's hereditary optic neuropathy. In each case, we have found oestrogen, or lack thereof, to have a role. We have also included discussion of how oestrogen-related pharmacological treatments for menopause and breast cancer can impact the pathology of the eye and a number of psychophysical aspects of vision. Finally, we have reviewed oestrogen's pharmacology and suggest potential mechanisms underlying its beneficial effects, with particular emphasis on anti-apoptotic and vascular effects. © 2014 Society for Endocrinology.

  12. Exercise-induced changes in tumour LDH-B and MCT1 expression are modulated by oestrogen-related receptor alpha in breast cancer-bearing BALB/c mice

    PubMed Central

    Aveseh, Malihe; Nikooie, Rohollah; Aminaie, Mohsen

    2015-01-01

    Several factors, including overexpression of lactate dehydrogenase (LDH) and monocarboxylate transporters (MCTs), promote an aerobic lactate production that allows some cancer cells to sustain higher proliferation rates in hostile environments outside the cell. To elucidate the effect of endurance training on the metabolic phenotype of solid tumours, we focused on the tumour expression of LDH-A, LDH-B, MCT1, MCT4, oestrogen-related receptor alpha (ERRα) and LDH isozymes in control (C), trained (T), control+XCT790 (CX) and trained+XCT790 (TX) mice. First, we found that the metabolically altered tumours from the trained animals exhibited lower values for lactate concentration than the control group. The decreased lactate concentration was associated with a shift in the tumour LDH isozyme profile towards LDH-1. These exercise-induced changes were also associated with decreases in the expression of the tumour MCT1, ERRα and CD147 in the trained animals. Secondly, the inhibition of ERRα by treatment of MC4-L2 human breast cancer cells with XCT790 (inverse agonist ligand of ERRα) before injection into the animals not only increased LDH-B expression in the tumour, but also decreased MCT1 expression in the CX group in comparison to the C group. The effects of ERRα inhibition were not additive to the training effects on the expressions of MCT1 and LDH-B in the solid tumours. In conclusion, our results suggest that exercise-induced suppression of ERRα expression modulates alterations in solid tumour expression of LDH-B and MCT1 and contributes towards the prevention of tumour development. PMID:25907793

  13. Oestrogen deficiency after tubal ligation.

    PubMed

    Cattanach, J

    1985-04-13

    4 of 7 women who had undergone tubal ligation within the past seven years were found to have oestrogen excretion concentrations at ovulation below the tenth percentile. A disturbance in the oestrogen/progesterone ratio as a consequence of localised hypertension at the ovary, when the utero-ovarian arterial loop is occluded at tubal ligation, is proposed as a possible cause of oestrogen deficiency syndrome, dysfunctional uterine bleeding, and menorrhagia after tubal ligation. Similar pathophysiology may occur after hysterectomy with ovarian conservation.

  14. The oestrogen metabolite 2-methoxyoestradiol alone or in combination with tumour necrosis factor-related apoptosis-inducing ligand mediates apoptosis in cancerous but not healthy cells of the human endometrium.

    PubMed

    Kato, Sumie; Sadarangani, Anil; Lange, Soledad; Villalón, Manuel; Brañes, Jorge; Brosens, Jan J; Owen, Gareth I; Cuello, Mauricio

    2007-06-01

    Cancers of the reproductive tract account for 12% of all malignancies in women. As previous studies have shown that oestrogen metabolites can cause apoptosis, we characterised the effect of oestrogen and oestrogen metabolites on non-cancerous and cancerous human endometrial cells. Herein, we demonstrate that 2-methoxyoestradiol (2ME), but not 17beta-oestradiol, induces apoptosis in cancer cell lines and primary cultured tumours of endometrial origin. In contrast, 2ME had no effect on cell viability of corresponding normal tissue. This ability of 2ME to induce apoptosis does not require oestrogen receptor activation, but is associated with increased entry into the G2/M phases of the cell cycle and the activation of both the intrinsic and the extrinsic apoptotic pathways. The selective behaviour of 2ME on cancerous as opposed to normal tissue may be due to a reduction in 17beta-hydroxysteroid dehydrogenase type II levels in cancer cells and to a differential down-regulation of superoxide dismutase. Furthermore, we demonstrate that pre-treatment with 2ME enhances the sensitivity of reproductive tract cancer cells to the apoptotic drug tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), without the loss in cell viability to normal cells incurred by currently chemotherapeutic drugs. In conclusion, 2ME, alone or in combination with TRAIL, may be an effective treatment for cancers of uterine origin with minimal toxicity to corresponding healthy female reproductive tissue.

  15. Oestrogen inhibition reverses pulmonary arterial hypertension and associated metabolic defects.

    PubMed

    Chen, Xinping; Austin, Eric D; Talati, Megha; Fessel, Joshua P; Farber-Eger, Eric H; Brittain, Evan L; Hemnes, Anna R; Loyd, James E; West, James

    2017-08-01

    Increased oestrogen is a strong epidemiological risk factor for development of pulmonary arterial hypertension (PAH) in patients, associated with metabolic defects. In addition, oestrogens drive penetrance in mice carrying mutations in bone morphogenetic protein receptor type II (BMPR2), the cause of most heritable PAH. The goal of the present study was to determine whether inhibition of oestrogens was effective in the treatment of PAH in these mice.The oestrogen inhibitors fulvestrant and anastrozole were used in a prevention and treatment paradigm in BMPR2 mutant mice, and tamoxifen was used for treatment. In addition, BMPR2 mutant mice were crossed onto oestrogen receptor (ESR)1 and ESR2 knockout backgrounds to assess receptor specificity. Haemodynamic and metabolic outcomes were measured.Oestrogen inhibition both prevented and treated PAH in BMPR2 mutant mice. This was associated with reduction in metabolic defects including oxidised lipid formation, insulin resistance and rescue of peroxisome proliferator-activated receptor-γ and CD36. The effect was mediated primarily through ESR2, but partially through ESR1.Our data suggest that trials of oestrogen inhibition in human PAH are warranted, and may improve pulmonary vascular disease through amelioration of metabolic defects. Although fulvestrant and anastrozole were more effective than tamoxifen, tamoxifen may be useful in premenopausal females, because of a reduced risk of induction of menopause. Copyright ©ERS 2017.

  16. Oestrogen inhibition reverses pulmonary arterial hypertension and associated metabolic defects

    PubMed Central

    Chen, Xinping; Austin, Eric D.; Talati, Megha; Fessel, Joshua P.; Farber-Eger, Eric H.; Brittain, Evan L.; Hemnes, Anna R.; Loyd, James E.

    2017-01-01

    Increased oestrogen is a strong epidemiological risk factor for development of pulmonary arterial hypertension (PAH) in patients, associated with metabolic defects. In addition, oestrogens drive penetrance in mice carrying mutations in bone morphogenetic protein receptor type II (BMPR2), the cause of most heritable PAH. The goal of the present study was to determine whether inhibition of oestrogens was effective in the treatment of PAH in these mice. The oestrogen inhibitors fulvestrant and anastrozole were used in a prevention and treatment paradigm in BMPR2 mutant mice, and tamoxifen was used for treatment. In addition, BMPR2 mutant mice were crossed onto oestrogen receptor (ESR)1 and ESR2 knockout backgrounds to assess receptor specificity. Haemodynamic and metabolic outcomes were measured. Oestrogen inhibition both prevented and treated PAH in BMPR2 mutant mice. This was associated with reduction in metabolic defects including oxidised lipid formation, insulin resistance and rescue of peroxisome proliferator-activated receptor-γ and CD36. The effect was mediated primarily through ESR2, but partially through ESR1. Our data suggest that trials of oestrogen inhibition in human PAH are warranted, and may improve pulmonary vascular disease through amelioration of metabolic defects. Although fulvestrant and anastrozole were more effective than tamoxifen, tamoxifen may be useful in premenopausal females, because of a reduced risk of induction of menopause. PMID:28775043

  17. Anti-oestrogens but not oestrogen deprivation promote cellular invasion in intercellular adhesion-deficient breast cancer cells

    PubMed Central

    Borley, Annabel C; Hiscox, Stephen; Gee, Julia; Smith, Chris; Shaw, Victoria; Barrett-Lee, Peter; Nicholson, Robert I

    2008-01-01

    Introduction Anti-oestrogens have been the mainstay of therapy in patients with oestrogen-receptor (ER) positive breast cancer and have provided significant improvements in survival. However, their benefits are limited by tumour recurrence in a significant proportion of initially drug-responsive breast cancer patients because of acquired anti-oestrogen resistance. Relapse on such therapies clinically presents as local and/or regional recurrences, frequently with distant metastases, and the prognosis for these patients is poor. The selective ER modulator, tamoxifen, classically exerts gene inhibitory effects during the drug-responsive phase in ER-positive breast cancer cells. Paradoxically, this drug is also able to induce the expression of genes, which in the appropriate cell context may contribute to an adverse cell phenotype. Here we have investigated the effects of tamoxifen and fulvestrant treatment on invasive signalling and compared this with the direct effects of oestrogen withdrawal to mimic the action of aromatase inhibitors. Methods The effect of oestrogen and 4-hydroxy-tamoxifen on the invasive capacity of endocrine-sensitive MCF-7 cells, in the presence or absence of functional E-cadherin, was determined by Matrigel invasion assays. Studies also monitored the impact of oestrogen withdrawal or treatment with fulvestrant on cell invasion. Western blotting using phospho-specific antibodies was performed to ascertain changes in invasive signalling in response to the two anti-oestrogens versus both oestradiol treatment and withdrawal. Results To the best of our knowledge, we report for the first time that tamoxifen can promote an invasive phenotype in ER-positive breast cancer cells under conditions of poor cell-cell contact and suggest a role for Src kinase and associated pro-invasive genes in this process. Our studies revealed that although this adverse effect is also apparent for further classes of anti-oestrogens, exemplified by the steroidal agent

  18. Obesity increases the incidence of distant metastases in oestrogen receptor-negative human epidermal growth factor receptor 2-positive breast cancer patients.

    PubMed

    Mazzarella, Luca; Disalvatore, Davide; Bagnardi, Vincenzo; Rotmensz, Nicole; Galbiati, Donata; Caputo, Sara; Curigliano, Giuseppe; Pelicci, Pier Giuseppe

    2013-11-01

    Obesity is a major negative determinant of breast cancer outcome. However, there are contrasting data on the differential impact of obesity on specific breast cancer subtypes. In particular, very little is known on human epidermal growth factor receptor 2-positive (HER2+) tumours. We assessed the prognostic role of increased body mass index (BMI) on a consecutive series of non-metastatic HER2+ patients treated at our institution before the introduction of adjuvant Trastuzumab. We separately analysed oestrogen receptor-positive (ER+) and -negative (ER-) HER2+ cases. In ER-/HER2+ tumours we observed a significantly worse overall survival (Hazard ratio (HR) 1.79, p-value 0.041) and cumulative incidence of distant metastases (HR 2.03, p-value 0.019) in obese (BMI>30) versus normal/underweight (BMI<25) patients. Local relapses appeared to be non-significantly reduced in obese patients, masking the overall effect on disease-free survival. Outcome in ER+ tumours, instead, was not significantly different between BMI groups. Obesity significantly correlates with worse overall survival and cumulative incidence of distant metastases in ER-/HER2 positive breast cancer. Differences in the biology of breast tumours may determine individual susceptibility to obesity. The biology of the underlying tumour should be taken into account in the design of dietary intervention trials in breast cancer. Copyright © 2013 Elsevier Ltd. All rights reserved.

  19. Development of a transient expression assay for detecting environmental oestrogens in zebrafish and medaka embryos

    PubMed Central

    2012-01-01

    Background Oestrogenic contaminants are widespread in the aquatic environment and have been shown to induce adverse effects in both wildlife (most notably in fish) and humans, raising international concern. Available detecting and testing systems are limited in their capacity to elucidate oestrogen signalling pathways and physiological impacts. Here we developed a transient expression assay to investigate the effects of oestrogenic chemicals in fish early life stages and to identify target organs for oestrogenic effects. To enhance the response sensitivity to oestrogen, we adopted the use of multiple tandem oestrogen responsive elements (EREc38) in a Tol2 transposon mediated Gal4ff-UAS system. The plasmid constructed (pTol2_ERE-TATA-Gal4ff), contains three copies of oestrogen response elements (3ERE) that on exposure to oestrogen induces expression of Gal4ff which this in turn binds Gal4-responsive Upstream Activated Sequence (UAS) elements, driving the expression of a second reporter gene, EGFP (Enhanced Green Fluorescent Protein). Results The response of our construct to oestrogen exposure in zebrafish embryos was examined using a transient expression assay. The two plasmids were injected into 1–2 cell staged zebrafish embryos, and the embryos were exposed to various oestrogens including the natural steroid oestrogen 17ß-oestradiol (E2), the synthetic oestrogen 17α- ethinyloestradiol (EE2), and the relatively weak environmental oestrogen nonylphenol (NP), and GFP expression was examined in the subsequent embryos using fluorescent microscopy. There was no GFP expression detected in unexposed embryos, but specific and mosaic expression of GFP was detected in the liver, heart, somite muscle and some other tissue cells for exposures to steroid oestrogen treatments (EE2; 10 ng/L, E2; 100 ng/L, after 72 h exposures). For the NP exposures, GFP expression was observed at 10 μg NP/L after 72 h (100 μg NP/L was toxic to the fish). We also demonstrate that

  20. Sex, the brain and hypertension: brain oestrogen receptors and high blood pressure risk factors.

    PubMed

    Hay, Meredith

    2016-01-01

    Hypertension is a major contributor to worldwide morbidity and mortality rates related to cardiovascular disease. There are important sex differences in the onset and rate of hypertension in humans. Compared with age-matched men, premenopausal women are less likely to develop hypertension. However, after age 60, the incidence of hypertension increases in women and even surpasses that seen in older men. It is thought that changes in levels of circulating ovarian hormones as women age may be involved in the increase in hypertension in older women. One of the key mechanisms involved in the development of hypertension in both men and women is an increase in sympathetic nerve activity (SNA). Brain regions important for the regulation of SNA, such as the subfornical organ, the paraventricular nucleus and the rostral ventral lateral medulla, also express specific subtypes of oestrogen receptors. Each of these brain regions has also been implicated in mechanisms underlying risk factors for hypertension such as obesity, stress and inflammation. The present review brings together evidence that links actions of oestrogen at these receptors to modulate some of the common brain mechanisms involved in the ability of hypertensive risk factors to increase SNA and blood pressure. Understanding the mechanisms by which oestrogen acts at key sites in the brain for the regulation of SNA is important for the development of novel, sex-specific therapies for treating hypertension.

  1. Oestrogen synthesis, oestrogen metabolism and functional oestrogen receptors in bovine aortic endothelial cells.

    PubMed

    Bayard, F; Clamens, S; Delsol, G; Blaes, N; Maret, A; Faye, J C

    1995-01-01

    In order to investigate the mechanisms by which oestrogenic hormones influence the vascular system, we have studied their metabolism and the functioning of oestrogen receptors in bovine aortic endothelial cells from primo-secondary cultures, a widely studied model of vascular pathophysiology. We have demonstrated the enzymic activity of oestradiol-17 beta-hydroxysteroid dehydrogenase, 17-ketoreductase and aromatase in these cells. Immunocytochemical analyses, using two different monoclonal antibodies that recognize epitopes in the A/B domain of the oestrogen receptor, showed that this molecule has a predominantly cytoplasmic localization even after the addition of oestrogen to the culture medium. We showed that the hormone-receptor complexes were functional by demonstrating their transactivating ability in transfection experiments using the luciferase gene reporter and an oestrogen-responsive element transcriptional enhancer, although the amplitude of the response was in the range of only 140-150%: this was not a consequence of the presence of a specific limiting factor, but instead might be related to the peculiar subcellular localization of the oestrogen receptor.

  2. Concordance between core needle biopsy and surgical specimen for oestrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status in breast cancer

    PubMed Central

    Asogan, Aravind Barathi; Hong, Ga Sze; Prabhakaran, Subash Kumar Arni

    2017-01-01

    INTRODUCTION This study aimed to analyse the concordance rate, sensitivity, specificity, positive predictive value (PPV) and negative predictive value of core needle biopsy (CNB) and subsequent surgical specimen (SS) in assessing levels of oestrogen receptor (ER), progesterone receptor (PgR) and human epidermal growth factor receptor 2 (HER2/neu). It also evaluated the revised American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines for ER/PgR positivity. METHODS We analysed the breast cancer database of KK Women’s and Children’s Hospital, Singapore, from 1 June 2005 to 30 December 2012. Invasive breast cancer patients who had CNB and subsequent SS were included. RESULTS A total of 560 patients were included. The concordance of ER, PgR and HER2/neu positivity between CNB and SS was 96.1%, 89.1% and 96.8%, respectively. When the ‘ER ≥ 10% positive’ group was compared with the ‘ER ≥ 1% positive’ group, specificity increased from 79.7% to 92.5% and PPV increased from 93.9% to 97.5%. When the ‘PgR ≥ 10% positive’ group was compared with the ‘PgR ≥ 1% positive’ group, specificity increased from 84.2% to 89.3% and PPV improved from 89.7% to 92.9%. The revised ASCO/CAP guidelines decreased discordant results by > 50% for ER and by 18.2% for PgR. CONCLUSION CNB has high concordance with SS in the evaluation of the molecular profile of invasive breast cancer. Thus, molecular evaluation does not need to be repeated with SS except for ER-, PgR- and HER2/neu-negative CNB results. The revised ASCO/CAP guidelines resulted in more precise ER and PgR status on CNB. PMID:27029805

  3. Exploiting the apoptotic actions of oestrogen to reverse antihormonal drug resistance in oestrogen receptor positive breast cancer patients

    PubMed Central

    Jordan, V. Craig; Lewis-Wambi, Joan; Kim, Helen; Cunliffe, Heather; Ariazi, Eric; Sharma, Catherine G. N.; Shupp, Heather A.; Swaby, Ramona

    2009-01-01

    Summary The ubiquitous application of selective oestrogen receptor modulators (SERMs) and aromatase inhibitors for the treatment and prevention of breast cancer has created a significant advance in patient care. However, the consequence of prolonged treatment with antihormonal therapy is the development of drug resistance. Nevertheless, the systematic description of models of drug resistance to SERMs and aromatase inhibitors has resulted in the discovery of a vulnerability in tumour homeostasis that can be exploited to improve patient care. Drug resistance to antihormones evolves, so that eventually the cells change to create novel signal transduction pathways for enhanced oestrogen (GPR30 + OER) sensitivity, a reduction in progesterone receptor production and an increased metastatic potential. Most importantly, antihormone resistant breast cancer cells adapt with an ability to undergo apoptosis with low concentrations of oestrogen. The oestrogen destroys antihormone resistant cells and reactivates sensitivity to prolonged antihormonal therapy. We have initiated a major collaborative program of genomics and proteomics to use our laboratory models to map the mechanism of subcellular survival and apoptosis in breast cancer. The laboratory program is integrated with a clinical program that seeks to determine the minimum dose of oestrogen necessary to create objective responses in patients who have succeeded and failed two consecutive antihormonal therapies. Once our program is complete, the new knowledge will be available to translate to clinical care for the long-term maintenance of patients on antihormone therapy. PMID:17719781

  4. New Hypotheses and Opportunities in Endocrine Therapy: Amplification of Oestrogen-Induced Apoptosis

    PubMed Central

    Jordan, V. Craig; Lewis-Wambi, Joan S.; Patel, Roshani R.; Kim, Helen; Ariazi, Eric A.

    2010-01-01

    Aims To outline the progress being made in the understanding of acquired resistance to long term therapy with the selective oestrogen receptor modulators (SERMs, tamoxifen and raloxifene) and aromatase inhibitors. The question to be addressed is how we can amplify the new biology of oestrogen-induced apoptosis to create more complete responses in exhaustively antihormone treated metastatic breast cancer. Methods and Results Three questions are posed and addressed. 1.) Do we know how oestrogen works? 2.) Can we improve adjuvant antihormonal therapy? 3.) Can we enhance oestrogen-induced apoptosis? The new player in oestrogen action is GPR30 and there are new drugs specific for this target to trigger apoptosis. Similarly, anti-angiogenic drugs can be integrated into adjuvant antihormone therapy or to enhance oestrogen-induced apoptosis in Phase II antihormone resistant breast cancer. The goal is to reduce the development of acquired antihormone resistance or undermine the ability of breast cancer cells to undergo apoptosis with oestrogen respectively. Finally, drugs to reduce the synthesis of glutathione, a subcellular molecule compound associated with drug resistance, can enhance oestradiol-induced apoptosis. Conclusions We propose an integrated approach for the rapid testing of agents to blunt survival pathways and amplify oestrogen-induced apoptosis and tumour regression in Phase II resistant metastatic breast cancer. This Pharma platform will provide rapid clinical results to predict efficacy in large scale clinical trials. PMID:19914527

  5. Clinical use of oestrogens and progestogens.

    PubMed

    Lauritzen, C

    1990-09-01

    Oestrogens cure climacteric complaints and prevent the late sequelae of oestrogen deficiency. Prevention of myocardial infarction and of osteoporosis is now the main argument for long-term substitution of oestrogens and progestogens in the post-menopause and leads to a reduction of overall morbidity and mortality in users. Indications, contraindications, some side effects, risk-benefit and cost-benefit considerations are discussed and practical advice for oestrogen medication with regard to doses, preparations and the addition of progestogens is given.

  6. Multiple Routes to Oestrogen Antagonism

    PubMed Central

    Glover, Hilary R.; Barker, Stewart; Malouitre, Sylvanie D. M.; Puddefoot, John R.; Vinson, Gavin P.

    2010-01-01

    Several lines of evidence attest to the existence of alternative ligand binding sites on the oestrogen receptor (ER), including non-competitive inhibition by trilostane or tamoxifen. It is possible that the inhibitory action of conventional oestrogen agonists at high concentrations may indicate that they too interact at alternative ER sites, albeit at low affinity. To test this possibility an oestrogen reporter assay was used to compare the activity of different oestrogens and antagonists in breast cancer and prostate cell lines. All four cell lines tested contained different amounts of oestrogen receptor α (ERα), ERβ, progesterone receptor and coregulator mRNA. Though differences were observed in response to stimulation and inhibition, these correlated only with the presence or absence of ERα, and not with the other components. Thus stimulation of the reporter by oestradiol and oestrone was biphasic in the breast cancer cells, while prostate cells were unable to respond. Only T47D cells were stimulated by oestriol or diethylstilboestrol, however reporter activity of all the cell lines was repressed by 10μM diethylstilboestrol. Reporter activity of MCF-7 cells was inhibited by tamoxifen, raloxifene and ICI 182,780, but stimulated by trilostane, yet all these antioestrogens inhibited agonist-stimulated activity. Trilostane also inhibited the agonism seen in cells co-treated with E2 and tamoxifen. It is clear that several of the compounds tested may have either agonist or antagonist effects under different conditions and at different concentrations, acting through ERα alone. Though biphasic dose response curves, or hormesis, have been attributed to various mechanisms, we here provide evidence that alternative ligand binding sites may contribute to this phenomenon.

  7. Oestrogens ameliorate mitochondrial dysfunction in Leber's hereditary optic neuropathy.

    PubMed

    Giordano, Carla; Montopoli, Monica; Perli, Elena; Orlandi, Maurizia; Fantin, Marianna; Ross-Cisneros, Fred N; Caparrotta, Laura; Martinuzzi, Andrea; Ragazzi, Eugenio; Ghelli, Anna; Sadun, Alfredo A; d'Amati, Giulia; Carelli, Valerio

    2011-01-01

    Leber's hereditary optic neuropathy, the most frequent mitochondrial disease due to mitochondrial DNA point mutations in complex I, is characterized by the selective degeneration of retinal ganglion cells, leading to optic atrophy and loss of central vision prevalently in young males. The current study investigated the reasons for the higher prevalence of Leber's hereditary optic neuropathy in males, exploring the potential compensatory effects of oestrogens on mutant cell metabolism. Control and Leber's hereditary optic neuropathy osteosarcoma-derived cybrids (11778/ND4, 3460/ND1 and 14484/ND6) were grown in glucose or glucose-free, galactose-supplemented medium. After having shown the nuclear and mitochondrial localization of oestrogen receptors in cybrids, experiments were carried out by adding 100 nM of 17β-oestradiol. In a set of experiments, cells were pre-incubated with the oestrogen receptor antagonist ICI 182780. Leber's hereditary optic neuropathy cybrids in galactose medium presented overproduction of reactive oxygen species, which led to decrease in mitochondrial membrane potential, increased apoptotic rate, loss of cell viability and hyper-fragmented mitochondrial morphology compared with control cybrids. Treatment with 17β-oestradiol significantly rescued these pathological features and led to the activation of the antioxidant enzyme superoxide dismutase 2. In addition, 17β-oestradiol induced a general activation of mitochondrial biogenesis and a small although significant improvement in energetic competence. All these effects were oestrogen receptor mediated. Finally, we showed that the oestrogen receptor β localizes to the mitochondrial network of human retinal ganglion cells. Our results strongly support a metabolic basis for the unexplained male prevalence in Leber's hereditary optic neuropathy and hold promises for a therapeutic use for oestrogen-like molecules.

  8. Oestrogen effects in schizophrenia and their potential therapeutic implications--review.

    PubMed

    Riecher-Rössler, A

    2002-11-01

    Increasing evidence from clinical as well as from epidemiological and basic research shows that oestrogens exert protective effects in schizophrenia. A brief overview of these protective effects will be provided, and potential therapeutic implications will be discussed. If these effects are confirmed, they could have important implications for prophylaxis and treatment. For instance, consideration would need to be given to oestrogen replacement in peri- and postmenopausal women with schizophrenia, adjunct oestrogen therapy in women with oestrogen deficiency syndromes, cycle-modulated neuroleptic therapy in women with frequent perimenstrual relapses, and/or emphasis on prolactin-sparing atypical neuroleptics in women with hypoestrogenism. Further research is urgently needed since there may be direct therapeutic benefits for women.

  9. The mystery of male dominance in oesophageal cancer and the potential protective role of oestrogen.

    PubMed

    Chandanos, Evangelos; Lagergren, Jesper

    2009-12-01

    Oesophageal cancer is the sixth most common form of cancer death globally with almost 400,000 deaths annually. More than 90% of all cases are either adenocarcinomas (OAC) or squamous-cell carcinomas (OSCC). There is a strong male predominance with up to 8 and 3 men for every woman affected with OAC and OSCC, respectively. It has been hypothesised that sex hormonal factors may play a role in the development of oesophageal cancer or more specifically that oestrogen prevents such development. This article reviews the available literature on this topic. Basic science studies suggest an inhibitory effect of oestrogen in the growth of oesophageal cancer cells, and a possible mechanism of any oestrogen protection might be mediated through oestrogen receptors. But from the few epidemiological studies in which the hypothesis of oestrogen protection has been tested, no firm conclusions can yet be drawn of the role of oestrogen in human oesophageal cancer aetiology. More evidence from valid and large human studies is needed before any conclusions can be drawn.

  10. Oestrogen-induced epithelial-mesenchymal transition of endometrial epithelial cells contributes to the development of adenomyosis.

    PubMed

    Chen, Yi-Jen; Li, Hsin-Yang; Huang, Chi-Hung; Twu, Nae-Fang; Yen, Ming-Shyen; Wang, Peng-Hui; Chou, Teh-Ying; Liu, Yen-Ni; Chao, Kuan-Chong; Yang, Muh-Hwa

    2010-11-01

    Adenomyosis is an oestrogen-dependent disease caused by a downward extension of the endometrium into the uterine myometrium. Epithelial-mesenchymal transition (EMT) endows cells with migratory and invasive properties and can be induced by oestrogen. We hypothesized that oestrogen-induced EMT is critical in the pathogenesis of adenomyosis. We first investigated whether EMT occurred in adenomyotic lesions and whether it correlated with serum 17β-oestradiol (E2) levels. Immunohistochemistry was performed on adenomyotic lesions and corresponding eutopic endometrium samples from women with adenomyosis. Endometria from women without endometrial disorders were used as a control. In the epithelial component of adenomyotic lesions, vimentin expression was up-regulated and E-cadherin expression was down-regulated compared to the eutopic endometrium, suggesting that EMT occurs in adenomyosis. In adenomyosis, the serum E2 level was negatively correlated with E-cadherin expression in the epithelial components of the eutopic endometrium and adenomyotic lesions, suggesting the involvement of oestrogen-induced EMT in endometrial cells. In oestrogen receptor-positive Ishikawa endometrial epithelial cells, oestrogen induced a morphological change to a fibroblast-like phenotype, a shift from epithelial marker expression to mesenchymal marker expression, increased migration and invasion, and up-regulation of the EMT regulator Slug. Raloxifene, a selective oestrogen receptor modulator, abrogated these effects. To determine the role of oestrogen-induced EMT in the implantation of ectopic endometrium, we xenotransplanted eutopic endometrium or adenomyotic lesions from adenomyosis patients into ovariectomized SCID mice. The implantation of endometrium was oestrogen-dependent and was suppressed by raloxifene. Collectively, these data highlight the crucial role of oestrogen-induced EMT in the development of adenomyosis and suggest that raloxifene may be a potential therapeutic agent for

  11. Long-term effects of early-life exposure to environmental oestrogens on ovarian function: role of epigenetics.

    PubMed

    Cruz, G; Foster, W; Paredes, A; Yi, K D; Uzumcu, M

    2014-09-01

    Oestrogens play an important role in development and function of the brain and reproductive tract. Accordingly, it is considered that developmental exposure to environmental oestrogens can disrupt neural and reproductive tract development, potentially resulting in long-term alterations in neurobehaviour and reproductive function. Many chemicals have been shown to have oestrogenic activity, whereas others affect oestrogen production and turnover, resulting in the disruption of oestrogen signalling pathways. However, these mechanisms and the concentrations required to induce these effects cannot account for the myriad adverse effects of environmental toxicants on oestrogen-sensitive target tissues. Hence, alternative mechanisms are assumed to underlie the adverse effects documented in experimental animal models and thus could be important to human health. In this review, the epigenetic regulation of gene expression is explored as a potential target of environmental toxicants including oestrogenic chemicals. We suggest that toxicant-induced changes in epigenetic signatures are important mechanisms underlying the disruption of ovarian follicular development. In addition, we discuss how exposure to environmental oestrogens during early life can alter gene expression through effects on epigenetic control potentially leading to permanent changes in ovarian physiology. © 2014 British Society for Neuroendocrinology.

  12. Instructor's Guide for Human Development Student Modules.

    ERIC Educational Resources Information Center

    South Carolina State Dept. of Education, Columbia. Office of Vocational Education.

    This instructor's guide is designed for use with an accompanying set of 61 student learning modules on human development. Included among the topics covered in the individual modules are the following: consumer and homemaking education (health and nutrition, personal appearance and grooming, puberty, menstruation, the human reproductive system,…

  13. The different role of sex hormones on female cardiovascular physiology and function: not only oestrogens.

    PubMed

    Salerni, Sara; Di Francescomarino, Samanta; Cadeddu, Christian; Acquistapace, Flavio; Maffei, Silvia; Gallina, Sabina

    2015-06-01

    Human response to different physiologic stimuli and cardiovascular (CV) adaptation to various pathologies seem to be gender specific. Sex-steroid hormones have been postulated as the major contributors towards these sex-related differences. This review will discuss current evidence on gender differences in CV function and remodelling, and will present the different role of the principal sex-steroid hormones on female heart. Starting from a review of sex hormones synthesis, receptors and CV signalling, we will summarize the current knowledge concerning the role of sex hormones on the regulation of our daily activities throughout the life, via the modulation of autonomic nervous system, excitation-contraction coupling pathway and ion channels activity. Many unresolved questions remain even if oestrogen effects on myocardial remodelling and function have been extensively studied. So this work will focus attention also on the controversial and complex relationship existing between androgens, progesterone and female heart. © 2015 Stichting European Society for Clinical Investigation Journal Foundation.

  14. Oestrogen receptors mediate oestrogen-induced increases in post-exercise rat skeletal muscle satellite cells.

    PubMed

    Enns, D L; Iqbal, S; Tiidus, P M

    2008-09-01

    Our laboratory recently demonstrated that increases in post-exercise muscle satellite cell numbers are augmented by oestrogen. We investigated whether muscle oestrogen receptors (ORs) mediate this effect through administration of an OR antagonist, ICI 182,780. Ovariectomized female rats were divided into three groups: sham, oestrogen (0.25 mg pellet) and oestrogen plus OR blocker (ICI 182,780). Each group was divided into control and exercised groups. ICI 182,780 (5 mg kg(-1) sc) was administered 1 day prior to and 6 days following oestrogen pellet implantation. After 8 days of oestrogen exposure, animals ran downhill for 90 min (17 m min(-1), -13.5 degrees grade) on a treadmill. Soleus and white vastus muscles were removed 24 and 72 h post-exercise and immunostained for total (Pax7), activated (MyoD) and proliferating (BrdU) satellite cells. Muscle damage was indirectly assessed by measuring beta-glucuronidase activity. Two markers (His48 and ED1) of leucocyte infiltration were also examined. beta-Glucuronidase activities and His48+ and ED1+ leucocytes increased post-exercise, and these increases were attenuated with oestrogen. ICI 182,780 did not influence the attenuating effect of oestrogen on leucocyte infiltration or beta-glucuronidase activities in muscle. Total (Pax7+), activated (MyoD+) and proliferating (BrdU+) satellite cells increased post-exercise, and these increases were augmented with oestrogen. Interestingly, ICI 182,780 abolished both exercise- and oestrogen-mediated increases in these satellite cell markers. Oestrogen may augment increases in muscle satellite cells following exercise through OR-mediated mechanisms; furthermore, the attenuation of post-exercise muscle damage and leucocyte infiltration by oestrogen appears to be a non-OR-mediated process.

  15. Modelling defined mixtures of environmental oestrogens found in domestic animal and sewage treatment effluents using an in vitro oestrogen-mediated transcriptional activation assay (T47D-KBluc).

    PubMed

    Bermudez, Dieldrich S; Gray, L Earl; Wilson, Vickie S

    2012-06-01

    There is growing concern of exposure of fish, wildlife and humans to water sources contaminated with oestrogens and the potential impact on reproductive health. Environmental oestrogens can come from various sources including concentrated animal feedlot operations (CAFO), municipal waste, agricultural and industrial effluents. US EPA's drinking water contaminant candidate list 3 (CCL3) includes several oestrogenic compounds. Although these contaminants are currently not subject to any proposed or promulgated national primary drinking water regulations, they are known or anticipated to occur in public water systems and may require future regulation under the Safe Drinking Water Act. Using an in vitro transcriptional activation assay, this study evaluated oestrogens from CCL3 both individually and as a seven oestrogen mixture (fixed ray design) over a broad range of concentrations, including environmentally relevant concentrations. Log EC(50) and Hillslope values for individual oestrogens were as follows: estrone, -11.92, 1.283; estradiol-17α, -9.61, 1.486; estradiol-17β, 11.77, 1.494; estriol, -11.14, 1.074; ethinyl estradiol-17α, -12.63, 1.562; Mestranol, -11.08, 0.809 and Equilin, -11.48, 0.946. In addition, mixtures that mirrored the primary oestrogens found in swine, poultry and dairy CAFO effluent (fixed-ratio ray design), and a ternary mixture (4 × 4 × 4 factorial design) of oestrogens found in hormone replacement therapy and/or oral contraceptives were tested. Mixtures were evaluated for additivity using both the concentration addition (CA) model and oestrogen equivalence (EEQ) model. For each of the mixture studies, a broad range of concentrations were tested, both above and below environmentally relevant concentrations. Results show that the observed data did not vary consistently from either the CA or EEQ predictions for any mixture. Therefore, either the CA or EEQ model should be useful predictors for modelling oestrogen mixtures. © 2012 The Authors

  16. The structural biology of oestrogen metabolism

    PubMed Central

    Thomas, Mark P.; Potter, Barry V.L.

    2013-01-01

    Many enzymes catalyse reactions that have an oestrogen as a substrate and/or a product. The reactions catalysed include aromatisation, oxidation, reduction, sulfonation, desulfonation, hydroxylation and methoxylation. The enzymes that catalyse these reactions must all recognise and bind oestrogen but, despite this, they have diverse structures. This review looks at each of these enzymes in turn, describing the structure and discussing the mechanism of the catalysed reaction. Since oestrogen has a role in many disease states inhibition of the enzymes of oestrogen metabolism may have an impact on the state or progression of the disease and inhibitors of these enzymes are briefly discussed. This article is part of a Special Issue entitled ‘CSR 2013’. PMID:23291110

  17. Oestrogen receptors in the central nervous system and evidence for their role in the control of cardiovascular function.

    PubMed

    Spary, Emma J; Maqbool, Azhar; Batten, Trevor F C

    2009-11-01

    Oestrogen is considered beneficial to cardiovascular health through protective effects not only on the heart and vasculature, but also on the autonomic nervous system via actions on oestrogen receptors. A plethora of evidence supports a role for the hormone within the central nervous system in modulating the pathways regulating cardiovascular function. A complex interaction of several brainstem, spinal and forebrain nuclei is required to receive, integrate and co-ordinate inputs that contribute appropriate autonomic reflex responses to changes in blood pressure and other cardiovascular parameters. Central effects of oestrogen and oestrogen receptors have already been demonstrated in many of these areas. In addition to the classical nuclear oestrogen receptors (ERalpha and ERbeta) a recently discovered G-protein coupled receptor, GPR30, has been shown to be a novel mediator of oestrogenic action. Many anatomical and molecular studies have described a considerable overlap in the regional expression of these receptors; however, the receptors do exhibit specific characteristics and subtype specific expression is found in many autonomic brain areas, for example ERbeta appears to predominate in the hypothalamic paraventricular nucleus, whilst ERalpha is important in the nucleus of the solitary tract. This review provides an overview of the available information on the localisation of oestrogen receptor subtypes and their multitude of possible modulatory actions in different groups of neurochemically and functionally defined neurones in autonomic-related areas of the brain.

  18. Phytoestrogens oestrogen synthesis and breast cancer.

    PubMed

    Rice, Suman; Whitehead, Saffron A

    2008-02-01

    Phytoestrogens are used as 'natural' alternatives to HRT and, although epidemiological evidence implies that diets rich in phytoestrogens reduce the incidence of breast cancer, their weak oestrogenicity is also known to stimulate growth in experimental models of breast cancer. This review addresses the question as to how phytoestrogens may protect against breast cancer through their ability to bind preferentially to oestrogen receptor beta, inhibit enzymes that convert circulating steroid precursors into oestradiol and inhibit cell signalling pathways of growth factors.

  19. Oestrogen alters adipocyte biology and protects female mice from adipocyte inflammation and insulin resistance.

    PubMed

    Stubbins, R E; Najjar, K; Holcomb, V B; Hong, J; Núñez, N P

    2012-01-01

    Obesity is associated with insulin resistance, liver steatosis and low-grade inflammation. The role of oestrogen in sex differences in the above co-morbidities is not fully understood. Our aim was to assess the role oestrogen has in modulating adipocyte size, adipose tissue oxidative stress, inflammation, insulin resistance and liver steatosis. To determine the role oestrogen has in the above co-morbidities related to obesity, we randomized C57BL/6J mice into four groups (15 mice per group): (i) male, (ii) non-ovariectomized female (novx), (iii) ovariectomized female (ovx) and (iv) ovariectomized female mice supplemented with 17β estradiol (ovx-E). Mice received either a low-fat (LF) or a high-fat (HF) diet for 10 weeks. Outcomes measured were bodyweight, body fat, adipocyte diameter, adipose tissue lipolysis markers, adipose tissue oxidative stress, inflammation, insulin resistance and liver steatosis. Male and ovx-female mice consuming the HF diet had a higher propensity of gaining weight, specifically in the form of body fat. Oestrogen protected female mice from adipocyte hypertrophy and from developing adipose tissue oxidative stress and inflammation. Moreover, novx-female and ovx-female+E mice had higher phosphorylated levels of protein kinase A and hormone sensitive lipase, markers associated with lipolysis. Additionally, male and ovx female mice had a higher propensity of developing liver steatosis and insulin resistance. In contrast, oestrogen protected female mice from developing liver steatosis and from becoming insulin resistant. We show that oestrogen protects female mice from adipocyte hypertrophy and adipose tissue oxidative stress and inflammation. Furthermore, oestrogen prevented female mice from developing liver steatosis and from becoming insulin resistant. © 2011 Blackwell Publishing Ltd.

  20. Augmented sympathetic vasoconstriction in exercising forearms of postmenopausal women is reversed by oestrogen therapy.

    PubMed

    Fadel, Paul J; Wang, Zhongyun; Watanabe, Hitoshi; Arbique, Debbie; Vongpatanasin, Wanpen; Thomas, Gail D

    2004-12-15

    Sympathetic vasoconstriction is normally attenuated in exercising muscles of young men and women. Recent evidence indicates that such modulation, termed functional sympatholysis, may be impaired in older men. Whether a similar impairment occurs in older women, and what role oestrogen deficiency might play in this impairment, are not known. Based on the strong positive correlation between circulating oestrogen levels and functional sympatholysis previously reported in female rats, we hypothesized that sympatholysis would be impaired in oestrogen-deficient postmenopausal women, and that this impairment would be reversed by oestrogen replacement. To test these hypotheses, we measured vasoconstrictor responses in the forearms of pre- and postmenopausal women using near infrared spectroscopy to detect decreases in muscle oxygenation in response to reflex activation of sympathetic nerves evoked by lower body negative pressure (LBNP). In eight premenopausal women, LBNP decreased muscle oxygenation by 20 +/- 1% in resting forearm, but only by 3 +/- 2% in exercising forearm (P < 0.05). In contrast, in eight postmenopausal women, LBNP decreased muscle oxygenation by 15 +/- 3% in resting forearm, and by 12 +/- 4% in exercising forearm (P > 0.05). After 1 month of transdermal oestradiol replacement in these women, the normal effect of exercise to blunt sympathetic vasoconstriction was restored (rest, -19 +/- 3%; exercise, -2 +/- 3%; P < 0.05). These data indicate that functional sympatholysis is impaired in oestrogen-deficient postmenopausal women. The effect of short-term unopposed oestrogen replacement to correct this impairment implicates a role for oestrogen in the sympathetic neural control of muscle haemodynamics during exercise.

  1. Integrating Oracle Human Resources with Other Modules

    NASA Technical Reports Server (NTRS)

    Sparks, Karl; Shope, Shawn

    1998-01-01

    One of the most challenging aspects of implementing an enterprise-wide business system is achieving integration of the different modules to the satisfaction of diverse customers. The Jet Propulsion Laboratory's (JPL) implementation of the Oracle application suite demonstrates the need to coordinate Oracle Human Resources Management System (HRMS) decision across the Oracle modules.

  2. Is oestrogen a ‘biological neuroleptic’?

    PubMed Central

    Chattopadyay, Subhagata

    2003-01-01

    Objective : Oestrogen-hypothesis in schizophrenia is a largely debated issue. Being a multifactor disorder, schizophrenia has gained importance in the field of psychiatric research, especially to dig out the tentative aetiologies (genetic, biological, environmental etc.), still under tested or not tested. The present article is an attempt only to understand the possible role of oestrogen as a ‘core’ biological factor at the backdrop of male-female differences (in the onset, course, treatment response, prognosis) in schizophrenia barring other factors. This is to reduce the level of ‘conflict’ and ‘confusion’ in the article. Method : Electronic data search is the mainstay of the literature bank, included in the article and only ’supportive’ evidences (direct and indirect) are incorporated to understand the role of oestrogen in the brain at the backdrop of schizophrenia. Result: The study comes out with a postulation that oestrogen has got a potential effect in moderating the process of schizophrenia in the females. Conclusion : Oestrogen could be tested as the ’novel’ therapeutic agent in the female schizophrenics with the necessary support from the modern Nuclear Imaging Techniques to get maximum therapeutic benefit in schizophrenia. PMID:21206859

  3. Immunohistochemical quantitation of oestrogen receptors and proliferative activity in oestrogen receptor positive breast cancer.

    PubMed Central

    Jensen, V; Ladekarl, M

    1995-01-01

    AIM--To evaluate the effect of the duration of formalin fixation and of tumour heterogeneity on quantitative estimates of oestrogen receptor content (oestrogen receptor index) and proliferative activity (MIB-1 index) in breast cancer. METHODS--Two monoclonal antibodies, MIB-1 and oestrogen receptor, were applied to formalin fixed, paraffin wax embedded tissue from 25 prospectively collected oestrogen receptor positive breast carcinomas, using a microwave antigen retrieval method. Tumour tissue was allocated systematically to different periods of fixation to ensure minimal intraspecimen variation. The percentages of MIB-1 positive and oestrogen receptor positive nuclei were estimated in fields of vision sampled systematically from the entire specimen and from the whole tumour area of one "representative" cross-section. RESULTS--No correlation was found between the oestrogen receptor and MIB-1 indices and the duration of formalin fixation. The estimated MIB-1 and oestrogen receptor indices in tissue sampled systematically from the entire tumour were closely correlated with estimates obtained in a "representative" section. The intra- and interobserver correlation of the MIB-1 index was good, although a slight systematical error at the second assessment of the intraobserver study was noted. CONCLUSION--Quantitative estimates of oestrogen receptor content and proliferative activity are not significantly influenced by the period of fixation in formalin, varying from less than four hours to more than 48 hours. The MIB-1 and the oestrogen receptor indices obtained in a "representative" section do not deviate significantly from average indices determined in tissue samples from the entire tumour. Finally, the estimation of MIB-1 index is reproducible, justifying its routine use. PMID:7629289

  4. Fluorene-9-bisphenol is anti-oestrogenic and may cause adverse pregnancy outcomes in mice

    PubMed Central

    Zhang, Zhaobin; Hu, Ying; Guo, Jilong; Yu, Tong; Sun, Libei; Xiao, Xuan; Zhu, Desheng; Nakanishi, Tsuyoshi; Hiromori, Youhei; Li, Junyu; Fan, Xiaolin; Wan, Yi; Cheng, Siyu; Li, Jun; Guo, Xuan; Hu, Jianying

    2017-01-01

    Bisphenol A (BPA) is used in the production of plastic but has oestrogenic activity. Therefore, BPA substitutes, such as fluorene-9-bisphenol (BHPF), have been introduced for the production of so-called ‘BPA-free' plastics. Here we show that BHPF is released from commercial ‘BPA-free' plastic bottles into drinking water and has anti-oestrogenic effects in mice. We demonstrate that BHPF has anti-oestrogenic activity in vitro and, in an uterotrophic assay in mice, induces low uterine weight, atrophic endometria and causes adverse pregnancy outcomes, even at doses lower than those of BPA for which no observed adverse effect have been reported. Female mice given water containing BHPF released from plastic bottles, have detectable levels of BHPF in serum, low uterine weights and show decreased expressions of oestrogen-responsive genes. We also detect BHPF in the plasma of 7/100 individuals, who regularly drink water from plastic bottles. Our data suggest that BPA substitutes should be tested for anti-oestrogenic activity and call for further study of the toxicological effects of BHPF on human health. PMID:28248286

  5. Efficiency of advanced oxidation processes in lowering bisphenol A toxicity and oestrogenic activity in aqueous samples.

    PubMed

    Plahuta, Maja; Tišler, Tatjana; Toman, Mihael Jožef; Pintar, Albin

    2014-03-01

    Bisphenol A (BPA) is a well-known endocrine disruptor with adverse oestrogen-like effects eliciting adverse effects in humans and wildlife. For this reason it is necessary to set up an efficient removal of BPA from wastewaters, before they are discharged into surface waters. The aim of this study was to compare the efficiency of BPA removal from aqueous samples with photolytic, photocatalytic, and UV/H₂O₂ oxidation. BPA solutions were illuminated with different bulbs (halogen; 17 W UV, 254 nm; and 150 W UV, 365 nm) with or without the TiO₂ P-25 catalyst or H₂O₂ (to accelerate degradation). Acute toxicity and oestrogenic activity of treated samples were determined using luminescent bacteria (Vibrio fischeri), water fleas (Daphnia magna), zebrafish embryos (Danio rerio), and Yeast Estrogen Screen (YES) assay with genetically modified yeast Saccharomyces cerevisiae. The results confirmed that BPA is toxic and oestrogenically active. Chemical analysis showed a reduction of BPA levels after photolytic treatment and 100 % conversion of BPA by photocatalytic and UV/H₂O₂ oxidation. The toxicity and oestrogenic activity of BPA were largely reduced in photolytically treated samples. Photocatalytic oxidation, however, either did not reduce BPA toxic and oestrogenic effects or even increased them in comparison with the baseline, untreated BPA solution. Our findings suggest that chemical analysis is not sufficient to determine the efficiency of advanced oxidation processes in removing pollutants from water and needs to be complemented with biological tests.

  6. In vivo relative quantitative proteomics reveals HMGB1 as a downstream mediator of oestrogen-stimulated keratinocyte migration.

    PubMed

    Shin, Jung U; Noh, Ji Yeon; Lee, Ju Hee; Lee, Won Jai; Yoo, Jong Shin; Kim, Jin Young; Kim, Hyeran; Jung, Inhee; Jin, Shan; Lee, Kwang Hoon

    2015-06-01

    It is known that oestrogen influences skin wound healing by modulating the inflammatory response, cytokine expression and extracellular matrix deposition; accelerating re-epithelialization; and stimulating angiogenesis. To identify novel proteins associated with effects of oestrogen on keratinocyte, stable isotope labelling by amino acids in cell culture (SILAC)-based mass spectrometry was performed. Using SILAC, quantification of 1085 proteins was achieved. Among these proteins, 60 proteins were upregulated and 32 proteins were downregulated. Among significantly upregulated proteins, high-mobility group protein B1 (HMGB1) has been further evaluated for its role in the effect of oestrogen on keratinocytes. HMGB1 expression was strongly induced in oestrogen-treated keratinocytes in dose- and time-dependent manner. Further, HMGB1 was able to significantly accelerate the rate of HaCaT cell migration. To determine whether HMGB1 is involved in E2-induced HaCaT cell migration, cells were transfected with HMGB1 siRNA. Knockdown of HMGB1 blocked oestrogen-induced keratinocyte migration. Collectively, these experiments demonstrate that HMGB1 is a novel downstream mediator of oestrogen-stimulated keratinocyte migration. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  7. Parabens, oestrogenicity, underarm cosmetics and breast cancer: a perspective on a hypothesis.

    PubMed

    Harvey, Philip W

    2003-01-01

    A recent review by Darbre (2003) published in this journal (J. Appi. Toxicol. 23: 89-95) has attracted public and scientific interest that requires perspective, particularly on the use of esters of p-hydroxybenzoic acid (parabens) as preservatives in underarm cosmetics. Although parabens are generally regarded as safe, recent reports suggest that they are oestrogenic in a variety of in vitro (including MCF7 and ZR-75-1 human breast cancer cell lines) and in vivo tests for oestrogenicity (uterotrophic assays in both rat and mouse). There are also recent reports of adverse reproductive and developmental outcomes in rodent toxicity studies. Of interest is the lack of activity by the oral route but clear activity by the subcutaneous and topical routes, which is of some relevance to the use of underarm cosmetics. There would seem to be a case now to supplement these emerging toxicity data with longer term regulatory standard tests examining other oestrogenic endpoints and at least to consider these findings in more up-to-date risk assessments specific for cosmetic use. Further, there are few data on the use of underarm cosmetics and the risk of breast cancer, and although one recent retrospective interview-based study found no association there is a need for more thorough investigation taking into account the type of chemicals used. Darbre has forwarded a hypothesis and called for further work to establish whether or not the use of underarm cosmetics (particularly containing oestrogenic formulants) contributes to the rising incidence of breast cancer. It would seem prudent to conduct this work because the current database is sparse and the effects of long-term low-level exposures to weakly oestrogenic chemicals on human health, particularly their application to the underarm and the risks of breast cancer, are unknown. The role of oestrogens in breast cancer, however, is undisputed.

  8. Oestrogen receptor negativity in breast cancer: a cause or consequence?

    PubMed Central

    Gajulapalli, Vijaya Narasihma Reddy; Malisetty, Vijaya Lakshmi; Chitta, Suresh Kumar; Manavathi, Bramanandam

    2016-01-01

    Endocrine resistance, which occurs either by de novo or acquired route, is posing a major challenge in treating hormone-dependent breast cancers by endocrine therapies. The loss of oestrogen receptor α (ERα) expression is the vital cause of establishing endocrine resistance in this subtype. Understanding the mechanisms that determine the causes of this phenomenon are therefore essential to reduce the disease efficacy. But how we negate oestrogen receptor (ER) negativity and endocrine resistance in breast cancer is questionable. To answer that, two important approaches are considered: (1) understanding the cellular origin of heterogeneity and ER negativity in breast cancers and (2) characterization of molecular regulators of endocrine resistance. Breast tumours are heterogeneous in nature, having distinct molecular, cellular, histological and clinical behaviour. Recent advancements in perception of the heterogeneity of breast cancer revealed that the origin of a particular mammary tumour phenotype depends on the interactions between the cell of origin and driver genetic hits. On the other hand, histone deacetylases (HDACs), DNA methyltransferases (DNMTs), miRNAs and ubiquitin ligases emerged as vital molecular regulators of ER negativity in breast cancers. Restoring response to endocrine therapy through re-expression of ERα by modulating the expression of these molecular regulators is therefore considered as a relevant concept that can be implemented in treating ER-negative breast cancers. In this review, we will thoroughly discuss the underlying mechanisms for the loss of ERα expression and provide the future prospects for implementing the strategies to negate ER negativity in breast cancers. PMID:27884978

  9. [Apoptosis modulation by human papillomavirus].

    PubMed

    Jave-Suárez, Luis Felipe; Ratkovich-González, Sarah; Olimón-Andalón, Vicente; Aguilar-Lemarroy, Adriana

    2015-01-01

    One of the most important processes to keep the homeostasis in organisms is the apoptosis, also called programmed cell death. This mechanism works through two pathways: The intrinsic or mitochondrial, which responds to DNA damage and extern agents like UV radiation; and the extrinsic or receptor-mediated, which binds to their ligands to initiate the apoptotic trail. The evasion of apoptosis is one of the main causes of cellular transformation to malignity. Many viruses had shown capacity to modify the apoptotic process; among them is the human papillomavirus, which, by means of its oncoproteins, interferes in pathways, reacting with the receptors and molecules and participating in the death mechanism. This creates ideal conditions for cancer development.

  10. Oestrogens ameliorate mitochondrial dysfunction in Leber’s hereditary optic neuropathy

    PubMed Central

    Giordano, Carla; Montopoli, Monica; Perli, Elena; Orlandi, Maurizia; Fantin, Marianna; Ross-Cisneros, Fred N.; Caparrotta, Laura; Martinuzzi, Andrea; Ragazzi, Eugenio; Ghelli, Anna; Sadun, Alfredo A.; d’Amati, Giulia

    2011-01-01

    Leber’s hereditary optic neuropathy, the most frequent mitochondrial disease due to mitochondrial DNA point mutations in complex I, is characterized by the selective degeneration of retinal ganglion cells, leading to optic atrophy and loss of central vision prevalently in young males. The current study investigated the reasons for the higher prevalence of Leber’s hereditary optic neuropathy in males, exploring the potential compensatory effects of oestrogens on mutant cell metabolism. Control and Leber’s hereditary optic neuropathy osteosarcoma-derived cybrids (11778/ND4, 3460/ND1 and 14484/ND6) were grown in glucose or glucose-free, galactose-supplemented medium. After having shown the nuclear and mitochondrial localization of oestrogen receptors in cybrids, experiments were carried out by adding 100 nM of 17β-oestradiol. In a set of experiments, cells were pre-incubated with the oestrogen receptor antagonist ICI 182780. Leber’s hereditary optic neuropathy cybrids in galactose medium presented overproduction of reactive oxygen species, which led to decrease in mitochondrial membrane potential, increased apoptotic rate, loss of cell viability and hyper-fragmented mitochondrial morphology compared with control cybrids. Treatment with 17β-oestradiol significantly rescued these pathological features and led to the activation of the antioxidant enzyme superoxide dismutase 2. In addition, 17β-oestradiol induced a general activation of mitochondrial biogenesis and a small although significant improvement in energetic competence. All these effects were oestrogen receptor mediated. Finally, we showed that the oestrogen receptor β localizes to the mitochondrial network of human retinal ganglion cells. Our results strongly support a metabolic basis for the unexplained male prevalence in Leber’s hereditary optic neuropathy and hold promises for a therapeutic use for oestrogen-like molecules. PMID:20943885

  11. Mediator kinase module and human tumorigenesis

    PubMed Central

    Clark, Alison D.; Oldenbroek, Marieke; Boyer, Thomas G.

    2016-01-01

    Mediator is a conserved multi-subunit signal processor through which regulatory informatiosn conveyed by gene-specific transcription factors is transduced to RNA Polymerase II (Pol II). In humans, MED13, MED12, CDK8 and Cyclin C (CycC) comprise a four-subunit “kinase” module that exists in variable association with a 26-subunit Mediator core. Genetic and biochemical studies have established the Mediator kinase module as a major ingress of developmental and oncogenic signaling through Mediator, and much of its function in signal-dependent gene regulation derives from its resident CDK8 kinase activity. For example, CDK8-targeted substrate phosphorylation impacts transcription factor half-life, Pol II activity and chromatin chemistry and functional status. Recent structural and biochemical studies have revealed a precise network of physical and functional subunit interactions required for proper kinase module activity. Accordingly, pathologic change in this activity through altered expression or mutation of constituent kinase module subunits can have profound consequences for altered signaling and tumor formation. Herein, we review the structural organization, biological function and oncogenic potential of the Mediator kinase module. We focus principally on tumor-associated alterations in kinase module subunits for which mechanistic relationships as opposed to strictly correlative associations are established. These considerations point to an emerging picture of the Mediator kinase module as an oncogenic unit, one in which pathogenic activation/deactivation through component change drives tumor formation through perturbation of signal-dependent gene regulation. It follows that therapeutic strategies to combat CDK8-driven tumors will involve targeted modulation of CDK8 activity or pharmacologic manipulation of dysregulated CDK8-dependent signaling pathways. PMID:26182352

  12. Striated muscle activator of Rho signalling (STARS) is a PGC-1α/oestrogen-related receptor-α target gene and is upregulated in human skeletal muscle after endurance exercise.

    PubMed

    Wallace, Marita A; Hock, M Benjamin; Hazen, Bethany C; Kralli, Anastasia; Snow, Rod J; Russell, Aaron P

    2011-04-15

    The striated muscle activator of Rho signalling (STARS) is an actin-binding protein specifically expressed in cardiac, skeletal and smooth muscle. STARS has been suggested to provide an important link between the transduction of external stress signals to intracellular signalling pathways controlling genes involved in the maintenance of muscle function. The aims of this study were firstly, to establish if STARS, as well as members of its downstream signalling pathway, are upregulated following acute endurance cycling exercise; and secondly, to determine if STARS is a transcriptional target of peroxisome proliferator-activated receptor gamma co-activator 1-α (PGC-1α) and oestrogen-related receptor-α (ERRα). When measured 3 h post-exercise, STARS mRNA and protein levels as well as MRTF-A and serum response factor (SRF) nuclear protein content, were significantly increased by 140, 40, 40 and 40%, respectively. Known SRF target genes, carnitine palmitoyltransferase-1β (CPT-1β) and jun B proto-oncogene (JUNB), as well as the exercise-responsive genes PGC-1α mRNA and ERRα were increased by 2.3-, 1.8-, 4.5- and 2.7-fold, 3 h post-exercise. Infection of C2C12 myotubes with an adenovirus-expressing human PGC-1α resulted in a 3-fold increase in Stars mRNA, a response that was abolished following the suppression of endogenous ERRα. Over-expression of PGC-1α also increased Cpt-1β, Cox4 and Vegf mRNA by 6.2-, 2.0- and 2.0-fold, respectively. Suppression of endogenous STARS reduced basal Cpt-1β levels by 8.2-fold and inhibited the PGC-1α-induced increase in Cpt-1β mRNA. Our results show for the first time that the STARS signalling pathway is upregulated in response to acute endurance exercise. Additionally, we show in C2C12 myotubes that the STARS gene is a PGC-1α/ERRα transcriptional target. Furthermore, our results suggest a novel role of STARS in the co-ordination of PGC-1α-induced upregulation of the fat oxidative gene, CPT-1β.

  13. Striated muscle activator of Rho signalling (STARS) is a PGC-1α/oestrogen-related receptor-α target gene and is upregulated in human skeletal muscle after endurance exercise

    PubMed Central

    Wallace, Marita A; Hock, M Benjamin; Hazen, Bethany C; Kralli, Anastasia; Snow, Rod J; Russell, Aaron P

    2011-01-01

    Abstract The striated muscle activator of Rho signalling (STARS) is an actin-binding protein specifically expressed in cardiac, skeletal and smooth muscle. STARS has been suggested to provide an important link between the transduction of external stress signals to intracellular signalling pathways controlling genes involved in the maintenance of muscle function. The aims of this study were firstly, to establish if STARS, as well as members of its downstream signalling pathway, are upregulated following acute endurance cycling exercise; and secondly, to determine if STARS is a transcriptional target of peroxisome proliferator-activated receptor gamma co-activator 1-α (PGC-1α) and oestrogen-related receptor-α (ERRα). When measured 3 h post-exercise, STARS mRNA and protein levels as well as MRTF-A and serum response factor (SRF) nuclear protein content, were significantly increased by 140, 40, 40 and 40%, respectively. Known SRF target genes, carnitine palmitoyltransferase-1β (CPT-1β) and jun B proto-oncogene (JUNB), as well as the exercise-responsive genes PGC-1α mRNA and ERRα were increased by 2.3-, 1.8-, 4.5- and 2.7-fold, 3 h post-exercise. Infection of C2C12 myotubes with an adenovirus-expressing human PGC-1α resulted in a 3-fold increase in Stars mRNA, a response that was abolished following the suppression of endogenous ERRα. Over-expression of PGC-1α also increased Cpt-1β, Cox4 and Vegf mRNA by 6.2-, 2.0- and 2.0-fold, respectively. Suppression of endogenous STARS reduced basal Cpt-1β levels by 8.2-fold and inhibited the PGC-1α-induced increase in Cpt-1β mRNA. Our results show for the first time that the STARS signalling pathway is upregulated in response to acute endurance exercise. Additionally, we show in C2C12 myotubes that the STARS gene is a PGC-1α/ERRα transcriptional target. Furthermore, our results suggest a novel role of STARS in the co-ordination of PGC-1α-induced upregulation of the fat oxidative gene, CPT-1β. PMID:21486805

  14. Circumventing the natural, frequent oestrogen waves of the female cheetah (Acinonyx jubatus) using oral progestin (Altrenogest).

    PubMed

    Crosier, Adrienne E; Comizzoli, Pierre; Koester, Diana C; Wildt, David E

    2016-08-03

    Cheetah are induced ovulators, experiencing short, variable oestrogen waves year-round. Exogenous gonadotrophin administration induces ovulation, but success is variable and often improves if ovaries are quiescent. After affirming the presence of short-term oestrogenic waves, we examined the effect of the timing of administration of exogenous equine and human chorionic gonadotrophins (eCG-hCG) within the oestrogen concentration pattern on subsequent follicle development and oocyte and corpus luteum quality. We also investigated ovarian suppression using an oral progestin (Altrenogest, 7 days) and assessed whether Altrenogest moderated adrenal activity by reducing glucocorticoid metabolites. All cheetahs exhibited short (every ~7-10 days), sporadic, year-round increases in faecal oestradiol punctuated by unpredictable periods (4-10 weeks) of baseline oestradiol (anoestrous). Gonadotrophin (eCG-hCG) efficacy was not affected by oestradiol 'wave' pattern if administered ≥3 days after an oestrogen peak. Such cheetahs produced normative faecal progestagen patterns and higher numbers (P<0.06) of mature oocytes than females given gonadotrophins ≤2 days after an oestradiol peak. Altrenogest supplementation expanded the interval between oestradiol peaks to 12.9 days compared with 7.3 days without progestin pretreatment. Altrenogest-fed females excreted less (P<0.05) glucocorticoid metabolites than non-supplemented counterparts. Results show that Altrenogest is effective for suppressing follicular activity, may contribute to reduced glucocorticoid production and may result in more effective ovulation induction via gonadotrophin therapy.

  15. Tissue Specificity of Human Disease Module

    PubMed Central

    Kitsak, Maksim; Sharma, Amitabh; Menche, Jörg; Guney, Emre; Ghiassian, Susan Dina; Loscalzo, Joseph; Barabási, Albert-László

    2016-01-01

    Genes carrying mutations associated with genetic diseases are present in all human cells; yet, clinical manifestations of genetic diseases are usually highly tissue-specific. Although some disease genes are expressed only in selected tissues, the expression patterns of disease genes alone cannot explain the observed tissue specificity of human diseases. Here we hypothesize that for a disease to manifest itself in a particular tissue, a whole functional subnetwork of genes (disease module) needs to be expressed in that tissue. Driven by this hypothesis, we conducted a systematic study of the expression patterns of disease genes within the human interactome. We find that genes expressed in a specific tissue tend to be localized in the same neighborhood of the interactome. By contrast, genes expressed in different tissues are segregated in distinct network neighborhoods. Most important, we show that it is the integrity and the completeness of the expression of the disease module that determines disease manifestation in selected tissues. This approach allows us to construct a disease-tissue network that confirms known and predicts unexpected disease-tissue associations. PMID:27748412

  16. Roles for oestrogen receptor β in adult brain function.

    PubMed

    Handa, R J; Ogawa, S; Wang, J M; Herbison, A E

    2012-01-01

    Oestradiol exerts a profound influence upon multiple brain circuits. For the most part, these effects are mediated by oestrogen receptor (ER)α. We review here the roles of ERβ, the other ER isoform, in mediating rodent oestradiol-regulated anxiety, aggressive and sexual behaviours, the control of gonadotrophin secretion, and adult neurogenesis. Evidence exists for: (i) ERβ located in the paraventricular nucleus underpinning the suppressive influence of oestradiol on the stress axis and anxiety-like behaviour; (ii) ERβ expressed in gonadotrophin-releasing hormone neurones contributing to oestrogen negative-feedback control of gonadotrophin secretion; (iii) ERβ controlling the offset of lordosis behaviour; (iv) ERβ suppressing aggressive behaviour in males; (v) ERβ modulating responses to social stimuli; and (vi) ERβ in controlling adult neurogenesis. This review highlights two major themes; first, ERβ and ERα are usually tightly inter-related in the oestradiol-dependent control of a particular brain function. For example, even though oestradiol feedback to control reproduction occurs principally through ERα-dependent mechanisms, modulatory roles for ERβ also exist. Second, the roles of ERα and ERβ within a particular neural network may be synergistic or antagonistic. Examples of the latter include the role of ERα to enhance, and ERβ to suppress, anxiety-like and aggressive behaviours. Splice variants such as ERβ2, acting as dominant negative receptors, are of further particular interest because their expression levels may reflect preceeding oestradiol exposure of relevance to oestradiol replacement therapy. Together, this review highlights the predominant modulatory, but nonetheless important, roles of ERβ in mediating the many effects of oestradiol upon adult brain function.

  17. Oestrogen promotes coronary angiogenesis even under normoxic conditions.

    PubMed

    Nematbakhsh, Mehdi; Ghadesi, Mehrzad; Hosseinbalam, Marzieh; Khazaei, Majid; Gharagozloo, Marjan; Gharagozlo, Marjan; Dashti, Gholamreza; Rajabi, Parvin; Rafieian, Shahram

    2008-09-01

    Angiogenic therapy is one of the new treatments of ischaemic heart disease. Oestrogen has angiogenic properties under hypoxic condition, and if oestrogen also induces angiogenesis under normoxic condition, it could be used in combination with other angiogenic therapies in the treatment of ischaemic heart disease. In this study, we evaluated the angiogenic effect of high-dose oestrogen treatment in normoxic rat heart tissue. Fifty-two ovariectomized rats were randomized in oestrogen-treated and control groups. 17beta-oestradiol (1 mg/week) and normal saline (1 mg/week) were administered intramuscularly in the treatment and control groups for 2 months. After that, coronary capillary density and coronary vessel permeability were measured. The serum vascular endothelial growth factor (VEGF) level was also measured before and after the treatment. The results indicate that coronary capillary density (number of capillary per square millimetre) and coronary vessel permeability (fluorescence intensity) were significantly higher in the oestrogen-treated group than in the control group (628 +/- 26 per mm(2) versus 540 +/- 26 per mm(2); P < 0.05 and 207 +/- 10 versus 147 +/- 19 per gram tissue; P < 0.05). Oestrogen treatment increased serum VEGF level in the oestrogen-treated group compared to the control group (52 +/- 3 versus 33 +/- 6 pg/ml; P < 0.05), but interestingly VEGF was also increased in the control group after placebo treatment. It seems that high-dose oestrogen administration has angiogenic properties even in normoxic conditions. These angiogenic properties may result from oestrogen's direct effect on VEGF or other mechanisms, such as endothelial progenitor cell mobilization. Because of the broad effect of oestrogen on angiogenic growth factors and endothelial cells, more studies are required to clarify angiogenic properties of high-dose oestrogen.

  18. Differential regulation of oestrogen receptor β isoforms by 5' untranslated regions in cancer.

    PubMed

    Smith, Laura; Brannan, Rebecca A; Hanby, Andrew M; Shaaban, Abeer M; Verghese, Eldo T; Peter, Mark B; Pollock, Steven; Satheesha, Sampoorna; Szynkiewicz, Marcin; Speirs, Valerie; Hughes, Thomas A

    2010-08-01

    Oestrogen receptors (ERs) are critical regulators of the behaviour of many cancers. Despite this, the roles and regulation of one of the two known ERs - ERβ- are poorly understood. This is partly because analyses have been confused by discrepancies between ERβ expression at mRNA and proteins levels, and because ERβ is expressed as several functionally distinct isoforms. We investigated human ERβ 5' untranslated regions (UTRs) and their influences on ERβ expression and function. We demonstrate that two alternative ERβ 5'UTRs have potent and differential influences on expression acting at the level of translation. We show that their influences are modulated by cellular context and in carcinogenesis, and demonstrate the contributions of both upstream open reading frames and RNA secondary structure. These regulatory mechanisms offer explanations for the non-concordance of ERβ mRNA and protein. Importantly, we also demonstrate that 5'UTRs allow the first reported mechanisms for differential regulation of the expression of the ERβ isoforms 1, 2 and 5, and thereby have critical influences on ERβ function.

  19. Endocrine disruption by dietary phyto-oestrogens: impact on dimorphic sexual systems and behaviours.

    PubMed

    Patisaul, Heather B

    2016-07-08

    A wide range of health benefits have been ascribed to soya intake including a lowered risk of osteoporosis, heart disease, breast cancer, and menopausal symptoms. Because it is a hormonally active diet, however, soya can also be endocrine disrupting, suggesting that intake has the potential to cause adverse health effects in certain circumstances, particularly when exposure occurs during development. Consequently, the question of whether or not soya phyto-oestrogens are beneficial or harmful to human health is neither straightforward nor universally applicable to all groups. Possible benefits and risks depend on age, health status, and even the presence or absence of specific gut microflora. As global consumption increases, greater awareness and consideration of the endocrine-disrupting properties of soya by nutrition specialists and other health practitioners is needed. Consumption by infants and small children is of particular concern because their hormone-sensitive organs, including the brain and reproductive system, are still undergoing sexual differentiation and maturation. Thus, their susceptibility to the endocrine-disrupting activities of soya phyto-oestrogens may be especially high. As oestrogen receptor partial agonists with molecular and cellular properties similar to anthropogenic endocrine disruptors such as bisphenol A, the soya phyto-oestrogens provide an interesting model for how attitudes about what is 'synthetic' v. what is 'natural,' shapes understanding and perception of what it means for a compound to be endocrine disrupting and/or potentially harmful. This review describes the endocrine-disrupting properties of soya phyto-oestrogens with a focus on neuroendocrine development and behaviour.

  20. Cell life and death in the anterior pituitary gland: role of oestrogens.

    PubMed

    Seilicovich, A

    2010-07-01

    Apoptotic processes play an important role in the maintenance of cell numbers in the anterior pituitary gland during physiological endocrine events. In this review, we summarise the regulation of apoptosis of anterior pituitary cells, particularly lactotrophs, somatotrophs and gonadotrophs, and analyse the possible mechanisms involved in oestrogen-induced apoptosis in anterior pituitary cells. Oestrogens exert apoptotic actions in several cell types and act as modulators of pituitary cell renewal, sensitising cells to both mitogenic and apoptotic signals. Local synthesis of growth factors and cytokines induced by oestradiol as well as changes in phenotypic features that enhance the responsiveness of anterior pituitary cells to pro-apoptotic factors may account for cyclical apoptotic activity in anterior pituitary cells during the oestrous cycle. Considering that tissue homeostasis results from a balance between cell proliferation and death and that mechanisms involved in apoptosis are tightly regulated, defects in cell death processes could have a considerable physiopathological impact.

  1. Local Oestrogen for Pelvic Floor Disorders: A Systematic Review

    PubMed Central

    Weber, M. A.; Kleijn, M. H.; Langendam, M.; Limpens, J.; Heineman, M. J.; Roovers, J. P.

    2015-01-01

    Objective The decline in available oestrogen after menopause is a possible etiological factor in pelvic floor disorders like vaginal atrophy (VA), urinary incontinence (UI), overactive bladder (OAB) and pelvic organ prolapse (POP). This systematic review will examine the evidence for local oestrogen therapy in the treatment of these pelvic floor disorders. Evidence Acquisition We performed a systematic search in MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials and the non-MEDLINE subset of PubMed from inception to May 2014. We searched for local oestrogens and VA (I), UI/OAB (II) and POP (III). Part I was combined with broad methodological filters for randomized controlled trials (RCTs) and secondary evidence. For part I and II two reviewers independently selected RCTs evaluating the effect of topical oestrogens on symptoms and signs of VA and UI/OAB. In part III all studies of topical oestrogen therapy in the treatment of POP were selected. Data extraction and the assessment of risk of bias using the Cochrane Risk of Bias Tool was undertaken independently by two reviewers. Evidence Synthesis The included studies varied in ways of topical application, types of oestrogen, dosage and treatment durations. Objective and subjective outcomes were assessed by a variety of measures. Overall, subjective and urodynamic outcomes, vaginal maturation and vaginal pH changed in favor of vaginal oestrogens compared to placebo. No obvious differences between different application methods were revealed. Low doses already seemed to have a beneficial effect. Studies evaluating the effect of topical oestrogen in women with POP are scarce and mainly assessed symptoms and signs associated with VA instead of POP symptoms. Conclusion Topical oestrogen administration is effective for the treatment of VA and seems to decrease complaints of OAB and UI. The potential for local oestrogens in the prevention as well as treatment of POP needs further research. PMID:26383760

  2. Orchidectomy versus oestrogen for prostatic cancer: cardiovascular effects.

    PubMed Central

    Henriksson, P; Edhag, O

    1986-01-01

    One hundred consecutive patients aged up to 75 with newly diagnosed cancer of the prostate suitable for hormonal treatment were included in a controlled study of the cardiovascular effects of oestrogen versus orchidectomy. In all cases pre-existing cardiovascular morbidity was excluded. Of the 100 patients, 91 were strictly randomised to receive either oestrogen (n = 47) or orchidectomy (n = 44) and 9 (6 given oestrogen, 3 orchidectomy) either chose their own treatment (five cases) or had it selected for them by the urologist (four). Oestrogen was given in the lowest recommended dosage in Sweden--namely, as 160 mg polyestradiol phosphate intramuscularly every month for the first three months, then 80 mg monthly, plus ethinyloestradiol 1 mg by mouth daily for the first two weeks, then 150 micrograms daily. At entry to the study the two treatment groups showed no difference in demographic characteristics or conventional risk factors for cardiovascular disease. During the first year, however, 13 (25%) of the patients given oestrogen suffered major cardiovascular events as compared with none of the patients after orchidectomy. Patients in the oestrogen treatment group who did not have minor signs of atherosclerosis at entry to the study suffered a similar incidence of cardiovascular complications to those who did have these signs at entry. The substantially increased risk of cardiovascular complications in patients given oestrogen for prostatic cancer warrants careful consideration when choosing treatment for this disorder. PMID:3091138

  3. Stressor controllability modulates fear extinction in humans.

    PubMed

    Hartley, Catherine A; Gorun, Alyson; Reddan, Marianne C; Ramirez, Franchesca; Phelps, Elizabeth A

    2014-09-01

    Traumatic events are proposed to play a role in the development of anxiety disorders, however not all individuals exposed to extreme stress experience a pathological increase in fear. Recent studies in animal models suggest that the degree to which one is able to control an aversive experience is a critical factor determining its behavioral consequences. In this study, we examined whether stressor controllability modulates subsequent conditioned fear expression in humans. Participants were randomly assigned to an escapable stressor condition, a yoked inescapable stressor condition, or a control condition involving no stress exposure. One week later, all participants underwent fear conditioning, fear extinction, and a test of extinction retrieval the following day. Participants exposed to inescapable stress showed impaired fear extinction learning and increased fear expression the following day. In contrast, escapable stress improved fear extinction and prevented the spontaneous recovery of fear. Consistent with the bidirectional controllability effects previously reported in animal models, these results suggest that one's degree of control over aversive experiences may be an important factor influencing the development of psychological resilience or vulnerability in humans.

  4. Stressor controllability modulates fear extinction in humans

    PubMed Central

    Hartley, Catherine A.; Gorun, Alyson; Reddan, Marianne C.; Ramirez, Franchesca; Phelps, Elizabeth A.

    2014-01-01

    Traumatic events are proposed to play a role in the development of anxiety disorders, however not all individuals exposed to extreme stress experience a pathological increase in fear. Recent studies in animal models suggest that the degree to which one is able to control an aversive experience is a critical factor determining its behavioral consequences. In this study, we examined whether stressor controllability modulates subsequent conditioned fear expression in humans. Participants were randomly assigned to an escapable stressor condition, a yoked inescapable stressor condition, or a control condition involving no stress exposure. One week later, all participants underwent fear conditioning, fear extinction, and a test of extinction retrieval the following day. Participants exposed to inescapable stress showed impaired fear extinction learning and increased fear expression the following day. In contrast, escapable stress improved fear extinction and prevented the spontaneous recovery of fear. Consistent with the bidirectional controllability effects previously reported in animal models, these results suggest that one's degree of control over aversive experiences may be an important factor influencing the development of psychological resilience or vulnerability in humans. PMID:24333646

  5. Tumour nuclear oestrogen receptor beta 1 correlates inversely with parathyroid tumour weight.

    PubMed

    Haglund, Felix; Rosin, Gustaf; Nilsson, Inga-Lena; Juhlin, C Christofer; Pernow, Ylva; Norenstedt, Sophie; Dinets, Andrii; Larsson, Catharina; Hartman, Johan; Höög, Anders

    2015-03-01

    Primary hyperparathyroidism (PHPT) is a common endocrinopathy, frequently caused by a parathyroid adenoma, rarely by a parathyroid carcinoma that lacks effective oncological treatment. As the majority of cases are present in postmenopausal women, oestrogen signalling has been implicated in the tumourigenesis. Oestrogen receptor beta 1 (ERB1) and ERB2 have been recently identified in parathyroid adenomas, the former inducing genes coupled to tumour apoptosis. We applied immunohistochemistry and slide digitalisation to quantify nuclear ERB1 and ERB2 in 172 parathyroid adenomas, atypical adenomas and carcinomas, and ten normal parathyroid glands. All the normal parathyroid glands expressed ERB1 and ERB2. The majority of tumours expressed ERB1 (70.6%) at varying intensities, and ERB2 (96.5%) at strong intensities. Parathyroid carcinomas expressed ERB1 in three out of six cases and ERB2 in five out of six cases. The intensity of tumour nuclear ERB1 staining significantly correlated inversely with tumour weight (P=0.011), and patients whose tumours were classified as ERB1-negative had significantly greater tumour weight as well as higher serum calcium (P=0.002) and parathyroid hormone levels (P=0.003). Additionally, tumour nuclear ERB1 was not expressed differentially with respect to sex or age of the patient. Levels of tumour nuclear ERB2 did not correlate with clinical characteristics. In conclusion, decreased ERB1 immunoreactivity is associated with increased tumour weight in parathyroid adenomas. Given the previously reported correlation with tumour-suppressive signalling, selective oestrogen receptor modulation (SERMs) may play a role in the treatment of parathyroid carcinomas. Future studies of SERMs and oestrogen treatment in PHPT should consider tumour weight as a potential factor in pharmacological responsiveness. © 2015 The authors.

  6. Tumour nuclear oestrogen receptor beta 1 correlates inversely with parathyroid tumour weight

    PubMed Central

    Haglund, Felix; Rosin, Gustaf; Nilsson, Inga-Lena; Juhlin, C Christofer; Pernow, Ylva; Norenstedt, Sophie; Dinets, Andrii; Larsson, Catharina; Hartman, Johan; Höög, Anders

    2015-01-01

    Primary hyperparathyroidism (PHPT) is a common endocrinopathy, frequently caused by a parathyroid adenoma, rarely by a parathyroid carcinoma that lacks effective oncological treatment. As the majority of cases are present in postmenopausal women, oestrogen signalling has been implicated in the tumourigenesis. Oestrogen receptor beta 1 (ERB1) and ERB2 have been recently identified in parathyroid adenomas, the former inducing genes coupled to tumour apoptosis. We applied immunohistochemistry and slide digitalisation to quantify nuclear ERB1 and ERB2 in 172 parathyroid adenomas, atypical adenomas and carcinomas, and ten normal parathyroid glands. All the normal parathyroid glands expressed ERB1 and ERB2. The majority of tumours expressed ERB1 (70.6%) at varying intensities, and ERB2 (96.5%) at strong intensities. Parathyroid carcinomas expressed ERB1 in three out of six cases and ERB2 in five out of six cases. The intensity of tumour nuclear ERB1 staining significantly correlated inversely with tumour weight (P=0.011), and patients whose tumours were classified as ERB1-negative had significantly greater tumour weight as well as higher serum calcium (P=0.002) and parathyroid hormone levels (P=0.003). Additionally, tumour nuclear ERB1 was not expressed differentially with respect to sex or age of the patient. Levels of tumour nuclear ERB2 did not correlate with clinical characteristics. In conclusion, decreased ERB1 immunoreactivity is associated with increased tumour weight in parathyroid adenomas. Given the previously reported correlation with tumour-suppressive signalling, selective oestrogen receptor modulation (SERMs) may play a role in the treatment of parathyroid carcinomas. Future studies of SERMs and oestrogen treatment in PHPT should consider tumour weight as a potential factor in pharmacological responsiveness. PMID:25648860

  7. Dopamine modulates egalitarian behavior in humans.

    PubMed

    Sáez, Ignacio; Zhu, Lusha; Set, Eric; Kayser, Andrew; Hsu, Ming

    2015-03-30

    Egalitarian motives form a powerful force in promoting prosocial behavior and enabling large-scale cooperation in the human species [1]. At the neural level, there is substantial, albeit correlational, evidence suggesting a link between dopamine and such behavior [2, 3]. However, important questions remain about the specific role of dopamine in setting or modulating behavioral sensitivity to prosocial concerns. Here, using a combination of pharmacological tools and economic games, we provide critical evidence for a causal involvement of dopamine in human egalitarian tendencies. Specifically, using the brain penetrant catechol-O-methyl transferase (COMT) inhibitor tolcapone [4, 5], we investigated the causal relationship between dopaminergic mechanisms and two prosocial concerns at the core of a number of widely used economic games: (1) the extent to which individuals directly value the material payoffs of others, i.e., generosity, and (2) the extent to which they are averse to differences between their own payoffs and those of others, i.e., inequity. We found that dopaminergic augmentation via COMT inhibition increased egalitarian tendencies in participants who played an extended version of the dictator game [6]. Strikingly, computational modeling of choice behavior [7] revealed that tolcapone exerted selective effects on inequity aversion, and not on other computational components such as the extent to which individuals directly value the material payoffs of others. Together, these data shed light on the causal relationship between neurochemical systems and human prosocial behavior and have potential implications for our understanding of the complex array of social impairments accompanying neuropsychiatric disorders involving dopaminergic dysregulation. Copyright © 2015 Elsevier Ltd. All rights reserved.

  8. Pharmacological modulation of human cardiac Na+ channels.

    PubMed

    Krafte, D S; Davison, K; Dugrenier, N; Estep, K; Josef, K; Barchi, R L; Kallen, R G; Silver, P J; Ezrin, A M

    1994-02-15

    Pharmacological modulation of human sodium current was examined in Xenopus oocytes expressing human heart Na+ channels. Na+ currents activated near -50 mV with maximum current amplitudes observed at -20 mV. Steady-state inactivation was characterized by a V1/2 value of -57 +/- 0.5 mV and a slope factor (k) of 7.3 +/- 0.3 mV. Sodium currents were blocked by tetrodotoxin with an IC50 value of 1.8 microM. These properties are consistent with those of Na+ channels expressed in mammalian myocardial cells. We have investigated the effects of several pharmacological agents which, with the exception of lidocaine, have not been characterized against cRNA-derived Na+ channels expressed in Xenopus oocytes. Lidocaine, quinidine and flecainide blocked resting Na+ channels with IC50 values of 521 microM, 198 microM, and 41 microM, respectively. Use-dependent block was also observed for all three agents, but concentrations necessary to induce block were higher than expected for quinidine and flecainide. This may reflect differences arising due to expression in the Xenopus oocyte system or could be a true difference in the interaction between human cardiac Na+ channels and these drugs compared to other mammalian Na+ channels. Importantly, however, this result would not have been predicted based upon previous studies of mammalian cardiac Na+ channels. The effects of DPI 201-106, RWJ 24517, and BDF 9148 were also tested and all three agents slowed and/or removed Na+ current inactivation, reduced peak current amplitudes, and induced use-dependent block. These data suggest that the alpha-subunit is the site of interaction between cardiac Na+ channels and Class I antiarrhythmic drugs as well as inactivation modifiers such as DPI 201-106.

  9. Tuning of Human Modulation Filters Is Carrier-Frequency Dependent

    PubMed Central

    Simpson, Andrew J. R.; Reiss, Joshua D.; McAlpine, David

    2013-01-01

    Recent studies employing speech stimuli to investigate ‘cocktail-party’ listening have focused on entrainment of cortical activity to modulations at syllabic (5 Hz) and phonemic (20 Hz) rates. The data suggest that cortical modulation filters (CMFs) are dependent on the sound-frequency channel in which modulations are conveyed, potentially underpinning a strategy for separating speech from background noise. Here, we characterize modulation filters in human listeners using a novel behavioral method. Within an ‘inverted’ adaptive forced-choice increment detection task, listening level was varied whilst contrast was held constant for ramped increments with effective modulation rates between 0.5 and 33 Hz. Our data suggest that modulation filters are tonotopically organized (i.e., vary along the primary, frequency-organized, dimension). This suggests that the human auditory system is optimized to track rapid (phonemic) modulations at high sound-frequencies and slow (prosodic/syllabic) modulations at low frequencies. PMID:24009759

  10. Hepatic effects of tartrazine (E 102) after systemic exposure are independent of oestrogen receptor interactions in the mouse.

    PubMed

    Meyer, Stephanie K; Probert, Philip M E; Lakey, Anne F; Axon, Andrew R; Leitch, Alistair C; Williams, Faith M; Jowsey, Paul A; Blain, Peter G; Kass, George E N; Wright, Matthew C

    2017-03-27

    Tartrazine is a food colour that activates the transcriptional function of the human oestrogen receptor alpha in an in vitro cell model. Since oestrogens are cholestatic, we hypothesised tartrazine will cause periportal injury to the liver in vivo. To test this hypothesis, tartrazine was initially administered systemically to mice resulting in a periportal recruitment of inflammatory cells, increased serum alkaline phosphatase activity and mild periportal fibrosis. To determine whether an oestrogenic effect may be a key event in this response, tartrazine, sulphonated metabolites and a food additive contaminant were screened for their ability to interact with murine oestrogen receptors. In all cases, there were no interactions as agonists or antagonists and further, no oestrogenicity was observed with tartrazine in an in vivo uterine growth assay. To examine the relevance of the hepatic effects of tartrazine to its use as a food additive, tartrazine was orally administered to transgenic NF-κB-Luc mice. Pre- and concurrent oral treatment with alcohol was incorporated given its potential to promote gut permeability and hepatic inflammation. Tartrazine alone induced NF- κB activities in the colon and liver but there was no periportal recruitment of inflammatory cells or fibrosis. Tartrazine, its sulphonated metabolites and the contaminant inhibited sulphotransferase activities in murine hepatic S9 extracts. Given the role of sulfotransferases in bile acid excretion, the initiating event giving rise to periportal inflammation and subsequent hepatic pathology through systemic tartrazine exposure is therefore potentially associated an inhibition of bile acid sulphation and excretion and not on oestrogen receptor-mediated transcriptional function. However, these effects were restricted to systemic exposures to tartrazine and did not occur to any significant effect after oral exposure.

  11. A model to estimate the oestrogen receptor mediated effects from exposure to soy isoflavones in food.

    PubMed

    Safford, Bob; Dickens, Andrea; Halleron, Nadine; Briggs, David; Carthew, Philip; Baker, Valerie

    2003-10-01

    The advantages that regular consumption of a diet containing soy may have on human health have been enshrined in a major health claim that has been approved by the Food and Drug Administration in the USA, regarding potential protection from heart disease by soy. This could have a major influence on the dietary consumption patterns of soy for consumers and lead to the development of soy enriched foods to enable consumers to achieve the benefits thought to be associated with increased soy consumption in a Western diet. If an increase in soy consumption is beneficial to particular disease conditions, there is always the possibility that there will be effects other than those that are desirable. For soy-containing foods there has been concern that the phytoestrogen content of soy, which is composed of several isoflavones, could be a separate health issue, due to the oestrogen-like activity of isoflavones. To address this, a method has been developed to estimate, relative to 17-beta oestradiol, the activity of the common isoflavones present in soy phytoestrogens, based on their binding to and transcriptional activation of the major oestrogen receptor sub-types alpha and beta. Using this approach, the additional oestrogen-like activity that would be expected from inclusion of soy supplemented foodstuffs in a Western diet, can be determined for different sub-populations, who may have different susceptibilities to the potential for the unwanted biological effects occurring with consumption of soy enriched foods. Because of the theoretical nature of this model, and the controversy over the nature of whether some of the oestrogen-like effects of phytoestrogens are adverse, the biological effects of soy isoflavones and their potential for adverse effects in man, is also reviewed. The question that is critical to the long term safe use of foods enriched in soy is, which observed biological effects in animal studies are likely to also occur in man and whether these would have

  12. Oestrogen-induced angiogenesis and implantation contribute to the development of parasitic myomas after laparoscopic morcellation.

    PubMed

    Huang, Ben-Shian; Yang, Muh-Hwa; Wang, Peng-Hui; Li, Hsin-Yang; Chou, Teh-Ying; Chen, Yi-Jen

    2016-10-06

    Iatrogenic parasitic myomas (PMs), caused by intra-corporeal power morcellation during laparoscopy is gradually increasing. However, the pathogenesis and medical treatment of PMs remain largely unelucidated. Laparoscopically-induced PM xenografted mouse model was conducted by xenografting human uterine myoma fragments into the abdominal cavity of SCID mice and hormonal manipulation was performed using this mouse model to demonstrate the role of oestrogen in the development of implanted PMs. Immunohistochemistry of oestrogen receptor α (ERα), progesterone receptor (PR), vimentin, vascular endothelial growth factor (VEGF), microvessel density (MVD) and Ki-67 index was performed and compared. In the patient with PMs, ERα, PR, angiogenesis and proliferative property expression were upregulated in PM lesions compared to uterine myomas. In the laparoscopically-induced PM mouse model, implanted myomas had more steroid receptor expressions, angiogenesis and proliferative property compared with pre-xenografted or non-implanted myoma. Depletion of oestrogen in the ovariectomized (OVX) mice decreased laparoscopically-induced PM implantations. In comparison, the implantations of PMs were increased with additional E2 supplement. Hormonal manipulation in the PM mouse model, including AI, GnRHa and SERM groups, were compared and AI significantly decreased the implantations, steroid receptor, angiogenesis, cell density, and proliferative index of PMs compared with control group. Furthermore, GnRHa significantly decreased VEGF and MVD expressions compared with control group. These data highlight the crucial role of oestrogen in the development of laparoscopically-induced PMs and suggest that hormone manipulation may be a potential therapeutic agent. This protocol was approved by the Human and Animal Institutional Review Board of Taipei Veterans General Hospital ( VGHIRB No 2014-10-002C on Nov. 17(th), 2014; IACUC 2014-119 on Aug. 22(nd), 2014).

  13. The oestrogenic effects of gestodene, a potent contraceptive progestin, are mediated by its A-ring reduced metabolites.

    PubMed

    Lemus, A E; Zaga, V; Santillán, R; García, G A; Grillasca, I; Damián-Matsumura, P; Jackson, K J; Cooney, A J; Larrea, F; Pérez-Palacios, G

    2000-06-01

    Gestodene (17 alpha-ethynyl-13 beta-ethyl-17 beta-hydroxy-4, 15-gonadien-3-one) is the most potent synthetic progestin currently available and it is widely used as a fertility regulating agent in a number of contraceptive formulations because of its high effectiveness, safety and acceptability. The observation that contraceptive synthetic progestins exert hormone-like effects other than their progestational activities, prompted us to investigate whether gestodene (GSD) administration may induce oestrogenic effects, even though the GSD molecule does not interact with intracellular oestrogen receptors (ER). To assess whether GSD may exert oestrogenic effects through some of its neutral metabolites, a series of experimental studies were undertaken using GSD and three of its A-ring reduced metabolites. Receptor binding studies by displacement analysis confirmed that indeed GSD does not bind to the ER, whereas its 3 beta,5 alpha-tetrahydro reduced derivative (3 beta GSD) interacts with a relative high affinity with the ER. The 3 alpha,5 alpha GSD isomer (3 alpha GSD) also binds to the ER, though to a lesser extent. The ability of the A-ring reduced GSD derivatives to induce oestrogenic actions was evaluated by the use of two different molecular bioassays: (a) transactivation of a yeast system co-transfected with the human ER alpha (hER alpha) gene and oestrogen responsive elements fused to the beta-galactosidase reporter vector and (b) transactivation of the hER alpha-mediated transcription of the chloramphenicol acetyl transferase (CAT) reporter gene in a HeLa cells expression system. The oestrogenic potency of 3 beta GSD was also assessed by its capability to induce oestrogen-dependent progestin receptors (PR) in the anterior pituitary of castrated female rats. The results demonstrated that 3 beta GSD and 3 alpha GSD were able to activate, in a dose-dependent manner, the hER alpha-mediated transcription of both the beta-galactosidase and the CAT reporter genes in the

  14. Detection of modulated tones in modulated noise by non-human primates.

    PubMed

    Bohlen, Peter; Dylla, Margit; Timms, Courtney; Ramachandran, Ramnarayan

    2014-10-01

    In natural environments, many sounds are amplitude-modulated. Amplitude modulation is thought to be a signal that aids auditory object formation. A previous study of the detection of signals in noise found that when tones or noise were amplitude-modulated, the noise was a less effective masker, and detection thresholds for tones in noise were lowered. These results suggest that the detection of modulated signals in modulated noise would be enhanced. This paper describes the results of experiments investigating how detection is modified when both signal and noise were amplitude-modulated. Two monkeys (Macaca mulatta) were trained to detect amplitude-modulated tones in continuous, amplitude-modulated broadband noise. When the phase difference of otherwise similarly amplitude-modulated tones and noise were varied, detection thresholds were highest when the modulations were in phase and lowest when the modulations were anti-phase. When the depth of the modulation of tones or noise was varied, detection thresholds decreased if the modulations were anti-phase. When the modulations were in phase, increasing the depth of tone modulation caused an increase in tone detection thresholds, but increasing depth of noise modulations did not affect tone detection thresholds. Changing the modulation frequency of tone or noise caused changes in threshold that saturated at modulation frequencies higher than 20 Hz; thresholds decreased when the tone and noise modulations were in phase and decreased when they were anti-phase. The relationship between reaction times and tone level were not modified by manipulations to the nature of temporal variations in the signal or noise. The changes in behavioral threshold were consistent with a model where the brain subtracted noise from signal. These results suggest that the parameters of the modulation of signals and maskers heavily influence detection in very predictable ways. These results are consistent with some results in humans and avians

  15. Wnt modulating agents inhibit human cytomegalovirus replication.

    PubMed

    Kapoor, Arun; He, Ran; Venkatadri, Rajkumar; Forman, Michael; Arav-Boger, Ravit

    2013-06-01

    Infection with human cytomegalovirus (HCMV) continues to be a threat for pregnant women and immunocompromised hosts. Although limited anti-HCMV therapies are available, development of new agents is desired. The Wnt signaling pathway plays a critical role in embryonic and cancer stem cell development and is targeted by gammaherpesviruses, Epstein-Barr virus (EBV), and Kaposi's sarcoma-associated herpesvirus (KSHV). HCMV infects stem cells, including neural progenitor cells, during embryogenesis. To investigate the role of Wnt in HCMV replication in vitro, we tested monensin, nigericin, and salinomycin, compounds that inhibit cancer stem cell growth by modulating the Wnt pathway. These compounds inhibited the replication of HCMV Towne and a clinical isolate. Inhibition occurred prior to DNA replication but persisted throughout the full replication cycle. There was a significant decrease in expression of IE2, UL44, and pp65 proteins. HCMV infection resulted in a significant and sustained decrease in expression of phosphorylated and total lipoprotein receptor-related protein 6 (pLRP6 and LRP6, respectively), Wnt 5a/b, and β-catenin and a modest decrease in Dvl2/3, while levels of the negative regulator axin 1 were increased. Nigericin decreased the expression of pLRP6, LRP6, axin 1, and Wnt 5a/b in noninfected and HCMV-infected cells. For all three compounds, a correlation was found between expression levels of Wnt 5a/b and axin 1 and HCMV inhibition. The decrease in Wnt 5a/b and axin 1 expression was more significant in HCMV-infected cells than noninfected cells. These data illustrate the complex effects of HCMV on the Wnt pathway and the fine balance between Wnt and HCMV, resulting in abrogation of HCMV replication. Additional studies are required to elucidate how HCMV targets Wnt for its benefit.

  16. Wnt Modulating Agents Inhibit Human Cytomegalovirus Replication

    PubMed Central

    Kapoor, Arun; He, Ran; Venkatadri, Rajkumar; Forman, Michael

    2013-01-01

    Infection with human cytomegalovirus (HCMV) continues to be a threat for pregnant women and immunocompromised hosts. Although limited anti-HCMV therapies are available, development of new agents is desired. The Wnt signaling pathway plays a critical role in embryonic and cancer stem cell development and is targeted by gammaherpesviruses, Epstein-Barr virus (EBV), and Kaposi's sarcoma-associated herpesvirus (KSHV). HCMV infects stem cells, including neural progenitor cells, during embryogenesis. To investigate the role of Wnt in HCMV replication in vitro, we tested monensin, nigericin, and salinomycin, compounds that inhibit cancer stem cell growth by modulating the Wnt pathway. These compounds inhibited the replication of HCMV Towne and a clinical isolate. Inhibition occurred prior to DNA replication but persisted throughout the full replication cycle. There was a significant decrease in expression of IE2, UL44, and pp65 proteins. HCMV infection resulted in a significant and sustained decrease in expression of phosphorylated and total lipoprotein receptor-related protein 6 (pLRP6 and LRP6, respectively), Wnt 5a/b, and β-catenin and a modest decrease in Dvl2/3, while levels of the negative regulator axin 1 were increased. Nigericin decreased the expression of pLRP6, LRP6, axin 1, and Wnt 5a/b in noninfected and HCMV-infected cells. For all three compounds, a correlation was found between expression levels of Wnt 5a/b and axin 1 and HCMV inhibition. The decrease in Wnt 5a/b and axin 1 expression was more significant in HCMV-infected cells than noninfected cells. These data illustrate the complex effects of HCMV on the Wnt pathway and the fine balance between Wnt and HCMV, resulting in abrogation of HCMV replication. Additional studies are required to elucidate how HCMV targets Wnt for its benefit. PMID:23571549

  17. Characteristics of spectro-temporal modulation frequency selectivity in humans.

    PubMed

    Oetjen, Arne; Verhey, Jesko L

    2017-03-01

    There is increasing evidence that the auditory system shows frequency selectivity for spectro-temporal modulations. A recent study of the authors has shown spectro-temporal modulation masking patterns that were in agreement with the hypothesis of spectro-temporal modulation filters in the human auditory system [Oetjen and Verhey (2015). J. Acoust. Soc. Am. 137(2), 714-723]. In the present study, that experimental data and additional data were used to model this spectro-temporal frequency selectivity. The additional data were collected to investigate to what extent the spectro-temporal modulation-frequency selectivity results from a combination of a purely temporal amplitude-modulation filter and a purely spectral amplitude-modulation filter. In contrast to the previous study, thresholds were measured for masker and target modulations with opposite directions, i.e., an upward pointing target modulation and a downward pointing masker modulation. The comparison of this data set with previous corresponding data with the same direction from target and masker modulations indicate that a specific spectro-temporal modulation filter is required to simulate all aspects of spectro-temporal modulation frequency selectivity. A model using a modified Gabor filter with a purely temporal and a purely spectral filter predicts the spectro-temporal modulation masking data.

  18. Reflections on Designing a Biology/Humanities Interdisciplinary Module

    ERIC Educational Resources Information Center

    Stack, David; Battey, Nicholas

    2013-01-01

    This paper uses the reflections of a recent workshop on biology and the humanities subject areas to consider the potential for designing a first year interdisciplinary module that brings together teachers and learners in the Biosciences with their counterparts in English and History. It considers three building blocks of module design: aims and…

  19. Oestrogen and progesterone action on endometrium: a translational approach to understanding endometrial receptivity.

    PubMed

    Young, Steven L

    2013-11-01

    Embryo attachment and implantation is critical to successful reproduction of all eutherian mammals, including humans; a better understanding of these processes could lead to improved infertility treatments and novel contraceptive methods. Experience with assisted reproduction, especially oocyte donation cycles, has established that despite the diverse set of hormones produced by the ovary in a cycle-dependent fashion, the sequential actions of only two of them, oestrogen and progesterone, are sufficient to prepare a highly receptive endometrium in humans. Further investigation on the endometrial actions of these two hormones is currently providing significant insight into the implantation process in women, strongly suggesting that an abnormal response to progesterone underlies infertility in some patients.

  20. Oestrogen inhibits BMP4-induced BMP4 expression in cardiomyocytes: a potential mechanism of oestrogen-mediated protection against cardiac hypertrophy.

    PubMed

    Wang, Yu-Chun; Xiao, Xiao-Lin; Li, Na; Yang, Di; Xing, Yue; Huo, Rong; Liu, Ming-Yu; Zhang, Yan-Qiu; Dong, De-Li

    2015-12-01

    Oestrogen inhibits cardiac hypertrophy and bone morphogenetic protein-4 (BMP4) induces cardiac hypertrophy. Here we have studied the inhibition by oestrogen of BMP4 expression in cardiomyocytes. Cultures of neonatal rat cardiomyocytes were used in in vitro experiments. Bilatαl ovariectomy (OVX) was carried out in female Kunming mice and cardiac hypertrophy was induced by transverse aortic constriction (TAC). Oestrogen inhibited BMP4-induced cardiomyocyte hypertrophy and BMP4 expression in vitro. The inhibition of BMP4-induced BMP4 protein expression by oestrogen was prevented by the inhibitor of oestrogen receptor-β, PHTPP, but not by the inhibitor of oestrogen receptor-α MPP. BMP4 induced smad1/5/8 activation, which was not affected by oestrogen in cardiomyocytes. BMP4 induced JNK but not ERK1/2 and p38 activation, and activated JNK was inhibited by oestrogen. Treatment with the p38 inhibitor SB203580 or the JNK inhibitor SP600125 inhibited BMP4-induced BMP4 expression in cardiomyocytes, but the ERK1/2 inhibitor U0126 increased BMP4-induced BMP4 expression, indicating that JNK, ERK1/2 and p38 MAPKs were all involved, although only JNK activation contributed to the inhibition of BMP4-induced BMP4 expression by oestrogen. TAC induced significant heart hypertrophy in OVX mice in vivo and oestrogen replacement inhibited TAC-induced heart hypertrophy in OVX mice. In parallel with the data of heart hypertrophy, oestrogen replacement significantly reduced the increased BMP4 protein expression in TAC-treated OVX mice. Oestrogen treatment inhibited BMP4-induced BMP4 expression in cardiomyocytes through stimulating oestrogen receptor-β and inhibiting JNK activation. Our results provide a novel mechanism underlying oestrogen-mediated protection against cardiac hypertrophy. © 2014 The British Pharmacological Society.

  1. Partial and weak oestrogenicity of the red wine constituent resveratrol: consideration of its superagonist activity in MCF-7 cells and its suggested cardiovascular protective effects.

    PubMed

    Ashby, J; Tinwell, H; Pennie, W; Brooks, A N; Lefevre, P A; Beresford, N; Sumpter, J P

    1999-01-01

    It was recently reported that the red wine phytoestrogen resveratrol (RES) acts as a superagonist to oestrogen-responsive MCF-7 cells. This activity of RES was speculated to be relevant to the 'French paradox' in which moderate red wine consumption is reported to yield cardiovascular health benefits to humans. We report here that RES binds to oestrogen receptors (ER) isolated from rat uterus with an affinity approximately 5 orders of magnitude lower than does either the reference synthetic oestrogen diethylstilboestrol (DES) or oestradiol (E2). In comparison with E2 or DES, RES is only a weak and partial agonist in a yeast hER-alpha transcription assay and in cos-1 cell assays employing transient transfections of ER-alpha or ER-beta associated with two different ER-response elements. Resveratrol was also concluded to be inactive in immature rat uterotrophic assays conducted using three daily administrations of 0.03-120 mgkg(-1)/day(-1) RES (administered by either oral gavage or subcutaneous injection). These data weaken the suggestion that the oestrogenicity of RES may account for the reported cardiovascular protective effects of red wine consumption, and they raise questions regarding the extent to which oestrogenicity data derived for a chemical using MCF-7 cells (or any other single in vitro assay) can be used to predict the hormonal effects likely to occur in animals or humans.

  2. [How corticoids, growth hormone and oestrogens influence lipids and atherosclerosis].

    PubMed

    Marek, J; Hána, V; Krsek, M

    2007-04-01

    The hormones with a strong influence on the lipid spectrum and the development of atherosclerosis include cortisol, growth hormone and oestrogens. Cortisol accelerates atherosclerosis both through dyslipidemia and through an increase in visceral fat, hypertension, increased insulin resistance and the development of reduced glucose tolerance which may result in diabetes mellitus. Even when a cortisol excess disappears, as is the case of patients cured of Cushing syndrome, arterial walls remain permanently vulnerable to the atherosclerotic process. In conditions involving a lack of growth hormone, dyslipidemia develops and increases the burden on the cardiovascular system if not treated in a timely manner by the substitution of growth hormone. Oestrogens have a double effect: they have an anti-atherogenic effect on artery walls that are not yet damaged by an atherosclerotic process, but where atherosclerosis has already developed they have a prothrombotic effect and destabilise the atheromatous plaques. If oestrogen is to be used as protection against the onset of atherogenesis, it is necessary to start in a period when the atherosclerotic process has not yet begun to damage the woman's arterial walls and it is best to use natural hormones (estradiol) and to prevent endometriosis it should be combined with crystalline progesterone applied locally--inravaginally. Oestrogens should be given in small doses, preferably parenterally. Even this will not prevent genetic oestrogen effects though.

  3. Estrogens as Antioxidant Modulators in Human Fertility

    PubMed Central

    Mancini, A.; Raimondo, S.; Persano, M.; Di Segni, C.; Cammarano, M.; Gadotti, G.; Silvestrini, A.; Pontecorvi, A.; Meucci, E.

    2013-01-01

    Among treatments proposed for idiopathic male infertility, antiestrogens, like tamoxifen, play a possible role. On the other hand, oxidative stress is a mechanism well recognized for deleterious effects on spermatozoa function. After reviewing the literature on the effects of estrogens in modulation of antioxidant systems, in both sexes, and in different in vivo and in vitro models, we suggest, also on the basis of personal data, that a tamoxifen treatment could be active via an increase in seminal antioxidants. PMID:24363671

  4. In vivo stimulation of oestrogen receptor α increases insulin-stimulated skeletal muscle glucose uptake.

    PubMed

    Gorres, Brittany K; Bomhoff, Gregory L; Morris, Jill K; Geiger, Paige C

    2011-04-15

    Previous studies suggest oestrogen receptor α (ERα) is involved in oestrogen-mediated regulation of glucose metabolism and is critical for maintenance of whole body insulin action. Despite this, the effect of direct ERα modulation in insulin-responsive tissues is unknown. The purpose of the current study was to determine the impact of ERα activation, using the ER subtype-selective ligand propylpyrazoletriyl (PPT), on skeletal muscle glucose uptake. Two-month-old female Sprague-Dawley rats, ovariectomized for 1 week, were given subcutaneous injections of PPT (10 mg kg⁻¹), oestradiol benzoate (EB; 20 μg kg⁻¹), the ERβ agonist diarylpropionitrile (DPN, 10 mg kg⁻¹) or vehicle every 24 h for 3 days. On the fourth day, insulin-stimulated skeletal muscle glucose uptake was measured in vitro and insulin signalling intermediates were assessed via Western blotting.Activation of ERα with PPT resulted in increased insulin-stimulated glucose uptake into the slow-twitch soleus and fast-twitch extensor digitorum longus (EDL)muscles, activation of insulin signalling intermediates (as measured by phospho-Akt (pAkt) and pAkt substrate (PAS)) and phosphorylation of AMP-activated protein kinase (AMPK). GLUT4 protein was increased only in the EDL muscle. Rats treated with EB or DPN for 3 days did not show an increase in insulin-stimulated skeletal muscle glucose uptake compared to vehicle-treated animals. These new findings reveal that direct activation of ERα positively mediates glucose uptake and insulin action in skeletal muscle. Evidence that oestrogens and ERα stimulate glucose uptake has important implications for understanding mechanisms of glucose homeostasis, particularly in postmenopausal women.

  5. Non-thermoregulatory modulation of sweating in humans

    NASA Technical Reports Server (NTRS)

    Shibasaki, Manabu; Kondo, Narihiko; Crandall, Craig G.

    2003-01-01

    Sweating in humans is critical for appropriate thermoregulation during exercise and/or exposure to warm environmental temperatures. In addition to thermal controllers of sweating, a number of non-thermal factors modulate the sweating response. This review summarizes the primary non-thermal neural modifiers of sweating in humans.

  6. Zinc content of maturing spermatozoa in oestrogen treated rats.

    PubMed

    Srivastava, A; Chowdhury, A R; Setty, B S

    1983-02-01

    Zinc content of spermatozoa collected from the caput and cauda portions of the rat epididymis was determined by atomic absorption spectroscopy. The results showed about 60% reduction in the spermatozoal zinc content by the time they reach the cauda epididymis. This reduction was inhibited in rats receiving micro dose oestrogen which induced 'functional' sterility. It appears that the fall in zinc content of spermatozoa during their transport in the epididymis is related to sperm maturation and that oestrogen treatment interferes with this reduction in sperm zinc content.

  7. Oestradiol decreases colonic permeability through oestrogen receptor β-mediated up-regulation of occludin and junctional adhesion molecule-A in epithelial cells

    PubMed Central

    Braniste, Viorica; Leveque, Mathilde; Buisson-Brenac, Claire; Bueno, Lionel; Fioramonti, Jean; Houdeau, Eric

    2009-01-01

    Oestradiol modulates paracellular permeability and tight junction (TJ) function in endothelia and reproductive tissues, but whether the ovarian hormones and cycle affect the paracellular pathway in the intestinal epithelium remains unclear. Oestrogen receptors (ERs) are expressed in intestinal epithelial cells, and oestradiol regulates epithelium formation. We examined the effects of oestrous cycle stage, oestradiol benzoate (EB), and progesterone (P) on colonic paracellular permeability (CPP) in the female rat, and whether EB affects expression of the TJ proteins in the rat colon and the human colon cell line Caco-2. In cyclic rats, CPP was determined through lumen-to-blood 51Cr-labelled EDTA clearance, and in Ussing chambers for dextran permeability. CPP was also examined in ovariectomized (OVX) rats treated with P or EB, with and without the ER antagonist ICI 182,780, or with the selective agonists for ERα (propyl pyrazole triol; PPT) or ERβ (diarylpropionitrile; DPN). In oestrus rats, CPP was reduced (P < 0.01) relative to dioestrus. In OVX rats, EB dose-dependently decreased CPP, an effect mimicked by DPN and blocked by ICI 182,780, whereas P had no effect. Oestradiol increased occludin mRNA and protein in the colon (P < 0.05), but not zona occludens (ZO)-1. Further, EB and DPN enhanced occludin and junctional adhesion molecule (JAM)-A expression in Caco-2 cells without change in ZO-1, an effect blocked by ICI 182,780. These data show that oestrogen reinforces intestinal epithelial barrier through ERβ-mediated up-regulation of the transmembrane proteins occludin and JAM-A determining paracellular spaces. These findings highlight the importance of the ERβ pathway in the control of colonic paracellular transport and mucosal homeostasis. PMID:19433574

  8. Characterization of Aromatase Expression in the Adult Male and Female Mouse Brain. I. Coexistence with Oestrogen Receptors α and β, and Androgen Receptors

    PubMed Central

    Stanić, Davor; Dubois, Sydney; Chua, Hui Kheng; Tonge, Bruce; Rinehart, Nicole; Horne, Malcolm K.; Boon, Wah Chin

    2014-01-01

    Aromatase catalyses the last step of oestrogen synthesis. There is growing evidence that local oestrogens influence many brain regions to modulate brain development and behaviour. We examined, by immunohistochemistry, the expression of aromatase in the adult male and female mouse brain, using mice in which enhanced green fluorescent protein (EGFP) is transcribed following the physiological activation of the Cyp19A1 gene. EGFP-immunoreactive processes were distributed in many brain regions, including the bed nucleus of the stria terminalis, olfactory tubercle, medial amygdaloid nucleus and medial preoptic area, with the densest distributions of EGFP-positive cell bodies in the bed nucleus and medial amygdala. Differences between male and female mice were apparent, with the density of EGFP-positive cell bodies and fibres being lower in some brain regions of female mice, including the bed nucleus and medial amygdala. EGFP-positive cell bodies in the bed nucleus, lateral septum, medial amygdala and hypothalamus co-expressed oestrogen receptor (ER) α and β, or the androgen receptor (AR), although single-labelled EGFP-positive cells were also identified. Additionally, single-labelled ERα−, ERβ- or AR-positive cell bodies often appeared to be surrounded by EGFP-immunoreactive nerve fibres/terminals. The widespread distribution of EGFP-positive cell bodies and fibres suggests that aromatase signalling is common in the mouse brain, and that locally synthesised brain oestrogens could mediate biological effects by activating pre- and post-synaptic oestrogen α and β receptors, and androgen receptors. The higher number of EGFP-positive cells in male mice may indicate that the autocrine and paracrine effects of oestrogens are more prominent in males than females. PMID:24646567

  9. Characterization of aromatase expression in the adult male and female mouse brain. I. Coexistence with oestrogen receptors α and β, and androgen receptors.

    PubMed

    Stanić, Davor; Dubois, Sydney; Chua, Hui Kheng; Tonge, Bruce; Rinehart, Nicole; Horne, Malcolm K; Boon, Wah Chin

    2014-01-01

    Aromatase catalyses the last step of oestrogen synthesis. There is growing evidence that local oestrogens influence many brain regions to modulate brain development and behaviour. We examined, by immunohistochemistry, the expression of aromatase in the adult male and female mouse brain, using mice in which enhanced green fluorescent protein (EGFP) is transcribed following the physiological activation of the Cyp19A1 gene. EGFP-immunoreactive processes were distributed in many brain regions, including the bed nucleus of the stria terminalis, olfactory tubercle, medial amygdaloid nucleus and medial preoptic area, with the densest distributions of EGFP-positive cell bodies in the bed nucleus and medial amygdala. Differences between male and female mice were apparent, with the density of EGFP-positive cell bodies and fibres being lower in some brain regions of female mice, including the bed nucleus and medial amygdala. EGFP-positive cell bodies in the bed nucleus, lateral septum, medial amygdala and hypothalamus co-expressed oestrogen receptor (ER) α and β, or the androgen receptor (AR), although single-labelled EGFP-positive cells were also identified. Additionally, single-labelled ERα-, ERβ- or AR-positive cell bodies often appeared to be surrounded by EGFP-immunoreactive nerve fibres/terminals. The widespread distribution of EGFP-positive cell bodies and fibres suggests that aromatase signalling is common in the mouse brain, and that locally synthesised brain oestrogens could mediate biological effects by activating pre- and post-synaptic oestrogen α and β receptors, and androgen receptors. The higher number of EGFP-positive cells in male mice may indicate that the autocrine and paracrine effects of oestrogens are more prominent in males than females.

  10. Norgestrel and gestodene stimulate breast cancer cell growth through an oestrogen receptor mediated mechanism.

    PubMed Central

    Catherino, W. H.; Jeng, M. H.; Jordan, V. C.

    1993-01-01

    There is great concern over the long-term influence of oral contraceptives on the development of breast cancer in women. Oestrogens are known to stimulate the growth of human breast cancer cells, and this laboratory has previously reported (Jeng & Jordan, 1991) that the 19-norprogestin norethindrone could stimulate the proliferation of MCF-7 human breast cancer cells. We studied the influence of the 19-norprogestins norgestrel and gestodene compared to a 'non' 19-norprogestin medroxyprogesterone acetate (MPA) on MCF-7 cell proliferation. The 19-norprogestins stimulated proliferation at a concentration of 10(-8) M, while MPA could not stimulate proliferation at concentrations as great as 3 x 10(-6) M. The stimulatory activity of the 19-norprogestins could be blocked by the antioestrogen ICI 164,384, but not by the antiprogestin RU486. Transfection studies with the reporter plasmids containing an oestrogen response element or progesterone response element (vitERE-CAT, pS2ERE-CAT, and PRE15-CAT) were performed to determine the intracellular action of norgestrel and gestodene. The 19-norprogestins stimulated the vitERE-CAT activity maximally at 10(-6) M, and this stimulation was inhibited by the addition of ICI 164,384. MPA did not stimulate vitERE-CAT activity. A single base pair alteration in the palindromic sequence of vitERE (resulting in the pS2ERE) led to a dramatic decrease in CAT expression by the 19-norprogestins, suggesting that the progestin activity required specific response element base sequencing. PRE15-CAT activity was stimulated by norgestrel, gestodene and MPA at concentrations well below growth stimulatory activity. This stimulation could be blocked by RU486. These studies suggest that the 19-norprogestins norgestrel and gestodene stimulate MCF-7 breast cancer cell growth by activating the oestrogen receptor. PMID:8494728

  11. An in vitro demonstration of oestrogenicity with potential for exploitation as a quantitative assay for oestrogenic potency.

    PubMed

    Pugh, D M; Sumano, H S

    1986-01-01

    The pre-implantation embryo of the mouse undergoes a histochemically detectable change in the properties of its trophoblastic cell-surface coat in the immediate pre-implantation period. This change is oestrogen-dependent in vivo and can be induced in vitro in a concentration-dependent manner by oestradiol-17 beta. There is evidence that this coat change is of functional importance in the process of implantation, and its demonstration is of potential value as the basis of an in vitro assay of oestrogenicity.

  12. Lack of Oestrogenic Inhibition of the Nuclear Factor-κB Pathway in Somatolactotroph Tumour Cells.

    PubMed

    Eijo, G; Gottardo, M F; Jaita, G; Magri, M L; Moreno Ayala, M; Zárate, S; Candolfi, M; Pisera, D; Seilicovich, A

    2015-09-01

    Activation of nuclear factor (NF)-κB promotes cell proliferation and inhibits apoptosis. We have previously shown that oestrogens sensitise normal anterior pituitary cells to the apoptotic effect of tumour necrosis factor (TNF)-α by inhibiting NF-κB nuclear translocation. In the present study, we examined whether oestrogens also modulate the NF-κB signalling pathway and apoptosis in GH3 cells, a rat somatolactotroph tumour cell line. As determined by Western blotting, 17β-oestradiol (E2 ) (10(-9) m) increased the nuclear concentration of NF-κB/p105, p65 and p50 in GH3 cells. However, E2 did not modify the expression of Bcl-xL, a NF-κB target gene. TNF-α induced apoptosis of GH3 cells incubated in either the presence or absence of E2 . Inhibition of the NF-kB pathway using BAY 11-7082 (BAY) (5 μm) decreased the viability of GH3 cells and increased the percentage of terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL)-positive GH3 cells. BAY also increased TNF-α-induced apoptosis of GH3 cells, an effect that was further increased by an inhibitor of the c-Jun N-terminal protein kinase pathway, SP600125 (10 μm). We also analysed the role of the NF-κB signalling pathway on proliferation and apoptosis of GH3 tumours in vivo. The administration of BAY to nude mice bearing GH3 tumours increased the number of TUNEL-positive cells and decreased the number of proliferating GH3 cells. These findings suggest that GH3 cells lose their oestrogenic inhibitory action on the NF-κB pathway and that the pro-apoptotic effect of TNF-α on these tumour pituitary cells does not require sensitisation by oestrogens as occurs in normal pituitary cells. NF-κB was required for the survival of GH3 cells, suggesting that pharmacological inhibition of the NF-κB pathway could interfere with pituitary tumour progression.

  13. [Comparison of vaginal cytologic effects and blood elimination curves of different oestrogen drugs (author's transl)].

    PubMed

    Hempel, E; Bruder, M; Eichhorn, K H; Claussen, C; Klinger, G

    1977-01-01

    With different oral oestrogens it was studied, if relations are existing between pharmacokinetic and vaginal effect. By means of Karyopycnotic Index and Dynamic Oestrogenicity Index the cytological effect was quantified from a single dose of oestradiol valerianate, mestranol, ethinyloestradiol and 3 depot oestrogens proved on postmenopause women and compared with adequate pharmacocinetical investigations. The courses of oestrogen levels did not correlate with indices. Both methods of investigation do not compensate, but complete one another. Depotoestrogens and short acting oestrogens are distinguishable with regard to proliferation maxium and steepness of index decline.

  14. Sensorimotor modulation of human cortical swallowing pathways.

    PubMed

    Hamdy, S; Aziz, Q; Rothwell, J C; Hobson, A; Thompson, D G

    1998-02-01

    1. Transcranial magnetic stimulation over motor areas of cerebral cortex in man can activate short latency bilateral cortical projections to the pharynx and oesophagus. In the present paper we investigate the interaction between pathways from each hemisphere and explore how activity in these pathways is modulated by afferent feedback from the face, pharynx and oesophagus. 2. Comparison of unilateral and bilateral stimulation (using interstimulus intervals (ISIs) of 1, 5 or 10 ms between shocks) showed spatial summation of responses from each hemisphere at an ISI of 1 ms, indicating that cortical efferents project onto a shared population of target neurones. Such summation was not evident at ISIs of 5 or 10 ms. There was little evidence for transcallosal inhibition of responses from each hemisphere, as described for limb muscles. 3. Single stimuli applied to the vagus nerve in the neck or the supraorbital nerve, which alone produce intermediate (onset 20-30 ms) and long (50-70 ms) latency reflex responses in the pharynx and oesophagus, were used to condition the cortical responses. Compared with rest, responses evoked by cortical stimulation were facilitated when they were timed to coincide with the late part of the reflex. The onset latency was reduced during both parts of the reflex response. No facilitation was observed with subthreshold reflex stimuli. 4. Single electrical stimuli applied to the pharynx or oesophagus had no effect on the response to cortical stimulation. However, trains of stimuli at frequencies varying from 0.2 to 10 Hz decreased the latency of the cortically evoked responses without consistently influencing their amplitudes. The effect was site specific: pharyngeal stimulation shortened both pharyngeal and oesophageal response latencies, whereas oesophageal stimulation shortened only the oesophageal response latencies. 5. Cortical swallowing motor pathways from each hemisphere interact and their excitability is modulated in a site

  15. Sensorimotor modulation of human cortical swallowing pathways

    PubMed Central

    Hamdy, Shaheen; Aziz, Qasim; Rothwell, John C; Hobson, Anthony; Thompson, David G

    1998-01-01

    Transcranial magnetic stimulation over motor areas of cerebral cortex in man can activate short latency bilateral cortical projections to the pharynx and oesophagus. In the present paper we investigate the interaction between pathways from each hemisphere and explore how activity in these pathways is modulated by afferent feedback from the face, pharynx and oesophagus.Comparison of unilateral and bilateral stimulation (using interstimulus intervals (ISIs) of 1, 5 or 10 ms between shocks) showed spatial summation of responses from each hemisphere at an ISI of 1 ms, indicating that cortical efferents project onto a shared population of target neurones. Such summation was not evident at ISIs of 5 or 10 ms. There was little evidence for transcallosal inhibition of responses from each hemisphere, as described for limb muscles.Single stimuli applied to the vagus nerve in the neck or the supraorbital nerve, which alone produce intermediate (onset 20-30 ms) and long (50-70 ms) latency reflex responses in the pharynx and oesophagus, were used to condition the cortical responses. Compared with rest, responses evoked by cortical stimulation were facilitated when they were timed to coincide with the late part of the reflex. The onset latency was reduced during both parts of the reflex response. No facilitation was observed with subthreshold reflex stimuli.Single electrical stimuli applied to the pharynx or oesophagus had no effect on the response to cortical stimulation. However, trains of stimuli at frequencies varying from 0.2 to 10 Hz decreased the latency of the cortically evoked responses without consistently influencing their amplitudes. The effect was site specific: pharyngeal stimulation shortened both pharyngeal and oesophageal response latencies, whereas oesophageal stimulation shortened only the oesophageal response latencies.Cortical swallowing motor pathways from each hemisphere interact and their excitability is modulated in a site-specific manner by sensory

  16. Molecular mechanism(s) of endocrine-disrupting chemicals and their potent oestrogenicity in diverse cells and tissues that express oestrogen receptors.

    PubMed

    Lee, Hye-Rim; Jeung, Eui-Bae; Cho, Myung-Haing; Kim, Tae-Hee; Leung, Peter C K; Choi, Kyung-Chul

    2013-01-01

    Endocrine-disrupting chemicals (EDCs) are natural or synthetic compounds present in the environment which can interfere with hormone synthesis and normal physiological functions of male and female reproductive organs. Most EDCs tend to bind to steroid hormone receptors including the oestrogen receptor (ER), progesterone receptor (PR) and androgen receptor (AR). As EDCs disrupt the actions of endogenous hormones, they may induce abnormal reproduction, stimulation of cancer growth, dysfunction of neuronal and immune system. Although EDCs represent a significant public health concern, there are no standard methods to determine effect of EDCs on human beings. The mechanisms underlying adverse actions of EDC exposure are not clearly understood. In this review, we highlighted the toxicology of EDCs and its effect on human health, including reproductive development in males and females as shown in in vitro and in vivo models. In addition, this review brings attention to the toxicity of EDCs via interaction of genomic and non-genomic signalling pathways through hormone receptors.

  17. Oestrogen-induced bone marrow aplasia in a dog.

    PubMed

    Bland-van den Berg, P; Bomzon, L; Lurie, A

    1978-12-01

    A case of oestrogen toxicity in the dog is described. The bone marrow was primarily affected with resultant non-regenerative anaemia, leukocytosis followed by leukopaenia, and thrombocytopaenia. Endometritis, toxaemia and disseminate intravascular coagulation were complicating factors. The case terminated fatally intensive therapy.

  18. An abnormality of oestrogen feedback in amenorrhoea-galactorrhoea.

    PubMed Central

    Glass, M R; Shaw, R W; Butt, W R; Edwards, R L; London, D R

    1975-01-01

    Fourteen patients with amenorrhoea and hyperprolactin-anemia but no evidence of pituitary tumours were each given an intramuscular injection of 1 mg oestradiol benzoate. Thirteen patients failed to release luteinizing hormone in response to the oestrogen. This hypothalamic abnormality may help to explain the menstrual disturbances in subjects with hyperprolactinaemia. PMID:1170923

  19. Poor histological healing of a femoral fracture following 12 months of oestrogen deficiency in rats.

    PubMed

    Oliver, R A; Yu, Y; Yee, G; Low, A K; Diwan, A D; Walsh, W R

    2013-10-01

    Fractures in post-menopausal osteoporosis cause significant morbidity; however, animal models for post-menopausal fracture healing lack the effect of ageing. Therefore, we developed a model using aged animals with chronic oestrogen deficiency, which demonstrates inferior fracture repair (decreased healing histologically, bone mineral density and content and strength). This novel model may help develop molecular strategies for osteoporotic fracture repair. The femur is susceptible to damage by both systemic conditions such as osteoporosis and locally by traumatic injury. The capacity for fracture repair decreases with age, while the risk of fracture increases. As studies of osteoporotic fracture healing in rats traditionally use a period of 3 months or less of oestrogen deficiency prior to fracturing, we aimed to establish a osteoporosis model in rats with chronic oestrogen deficiency by 12 months to better mimic human female osteoporosis. Seventy female Sprague-Dawley rats (10 weeks old) were ovariectomised or sham operated and housed for 12 months. The right femur was fractured by way of an open osteotomy and fixed with an intramedullary Kirschner wire. Animals were sacrificed at 1, 3 and 6 weeks for radiography, dual-energy X-ray absorptiometry, tensile testing and histology. Bone mineral density and bone mineral content were lower by 60 and 63 %, respectively, (p < 0.05) in the bilaterally ovariectomized (OVX) groups than those in the sham groups at 6 weeks in the right fractured femurs. Maximum breaking force of the OVX group was lower than that of the sham group, with the greatest difference seen at 6 weeks following osteotomy. Histologically, the OVX groups demonstrated a delay in cellular differentiation within the fracture callus and the presence of bone resorption. The sham animals had a superior histological healing pattern with an Allen score of 4 at 6 weeks compared to a score of 1 for the OVX groups (p < 0.01). Long-term ovariectomy has a

  20. Regulation of bradykinin B2-receptor expression by oestrogen

    PubMed Central

    Madeddu, Paolo; Emanueli, Costanza; Varoni, Maria Vittoria; Demontis, Maria Piera; Anania, Vittorio; Gorioso, Nicola; Chao, Julie

    1997-01-01

    Tissue kallikrein is overexpressed in the kidney of female rats, this sexual dimorphism being associated with a greater effect of early blockade of bradykinin B2-receptors on female blood pressure phenotype. We evaluated the effect of ovariectomy and oestradiol benzoate (50 μg kg−1 every two days for two weeks) on the vasodepressor response to intra-arterial injection of bradykinin (150–900 ng kg−1) and on the expression of bradykinin B2-receptors.Ovariectomy reduced the magnitude of the vasodepressor response to bradykinin and unmasked a secondary vasopressor effect. Oestrogen replacement restored the vasodepressor response to bradykinin in ovariectomized rats.The vasodepressor responses to sodium nitroprusside (3–18 μg kg−1), acetylcholine (30–600 ng kg−1), desArg9-bradykinin (150–900 ng kg−1) or prostaglandin E2 (30–600 ng kg−1) were significantly reduced by ovariectomy. Oestrogen restored to normal the responses to desArg9-bradykinin, acetylcholine and prostaglandin E2, but not that to sodium nitroprusside.B2-receptor mRNA levels were decreased by ovariectomy in the aorta and kidney and they were restored to normal levels by oestrogen. Neither ovariectomy nor oestradiol affected receptor expression in the heart and uterus.These results indicate that oestrogen regulates B2-receptor gene expression and function. Since kinins exert a cardiovascular protective action, reduction in their vasodilator activity after menopause might contribute to the increased risk of pathological cardiovascular events. Conversely, the cardioprotective effects of oestrogen replacement might be, at least in part, mediated by activation of the kallikrein-kinin system. PMID:9283715

  1. Performance of different composting techniques in reducing oestrogens content in manure from livestock in a Vietnamese setting.

    PubMed

    Le, Thi Anh Hong; Clemens, Joachim; Nguyen, Thai Hoa

    2013-01-01

    Steroid oestrogens (SE) are released by humans and animals into the environment. In the Mekong Delta animal excrement is directly discharged into surface water and can pollute the water. Only a few animal production sites are currently treating the excrement in either biogas plants or vermicomposting systems. The concentration of SE in manures from pigs and cattle was monitored in the Mekong Delta, Vietnam. Fresh cow faeces had an oestrogen concentration of 3.3 ng E2 eq/g dry weight. The SE concentration in effluent from biogas plants fed with animal manures was 341 ng E2 eq/L. Most of the SE were in the solid phase (77.9-98.7%). Vermicomposting reduced SE to 95% of the original input.

  2. Do dietary phytoestrogens influence susceptibility to hormone-dependent cancer by disrupting the metabolism of endogenous oestrogens?

    PubMed

    Kirk, C J; Harris, R M; Wood, D M; Waring, R H; Hughes, P J

    2001-05-01

    Phytoestrogens are natural constituents of our diets that have been suggested to protect against hormone-dependent breast cancer. Some of the diverse effects of these compounds may be attributed to ligand-dependent differences in their interaction with oestrogen receptor sub-classes. However, phytoestrogens can also inhibit enzymes that are involved in the generation and removal of endogenous steroid hormones. Among the most potent effects of dietary phytoestrogens is their ability to inhibit the sulphotransferases that sulphate both oestrogenic steroids and a variety of environmental chemicals, including dietary pro-carcinogens. Circulating steroid sulphates are thought to be the major source of oestradiol in post-menopausal breast tumours and sulphation is a key step in the activation of some dietary pro-carcinogens. Hence the inhibition of sulphotransferases by dietary phytoestrogens may have complex effects upon human susceptibility to breast cancer.

  3. Modulation of stimulus contrast on the human pupil orienting response.

    PubMed

    Wang, Chin-An; Munoz, Douglas P

    2014-09-01

    The sudden appearance of a novel stimulus initiates a series of responses to orient the body for appropriate actions, including not only shifts of gaze and attention, but also transient pupil dilation. Modulation of pupil dynamics by stimulus properties is less understood, although its effects on other components of orienting have been extensively explored. Microstimulation of the superior colliculus evoked transient pupil dilation, and the initial component of pupil dilation evoked by microstimulation was similar to that elicited by the presentation of salient sensory stimuli, suggesting a coordinated role of the superior colliculus on this behavior, although evidence in humans is yet to be established. To examine pupil orienting responses in humans, we presented visual stimuli while participants fixated on a central visual spot. Transient pupil dilation in humans was elicited after presentation of a visual stimulus in the periphery. The evoked pupil responses were modulated systematically by stimulus contrast, with faster and larger pupil responses triggered by higher contrast stimuli. The pupil response onset latencies for high contrast stimuli were similar to those produced by the light reflex and significantly faster than the darkness reflex, suggesting that the initial component of pupil dilation is probably mediated by inhibition of the parasympathetic pathway. The contrast modulation was pronounced under different levels of baseline pupil size. Together, our results demonstrate visual contrast modulation on the orienting pupil response in humans.

  4. RNA Directed Modulation of Phenotypic Plasticity in Human Cells

    PubMed Central

    Burdach, Jon; Morris, Kevin V.

    2016-01-01

    Natural selective processes have been known to drive phenotypic plasticity, which is the emergence of different phenotypes from one genome following environmental stimulation. Long non-coding RNAs (lncRNAs) have been observed to modulate transcriptional and epigenetic states of genes in human cells. We surmised that lncRNAs are governors of phenotypic plasticity and drive natural selective processes through epigenetic modulation of gene expression. Using heat shocked human cells as a model we find several differentially expressed transcripts with the top candidates being lncRNAs derived from retro-elements. One particular retro-element derived transcripts, Retro-EIF2S2, was found to be abundantly over-expressed in heat shocked cells. Over-expression of Retro-EIF2S2 significantly enhanced cell viability and modulated a predisposition for an adherent cellular phenotype upon heat shock. Mechanistically, we find that this retro-element derived transcript interacts directly with a network of proteins including 40S ribosomal protein S30 (FAU), Eukaryotic translation initiation factor 5A (EIF5A), and Ubiquitin-60S ribosomal protein L40 (UBA52) to affect protein modulated cell adhesion pathways. We find one motif in Retro-EIF2S2 that exhibits binding to FAU and modulates phenotypic cell transitions from adherent to suspension states. The observations presented here suggest that retroviral derived transcripts actively modulate phenotypic plasticity in human cells in response to environmental selective pressures and suggest that natural selection may play out through the action of retro-elements in human cells. PMID:27082860

  5. Frequency Specific Modulation of Human Somatosensory Cortex

    PubMed Central

    Feurra, Matteo; Paulus, Walter; Walsh, Vincent; Kanai, Ryota

    2011-01-01

    Oscillatory neuronal activities are commonly observed in response to sensory stimulation. However, their functional roles are still the subject of debate. One-way to probe the roles of oscillatory neural activities is to deliver alternating current to the cortex at biologically relevant frequencies and examine whether such stimulation influences perception and cognition. In this study, we tested whether transcranial alternating current stimulation (tACS) over the primary somatosensory cortex (SI) could elicit tactile sensations in humans in a frequency-dependent manner. We tested the effectiveness of tACS over SI at frequency bands ranging from 2 to 70 Hz. Our results show that stimulation in alpha (10–14 Hz) and high gamma (52–70 Hz) frequency range produces a tactile sensation in the contralateral hand. A weaker effect was also observed for beta (16–20 Hz) stimulation. These findings highlight the frequency dependency of effective tACS over SI with the effective frequencies corresponding to those observed in previous electroencephalography/magnetoencephalography studies of tactile perception. Our present study suggests that tACS could be used as a powerful online stimulation technique to reveal the causal roles of oscillatory brain activities. PMID:21713181

  6. Cerebellar modulation of human associative plasticity

    PubMed Central

    Hamada, Masashi; Strigaro, Gionata; Murase, Nagako; Sadnicka, Anna; Galea, Joseph M; Edwards, Mark J; Rothwell, John C

    2012-01-01

    Paired associative stimulation (PAS) is a method commonly used in human studies of motor cortex synaptic plasticity. It involves repeated pairs of electrical stimuli to the median nerve and transcranial magnetic stimulation (TMS) of the motor cortex. If the interval between peripheral and TMS stimulation is around 21–25 ms, corticospinal excitability is increased for the following 30–60 min via a long term potentiation (LTP)-like effect within the primary motor cortex. Previous work has shown that PAS depends on the present and previous levels of activity in cortex, and that it can be modified by motor learning or attention. Here we show that simultaneous transcranial direct current stimulation (TDCS; 2 mA) over the cerebellum can abolish the PAS effect entirely. Surprisingly, the effect is seen when the PAS interval is 25 ms but not when it is 21.5 ms. There are two implications from this work. First, the cerebellum influences PAS effects in motor cortex; second, LTP-like effects of PAS have at least two different mechanisms. The results are relevant for interpretation of pathological changes that have been reported in response to PAS in people with movement disorders and to changes in healthy individuals following exercise or other interventions. PMID:22473780

  7. In vitro evaluation of oestrogenic/androgenic activity of the serum organochlorine pesticide mixtures previously described in a breast cancer case-control study.

    PubMed

    Rivero, Javier; Luzardo, Octavio P; Henríquez-Hernández, Luis A; Machín, Rubén P; Pestano, José; Zumbado, Manuel; Boada, Luis D; Camacho, María; Valerón, Pilar F

    2015-12-15

    Some organochlorine pesticides (OCs) have been individually linked to breast cancer (BC) because they exert oestrogenic effects on mammary cells. However, humans are environmentally exposed to more or less complex mixtures of these organochlorines, and the biological effects of these mixtures must be elucidated. In this work we evaluated the in vitro effects exerted on human BC cells by the OC mixtures that were most frequently detected in two groups of women who participated in a BC case-control study developed in Spain: healthy women and women diagnosed with BC. The cytotoxicity, oestrogenicity, and androgenicity of the most prevalent OC mixtures found in healthy women (H-mixture) and in BC patients (BC-mixture) were tested at concentrations that resembled those found in the serum of the evaluated women. Our results showed that both OC mixtures presented a similar oestrogenic activity and effect on cell viability, but BC-mixture showed an additional anti-androgenic effect. These results indicate that although the proliferative effect exerted by these mixtures on human breast cells seems to depend mainly on their oestrogenic action, the BC-mixture might additionally induce cell proliferation due to its anti-androgenic activity, therefore increasing the carcinogenic potential of this mixture. The findings of this study demonstrate that subtle variations in the composition of a mixture may induce relevant changes in its biological action.

  8. Sitting, physical activity, and serum oestrogen metabolism in postmenopausal women: the Women's Health Initiative Observational Study.

    PubMed

    Oh, Hannah; Arem, Hannah; Matthews, Charles E; Wentzensen, Nicolas; Reding, Kerryn W; Brinton, Louise A; Anderson, Garnet L; Coburn, Sally B; Cauley, Jane A; Chen, Chu; Goodman, Deborah; Pfeiffer, Ruth M; Falk, Roni T; Xu, Xia; Trabert, Britton

    2017-09-26

    Prolonged sitting and lower levels of physical activity have been associated with increased levels of parent oestrogens (oestrone and oestradiol), the key hormones in female cancers, in postmenopausal women. However, it is unknown whether sitting and physical activity are associated with circulating oestrogen metabolite levels. Among 1804 postmenopausal women enrolled in the Women's Health Initiative Observational Study, 15 serum oestrogens/oestrogen metabolites were quantified using liquid chromatography-tandem mass spectrometry. Physical activity and sitting were self-reported via questionnaire. Using baseline, cross-sectional data, geometric means (GM) of oestrogens/oestrogen metabolites (pmol l(-1)) were estimated using inverse probability weighted linear regression, adjusting for potential confounders and stratified on menopausal hormone therapy (MHT) use. Longer time spent sitting (⩾10 vs ⩽5h per day) was associated with higher levels of unconjugated oestrone, independent of moderate- to vigorous-intensity physical activity and body mass index, among both never/former (GM=70.6 vs 57.7) and current MHT users (GM=242 vs 179) (P-trend ⩽0.03). Among never/former MHT users, sitting (⩾10 vs ⩽5h per day) was positively associated with 2-methoxyestradiol (GM=16.4 vs 14.4) and 4-methoxyestradiol (GM=2.36 vs 1.98) (P-trend ⩽0.04), independent of parent oestrogens. Inverse associations between moderate- to vigorous-intensity physical activity (⩾15 vs 0 metabolic equivalent task-hours per week) and parent oestrogens were found as expected. After adjustment for parent oestrogens, physical activity was not associated with oestrogen metabolites. Our data suggest that prolonged sitting and lower moderate- to vigorous-intensity physical activity are associated with higher levels of postmenopausal oestrogens/oestrogen metabolites, the oestrogen metabolism patterns that have previously been associated with higher endometrial and breast cancer risk.

  9. Rapid oestrogenic regulation of social and nonsocial learning.

    PubMed

    Ervin, K S J; Phan, A; Gabor, C S; Choleris, E

    2013-11-01

    Much research on oestrogens has focused on their long-term action, exerting behavioural effects within hours to days through gene transcription. Oestrogens also affect behaviour on a much shorter time scale. These rapid effects are assumed to occur through cell signalling and can elicit a behavioural effect as early as 15 min after treatment. These effects on behaviour have primarily been explored through the action of oestradiol at three well-known oestrogen receptors (ERs): ERα, ERβ and the more recently described G protein-coupled ER1 (GPER1). The rapid effects of oestradiol and ER agonists have been tested on both social and nonsocial learning paradigms. Social learning refers to a paradigm in which an animal acquires information and modifies its behaviour based on observation of another animal, commonly studied using the social transmission of food preferences paradigm. When administered shortly before testing, oestradiol rapidly improves social learning on this task, although no ER agonist has definitive, comparable improving effects. Some evidence points to GPER1, whereas ERα impairs, and ERβ activation has no effect on social learning. Conversely, ERα and GPER1 play a larger role than ERβ in the rapid improving effect of oestrogens on nonsocial learning, including social and object recognition. In addition, when administered immediately post-acquisition, oestrogens also rapidly improve memory consolidation in a variety of learning paradigms: object recognition, object placement, inhibitory avoidance and the Morris water maze, indicating that oestradiol affects the consolidation of multiple types of memory. Evidence suggests that these improvements are the result of oestrogens acting in the dorsal hippocampus where selective activation of all three ERs shows rapid improving effects on spatial learning comparable to oestradiol. However, the hippocampus is not necessary for rapid oestradiol improvements on social recognition. Although acute treatment

  10. Genistein and daidzein induced apoA-1 transactivation in hepG2 cells expressing oestrogen receptor-alpha.

    PubMed

    Yuen, Yee M; Leung, Lai K

    2008-05-01

    Studies have shown that soya consumption has been associated with low incidence of CVD. Because the chemical structures of soya isoflavones are similar to oestrogen, the beneficial outcome may be attributed to the oestrogenicity of these compounds. In this study, effect of the soya isoflavone genistein on the mRNA expression of apoA-1 in the human hepatoma HepG2 cell was investigated. Without oestrogen receptor (ER) alpha transfection, soya isoflavones in the physiological range had no effect on the apoA-1 transcription. Once ERalpha was ectopically expressed in these cells, soya isoflavone dramatically increased the apoA-1 mRNA abundance quantified by real-time PCR. ApoA-1-reporter assays with plasmid constructed from the 5'-flanking segment upstream to the coding region revealed that the transactivation of the apoA-1 promoter was induced by the soya isoflavone in HepG2 cells expressing ERalpha. This induction was reduced by the anti-oestrogen ICI 182780, but not the inhibitors of protein kinase (PK) C, PKA, or mitogen-activated PK. Based on the previously identified response elements on the promoter, a series of truncated promoter reporter plasmids were then constructed. An induction profile of genistein was built and insulin response core element at -411 to -404 appeared to be a potential site of interaction. This study illustrated that soya isoflavones at physiological concentrations could up regulate apoA-1 mRNA expression in ERalpha-transfected HepG2 cells.

  11. Oestrogen receptor-α contributes to the regulation of the hedgehog signalling pathway in ERα-positive gastric cancer

    PubMed Central

    Kameda, C; Nakamura, M; Tanaka, H; Yamasaki, A; Kubo, M; Tanaka, M; Onishi, H; Katano, M

    2010-01-01

    Background: Oestrogen receptor-alpha (ERα) is highly expressed in diffuse-type gastric cancer and oestrogen increases the proliferation of ERα-positive gastric cancer. However, a detailed mechanism by which oestrogen increases the proliferation of these cells is still unclear. Methods: We used 17-β-oestradiol (E2) as a stimulator against the ERα pathway. Pure anti-oestrogen drug ICI 182 780 (ICI) and small interfering RNA against ERα (ERα siRNA) were used as inhibitors. Cyclopamine (Cyc) was used as the hedgehog (Hh) pathway inhibitor. Two human ERα-positive gastric cancer cells were used as target cells. Effects of the stimulator and inhibitor on E2-induced cell proliferation were also examined. Results: In ERα-positive cells, E2 increased not only cell proliferation but also one of the ligands of the Hh pathway, Shh expression. 17-β-Oestradiol-induced cell proliferation was suppressed by ICI, ERα siRNA or Cyc. The increased expression of Shh induced by E2 was suppressed by ICI and ERα siRNA but not by Cyc. Furthermore, recombinant Shh activated the Hh pathway and increased cell proliferation, whereas anti-Shh antibody suppressed E2-induced cell proliferation. When a relationship between ERα and Shh expressions was analysed using surgically resected gastric cancer specimens, a positive correlation was found, suggesting a linkage between the ERα and Hh pathways. Conclusion: Our data indicate that activation of the ERα pathway promotes cell proliferation by activating the Hh pathway in a ligand-dependent manner through Shh induction of ERα-positive gastric cancer. PMID:20087349

  12. Mechanisms of oestrogen receptor (ER) gene regulation in breast cancer

    PubMed Central

    2016-01-01

    Most breast cancers are driven by a transcription factor called oestrogen receptor (ER). Understanding the mechanisms of ER activity in breast cancer has been a major research interest and recent genomic advances have revealed extraordinary insights into how ER mediates gene transcription and what occurs during endocrine resistance. This review discusses our current understanding on ER activity, with an emphasis on several evolving, but important areas of ER biology. PMID:26884552

  13. Oestrogen-mediated hormonal imbalance precipitates erectile dysfunction.

    PubMed

    Adaikan, P G; Srilatha, B

    2003-02-01

    Declining testosterone (T) in an aging male offsets the equilibrium between androgen and oestrogen (oestradiol, E(2)) with a resultant increase in E(2)-T ratio. Similar functional hormone imbalance is existent in clinical states of hypogonadism and is likely to arise from exposure of males to environmental oestrogens. The pathophysiological significance of this derangement on erectile function, hitherto unknown, was estimated in sexually mature male rats following acute and chronic treatment with oestrogen. A total of 60 male Sprague-Dawley rats (200-250 g) were divided into control and two treatment groups, administered 0.01 and 0.1 mg of oestradiol through oral gavage daily for 1 week (n=30, acute study) and 12 weeks (n=30, long-term study), respectively. Sexual activity in the presence of hormonally primed female rats and intracavernous pressure (ICP) response to electrical stimulation estimated treatment-induced changes, which were correlated with hormone levels and penile morphology at 12 weeks. Following two to five-fold elevation in serum E(2) levels (and simultaneous reduction in testosterone), there was a significant prolongation of mount, intromission, ejaculation latencies and some decrease in frequencies. The ICP response to nerve stimulation was also impaired in all the treated groups. Histologically, trichrome staining highlighted the cavernosal connective tissue hyperplasia in the long-term study groups. Results of this investigation indicate that oestradiol causes pathophysiological changes in erectile function. These observations provide an indirect evidence for the possible sexual health hazards in man upon inadvertent exposure to environmental oestrogens, ageing and derangement of E(2)-T ratio.

  14. Endocrine disruption of oestrogen action and female reproductive tract cancers.

    PubMed

    Gibson, Douglas A; Saunders, Philippa T K

    2014-04-01

    Endocrine disrupting chemicals (EDC) are ubiquitous and persistent compounds that have the capacity to interfere with normal endocrine homoeostasis. The female reproductive tract is exquisitely sensitive to the action of sex steroids, and oestrogens play a key role in normal reproductive function. Malignancies of the female reproductive tract are the fourth most common cancer in women, with endometrial cancer accounting for most cases. Established risk factors for development of endometrial cancer include high BMI and exposure to oestrogens or synthetic compounds such as tamoxifen. Studies on cell and animal models have provided evidence that many EDC can bind oestrogen receptors and highlighted early life exposure as a window of risk for adverse lifelong effects on the reproductive system. The most robust evidence for a link between early life exposure to EDC and adverse reproductive health has come from studies on women who were exposed in utero to diethylstilbestrol. Demonstration that EDC can alter expression of members of the HOX gene cluster highlights one pathway that might be vulnerable to their actions. In summary, evidence for a direct link between EDC exposure and cancers of the reproductive system is currently incomplete. It will be challenging to attribute causality to any single EDC when exposure and development of malignancy may be separated by many years and influenced by lifestyle factors such as diet (a source of phytoestrogens) and adiposity. This review considers some of the evidence collected to date.

  15. Local oestrogenic/androgenic balance in the cerebral vasculature.

    PubMed

    Krause, D N; Duckles, S P; Gonzales, R J

    2011-09-01

    Reproductive effects of sex steroids are well-known; however it is increasingly apparent that these hormones have important actions on non-reproductive tissues such as the vasculature. The latter effects can be relevant throughout the lifespan, not just limited to reproductive years, and are not necessarily restricted to one gender or the other. Our work has established that cerebral blood vessels are a non-reproductive target tissue for sex steroids. We have found that oestrogen and androgens alter vascular tone, endothelial function, oxidative stress and inflammatory responses in cerebral vessels. Often the actions of oestrogen and androgens oppose each other. Moreover, it is clear that cerebral vessels are directly targeted by sex steroids, as they express specific receptors for these hormones. Interestingly, cerebral blood vessels also express enzymes that metabolize sex steroids. These findings suggest that local synthesis of 17ß-estradiol and dihydrotestosterone can occur within the vessel wall. One of the enzymes present, aromatase, converts testosterone to 17ß-estradiol, which would alter the local balance of androgenic and oestrogenic influences. Thus cerebral vessels are affected by circulating sex hormones as well as locally synthesized sex steroids. The presence of vascular endocrine effector mechanisms has important implications for male-female differences in cerebrovascular function and disease. Moreover, the cerebral circulation is a target for gonadal hormones as well as anabolic steroids and therapeutic drugs used to manipulate sex steroid actions. The long-term consequences of these influences are yet to be determined.

  16. Oestrogens and Progestagens: Synthesis and Action in the Brain.

    PubMed

    Rossetti, M F; Cambiasso, M J; Holschbach, M A; Cabrera, R

    2016-07-01

    When steroids, such as pregnenolone, progesterone and oestrogen, are synthesised de novo in neural tissues, they are more specifically referred to as neurosteroids. These neurosteroids bind specific receptors to promote essential brain functions. Pregnenolone supports cognition and protects mouse hippocampal cells against glutamate and amyloid peptide-induced cell death. Progesterone promotes myelination, spinogenesis, synaptogenesis, neuronal survival and dendritic growth. Allopregnanolone increases hippocampal neurogenesis, neuronal survival and cognitive functions. Oestrogens, such as oestradiol, regulate synaptic plasticity, reproductive behaviour, aggressive behaviour and learning. In addition, neurosteroids are neuroprotective in animal models of Alzheimer's disease, Parkinson's disease, brain injury and ageing. Using in situ hybridisation and/or immunohistochemistry, steroidogenic enzymes, including cytochrome P450 side-chain cleavage, 3β-hydroxysteroid dehydrogenase/Δ5-Δ4 isomerase, cytochrome P450arom, steroid 5α-reductase and 3α-hydroxysteroid dehydrogenase, have been detected in numerous brain regions, including the hippocampus, hypothalamus and cerebral cortex. In the present review, we summarise some of the studies related to the synthesis and function of oestrogens and progestagens in the central nervous system. © 2016 British Society for Neuroendocrinology.

  17. Expectation modulates neural representations of valence throughout the human brain

    PubMed Central

    Ramayya, Ashwin G.; Pedisich, Isaac; Kahana, Michael J.

    2015-01-01

    The brain's sensitivity to unexpected gains or losses plays an important role in our ability to learn new behaviors (Rescorla and Wagner, 1972; Sutton and Barto, 1990). Recent work suggests that gains and losses are ubiquitously encoded throughout the human brain (Vickery et al., 2011), however, the extent to which reward expectation modulates these valence representations is not known. To address this question we analyzed recordings from 4,306 intracranially implanted electrodes in 39 neurosurgical patients as they performed a two-alternative probability learning task. Using high-frequency activity (HFA, 70-200 Hz) as an indicator of local firing rates, we found that expectation modulated reward-related neural activity in widespread brain regions, including regions that receive sparse inputs from midbrain dopaminergic neurons. The strength of unexpected gain signals predicted subjects’ abilities to encode stimulus-reward associations. Thus, neural signals that are functionally related to learning are widely distributed throughout the human brain. PMID:25937489

  18. Immune Modulation in Primary Vaccinia virus Zoonotic Human Infections

    PubMed Central

    Gomes, Juliana Assis Silva; de Araújo, Fernanda Fortes; Trindade, Giliane de Souza; Quinan, Bárbara Resende; Drumond, Betânia Paiva; Ferreira, Jaqueline Maria Siqueira; Mota, Bruno Eduardo Fernandes; Nogueira, Maurício Lacerda; Kroon, Erna Geessien; Abrahão, Jônatas Santos; Côrrea-Oliveira, Rodrigo; da Fonseca, Flávio Guimarães

    2012-01-01

    In 2010, the WHO celebrated the 30th anniversary of the smallpox eradication. Ironically, infections caused by viruses related to smallpox are being increasingly reported worldwide, including Monkeypox, Cowpox, and Vaccinia virus (VACV). Little is known about the human immunological responses elicited during acute infections caused by orthopoxviruses. We have followed VACV zoonotic outbreaks taking place in Brazil and analyzed cellular immune responses in patients acutely infected by VACV. Results indicated that these patients show a biased immune modulation when compared to noninfected controls. Amounts of B cells are low and less activated in infected patients. Although present, T CD4+ cells are also less activated when compared to noninfected individuals, and so are monocytes/macrophages. Similar results were obtained when Balb/C mice were experimentally infected with a VACV sample isolated during the zoonotic outbreaks. Taking together, the data suggest that zoonotic VACVs modulate specific immune cell compartments during an acute infection in humans. PMID:22229039

  19. Real-time modulation of perceptual eye dominance in humans

    PubMed Central

    Zhou, Jiawei; Reynaud, Alexandre; Hess, Robert F.

    2014-01-01

    Ocular dominance (OD) has long served as the model for neural plasticity. The shift of OD has been demonstrated by monocular deprivation in animals only during early visual development. Here, for the first time, we show that perceptual eye dominance can be modulated in real time in normal human adults by varying the spatial image content of movies seen dichoptically by the two eyes over a period as short as 2.5 h. Unlike OD shifts seen in early visual development, this modulation in human eye dominance is not simply a consequence of reduced interocular correlation (e.g. synchronicity) or overall contrast energy, but due to the amplitude reductions of specific image components in one eye's view. The spatial properties driving this eye dominance change suggest that the underlying mechanism is binocular but not orientationally selective, therefore uniquely locating it to layer 4 B of area V1. PMID:25274364

  20. Synchronization and modulation in the human cardiorespiratory system

    NASA Astrophysics Data System (ADS)

    Lotrič, Maja Bračič; Stefanovska, Aneta

    2000-08-01

    We analyse phase and frequency synchronization in the human cardio-respiratory system. The method for analysis of noisy nonstationary bivariate data is applied to simultaneously measured cardiac and respiratory activity. Short epochs of phase and/or frequency locking between respiratory and cardiac rhythms are detected in healthy relaxed subjects (non-athletes). We reveal that the strength of phase synchronization is inversely related to the extent of respiratory modulation of the heart rate.

  1. The Effect of Protein Mass Modulation on Human Dihydrofolate Reductase

    PubMed Central

    Francis, Kevin; Sapienza, Paul J.; Lee, Andrew L.; Kohen, Amnon

    2016-01-01

    Dihydrofolate reductase (DHFR) from Escherichia coli has long served as a model enzyme with which to elucidate possible links between protein dynamics and the catalyzed reaction. Such physical properties of its human counterpart have not been rigorously studied so far, but recent computer-based simulations suggest that these two DHFRs differ significantly in how closely coupled the protein dynamics and the catalyzed C-H→C hydride transfer step are. To test this prediction, two contemporary probes for studying the effect of protein dynamics on catalysis were combined here: temperature dependence of intrinsic kinetic isotope effects (KIEs) that are sensitive to the physical nature of the chemical step, and protein mass-modulation that slows down fast dynamics (femto- to picosecond timescale) throughout the protein. The intrinsic H/T KIEs of human DHFR, like those of E. coli DHFR, are shown to be temperature-independent in the range from 5–45 °C, indicating fast sampling of donor and acceptor distances (DADs) at the reaction’s transition state (or tunneling ready state – TRS). Mass modulation of these enzymes through isotopic labeling with 13C, 15N, and 2H at nonexchangeable hydrogens yield an 11% heavier enzyme. The additional mass has no effect on the intrinsic KIEs of the human enzyme. This finding indicates that the mass-modulation of the human DHFR affects neither DAD distribution nor the DAD’s conformational sampling dynamics. Furthermore, reduction in the enzymatic turnover number and the dissociation rate constant for the product indicate that the isotopic substitution affects kinetic steps that are not the catalyzed C-H→C hydride transfer. The findings are discussed in terms of fast dynamics and their role in catalysis, the comparison of calculations and experiments, and the interpretation of isotopically-modulated heavy enzymes in general. PMID:26813442

  2. Oestrogen and progesterone action on endometrium: a translational approach to understanding endometrial receptivity

    PubMed Central

    Young, Steven L.

    2013-01-01

    Embryo attachment and implantation is critical to successful reproduction of all eutherian mammals, including humans; a better understanding of these processes could lead to improved infertility treatments and novel contraceptive methods. Experience with assisted reproduction, especially oocyte donation cycles, has established that despite the diverse set of hormones produced by the ovary in a cycle-dependent fashion, the sequential actions of only two of them, oestrogen and progesterone, are sufficient to prepare a highly receptive endometrium in humans. Further investigation on the endometrial actions of these two hormones is currently providing significant insight into the implantation process in women, strongly suggesting that an abnormal response to progesterone underlies infertility in some patients. PMID:23933037

  3. Human genome-guided identification of memory-modulating drugs.

    PubMed

    Papassotiropoulos, Andreas; Gerhards, Christiane; Heck, Angela; Ackermann, Sandra; Aerni, Amanda; Schicktanz, Nathalie; Auschra, Bianca; Demougin, Philippe; Mumme, Eva; Elbert, Thomas; Ertl, Verena; Gschwind, Leo; Hanser, Edveena; Huynh, Kim-Dung; Jessen, Frank; Kolassa, Iris-Tatjana; Milnik, Annette; Paganetti, Paolo; Spalek, Klara; Vogler, Christian; Muhs, Andreas; Pfeifer, Andrea; de Quervain, Dominique J-F

    2013-11-12

    In the last decade there has been an exponential increase in knowledge about the genetic basis of complex human traits, including neuropsychiatric disorders. It is not clear, however, to what extent this knowledge can be used as a starting point for drug identification, one of the central hopes of the human genome project. The aim of the present study was to identify memory-modulating compounds through the use of human genetic information. We performed a multinational collaborative study, which included assessment of aversive memory--a trait central to posttraumatic stress disorder--and a gene-set analysis in healthy individuals. We identified 20 potential drug target genes in two genomewide-corrected gene sets: the neuroactive ligand-receptor interaction and the long-term depression gene set. In a subsequent double-blind, placebo-controlled study in healthy volunteers, we aimed at providing a proof of concept for the genome-guided identification of memory modulating compounds. Pharmacological intervention at the neuroactive ligand-receptor interaction gene set led to significant reduction of aversive memory. The findings demonstrate that genome information, along with appropriate data mining methodology, can be used as a starting point for the identification of memory-modulating compounds.

  4. Human genome–guided identification of memory-modulating drugs

    PubMed Central

    Papassotiropoulos, Andreas; Gerhards, Christiane; Heck, Angela; Ackermann, Sandra; Aerni, Amanda; Schicktanz, Nathalie; Auschra, Bianca; Demougin, Philippe; Mumme, Eva; Elbert, Thomas; Ertl, Verena; Gschwind, Leo; Hanser, Edveena; Huynh, Kim-Dung; Jessen, Frank; Kolassa, Iris-Tatjana; Milnik, Annette; Paganetti, Paolo; Spalek, Klara; Vogler, Christian; Muhs, Andreas; Pfeifer, Andrea; de Quervain, Dominique J.-F.

    2013-01-01

    In the last decade there has been an exponential increase in knowledge about the genetic basis of complex human traits, including neuropsychiatric disorders. It is not clear, however, to what extent this knowledge can be used as a starting point for drug identification, one of the central hopes of the human genome project. The aim of the present study was to identify memory-modulating compounds through the use of human genetic information. We performed a multinational collaborative study, which included assessment of aversive memory—a trait central to posttraumatic stress disorder—and a gene-set analysis in healthy individuals. We identified 20 potential drug target genes in two genomewide-corrected gene sets: the neuroactive ligand–receptor interaction and the long-term depression gene set. In a subsequent double-blind, placebo-controlled study in healthy volunteers, we aimed at providing a proof of concept for the genome-guided identification of memory modulating compounds. Pharmacological intervention at the neuroactive ligand–receptor interaction gene set led to significant reduction of aversive memory. The findings demonstrate that genome information, along with appropriate data mining methodology, can be used as a starting point for the identification of memory-modulating compounds. PMID:24145423

  5. Serotonin modulates striatal responses to fairness and retaliation in humans

    PubMed Central

    Crockett, MJ; Apergis-Schoute, AM; Herrmann, B; Lieberman, MD; Müller, U; Robbins, TW; Clark, L

    2013-01-01

    Humans are willing to incur personal costs to punish others who violate social norms. Such ‘costly punishment’ is an important force for sustaining human cooperation, but the causal neurobiological determinants of punishment decisions remain unclear. Using a combination of behavioral, pharmacological and neuroimaging techniques, we show that manipulating the serotonin system in humans alters costly punishment decisions by modulating responses to fairness and retaliation in the striatum. Following dietary depletion of the serotonin precursor tryptophan, participants were more likely to punish those who treated them unfairly, and were slower to accept fair exchanges. Neuroimaging data revealed activations in the ventral and dorsal striatum that were associated with fairness and punishment, respectively. Depletion simultaneously reduced ventral striatal responses to fairness and increased dorsal striatal responses during punishment, an effect that predicted its influence on punishment behavior. Finally, we provide behavioral evidence that serotonin modulates specific retaliation, rather than general norm enforcement: depleted participants were more likely to punish unfair behavior directed toward themselves, but not unfair behavior directed toward others. Our findings demonstrate that serotonin modulates social value processing in the striatum, producing context-dependent effects on social behavior. PMID:23426678

  6. G protein-coupled oestrogen receptor 1 (GPER1)/GPR30: a new player in cardiovascular and metabolic oestrogenic signalling

    PubMed Central

    Nilsson, Bengt-Olof; Olde, Björn; Leeb-Lundberg, LM Fredrik

    2011-01-01

    Oestrogens are important sex hormones central to health and disease in both genders that have protective effects on the cardiovascular and metabolic systems. These hormones act in complex ways via both genomic and non-genomic mechanisms. The genomic mechanisms are relatively well characterized, whereas the non-genomic ones are only beginning to be explored. Two oestrogen receptors (ER), ERα and ERβ, have been described that act as nuclear transcription factors but can also associate with the plasma membrane and influence cytosolic signalling. ERα has been shown to mediate both anti-atherogenic effects and pro-survival effects in pancreatic β-cells. In recent years, a third membrane-bound ER has emerged, G protein-coupled receptor 30 or G protein-coupled oestrogen receptor 1 (GPER1), which mediates oestrogenic responses in cardiovascular and metabolic regulation. Both GPER1 knock-out models and pharmacological agents are now available to study GPER1 function. These tools have revealed that GPER1 activation may have several beneficial effects in the cardiovascular system including vasorelaxation, inhibition of smooth muscle cell proliferation, and protection of the myocardium against ischaemia/reperfusion injury, and in the metabolic system including stimulation of insulin release and protection against pancreatic β-cell apoptosis. Thus, GPER1 is emerging as a candidate therapeutic target in both cardiovascular and metabolic disease. LINKED ARTICLES This article is one of a set of reviews submitted to BJP in connection with talks given at the September 2010 meeting of the International Society of Hypertension in Vancouver, Canada. To view the other articles in this collection visit http://dx.doi.org/10.1111/j.1476-5381.2010.01167.x, http://dx.doi.org/10.1111/j.1476-5381.2011.01260.x and http://dx.doi.org/10.1111/j.1476-5381.2011.01366.x PMID:21250980

  7. Environmental concentrations of anti-androgenic pharmaceuticals do not impact sexual disruption in fish alone or in combination with steroid oestrogens.

    PubMed

    Green, Christopher; Brian, Jayne; Kanda, Rakesh; Scholze, Martin; Williams, Richard; Jobling, Susan

    2015-03-01

    Sexual disruption in wild fish has been linked to the contamination of river systems with steroid oestrogens, including the pharmaceutical 17α-ethinylestradiol, originating from domestic wastewaters. As analytical chemistry has advanced, more compounds derived from the human use of pharmaceuticals have been identified in the environment and questions have arisen as to whether these additional pharmaceuticals may also impact sexual disruption in fish. Indeed, pharmaceutical anti-androgens have been shown to induce such effects under laboratory conditions. These are of particular interest since anti-androgenic biological activity has been identified in the aquatic environment and is potentially implicated in sexual disruption alone and in combination with steroid oestrogens. Consequently, predictive modelling was employed to determine the concentrations of two anti-androgenic human pharmaceuticals, bicalutamide and cyproterone acetate, in UK sewage effluents and river catchments and their combined impacts on sexual disruption were then assessed in two fish models. Crucially, fish were also exposed to the anti-androgens in combination with steroid oestrogens to determine whether they had any additional impact on oestrogen induced feminisation. Modelling predicted that the anti-androgenic pharmaceuticals were likely to be widespread in UK river catchments. However, their concentrations were not sufficient to induce significant responses in plasma vitellogenin concentrations, secondary sexual characteristics or gross indices in male fathead minnow or intersex in Japanese medaka alone or in combination with steroid oestrogens. However, environmentally relevant mixtures of oestrone, 17β-oestradiol and 17α-ethinylestradiol did induce vitellogenin and intersex, supporting their role in sexual disruption in wild fish populations. Unexpectedly, a male dominated sex ratio (100% in controls) was induced in medaka and the potential cause and implications are briefly discussed

  8. Modulation of the insulin-like growth factor-I system by N-(4-hydroxyphenyl)-retinamide in human breast cancer cell lines.

    PubMed Central

    Favoni, R. E.; de Cupis, A.; Bruno, S.; Yee, D.; Ferrera, A.; Pirani, P.; Costa, A.; Decensi, A.

    1998-01-01

    The potent mitogenic activity of insulin-like growth factor I (IGF-I) on breast epithelium is inhibited by retinoic acid in oestrogen receptor-positive (ER+) breast cancer cell lines. We studied and compared the effects of N-(4-hydroxyphenyl)-retinamide (4-HPR) in terms of growth inhibition and modulation of the IGF-I system in ER+ (MCF-7) and oestrogen receptor-negative (ER-) (MDA-MB231) breast cancer cell lines. Treatment with 1-10 microM 4-HPR for up to 96 h induced a dose- and time-dependent inhibition of proliferation in both breast cancer cell lines. Induction of apoptosis was much more evident in MCF-7 than in MDA-MB231 cells (30-40% compared with 0-5% respectively at 5 microM for 48 h). Exogenous human recombinant IGF-I (hr-IGF-I)-stimulated cell proliferation was abolished by 1 microM 4-HPR in MCF-7 cells. Immunoreactive IGF-I-like protein concentration in conditioned medium was reduced by 38% in MCF-7 and by 90% in MDA-MB231 cell lines following treatment for 48 h with 5 microM 4-HPR. Western ligand blot analysis showed a reduction of IGF-binding protein 4 (BP4) and BP5 by 67% and 87%, respectively, in MCF-7, whereas IGF-BP4 and -BP1 were reduced by approximately 20% in MDA-MB231 cells. Exposure to 5 microM 4-HPR for 48 h inhibited [125I]IGF-I binding and Scatchard analysis revealed a decrease of more than 50% in maximum binding capacity (Bmax) and a reduced receptor number/cell in both cancer cell lines. Steady-state type I IGF-receptor mRNA levels were reduced by approximately 30% in both tumour cell lines. We conclude that 4-HPR induces a significant down-regulation of the IGF-I system in both ER+ (MCF-7) and ER- (MDA-MB231) breast cancer cell lines. These findings suggest that, in our model, interference with the ER signalling pathway is not the only mechanism of breast cancer growth inhibition by 4-HPR. Images Figure 6 Figure 8 PMID:9649125

  9. The Way Humans Behave Modulates the Emotional State of Piglets.

    PubMed

    Brajon, Sophie; Laforest, Jean-Paul; Schmitt, Océane; Devillers, Nicolas

    2015-01-01

    The emotional state can influence decision-making under ambiguity. Cognitive bias tests (CBT) proved to be a promising indicator of the affective valence of animals in a context of farm animal welfare. Although it is well-known that humans can influence the intensity of fear and reactions of animals, research on cognitive bias often focusses on housing and management conditions and neglects the role of humans on emotional states of animals. The present study aimed at investigating whether humans can modulate the emotional state of weaned piglets. Fifty-four piglets received a chronic experience with humans: gentle (GEN), rough (ROU) or minimal contact (MIN). Simultaneously, they were individually trained on a go/no-go task to discriminate a positive auditory cue, associated with food reward in a trough, from a negative one, associated with punishments (e.g. water spray). Independently of the treatment (P = 0.82), 59% of piglets completed the training. Successfully trained piglets were then subjected to CBT, including ambiguous cues in presence or absence of a human observer. As hypothesized, GEN piglets showed a positive judgement bias, as shown by their higher percentage of go responses following an ambiguous cue compared to ROU (P = 0.03) and MIN (P = 0.02) piglets, whereas ROU and MIN piglets did not differ (P > 0.10). The presence of an observer during CBT did not modulate the percentage of go responses following an ambiguous cue (P > 0.10). However, regardless of the treatment, piglets spent less time in contact with the trough following positive cues during CBT in which the observer was present than absent (P < 0.0001). This study originally demonstrates that the nature of a chronic experience with humans can induce a judgement bias indicating that the emotional state of farm animals such as piglets can be affected by the way humans interact with them.

  10. The Way Humans Behave Modulates the Emotional State of Piglets

    PubMed Central

    Brajon, Sophie; Laforest, Jean-Paul; Schmitt, Océane; Devillers, Nicolas

    2015-01-01

    The emotional state can influence decision-making under ambiguity. Cognitive bias tests (CBT) proved to be a promising indicator of the affective valence of animals in a context of farm animal welfare. Although it is well-known that humans can influence the intensity of fear and reactions of animals, research on cognitive bias often focusses on housing and management conditions and neglects the role of humans on emotional states of animals. The present study aimed at investigating whether humans can modulate the emotional state of weaned piglets. Fifty-four piglets received a chronic experience with humans: gentle (GEN), rough (ROU) or minimal contact (MIN). Simultaneously, they were individually trained on a go/no-go task to discriminate a positive auditory cue, associated with food reward in a trough, from a negative one, associated with punishments (e.g. water spray). Independently of the treatment (P = 0.82), 59% of piglets completed the training. Successfully trained piglets were then subjected to CBT, including ambiguous cues in presence or absence of a human observer. As hypothesized, GEN piglets showed a positive judgement bias, as shown by their higher percentage of go responses following an ambiguous cue compared to ROU (P = 0.03) and MIN (P = 0.02) piglets, whereas ROU and MIN piglets did not differ (P > 0.10). The presence of an observer during CBT did not modulate the percentage of go responses following an ambiguous cue (P > 0.10). However, regardless of the treatment, piglets spent less time in contact with the trough following positive cues during CBT in which the observer was present than absent (P < 0.0001). This study originally demonstrates that the nature of a chronic experience with humans can induce a judgement bias indicating that the emotional state of farm animals such as piglets can be affected by the way humans interact with them. PMID:26244335

  11. Polymeric membranes modulate human keratinocyte differentiation in specific epidermal layers.

    PubMed

    Salerno, Simona; Morelli, Sabrina; Giordano, Francesca; Gordano, Amalia; Bartolo, Loredana De

    2016-10-01

    In vitro models of human bioengineered skin substitutes are an alternative to animal experimentation for testing the effects and toxicity of drugs, cosmetics and pollutants. For the first time specific and distinct human epidermal strata were engineered by using membranes and keratinocytes. To this purpose, biodegradable membranes of chitosan (CHT), polycaprolactone (PCL) and a polymeric blend of CHT-PCL were prepared by phase-inversion technique and characterized in order to evaluate their morphological, physico-chemical and mechanical properties. The capability of membranes to modulate keratinocyte differentiation inducing specific interactions in epidermal membrane systems was investigated. The overall results demonstrated that the membrane properties strongly influence the cell morpho-functional behaviour of human keratinocytes, modulating their terminal differentiation, with the creation of specific epidermal strata or a fully proliferative epidermal multilayer system. In particular, human keratinocytes adhered on CHT and CHT-PCL membranes, forming the structure of the epidermal top layers, such as the corneum and granulosum strata, characterized by withdrawal or reduction from the cell cycle and cell proliferation. On the PCL membrane, keratinocytes developed an epidermal basal lamina, with high proliferating cells that stratified and migrated over time to form a complete differentiating epidermal multilayer system.

  12. Amplitude modulation detection by human listeners in sound fields

    PubMed Central

    Zahorik, Pavel; Kim, Duck O.; Kuwada, Shigeyuki; Anderson, Paul W.; Brandewie, Eugene; Srinivasan, Nirmal

    2011-01-01

    The temporal modulation transfer function (TMTF) approach allows techniques from linear systems analysis to be used to predict how the auditory system will respond to arbitrary patterns of amplitude modulation (AM). Although this approach forms the basis for a standard method of predicting speech intelligibility based on estimates of the acoustical modulation transfer function (MTF) between source and receiver, human sensitivity to AM as characterized by the TMTF has not been extensively studied under realistic listening conditions, such as in reverberant sound fields. Here, TMTFs (octave bands from 2 – 512 Hz) were obtained in 3 listening conditions simulated using virtual auditory space techniques: diotic, anechoic sound field, reverberant room sound field. TMTFs were then related to acoustical MTFs estimated using two different methods in each of the listening conditions. Both diotic and anechoic data were found to be in good agreement with classic results, but AM thresholds in the reverberant room were lower than predictions based on acoustical MTFs. This result suggests that simple linear systems techniques may not be appropriate for predicting TMTFs from acoustical MTFs in reverberant sound fields, and may be suggestive of mechanisms that functionally enhance modulation during reverberant listening. PMID:22822417

  13. Human Intellectual Disability Genes Form Conserved Functional Modules in Drosophila

    PubMed Central

    Oortveld, Merel A. W.; Keerthikumar, Shivakumar; Oti, Martin; Nijhof, Bonnie; Fernandes, Ana Clara; Kochinke, Korinna; Castells-Nobau, Anna; van Engelen, Eva; Ellenkamp, Thijs; Eshuis, Lilian; Galy, Anne; van Bokhoven, Hans; Habermann, Bianca; Brunner, Han G.; Zweier, Christiane; Verstreken, Patrik; Huynen, Martijn A.; Schenck, Annette

    2013-01-01

    Intellectual Disability (ID) disorders, defined by an IQ below 70, are genetically and phenotypically highly heterogeneous. Identification of common molecular pathways underlying these disorders is crucial for understanding the molecular basis of cognition and for the development of therapeutic intervention strategies. To systematically establish their functional connectivity, we used transgenic RNAi to target 270 ID gene orthologs in the Drosophila eye. Assessment of neuronal function in behavioral and electrophysiological assays and multiparametric morphological analysis identified phenotypes associated with knockdown of 180 ID gene orthologs. Most of these genotype-phenotype associations were novel. For example, we uncovered 16 genes that are required for basal neurotransmission and have not previously been implicated in this process in any system or organism. ID gene orthologs with morphological eye phenotypes, in contrast to genes without phenotypes, are relatively highly expressed in the human nervous system and are enriched for neuronal functions, suggesting that eye phenotyping can distinguish different classes of ID genes. Indeed, grouping genes by Drosophila phenotype uncovered 26 connected functional modules. Novel links between ID genes successfully predicted that MYCN, PIGV and UPF3B regulate synapse development. Drosophila phenotype groups show, in addition to ID, significant phenotypic similarity also in humans, indicating that functional modules are conserved. The combined data indicate that ID disorders, despite their extreme genetic diversity, are caused by disruption of a limited number of highly connected functional modules. PMID:24204314

  14. Human Colon-Derived Soluble Factors Modulate Gut Microbiota Composition

    PubMed Central

    Hevia, Arancha; Bernardo, David; Montalvillo, Enrique; Al-Hassi, Hafid O.; Fernández-Salazar, Luis; Garrote, Jose A.; Milani, Christian; Ventura, Marco; Arranz, Eduardo; Knight, Stella C.; Margolles, Abelardo; Sánchez, Borja

    2015-01-01

    The commensal microbiota modulates immunological and metabolic aspects of the intestinal mucosa contributing to development of human gut diseases including inflammatory bowel disease. The host/microbiota interaction often referred to as a crosstalk, mainly focuses on the effect of the microbiota on the host neglecting effects that the host could elicit on the commensals. Colonic microenvironments from three human healthy controls (obtained from the proximal and distal colon, both in resting conditions and after immune – IL-15- and microbiota – LPS-in vitro challenges) were used to condition a stable fecal population. Subsequent 16S rRNA gene-based analyses were performed to study the effect induced by the host on the microbiota composition and function. Non-supervised principal component analysis (PCA) showed that all microbiotas, which had been conditioned with colonic microenvironments clustered together in terms of relative microbial composition, suggesting that soluble factors were modulating a stable fecal population independently from the treatment or the origin. Our findings confirmed that the host intestinal microenvironment has the capacity to modulate the gut microbiota composition via yet unidentified soluble factors. These findings indicate that an appropriate understanding of the factors of the host mucosal microenvironment affecting microbiota composition and function could improve therapeutic manipulation of the microbiota composition. PMID:25918688

  15. Cholinergic modulation of cognition: Insights from human pharmacological functional neuroimaging

    PubMed Central

    Bentley, Paul; Driver, Jon; Dolan, Raymond J.

    2011-01-01

    Evidence from lesion and cortical-slice studies implicate the neocortical cholinergic system in the modulation of sensory, attentional and memory processing. In this review we consider findings from sixty-three healthy human cholinergic functional neuroimaging studies that probe interactions of cholinergic drugs with brain activation profiles, and relate these to contemporary neurobiological models. Consistent patterns that emerge are: (1) the direction of cholinergic modulation of sensory cortex activations depends upon top-down influences; (2) cholinergic hyperstimulation reduces top-down selective modulation of sensory cortices; (3) cholinergic hyperstimulation interacts with task-specific frontoparietal activations according to one of several patterns, including: suppression of parietal-mediated reorienting; decreasing ‘effort’-associated activations in prefrontal regions; and deactivation of a ‘resting-state network’ in medial cortex, with reciprocal recruitment of dorsolateral frontoparietal regions during performance-challenging conditions; (4) encoding-related activations in both neocortical and hippocampal regions are disrupted by cholinergic blockade, or enhanced with cholinergic stimulation, while the opposite profile is observed during retrieval; (5) many examples exist of an ‘inverted-U shaped’ pattern of cholinergic influences by which the direction of functional neural activation (and performance) depends upon both task (e.g. relative difficulty) and subject (e.g. age) factors. Overall, human cholinergic functional neuroimaging studies both corroborate and extend physiological accounts of cholinergic function arising from other experimental contexts, while providing mechanistic insights into cholinergic-acting drugs and their potential clinical applications. PMID:21708219

  16. Modulating the human gut microbiome as an emerging therapeutic paradigm.

    PubMed

    Rajpal, Deepak K; Brown, James R

    2013-01-01

    The human body is actually a vast and changing ecosystem comprised of billions of microbial organisms, known collectively as the microbiome. Within the last few years, the study of the microbiome and its impact on human health has been a rapidly growing area of biomedical science. The gut intestinal tract microbiome has been a particular focus of research given its potential role in many inflammatory and metabolic diseases as well as drug metabolism. Although a nascent field, the potential for modulating the gut microbiome or human host interactions associated with these microbes offers new therapeutic strategies for many chronic diseases, in particular obesity, diabetes and inflammatory bowel diseases. Here we provide an overview of present knowledge about the gut microbiome, its putative role in metabolic diseases and the potential for microbiome focused treatments from the drug development perspective.

  17. Human Health in the Balance. Hands-On! Developing Active Learning Modules on the Human Dimensions of Global Change.

    ERIC Educational Resources Information Center

    Meade, Melinda S.; Washburn, Sarah; Holman, Jeremy T.

    This learning module aims to engage students in problem solving, critical thinking, scientific inquiry, and cooperative learning. The module is appropriate for use in any introductory or intermediate undergraduate course that focuses on human-environment relationships. The module states that human health is a product of complex interactions among…

  18. Attention modulates responses in the human lateral geniculate nucleus.

    PubMed

    O'Connor, Daniel H; Fukui, Miki M; Pinsk, Mark A; Kastner, Sabine

    2002-11-01

    Attentional mechanisms are important for selecting relevant information and filtering out irrelevant information from cluttered visual scenes. Selective attention has previously been shown to affect neural activity in both extrastriate and striate visual cortex. Here, evidence from functional brain imaging shows that attentional response modulation is not confined to cortical processing, but can occur as early as the thalamic level. We found that attention modulated neural activity in the human lateral geniculate nucleus (LGN) in several ways: it enhanced neural responses to attended stimuli, attenuated responses to ignored stimuli and increased baseline activity in the absence of visual stimulation. The LGN, traditionally viewed as the gateway to visual cortex, may also serve as a 'gatekeeper' in controlling attentional response gain.

  19. Human Skin Hypoxia Modulates Cerebrovascular and Autonomic Functions

    PubMed Central

    Pucci, Olivia; Qualls, Clifford; Battisti-Charbonney, Anne; Balaban, Dahlia Y.; Fisher, Joe A.; Duffin, Jim; Appenzeller, Otto

    2012-01-01

    Because the skin is an oxygen sensor in amphibians and mice, we thought to confirm this function also in humans. The human upright posture, however, introduces additional functional demands for the maintenance of oxygen homeostasis in which cerebral blood flow and autonomic nervous system (ANS) function may also be involved. We examined nine males and three females. While subjects were breathing ambient air, at sea level, we changed gases in a plastic body-bag during two conditions of the experiment such as to induce skin hypoxia (with pure nitrogen) or skin normoxia (with air). The subjects performed a test of hypoxic ventilatory drive during each condition of the experiment. We found no differences in the hypoxic ventilatory drive tests. However, ANS function and cerebral blood flow velocities were modulated by skin hypoxia and the effect was significantly greater on the left than right middle cerebral arteries. We conclude that skin hypoxia modulates ANS function and cerebral blood flow velocities and this might impact life styles and tolerance to ambient hypoxia at altitude. Thus the skin in normal humans, in addition to its numerous other functions, is also an oxygen sensor. PMID:23056597

  20. Ion channels in human erythroblasts. Modulation by erythropoietin.

    PubMed Central

    Cheung, J Y; Elensky, M B; Brauneis, U; Scaduto, R C; Bell, L L; Tillotson, D L; Miller, B A

    1992-01-01

    To investigate the mechanism of intracellular Ca2+ ([Cai]) increase in human burst-forming unit-erythroid-derived erythroblasts by erythropoietin, we measured [Cai] with digital video imaging, cellular phosphoinositides with high performance liquid chromatography, and plasma membrane potential and currents with whole cell patch clamp. Chelation of extracellular free Ca2+ abolished [Cai] increase induced by erythropoietin. In addition, the levels of inositol-1,4,5-trisphosphate did not increase in erythropoietin-treated erythroblasts. These results indicate that in erythropoietin-stimulated cells, Ca2+ influx rather than intracellular Ca2+ mobilization was responsible for [Cai] rise. Both Ni2+ and moderately high doses of nifedipine blocked [Cai] increase, suggesting involvement of ion channels. Resting membrane potential in human erythroblasts was -10.9 +/- 1.0 mV and was not affected by erythropoietin, suggesting erythropoietin modulated a voltage-independent ion channel permeable to Ca2+. No voltage-dependent ion channel but a Ca(2+)-activated K+ channel was detected in human erythroblasts. The magnitude of erythropoietin-induced [Cai] increase, however, was insufficient to open Ca(2+)-activated K+ channels. Our data suggest erythropoietin modulated a voltage-independent ion channel permeable to Ca2+, resulting in sustained increases in [Cai]. PMID:1385476

  1. Methylene blue modulates functional connectivity in the human brain.

    PubMed

    Rodriguez, Pavel; Singh, Amar P; Malloy, Kristen E; Zhou, Wei; Barrett, Douglas W; Franklin, Crystal G; Altmeyer, Wilson B; Gutierrez, Juan E; Li, Jinqi; Heyl, Betty L; Lancaster, Jack L; Gonzalez-Lima, F; Duong, Timothy Q

    2016-03-10

    Methylene blue USP (MB) is a FDA-grandfathered drug used in clinics to treat methemoglobinemia, carbon monoxide poisoning and cyanide poisoning that has been shown to increase fMRI evoked blood oxygenation level dependent (BOLD) response in rodents. Low dose MB also has memory enhancing effect in rodents and humans. However, the neural correlates of the effects of MB in the human brain are unknown. We tested the hypothesis that a single low oral dose of MB modulates the functional connectivity of neural networks in healthy adults. Task-based and task-free fMRI were performed before and one hour after MB or placebo administration utilizing a randomized, double-blinded, placebo-controlled design. MB administration was associated with a reduction in cerebral blood flow in a task-related network during a visuomotor task, and with stronger resting-state functional connectivity in multiple regions linking perception and memory functions. These findings demonstrate for the first time that low-dose MB can modulate task-related and resting-state neural networks in the human brain. These neuroimaging findings support further investigations in healthy and disease populations.

  2. Therapeutic modulators of STAT signalling for human diseases

    PubMed Central

    Miklossy, Gabriella; Hilliard, Tyvette S.; Turkson, James

    2014-01-01

    The signal transducer and activator of transcription (STAT) proteins have important roles in biological processes. The abnormal activation of STAT signalling pathways is also implicated in many human diseases, including cancer, autoimmune diseases, rheumatoid arthritis, asthma and diabetes. Over a decade has passed since the first inhibitor of a STAT protein was reported and efforts to discover modulators of STAT signalling as therapeutics continue. This Review discusses the outcomes of the ongoing drug discovery research endeavours against STAT proteins, provides perspectives on new directions for accelerating the discovery of drug candidates, and highlights the noteworthy candidate therapeutics that have progressed to clinical trials. PMID:23903221

  3. Identifying gene expression modules that define human cell fates.

    PubMed

    Germanguz, I; Listgarten, J; Cinkornpumin, J; Solomon, A; Gaeta, X; Lowry, W E

    2016-05-01

    Using a compendium of cell-state-specific gene expression data, we identified genes that uniquely define cell states, including those thought to represent various developmental stages. Our analysis sheds light on human cell fate through the identification of core genes that are altered over several developmental milestones, and across regional specification. Here we present cell-type specific gene expression data for 17 distinct cell states and demonstrate that these modules of genes can in fact define cell fate. Lastly, we introduce a web-based database to disseminate the results. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

  4. Oestrogen regulates mitochondrial respiratory chain enzyme transcription in the mouse spinal cord.

    PubMed

    Johann, S; Dahm, M; Kipp, M; Beyer, C; Arnold, S

    2010-08-01

    The regulation of mitochondrial energy metabolism is not only important for normal functioning of neurones, but also appears to be essential during acute damage and neurodegeneration in the central nervous system. This makes mitochondria an interesting regulatory target for therapeutic approaches. Oestrogen is well-recognised as a protective hormone in the central nervous system under pathological threats. In the present study, we analysed the influence of oestrogen on the expression of mitochondria-encoded genes and mitochondrial activity in spinal cord cells both in vitro and vivo. Hormone application increased the transcription of mitochondrial respiratory chain enzymes (MRCE). This effect was observed in cultured spinal cord neurones, where it was inhibited by a nuclear oestrogen receptor (ER) antagonist and mainly mediated by the activation of ERbeta. No effect of oestrogen was observed in cultured spinal cord astroglia. In addition, the mitochondrial transcription factor A and nuclear respiratory factor 1 were up-regulated by oestrogen in a similar way as MRCE in vitro, and ATP levels were elevated after the application of the specific ERbeta agonist 2,3-bis(4-hydroxyphenyl)-propionitrile in cultured spinal cord nerve cells. The exposure of young male mice to oestrogen yielded increased levels of MRCE transcripts in the spinal cord. These data clearly show that systemic application of oestrogen stimulates MRCE expression in the spinal cord and predominantly in neurones. Further studies are required to demonstrate the potency of oestrogen to counteract pathological damage by stabilising mitochondrial performance.

  5. Cyclical modulation of human ventricular repolarization by respiration

    PubMed Central

    Hanson, Ben; Gill, Jaswinder; Western, David; Gilbey, Michael P.; Bostock, Julian; Boyett, Mark R.; Zhang, Henggui; Coronel, Ruben; Taggart, Peter

    2012-01-01

    Background: Respiratory modulation of autonomic input to the sinus node results in cyclical modulation of heart rate, known as respiratory sinus arrhythmia (RSA). We hypothesized that the respiratory cycle may also exert cyclical modulation on ventricular repolarization, which may be separately measurable using local endocardial recordings. Methods and Results: The study included 16 subjects with normal ventricles undergoing routine clinical electrophysiological procedures for supraventricular arrhythmias. Unipolar electrograms were recorded from 10 right and 10 left ventricular endocardial sites. Breathing was voluntarily regulated at 5 fixed frequencies (6, 9, 12, 15, and 30 breaths per min) and heart rate was clamped by RV pacing. Activation-recovery intervals (ARI: a surrogate for APD) exhibited significant (p < 0.025) cyclical variation at the respiratory frequency in all subjects; ARI shortened with inspiration and lengthened with expiration. Peak-to-peak ARI variation ranged from 0–26 ms; the spatial pattern varied with subject. Arterial blood pressure also oscillated at the respiratory frequency (p < 0.025) and lagged behind respiration by between 1.5 s and 0.65 s from slowest to fastest breathing rates respectively. Systolic oscillation amplitude was significantly greater than diastolic (14 ± 5 vs. 8 ± 4 mm Hg ± SD, p < 0.001). Conclusions: Observations in humans with healthy ventricles using multiple left and right ventricular endocardial recordings showed that ARI action potential duration (APD) varied cyclically with respiration. PMID:23055983

  6. CREME: Cis-Regulatory Module Explorer for the Human Genome

    SciTech Connect

    Loots, G G; Sharan, R; Ovcharenko, I; Ben-Hur, A

    2004-02-11

    The binding of transcription factors to specific regulatory sequence elements is a primary mechanism for controlling gene transcription. Eukaryotic genes are often regulated by several transcription factors, whose binding sites are tightly clustered and form cis-regulatory modules. In this paper we present a web-server, CREME, for identifying and visualizing cis-regulatory modules in the promoter regions of a given set of potentially co-regulated genes. CREME relies on a database of putative transcription factor binding sites that have been annotated across the human genome using a library of position weight matrices and evolutionary conservation with the mouse and rat genomes. A search algorithm is applied to this dataset to identify combinations of transcription factors whose binding sites tend to co-occur in close proximity in the promoter regions of the input gene set. The identified cis-regulatory modules are statistically scored and significant combinations are reported and graphically visualized. Our web-server is available at http://creme.dcode.org/.

  7. Oestrogen and the cardiovascular system: the good, the bad and the puzzling.

    PubMed

    Gray, G A; Sharif, I; Webb, D J; Seckl, J R

    2001-03-01

    The concept that oestrogen replacement therapy is cardioprotective has been challenged recently by the negative results of randomized clinical trials in coronary heart disease. These data have come at a time of rapid advances in our understanding of the cellular mechanisms of oestrogen. In particular, the cloning of the classical oestrogen receptor (ERalpha), the identification of a novel ER isoform (ERbeta), the availability of specific ERalpha and ERbeta knockout mice models, and the elucidation of receptor functions and signalling pathways linked to non-genomic actions of oestrogen are helping to unravel this complex biology. In this article, these advances will be discussed with particular emphasis on the regulation of nitric oxide synthesis by oestrogen. Furthermore, the puzzling issues that have emerged and the potential for development of novel and specific therapeutic approaches will be highlighted.

  8. Higher cortical modulation of pain perception in the human brain: Psychological determinant.

    PubMed

    Chen, Andrew Cn

    2009-10-01

    Pain perception and its genesis in the human brain have been reviewed recently. In the current article, the reports on pain modulation in the human brain were reviewed from higher cortical regulation, i.e. top-down effect, particularly studied in psychological determinants. Pain modulation can be examined by gene therapy, physical modulation, pharmacological modulation, psychological modulation, and pathophysiological modulation. In psychological modulation, this article examined (a) willed determination, (b) distraction, (c) placebo, (d) hypnosis, (e) meditation, (f) qi-gong, (g) belief, and (h) emotions, respectively, in the brain function for pain modulation. In each, the operational definition, cortical processing, neuroimaging, and pain modulation were systematically deliberated. However, not all studies had featured the brain modulation processing but rather demonstrated potential effects on human pain. In our own studies on the emotional modulation on human pain, we observed that emotions could be induced from music melodies or pictures perception for reduction of tonic human pain, mainly in potentiation of the posterior alpha EEG fields, likely resulted from underneath activities of precuneous in regulation of consciousness, including pain perception. To sum, higher brain functions become the leading edge research in all sciences. How to solve the information bit of thinking and feeling in the brain can be the greatest challenge of human intelligence. Application of higher cortical modulation of human pain and suffering can lead to the progress of social humanity and civilization.

  9. Oestrogen-mediated suppression of tumour necrosis factor alpha-induced apoptosis in MCF-7 cells: subversion of Bcl-2 by anti-oestrogens.

    PubMed

    Burow, M E; Weldon, C B; Tang, Y; McLachlan, J A; Beckman, B S

    2001-11-01

    In oestrogen receptor (ER)-positive breast carcinoma cells, 17beta-oestradiol suppresses a dose-dependent induction of cell death by tumour necrosis factor alpha (TNF). The ability of oestrogens to promote cell survival in ER-positive breast carcinoma cells is linked to a coordinate increase in Bcl-2 expression, an effect that is blocked with the pure anti-oestrogen ICI 182,780. The role of Bcl-2 in MCF-7 cell survival was confirmed by stable overexpression of Bcl-2 which resulted in suppression of apoptosis induced by doxorubicin (DOX), paclitaxel (TAX) and TNF as compared to vector-control cells. The pure anti-oestrogen ICI 182,780 in combination with TNF, DOX or TAX potentiated apoptosis in vector-transfected cells. Interestingly, pre-treatment with ICI 182,780 markedly enhanced chemotherapeutic drug- or TNF-induced apoptosis in Bcl-2 expressing cells, an effect that was correlated with ICI 182,780 induced activation of c-Jun N-terminal kinase. Our results suggest that the effects of oestrogens/anti-oestrogens on the regulation of apoptosis may involve coordinate activation of signalling events and Bcl-2 expression.

  10. Oestrogen influence on myogenic satellite cells following downhill running in male rats: a preliminary study.

    PubMed

    Tiidus, P M; Deller, M; Liu, X L

    2005-05-01

    This study examined the effect of oestrogen supplementation in rats on myogenic satellite cell quantities in type I and II muscles following eccentric exercise. Gonad intact adult male rats divided into four groups, oestrogen supplemented (25 mg oestrogen pellet) control (EC), oestrogen supplemented, exercised (EE), sham (no oestrogen) control (SC) and sham, exercised (SE). After 1 week of oestrogen exposure the EE and SE animals performed 90 min of intermittent downhill running (5 min running/2 min rest @-13.5 degrees incline and 17 m min(-1) speed). Seventy-two hours later exercised (EE and SE) and control (EC and SC) animals were killed and blood samples taken and soleus and white (superficial) vastus muscles surgically removed. Histochemical sections of soleus and white vastus muscles were examined for myogenic satellite cell content by use of Pax7 antibody and for neutrophil content by use of haematoxylin and eosin (H and E) staining procedures. Downhill running resulted in significant elevations in satellite cells and neutrophils detected in both soleus and white vastus muscle samples (P < 0.01). Interestingly, oestrogen supplementation resulted in significantly greater (P < 0.01) post-exercise elevations in satellite cells detected in both soleus and white vastus muscle samples compared with sham (no oestrogen) rats. Increases in neutrophils were significantly (P < 0.05) attenuated in oestrogen supplemented rats relative to sham in soleus but not in white vastus muscles. Oestrogen supplementation in male rats may have accentuated the 72 h post-downhill running increase in Pax7 detected myogenic satellite cell number in both soleus and white vastus muscles relative to unsupplemented rats. The mechanisms and physiological consequences of this effect are yet to be determined.

  11. Effects of oestrogens and anti-oestrogens on normal breast tissue from women bearing BRCA1 and BRCA2 mutations

    PubMed Central

    Bramley, M; Clarke, R B; Howell, A; Evans, D G R; Armer, T; Baildam, A D; Anderson, E

    2006-01-01

    There is considerable interest in whether anti-oestrogens can be used to prevent breast cancer in women bearing mutations in the BRCA1 and BRCA2 genes. The effects of oestradiol (E2), tamoxifen (TAM) and fulvestrant (FUL) on proliferation and steroid receptor expression were assessed in normal breast epithelium taken from women at varying risks of breast cancer and implanted into athymic nude mice, which were treated with E2 in the presence and absence of TAM or FUL. Tissue samples were taken at various time points thereafter for assessment of proliferative activity and expression of oestrogen and progesterone receptors (ERα and PgR) by immunohistochemistry. Oestradiol increased proliferation in the breast epithelium from women carrying mutations in the BRCA1/2 genes, those otherwise at increased risk and those at population risk of breast cancer. This increase was reduced by both TAM and FUL in all risk groups. In the absence of E2, PgR expression was reduced in all risk groups but significantly more so in the BRCA-mutated groups. Subsequent E2 treatment caused a rapid, complete induction of PgR expression in the population-risk group but not in the high-risk or BRCA-mutated groups in which PgR induction was significantly delayed. These data suggest that the mechanisms by which E2 induces breast epithelial PgR expression are impaired in BRCA1/2 mutation carriers, whereas those regulating proliferation remain intact. We conclude that early anti-oestrogen treatment should prevent breast cancer in very high-risk women. PMID:16538216

  12. A mechanism for frequency modulation in songbirds shared with humans.

    PubMed

    Amador, Ana; Margoliash, Daniel

    2013-07-03

    In most animals that vocalize, control of fundamental frequency is a key element for effective communication. In humans, subglottal pressure controls vocal intensity but also influences fundamental frequency during phonation. Given the underlying similarities in the biomechanical mechanisms of vocalization in humans and songbirds, songbirds offer an attractive opportunity to study frequency modulation by pressure. Here, we present a novel technique for dynamic control of subsyringeal pressure in zebra finches. By regulating the opening of a custom-built fast valve connected to the air sac system, we achieved partial or total silencing of specific syllables, and could modify syllabic acoustics through more complex manipulations of air sac pressure. We also observed that more nuanced pressure variations over a limited interval during production of a syllable concomitantly affected the frequency of that syllable segment. These results can be explained in terms of a mathematical model for phonation that incorporates a nonlinear description for the vocal source capable of generating the observed frequency modulations induced by pressure variations. We conclude that the observed interaction between pressure and frequency was a feature of the source, not a result of feedback control. Our results indicate that, beyond regulating phonation or its absence, regulation of pressure is important for control of fundamental frequencies of vocalizations. Thus, although there are separate brainstem pathways for syringeal and respiratory control of song production, both can affect airflow and frequency. We hypothesize that the control of pressure and frequency is combined holistically at higher levels of the vocalization pathways.

  13. A Mechanism for Frequency Modulation in Songbirds Shared with Humans

    PubMed Central

    Margoliash, Daniel

    2013-01-01

    In most animals that vocalize, control of fundamental frequency is a key element for effective communication. In humans, subglottal pressure controls vocal intensity but also influences fundamental frequency during phonation. Given the underlying similarities in the biomechanical mechanisms of vocalization in humans and songbirds, songbirds offer an attractive opportunity to study frequency modulation by pressure. Here, we present a novel technique for dynamic control of subsyringeal pressure in zebra finches. By regulating the opening of a custom-built fast valve connected to the air sac system, we achieved partial or total silencing of specific syllables, and could modify syllabic acoustics through more complex manipulations of air sac pressure. We also observed that more nuanced pressure variations over a limited interval during production of a syllable concomitantly affected the frequency of that syllable segment. These results can be explained in terms of a mathematical model for phonation that incorporates a nonlinear description for the vocal source capable of generating the observed frequency modulations induced by pressure variations. We conclude that the observed interaction between pressure and frequency was a feature of the source, not a result of feedback control. Our results indicate that, beyond regulating phonation or its absence, regulation of pressure is important for control of fundamental frequencies of vocalizations. Thus, although there are separate brainstem pathways for syringeal and respiratory control of song production, both can affect airflow and frequency. We hypothesize that the control of pressure and frequency is combined holistically at higher levels of the vocalization pathways. PMID:23825417

  14. Molecular mechanism(s) of endocrine-disrupting chemicals and their potent oestrogenicity in diverse cells and tissues that express oestrogen receptors

    PubMed Central

    Lee, Hye-Rim; Jeung, Eui-Bae; Cho, Myung-Haing; Kim, Tae-Hee; Leung, Peter C K; Choi, Kyung-Chul

    2013-01-01

    Endocrine-disrupting chemicals (EDCs) are natural or synthetic compounds present in the environment which can interfere with hormone synthesis and normal physiological functions of male and female reproductive organs. Most EDCs tend to bind to steroid hormone receptors including the oestrogen receptor (ER), progesterone receptor (PR) and androgen receptor (AR). As EDCs disrupt the actions of endogenous hormones, they may induce abnormal reproduction, stimulation of cancer growth, dysfunction of neuronal and immune system. Although EDCs represent a significant public health concern, there are no standard methods to determine effect of EDCs on human beings. The mechanisms underlying adverse actions of EDC exposure are not clearly understood. In this review, we highlighted the toxicology of EDCs and its effect on human health, including reproductive development in males and females as shown in in vitro and in vivo models. In addition, this review brings attention to the toxicity of EDCs via interaction of genomic and non-genomic signalling pathways through hormone receptors. PMID:23279634

  15. Feature-Selective Attentional Modulations in Human Frontoparietal Cortex

    PubMed Central

    Sutterer, David W.; Serences, John T.

    2016-01-01

    Control over visual selection has long been framed in terms of a dichotomy between “source” and “site,” where top-down feedback signals originating in frontoparietal cortical areas modulate or bias sensory processing in posterior visual areas. This distinction is motivated in part by observations that frontoparietal cortical areas encode task-level variables (e.g., what stimulus is currently relevant or what motor outputs are appropriate), while posterior sensory areas encode continuous or analog feature representations. Here, we present evidence that challenges this distinction. We used fMRI, a roving searchlight analysis, and an inverted encoding model to examine representations of an elementary feature property (orientation) across the entire human cortical sheet while participants attended either the orientation or luminance of a peripheral grating. Orientation-selective representations were present in a multitude of visual, parietal, and prefrontal cortical areas, including portions of the medial occipital cortex, the lateral parietal cortex, and the superior precentral sulcus (thought to contain the human homolog of the macaque frontal eye fields). Additionally, representations in many—but not all—of these regions were stronger when participants were instructed to attend orientation relative to luminance. Collectively, these findings challenge models that posit a strict segregation between sources and sites of attentional control on the basis of representational properties by demonstrating that simple feature values are encoded by cortical regions throughout the visual processing hierarchy, and that representations in many of these areas are modulated by attention. SIGNIFICANCE STATEMENT Influential models of visual attention posit a distinction between top-down control and bottom-up sensory processing networks. These models are motivated in part by demonstrations showing that frontoparietal cortical areas associated with top-down control

  16. Feature-Selective Attentional Modulations in Human Frontoparietal Cortex.

    PubMed

    Ester, Edward F; Sutterer, David W; Serences, John T; Awh, Edward

    2016-08-03

    Control over visual selection has long been framed in terms of a dichotomy between "source" and "site," where top-down feedback signals originating in frontoparietal cortical areas modulate or bias sensory processing in posterior visual areas. This distinction is motivated in part by observations that frontoparietal cortical areas encode task-level variables (e.g., what stimulus is currently relevant or what motor outputs are appropriate), while posterior sensory areas encode continuous or analog feature representations. Here, we present evidence that challenges this distinction. We used fMRI, a roving searchlight analysis, and an inverted encoding model to examine representations of an elementary feature property (orientation) across the entire human cortical sheet while participants attended either the orientation or luminance of a peripheral grating. Orientation-selective representations were present in a multitude of visual, parietal, and prefrontal cortical areas, including portions of the medial occipital cortex, the lateral parietal cortex, and the superior precentral sulcus (thought to contain the human homolog of the macaque frontal eye fields). Additionally, representations in many-but not all-of these regions were stronger when participants were instructed to attend orientation relative to luminance. Collectively, these findings challenge models that posit a strict segregation between sources and sites of attentional control on the basis of representational properties by demonstrating that simple feature values are encoded by cortical regions throughout the visual processing hierarchy, and that representations in many of these areas are modulated by attention. Influential models of visual attention posit a distinction between top-down control and bottom-up sensory processing networks. These models are motivated in part by demonstrations showing that frontoparietal cortical areas associated with top-down control represent abstract or categorical stimulus

  17. Impact of mutational profiles on response of primary oestrogen receptor-positive breast cancers to oestrogen deprivation

    PubMed Central

    Gellert, Pascal; Segal, Corrinne V.; Gao, Qiong; López-Knowles, Elena; Martin, Lesley-Ann; Dodson, Andrew; Li, Tiandao; Miller, Christopher A.; Lu, Charles; Mardis, Elaine R.; Gillman, Alexa; Morden, James; Graf, Manuela; Sidhu, Kally; Evans, Abigail; Shere, Michael; Holcombe, Christopher; McIntosh, Stuart A.; Bundred, Nigel; Skene, Anthony; Maxwell, William; Robertson, John; Bliss, Judith M.; Smith, Ian; Dowsett, Mitch; Johnston, Stephen; Todd, Radha; Horgan, Kieran; Chan, Stephen; Holt, Simon D. H.; Parton, Marina; Laidlaw, Ian; Vaidya, Jayant S.; Irvine, Tracey; Hoar, Fiona; Khattak, Ilyas; Kothari, Ashutosh; Brazil, Lucy; Gallegos, Nicholas; Wheatley, Duncan; Johnson, Tayo; Sparrow, Geoffrey; Ledwidge, Serena; Mortimer, Caroline; Ornstein, Marcus; Ferguson, Douglas; Adamson, Douglas; Cutress, Ramsey; Johnson, Richard; Crowley, Clare; Winters, Zoe; Hamed, Hisham; Burcombe, Russell; Cleator, Susan; Kelleher, Muireann; Roberts, Jonathan; Vesty, Sarah; Hadaki, Maher; Quigley, Mary; Doughty, Julie; Laws, Siobhan; Seetharam, Seema; Thorne, Amanda; Donnelly, Peter

    2016-01-01

    Pre-surgical studies allow study of the relationship between mutations and response of oestrogen receptor-positive (ER+) breast cancer to aromatase inhibitors (AIs) but have been limited to small biopsies. Here in phase I of this study, we perform exome sequencing on baseline, surgical core-cuts and blood from 60 patients (40 AI treated, 20 controls). In poor responders (based on Ki67 change), we find significantly more somatic mutations than good responders. Subclones exclusive to baseline or surgical cores occur in ∼30% of tumours. In phase II, we combine targeted sequencing on another 28 treated patients with phase I. We find six genes frequently mutated: PIK3CA, TP53, CDH1, MLL3, ABCA13 and FLG with 71% concordance between paired cores. TP53 mutations are associated with poor response. We conclude that multiple biopsies are essential for confident mutational profiling of ER+ breast cancer and TP53 mutations are associated with resistance to oestrogen deprivation therapy. PMID:27827358

  18. Xanthohumol suppresses oestrogen-signalling in breast cancer through the inhibition of BIG3-PHB2 interactions

    PubMed Central

    Yoshimaru, Tetsuro; Komatsu, Masato; Tashiro, Etsu; Imoto, Masaya; Osada, Hiroyuki; Miyoshi, Yasuo; Honda, Junko; Sasa, Mitsunori; Katagiri, Toyomasa

    2014-01-01

    Xanthohumol (XN) is a natural anticancer compound that inhibits the proliferation of oestrogen receptor-α (ERα)-positive breast cancer cells. However, the precise mechanism of the antitumour effects of XN on oestrogen (E2)-dependent cell growth, and especially its direct target molecule(s), remain(s) largely unknown. Here, we focus on whether XN directly binds to the tumour suppressor protein prohibitin 2 (PHB2), forming a novel natural antitumour compound targeting the BIG3-PHB2 complex and acting as a pivotal modulator of E2/ERα signalling in breast cancer cells. XN treatment effectively prevented the BIG3-PHB2 interaction, thereby releasing PHB2 to directly bind to both nuclear- and cytoplasmic ERα. This event led to the complete suppression of the E2-signalling pathways and ERα-positive breast cancer cell growth both in vitro and in vivo, but did not suppress the growth of normal mammary epithelial cells. Our findings suggest that XN may be a promising natural compound to suppress the growth of luminal-type breast cancer. PMID:25483453

  19. Xanthohumol suppresses oestrogen-signalling in breast cancer through the inhibition of BIG3-PHB2 interactions.

    PubMed

    Yoshimaru, Tetsuro; Komatsu, Masato; Tashiro, Etsu; Imoto, Masaya; Osada, Hiroyuki; Miyoshi, Yasuo; Honda, Junko; Sasa, Mitsunori; Katagiri, Toyomasa

    2014-12-08

    Xanthohumol (XN) is a natural anticancer compound that inhibits the proliferation of oestrogen receptor-α (ERα)-positive breast cancer cells. However, the precise mechanism of the antitumour effects of XN on oestrogen (E2)-dependent cell growth, and especially its direct target molecule(s), remain(s) largely unknown. Here, we focus on whether XN directly binds to the tumour suppressor protein prohibitin 2 (PHB2), forming a novel natural antitumour compound targeting the BIG3-PHB2 complex and acting as a pivotal modulator of E2/ERα signalling in breast cancer cells. XN treatment effectively prevented the BIG3-PHB2 interaction, thereby releasing PHB2 to directly bind to both nuclear- and cytoplasmic ERα. This event led to the complete suppression of the E2-signalling pathways and ERα-positive breast cancer cell growth both in vitro and in vivo, but did not suppress the growth of normal mammary epithelial cells. Our findings suggest that XN may be a promising natural compound to suppress the growth of luminal-type breast cancer.

  20. Modulation of intracellular pH in human ovarian cancer.

    PubMed

    Sanhueza, C; Araos, J; Naranjo, L; Villalobos, R; Westermeier, F; Salomon, C; Beltrán, A R; Ramírez, M A; Gutiérrez, J; Pardo, F; Leiva, A; Sobrevia, L

    2016-01-01

    To sustain tumor growth, the cancer cells need to adapt to low levels of oxygen (i.e., hypoxia) in the tumor tissue and to the tumor-associated acidic microenvironment. In this phenomenon, the activation of the sodium/proton exchanger 1 (NHE1) at the plasma membrane and the hypoxia-inducible factor (HIF) are critical for the control of the intracellular pH (pHi) and for hypoxia adaptation, respectively. Interestingly, both of these mechanisms end in sustaining cancer cell proliferation. However, regulatory mechanisms of pHi in human ovary tissue and in malignant ascites are unknown. Additionally, a potential role of NHE1 in the modulation of H(+) efflux in human ovarian cancer cells is unknown. In this review, we discussed the characteristics of tumor microenvironment of primary human ovarian tumors and tumor ascites, in terms of pHi regulatory mechanisms and oxygen level. The findings described in the literature suggest that NHE1 may likely play a role in pHi regulation and cell proliferation in human ovarian cancer, potentially involving HIF2α activation. Since ovarian cancer is the fifth cause of prevalence of women cancer in Chile and is usually of late diagnosis, i.e., when the disease jeopardizes peritoneal cavity and other organs, resulting in reduced patient survival, new efforts are required to improve patient-life span and for a better understanding of the pathophysiology of the disease. The potential advantage of the use of amiloride and amiloride-derivatives for cancer treatment in terms of NHE1 expression and activity is also discussed as a therapeutic approach in human ovarian cancer.

  1. C-reactive protein modulates human lung fibroblast migration.

    PubMed

    Kikuchi, Kazuhiko; Kohyama, Tadashi; Yamauchi, Yasuhiro; Kato, Jun; Takami, Kazutaka; Okazaki, Hitoshi; Desaki, Masashi; Nagase, Takahide; Rennard, Stephen I; Takizawa, Hajime

    2009-02-01

    C-reactive protein (CRP) has been classically used as a marker of inflammation. The aim of this study was to investigate the effect of CRP on migration of human fetal lung fibroblasts (HFL-1) to human plasma fibronectin (HFn). Using the blindwell chamber technique, CRP inhibited HFL-1 migration in a dose-dependent fashion (at 1 microg/mL, inhibition: 32.5% +/- 7.1%; P < .05). Western blot analysis showed that CRP inhibited the p38 mitogen-activated protein kinase (MAPK) activity in the presence of HFn. Moreover, the MAPK inhibitors SB202190 (25 microM) and SB203580 (25 microM) inhibited HFn-induced cell migration, suggesting an important role of p38 MAPK in HFn-induced migration. Taken together, these results suggest that the inhibitory effect of CRP is mediated by blocking MAPK. In summary, this study demonstrates that CRP directly modulates human lung fibroblasts migration. Thus, CRP may contribute to regulation of wound healing and may be endogenous antifibrotic factor acting on lung fibrosis.

  2. Oestrogen receptor beta ligand: a novel treatment to enhance endogenous functional remyelination.

    PubMed

    Crawford, Daniel K; Mangiardi, Mario; Song, Bingbing; Patel, Rhusheet; Du, Sienmi; Sofroniew, Michael V; Voskuhl, Rhonda R; Tiwari-Woodruff, Seema K

    2010-10-01

    Demyelinating diseases, such as multiple sclerosis, are characterized by inflammatory demyelination and neurodegeneration of the central nervous system. Therapeutic strategies that induce effective neuroprotection and enhance intrinsic repair mechanisms are central goals for future therapy of multiple sclerosis. Oestrogens and oestrogen receptor ligands are promising treatments to prevent multiple sclerosis-induced neurodegeneration. In the present study we investigated the capacity of oestrogen receptor β ligand treatment to affect callosal axon demyelination and stimulate endogenous myelination in chronic experimental autoimmune encephalomyelitis using electrophysiology, electron microscopy, immunohistochemistry and tract-tracing methods. Oestrogen receptor β ligand treatment of experimental autoimmune encephalomyelitis mice prevented both histopathological and functional abnormalities of callosal axons despite the presence of inflammation. Specifically, there were fewer demyelinated, damaged axons and more myelinated axons with intact nodes of Ranvier in oestrogen receptor β ligand-treated mice. In addition, oestrogen receptor β ligand treatment caused an increase in mature oligodendrocyte numbers, a significant increase in myelin sheath thickness and axon transport. Functional analysis of callosal axon conduction showed a significant improvement in compound action potential amplitudes, latency and in axon refractoriness. These findings show a direct neuroprotective effect of oestrogen receptor β ligand treatment on oligodendrocyte differentiation, myelination and axon conduction during experimental autoimmune encephalomyelitis.

  3. Intestinal Microbiota Modulates Gluten-Induced Immunopathology in Humanized Mice

    PubMed Central

    Galipeau, Heather J.; McCarville, Justin L.; Huebener, Sina; Litwin, Owen; Meisel, Marlies; Jabri, Bana; Sanz, Yolanda; Murray, Joseph A.; Jordana, Manel; Alaedini, Armin; Chirdo, Fernando G.; Verdu, Elena F.

    2016-01-01

    Celiac disease (CD) is an immune-mediated enteropathy triggered by gluten in genetically susceptible individuals. The recent increase in CD incidence suggests that additional environmental factors, such as intestinal microbiota alterations, are involved in its pathogenesis. However, there is no direct evidence of modulation of gluten-induced immunopathology by the microbiota. We investigated whether specific microbiota compositions influence immune responses to gluten in mice expressing the human DQ8 gene, which confers moderate CD genetic susceptibility. Germ-free mice, clean specific-pathogen-free (SPF) mice colonized with a microbiota devoid of opportunistic pathogens and Proteobacteria, and conventional SPF mice that harbor a complex microbiota that includes opportunistic pathogens were used. Clean SPF mice had attenuated responses to gluten compared to germ-free and conventional SPF mice. Germ-free mice developed increased intraepithelial lymphocytes, markers of intraepithelial lymphocyte cytotoxicity, gliadin-specific antibodies, and a proinflammatory gliadin-specific T-cell response. Antibiotic treatment, leading to Proteobacteria expansion, further enhanced gluten-induced immunopathology in conventional SPF mice. Protection against gluten-induced immunopathology in clean SPF mice was reversed after supplementation with a member of the Proteobacteria phylum, an enteroadherent Escherichia coli isolated from a CD patient. The intestinal microbiota can both positively and negatively modulate gluten-induced immunopathology in mice. In subjects with moderate genetic susceptibility, intestinal microbiota changes may be a factor that increases CD risk. PMID:26456581

  4. Intestinal microbiota modulates gluten-induced immunopathology in humanized mice.

    PubMed

    Galipeau, Heather J; McCarville, Justin L; Huebener, Sina; Litwin, Owen; Meisel, Marlies; Jabri, Bana; Sanz, Yolanda; Murray, Joseph A; Jordana, Manel; Alaedini, Armin; Chirdo, Fernando G; Verdu, Elena F

    2015-11-01

    Celiac disease (CD) is an immune-mediated enteropathy triggered by gluten in genetically susceptible individuals. The recent increase in CD incidence suggests that additional environmental factors, such as intestinal microbiota alterations, are involved in its pathogenesis. However, there is no direct evidence of modulation of gluten-induced immunopathology by the microbiota. We investigated whether specific microbiota compositions influence immune responses to gluten in mice expressing the human DQ8 gene, which confers moderate CD genetic susceptibility. Germ-free mice, clean specific-pathogen-free (SPF) mice colonized with a microbiota devoid of opportunistic pathogens and Proteobacteria, and conventional SPF mice that harbor a complex microbiota that includes opportunistic pathogens were used. Clean SPF mice had attenuated responses to gluten compared to germ-free and conventional SPF mice. Germ-free mice developed increased intraepithelial lymphocytes, markers of intraepithelial lymphocyte cytotoxicity, gliadin-specific antibodies, and a proinflammatory gliadin-specific T-cell response. Antibiotic treatment, leading to Proteobacteria expansion, further enhanced gluten-induced immunopathology in conventional SPF mice. Protection against gluten-induced immunopathology in clean SPF mice was reversed after supplementation with a member of the Proteobacteria phylum, an enteroadherent Escherichia coli isolated from a CD patient. The intestinal microbiota can both positively and negatively modulate gluten-induced immunopathology in mice. In subjects with moderate genetic susceptibility, intestinal microbiota changes may be a factor that increases CD risk.

  5. Host cell modulation by human, animal and plant pathogens.

    PubMed

    Andersson, Siv G E; Kempf, Volkhard A J

    2004-04-01

    Members of the alpha-proteobacteria display a broad range of interactions with higher eukaryotes. Some are pathogens of humans, such as Rickettsia and Bartonella that are associated with diseases like epidemic typhus, trench fever, cat scratch disease and bacillary angiomatosis. Others like the Brucella cause abortions in pregnant animals. Yet other species have evolved elaborate interactions with plants; in this group we find both plant symbionts and parasites. Despite radically different host preferences, extreme genome size variations and the absence of toxin genes, similarities in survival strategies and host cell interactions can be recognized among members of the alpha-proteobacteria. Here, we review some of these similarities, with a focus on strategies for modulation of the host target cell.

  6. Modules of human micro-RNA co-target network

    NASA Astrophysics Data System (ADS)

    Basu, Mahashweta; Bhattacharyya, Nitai P.; Mohanty, P. K.

    2011-05-01

    Human micro RNAs (miRNAs) target about 90% of the coding genes and form a complex regulatory network. We study the community structure of the miRNA co-target network considering miRNAs as the nodes which are connected by weighted links. The weight of link that connects a pair of miRNAs denote the total number of common transcripts targeted by that pair. We argue that the network consists of about 74 modules, quite similar to the components (or clusters) obtained earlier [Online J Bioinformatics, 10,280], indicating that the components of the miRNA co-target network are self organized in a way to maximize the modularity.

  7. Hepcidin modulation in human diseases: From research to clinic

    PubMed Central

    Piperno, Alberto; Mariani, Raffaella; Trombini, Paola; Girelli, Domenico

    2009-01-01

    By modulating hepcidin production, an organism controls intestinal iron absorption, iron uptake and mobilization from stores to meet body iron need. In recent years there has been important advancement in our knowledge of hepcidin regulation that also has implications for understanding the physiopathology of some human disorders. Since the discovery of hepcidin and the demonstration of its pivotal role in iron homeostasis, there has been a substantial interest in developing a reliable assay of the hormone in biological fluids. Measurement of hepcidin in biological fluids can improve our understanding of iron diseases and be a useful tool for diagnosis and clinical management of these disorders. We reviewed the literature and our own research on hepcidin to give an updated status of the situation in this rapidly evolving field. PMID:19195055

  8. Modulation of human nucleotide excision repair by 5-methylcytosines.

    PubMed

    Muheim, Regula; Buterin, Tonko; Colgate, Katharine C; Kolbanovsij, Alexander; Geacintov, Nicholas E; Naegeli, Hanspeter

    2003-03-25

    Previous reports showed that methylated CpG sites are primary targets of bulky lesions induced by UV radiation, benzo[a]pyrene (B[a]P), or other environmental genotoxic agents. This study was performed to determine whether the repair of DNA damage formed preferentially at CpG dinucleotides is sensitive to 5-methylcytosine substitutions. Reactivation assays using UV- or B[a]P diol epoxide-damaged shuttle vectors established that human nucleotide excision repair enzymes are able to process fully methylated target DNA molecules. Repair reactions in human cell extracts suggested that 5-methylcytosines modulate local repair efficiency in a seemingly unpredictable manner. In fact, excision of the predominant (+)-trans-anti-B[a]P-dG adduct situated in a mutational hot spot sequence (codon 273 of the p53 gene) was stimulated by CpG methylation. Interestingly, excision activity was increased by a single 5-methylcytosine residue flanking the adduct in the damaged strand, but the same stimulatory effect was also induced by a single 5-methylcytosine residue located opposite the adduct in the undamaged strand. No such stimulation was observed when the (+)-trans-anti-B[a]P-dG lesion was placed in a different site containing a sequence of contiguous guanines, and strong inhibition was detected when a representative of the rare (+)-cis-anti-B[a]P-dG isomer was tested in the same assay. These results raise the possibility that 5-methylcytosines in CpG dinucleotides modulate not only the distribution of bulky DNA lesions but, at least in some cases, also the kinetics of subsequent excision repair reactions. This study confirms that the efficiency of bulky lesion repair is determined by the configuration of base pairs at damaged sites.

  9. Environmental levels of oestrogenic and antiandrogenic compounds feminize digit ratios in male rats and their unexposed male progeny

    PubMed Central

    Auger, Jacques; Le Denmat, Dominique; Berges, Raymond; Doridot, Ludivine; Salmon, Benjamin; Canivenc-Lavier, Marie Chantal; Eustache, Florence

    2013-01-01

    Digit length ratios, especially the second-to-fourth digit ratio (2D : 4D), are associated with various pathological and behavioural conditions in many species including humans and are dependent upon prenatal androgen to oestrogen balance. It is unknown whether digit ratios are modified by environmental exposure to ubiquitous endocrine disruptors. We studied the effect on adult male Wistar rat digit ratios of a gestational exposure to the oestrogenic and antiandrogenic compounds bisphenol A (BPA), genistein and vinclozolin, in low doses, and in combination with investigating in parallel a possible sexual dimorphism of this trait. We also investigated the effects on the male progeny not exposed during gestation. X-rays were taken of the left and right forepaws, and 2D–5D proximal to distal phalanx distances were measured by a standardized procedure based on semi-automatic image analysis. We provide evidence that there is a sexual dimorphism of digit ratios in the Wistar rat, and we found that BPA alone or in combination with genistein and vinclozolin significantly feminized digit ratios in male rats. Intriguingly, significant feminization of digit ratios was also found in the unexposed male progeny of males that had been exposed to compound mixtures. In conclusion, prenatal environmental levels of endocrine-active substances permanently disrupt digit ratios. Digit ratio measurement in adults is thus a promising biomarker of prenatal exposure to low-dose endocrine disruptors in rodents, with potential implications for future studies in humans. PMID:23926155

  10. Impact of oestrogenic substances from oil production at sea.

    PubMed

    Lye, C M

    2000-03-15

    The possibility that chemicals present in the environment may mimic hormones, causing deleterious physiological effects to wildlife, has been given considerable attention. Although the question of ecological significance of 'endocrine disrupters' is not yet settled, and standard assessment procedures have not yet been established, proposals to control these chemicals into the marine environment are now being made under the Oslo and Paris Commission (OSPAR) and the Helsinki Commission (HELCOM). A possible source of such emissions is offshore-drilling, where applications containing polyaromatic hydrocarbons (PAHs) and alkylphenols, indicated as environmental oestrogens, historically have been used. This paper examines available evidence regarding the potential impact of these substances on aquatic organisms living around offshore platforms.

  11. Cinobufagin Modulates Human Innate Immune Responses and Triggers Antibacterial Activity

    PubMed Central

    Xie, Shanshan; Spelmink, Laura; Codemo, Mario; Subramanian, Karthik; Pütsep, Katrin

    2016-01-01

    The traditional Chinese medicine Chan-Su is widely used for treatment of cancer and cardiovascular diseases, but also as a remedy for infections such as furunculosis, tonsillitis and acute pharyngitis. The clinical use of Chan-Su suggests that it has anti-infective effects, however, the mechanism of action is incompletely understood. In particular, the effect on the human immune system is poorly defined. Here, we describe previously unrecognized immunomodulatory activities of cinobufagin (CBG), a major bioactive component of Chan-Su. Using human monocyte-derived dendritic cells (DCs), we show that LPS-induced maturation and production of a number of cytokines was potently inhibited by CBG, which also had a pro-apoptotic effect, associated with activation of caspase-3. Interestingly, CBG triggered caspase-1 activation and significantly enhanced IL-1β production in LPS-stimulated cells. Finally, we demonstrate that CBG upregulates gene expression of the antimicrobial peptides (AMPs) hBD-2 and hBD-3 in DCs, and induces secretion of HNP1-3 and hCAP-18/LL-37 from neutrophils, potentiating neutrophil antibacterial activity. Taken together, our data indicate that CBG modulates the inflammatory phenotype of DCs in response to LPS, and triggers an antibacterial innate immune response, thus proposing possible mechanisms for the clinical effects of Chan-Su in anti-infective therapy. PMID:27529866

  12. Modulating Human Auditory Processing by Transcranial Electrical Stimulation

    PubMed Central

    Heimrath, Kai; Fiene, Marina; Rufener, Katharina S.; Zaehle, Tino

    2016-01-01

    Transcranial electrical stimulation (tES) has become a valuable research tool for the investigation of neurophysiological processes underlying human action and cognition. In recent years, striking evidence for the neuromodulatory effects of transcranial direct current stimulation, transcranial alternating current stimulation, and transcranial random noise stimulation has emerged. While the wealth of knowledge has been gained about tES in the motor domain and, to a lesser extent, about its ability to modulate human cognition, surprisingly little is known about its impact on perceptual processing, particularly in the auditory domain. Moreover, while only a few studies systematically investigated the impact of auditory tES, it has already been applied in a large number of clinical trials, leading to a remarkable imbalance between basic and clinical research on auditory tES. Here, we review the state of the art of tES application in the auditory domain focussing on the impact of neuromodulation on acoustic perception and its potential for clinical application in the treatment of auditory related disorders. PMID:27013969

  13. An adjuvant-modulated vaccine response in human whole blood.

    PubMed

    Hakimi, Jalil; Azizi, Ali; Ausar, Salvador F; Todryk, Stephen M; Rahman, Nausheen; Brookes, Roger H

    2017-09-02

    The restimulation of an immune memory response by in vitro culture of blood cells with a specific antigen has been used as a way to gauge immunity to vaccines for decades. In this commentary we discuss a less appreciated application to support vaccine process development. We report that human whole blood from pre-primed subjects can generate a profound adjuvant-modulated, antigen-specific response to several different vaccine formulations. The response is able to differentiate subtle changes in the quality of an immune memory response to vaccine formulations and can be used to select optimal conditions relating to a particular manufacture process step. While questions relating to closeness to in vivo vaccination remain, the approach is another big step nearer to the more relevant human response. It has special importance for new adjuvant development, complementing other preclinical in vivo and in vitro approaches to considerably de-risk progression of novel vaccines before and throughout early clinical development. Broader implications of the approach are discussed.

  14. Cranial nerve modulation of human cortical swallowing motor pathways.

    PubMed

    Hamdy, S; Aziz, Q; Rothwell, J C; Hobson, A; Barlow, J; Thompson, D G

    1997-04-01

    Animal data indicate that cortical swallowing pathways can be modulated by cranial nerve afferent stimulation. We therefore studied the effects of human trigeminal and vagal nerve excitation on the corticofugal pathways to the oropharynx and esophagus, using electromagnetic stimulation. Unilateral stimulation of either the trigeminal or vagus nerve evoked two distinct reflex electromyographic responses in the pharynx and esophagus, an early response (latency range 19-30 ms) and a late response (latency range 42-72 ms). In the mylohyoid muscles, however, only a single response was seen (latency range 36-64 ms). Cortical stimulation also evoked electromyographic responses in the mylohyoid muscles, pharynx, and esophagus, with latencies of 8.5 +/- 0.3, 9.3 +/- 0.3, and 10.1 +/- 0.4 ms, respectively. When either trigeminal or vagus nerve stimulation preceded cortical stimulation, the cortically evoked responses were facilitated, with maximal effects at interstimulation intervals of 30-200 ms for pharynx and esophagus (P < 0.02) and at interstimulation intervals of 50-100 ms for mylohyoid muscles (P < 0.05). Our results demonstrate that stimulation of human cranial nerve afferent fibers facilitates cortical swallowing motor pathways.

  15. Co-regulated gene expression by oestrogen receptor α and liver receptor homolog-1 is a feature of the oestrogen response in breast cancer cells.

    PubMed

    Lai, Chun-Fui; Flach, Koen D; Alexi, Xanthippi; Fox, Stephen P; Ottaviani, Silvia; Thiruchelvam, Paul T R; Kyle, Fiona J; Thomas, Ross S; Launchbury, Rosalind; Hua, Hui; Callaghan, Holly B; Carroll, Jason S; Charles Coombes, R; Zwart, Wilbert; Buluwela, Laki; Ali, Simak

    2013-12-01

    Oestrogen receptor α (ERα) is a nuclear receptor that is the driving transcription factor expressed in the majority of breast cancers. Recent studies have demonstrated that the liver receptor homolog-1 (LRH-1), another nuclear receptor, regulates breast cancer cell proliferation and promotes motility and invasion. To determine the mechanisms of LRH-1 action in breast cancer, we performed gene expression microarray analysis following RNA interference for LRH-1. Interestingly, gene ontology (GO) category enrichment analysis of LRH-1-regulated genes identified oestrogen-responsive genes as the most highly enriched GO categories. Remarkably, chromatin immunoprecipitation coupled to massively parallel sequencing (ChIP-seq) to identify genomic targets of LRH-1 showed LRH-1 binding at many ERα binding sites. Analysis of select binding sites confirmed regulation of ERα-regulated genes by LRH-1 through binding to oestrogen response elements, as exemplified by the TFF1/pS2 gene. Finally, LRH-1 overexpression stimulated ERα recruitment, while LRH-1 knockdown reduced ERα recruitment to ERα binding sites. Taken together, our findings establish a key role for LRH-1 in the regulation of ERα target genes in breast cancer cells and identify a mechanism in which co-operative binding of LRH-1 and ERα at oestrogen response elements controls the expression of oestrogen-responsive genes.

  16. Human protein status modulates brain reward responses to food cues.

    PubMed

    Griffioen-Roose, Sanne; Smeets, Paul Am; van den Heuvel, Emmy; Boesveldt, Sanne; Finlayson, Graham; de Graaf, Cees

    2014-07-01

    Protein is indispensable in the human diet, and its intake appears tightly regulated. The role of sensory attributes of foods in protein intake regulation is far from clear. We investigated the effect of human protein status on neural responses to different food cues with the use of functional magnetic resonance imaging (fMRI). The food cues varied by taste category (sweet compared with savory) and protein content (low compared with high). In addition, food preferences and intakes were measured. We used a randomized crossover design whereby 23 healthy women [mean ± SD age: 22 ± 2 y; mean ± SD body mass index (in kg/m(2)): 22.5 ± 1.8] followed two 16-d fully controlled dietary interventions involving consumption of either a low-protein diet (0.6 g protein · kg body weight(-1) · d(-1), ~7% of energy derived from protein, approximately half the normal protein intake) or a high-protein diet (2.2 g protein · kg body weight(-1) · d(-1), ~25% of energy, approximately twice the normal intake). On the last day of the interventions, blood oxygen level-dependent (BOLD) responses to odor and visual food cues were measured by using fMRI. The 2 interventions were followed by a 1-d ad libitum phase, during which a large array of food items was available and preference and intake were measured. When exposed to food cues (relative to the control condition), the BOLD response was higher in reward-related areas (orbitofrontal cortex, striatum) in a low-protein state than in a high-protein state. Specifically, BOLD was higher in the inferior orbitofrontal cortex in response to savory food cues. In contrast, the protein content of the food cues did not modulate the BOLD response. A low protein state also increased preferences for savory food cues and increased protein intake in the ad libitum phase as compared with a high-protein state. Protein status modulates brain responses in reward regions to savory food cues. These novel findings suggest that dietary protein status

  17. Effects of dexmedetomidine on conditioned pain modulation in humans.

    PubMed

    Baba, Y; Kohase, H; Oono, Y; Fujii-Abe, K; Arendt-Nielsen, L

    2012-09-01

    Systemic administration of dexmedetomidine (DEX; selective α(2) -adrenoceptor agonist) is found to inhibit diffuse noxious inhibitory control in rats, now referred to as conditioned pain modulation (CPM) in humans. The present study was designed to investigate the effect of intravenous administration of DEX on CPM in humans. There were two sequential sessions in this double blind, randomized study. The first session was the control with normal saline infusion (N(1st), L(1st), H(1st)). During the second session, three types of agents were infused: normal saline (N(2nd)); a low plasma concentration of DEX (0.04 ng/mL; L(2nd)); and a high plasma concentration of DEX (0.08 ng/mL; H(2nd)). The amplitude of somatosensory evoked potentials (ampSEP)s and the visual analogue scale of tooth pain (VASt) induced by electrical tooth stimulation were evaluated with and without conditioning CO(2) laser stimulation of the hand. The inhibition rate (% inhibition) was calculated [= (1-[ampSEP or VASt with conditioning stimuli]/[ampSEP or VASt without conditioning stimuli]) × 100] to compare the magnitude of the DEX effects on CPM. The inhibition rates of ampSEPs and VASt in Types N, L and H varied significantly, demonstrating a dose-dependent reduction of CPM effects of ampSEP and VASt during randomized DEX administration, consistent with results from animal studies. The present study shows that systemic administration of an α(2) -adrenoceptor agonist (DEX), less than the clinical dose, inhibited CPM in humans. These results may provide some mechanistic insight into why many chronic pain patients show impaired CPM. © 2012 European Federation of International Association for the Study of Pain Chapters.

  18. Transillumination spatially modulated illumination microscopy for human chromosome imaging

    NASA Astrophysics Data System (ADS)

    Pitris, Costas; Heracleous, Peter; Patsalis, Philippos

    2005-03-01

    Human chromosome analysis is an essential task in cytogenetics, especially in prenatal screening, genetic syndrome diagnosis, cancer pathology research and mutagen dosimetry. Chromosomal analysis begins with the creation of a karyotype, which is a layout of chromosome images organized by decreasing size in pairs. Both manual and automatic classification of chromosomes are limited by the resolution of the microscope and imaging system used. One way to improve the results of classification and even detect subtleties now remaining undetected, is to enhance the resolution of the images. It is possible to achieve lateral resolution beyond the classical limit, by using spatially modulated illumination (SMI) in a wide-field, non-confocal microscope. In this case, the sample is illuminated with spatially modulated light, which makes normally inaccessible high-resolution information visible in the observed image by shifting higher frequencies within the OTF limits of the microscope. Although, SMI microscopes have been reported in the past, this manuscript reports the development of a transillumination microscope for opaque, non-fluorescent samples. The illumination path consisted of a light source illuminating a ruled grating which was subsequently imaged on the sample. The grating was mounted on a rotating and translating stage so that the magnification and rotation of the pattern could be adjusted. The imaging lens was a 1.25 NA oil immersion objective. Test samples showed resolution improvement, as judged from a comparison of the experimentally obtained FWHM. Further studies using smaller fringe distance or laser interference pattern illumination will be evaluated to further optimize the SMI results.

  19. Endocannabinoids modulate human blood-brain barrier permeability in vitro.

    PubMed

    Hind, William H; Tufarelli, Cristina; Neophytou, Maria; Anderson, Susan I; England, Timothy J; O'Sullivan, Saoirse E

    2015-06-01

    Endocannabinoids alter permeability at various epithelial barriers, and cannabinoid receptors and endocannabinoid levels are elevated by stroke, with potential neuroprotective effects. We therefore explored the role of endocannabinoids in modulating blood-brain barrier (BBB) permeability in normal conditions and in an ischaemia/reperfusion model. Human brain microvascular endothelial cell and astrocyte co-cultures modelled the BBB. Ischaemia was modelled by oxygen-glucose deprivation (OGD) and permeability was measured by transepithelial electrical resistance. Endocannabinoids or endocannabinoid-like compounds were assessed for their ability to modulate baseline permeability or OGD-induced hyperpermeability. Target sites of action were investigated using receptor antagonists and subsequently identified with real-time PCR. Anandamide (10 μM) and oleoylethanolamide (OEA, 10 μM) decreased BBB permeability (i.e. increased resistance). This was mediated by cannabinoid CB2 receptors, transient receptor potential vanilloid 1 (TRPV1) channels, calcitonin gene-regulated peptide (CGRP) receptor (anandamide only) and PPARα (OEA only). Application of OEA, palmitoylethanolamide (both PPARα mediated) or virodhamine (all 10 μM) decreased the OGD-induced increase in permeability during reperfusion. 2-Arachidonoyl glycerol, noladin ether and oleamide did not affect BBB permeability in normal or OGD conditions. N-arachidonoyl-dopamine increased permeability through a cytotoxic mechanism. PPARα and γ, CB1 receptors, TRPV1 channels and CGRP receptors were expressed in both cell types, but mRNA for CB2 receptors was only present in astrocytes. The endocannabinoids may play an important modulatory role in normal BBB physiology, and also afford protection to the BBB during ischaemic stroke, through a number of target sites. © 2015 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of The British Pharmacological Society.

  20. Novel female sex-dependent actions of oestrogen in the intestine.

    PubMed

    O'Mahony, Fiona; Thomas, Warren; Harvey, Brian J

    2009-11-01

    The intestine is an oestrogen responsive organ and circulatory oestrogens suppress Cl(-) secretion across the epithelium of the colon to promote fluid retention at the luteal stage of the menstrual cycle. Ion transporters in the colon which are involved in Cl(-) secretion show differential expression between males and females as do the signalling protein kinase intermediates involved in acutely regulating these transporters. Work from our laboratory has identified the KCNQ1/KCNE3 channel as one of the principal targets for oestrogen-induced signalling cascades in the distal colon. Through inhibition of the KCNQ1 channel, basolateral K(+) recycling is decreased so reducing the favourable electrochemical gradient for Cl(-) extrusion at the apical membrane. The actions of oestrogen on non-reproductive tissues such as the colon, kidney, lung and sweat gland will affect whole body electrolyte and fluid homeostasis and also have consequences for reproductive potential.

  1. Screening for oestrogenic activity of plant and food extracts using in vitro trout hepatocyte cultures.

    PubMed

    Bennetau-Pelissero, C; Latonnelle, K Gontier; Lamothe, V; Shinkaruk-Poix, S; Kaushik, S J

    2004-01-01

    The use of in vitro trout hepatocyte cultures is shown to provide a simple and effective way to screen plant and food products for oestrogenic activity. The relative oestrogenic activities of 0.1 g each of extracts of phytosterol, soy isoflavone, red clover, kudzu and soybean extracts were determined using this assay and found to be equivalent to 212, 1, 3.2, 132 and 1025 nM of 17beta-estradiol, respectively. Controls were performed on soybean and kudzu extracts using specific ELISAs for isoflavones and these confirmed the validity of the cell culture assay. The method described offers an advantage over current methods in that it can detect increased oestrogenic activity that may occur as a result of metabolic activation of pre- or pro-oestrogens liver cells.

  2. Reminder Cues Modulate the Renewal Effect in Human Predictive Learning

    PubMed Central

    Bustamante, Javier; Uengoer, Metin; Lachnit, Harald

    2016-01-01

    Associative learning refers to our ability to learn about regularities in our environment. When a stimulus is repeatedly followed by a specific outcome, we learn to expect the outcome in the presence of the stimulus. We are also able to modify established expectations in the face of disconfirming information (the stimulus is no longer followed by the outcome). Both the change of environmental regularities and the related processes of adaptation are referred to as extinction. However, extinction does not erase the initially acquired expectations. For instance, following successful extinction, the initially learned expectations can recover when there is a context change – a phenomenon called the renewal effect, which is considered as a model for relapse after exposure therapy. Renewal was found to be modulated by reminder cues of acquisition and extinction. However, the mechanisms underlying the effectiveness of reminder cues are not well understood. The aim of the present study was to investigate the impact of reminder cues on renewal in the field of human predictive learning. Experiment I demonstrated that renewal in human predictive learning is modulated by cues related to acquisition or extinction. Initially, participants received pairings of a stimulus and an outcome in one context. These stimulus-outcome pairings were preceded by presentations of a reminder cue (acquisition cue). Then, participants received extinction in a different context in which presentations of the stimulus were no longer followed by the outcome. These extinction trials were preceded by a second reminder cue (extinction cue). During a final phase conducted in a third context, participants showed stronger expectations of the outcome in the presence of the stimulus when testing was accompanied by the acquisition cue compared to the extinction cue. Experiment II tested an explanation of the reminder cue effect in terms of simple cue-outcome associations. Therefore, acquisition and

  3. Oestrogen and progesterone concentrations in peripheral blood in pregnant red foxes (Vulpes vulpes).

    PubMed

    Bonnin, M; Mondain-Monval, M; Dutourné, B

    1978-09-01

    Oestrogen levels were low during most of gestation, but there was a significant increase (P less than 0.05) in oestradiol concentrations at implantation. Early pregnancy was characterized by high levels of progesterone which decreased significantly (P less than 0.001) thereafter, but there was no decline in progesterone or rise in oestrogen levels at parturition. There was no difference in the length of progesterone secretion between pregnant and non-pregnant females.

  4. Oestrogens and temperature-dependent sex determination in reptiles: all is in the gonads.

    PubMed

    Pieau, C; Dorizzi, M

    2004-06-01

    In many species of oviparous reptiles, the first steps of gonadal sex differentiation depend on the incubation temperature of the eggs. Feminization of gonads by exogenous oestrogens at a male-producing temperature and masculinization of gonads by antioestrogens and aromatase inhibitors at a female-producing temperature have irrefutably demonstrated the involvement of oestrogens in ovarian differentiation. Nevertheless, several studies performed on the entire gonad/adrenal/mesonephros complex failed to find differences between male- and female-producing temperatures in oestrogen content, aromatase activity and aromatase gene expression during the thermosensitive period for sex determination. Thus, the key role of aromatase and oestrogens in the first steps of ovarian differentiation has been questioned, and extragonadal organs or tissues, such as adrenal, mesonephros, brain or yolk, were considered as possible targets of temperature and sources of the oestrogens acting on gonadal sex differentiation. In disagreement with this view, experiments and assays carried out on the gonads alone, i.e. separated from the adrenal/mesonephros, provide evidence that the gonads themselves respond to temperature shifts by modifying their sexual differentiation and are the site of aromatase activity and oestrogen synthesis during the thermosensitive period. Oestrogens act locally on both the cortical and the medullary part of the gonad to direct ovarian differentiation. We have concluded that there is no objective reason to search for the implication of other organs in the phenomenon of temperature-dependent sex determination in reptiles. From the comparison with data obtained in other vertebrates, we propose two main directions for future research: to examine how transcription of the aromatase gene is regulated and to identify molecular and cellular targets of oestrogens in gonads during sex differentiation, in species with strict genotypic sex determination and species with

  5. Different forms of oestrogen rapidly upregulate cell proliferation in the dentate gyrus of adult female rats.

    PubMed

    Barha, C K; Lieblich, S E; Galea, L A M

    2009-03-01

    Oestrogens are known to exert significant structural and functional effects in the hippocampus of adult rodents. The dentate gyrus of the hippocampus retains the ability to produce neurones throughout adulthood and 17beta-oestradiol has been shown to influence hippocampal neurogenesis in adult female rats. The effects of other oestrogens, such as oestrone and 17alpha-oestradiol, on neurogenesis have not been investigated. The present study aimed to investigate the effects of 17beta-oestradiol, oestradiol benzoate, oestrone, and 17alpha-oestradiol on cell proliferation in ovariectomised adult female rats at two different time points. Young ovariectomised female rats were injected with one of the oestrogens at one of three doses. In Experiment 1, rats were exposed to the hormone for 4 h and, in Experiment 2, rats were exposed to the hormone for 30 min prior to 5-bromo-2-deoxyuridine injection to label proliferating cells and their progeny. We found that young ovariectomised females responded with increased cell proliferation to most oestrogens, except oestradiol benzoate, after 30 min of exposure. However, administration of oestrogens for a longer time interval was ineffective at increasing cell proliferation. After 30 min, 17beta-oestradiol and oestrone increased cell proliferation at low (0.3 microg) and high (10 microg) doses, whereas 17alpha-oestradiol increased cell proliferation at medium (1 microg) and high doses. The results of the present study indicate that different oestrogens rapidly increase cell proliferation in a dose-dependent manner, possibly through a nonclassical, nongenomic mechanism. Future experiments should focus on further elucidating the specific pathways utilised by each oestrogen. These results have important therapeutic implications because it may be possible to use 17alpha-oestradiol and lower doses of oestrogens in hormone replacement therapies.

  6. On the existence in human auditory pathways of channels selectively tuned to the modulation present in frequency-modulated tones

    PubMed Central

    Kay, R. H.; Matthews, D. R.

    1972-01-01

    amplitude modulation in a tone is conditioned by prior exposure to either amplitude- or frequency-modulated tones, in contrast the detectability of 8/sec frequency-modulated signals is conditioned only by prior exposure to frequency-modulated tones and not by amplitude-modulated conditioning tones. This underlines the special place of frequency modulation in human audition and emphasizes that the operative stimulus cannot be some aspect common to amplitude modulation and frequency modulation, like identical periodicity or coincident positioning of bands in the integrated spectra of the tones, but points to the instantaneous frequency-modulated wave form as the adequate stimulus. 8. These findings strongly suggest that the human auditory pathways contain `channels' in their organization which determine a final response selectively tuned to particular frequency-modulations. Periodicity coding alone cannot adequately explain this effect which may well only be understood in terms of a `place' theory of frequency selectivity. 9. This organization is well suited to subserve the recognition of frequency-modulation patterns in acoustic signals rather independently of the mean audiofrequency that carries the frequency modulation. PMID:5076392

  7. Acquired resistance to oestrogen deprivation: role for growth factor signalling kinases/oestrogen receptor cross-talk revealed in new MCF-7X model.

    PubMed

    Staka, Cindy M; Nicholson, Robert I; Gee, Julia M W

    2005-07-01

    In vitro models of long-term oestrogen deprivation utilise increased oestrogen receptor (ER) and are oestrogen hypersensitive, with emerging evidence that growth factor signalling contributes and interacts with ER. However, such models are commonly derived in the presence of serum growth factors that may force the resistance mechanism. Our new in vitro model, MCF-7X, has thus been developed under conditions of both oestrogen and growth factor depletion. ER expression, serine 118 phosphorylation on this receptor and its transcriptional activity were modestly increased compared to the parental MCF-7 cells, although MCF-7X cells were not oestrogen hypersensitive. Faslodex (0.1 microM) partially decreased ER and its transcriptional activity, with associated decreases in serine 118 phosphorylation. Faslodex inhibited MCF-7X growth by 50% for 10 weeks. Classical growth factor receptors did not impact on MCF-7X growth and only a modest contribution for MAP kinase was revealed using PD98059 (25 microM; 35% inhibition for 3 weeks). However, the phosphatidylinositol-3-OH (PI3)-kinase inhibitor LY294002 (5 microM) inhibited MCF-7X growth by 65% for 10 weeks. In contrast to PD98059, LY294002 also partially-inhibited ER transcriptional activity and decreased serine 167 ER phosphorylation. Co-treatment with faslodex plus LY294002 to decrease activity of both serine 118 and 167 proved superior vs the single agents in decreasing ER transcriptional activity and MCF-7X growth (90% inhibition for 25 weeks). However, triple treatment including PD98059 was required to prevent resistance in MCF-7X, an event dependent on maximal depletion of serine 118 phosphorylation and ER transcriptional activity. Kinases clearly contribute in resistance to oestrogen deprivation, cross-talking with ER signalling via AF-1 phosphorylation. While inhibiting each pathway has potential to treat this state, combined therapy targeting all regulators of ER phosphorylation may be required to block subsequent

  8. Nanostructured lipid carriers loaded with resveratrol modulate human dendritic cells

    PubMed Central

    Barbosa, João P; Neves, Ana R; Silva, Andreia M; Barbosa, Mário A; Reis, M Salette; Santos, Susana G

    2016-01-01

    needed to promote a similar effect. Taken together, the results presented show that NLC are suitable carriers of fluorescent labels or bioactive molecules for human DCs, leading to inflammation modulation. PMID:27555771

  9. Deep vein thrombosis and the oestrogen content in oral contraceptives. An epidemiological analysis.

    PubMed

    Kierkegaard, A

    1985-01-01

    Epidemiological studies have pointed to a correlation between the oestrogen content of oral contraceptives and the risk of deep vein thrombosis (DVT). The correlation has been strongest in studies which partially consisted of adverse drug reaction reports to the Swedish Adverse Drug Reaction Advisory Committee (SADRAC). The present study analyzes the epidemiological basis of the adverse drug reaction reports on DVT in women on oral contraceptives to SADRAC. It verifies the reported correlation between the oestrogen content of the pills and the risk of DVT but it also demonstrates that this correlation probably was secondary to differences in the diagnostic standard of DVT, to differences in reporting policies to SADRAC and to an age difference between women on low-oestrogen-pills and those on high-oestrogen pills and is thus due to bias. It is concluded that adverse drug reaction reporting on oral contraceptives has been very unreliable, for which reason it cannot support any epidemiological conclusion concerning the relative thrombogenicity of high-oestrogen pills compared with that of low-oestrogen pills.

  10. Modulation of fibronectin gene expression in human mononuclear phagocytes.

    PubMed Central

    Yamauchi, K; Martinet, Y; Crystal, R G

    1987-01-01

    Under some conditions, mononuclear phagocytes spontaneously synthesize and release fibronectin, an extracellular matrix glycoprotein with versatile effects on cell-matrix interactions. To gain insight into the processes that modulate the level of fibronectin secretion by these cells, we used monocytes, in vitro matured monocytes and alveolar macrophages as models to compare fibronectin mRNA levels and fibronectin secretion in a variety of circumstances. Using Northern analysis and dot-blot analysis with a 32P-labeled human fibronectin cDNA probe, we evaluated steady-state mRNA levels and a human fibronectin-specific ELISA was used to evaluate fibronectin secretion. In all cases the amounts of fibronectin secreted paralleled fibronectin mRNA levels. Specifically (a) when fibronectin mRNA was undetectable, as in the case of normal blood monocytes, no fibronectin was secreted, but whenever fibronectin mRNA was present, as in normal alveolar macrophages, fibronectin was secreted by the cells; (b) as monocytes matured into macrophages in vitro, the cells began to express fibronectin mRNA and the cells secreted fibronectin; (c) when alveolar macrophages were activated with surface stimuli such as lipopolysaccharide (LPS) or immune complexes, fibronectin mRNA levels decreased and in parallel, the cells secreted less fibronectin; (d) in idiopathic pulmonary fibrosis (IPF), alveolar macrophages contained severalfold more fibronectin mRNA transcripts that normal and the cells spontaneously secreted severalfold more fibronectin than normal; and (e) when IPF alveolar macrophages were placed in culture the fibronectin mRNA levels in the cells decreased with time, and concurrently the amounts of fibronectin produced per unit time continually decreased. The observation of a strict concordance of fibronectin mRNA levels and fibronectin release by mononuclear phagocytes suggests that, at least in many circumstances, fibronectin secretion by mononuclear phagocytes is controlled by

  11. Human Decidual Stromal Cells as a Component of the Implantation Niche and a Modulator of Maternal Immunity

    PubMed Central

    Vinketova, Kameliya; Mourdjeva, Milena

    2016-01-01

    The human decidua is a specialized tissue characterized by embryo-receptive properties. It is formed during the secretory phase of menstrual cycle from uterine mucosa termed endometrium. The decidua is composed of glands, immune cells, blood and lymph vessels, and decidual stromal cells (DSCs). In the process of decidualization, which is controlled by oestrogen and progesterone, DSCs acquire specific functions related to recognition, selection, and acceptance of the allogeneic embryo, as well as to development of maternal immune tolerance. In this review we discuss the relationship between the decidualization of DSCs and pathological obstetrical and gynaecological conditions. Moreover, the critical influence of DSCs on local immune cells populations as well as their relationship to the onset and maintenance of immune tolerance is described. PMID:27239344

  12. Mechanisms of Nicotinic Modulation of Glutamatergic Neuroplasticity in Humans.

    PubMed

    Lugon, Marcelo Di Marcello Valladão; Batsikadze, Giorgi; Fresnoza, Shane; Grundey, Jessica; Kuo, Min-Fang; Paulus, Walter; Nakamura-Palacios, Ester Miyuki; Nitsche, Michael A

    2015-10-22

    The impact of nicotine (NIC) on plasticity is thought to be primarily determined via calcium channel properties of nicotinic receptor subtypes, and glutamatergic plasticity is likewise calcium-dependent. Therefore glutamatergic plasticity is likely modulated by the impact of nicotinic receptor-dependent neuronal calcium influx. We tested this hypothesis for transcranial direct current stimulation (tDCS)-induced long-term potentiation-like plasticity, which is abolished by NIC in nonsmokers. To reduce calcium influx under NIC, we blocked N-methyl-d-aspartate (NMDA) receptors. We applied anodal tDCS combined with 15 mg NIC patches and the NMDA-receptor antagonist dextromethorphan (DMO) in 3 different doses (50, 100, and 150 mg) or placebo medication. Corticospinal excitability was monitored by single-pulse transcranial magnetic stimulation-induced motor-evoked potential amplitudes after plasticity induction. NIC abolished anodal tDCS-induced motor cortex excitability enhancement, which was restituted under medium dosage of DMO. Low-dosage DMO did not affect the impact of NIC on tDCS-induced plasticity and high-dosage DMO abolished plasticity. For DMO alone, the low dosage had no effect, but medium and high dosages abolished tDCS-induced plasticity. These results enhance our knowledge about the proposed calcium-dependent impact of NIC on plasticity in humans and might be relevant for the development of novel nicotinic treatments for cognitive dysfunction.

  13. A human phospholipid phosphatase activated by a transmembrane control module.

    PubMed

    Halaszovich, Christian R; Leitner, Michael G; Mavrantoni, Angeliki; Le, Audrey; Frezza, Ludivine; Feuer, Anja; Schreiber, Daniela N; Villalba-Galea, Carlos A; Oliver, Dominik

    2012-11-01

    In voltage-sensitive phosphatases (VSPs), a transmembrane voltage sensor domain (VSD) controls an intracellular phosphoinositide phosphatase domain, thereby enabling immediate initiation of intracellular signals by membrane depolarization. The existence of such a mechanism in mammals has remained elusive, despite the presence of VSP-homologous proteins in mammalian cells, in particular in sperm precursor cells. Here we demonstrate activation of a human VSP (hVSP1/TPIP) by an intramolecular switch. By engineering a chimeric hVSP1 with enhanced plasma membrane targeting containing the VSD of a prototypic invertebrate VSP, we show that hVSP1 is a phosphoinositide-5-phosphatase whose predominant substrate is PI(4,5)P(2). In the chimera, enzymatic activity is controlled by membrane potential via hVSP1's endogenous phosphoinositide binding motif. These findings suggest that the endogenous VSD of hVSP1 is a control module that initiates signaling through the phosphatase domain and indicate a role for VSP-mediated phosphoinositide signaling in mammals.

  14. Dietary modulation of the human gut microflora using prebiotics.

    PubMed

    Gibson, G R

    1998-10-01

    The human colonic flora has both beneficial and pathogenic potentials with respect to host health. There is now much interest in manipulation of the microbiota composition in order to improve the potentially beneficial aspects. The prebiotic approach dictates that non-viable food components are specifically fermented in the colon by indigenous bacteria thought to be of positive value, e.g. bifidobacteria, lactobacilli. Any food ingredient that enters the large intestine is a candidate prebiotic. However, to be effective, selectivity of the fermentation is essential. Most current attention and success has been derived using non-digestible oligosaccharides. Types primarily being looked at include those which contain fructose, xylose, soya, galactose, glucose and mannose. In particular, fructose-containing oligosaccharides, which occur naturally in a variety of plants such as onion, asparagus, chicory, banana and artichoke, fulfil the prebiotic criteria. Various data have shown that fructo-oligosaccharides (FOS) are specifically fermented by bifidobacteria. During controlled feeding studies, ingestion of these prebiotics causes bifidobacteria to become numerically dominant in faeces. Recent studies have indicated that a FOS dose of 4 g/d is prebiotic. To exploit this concept more fully, there is a need for assessments of (a) improved determination of the gut microbiota composition and activity; (b) the use of molecular methodologies to assess accurately prebiotic identities and develop efficient bacterial probing strategies; (c) the prebiotic potential of raw and processed foods; and (d) the health consequences of dietary modulation.

  15. Calcium modulation of doxorubicin cytotoxicity in yeast and human cells.

    PubMed

    Nguyen, Thi Thuy Trang; Lim, Ying Jun; Fan, Melanie Hui Min; Jackson, Rebecca A; Lim, Kim Kiat; Ang, Wee Han; Ban, Kenneth Hon Kim; Chen, Ee Sin

    2016-03-01

    Doxorubicin is a widely used chemotherapeutic agent, but its utility is limited by cellular resistance and off-target effects. To understand the molecular mechanisms regulating chemotherapeutic responses to doxorubicin, we previously carried out a genomewide search of doxorubicin-resistance genes in Schizosaccharomyces pombe fission yeast and showed that these genes are organized into networks that counteract doxorubicin cytotoxicity. Here, we describe the identification of a subgroup of doxorubicin-resistance genes that, when disrupted, leads to reduced tolerance to exogenous calcium. Unexpectedly, we observed a suppressive effect of calcium on doxorubicin cytotoxicity, where concurrent calcium and doxorubicin treatment resulted in significantly higher cell survival compared with cells treated with doxorubicin alone. Conversely, inhibitors of voltage-gated calcium channels enhanced doxorubicin cytotoxicity in the mutants. Consistent with these observations in fission yeast, calcium also suppressed doxorubicin cytotoxicity in human breast cancer cells. Further epistasis analyses in yeast showed that this suppression of doxorubicin toxicity by calcium was synergistically dependent on Rav1 and Vph2, two regulators of vacuolar-ATPase assembly; this suggests potential modulation of the calcium-doxorubicin interaction by fluctuating proton concentrations within the cellular environment. Thus, the modulatory effects of drugs or diet on calcium concentrations should be considered in doxorubicin treatment regimes.

  16. Human colostrum oligosaccharides modulate major immunologic pathways of immature human intestine

    PubMed Central

    He, YingYing; Liu, ShuBai; Leone, Serena; Newburg, David S.

    2014-01-01

    The immature neonatal intestinal immune system hyperreacts to newly colonizing unfamiliar bacteria. The hypothesis that human milk oligosaccharides from colostrum (cHMOS) can directly modulate the signaling pathways of the immature mucosa was tested. Modulation of cytokine immune signaling by HMOS was measured ex vivo in intact immature (fetal) human intestinal mucosa. From the genes whose transcription was modulated by colostrum HMOS (cHMOS), Ingenuity Pathway Analysis identified networks controlling immune cell communication, intestinal mucosal immune system differentiation, and homeostasis. cHMOS attenuate pathogen-associated molecular pattern (PAMP)-stimulated acute phase inflammatory cytokine protein levels (IL-8, IL-6, MCP-1/2, IL-1β), while elevating cytokines involved in tissue repair and homeostasis. 3’-, 4-, and 6’-galactosyllactoses of cHMOS account for specific immunomodulation of PIC-induced IL-8 levels. cHMOS attenuate mucosal responses to surface inflammatory stimuli during early development, while enhancing signals that support maturation of the intestinal mucosal immune system. PMID:24691111

  17. Encoding of frequency-modulation (FM) rates in human auditory cortex

    PubMed Central

    Okamoto, Hidehiko; Kakigi, Ryusuke

    2015-01-01

    Frequency-modulated sounds play an important role in our daily social life. However, it currently remains unclear whether frequency modulation rates affect neural activity in the human auditory cortex. In the present study, using magnetoencephalography, we investigated the auditory evoked N1m and sustained field responses elicited by temporally repeated and superimposed frequency-modulated sweeps that were matched in the spectral domain, but differed in frequency modulation rates (1, 4, 16, and 64 octaves per sec). The results obtained demonstrated that the higher rate frequency-modulated sweeps elicited the smaller N1m and the larger sustained field responses. Frequency modulation rate had a significant impact on the human brain responses, thereby providing a key for disentangling a series of natural frequency-modulated sounds such as speech and music. PMID:26656920

  18. Encoding of frequency-modulation (FM) rates in human auditory cortex.

    PubMed

    Okamoto, Hidehiko; Kakigi, Ryusuke

    2015-12-14

    Frequency-modulated sounds play an important role in our daily social life. However, it currently remains unclear whether frequency modulation rates affect neural activity in the human auditory cortex. In the present study, using magnetoencephalography, we investigated the auditory evoked N1m and sustained field responses elicited by temporally repeated and superimposed frequency-modulated sweeps that were matched in the spectral domain, but differed in frequency modulation rates (1, 4, 16, and 64 octaves per sec). The results obtained demonstrated that the higher rate frequency-modulated sweeps elicited the smaller N1m and the larger sustained field responses. Frequency modulation rate had a significant impact on the human brain responses, thereby providing a key for disentangling a series of natural frequency-modulated sounds such as speech and music.

  19. Oestrogen signalling inhibits invasive phenotype by repressing RelB and its target BCL2.

    PubMed

    Wang, Xiaobo; Belguise, Karine; Kersual, Nathalie; Kirsch, Kathrin H; Mineva, Nora D; Galtier, Florence; Chalbos, Dany; Sonenshein, Gail E

    2007-04-01

    Aberrant constitutive expression of c-Rel, p65 and p50 NF-kappaB subunits has been reported in over 90% of breast cancers. Recently, we characterized a de novo RelB NF-kappaB subunit synthesis pathway, induced by the cytomegalovirus (CMV) IE1 protein, in which binding of p50-p65 NF-kappaB and c-Jun-Fra-2 AP-1 complexes to the RELB promoter work in synergy to potently activate transcription. Although RelB complexes were observed in mouse mammary tumours induced by either ectopic c-Rel expression or carcinogen exposure, little is known about RelB in human breast disease. Here, we demonstrate constitutive de novo RelB synthesis is selectively active in invasive oestrogen receptor alpha (ERalpha)-negative breast cancer cells. ERalpha signalling reduced levels of functional NF-kappaB and Fra-2 AP-1 and inhibited de novo RelB synthesis, leading to an inverse correlation between RELB and ERalpha gene expression in human breast cancer tissues and cell lines. Induction of Bcl-2 by RelB promoted the more invasive phenotype of ERalpha-negative cancer cells. Thus, inhibition of de novo RelB synthesis represents a new mechanism whereby ERalpha controls epithelial to mesenchymal transition (EMT).

  20. Exogenous oxytocin modulates human myometrial microRNAs.

    PubMed

    Cook, Joanna R; MacIntyre, David A; Samara, Eleni; Kim, Sung Hye; Singh, Natasha; Johnson, Mark R; Bennett, Phillip R; Terzidou, Vasso

    2015-07-01

    MicroRNAs (miRNAs) play a modulatory role in pathways that lead to labor onset, although oxytocin is known to modulate gene expression within the myometrium. We aimed to identify miRNAs whose expression is regulated by oxytocin in pregnant human myometrium. Myometrial miRNA expression profiles were compared between samples collected from women at term before the onset of labor (no labor; n = 8) and after labor onset after early exogenous oxytocin treatment (n = 8). Multivariate modelling was used to assess differences in miRNA profiles. Biologic validation was undertaken on 3 independent patient cohorts (no labor, n = 10; labor induced with oxytocin, n = 8; and spontaneous labor with no oxytocin treatment, n = 10). In vitro studies that used primary myocytes were undertaken to assess target miRNA expression after oxytocin treatment. Target genes of candidate miRNAs were identified in silico and cross-referenced with genes that are known to be associated with labor or expressed in myometrium. In total, 1309 miRNAs were analyzed by microarray, of which 494 were detected in human myometrium. Multivariate modeling identified 12 target miRNAs the differential expression of which was most responsible for the observed separation of the 2 patient populations in the primary discovery cohorts. Biologic validation in the independent secondary sample cohorts showed that oxytocin independently regulated 5 miRNAs (hsa-miR-146b-3p, hsa-miR-196b-3p, hsa-miR-223-3p, hsa-miR-873-5p, and hsa-miR-876-5p). Additionally, hsa-miR-146b-3p was increased both in labor that was induced with oxytocin and in myometrium from spontaneous labor with no oxytocin treatment compared with no labor samples. Four of the validated miRNAs (hsa-miR-146a-5p, hsa-miR-146b-3p, hsa-miR-196b-3p, and hsa-miR-876-5p) were expressed in primary human myocytes; oxytocin treatment of these cells replicated the directional changes that were observed in vivo. Oxytocin alters the expression of a unique set of

  1. Human platelet Fc (IgG) receptor and its modulation

    SciTech Connect

    King, M.; McDermott, P.; Schreiber, A.D.

    1986-03-01

    The authors demonstrated that IgG oligomers bind to washed human platelets (P) by an Fc dependent process optimally at low ionic strength (/sup +/0.07) in 3 hrs at 4/sup 0/, while IgG monomer binds immeasurably. The authors studied the modulation of this Fc (IgG) binding site (Rc) on P by measuring /sup 125/I-IgG trimer binding to P at equilibrium and assessing Rc number of affinity. At ..mu.. = 0.07, P expressed 2 fold more Rc than at ..mu.. = 0.15, without a change in affinity; this effect was reversed upon re-exposure of P to ionic strength ..mu.. = 0.15. Equal numbers and affinities of Rc were observed in the presence of either 2mM EDTA, 2 mM EGTA or 2 mM EGTA + 2 mM Mg/sup + +/. Cytochalasin B (10 ..mu..g/ml) did not alter Rc (4987 sites/P, Ka = 0.9 x 10/sup 7/M/sup -1/ vs 5098 sites/P, Ka = 1.1 x 10/sup 7/M/sup -1/). Incubation with P alloreactive plasma at a concentration which depleted 33% of plasma C3, decreased Rc by 50%. However, activation of P by 10..mu..M ADP with Ca/sup + +/, Mg/sup + +/ and 100 ..mu..g/ml fibrinogen did not affect Rc number of affinity (2825 sites/P, Ka = 1.1 x 10/sup 7/M/sup -1/ vs 2551 sites/P, Ka = 0.9 x 10/sup 7/M/sup -1/). Thrombin (0.01 - 10 U/ml) also did not alter the number or affinity of Rc. P from 2 patients with thrombastenia expressed normal Rc number and affinity. Binding of IgG trimer to P occurs independent of actin filament interaction, Mg/sup + +/, modulation of P by ADP or thrombin, and of GPIIb/IIIa orGPIIb/IIIa-fibrogen interaction.

  2. Differential effect of oestrogen on post-exercise cardiac muscle myeloperoxidase and calpain activities in female rats.

    PubMed

    Tiidus, P M; Zajchowski, S; Enns, D; Holden, D; Bombardier, E; Belcastro, A N

    2002-02-01

    The effects of oestrogen administration on 1 h post-exercise cardiac muscle myeloperoxidase (MPO) and calpain activities were determined in female rats. Rats were ovariectomized and implanted for 2 weeks with either oestrogen (25 mg 17-oestradiol) or placebo pellets or left with ovaries intact. Rats were then run for 1 h at 21 m min-1, 12% grade, killed 1 h post-exercise and cardiac muscle and blood samples were removed. Control animals from each group were killed without prior exercise. Serum oestrogen levels in the order of the highest to lowest were; ovariectomized oestrogen replaced rats > intact ovaries rats > ovariectomized placebo rats. Oestrogen induced significant (P < 0.05) elevations in cardiac MPO activity at rest and at 1 h post-exercise in ovariectomized rats. No significant elevations in cardiac MPO activity were evident in placebo ovariectomized or normal ovary rats at rest or post-exercise. Cardiac calpain activities were similar in all unexercised groups. Ovariectomized placebo and intact ovary rats had significantly (P < 0.05) elevated cardiac calpain activities 1 h post-exercise while calpain activity was not significantly elevated in hearts from ovariectomized oestrogen rats. These results demonstrate that oestrogen supplementation in ovariectomized rats induces elevations in cardiac muscle MPO activities at rest and at 1 h post-exercise. This is opposite to the effect of oestrogen in post-exercise skeletal muscle and implies a greater neutrophil infiltration into cardiac muscle caused by oestrogen. This effect cannot be explained by changes in 1 h post-exercise cardiac muscle calpain activity, the elevation of which was suppressed by oestrogen administration. Oestrogen influences cardiac calpain activity similarly to its effect in skeletal muscle. Thus, oestrogen administration to ovariectomized rats induces elevations in cardiac MPO activity while suppressing cardiac calpain activity.

  3. The somatotropic axis may not modulate ageing and longevity in humans.

    PubMed

    Le Bourg, Éric

    2016-04-01

    Studies in nematodes and mice have shown that the somatotropic axis can modulate their longevity and it has been argued that it could also modulate human longevity. Thus, like nematodes and mice, human beings should live longer when facing starvation and genetic variation of the somatotropic axis should be linked to longevity. This article argues that, because the life-history strategies of humans are very different from those of mice, these hypotheses are not warranted.

  4. Modulation of human vestibular reflexes with increased postural threat.

    PubMed

    Horslen, Brian C; Dakin, Christopher J; Inglis, J Timothy; Blouin, Jean-Sébastien; Carpenter, Mark G

    2014-08-15

    Anxiety and arousal have been shown to facilitate human vestibulo-ocular reflexes, presumably through direct neural connections between the vestibular nuclei and emotional processing areas of the brain. However, the effects of anxiety, fear and arousal on balance-relevant vestibular reflexes are currently unknown. The purpose of this study was to manipulate standing height to determine whether anxiety and fear can modulate the direct relationship between vestibular signals and balance reflexes during stance. Stochastic vestibular stimulation (SVS; 2-25 Hz) was used to evoke ground reaction forces (GRF) while subjects stood in both LOW and HIGH surface height conditions. Two separate experiments were conducted to investigate the SVS-GRF relationship, in terms of coupling (coherence and cumulant density) and gain, in the medio-lateral (ML) and antero-posterior (AP) directions. The short- and medium-latency cumulant density peaks were both significantly increased in the ML and AP directions when standing in HIGH, compared to LOW, conditions. Likewise, coherence was statistically greater between 4.3 Hz and 6.7 Hz in the ML, and between 5.5 and 17.7 Hz in the AP direction. When standing in the HIGH condition, the gain of the SVS-GRF relationship was increased 81% in the ML direction, and 231% in the AP direction. The significant increases in coupling and gain observed in both experiments demonstrate that vestibular-evoked balance responses are augmented in states of height-induced postural threat. These data support the possibility that fear or anxiety-mediated changes to balance control are affected by altered central processing of vestibular information. © 2014 The Authors. The Journal of Physiology © 2014 The Physiological Society.

  5. Modulation of human vestibular reflexes with increased postural threat

    PubMed Central

    Horslen, Brian C; Dakin, Christopher J; Inglis, J Timothy; Blouin, Jean-Sébastien; Carpenter, Mark G

    2014-01-01

    Anxiety and arousal have been shown to facilitate human vestibulo-ocular reflexes, presumably through direct neural connections between the vestibular nuclei and emotional processing areas of the brain. However, the effects of anxiety, fear and arousal on balance-relevant vestibular reflexes are currently unknown. The purpose of this study was to manipulate standing height to determine whether anxiety and fear can modulate the direct relationship between vestibular signals and balance reflexes during stance. Stochastic vestibular stimulation (SVS; 2–25 Hz) was used to evoke ground reaction forces (GRF) while subjects stood in both LOW and HIGH surface height conditions. Two separate experiments were conducted to investigate the SVS–GRF relationship, in terms of coupling (coherence and cumulant density) and gain, in the medio-lateral (ML) and antero-posterior (AP) directions. The short- and medium-latency cumulant density peaks were both significantly increased in the ML and AP directions when standing in HIGH, compared to LOW, conditions. Likewise, coherence was statistically greater between 4.3 Hz and 6.7 Hz in the ML, and between 5.5 and 17.7 Hz in the AP direction. When standing in the HIGH condition, the gain of the SVS–GRF relationship was increased 81% in the ML direction, and 231% in the AP direction. The significant increases in coupling and gain observed in both experiments demonstrate that vestibular-evoked balance responses are augmented in states of height-induced postural threat. These data support the possibility that fear or anxiety-mediated changes to balance control are affected by altered central processing of vestibular information. PMID:24973412

  6. Protein Stability and Dynamics Modulation: The Case of Human Frataxin

    PubMed Central

    Gallo, Mariana; Salvay, Andres G.; Ferreiro, Diego U.; Santos, Javier

    2012-01-01

    Frataxin (FXN) is an α/β protein that plays an essential role in iron homeostasis. Apparently, the function of human FXN (hFXN) depends on the cooperative formation of crucial interactions between helix α1, helix α2, and the C-terminal region (CTR) of the protein. In this work we quantitatively explore these relationships using a purified recombinant fragment hFXN90–195. This variant shows the hydrodynamic behavior expected for a monomeric globular domain. Circular dichroism, fluorescence, and NMR spectroscopies show that hFXN90–195 presents native-like secondary and tertiary structure. However, chemical and temperature induced denaturation show that CTR truncation significantly destabilizes the overall hFXN fold. Accordingly, limited proteolysis experiments suggest that the native-state dynamics of hFXN90–195 and hFXN90–210 are indeed different, being the former form much more sensitive to the protease at specific sites. The overall folding dynamics of hFXN fold was further explored with structure-based protein folding simulations. These suggest that the native ensemble of hFXN can be decomposed in at least two substates, one with consolidation of the CTR and the other without consolidation of the CTR. Explicit-solvent all atom simulations identify some of the proteolytic target sites as flexible regions of the protein. We propose that the local unfolding of CTR may be a critical step for the global unfolding of hFXN, and that modulation of the CTR interactions may strongly affect hFXN physiological function. PMID:23049850

  7. Sarcoptes scabiei mites modulate gene expression in human skin equivalents.

    PubMed

    Morgan, Marjorie S; Arlian, Larry G; Markey, Michael P

    2013-01-01

    The ectoparasitic mite, Sarcoptes scabiei that burrows in the epidermis of mammalian skin has a long co-evolution with its hosts. Phenotypic studies show that the mites have the ability to modulate cytokine secretion and expression of cell adhesion molecules in cells of the skin and other cells of the innate and adaptive immune systems that may assist the mites to survive in the skin. The purpose of this study was to identify genes in keratinocytes and fibroblasts in human skin equivalents (HSEs) that changed expression in response to the burrowing of live scabies mites. Overall, of the more than 25,800 genes measured, 189 genes were up-regulated >2-fold in response to scabies mite burrowing while 152 genes were down-regulated to the same degree. HSEs differentially expressed large numbers of genes that were related to host protective responses including those involved in immune response, defense response, cytokine activity, taxis, response to other organisms, and cell adhesion. Genes for the expression of interleukin-1α (IL-1α) precursor, IL-1β, granulocyte/macrophage-colony stimulating factor (GM-CSF) precursor, and G-CSF precursor were up-regulated 2.8- to 7.4-fold, paralleling cytokine secretion profiles. A large number of genes involved in epithelium development and keratinization were also differentially expressed in response to live scabies mites. Thus, these skin cells are directly responding as expected in an inflammatory response to products of the mites and the disruption of the skin's protective barrier caused by burrowing. This suggests that in vivo the interplay among these skin cells and other cell types, including Langerhans cells, dendritic cells, lymphocytes and endothelial cells, is responsible for depressing the host's protective response allowing these mites to survive in the skin.

  8. Sarcoptes scabiei Mites Modulate Gene Expression in Human Skin Equivalents

    PubMed Central

    Morgan, Marjorie S.; Arlian, Larry G.; Markey, Michael P.

    2013-01-01

    The ectoparasitic mite, Sarcoptes scabiei that burrows in the epidermis of mammalian skin has a long co-evolution with its hosts. Phenotypic studies show that the mites have the ability to modulate cytokine secretion and expression of cell adhesion molecules in cells of the skin and other cells of the innate and adaptive immune systems that may assist the mites to survive in the skin. The purpose of this study was to identify genes in keratinocytes and fibroblasts in human skin equivalents (HSEs) that changed expression in response to the burrowing of live scabies mites. Overall, of the more than 25,800 genes measured, 189 genes were up-regulated >2-fold in response to scabies mite burrowing while 152 genes were down-regulated to the same degree. HSEs differentially expressed large numbers of genes that were related to host protective responses including those involved in immune response, defense response, cytokine activity, taxis, response to other organisms, and cell adhesion. Genes for the expression of interleukin-1α (IL-1α) precursor, IL-1β, granulocyte/macrophage-colony stimulating factor (GM-CSF) precursor, and G-CSF precursor were up-regulated 2.8- to 7.4-fold, paralleling cytokine secretion profiles. A large number of genes involved in epithelium development and keratinization were also differentially expressed in response to live scabies mites. Thus, these skin cells are directly responding as expected in an inflammatory response to products of the mites and the disruption of the skin’s protective barrier caused by burrowing. This suggests that in vivo the interplay among these skin cells and other cell types, including Langerhans cells, dendritic cells, lymphocytes and endothelial cells, is responsible for depressing the host’s protective response allowing these mites to survive in the skin. PMID:23940705

  9. Expression and modulation of CD44 variant isoforms in humans

    PubMed Central

    1994-01-01

    CD44 is a ubiquitous surface molecule that exists as a number of isoforms, generated by alternative splicing of 10 "variant" exons. Little is known about the expression and function of the variant isoforms, except that certain isoforms may play a role in cancer metastasis. We produced mAbs against CD44 variant regions encoded by exons 4v, 6v, and 9v, by immunizing mice with a fusion protein spanning variant exons 3v to 10v. A comprehensive analysis of human tissues revealed that CD44 variant isoforms were expressed widely throughout the body, principally by epithelial cells. However there was differential expression of CD44 variant exons by different epithelia. Most epithelia expressed exon 9v, but much fewer expressed 6v or 4v. The regions of epithelia that expressed the highest levels of the variant isoforms were the generative cells, particularly the basal cells of stratified squamous epithelium, and of glandular epithelium. CD44 variant isoforms were also expressed differentially by leukocytes, with CD44-9v expressed at very low levels and CD44-6v and 4v virtually absent. However, CD44-9v and CD44-6v were the main variants that were transiently upregulated on T cells after mitogenic stimulation and on myelomonocytic cell lines by TNF alpha and IFN gamma treatment. Some epithelial cell lines could preferentially upregulate CD44-6v upon IFN gamma incubation. These results show that CD44 variant isoforms are expressed much more widely than first appreciated, and that expression of the variant isoforms on some cell types can be modulated by particular cytokines. PMID:7507492

  10. Disease association and inter-connectivity analysis of human brain specific co-expressed functional modules.

    PubMed

    Oh, Kimin; Hwang, Taeho; Cha, Kihoon; Yi, Gwan-Su

    2015-12-16

    In the recent studies, it is suggested that the analysis of transcriptomic change of functional modules instead of individual genes would be more effective for system-wide identification of cellular functions. This could also provide a new possibility for the better understanding of difference between human and chimpanzee. In this study, we analyzed to find molecular characteristics of human brain functions from the difference of transcriptome between human and chimpanzee's brain using the functional module-centric co-expression analysis. We performed analysis of brain disease association and systems-level connectivity of species-specific co-expressed functional modules. Throughout the analyses, we found human-specific functional modules and significant overlap between their genes in known brain disease genes, suggesting that human brain disorder could be mediated by the perturbation of modular activities emerged in human brain specialization. In addition, the human-specific modules having neurobiological functions exhibited higher networking than other functional modules. This finding suggests that the expression of neural functions are more connected than other functions, and the resulting high-order brain functions could be identified as a result of consolidated inter-modular gene activities. Our result also showed that the functional module based transcriptome analysis has a potential to expand molecular understanding of high-order complex functions like cognitive abilities and brain disorders.

  11. The effects of oestrogens and their receptors on cardiometabolic health.

    PubMed

    Morselli, Eugenia; Santos, Roberta S; Criollo, Alfredo; Nelson, Michael D; Palmer, Biff F; Clegg, Deborah J

    2017-03-17

    Cardiovascular disease (CVD) is one of the leading causes of mortality in developed countries. The incidence of CVD is sexually dimorphic, and research has focused on the contribution of sex steroids to the development and progression of the cardiometabolic syndrome, which is defined as a clustering of interrelated risk factors that promote the development of atherosclerosis (which can lead to CVD) and type 2 diabetes mellitus. Data are inconclusive as to how sex steroids and their respective receptors increase or suppress the risk of developing the cardiometabolic syndrome and thus CVD. In this Review, we discuss the potential role, or roles, of sex hormones in cardiometabolic health by first focusing on the influence of oestrogens and their receptors on the risk of developing cardiometabolic syndrome and CVD. We also highlight what is known about testosterone and its potential role in protecting against the development of the cardiometabolic syndrome and CVD. Given the inconclusive nature of the data regarding the direct effects of each sex hormone, we advocate and highlight the importance of studying the relative levels and the ratio of sex hormones to each other, as well as the use of cross sex hormone therapy and its effect on cardiometabolic health.

  12. FGFR2 risk SNPs confer breast cancer risk by augmenting oestrogen responsiveness.

    PubMed

    Campbell, Thomas M; Castro, Mauro A A; de Santiago, Ines; Fletcher, Michael N C; Halim, Silvia; Prathalingam, Radhika; Ponder, Bruce A J; Meyer, Kerstin B

    2016-08-01

    The fibroblast growth factor receptor 2 (FGFR2) locus is consistently the top hit in genome-wide association studies for oestrogen receptor-positive (ER(+)) breast cancer. Yet, its mode of action continues to be controversial. Here, we employ a systems biology approach to demonstrate that signalling via FGFR2 counteracts cell activation by oestrogen. In the presence of oestrogen, the oestrogen receptor (ESR1) regulon (set of ESR1 target genes) is in an active state. However, signalling by FGFR2 is able to reverse the activity of the ESR1 regulon. This effect is seen in multiple distinct FGFR2 signalling model systems, across multiple cells lines and is dependent on the presence of FGFR2. Increased oestrogen exposure has long been associated with an increased risk of breast cancer. We therefore hypothesized that risk variants should reduce FGFR2 expression and subsequent signalling. Indeed, transient transfection experiments assaying the three independent variants of the FGFR2 risk locus (rs2981578, rs35054928 and rs45631563) in their normal chromosomal context show that these single-nucleotide polymorphisms (SNPs) map to transcriptional silencer elements and that, compared with wild type, the risk alleles augment silencer activity. The presence of risk variants results in lower FGFR2 expression and increased oestrogen responsiveness. We thus propose a molecular mechanism by which FGFR2 can confer increased breast cancer risk that is consistent with oestrogen exposure as a major driver of breast cancer risk. Our findings may have implications for the clinical use of FGFR2 inhibitors.

  13. Ketoprofen and antinociception in hypo-oestrogenic Wistar rats fed on a high sucrose diet.

    PubMed

    Jaramillo-Morales, Osmar Antonio; Espinosa-Juárez, Josué Vidal; García-Martínez, Betzabeth Anali; López-Muñoz, Francisco Javier

    2016-10-05

    Non-steroidal anti-inflammatory drugs such as ketoprofen are the most commonly used analgesics for the treatment of pain. However, no studies have evaluated the analgesic response to ketoprofen in conditions of obesity. The aim of this study was to analyse the time course of nociceptive pain in Wistar rats with and without hypo-oestrogenism on a high sucrose diet and to compare the antinociceptive response using ketoprofen. Hypo-oestrogenic and naïve rats received a hyper caloric diet (30% sucrose) or water ad libitum for 17 weeks, the thermal nociception ("plantar test" method) and body weight were tested during this period. A biphasic response was observed: thermal latency decreased in the 4th week (hyperalgesia), while from 12th to 17th week, thermal latency increased (hypoalgesia) in hypo-oestrogenic rats fed with high sucrose diet compared with the hypo-oestrogenic control group. At 4th and 17th weeks, different doses of ketoprofen (1.8-100mg/kg p.o.), were evaluated in all groups. The administration of ketoprofen at 4th and 17th weeks showed dose-dependent effects in the all groups; however, a greater pharmacological efficacy was observed in the 4th week in the hypo-oestrogenic animals that received sucrose. Nevertheless, in all the groups significantly diminish the antinociceptive effects in the 17th week. Our data showed that nociception was altered in the hypo-oestrogenic animals that were fed sucrose (hyperalgesia and hypoalgesia). Ketoprofen showed a dose-dependent antinociceptive effect at both time points. However, hypo-oestrogenism plus high-sucrose diet modifies the antinociceptive effect of ketoprofen.

  14. Frovatriptan vs. transdermal oestrogens or naproxen sodium for the prophylaxis of menstrual migraine.

    PubMed

    Guidotti, Mario; Mauri, Michela; Barrilà, Caterina; Guidotti, Francesca; Belloni, Carlo

    2007-10-01

    Acute treatment of menstrual migraine (MM) attacks is often incomplete and unsatisfactory, and perimenstrual prophylaxis with triptans, oestrogen supplementation or naproxen sodium may be needed for decreasing frequency and severity of the attack. In this pilot, open-label, non-randomised, parallel group study we evaluated, in 38 women with a history of MM, the efficacy of frovatriptan (n=14) 2.5 mg per os or transdermal oestrogens (n=10) 25 microg or naproxen sodium (n=14) 500 mg per os once-daily for the short-term prevention of MM. All treatments were administered in the morning for 6 days, beginning 2 days before the expected onset of menstrual headache. All women were asked to fill in a diary card, in the absence of (baseline) and under treatment, in order to score headache severity. All women reported at least one episode of MM at baseline. During treatment all patients taking transdermal oestrogens or naproxen sodium and 13 out of the 14 patients (93%) taking frovatriptan had at least one migraine attack (p=0.424). Daily incidence of migraine was significantly (p=0.045) lower under frovatriptan than under transdermal oestrogens or NS. At baseline, the overall median score of headache severity was 4.6, 4.2 and 4.3 in the group subsequently treated with frovatriptan, transdermal oestrogens and naproxen sodium, respectively (p=0.819). During treatment the median score was significantly lower under frovatriptan (2.5) than under transdermal oestrogens (3.0) and naproxen sodium (3.9, p=0.049). This was evident also for each single day of observation (p=0.016). Among treatments differences were particularly evident for the subgroup of patients with true MM (n=22) and for frovatriptan vs. naproxen sodium. This study suggests that short-term prophylaxis of MM with frovatriptan may be more effective than that based on transdermal oestrogens or naproxen sodium.

  15. Oestrogen receptor-alpha and -beta expression in breast implant capsules: experimental findings and clinical correlates.

    PubMed

    Persichetti, Paolo; Segreto, Francesco; Carotti, Simone; Marangi, Giovanni Francesco; Tosi, Daniele; Morini, Sergio

    2014-03-01

    Myofibroblasts provide a force to decrease the surface area of breast implant capsules as the collagen matrix matures. 17-β-Oestradiol promotes myofibroblast differentiation and contraction. The aim of the study was to investigate the expression of oestrogen receptors α and β in capsular tissue. The study enrolled 70 women (80 capsules) who underwent expander or implant removal, following breast reconstruction. Specimens were stained with haematoxylin/eosin, Masson trichrome and immunohistochemistry and immunofluorescence stainings for alpha-smooth muscle actin (α-SMA), oestrogen receptor-alpha (ER-α) and oestrogen receptor-beta (ER-β). The relationship between anti-oestrogenic therapy and capsular severity was evaluated. A retrospective analysis of 233 cases of breast reconstruction was conducted. Myofibroblasts expressed ER-α, ER-β or both. In the whole sample, α-SMA score positively correlated with ER-α (p = 0.022) and ER-β expression (p < 0.004). ER-β expression negatively correlated with capsular thickness (p < 0.019). In capsules surrounding expanders α-SMA and ER-α, expressions negatively correlated with time from implantation (p = 0.002 and p = 0.016, respectively). The incidence of grade III-IV contracture was higher in patients who did not have anti-oestrogenic therapy (p < 0.036); retrospective analysis of 233 cases confirmed this finding (p < 0.0001). This study demonstrates the expression of oestrogen receptors in myofibroblasts of capsular tissue. A lower contracture severity was found in patients who underwent anti-oestrogenic therapy.

  16. Effect of oestrogen on T cell apoptosis in patients with systemic lupus erythematosus

    PubMed Central

    Kim, W-U; Min, S-Y; Hwang, S-H; Yoo, S-A; Kim, K-J; Cho, C-S

    2010-01-01

    Defective control of T cell apoptosis is considered to be one of the pathogenetic mechanisms in systemic lupus erythematosus (SLE). Oestrogen has been known to predispose women to SLE and also to exacerbate activity of SLE; however, the role of oestrogen in the apoptosis of SLE T cells has not yet been documented. In this study, we investigated the direct effect of oestrogen on the activation-induced cell death of T cells in SLE patients. The results demonstrated that oestradiol decreased the apoptosis of SLE T cells stimulated with phorbol 12-myristate 13-acetate (PMA) plus ionomycin in a dose-dependent manner. In addition, oestradiol down-regulated the expression of Fas ligand (FasL) in activated SLE T cells at the both protein and mRNA levels. In contrast, testosterone increased FasL expression dose-dependently in SLE T cells stimulated with PMA plus ionomycin. The inhibitory effect of oestradiol on FasL expression was mediated through binding to its receptor, as co-treatment of tamoxifen, an oestrogen receptor inhibitor, completely nullified the oestradiol-induced decrease in FasL mRNA expression. Moreover, pre-treatment of FasL-transfected L5178Y cells with either oestradiol or anti-FasL antibody inhibited significantly the apoptosis of Fas-sensitive Hela cells when two types of cells were co-cultured. These data suggest that oestrogen inhibits activation-induced apoptosis of SLE T cells by down-regulating the expression of FasL. Oestrogen inhibition of T cell apoptosis may allow for the persistence of autoreactive T cells, thereby exhibiting the detrimental action of oestrogen on SLE activity. PMID:20529085

  17. The therapeutic effects of docosahexaenoic acid on oestrogen/androgen-induced benign prostatic hyperplasia in rats.

    PubMed

    Wang, Chao; Luo, Fei; Zhou, Ying; Du, Xiaoling; Shi, Jiandang; Zhao, Xiaoling; Xu, Yong; Zhu, Yan; Hong, Wei; Zhang, Ju

    2016-07-15

    Benign prostatic hyperplasia (BPH) is one of the major disorders of the urinary system in elderly men. Docosahexaenoic acid (DHA) is the main component of n-3 polyunsaturated fatty acids (n-3 PUFAs) and has nerve protective, anti-inflammatory and tumour-growth inhibitory effects. Here, the therapeutic potential of DHA in treating BPH was investigated. Seal oil effectively prevented the development of prostatic hyperplasia induced by oestradiol/testosterone in a rat model by suppressing the increase of the prostatic index (PI), reducing the thickness of the peri-glandular smooth muscle layer, inhibiting the proliferation of both prostate epithelial and stromal cells, and downregulating the expression of androgen receptor (AR) and oestrogen receptor α (ERα). An in vitro study showed that DHA inhibited the growth of the human prostate stromal cell line WPMY-1 and the epithelial cell line RWPE-1 in a dose- and time-dependent manner. In both cell lines, the DHA arrested the cell cycle in the G2/M phase. In addition, DHA also reduced the expression of ERα and AR in the WPMY-1 and RWPE-1 cells. These results indicate that DHA inhibits the multiplication of prostate stromal and epithelial cells through a mechanism that may involve cell cycle arrest and the downregulation of ERα and AR expression.

  18. Standardization and evaluation of botanical mixtures: lessons from a traditional Chinese herb, Epimedium, with oestrogenic properties.

    PubMed

    Yong, E L; Wong, S P; Shen, P; Gong, Y H; Li, J; Hong, Y

    2007-01-01

    Botanical extracts differ from conventional supplements in that they are complicated mixtures of many bioactive compounds. Here we describe our experience with a traditional Chinese medicinal plant Epimedium sp. to illustrate the scientific challenges of firstly, obtaining a standardized product from a complex mixture and secondly, evaluating that product for preclinical and clinical efficacy. In contrast, to its colloquial name 'Horny goat weed' and Internet advertisements as a herbal 'Viagra' for men, extracts of Epimedium are strongly oestrogenic due to the presence of novel potent phytoestrogens of the prenyl-flavone family. Since Epimedium is not cultivated, it was necessary to source for taxonomically identified samples and to authenticate their species by phylogenetic, chemical and bioresponse profiling. The feasibility of using a panel of oestrogen-responsive cell-based bioassays to measure summated oestrogenic effects at close time points for pharmacokinetic/pharmacodynamic (PK/PD) modelling was evaluated. We document proportionate oestrogenic responses in sera of animals fed oestrogenic drugs and botanical extracts, indicating that these target molecule responsive cell-based bioassays may have utility to capture the global effects of the myriad bioactive compounds in botanical extracts, informing the design of rigorous clinical trials for safety and efficacy.

  19. Oestrogens have no hormonal effect on the development and reproduction of the harpacticoid copepod Nitocra spinipes.

    PubMed

    Breitholtz, M; Bengtsson, B E

    2001-10-01

    In recent years, reports have described endocrine-disruptive effects of environmental oestrogens in fish, but little is known about similar effects in crustaceans. The objective of the present study was therefore to examine whether the oestrogens 17-beta-oestradiol, 17-alpha-ethynylestradiol and diethylstilbestrol (DES), could affect mortality, larval development rate, fecundity and sex ratio in the sexually reproducing harpacticoid copepod Nitocra spinipes. Newly released nauplii (<24-h old) were exposed to 1/1,000, 1/100 and 1/10 (nominal concentrations) of each oestrogen's 96 h-LC50 value for < or = 18 days at 22 +/- 1 degrees C. The percentage of gravid females and the number of developed copepodites were both reduced at 0.03 mg l(-1) DES, although the latter response was not significant. None of the other two oestrogens induced any measurable effects. Since the only observed significant response appeared at a DES concentration no more than 10 times below the 96 h-LC50 value, there is no evidence of endocrine-disruptive activity in N. spinipes exposed to oestrogens.

  20. Autonomous prolactin secretion in two male-to-female transgender patients using conventional oestrogen dosages

    PubMed Central

    Bunck, Mathijs C; Debono, Miguel; Giltay, Erik J; Verheijen, Andreas T; Diamant, Michaela; Gooren, Louis J

    2009-01-01

    Oestrogen-induced prolactinomas have been reported in male-to-female (MTF) transgender patients after excessive oestrogen self-administration. Here, two prolactinoma cases after 14 years (case 1) and 30 years (case 2) of relatively low-dose oestrogen treatment are reported. Both resolved after treatment with dopamine agonists. During the first year of oestrogen treatment the patient in case 1 showed a remarkable (7.2-fold) increase in serum prolactin concentration, returning to within the normal range for 13 years until the start of autonomous prolactin secretion. It is hypothesised that this strong first-year prolactin response may be a sign of increased pituitary oestrogen sensitivity. Therefore the patient’s increase in prolactin concentration during the first 18 months was compared to 74 matched control patients from a database, and this increase was found to be significantly greater in the case patient. It is suggested that in MTF patients an excessive first year increase in serum prolactin concentration may identify patients at risk for autonomous prolactin secretion later in life. PMID:21829422

  1. Endocrine factors in the hypothalamic regulation of food intake in females: a review of the physiological roles and interactions of ghrelin, leptin, thyroid hormones, oestrogen and insulin.

    PubMed

    Somogyi, V; Gyorffy, A; Scalise, T J; Kiss, D S; Goszleth, G; Bartha, T; Frenyo, V L; Zsarnovszky, A

    2011-06-01

    Controlling energy homeostasis involves modulating the desire to eat and regulating energy expenditure. The controlling machinery includes a complex interplay of hormones secreted at various peripheral endocrine endpoints, such as the gastrointestinal tract, the adipose tissue, thyroid gland and thyroid hormone-exporting organs, the ovary and the pancreas, and, last but not least, the brain itself. The peripheral hormones that are the focus of the present review (ghrelin, leptin, thyroid hormones, oestrogen and insulin) play integrated regulatory roles in and provide feedback information on the nutritional and energetic status of the body. As peripheral signals, these hormones modulate central pathways in the brain, including the hypothalamus, to influence food intake, energy expenditure and to maintain energy homeostasis. Since the growth of the literature on the role of various hormones in the regulation of energy homeostasis shows a remarkable and dynamic expansion, it is now becoming increasingly difficult to understand the individual and interactive roles of hormonal mechanisms in their true complexity. Therefore, our goal is to review, in the context of general physiology, the roles of the five best-known peripheral trophic hormones (ghrelin, leptin, thyroid hormones, oestrogen and insulin, respectively) and discuss their interactions in the hypothalamic regulation of food intake.

  2. Red wine interferes with oestrogen signalling in rat hippocampus.

    PubMed

    Monteiro, Rosário; Faria, Ana; Mateus, Nuno; Calhau, Conceição; Azevedo, Isabel

    2008-07-01

    Oestrogens have neuroprotective properties, resulting in memory and learning preservation. Red wine (RW) has been linked to neuroprotection, but mechanisms are largely unknown. The aim of this work was to test the effect of RW or 13% ethanol solution consumption on the expression of aromatase and estrogen receptors (ER) in the rat hippocampus. Beverages were supplied to male Wistar rats and after 8 weeks of treatment animals were euthanised, hippocampus was removed, aromatase expression assessed by western blotting and aromatase and ER transcription determined by RT-PCR. The effects of treatments on hippocampal aromatase activity were also determined, as well as the effect of several red wine polyphenols in hippocampal homogenates from untreated animals. Aromatase transcription was increased by ethanol (to 158+/-7%) but only significantly by RW (to 180+/-9%). No difference was found in ERalpha expression among groups, whereas RW significantly decreased ERbeta expression (to 63+/-10%). Resveratrol, quercetin, myricetin and kaempferol had no effect on aromatase activity and catechin (300 microM), epicatechin (200 microM), procyanidin extract (200 mg/L) and fractioned procyanidins (FI and FII; 200 mg/L) significantly decreased aromatase activity. The contribution of procyanidins in wine to the effect observed in aromatase was investigated in animals treated for the same period with these compounds (200 mg/L), although no effect was seen in aromatase activity, mRNA or protein levels, meaning that this group of compounds had little contribution, if any, to the effects observed. Nevertheless, the increase in aromatase expression induced by RW may corroborate the neuroprotective ability attributed to this beverage. Alterations in the relative abundance of ER expression may also play an important role in the protection.

  3. Oestrogen receptors enhance dopamine neurone survival in rat midbrain.

    PubMed

    Johnson, M L; Ho, C C; Day, A E; Walker, Q D; Francis, R; Kuhn, C M

    2010-04-01

    Previous findings in our laboratory and elsewhere have shown that ovariectomy of rats in adulthood attenuates cocaine-stimulated locomotor behaviour. Ovarian hormones enhance both cocaine-stimulated behaviour and increase dopamine overflow after psychomotor stimulants. The present study aimed to determine whether ovarian hormones have these effects in part by maintaining dopamine neurone number in the substantia nigra pars compacta (SNpc) and ventral tegmental area (VTA) and to investigate the roles of specific oestrogen receptors (ERs) in the maintenance of mesencephalic dopamine neurones. To accomplish this goal, we used unbiased stereological techniques to estimate the number of tyrosine hydroxylase-immunoreactive (TH-IR) cell bodies in midbrain regions of intact, ovariectomised and hormone-replaced female rats and mice. Animals received active or sham gonadectomy on postnatal day 60 and received vehicle, 17beta-oestradiol (E(2)) or selective ER agonists propyl-pyrazole-triol (PPT, ERalpha) or diarylpropionitrile (DPN, ERbeta) for 1 month post-surgery. In both rats and mice, ovariectomy reduced the number of TH-IR cells in the SNpc and VTA. Replacement with E(2), PPT or DPN prevented or attenuated the loss observed with ovariectomy in both rats and mice. An additional study using ER knockout mice revealed that adult female mice lacking ERalpha had fewer TH-IR cells in midbrain regions than wild-type mice, whereas mice lacking ERbeta had TH-IR cell counts comparable to wild-type. These findings suggest that, although both ER subtypes play a role in the maintenance of TH-IR cell number in the SNpc and VTA, ERalpha may play a more significant role.

  4. Cross-talk between membrane-initiated and nuclear-initiated oestrogen signaling in the hypothalamus

    PubMed Central

    Roepke, Troy A.; Qiu, Jian; Bosch, Martha A.; Rønnekleiv, Oline K.; Kelly, Martin J.

    2009-01-01

    It is increasingly evident that 17β-oestradiol (E2) via a distinct membrane oestrogen receptor (Gq-mER) can rapidly activate kinase pathways to have multiple downstream actions in CNS neurons. We have found that E2 can rapidly reduce the potency of the GABAB receptor agonist baclofen and mu-opioid receptor agonist DAMGO to activate G protein-coupled, inwardly rectifying K+ (GIRK) channels in hypothalamic neurons, thereby increasing the excitability (firing activity) of POMC and dopamine neurons. These effects are mimicked by the membrane impermeant E2-BSA and a new ligand (STX) that is selective for the Gq-mER that does not bind to ERα or ERβ. Both E2 and STX are fully efficacious in attenuating the GABAB response in ERα, ERβ and GPR 30 knockout mice in an ICI 182,780 reversible manner. These findings are further proof that E2 signals through a unique plasma membrane ER. We have characterised the coupling of this Gq-mER to a Gq-mediated activation of phospholipase C leading to the up-regulation of protein kinase Cδ and protein kinase A activity in these neurons, which ultimately alters gene transcription. Finally as proof of principle, we have found that STX, like E2, reduces food intake and body weight gain in ovariectomised females. STX, presumably via the Gq-mER, also regulates gene expression of a number of relevant targets including cation channels and signalling molecules that are critical for regulating (as a prime example) POMC neuronal excitability. Therefore, E2 can activate multiple receptor-mediated pathways to modulate excitability and gene transcription in CNS neurons that are critical for controlling homeostasis and motivated behaviors. PMID:19187465

  5. Oestrogen and parathyroid hormone alleviate lumbar intervertebral disc degeneration in ovariectomized rats and enhance Wnt/β-catenin pathway activity

    PubMed Central

    Jia, Haobo; Ma, Jianxiong; Lv, Jianwei; Ma, Xinlong; Xu, Weiguo; Yang, Yang; Tian, Aixian; Wang, Ying; Sun, Lei; Xu, Liyan; Fu, Lin; Zhao, Jie

    2016-01-01

    To investigate the mitigation effect and mechanism of oestrogen and PTH on disc degeneration in rats after ovariectomy, as well as on Wnt/β-catenin pathway activity, thirty 3-month-old rats were ovariectomized and divided into three groups. Ten additional rats were used as controls. Eight weeks later, the rats were administered oestrogen or PTH for 12 weeks, and then discs were collected for tests. Results showed that nucleus pulposus cells in the Sham group were mostly notochord cells, while in the OVX group, cells gradually developed into chondrocyte-like cells. Oestrogen or PTH could partly recover the notochord cell number. After ovariectomy, the endplate roughened and endplate porosity decreased. After oestrogen or PTH treatment, the smoothness and porosity of endplate recovered. Compared with the Sham group, Aggrecan, Col2a and Wnt/β-catenin pathway expression in OVX group decreased, and either oestrogen or PTH treatment improved their expression. The biomechanical properties of intervertebral disc significantly changed after ovariectomy, and oestrogen or PTH treatment partly recovered them. Disc degeneration occurred with low oestrogen, and the underlying mechanisms involve nutrition supply disorders, cell type changes and decreased Wnt/β-catenin pathway activity. Oestrogen and PTH can retard disc degeneration in OVX rats and enhance Wnt/β-catenin pathway activity in nucleus pulposus. PMID:27279629

  6. In vitro metabolism of gestodene in target organs: formation of A-ring reduced derivatives with oestrogenic activity.

    PubMed

    Lemus, A E; Santillán, R; Damián-Matsumura, P; García, G A; Grillasca, I; Pérez-Palacios, G

    2001-04-13

    Gestodene (13beta-ethyl-17alpha-ethynyl-17beta-hydroxy-4,5-gonadien-3-one), the most potent progestin ever synthesized, stimulates breast cancer cell growth through an oestrogen receptor-mediated mechanism, and its use in hormonal contraception has been associated with side effects attributable to oestrogenic actions. These observations have remained controversial, since gestodene does not bind to the oestrogen receptor or exert oestrogen-like activities. Recently, we have demonstrated that non-phenolic gestodene derivatives interact with oestrogen receptors and induce oestrogenic effects in cell expression systems. To assess whether gestodene is biotransformed to metabolites with intrinsic oestrogenic potency, [3H]- and [14C]-labelled gestodene were incubated in vitro with rat anterior pituitary, hypothalamus and ventral prostate homogenates under different experimental conditions. The most remarkable finding was the isolation and identification of 3beta,5alpha-tetrahydrogestodene and 3alpha,5alpha-tetrahydrogestodene as metabolic conversion products of gestodene, presumably with 5alpha-dihydrogestodene as intermediate. The overall results seem to indicate that the weak oestrogenic effects attributable to gestodene could be mediated by its tetrahydro metabolites.

  7. A modified oestrogen receptor ligand-binding domain as an improved switch for the regulation of heterologous proteins.

    PubMed Central

    Littlewood, T D; Hancock, D C; Danielian, P S; Parker, M G; Evan, G I

    1995-01-01

    A number of proteins have been rendered functionally oestrogen-dependent by fusion with the hormone-binding domain of the oestrogen receptor. There are, however, several significant disadvantages with such fusion proteins. First, their use in cells in vitro requires phenol red-free medium and laborious stripping of steroid hormones from serum in order to avoid constitutive activation. Secondly, control of oestrogen receptor fusion proteins in vivo is precluded by high endogenous levels of circulating oestrogens. Thirdly, the hormone-binding domain of the oestrogen receptor functions as a hormone-dependent transcriptional activation domain making interpretation of fusions with transcription factors problematical. In order to overcome these drawbacks we have used a transcriptionally inactive mutant of the murine oestrogen receptor which is unable to bind oestrogen yet retains normal affinity for the synthetic ligand, 4-hydroxytamoxifen. When the hormone-binding domain of this mutant oestrogen receptor is fused to the C-terminus of the c-Myc protein, Myc-induced proliferation and apoptosis in fibroblasts becomes dependent on 4-hydroxytamoxifen, but remains refractory to 17 beta-oestradiol. Images PMID:7784172

  8. Recombinant human lactoferrin modulates human PBMC derived macrophage responses to BCG and LPS.

    PubMed

    Hwang, Shen-An; Kruzel, Marian L; Actor, Jeffrey K

    2016-12-01

    Lactoferrin, an iron-binding glycoprotein found in mammalian mucosal secretions and granules of neutrophils, possesses several immune modulatory properties. Published reports indicate that lactoferrin enhances the efficacy of the tuberculosis vaccine, BCG (Bacillus Calmette Guerin), both by increasing macrophage and dendritic cell ability to stimulate receptive T cells and by modulating the inflammatory response. This report is the first to demonstrate the effects of a recombinant human lactoferrin (10 μg/mL) on human PBMC derived CD14(+) and CD16(+) macrophages stimulated with a strong (LPS, 10 ng/mL) or weaker (BCG, MOI 1:1) stimulator of inflammation. After 3 days culture, LPS and human lactoferrin treated CD14(+) cells significantly increased production of IL-10, IL-6, and MCP-1 compared to the LPS only group. In contrast, similarly treated CD16(+) macrophages increased production of IL-12p40 and IL-10 and decreased TNF-α. Limited changes were observed in BCG stimulated CD14(+) and CD16(+) macrophages with and without lactoferrin. Analysis of surface expression of antigen presentation and co-stimulatory molecules demonstrated that CD14(+) macrophages, when stimulated with BCG or LPS and cultured with lactoferrin, increased expression of CD86. CD16(+) macrophages treated with lactoferrin showed a similar trend of increase in CD86 expression, but only when stimulated with BCG.

  9. Reassessment of models used to test xenobiotics for oestrogenic potency is overdue.

    PubMed

    Spearow, J L; Barkley, M

    2001-05-01

    Product safety bioassays need to include data from animals with susceptible genotypes or the potential for environmental compounds to disrupt reproductive development in hormonally sensitive populations may be greatly underestimated. The continued use of resistant animal models is likely to result in allowable releases of toxic levels of oestrogenic agents that could differentially disrupt reproductive development and function of sensitive genotypes, leading to reproductive failure and loss or extinction of susceptible individuals, populations and species. Rather than ignoring the role of genetic differences in susceptibility to oestrogenic agent-induced carcinogenicity and endocrine disruption, government agencies should support efforts to identify the genetic mechanisms involved in these responses, and to screen for and develop strains of mice and rats which are sensitive to the induction of genotoxicity/carcinogenicity as well as the inhibition of reproductive development and function by oestrogenic agents. Such sensitive strains would be even more optimal for testing chemicals for endocrine disruptor activity.

  10. Functional association of oestrogen receptors with HPV infection in cervical carcinogenesis.

    PubMed

    Ramachandran, Balaji

    2017-04-01

    Repeated parity and usage of oral contraceptives have demonstrated an increased risk of cervical cancer (CC) in HPV-infected women. These lifestyle observations raise the likelihood that oestrogens and HPV infection might act synergistically to affect cancers of the cervix. In vivo studies have indicated the requirement of oestrogens and ERα in the development of atypical squamous metaplasia followed by cervical intraepithelial neoplasia (CIN) I, II and III. CIN II and III are precancerous cervical lesions that can progress over time to CC as an invasive carcinoma. Recently, there has been evidence suggesting that ERα signalling in the tumour epithelium is a preliminary requisite during cancer initiation that is subsequently lost during tumorigenic progression. Conversely, continued expression of stromal ERα gains control over tumour maintenance. This review summarises the current information on the association between oestrogens and HPV infection in contributing to CC and the possibility of SERMs as a therapeutic option.

  11. Comparison between Urinary Oestrogen Assay and Serial Ultrasonic Cephalometry in Assessment of Fetal Growth Retardation

    PubMed Central

    Campbell, Stuart; Kurjak, Asim

    1972-01-01

    Urinary oestrogen assay and serial ultrasonic cephalometry were performed on 284 patients who were considered on clinical grounds to be at risk of having a growth-retarded fetus. It was found that ultrasonic cephalometry was significantly better than oestrogens in diagnosing the small-for-dates baby, but that there was no significant difference between the two methods in predicting perinatal asphyxia. Of the 14 stillbirths, three were in the normal ultrasonic growth rate group and five had normal oestrogen excretion. Both methods were found to be of value in the diagnosis of fetal growth-retardation, although cephalometry would seem to have some advantages, especially in distinguishing between fetal growth-retardation and mistaken maturity. PMID:4673993

  12. Mining a human transcriptome database for Nrf2 modulators

    EPA Science Inventory

    Nuclear factor erythroid-2 related factor 2 (Nrf2) is a key transcription factor important in the protection against oxidative stress. We developed computational procedures to enable the identification of chemical, genetic and environmental modulators of Nrf2 in a large database ...

  13. Mining a human transcriptome database for Nrf2 modulators

    EPA Science Inventory

    Nuclear factor erythroid-2 related factor 2 (Nrf2) is a key transcription factor important in the protection against oxidative stress. We developed computational procedures to enable the identification of chemical, genetic and environmental modulators of Nrf2 in a large database ...

  14. Dynamics of contextual modulation of perceived shape in human vision

    PubMed Central

    Gheorghiu, Elena; Kingdom, Frederick A. A.

    2017-01-01

    In biological vision, contextual modulation refers to the influence of a surround pattern on either the perception of, or the neural responses to, a target pattern. One studied form of contextual modulation deals with the effect of a surround texture on the perceived shape of a contour, in the context of the phenomenon known as the shape aftereffect. In the shape aftereffect, prolonged viewing, or adaptation to a particular contour’s shape causes a shift in the perceived shape of a subsequently viewed contour. Shape aftereffects are suppressed when the adaptor contour is surrounded by a texture of similarly-shaped contours, a surprising result given that the surround contours are all potential adaptors. Here we determine the motion and temporal properties of this form of contextual modulation. We varied the relative motion directions, speeds and temporal phases between the central adaptor contour and the surround texture and measured for each manipulation the degree to which the shape aftereffect was suppressed. Results indicate that contextual modulation of shape processing is selective to motion direction, temporal frequency and temporal phase. These selectivities are consistent with one aim of vision being to segregate contours that define objects from those that form textured surfaces. PMID:28230085

  15. Case-control study of oestrogen replacement therapy and risk of cervical cancer.

    PubMed Central

    Parazzini, F.; La Vecchia, C.; Negri, E.; Franceschi, S.; Moroni, S.; Chatenoud, L.; Bolis, G.

    1997-01-01

    OBJECTIVE: To examine the relation between use of oestrogen replacement therapy and risk of cervical cancer. DESIGN: Case-control study. SETTING: Northern Italy. SUBJECTS: 645 women aged 40-75 years with cervical cancer admitted between 1981 and 1993 to university and general hospitals. The control group consisted of 749 women aged 40-75 years admitted to the same hospitals with acute conditions judged to be unrelated to any of the known or suspected risk factors for cervical cancer. MAIN OUTCOME MEASURES: Use of oestrogen replacement therapy and risk of cervical cancer. RESULTS: 40 cases versus 86 controls had ever used oestrogens, and the corresponding multivariate odds ratio was 0.5 (95% confidence interval 0.3 to 0.8). The odds ratios of cervical cancer decreased with duration of use, being 0.6 (0.4 to 1.1) for less than 12 months' use and 0.5 (0.2 to 1.0) for use for 12 months or more compared with never users. The protection tended to be somewhat stronger for women reporting first oestrogen use before age 50. The odds ratio was 0.9 (0.5 to 1.7) for women who had taken oestrogens within the past 10 years and 0.4 (0.2 to 0.7) for those who had taken them 10 or more years ago. CONCLUSION: These findings suggest that exogenous oestrogens do not increase the risk of cervical cancer and may decrease the risk. PMID:9240046

  16. Human milk oligosaccharides: the novel modulator of intestinal microbiota.

    PubMed

    Jeong, Kyunghun; Nguyen, Vi; Kim, Jaehan

    2012-08-01

    Human milk, which nourishes the early infants, is a source of bioactive components for the infant growth, development and commensal formulation as well. Human milk oligosaccharide is a group of complex and diverse glycans that is apparently not absorbed in human gastrointestinal tract. Although most mammalian milk contains oligosaccharides, oligosaccharides in human milk exhibit unique features in terms of their types, amounts, sizes, and functionalities. In addition to the prevention of infectious bacteria and the development of early immune system, human milk oligosaccharides are able to facilitate the healthy intestinal microbiota. Bifidobacterial intestinal microbiota appears to be established by the unilateral interaction between milk oligosaccharides, human intestinal activity and commensals. Digestibility, membrane transportation and catabolic activity by bacteria and intestinal epithelial cells, all of which are linked to the structural of human milk oligosaccharides, are crucial in determining intestinal microbiota.

  17. Increase in plasma cortisol concentrations in ewes fed oestrogenic subterranean clover.

    PubMed

    Tang, B Y; Adams, N R; Sawyer, G J

    1979-11-01

    Pen-feeding oestrogenic clover to ewes increased their plasma cortisol concentration by the third day. This was not due to any change in the variation of cortisol concentration with time of day. Ovulation rate was not affected during the experiment as judged by the levels of plasma progesterone and laparoscopy. The plasma cortisol concentration of ewes also rose within three days of their being placed on oestrogenic clover pasture. During the next 21 days, their mean plasma cortisol was increased by 58 per cent. A previous history of clover disease did not affect this response.

  18. The Geography of Greenhouse Gas Emissions: Hands-On! Developing Active Learning Modules on the Human Dimensions of Global Change.

    ERIC Educational Resources Information Center

    Liverman, Diana; Solem, Michael

    This learning module aims to engage students in problem solving, critical thinking, scientific inquiry, and cooperative learning. The module is appropriate for use in any introductory or intermediate undergraduate course that focuses on human-environment relationships. The module examines the geography of human activities that produce the major…

  19. Modulation of inflammation by autophagy: Consequences for human disease.

    PubMed

    Netea-Maier, Romana T; Plantinga, Theo S; van de Veerdonk, Frank L; Smit, Johannes W; Netea, Mihai G

    2016-01-01

    Autophagy and inflammation are 2 fundamental biological processes involved in both physiological and pathological conditions. Through its crucial role in maintaining cellular homeostasis, autophagy is involved in modulation of cell metabolism, cell survival, and host defense. Defective autophagy is associated with pathological conditions such as cancer, autoimmune disease, neurodegenerative disease, and senescence. Inflammation represents a crucial line of defense against microorganisms and other pathogens, and there is increasing evidence that autophagy has important effects on the induction and modulation of the inflammatory reaction; understanding the balance between these 2 processes may point to important possibilities for therapeutic targeting. This review focuses on the crosstalk between autophagy and inflammation as an emerging field with major implications for understanding the host defense on the one hand, and for the pathogenesis and treatment of immune-mediated diseases on the other hand.

  20. Introduction to the Human Dimensions of Global Change. Hands-On! Developing Active Learning Modules on the Human Dimensions of Global Change.

    ERIC Educational Resources Information Center

    Archer, Emma R. M.; Turner, Billie L., II

    This learning module aims to engage students in problem solving, critical thinking, scientific inquiry, and cooperative learning. The module is appropriate for use in any introductory or intermediate undergraduate course that focuses on human-environment relationships. The module provides students with a broad overview of the human dimensions of…

  1. Modulation of human GABArho1 receptors by taurine.

    PubMed

    Ochoa-de la Paz, L D; Martínez-Dávila, I A; Miledi, R; Martínez-Torres, A

    2008-07-01

    A study was made of the effects of taurine on GABArho1 receptors expressed in Xenopus oocytes. The EC(50) and reversal potentials for GABA, taurine and glycine currents were 2.3+/-0.4 microM (-25+/-0.9 mV), 5+/-0.8mM (-27+/-0.4 mV) and 7+/-0.5mM (-22+/-0.6 mV), respectively. Co-application of GABA and taurine, revealed a taurine concentration-dependent biphasic-modulation of the receptor: at 0.3-30 microM taurine potentiated the GABA-currents, whereas at 0.3-30 mM the GABA-currents were reduced. In contrast glycine potentiated the GABA-currents at all concentrations tested. TPMPA, a GABA(C) specific receptor antagonist, also blocked effectively and reversibly the taurine and glycine currents. Finally, lanthanum and zinc modulated the currents generated by the three amino acids. Taurine is abundant in the retina and our observations suggest that taurine may play an important role modulating the retinal GABAergic transmission.

  2. Invariance of firing rate and field potential dynamics to stimulus modulation rate in human auditory cortex.

    PubMed

    Mukamel, Roy; Nir, Yuval; Harel, Michal; Arieli, Amos; Malach, Rafael; Fried, Itzhak

    2011-08-01

    The effect of stimulus modulation rate on the underlying neural activity in human auditory cortex is not clear. Human studies (using both invasive and noninvasive techniques) have demonstrated that at the population level, auditory cortex follows stimulus envelope. Here we examined the effect of stimulus modulation rate by using a rare opportunity to record both spiking activity and local field potentials (LFP) in auditory cortex of patients during repeated presentations of an audio-visual movie clip presented at normal, double, and quadruple speeds. Mean firing rate during evoked activity remained the same across speeds and the temporal response profile of firing rate modulations at increased stimulus speeds was a linearly scaled version of the response during slower speeds. Additionally, stimulus induced power modulation of local field potentials in the high gamma band (64-128 Hz) exhibited similar temporal scaling as the neuronal firing rate modulations. Our data confirm and extend previous studies in humans and anesthetized animals, supporting a model in which both firing rate, and high-gamma LFP power modulations in auditory cortex follow the temporal envelope of the stimulus across different modulation rates.

  3. Oestrogenic activity of a textile industrial wastewater treatment plant effluent evaluated by the E-screen test and MELN gene-reporter luciferase assay.

    PubMed

    Schilirò, Tiziana; Porfido, Arianna; Spina, Federica; Varese, Giovanna Cristina; Gilli, Giorgio

    2012-08-15

    This study quantified the biological oestrogenic activity in the effluent of a textile industrial wastewater treatment plant (IWWTP) in northwestern Italy. Samples of the IWWTP effluent were collected monthly, both before and after tertiary treatment (ozonation). After solid phase extraction, all samples were subjected to two in vitro tests of total estrogenic activity, the human breast cancer cell line (MCF-7 BUS) proliferation assay, or E-screen test, and the luciferase-transfected human breast cancer cell line (MELN) gene-reporter assay, to measure the 17β-oestradiol equivalent quantity (EEQ). In the E-screen test, the mean EEQ values were 2.35±1.68 ng/L pre-ozonation and 0.72±0.58 ng/L post-ozonation; in the MELN gene-reporter luciferase assay, the mean EEQ values were 4.18±3.54 ng/L pre-ozonation and 2.53±2.48 ng/L post-ozonation. These results suggest that the post-ozonation IWWTP effluent had a lower oestrogenic activity (simple paired t-tests, p<0.05). The average reduction of estrogenic activity of IWWTP effluent after ozonation was 67±26% and 52±27% as measured by E-screen test and MELN gene-reporter luciferase assay, respectively. There was a positive and significant correlation between the two tests (Rho S=0.650, p=0.022). This study indicates that the environmental risk is low because oestrogenic substances are deposited into the river via IWWTP at concentrations lower than those at which chronic exposure has been reported to affect the endocrine system of living organisms.

  4. Inflammation modulates human HDL composition and function in vivo

    USDA-ARS?s Scientific Manuscript database

    Inflammation may directly impair HDL functions, in particular reverse cholesterol transport (RCT), but limited data support this concept in humans. Our study was designed to investigate this relationship. We employed low-dose human endotoxemia to assess the effects of inflammation on HDL and RCT-rel...

  5. Enzymic synthesis of steroid sulphates. XI. Study of the oestrogen binding site of oestrogen sulphotransferase by affinity labelling with 4-mercuri-17beta-oestradiol.

    PubMed

    Dodsworth, A I; Jackson, D E

    1975-04-19

    Oistrogen sulphotransferase (3"-phosphoadenylylsulphate: oestrone sulphotransferase, EC 2.8.2.4) contains asingle sulphydryl group thought to be at, or near, the oestrogen-binding site. 4-mercuri-17beta-oestradiol, the activity of the enzyme decreased with increasing concentration of the oestrogen derivative. However, some 40% of the activity remained when all the sulphydryl had reacted to form mercaptide. Formation of mercaptide was only marginally decreased in the presence of the substrate 17beta-oestradiol. Other steroids, such as 11-deoxycorticosterone and testosterone, which are non-substrates for the enzyme, were more effective than 17beta-oestradiol in inhibiting mercaptide formation. Bovine serum albumin also reacted with 4-mercure-17beta-oestradiol and the effects of various steroids on mercaptide formation by the affinity label closely paralleled those found for the enzyme. 2t is concluded that the single sulphydryl group in the enzyme is not directly involved in the binding of oestrogen at the active site but is perhaps in closer proximity to a second site capable of binding certain non-substrate steroids.

  6. Toxoplasma Modulates Signature Pathways of Human Epilepsy, Neurodegeneration & Cancer.

    PubMed

    Ngô, Huân M; Zhou, Ying; Lorenzi, Hernan; Wang, Kai; Kim, Taek-Kyun; Zhou, Yong; El Bissati, Kamal; Mui, Ernest; Fraczek, Laura; Rajagopala, Seesandra V; Roberts, Craig W; Henriquez, Fiona L; Montpetit, Alexandre; Blackwell, Jenefer M; Jamieson, Sarra E; Wheeler, Kelsey; Begeman, Ian J; Naranjo-Galvis, Carlos; Alliey-Rodriguez, Ney; Davis, Roderick G; Soroceanu, Liliana; Cobbs, Charles; Steindler, Dennis A; Boyer, Kenneth; Noble, A Gwendolyn; Swisher, Charles N; Heydemann, Peter T; Rabiah, Peter; Withers, Shawn; Soteropoulos, Patricia; Hood, Leroy; McLeod, Rima

    2017-09-13

    One third of humans are infected lifelong with the brain-dwelling, protozoan parasite, Toxoplasma gondii. Approximately fifteen million of these have congenital toxoplasmosis. Although neurobehavioral disease is associated with seropositivity, causality is unproven. To better understand what this parasite does to human brains, we performed a comprehensive systems analysis of the infected brain: We identified susceptibility genes for congenital toxoplasmosis in our cohort of infected humans and found these genes are expressed in human brain. Transcriptomic and quantitative proteomic analyses of infected human, primary, neuronal stem and monocytic cells revealed effects on neurodevelopment and plasticity in neural, immune, and endocrine networks. These findings were supported by identification of protein and miRNA biomarkers in sera of ill children reflecting brain damage and T. gondii infection. These data were deconvoluted using three systems biology approaches: "Orbital-deconvolution" elucidated upstream, regulatory pathways interconnecting human susceptibility genes, biomarkers, proteomes, and transcriptomes. "Cluster-deconvolution" revealed visual protein-protein interaction clusters involved in processes affecting brain functions and circuitry, including lipid metabolism, leukocyte migration and olfaction. Finally, "disease-deconvolution" identified associations between the parasite-brain interactions and epilepsy, movement disorders, Alzheimer's disease, and cancer. This "reconstruction-deconvolution" logic provides templates of progenitor cells' potentiating effects, and components affecting human brain parasitism and diseases.

  7. Modulation of carcinogen-metabolizing cytochromes P450 by phytochemicals in humans.

    PubMed

    Baer-Dubowska, Wanda; Szaefer, Hanna

    2013-08-01

    Cytochrome P450 (CYP) families 1 - 3, besides oxidizing environmental and dietary chemicals, leading to their elimination, catalyze the bioactivation of exogenous as well as endogenous carcinogens. Phytochemicals, particularly those which are active food components, were shown to be able to affect specific CYP expression and/or activity in animal models and in human in vitro systems. Human intervention studies involving healthy volunteers were also performed. This review describes human CYP modulation by naturally occurring phytochemicals which can not only affect carcinogen metabolism in humans, but also change the drug response. The authors present an overview of carcinogens metabolizing human CYP modulation in different model systems as well as studies on human dietary intervention. Furthermore, the authors provide examples of the phytochemicals that affect CYP expression and activity. CYP, which are involved in carcinogen activation, can metabolize a range of substrates and inducing CYP by one substrate may also increase the metabolism of another. The ultimate proof of the efficacy of CYP modulation strategy for chemoprevention may be provided by clinical trials involving risk populations, which are difficult to perform. The new human-like models are highly desired for the study of modulation of carcinogen-metabolizing CYP.

  8. Perceptual learning evidence for tuning to spectro-temporal modulation in the human auditory system

    PubMed Central

    Sabin, Andrew T.; Eddins, David A.; Wright, Beverly A.

    2012-01-01

    Natural sounds are characterized by complex patterns of sound intensity distributed across both frequency (spectral modulation) and time (temporal modulation). Perception of these patterns has been proposed to depend upon a bank of modulation filters, each tuned to a unique combination of a spectral and a temporal modulation frequency. There is considerable physiological evidence for such combined spectro-temporal tuning. However direct behavioral evidence is lacking. Here we examined the processing of spectro-temporal modulation behaviorally using a perceptual-learning paradigm. We trained human listeners ~1 hr/day for 7 days to discriminate the depth of either spectral (0.5 cyc/oct; 0 Hz), temporal (0 cyc/oct; 32 Hz), or upward spectro-temporal (0.5 cyc/oct; 32 Hz) modulation. Each trained group learned more on their respective trained condition than controls who received no training. Critically, this depth-discrimination learning did not generalize to the trained stimuli of the other groups or to downward spectro-temporal (0.5 cyc/oct; −32 Hz) modulation. Learning on discrimination also led to worsening on modulation detection, but only when the same spectro-temporal modulation was used for both tasks. Thus, these influences of training were specific to the trained combination of spectral and temporal modulation frequencies, even when the trained and untrained stimuli had one modulation frequency in common. This specificity indicates that training modified circuitry that had combined spectro-temporal tuning, and therefore that circuits with such tuning can influence perception. These results are consistent with the possibility that the auditory system analyzes sounds through filters tuned to combined spectro-temporal modulation. PMID:22573676

  9. Modulation of Itch by Conditioning Itch and Pain Stimulation in Healthy Humans.

    PubMed

    Andersen, Hjalte H; van Laarhoven, Antoinette I M; Elberling, Jesper; Arendt-Nielsen, Lars

    2017-07-12

    Little is known about endogenous descending control of itch. In chronic pain, descending pain inhibition is reduced as signified by lowered conditioned pain modulation. There are indications that patients with chronic itch may also exhibit reduced endogenous descending inhibition of itch and pain. This study aimed to investigate whether and the extent to which itch can be modulated by conditioning itch and pain stimuli. Twenty-six healthy volunteers participated. The study consisted of 5 conditions designed to systematically assess endogenous modulation of itch or pain: 1) itch-induced modulation of contralateral itch, 2) pain-induced modulation of contralateral itch, 3) pain-induced modulation of ipsilateral itch, 4) pain-induced modulation of contralateral pain, and 5) itch-induced modulation of contralateral pain. Conditioning stimuli were cold pressor-induced pain and histamine-evoked itch, whereas the test stimuli were electrical stimulation paradigms designed to evoke itch or pain. Pain was significantly reduced (conditioned pain modulation-effect) by the conditioning pain stimulus (P < .001), but not by the conditioning itch stimulus (negative control condition). Itch was significantly reduced (conditioned itch modulation-effect) by contra- as well as ipsilateral applied conditioning pain (both P < .001), whereas conditioning itch stimulation only marginally reduced itch. Endogenous descending itch inhibition through mechanisms that are independent of segmental gating can be readily evoked by heterotopic conditioning pain stimulation. However, robust descending inhibition of itch cannot be evoked with conditioning itch stimulation. The study showed a hierarchical prioritization favoring pain-induced central descending modulation of itch as well as pain in humans. Future studies addressing potential aberrations in pain-evoked descending modulation of itch in chronic itch patients are warranted. Copyright © 2017 American Pain Society. Published by

  10. Prediction of in vitro and in vivo oestrogen receptor activity using hierarchical clustering

    EPA Science Inventory

    In this study, hierarchical clustering classification models were developed to predict in vitro and in vivo oestrogen receptor (ER) activity. Classification models were developed for binding, agonist, and antagonist in vitro ER activity and for mouse in vivo uterotrophic ER bindi...

  11. The oestrogenic activity of danazol in the female gerbil (Meriones hurrianae Jerdon).

    PubMed

    Lohiya, N K; Arya, M; Shivapuri, V S

    1977-07-01

    Antifertility and estrogenic effects of Danazol have been studied in female gerbils. Danazol brings about supression of ovarian weight, presumably by inhibiting gonadotrophin secretion. Enlargement of uterine horns and well defined vaginal keratinization was seen in Danazol treated ovariectomized animals. The results were similar to that of oestradiol dipropionate confirming the oestrogenic activity of Danazol.

  12. Prediction of in vitro and in vivo oestrogen receptor activity using hierarchical clustering

    EPA Science Inventory

    In this study, hierarchical clustering classification models were developed to predict in vitro and in vivo oestrogen receptor (ER) activity. Classification models were developed for binding, agonist, and antagonist in vitro ER activity and for mouse in vivo uterotrophic ER bindi...

  13. Environmental exposure to xenoestrogens and oestrogen related cancers: reproductive system, breast, lung, kidney, pancreas, and brain

    PubMed Central

    2012-01-01

    The role of steroids in carcinogenesis has become a major concern in environmental protection, biomonitoring, and clinical research. Although historically oestrogen has been related to development of reproductive system, research over the last decade has confirmed its crucial role in the development and homeostasis of other organ systems. As a number of anthropogenic agents are xenoestrogens, environmental health research has focused on oestrogen receptor level disturbances and of aromatase polymorphisms. Oestrogen and xenoestrogens mediate critical points in carcinogenesis by binding to oestrogen receptors, whose distribution is age-, gender-, and tissue-specific. This review brings data about cancer types whose eatiology may be found in environmental exposure to xenoestrogens. Cancer types that have been well documented in literature to be related with environmental exposure include the reproductive system, breast, lung, kidney, pancreas, and brain. The results of our data mining show (a) a significant correlation between exposure to xenoestrogens and increased, gender-related, cancer risk and (b) a need to re-evaluate agents so far defined as endocrine disruptors, as they are also key molecules in carcinogenesis. This revision may be used to further research of cancer aetiology and to improvement of related legislation. Investigation of cancers caused by xenoestrogens may elucidate yet unknown mechanisms also valuable for oncology and the development of new therapies. PMID:22759508

  14. The complex nature of oestrogen signalling in breast cancer: enemy or ally?

    PubMed Central

    Lipovka, Yulia; Konhilas, John P.

    2016-01-01

    The pleiotropic nature of oestradiol, the main oestrogen found in women, has been well described in the literature. Oestradiol is positioned to play a unique role since it can respond to environmental, genetic and non-genetic cues to affect genetic expression and cellular signalling. In breast cancer, oestradiol signalling has a dual effect, promoting or inhibiting cancer growth. The potential impact of oestradiol on tumorigenesis depends on the molecular and cellular characteristics of the breast cancer cell. In this review, we provide a broad survey discussing the cellular and molecular consequences of oestrogen signalling in breast cancer. First, we review the structure of the classical oestrogen receptors and resultant transcriptional (genomic) and non-transcriptional (non-genomic) signalling. We then discuss the nature of oestradiol signalling in breast cancer including the specific receptors that initiate these signalling cascades as well as potential outcomes, such as cancer growth, proliferation and angiogenesis. Finally, we examine cellular and molecular mechanisms underlying the dimorphic effect of oestrogen signalling in breast cancer. PMID:27160081

  15. Advances in the treatment of advanced oestrogen-receptor-positive breast cancer.

    PubMed

    Turner, Nicholas C; Neven, Patrick; Loibl, Sibylle; Andre, Fabrice

    2016-12-06

    Oestrogen-receptor-positive breast cancer is the most common subtype of breast cancer. Endocrine therapies that target the dependence of this subtype on the oestrogen receptor have substantial activity, yet the development of resistance to therapy is inevitable in advanced cancer. Major progress has been made in identifying the drivers of oestrogen-receptor-positive breast cancer and the mechanisms of resistance to endocrine therapy. This progress has translated into major advances in the treatment of advanced breast cancer, with several targeted therapies that enhance the efficacy of endocrine therapy; inhibitors of mTOR and inhibitors of the cyclin-dependent kinases CDK4 and CDK6 substantially improve progression-free survival. A new wave of targeted therapies is being developed, including inhibitors of PI3K, AKT, and HER2, and a new generation of oestrogen-receptor degraders. Considerable challenges remain in patient selection, deciding on the most appropriate order in which to administer therapies, and establishing whether cross-resistance occurs between therapies.

  16. Hormonal therapy with megestrol in inoperable hepatocellular carcinoma characterized by variant oestrogen receptors.

    PubMed

    Villa, E; Ferretti, I; Grottola, A; Buttafoco, P; Buono, M G; Giannini, F; Manno, M; Bertani, H; Dugani, A; Manenti, F

    2001-04-06

    Variant liver oestrogen receptor transcripts in hepatocellular carcinoma are associated with aggressive clinical course and unresponsiveness to tamoxifen. To evaluate the impact on survival and on tumour growth of megestrol (progestin drug acting at post-receptorial level) we enrolled 45 patients with HCC characterized by variant liver oestrogen receptors in a prospective, randomized study with megestrol vs. placebo. Presence of variant oestrogen receptors was determined by RT/PCR. 24 patients were randomized to no treatment and 21 to therapy with megestrol 160 mg day(-1). Results were analysed by Kaplan-Meier and Cox methods. Survival of hepatocellular carcinoma characterized by variant oestrogen receptors was extremely poor (median survival 7 months); megestrol significantly improved survival (18 months) (P = 0.0090). Tumour growth at one year was significantly slowed down in megestrol-treated patients (P = 0.0212). Bilirubin levels, presence of portal thrombosis, HBV aetiology and treatment were identified at univariate analysis as factors significantly associated with survival; at multivariate analysis, only megestrol therapy (P = 0.0003), presence of HBV infection (P = 0.0009) and presence of portal vein thrombosis (P = 0.0051) were factors independently related with survival. (1) Megestrol slows down the aggressive tumour growth of patients with hepatocellular carcinoma characterized by variant estrogen receptors and (2) is also able to favourably influence the course of disease, more than doubling median survival.

  17. Oestrogen directly inhibits the cardiovascular L-type Ca{sup 2+} channel Ca{sub v}1.2

    SciTech Connect

    Ullrich, Nina D. . E-mail: ullrich@pyl.unibe.ch; Koschak, Alexandra; MacLeod, Kenneth T.

    2007-09-21

    Oestrogen can modify the contractile function of vascular smooth muscle and cardiomyocytes. The negative inotropic actions of oestrogen on the heart and coronary vasculature appear to be mediated by L-type Ca{sup 2+} channel (Ca{sub v}1.2) inhibition, but the underlying mechanisms remain elusive. We tested the hypothesis that oestrogen directly inhibits the cardiovascular L-type Ca{sup 2+} current, I {sub CaL}. The effect of oestrogen on I {sub CaL} was measured in Ca{sub v}1.2-transfected HEK-293 cells using the whole-cell patch-clamp technique. The current revealed typical activation and inactivation profiles of nifedipine- and cadmium-sensitive I {sub CaL}. Oestrogen (50 {mu}M) rapidly reduced I {sub CaL} by 50% and shifted voltage-dependent activation and availability to more negative potentials. Furthermore, oestrogen blocked the Ca{sup 2+} channel in a rate-dependent way, exhibiting higher efficiency of block at higher stimulation frequencies. Our data suggest that oestrogen inhibits I {sub CaL} through direct interaction of the steroid with the channel protein.

  18. Screening the foods of an endangered parrot, the kakapo (Strigops habroptilus), for oestrogenic activity using a recombinant yeast bioassay.

    PubMed

    Fidler, A E; Zwart, S; Pharis, R P; Weston, R J; Lawrence, S B; Jansen, P; Elliott, G; Merton, D V

    2000-01-01

    In recent years the possibility of environmental oestrogens affecting the reproduction of vertebrates has become an issue of both public and scientific interest. Although the significance of such chemicals remains controversial there is clear evidence that, in some contexts, environmental oestrogens can influence the fertility of vertebrates. Highly endangered species represent a situation in which even modest reductions in the fertility of key individuals may have implications for the survival of the entire species. This paper reports the screening of both natural and supplementary foods of the kakapo (Strigops habroptilus), a critically endangered New Zealand nocturnal parrot, for oestrogenic activity using a recombinant yeast based bioassay. Low levels of oestrogenic activity were detected in one of the 'chick-raising' foods, but no oestrogenic activity was detected in the adult supplementary foods. The oestrogenicity of a range of phytochemicals possibly associated with the kakapo natural diet was also examined. Two such phytochemicals, podocarpic acid and its reduced derivative podocarpinol, showed weak oestrogenic activity (approximately 10(-6) and 10(-4) of the activity of 17-beta-oestradiol, respectively).

  19. Binding of modulators to mouse and human multidrug resistance P-glycoprotein. A computational study.

    PubMed

    Jara, Gabriel E; Vera, D Mariano A; Pierini, Adriana B

    2013-11-01

    The human multidrug resistance (MDR) P-glycoprotein (P-gp) mediates the extrusion of chemotherapeutic drugs from cancer cells. Modulators are relevant pharmaceutical targets since they are intended to control or to inhibit its pumping activity. In the present work, a common binding site for Rhodamine 123 and modulators with different modulation activity was found by molecular docking over the crystal structure of the mouse P-gp. The modulators involved a family of compounds, including derivatives of propafenone (3-phenylpropiophenone nucleus) and XR9576 (tariquidar). Our results showed that the relative binding energies estimated by molecular docking were in good correlation with the experimental activities. Preliminary classical molecular dynamics results on selected P-gp/modulator complexes were also performed in order to understand the nature of the prevalent molecular interactions and the possible main molecular features that characterize a modulator. Besides, the results obtained with a human P-gp homology model from the mouse structure are also presented and analyzed. Our observations suggest that the hydrophobicity and molecular flexibility are the main features related to the inhibitory activity. The latter factor would increase the modulator ability to fit the aromatic rings inside the transmembrane domain.

  20. Nutrition modulation of human aging: The calorie restriction paradigm.

    PubMed

    Das, Sai Krupa; Balasubramanian, Priya; Weerasekara, Yasoma K

    2017-11-05

    Globally, the aging population is growing rapidly, creating an urgent need to attenuate age-related health conditions, including metabolic disease and disability. A promising strategy for healthy aging based on consistently positive results from studies with a variety of species, including non-human primates (NHP), is calorie restriction (CR), or the restriction of energy intake while maintaining intake of essential nutrients. The burgeoning evidence for this approach in humans is reviewed and the major study to date to address this question, CALERIE (Comprehensive Assessment of the Long-term Effects of Reducing Intake of Energy), is described. CALERIE findings indicate the feasibility of CR in non-obese humans, confirm observations in NHP, and are consistent with improvements in disease risk reduction and potential anti-aging effects. Finally, the mechanisms of CR in humans are reviewed which sums up the fact that evolutionarily conserved mechanisms mediate the anti-aging effects of CR. Overall, the prospect for further research in both NHP and humans is highly encouraging. Copyright © 2017 Elsevier B.V. All rights reserved.

  1. Is colour modulation an independent factor in human visual photosensitivity?

    PubMed

    Parra, Jaime; Lopes da Silva, Fernando H; Stroink, Hans; Kalitzin, Stiliyan

    2007-06-01

    Considering that the role of colour in photosensitive epilepsy (PSE) remains unclear, we designed a study to determine the potential of different colours, colour combinations and white light to trigger photoparoxysmal responses (PPRs) under stringent controlled conditions. After assessing their photosensitivity to stroboscopic white light and black and white patterns, we studied 43 consecutive PSE patients (mean age 19 years, 34 women), using a specially designed colour stimulator. Stimuli included: pulse trains between 10 and 30 Hz of white light and of all primary colours, and also isoluminant alternating time-sequences of colours. Illuminance was kept constant at 100 lux. A progressive stepwise increase of the modulation-depth (MD) of the stimuli was used to determine PPRs threshold. Whereas all the 43 patients were found to be sensitive during the stroboscopic and pattern protocol, only 25 showed PPRs (Waltz's score >2) at least in one session when studied with the colour stimulator. Coloured stimuli elicited PPRs in all these patients, whereas white light did so only in 17 patients. Of the primary colours, red elicited more PPRs (54 in 22 patients) and at a lower MD (max Z-score 0.93 at 10 Hz). Of the alternating sequences, the red-blue was the most provocative stimulus, especially below 30 Hz (100% of patients, max Z-score: 1.65 at 15 Hz). Blue-green was the least provocative stimulus, since it elicited only seven PPRs in seven (28%) patients (max Z-score 0.44 at 10 Hz). Sensitivity to alternating colours was not correlated to sensitivity to individual colours. We conclude that colour sensitivity follows two different mechanisms: one, dependent on colour modulation, plays a role at lower frequencies (<30 Hz). Another, dependent on single-colour light intensity modulation correlates to white light sensitivity and is activated at higher frequencies. Our results suggest that the prescription of spectacles with coloured lenses, tailored to the patient, can be an

  2. Human Envelope Following Responses to Amplitude Modulation: Effects of Aging and Modulation Depth.

    PubMed

    Dimitrijevic, Andrew; Alsamri, Jamal; John, M Sasha; Purcell, David; George, Sahara; Zeng, Fan-Gang

    2016-01-01

    To record envelope following responses (EFRs) to monaural amplitude-modulated broadband noise carriers in which amplitude modulation (AM) depth was slowly changed over time and to compare these objective electrophysiological measures to subjective behavioral thresholds in young normal hearing and older subjects. three groups of subjects included a young normal-hearing group (YNH 18 to 28 years; pure-tone average = 5 dB HL), a first older group ("O1"; 41 to 62 years; pure-tone average = 19 dB HL), and a second older group ("O2"; 67 to 82 years; pure-tone average = 35 dB HL). Electrophysiology: In condition 1, the AM depth (41 Hz) of a white noise carrier, was continuously varied from 2% to 100% (5%/s). EFRs were analyzed as a function of the AM depth. In condition 2, auditory steady-state responses were recorded to fixed AM depths (100%, 75%, 50%, and 25%) at a rate of 41 Hz. Psychophysics: A 3 AFC (alternative forced choice) procedure was used to track the AM depth needed to detect AM at 41 Hz (AM detection). The minimum AM depth capable of eliciting a statistically detectable EFR was defined as the physiological AM detection threshold. Across all ages, the fixed AM depth auditory steady-state response and swept AM EFR yielded similar response amplitudes. Statistically significant correlations (r = 0.48) were observed between behavioral and physiological AM detection thresholds. Older subjects had slightly higher (not significant) behavioral AM detection thresholds than younger subjects. AM detection thresholds did not correlate with age. All groups showed a sigmoidal EFR amplitude versus AM depth function but the shape of the function differed across groups. The O2 group reached EFR amplitude plateau levels at lower modulation depths than the normal-hearing group and had a narrower neural dynamic range. In the young normal-hearing group, the EFR phase did not differ with AM depth, whereas in the older group, EFR phase showed a consistent decrease with increasing

  3. Modulation of early human preadipocyte differentiation by glucocorticoids.

    PubMed

    Tomlinson, Julianna J; Boudreau, Adèle; Wu, Dongmei; Atlas, Ella; Haché, Robert J G

    2006-11-01

    Glucocorticoids provide an adipogenic stimulus that is most obvious in the truncal obesity of patients with Cushing's syndrome. Glucocorticoid treatment also strongly potentiates the differentiation of human preadipocytes in culture. However, the molecular basis of these stimulatory effects remains to be defined. In this study, we provide a detailed analysis of the specific contribution of glucocorticoid treatment to the differentiation of primary human preadipocytes cultured in chemically defined medium. Contrary to previous descriptions of glucocorticoids being required throughout the course of differentiation, our results show that glucocorticoid treatment is stimulatory only during the first 48 h of differentiation. Furthermore, stimulation by glucocorticoids and the peroxisome proliferator activator receptor-gamma agonist troglitazone is mediated sequentially. Several details of the early events in the differentiation of human preadipocytes and the contribution of steroid to these events differ from the responses observed previously in murine preadipocyte models. First, glucocorticoid treatment stimulated the early accumulation of CCAAT enhancer binding protein-beta (C/EBPbeta) in primary human preadipocytes. Second, induction of C/EBPalpha in primary human preadipocytes was noted within 4 h of adipogenic stimulus, whereas C/EBPalpha induction is not detected until 24-48 h in the murine 3T3 L1 preadipocyte model. Remarkably, by contrast to human primary preadipocytes, which do not undergo postconfluent mitosis, 3T3 L1 murine preadipocytes stimulated to differentiate under chemically defined conditions required glucocorticoids to survive the clonal expansion that precedes terminal differentiation, revealing a novel signal imparted by glucocorticoids in this immortalized murine cell system.

  4. Effects of chronic oestrogen treatment are not selective for uterine noradrenaline-containing sympathetic nerves: a transplantation study

    PubMed Central

    BRAUER, M. MONICA; CHAVEZ-GENARO, REBECA; LLODRA, JAIME; RICHERI, ANALIA; SCORZA, M. CECILIA

    2000-01-01

    Previous studies have shown that chronic administration of oestrogen during postnatal rat development dramatically reduces the total content of noradrenaline in the uterine horn, abolishes myometrial noradrenergic innervation and reduces noradrenaline-fluorescence intensity of intrauterine perivascular nerve fibres. In the present study we analysed if this response is due to a direct and selective effect of oestrogen on the uterine noradrenaline-containing sympathetic nerves, using the in oculo transplantation method. Small pieces of myometrium from prepubertal rats were transplanted into the anterior eye chamber of adult ovariectomised host rats. The effect of systemic chronic oestrogen treatment on the reinnervation of the transplants by noradrenaline-containing sympathetic fibres from the superior cervical ganglion was analysed on cryostat tissue sections processed by the glyoxylic acid technique. In addition, the innervation of the host iris was assessed histochemically and biochemically. The histology of the transplants and irises was examined in toluidine blue-stained semithin sections. These studies showed that after 5 wk in oculo, the overall size of the oestrogen-treated transplants was substantially larger than controls, and histology showed that this change was related to an increase in the size and number of smooth muscle cells within the transplant. Chronic oestrogen treatment did not provoke trophic changes in the irideal muscle. Histochemistry showed that control transplants had a rich noradrenergic innervation, associated with both myometrium and blood vessels. Conversely, in oestrogen-treated transplants only occasional fibres were recognised, showing a reduced NA fluorescence intensity. No changes in the pattern and density of innervation or in the total content of noradrenaline of the host irises were detected after chronic exposure to oestrogen. We interpreted these results to indicate that the effects of oestrogen on uterine noradrenaline

  5. Prolonged oestrogen treatment does not correlate with a sustained increase in anterior pituitary mitotic index in ovariectomized Wistar rats.

    PubMed

    Nolan, L A; Levy, A

    2009-03-01

    Oestrogen is a powerful mitogen that is believed to exert a continuous, dose-dependent trophic stimulus at the anterior pituitary. This persistent mitotic effect contrasts with corticosterone and testosterone, changes in the levels of which induce only transient, self-limiting fluctuations in pituitary mitotic activity. To further define the putative long-term trophic effects of oestrogen, we have accurately analysed the effects of 7 and 28 days oestrogen treatment on anterior pituitary mitotic activity in ovariectomized 10-week-old Wistar rats using both bromodeoxyuridine (BrdU) and timed colchicine-induced mitotic arrest. An oestrogen dose-dependent increase in mitotic index was seen 7 days after the start of treatment as expected, representing an acceleration in gross mitotic activity from 1.7%/day in ovariectomized animals in the absence of any oestrogen replacement to 3.7%/day in the presence of a pharmacological dose of oestrogen (50 mcg/rat per day: approximately 230 mcg/kg per day). Despite continued exposure to high-dose oestrogen and persistence of the increase in pituitary wet weight, the increase in mitotic index was unexpectedly not sustained. After 28 days of high-dose oestrogen treatment, anterior pituitary mitotic index and BrdU-labelling index were not significantly different from baseline. Although a powerful pituitary mitogen in the short term, responsible, presumably, for increased trophic variability in oestrus cycling females, these data indicate that in keeping with other trophic stimuli to the pituitary and in contrast to a much established dogma, the mitotic response to longer-term high-dose oestrogen exposure is transient and is not the driver of persistent pituitary growth, at least in female Wistar rats.

  6. Attentional modulation of temporal contrast sensitivity in human vision.

    PubMed

    Motoyoshi, Isamu

    2011-04-25

    Recent psychophysical studies have shown that attention can alter contrast sensitivities for temporally broadband stimuli such as flashed gratings. The present study examined the effect of attention on the contrast sensitivity for temporally narrowband stimuli with various temporal frequencies. Observers were asked to detect a drifting grating of 0-40 Hz presented gradually in the peripheral visual field with or without a concurrent letter identification task in the fovea. We found that removal of attention by the concurrent task reduced the contrast sensitivity for gratings with low temporal frequencies much more profoundly than for gratings with high temporal frequencies and for flashed gratings. The analysis revealed that the temporal contrast sensitivity function had a more band-pass shape with poor attention. Additional experiments showed that this was also true when the target was presented in various levels of luminance noise. These results suggest that regardless of the presence of external noise, attention extensively modulates visual sensitivity for sustained retinal inputs.

  7. Effects of intensity-modulated radiotherapy on human oral microflora.

    PubMed

    Shao, Zi-Yang; Tang, Zi-Sheng; Yan, Chao; Jiang, Yun-Tao; Ma, Rui; Liu, Zheng; Huang, Zheng-Wei

    2011-01-01

    This study aimed to evaluate changes in the biodiversity of the oral microflora of patients with head and neck cancer treated with postoperative intensity-modulated radiotherapy (IMRT) or conventional radiotherapy (CRT). Pooled dental plaque samples were collected during the radiation treatment from patients receiving IMRT (n = 13) and CRT (n = 12). Denaturing gradient gel electrophoresis (DGGE) was used to analyze the temporal variation of these plaque samples. The stimulated and unstimulated salivary flow rates were also compared between IMRT and CRT patients. Reductions in the severity of hyposalivation were observed in IMRT patients compared with CRT patients. We also observed that the temporal stability of the oral ecosystem was significantly higher in the IMRT group (69.96 ± 7.82%) than in the CRT group (51.98 ± 10.45%) (P < 0.05). The findings of the present study suggest that IMRT is more conducive to maintaining the relative stability of the oral ecosystem than CRT.

  8. Modulation of Human Immune Response by Fungal Biocontrol Agents

    PubMed Central

    Konstantinovas, Cibele; de Oliveira Mendes, Tiago A.; Vannier-Santos, Marcos A.; Lima-Santos, Jane

    2017-01-01

    Although the vast majority of biological control agents is generally regarded as safe for humans and environment, the increased exposure of agriculture workers, and consumer population to fungal substances may affect the immune system. Those compounds may be associated with both intense stimulation, resulting in IgE-mediated allergy and immune downmodulation induced by molecules such as cyclosporin A and mycotoxins. This review discusses the potential effects of biocontrol fungal components on human immune responses, possibly associated to infectious, inflammatory diseases, and defective defenses. PMID:28217107

  9. Modulation of human sinus node function by systemic hypoxia

    NASA Technical Reports Server (NTRS)

    Eckberg, D. L.; Bastow, H., III; Scruby, A. E.

    1982-01-01

    The present study was conducted to determine whether bradycardia develops during systemic hypoxia in supine conscious human volunteers when respiratory frequency and tidal volume are maintained at constant levels. The obtained results suggest that mild hypoxia provokes cardioacceleration in humans, independent of changes of ventilation or baroreflex responsiveness. The earliest cardioacceleration is more prominent in the inspiratory than in the expiratory phase of respiration, and occurs with very small reductions of arterial oxygen saturation. Moderate systemic hypoxia dampens fluctuations of heart rate during the respiratory cycle.

  10. Modulation of Human Immune Response by Fungal Biocontrol Agents.

    PubMed

    Konstantinovas, Cibele; de Oliveira Mendes, Tiago A; Vannier-Santos, Marcos A; Lima-Santos, Jane

    2017-01-01

    Although the vast majority of biological control agents is generally regarded as safe for humans and environment, the increased exposure of agriculture workers, and consumer population to fungal substances may affect the immune system. Those compounds may be associated with both intense stimulation, resulting in IgE-mediated allergy and immune downmodulation induced by molecules such as cyclosporin A and mycotoxins. This review discusses the potential effects of biocontrol fungal components on human immune responses, possibly associated to infectious, inflammatory diseases, and defective defenses.

  11. A new module for quantitative evaluation of repellent efficacy using human subjects.

    PubMed

    Klun, J A; Debboun, M

    2000-01-01

    A new module for quantitative evaluation of arthropod repellents in human subjects was designed, constructed, and protocols for use of the module were developed. Doses of 3 arthropod repellents, 1-[3-cyclohexen-1-ylcarbonyl] piperidine (AI3-35765), 1-[3-cyclohexen-1-ylcarbonyl]-2-methylpiperidine (AI3-37220), and N,N-diethyl-3-methylbenzamide (deet), were evaluated using the mosquito, Anopheles stephensi Liston. Biting responses to varied doses of the repellents on human skin were quantified, and the effectiveness of the 3 repellents was compared. The new module consists of 6 test cells and permits the simultaneous comparison of up to 5 repellent doses or chemical types and a control using a complete randomized block design with minimal treatment interaction and with > or = 6 replicates per human subject.

  12. Human connectome module pattern detection using a new multi-graph MinMax cut model.

    PubMed

    De, Wang; Wang, Yang; Nie, Feiping; Yan, Jingwen; Cai, Weidong; Saykin, Andrew J; Shen, Li; Huang, Heng

    2014-01-01

    Many recent scientific efforts have been devoted to constructing the human connectome using Diffusion Tensor Imaging (DTI) data for understanding the large-scale brain networks that underlie higher-level cognition in human. However, suitable computational network analysis tools are still lacking in human connectome research. To address this problem, we propose a novel multi-graph min-max cut model to detect the consistent network modules from the brain connectivity networks of all studied subjects. A new multi-graph MinMax cut model is introduced to solve this challenging computational neuroscience problem and the efficient optimization algorithm is derived. In the identified connectome module patterns, each network module shows similar connectivity patterns in all subjects, which potentially associate to specific brain functions shared by all subjects. We validate our method by analyzing the weighted fiber connectivity networks. The promising empirical results demonstrate the effectiveness of our method.

  13. Distinct sets of locomotor modules control the speed and modes of human locomotion

    PubMed Central

    Yokoyama, Hikaru; Ogawa, Tetsuya; Kawashima, Noritaka; Shinya, Masahiro; Nakazawa, Kimitaka

    2016-01-01

    Although recent vertebrate studies have revealed that different spinal networks are recruited in locomotor mode- and speed-dependent manners, it is unknown whether humans share similar neural mechanisms. Here, we tested whether speed- and mode-dependence in the recruitment of human locomotor networks exists or not by statistically extracting locomotor networks. From electromyographic activity during walking and running over a wide speed range, locomotor modules generating basic patterns of muscle activities were extracted using non-negative matrix factorization. The results showed that the number of modules changed depending on the modes and speeds. Different combinations of modules were extracted during walking and running, and at different speeds even during the same locomotor mode. These results strongly suggest that, in humans, different spinal locomotor networks are recruited while walking and running, and even in the same locomotor mode different networks are probably recruited at different speeds. PMID:27805015

  14. Flexion reflex modulation during stepping in human spinal cord injury.

    PubMed

    Knikou, Maria; Angeli, Claudia A; Ferreira, Christie K; Harkema, Susan J

    2009-07-01

    The flexion reflex modulation pattern was investigated in nine people with a chronic spinal cord injury during stepping using body weight support on a treadmill and manual assistance by therapists. Body weight support was provided by an upper body harness and was adjusted for each subject to promote the best stepping pattern with the least manual assistance required by the therapists. The flexion reflex was elicited by sural nerve stimulation with a 30 ms pulse train at 1.2-2 times the tibialis anterior reflex threshold. During stepping, stimuli were randomly dispersed across the gait cycle which was divided into 16 equal bins. A long latency (>110 ms) flexion reflex was present in all subjects, while a short (>30 ms) and a medium latency (>70 ms) flexion reflex were present only in three subjects. For each response, the non-stimulated EMG was subtracted from the stimulated EMG at identical time windows and bins, normalized to the maximal corresponding EMG, and significant differences were established with a Wilcoxon rank-sum test. The long latency flexion reflex was facilitated at late stance and during the swing-to-stance transition phase. A reflex depression was present from heel strike until mid-stance and during the swing-to-stance transition phase. The short and medium latency flexion reflexes were depressed during mid-stance followed by facilitation during the stance-to-swing transition phase. Regardless of the latency, facilitatory flexion responses during the swing phase coincided with decreased activity of ipsilateral ankle extensors. The flexion reflex was modulated in a phase dependent manner, a behavior that was absent for the soleus H-reflex in most of these patients (Knikou et al. in Exp Brain Res 193:397-407, 2009). We propose that training should selectively target spinal reflex circuits in which extensor muscles and reflexes are involved in order to maximize sensorimotor recovery in these patients.

  15. Head temperature modulates thermal behavior in the cold in humans

    PubMed Central

    Mündel, Toby; Raman, Aaron; Schlader, Zachary J.

    2016-01-01

    ABSTRACT We tested the hypothesis that skin temperature, specifically of the head, is capable of modulating thermal behavior during exercise in the cold. Following familiarization 8 young, healthy, recreationally active males completed 3 trials, each consisting of 30 minutes of self-paced cycle ergometry in 6°C. Participants were instructed to control their exercise work rate to achieve and maintain thermal comfort. On one occasion participants wore only shorts and shoes (Control) and on the 2 other occasions their head was either warmed (Warming) or cooled (Cooling). Work rate, rate of metabolic heat production, thermal perceptions, rectal, mean weighted skin and head temperatures were measured. Exercise work rate was reduced during Warming and augmented during Cooling after the first and second minutes of exercise, respectively (P ≤ 0.04), with the rate of metabolic heat production mirroring work rate. At this early stage of exercise (≤5 min) the changes over time for rectal temperature were negligible and similar (0.1 ± 0.1°C, P = 0.51), while the decrease in mean skin temperature was not different between all trials (1.7 ± 0.6°C, P = 0.13). Mean head temperature was either decreased (Control: 1.5 ± 1.1°C, Cooling: 2.9 ± 0.8°C, both P < 0.01) or increased (Warming: 1.7 ± 0.9°C, P < 0.01). Head thermal perception was warmer and more comfortable in Warming and cooler and less comfortable in Cooling (P < 0.01). Participants achieved thermal comfort similarly in all trials (P > 0.09) after 10 ± 7 min and this was maintained until the end of exercise. These results indicate that peripheral temperatures modulate thermal behavior in the cold. PMID:27857959

  16. Modulation of head movement control in humans during treadmill walking.

    PubMed

    Mulavara, Ajitkumar P; Verstraete, Mary C; Bloomberg, Jacob J

    2002-12-01

    The purpose of this study was to investigate the coordination of the head relative to the trunk within a gait cycle during gaze fixation. Nine normal subjects walked on a motorized treadmill driven at 1.79 m/s (20 s trials) while fixing their gaze on a centrally located earth-fixed target positioned at a distance of 2 m from their eyes. The net and relative angular motions of the head about the three axes of rotations, as well as the corresponding values for the moments acting on it relative to the trunk during the gait cycle were quantified and used as measures of coordination. The average net moment, as well as the average moments about the different axes were significantly different (P<0.01) between the high impact and low/no impact phases of the gait cycle. However, the average net angular displacement as well as the average angular displacement about the axial rotation axis of the head relative to the trunk was maintained uniform (P>0.01) throughout the gait cycle. The average angular displacement about the lateral bending axis was significantly increased (P<0.01) during the high impact phase while that about the flexion-extension axis was significantly decreased (P<0.01) throughout the gait cycle. Thus, the coordination of the motion of the head relative to the trunk during walking is dynamically modulated depending on the behavioral events occurring in the gait cycle. This modulation may serve to aid stabilization of the head by counteracting the force variations acting on the upper body that may aid in the visual fixation of targets during walking.

  17. Modulation of head movement control in humans during treadmill walking

    NASA Technical Reports Server (NTRS)

    Mulavara, Ajitkumar P.; Verstraete, Mary C.; Bloomberg, Jacob J.

    2002-01-01

    The purpose of this study was to investigate the coordination of the head relative to the trunk within a gait cycle during gaze fixation. Nine normal subjects walked on a motorized treadmill driven at 1.79 m/s (20 s trials) while fixing their gaze on a centrally located earth-fixed target positioned at a distance of 2 m from their eyes. The net and relative angular motions of the head about the three axes of rotations, as well as the corresponding values for the moments acting on it relative to the trunk during the gait cycle were quantified and used as measures of coordination. The average net moment, as well as the average moments about the different axes were significantly different (P<0.01) between the high impact and low/no impact phases of the gait cycle. However, the average net angular displacement as well as the average angular displacement about the axial rotation axis of the head relative to the trunk was maintained uniform (P>0.01) throughout the gait cycle. The average angular displacement about the lateral bending axis was significantly increased (P<0.01) during the high impact phase while that about the flexion-extension axis was significantly decreased (P<0.01) throughout the gait cycle. Thus, the coordination of the motion of the head relative to the trunk during walking is dynamically modulated depending on the behavioral events occurring in the gait cycle. This modulation may serve to aid stabilization of the head by counteracting the force variations acting on the upper body that may aid in the visual fixation of targets during walking.

  18. Cytokine modulation of human blood viscosity from vivax malaria patients.

    PubMed

    Scherer, Edson Fredulin; Cantarini, Déborah Giovanna; Siqueira, Renan; Ribeiro, Elton Brito; Braga, Érika Martins; Honório-França, Adenilda Cristina; França, Eduardo Luzía

    2016-06-01

    Malaria is a major infectious disease in several countries and is caused by protozoa of the genus Plasmodium. In vivax malaria patients, inflammatory processes occur, as well as changes in cytokines and blood flow. The present study analyzed the cytokine modulation of blood viscosity from patients infected with Plasmodium vivax (P. vivax). Blood samples were collected from 42 non-infected individuals (control group) and 37 individuals infected with P. vivax. The IL-2, IL-4, IL-6, IL-10, TNFα, TGF-β and IL-17 cytokine concentrations in the serum were assessed, and the blood rheological properties were determined. The analysis of blood viscosity for shear rates revealed that the blood viscosity of the infected patients was significantly greater than that of the non-infected individuals. The viscosity of the blood was greater in the infected individuals than in the non-infected subjects. The serum from individuals with P. vivax infections exhibited higher IFN-γ and IL-17 concentrations and lower TGF-β levels. Incubation of the blood from infected individuals with IL-17 or IL-17 associated with IFN-γ reduced the viscosity to rates equivalent to the blood from non-infected individuals. Independently of cytokine modulation, no correlation was found between the parasitemia and blood viscosity of the infected patients. These data suggest that the alterations of blood viscosity are relevant as an auxiliary tool for the clinical diagnosis of disease. In malaria, erythrocytes are more sensitive to osmotic shock, and the reduction of viscosity by IL-17 may be related to a possible immunomodulator agent during infection.

  19. Modulation of head movement control in humans during treadmill walking

    NASA Technical Reports Server (NTRS)

    Mulavara, Ajitkumar P.; Verstraete, Mary C.; Bloomberg, Jacob J.

    2002-01-01

    The purpose of this study was to investigate the coordination of the head relative to the trunk within a gait cycle during gaze fixation. Nine normal subjects walked on a motorized treadmill driven at 1.79 m/s (20 s trials) while fixing their gaze on a centrally located earth-fixed target positioned at a distance of 2 m from their eyes. The net and relative angular motions of the head about the three axes of rotations, as well as the corresponding values for the moments acting on it relative to the trunk during the gait cycle were quantified and used as measures of coordination. The average net moment, as well as the average moments about the different axes were significantly different (P<0.01) between the high impact and low/no impact phases of the gait cycle. However, the average net angular displacement as well as the average angular displacement about the axial rotation axis of the head relative to the trunk was maintained uniform (P>0.01) throughout the gait cycle. The average angular displacement about the lateral bending axis was significantly increased (P<0.01) during the high impact phase while that about the flexion-extension axis was significantly decreased (P<0.01) throughout the gait cycle. Thus, the coordination of the motion of the head relative to the trunk during walking is dynamically modulated depending on the behavioral events occurring in the gait cycle. This modulation may serve to aid stabilization of the head by counteracting the force variations acting on the upper body that may aid in the visual fixation of targets during walking.

  20. Oestrogen action on thyroid progenitor cells: relevant for the pathogenesis of thyroid nodules?

    PubMed

    Xu, Shuhang; Chen, Guofang; Peng, Wen; Renko, Kostja; Derwahl, Michael

    2013-07-01

    Benign and malignant thyroid nodules are more prevalent in females than in males. Experimental data suggest that the proliferative effect of oestrogen rather than polymorphisms is responsible for this gender difference. This study analysed whether both differentiated thyroid cells and thyroid stem and progenitor cells are targets of oestrogen action. In thyroid stem/progenitor cells derived from nodular goitres, the ability of 17β-oestradiol (E₂) to induce the formation of thyrospheres and the expression of oestrogen receptors (ERs) and the effect of E₂ on the growth and expression of markers of stem cells and thyroid differentiation (TSH receptor, thyroperoxidase, thyroglobulin and sodium iodide symporter (NIS)) were analysed. E₂ induced thyrosphere formation, albeit to a lower extent than other growth factors. Thyroid stem and progenitor cells expressed ERα (ESR1) and ERβ (ESR2) with eight times higher expression levels of ERα mRNA compared with the differentiated thyrocytes. E₂ was a potent stimulator of the growth of thyroid stem/progenitor cells. In contrast, TSH-induced differentiation of progenitor cells, in particular, the expression of NIS, was significantly inhibited by E₂. In conclusion, oestrogen stimulated the growth and simultaneously inhibited the differentiation of thyroid nodule-derived stem/progenitor cells. From these data and based on the concept of cellular heterogeneity, we hypothesize a supportive role of oestrogen in the propagation of thyroid stem/progenitor cells leading to the selection of a progeny of growth-prone cells with a decreased differentiation. These cells may be the origin of hypofunctioning or non-functioning thyroid nodules in females.

  1. Oestrogen levels in serum and urine of premenopausal women eating low and high amounts of meat.

    PubMed

    Harmon, Brook E; Morimoto, Yukiko; Beckford, Fanchon; Franke, Adrian A; Stanczyk, Frank Z; Maskarinec, Gertraud

    2014-09-01

    Based on the hypothesis that high-meat diets may increase breast cancer risk through hormonal pathways, the present analysis compared oestrogens in serum and urine by meat-eating status. Intervention with repeated measures. Two randomized soya trials (BEAN1 and BEAN2) among premenopausal healthy women. BEAN1 participants completed seven unannounced 24 h dietary recalls and donated five blood and urine samples over 2 years. BEAN2 women provided seven recalls and three samples over 13 months. Serum samples were analysed for oestrone (E₁) and oestradiol (E₂) using RIA. Nine oestrogen metabolites were measured in urine by LC-MS. Semi-vegetarians included women who reported consuming <30 g of red meat, poultry and fish daily, and pescatarians those who reported consuming <20 g of meat/poultry but >10 g of fish daily. All other women were classified as non-vegetarians. We applied mixed models to compute least-square means by vegetarian status adjusted for potential confounders. The mean age of the 272 participants was 41·9 (SD 4·5) years. Serum E₁ (85 v. 100 pg/ml, P = 0·04) and E₂ (140 v. 154 pg/ml, P = 0·04) levels were lower in the thirty-seven semi-vegetarians than in the 235 non-vegetarians. The sum of the nine urinary oestrogen metabolites (183 v. 200 pmol/mg creatinine, P = 0·27) and the proportions of individual oestrogens and pathways did not differ by meat-eating status. Restricting the models to the samples collected during the luteal phase strengthened the associations. Given the limitations of the study, the lower levels of serum oestrogens in semi-vegetarians than non-vegetarians need confirmation in larger populations.

  2. Endogenous oestrogens predict 4-year decline in verbal fluency in postmenopausal women: the Rancho Bernardo Study.

    PubMed

    Laughlin, Gail A; Kritz-Silverstein, Donna; Barrett-Connor, Elizabeth

    2010-01-01

    Despite overwhelming biological plausibility, evidence for a protective effect of oestrogen on cognitive function in postmenopausal women is inconsistent. This study examines the association between endogenous oestrogen levels and subsequent 4-year decline in cognitive function test performance in community-dwelling older women. Longitudinal cohort study. Three hundred and forty-three postmenopausal women (median age 70 years). Between 1984 and 1987, serum for measurement of sex hormones was obtained along with relevant covariates. Cognitive function was assessed in 1988-1991 and again in 1992-1996 using the Category Fluency test, the Mini-Mental Status Exam (MMSE) and Trail Making Test B (Trails B). Women in the highest tertile of oestrone and bioavailable oestradiol had respectively 1.75 (95% CI 1.02, 3.07) and 1.79 (95% CI 1.04, 3.10) higher odds of 4 year decline in Category Fluency, a test of frontal lobe function, compared to those in the lowest tertile, independent of age and education. The 20% of women with highest tertile levels of both oestrone and bioavailable oestradiol had a twofold higher odds of verbal fluency loss (OR = 2.17; 95% CI 1.21, 3.89). Adjustment for testosterone levels or for obesity-related factors associated with high endogenous oestrogens (higher body mass index, waist girth, and triglycerides and lower high-density lipoprotein cholesterol) did not alter results. Neither oestrogen was associated with change in MMSE or Trails B scores. Higher endogenous oestrogen levels were associated with a greater decline in verbal fluency in postmenopausal women. This association was not explained by elevated androgens or by obesity or obesity-related factors.

  3. Adrenal progesterone facilitates the negative feedback of oestrogen on LH release in ovariectomized rats.

    PubMed

    Salicioni, A M; Carón, R W; Deis, R P

    1993-11-01

    There is evidence that the adrenals play a role in the regulation of the synthesis and release of gonadotrophins in various vertebrates. The aim of this study was to determine the part played by adrenal steroids, with special reference to progesterone, on the concentration of LH in ovariectomized (OVX) and oestrogen-primed rats. OVX rats received a single s.c. injection of vehicle or oestradiol benzoate (OB, 20 micrograms/rat). This day was designated as day 0. Three or four days later (day 3-day 4), the rats were treated with mifepristone (10 mg/kg) or with two doses of progesterone antiserum and blood samples were obtained at 13.00 and 18.00 h. OB treatment of OVX rats reduced serum LH at 13.00 h and 18.00 h on day 3 but only at 13.00 h on day 4. The administration of mifepristone at 08.00 h to OVX and oestrogen-treated rats induced a significant increase in serum LH at 18.00 h on days 3 and 4, without modifying the values at 13.00 h. When mifepristone was given at 13.00 h a much larger increase in serum LH was obtained at 18.00 h. In OVX and oestrogen-treated rats, adrenalectomy on day 2 (08.00-09.00 h) induced an increase in serum LH at 18.00 h similar to that observed in the OVX and oestrogen-primed rats after mifepristone treatment. In order to determine the specificity of the effect of mifepristone, a group of OVX and oestrogen-treated rats was injected with progesterone antiserum at 08.00 and 13.00 h on day 3.(ABSTRACT TRUNCATED AT 250 WORDS)

  4. Student feedback about the use of role plays in Sparshanam, a medical humanities module

    PubMed Central

    Shankar, P Ravi

    2012-01-01

    Background: At KIST Medical College, Lalitpur, Nepal, a Medical Humanities module for first year medical students has been conducted. Role plays are used to explore social, medical and sexual issues in the Nepalese context. The present study obtained student feedback about the role plays used in the module, the difficulties faced, and obtained suggestions for further improvement. Method: The module was conducted from January to August 2011 using a total of 15 role plays. Student feedback was obtained using a semi-structured questionnaire. Informal discussions were held and a questionnaire was circulated among the first year students who had participated in the module. Results: Ninety-eight of the 100 students in the module participated in the study. The overall opinion regarding the role plays was positive. Students stated role plays helped to make module objectives concrete and interesting, made students identify with the problem being investigated and improved communication skills. Role plays were designed to address important health issues in Nepal and prepare students for addressing these issues in future practice. A lack of sufficient time for preparing the role plays and initial problems with group dynamics were mentioned by the respondents during the study. Conclusions: Student feedback about the use of role plays during the module was positive. Role plays helped in making module objectives more concrete and interesting, improved communication skills and addressed important health issues in Nepal. Role plays are not resource intensive and can be considered for use in medical schools in developing nations. PMID:24358816

  5. Novel factors modulating human β-cell proliferation.

    PubMed

    Shirakawa, J; Kulkarni, R N

    2016-09-01

    β-Cell dysfunction in type 1 and type 2 diabetes is accompanied by a progressive loss of β-cells, and an understanding of the cellular mechanism(s) that regulate β-cell mass will enable approaches to enhance hormone secretion. It is becoming increasingly recognized that enhancement of human β-cell proliferation is one potential approach to restore β-cell mass to prevent and/or cure type 1 and type 2 diabetes. While several reports describe the factor(s) that enhance β-cell replication in animal models or cell lines, promoting effective human β-cell proliferation continues to be a challenge in the field. In this review, we discuss recent studies reporting successful human β-cell proliferation including WS6, an IkB kinase and EBP1 inhibitor; harmine and 5-IT, both DYRK1A inhibitors; GNF7156 and GNF4877, GSK-3β and DYRK1A inhibitors; osteoprotegrin and Denosmab, receptor activator of NF-kB (RANK) inhibitors; and SerpinB1, a protease inhibitor. These studies provide important examples of proteins and pathways that may prove useful for designing therapeutic strategies to counter the different forms of human diabetes. © 2016 John Wiley & Sons Ltd.

  6. Biphasic modulation of cell growth by recombinant human galectin-1.

    PubMed

    Adams, L; Scott, G K; Weinberg, C S

    1996-06-13

    Human soluble galactose-binding lectin (galectin-1) has been expressed as an Escherichia coli fusion protein, following the amplification by polymerase chain reaction of cDNA prepared from a human osteosarcoma cell line. The fusion protein is a functional beta-galactoside-binding lectin, as is the recombinant galectin when purified from the cleaved fusion protein. The recombinant galectin has a biphasic effect on cell proliferation. Unlike the fusion protein, it functions as a human cell growth inhibitor, confirming earlier findings with natural human galectin-1, though it is less effective than the natural galectin. This reaction is not significantly inhibited by lactose, and is thus largely independent of the beta-galactoside-binding site. At lower concentrations, recombinant galectin-1 is mitogenic, this activity being susceptible to inhibition by lactose, and thus attributable to the beta-galactoside-binding ability of the protein. Some tumour cells are susceptible to the growth-inhibitory effect, and the galectin-1 gene is expressed in both normal and tumour cells.

  7. Human epidermal plasminogen activator. Characterization, localization, and modulation.

    PubMed

    Morioka, S; Jensen, P J; Lazarus, G S

    1985-12-01

    Using biochemical and immunocytochemical approaches, we have investigated the plasminogen activator (PA) of primary human epidermal cell cultures. A rabbit antibody raised against human urinary PA (urokinase) inhibited greater than or equal to 96% of the PA activity in the keratinocyte cultures. Immunoblot and double immunodiffusion analyses of keratinocyte PA with anti-urokinase antibody confirmed that epidermal PA was of the urokinase type. Immunocytochemical investigation of human keratinocyte cultures with anti-urokinase antibody revealed two characteristic staining patterns for PA. First, cells at the advancing edge of subconfluent colonies were cytoplasmically stained in a granular pattern. Similar staining was observed at the migrating edges of confluent epidermal cell cultures that had been wounded by cutting with a blade. This induction of PA staining was independent of cell division. Secondly, differentiated epidermal cells located on the surface of colonies were stained either at the plasma membrane or homogeneously throughout the cell. The highly differentiated, spontaneously shed cells were usually very heavily stained by anti-urokinase antibody. These immunocytochemical experiments suggest that PA expression is highly regulated in human epidermal cells. Specifically, PA expression appears to be related to cellular differentiation and to cell movement in expanding or wounded keratinocyte colonies.

  8. Modulation of Human β-Defensin-1 Production by Viruses.

    PubMed

    Ryan, Lisa Kathleen; Diamond, Gill

    2017-06-21

    While initially identified as a broad-spectrum antimicrobial peptide, constitutively expressed in epithelia, human β-defensin (hBD)-1 is now recognized to have a more complex pattern of expression of its gene, DEFB1, as well as activities that extend beyond direct antimicrobial. These observations suggest a complex role for hBD-1 in the host defense against viral infections, as evidenced by its expression in cells involved in viral defense, and its gene regulation in response to viral challenge. This regulation is observed both in vitro and in vivo in humans, as well as with the murine homolog, mBD-1. While numerous reviews have summarized the existing literature on β-defensin gene expression and activity, here we provide a focused review of relevant studies on the virus-mediated regulation of hBD-1 and how this regulation can provide a crucial aspect of the innate immune defense against viral infection.

  9. Macrophages modulate engineered human tissues for enhanced vascularization and healing

    PubMed Central

    Spiller, Kara L.; Freytes, Donald O.; Vunjak-Novakovic, Gordana

    2014-01-01

    Tissue engineering is increasingly based on recapitulating human physiology, through integration of biological principles into engineering designs. In spite of all progress in engineering functional human tissues, we are just beginning to develop effective methods for establishing blood perfusion and controlling the inflammatory factors following implantation into the host. Functional vasculature largely determines tissue survival and function in vivo. The inflammatory response is a major regulator of vascularization and overall functionality of engineered tissues, through the activity of different types of macrophages and the cytokines they secrete. We discuss cell-scaffold-bioreactor systems for harnessing the inflammatory response for enhanced tissue vascularization and healing. To this end, inert scaffolds that have been considered for many decades a “gold standard” in regenerative medicine are beginning to be replaced by a new generation of “smart” tissue engineering systems designed to actively mediate tissue survival and function. PMID:25331098

  10. Pharmacological modulation of human platelet leukotriene C4-synthase.

    PubMed

    Sala, A; Folco, G; Henson, P M; Murphy, R C

    1997-03-21

    The aim of this study was to test if human platelet leukotriene C4-synthase (LTC4-S) is pharmacologically different from cloned and expressed LTC4-S and, in light of the significant homologies between 5-lipoxygenase activating protein (FLAP) and LTC4-S, if different potencies of leukotriene synthesis inhibitors acting through binding with FLAP (FLAP inhibitors) reflect in different potencies as LTC4-S inhibitors. Leukotriene C4 (LTC4) synthesis by washed human platelets supplemented with synthetic leukotriene A4 (LTA4) was studied in the absence and presence of two different, structurally unrelated FLAP inhibitors (MK-886 and BAY-X1005) as well as a direct 5-lipoxygenase inhibitor (zileuton). LTC4 production was analyzed by RP-HPLC coupled to diode array detection. We report that human platelet LTC4-S was inhibited by MK-886 and BAY-X1005 (IC50 of 4.7 microM and 91.2 microM, respectively), but not by zileuton (inactive up to 300 microM); all 3 compounds were able to inhibit 5-lipoxygenase metabolite biosynthesis in intact human polymorphonuclear leukocytes (IC50 of 0.044 microM, 0.85 microM, and 1.5 microM, respectively). Platelet LTC4-S does not appear pharmacologically different from expression cloned LTC4-S. LTC4-S inhibition by FLAP inhibitors is in agreement with the significant homology reported for expression-cloned LTC4-S with FLAP, Furthermore, functional homology of the binding sites for inhibitors on LTC4-S and FLAP is suggested by the conservation of the relative potencies of MK-886 and BAY-X1005 vs FLAP-dependent 5-lipoxygenase activity and LTC4-S inhibition: MK-886 was 19.3-fold more potent than BAY-X1005 as FLAP inhibitor and 19.6-fold more potent than BAY-X1005 as LTC4-S inhibitor.

  11. Modulation of Progesterone Receptor Isoform Expression in Pregnant Human Myometrium

    PubMed Central

    2017-01-01

    Background. Regulation of myometrial progesterone receptor (PR) expression is an unresolved issue central to understanding the mechanism of functional progesterone withdrawal and initiation of labor in women. Objectives. To determine whether pregnant human myometrium undergoes culture-induced changes in PR isoform expression ex situ and, further, to determine if conditions approaching the in vivo environment stabilise PR isoform expression in culture. Methods. Term nonlaboring human myometrial tissues were cultured under specific conditions: serum supplementation, steroids, stretch, cAMP, PMA, PGF2α, NF-κB inhibitors, or TSA. Following 48 h culture, PR-T, PR-A, and PR-B mRNA levels were determined using qRT-PCR. PR-A/PR-B ratios were calculated. Results. PR-T and PR-A expression and the PR-A/PR-B ratio significantly increased in culture. Steroids prevented the culture-induced increase in PR-T and PR-A expression. Stretch blocked the effects of steroids on PR-T and PR-A expression. PMA further increased the PR-A/PR-B ratio, while TSA blocked culture-induced increases of PR-A expression and the PR-A/PR-B ratio. Conclusion. Human myometrial tissue in culture undergoes changes in PR gene expression consistent with transition toward a laboring phenotype. TSA maintained the nonlaboring PR isoform expression pattern. This suggests that preserving histone and/or nonhistone protein acetylation is critical for maintaining the progesterone dependent quiescent phenotype of human myometrium in culture. PMID:28540297

  12. Novel factors modulating human β-cell proliferation

    PubMed Central

    Shirakawa, Jun; Kulkarni, Rohit N.

    2016-01-01

    β-cell dysfunction in type 1 and type 2 diabetes is accompanied by a progressive loss of β-cells, and an understanding of the cellular mechanism(s) that regulate β-cell mass will enable approaches to enhance hormone secretion. It is becoming increasingly recognized that enhancement of human β-cell proliferation is one potential approach to restore β-cell mass to prevent and/or cure type 1 and type 2 diabetes. While several reports describe the factor(s) that enhance β-cell replication in animal models or cell lines, promoting effective human β-cell proliferation continues to be a challenge in the field. In this review, we discuss recent studies reporting successful human β-cell proliferation including WS6, an IκB kinase and EBP1 inhibitor; harmine and 5-IT, both DYRK1A inhibitors; GNF7156 and GNF4877, GSK-3β and DYRK1A inhibitors; osteoprotegrin and Denosmab, RANK inhibitors; and SerpinB1, a protease inhibitor. These studies provide important examples of proteins and pathways that may prove useful for designing therapeutic strategies to counter the different forms of diabetes. PMID:27615134

  13. Kisspeptin modulates sexual and emotional brain processing in humans

    PubMed Central

    Comninos, Alexander N.; Wall, Matthew B.; Demetriou, Lysia; Shah, Amar J.; Clarke, Sophie A.; Narayanaswamy, Shakunthala; Nesbitt, Alexander; Izzi-Engbeaya, Chioma; Prague, Julia K.; Abbara, Ali; Ratnasabapathy, Risheka; Salem, Victoria; Nijher, Gurjinder M.; Jayasena, Channa N.; Tanner, Mark; Bassett, Paul; Mehta, Amrish; Rabiner, Eugenii A.; Hönigsperger, Christoph; Silva, Meire Ribeiro; Brandtzaeg, Ole Kristian; Wilson, Steven Ray; Brown, Rachel C.; Thomas, Sarah A.; Bloom, Stephen R.; Dhillo, Waljit S.

    2017-01-01

    BACKGROUND. Sex, emotion, and reproduction are fundamental and tightly entwined aspects of human behavior. At a population level in humans, both the desire for sexual stimulation and the desire to bond with a partner are important precursors to reproduction. However, the relationships between these processes are incompletely understood. The limbic brain system has key roles in sexual and emotional behaviors, and is a likely candidate system for the integration of behavior with the hormonal reproductive axis. We investigated the effects of kisspeptin, a recently identified key reproductive hormone, on limbic brain activity and behavior. METHODS. Using a combination of functional neuroimaging and hormonal and psychometric analyses, we compared the effects of kisspeptin versus vehicle administration in 29 healthy heterosexual young men. RESULTS. We demonstrated that kisspeptin administration enhanced limbic brain activity specifically in response to sexual and couple-bonding stimuli. Furthermore, kisspeptin’s enhancement of limbic brain structures correlated with psychometric measures of reward, drive, mood, and sexual aversion, providing functional significance. In addition, kisspeptin administration attenuated negative mood. CONCLUSIONS. Collectively, our data provide evidence of an undescribed role for kisspeptin in integrating sexual and emotional brain processing with reproduction in humans. These results have important implications for our understanding of reproductive biology and are highly relevant to the current pharmacological development of kisspeptin as a potential therapeutic agent for patients with common disorders of reproductive function. FUNDING. National Institute for Health Research (NIHR), Wellcome Trust (Ref 080268), and the Medical Research Council (MRC). PMID:28112678

  14. Sympathetic modulation of sensory nerve activity with age: human and rodent skin models.

    PubMed

    Khalil, Z; LeVasseur, S; Merhi, M; Helme, R D

    1997-11-01

    1. Sensory nerves serve an afferent role and mediate neurogenic components of inflammation and tissue repair via an axon reflex release of sensory peptides at sites of injury. Dysfunction of these nerves with age could contribute to delayed tissue healing. 2. Complementary animal and human skin models were used in the present studies to investigate changes in the modulation of sensory nerve function by sympathetic efferents during ageing. Laser Doppler flowmetry was used to monitor neurogenic skin vascular responses. 3. The animal model used skin of the hind footpad of anaesthetized rats combined with electrical stimulation of the sciatic nerve, while the human model comprised capsaicin electrophoresis to the volar surface of the forearm. Sympathetic modulation was effected by systemic phentolamine pretreatment in animals and local application in the human model. 4. The results obtained from the human model confirmed the reported decline in sensory nerve function and showed no change in sympathetic modulation with age. The results from the animal model confirm and expand results obtained from the human model. 5. The use of low (5 Hz) and high (15 Hz) frequency electrical stimulation (20 V, 2 ms for 1 min) revealed a preferential response of aged sensory nerves to low-frequency electrical stimulation parameters with differential sympathetic modulation that is dependent on the frequency of stimulation.

  15. Modulation of human motoneuron activity by a mental arithmetic task.

    PubMed

    Bensoussan, Laurent; Duclos, Yann; Rossi-Durand, Christiane

    2012-10-01

    This study aimed to determine whether the performance of a mental task affects motoneuron activity. To this end, the tonic discharge pattern of wrist extensor motor units was analyzed in healthy subjects while they were required to maintain a steady wrist extension force and to concurrently perform a mental arithmetic (MA) task. A shortening of the mean inter-spike interval (ISI) and a decrease in ISI variability occurred when MA task was superimposed to the motor task. Aloud and silent MA affected equally the rate and variability of motoneuron discharge. Increases in surface EMG activity and force level were consistent with the modulation of the motor unit discharge rate. Trial-by-trial analysis of the characteristics of motor unit firing revealed that performing MA increases activation of wrist extensor SMU. It is suggested that increase in muscle spindle afferent activity, resulting from fusimotor drive activation by MA, may have contributed to the increase in synaptic inputs to motoneurons during the mental task performance, likely together with enhancement in the descending drive. The finding that a mental task affects motoneuron activity could have consequences in assessment of motor disabilities and in rehabilitation in motor pathologies.

  16. Both happy and sad melodies modulate tonic human heat pain.

    PubMed

    Zhao, Huixuan; Chen, Andrew C N

    2009-09-01

    The mechanism of music effects on pain perception remains to be elucidated. To determine which component (mood or valence) of music is more important in music-induced hypoalgesia, we compared the effects of 2 melodies with different moods (happy vs sad) but with the same degree of valence (pleasant vs unpleasant) to an affective neutral lecture and a control (baseline) on the objective and subjective responses to tonic heat pain. Our hypothesis was that if mood was the key component, the happy melody would reduce pain, whereas the sad one would exacerbate pain; and if valence is the key component, the 2 melodies would both alleviate pain. Twenty females participated in this study which consisted of 4 conditions (baseline, happy melody, sad melody, and lecture). Pain tolerance time (PTT), pain intensity, and distress dynamics and the characteristics of pain were measured. A newly devised multiple affective rating scale (MARS) was employed to assess the subjective experience of auditory perception. Both happy and sad melodies of equal valence resulted in significant lower pain ratings during the pain test and were in contrast to the mood prediction. These results indicate that the valence of music, rather than the mood it induced, appears to be the most likely mediator of the hypoalgesic effect of the different music. This article provides new evidence that the valence of music is more crucial than mood in affective pain modulation. This finding gives impetus for health professionals to manage pain more effectively in patients with proper music.

  17. Synthetic cationic peptide IDR-1018 modulates human macrophage differentiation.

    PubMed

    Pena, Olga M; Afacan, Nicole; Pistolic, Jelena; Chen, Carol; Madera, Laurence; Falsafi, Reza; Fjell, Christopher D; Hancock, Robert E W

    2013-01-01

    Macrophages play a critical role in the innate immune response. To respond in a rapid and efficient manner to challenges in the micro-environment, macrophages are able to differentiate towards classically (M1) or alternatively (M2) activated phenotypes. Synthetic, innate defense regulators (IDR) peptides, designed based on natural host defence peptides, have enhanced immunomodulatory activities and reduced toxicity leading to protection in infection and inflammation models that is dependent on innate immune cells like monocytes/macrophages. Here we tested the effect of IDR-1018 on macrophage differentiation, a process essential to macrophage function and the immune response. Using transcriptional, protein and systems biology analysis, we observed that differentiation in the presence of IDR-1018 induced a unique signature of immune responses including the production of specific pro and anti-inflammatory mediators, expression of wound healing associated genes, and increased phagocytosis of apoptotic cells. Transcription factor IRF4 appeared to play an important role in promoting this IDR-1018-induced phenotype. The data suggests that IDR-1018 drives macrophage differentiation towards an intermediate M1-M2 state, enhancing anti-inflammatory functions while maintaining certain pro-inflammatory activities important to the resolution of infection. Synthetic peptides like IDR-1018, which act by modulating the immune system, could represent a powerful new class of therapeutics capable of treating the rising number of multidrug resistant infections as well as disorders associated with dysregulated immune responses.

  18. Synthetic Cationic Peptide IDR-1018 Modulates Human Macrophage Differentiation

    PubMed Central

    Pena, Olga M.; Afacan, Nicole; Pistolic, Jelena; Chen, Carol; Madera, Laurence; Falsafi, Reza; Fjell, Christopher D.; Hancock, Robert E. W.

    2013-01-01

    Macrophages play a critical role in the innate immune response. To respond in a rapid and efficient manner to challenges in the micro-environment, macrophages are able to differentiate towards classically (M1) or alternatively (M2) activated phenotypes. Synthetic, innate defense regulators (IDR) peptides, designed based on natural host defence peptides, have enhanced immunomodulatory activities and reduced toxicity leading to protection in infection and inflammation models that is dependent on innate immune cells like monocytes/macrophages. Here we tested the effect of IDR-1018 on macrophage differentiation, a process essential to macrophage function and the immune response. Using transcriptional, protein and systems biology analysis, we observed that differentiation in the presence of IDR-1018 induced a unique signature of immune responses including the production of specific pro and anti-inflammatory mediators, expression of wound healing associated genes, and increased phagocytosis of apoptotic cells. Transcription factor IRF4 appeared to play an important role in promoting this IDR-1018-induced phenotype. The data suggests that IDR-1018 drives macrophage differentiation towards an intermediate M1–M2 state, enhancing anti-inflammatory functions while maintaining certain pro-inflammatory activities important to the resolution of infection. Synthetic peptides like IDR-1018, which act by modulating the immune system, could represent a powerful new class of therapeutics capable of treating the rising number of multidrug resistant infections as well as disorders associated with dysregulated immune responses. PMID:23308112

  19. Modulation of intercellular ROS signaling of human tumor cells.

    PubMed

    Bechtel, Wibke; Bauer, Georg

    2009-11-01

    Tumor cells are resistant against apoptosis-inducing intercellular reactive oxygen species (ROS) signaling but can be resensitized by the inhibition of catalase. Hydrogen peroxide exhibits a dual role in the modulation of intercellular ROS signaling. When suboptimal concentrations of the catalase inhibitior 3-aminotriazole (3-AT) are applied, additional exogenous hydrogen peroxide shifts apoptosis induction to its optimum. When hydrogen peroxide is added at optimal concentrations of 3-AT, or when higher concentrations of 3-AT are applied, the subsequent consumption between HOCl and hydrogen peroxide blunts overall apoptosis induction. These supraoptimal conditions can be brought back to the optimum through excess myeloperoxidase (MPO), partial removal of hydrogen peroxide through the catalase mimetic EUK-134 or partial inhibition of NADPH oxidase. Exogenous nitric oxide (NO) interferes with HOCl signaling through consumption of hydrogen peroxide. Site-specific generation of hydroxyl radicals at the cell membrane of tumor cells induces apoptosis, whereas random HOCl-superoxide anion interaction, and ferrous iron-induced Fenton chemistry of HOCl inhibit intercellular ROS signaling.

  20. Genotype and ancestry modulate brain's DAT availability in healthy humans

    SciTech Connect

    Shumay, E.; Shumay, E.; Chen, J.; Fowler, J.S.; Volkow, N.D.

    2011-08-01

    The dopamine transporter (DAT) is a principal regulator of dopaminergic neurotransmission and its gene (the SLC6A3) is a strong biological candidate gene for various behavioral- and neurological disorders. Intense investigation of the link between the SLC6A3 polymorphisms and behavioral phenotypes yielded inconsistent and even contradictory results. Reliance on objective brain phenotype measures, for example, those afforded by brain imaging, might critically improve detection of DAT genotype-phenotype association. Here, we tested the relationship between the DAT brain availability and the SLC6A3 genotypes using an aggregate sample of 95 healthy participants of several imaging studies. These studies employed positron emission tomography (PET) with [{sup 11}C] cocaine wherein the DAT availability was estimated as Bmax/Kd; while the genotype values were obtained on two repeat polymorphisms - 3-UTR- and intron 8- VNTRs. The main findings are the following: (1) both polymorphisms analyzed as single genetic markers and in combination (haplotype) modulate DAT density in midbrain; (2) ethnic background and age influence the strength of these associations; and (3) age-related changes in DAT availability differ in the 3-UTR and intron8 - genotype groups.

  1. Nasal Respiration Entrains Human Limbic Oscillations and Modulates Cognitive Function

    PubMed Central

    Jiang, Heidi; Zhou, Guangyu; Arora, Nikita; Schuele, Stephan; Rosenow, Joshua; Gottfried, Jay A.

    2016-01-01

    The need to breathe links the mammalian olfactory system inextricably to the respiratory rhythms that draw air through the nose. In rodents and other small animals, slow oscillations of local field potential activity are driven at the rate of breathing (∼2–12 Hz) in olfactory bulb and cortex, and faster oscillatory bursts are coupled to specific phases of the respiratory cycle. These dynamic rhythms are thought to regulate cortical excitability and coordinate network interactions, helping to shape olfactory coding, memory, and behavior. However, while respiratory oscillations are a ubiquitous hallmark of olfactory system function in animals, direct evidence for such patterns is lacking in humans. In this study, we acquired intracranial EEG data from rare patients (Ps) with medically refractory epilepsy, enabling us to test the hypothesis that cortical oscillatory activity would be entrained to the human respiratory cycle, albeit at the much slower rhythm of ∼0.16–0.33 Hz. Our results reveal that natural breathing synchronizes electrical activity in human piriform (olfactory) cortex, as well as in limbic-related brain areas, including amygdala and hippocampus. Notably, oscillatory power peaked during inspiration and dissipated when breathing was diverted from nose to mouth. Parallel behavioral experiments showed that breathing phase enhances fear discrimination and memory retrieval. Our findings provide a unique framework for understanding the pivotal role of nasal breathing in coordinating neuronal oscillations to support stimulus processing and behavior. SIGNIFICANCE STATEMENT Animal studies have long shown that olfactory oscillatory activity emerges in line with the natural rhythm of breathing, even in the absence of an odor stimulus. Whether the breathing cycle induces cortical oscillations in the human brain is poorly understood. In this study, we collected intracranial EEG data from rare patients with medically intractable epilepsy, and found evidence

  2. Nasal Respiration Entrains Human Limbic Oscillations and Modulates Cognitive Function.

    PubMed

    Zelano, Christina; Jiang, Heidi; Zhou, Guangyu; Arora, Nikita; Schuele, Stephan; Rosenow, Joshua; Gottfried, Jay A

    2016-12-07

    The need to breathe links the mammalian olfactory system inextricably to the respiratory rhythms that draw air through the nose. In rodents and other small animals, slow oscillations of local field potential activity are driven at the rate of breathing (∼2-12 Hz) in olfactory bulb and cortex, and faster oscillatory bursts are coupled to specific phases of the respiratory cycle. These dynamic rhythms are thought to regulate cortical excitability and coordinate network interactions, helping to shape olfactory coding, memory, and behavior. However, while respiratory oscillations are a ubiquitous hallmark of olfactory system function in animals, direct evidence for such patterns is lacking in humans. In this study, we acquired intracranial EEG data from rare patients (Ps) with medically refractory epilepsy, enabling us to test the hypothesis that cortical oscillatory activity would be entrained to the human respiratory cycle, albeit at the much slower rhythm of ∼0.16-0.33 Hz. Our results reveal that natural breathing synchronizes electrical activity in human piriform (olfactory) cortex, as well as in limbic-related brain areas, including amygdala and hippocampus. Notably, oscillatory power peaked during inspiration and dissipated when breathing was diverted from nose to mouth. Parallel behavioral experiments showed that breathing phase enhances fear discrimination and memory retrieval. Our findings provide a unique framework for understanding the pivotal role of nasal breathing in coordinating neuronal oscillations to support stimulus processing and behavior. Animal studies have long shown that olfactory oscillatory activity emerges in line with the natural rhythm of breathing, even in the absence of an odor stimulus. Whether the breathing cycle induces cortical oscillations in the human brain is poorly understood. In this study, we collected intracranial EEG data from rare patients with medically intractable epilepsy, and found evidence for respiratory entrainment

  3. Volitional exaggeration of body size through fundamental and formant frequency modulation in humans

    PubMed Central

    Pisanski, Katarzyna; Mora, Emanuel C.; Pisanski, Annette; Reby, David; Sorokowski, Piotr; Frackowiak, Tomasz; Feinberg, David R.

    2016-01-01

    Several mammalian species scale their voice fundamental frequency (F0) and formant frequencies in competitive and mating contexts, reducing vocal tract and laryngeal allometry thereby exaggerating apparent body size. Although humans’ rare capacity to volitionally modulate these same frequencies is thought to subserve articulated speech, the potential function of voice frequency modulation in human nonverbal communication remains largely unexplored. Here, the voices of 167 men and women from Canada, Cuba, and Poland were recorded in a baseline condition and while volitionally imitating a physically small and large body size. Modulation of F0, formant spacing (∆F), and apparent vocal tract length (VTL) were measured using Praat. Our results indicate that men and women spontaneously and systemically increased VTL and decreased F0 to imitate a large body size, and reduced VTL and increased F0 to imitate small size. These voice modulations did not differ substantially across cultures, indicating potentially universal sound-size correspondences or anatomical and biomechanical constraints on voice modulation. In each culture, men generally modulated their voices (particularly formants) more than did women. This latter finding could help to explain sexual dimorphism in F0 and formants that is currently unaccounted for by sexual dimorphism in human vocal anatomy and body size. PMID:27687571

  4. Endotoxin down-modulates granulocyte colony-stimulating factor receptor (CD114) on human neutrophils.

    PubMed

    Hollenstein, U; Homoncik, M; Stohlawetz, P J; Marsik, C; Sieder, A; Eichler, H G; Jilma, B

    2000-07-01

    During infection, the development of nonresponsiveness to granulocyte colony-stimulating factor (G-CSF) may be influenced by the down-modulation of G-CSF receptor (G-CSFR) by cytokines. This down-modulation was studied during experimental human endotoxemia. Healthy volunteers received either 2 ng/kg endotoxin (lipopolysaccharide [LPS], n=20) or placebo (n=10) in a randomized, controlled trial. Endotoxin infusion increased the mean fluorescence intensity of the neutrophil activation marker CD11b >300% after 1 h (P<.001 vs. placebo). LPS infusion down-modulated G-CSFR expression in as early as 60 min (-17%; P=.001 vs. placebo). Down-modulation was almost maximal at 90 min and persisted for 6 h (-50% from baseline; P<.0001 vs. placebo). Plasma levels of G-CSF started to increase only after G-CSFR down-modulation had occurred and peaked 37-fold above baseline at 4 h (P<.0001 vs. placebo). In conclusion, LPS down-modulates G-CSFR expression in humans, which may render neutrophils less responsive to the effects of G-CSF and, thereby, compromise host defense mechanisms.

  5. Acute Exercise Modulates Feature-selective Responses in Human Cortex.

    PubMed

    Bullock, Tom; Elliott, James C; Serences, John T; Giesbrecht, Barry

    2017-04-01

    An organism's current behavioral state influences ongoing brain activity. Nonhuman mammalian and invertebrate brains exhibit large increases in the gain of feature-selective neural responses in sensory cortex during locomotion, suggesting that the visual system becomes more sensitive when actively exploring the environment. This raises the possibility that human vision is also more sensitive during active movement. To investigate this possibility, we used an inverted encoding model technique to estimate feature-selective neural response profiles from EEG data acquired from participants performing an orientation discrimination task. Participants (n = 18) fixated at the center of a flickering (15 Hz) circular grating presented at one of nine different orientations and monitored for a brief shift in orientation that occurred on every trial. Participants completed the task while seated on a stationary exercise bike at rest and during low- and high-intensity cycling. We found evidence for inverted-U effects; such that the peak of the reconstructed feature-selective tuning profiles was highest during low-intensity exercise compared with those estimated during rest and high-intensity exercise. When modeled, these effects were driven by changes in the gain of the tuning curve and in the profile bandwidth during low-intensity exercise relative to rest. Thus, despite profound differences in visual pathways across species, these data show that sensitivity in human visual cortex is also enhanced during locomotive behavior. Our results reveal the nature of exercise-induced gain on feature-selective coding in human sensory cortex and provide valuable evidence linking the neural mechanisms of behavior state across species.

  6. Impact of shear rate modulation on vascular function in humans

    PubMed Central

    Tinken, Toni M.; Thijssen, Dick H.J.; Hopkins, Nicola; Black, Mark A.; Dawson, Ellen A.; Minson, Christopher T.; Newcomer, Sean C.; Laughlin, M. Harold; Cable, N. Timothy; Green, Daniel J.

    2010-01-01

    Shear stress is an important stimulus to arterial adaptation in response to exercise and training in humans. We recently observed significant reverse arterial flow and shear during exercise and different antegrade/retrograde patterns of shear and flow in response to different types of exercise. The purpose of this study was to simultaneously examine flow mediated dilation (FMD), a largely nitric oxide mediated vasodilator response, in both brachial arteries of healthy young men before and after 30-minute interventions consisting of bilateral forearm heating, recumbent leg cycling and bilateral handgrip exercise. During each intervention, a cuff inflated to 60mmHg was placed on one arm to unilaterally manipulate the shear rate stimulus. In the non-cuffed arm, antegrade flow and shear increased similarly in response to each intervention (ANOVA; P<0.001, no interaction between interventions; P=0.71). Baseline FMD (4.6, 6.9 and 6.7%) increased similarly in response to heating, handgrip and cycling (8.1, 10.4 and 8.9%, ANOVA; P<0.001, no interaction; 0.89). In contrast, cuffed arm antegrade shear rate was lower than in the non-cuffed arm for all conditions (P<0.05) and the increase in FMD was abolished in this arm (4.7, 6.7 and 6.1%) (2-way ANOVA: all conditions interacted P<0.05). These results suggest that differences in the magnitude of antegrade shear rate transduce differences in endothelial vasodilator function in humans, a finding which may have relevance for the impact of different exercise interventions on vascular adaptation in humans. PMID:19546374

  7. Identifying colon cancer risk modules with better classification performance based on human signaling network.

    PubMed

    Qu, Xiaoli; Xie, Ruiqiang; Chen, Lina; Feng, Chenchen; Zhou, Yanyan; Li, Wan; Huang, Hao; Jia, Xu; Lv, Junjie; He, Yuehan; Du, Youwen; Li, Weiguo; Shi, Yuchen; He, Weiming

    2014-10-01

    Identifying differences between normal and tumor samples from a modular perspective may help to improve our understanding of the mechanisms responsible for colon cancer. Many cancer studies have shown that signaling transduction and biological pathways are disturbed in disease states, and expression profiles can distinguish variations in diseases. In this study, we integrated a weighted human signaling network and gene expression profiles to select risk modules associated with tumor conditions. Risk modules as classification features by our method had a better classification performance than other methods, and one risk module for colon cancer had a good classification performance for distinguishing between normal/tumor samples and between tumor stages. All genes in the module were annotated to the biological process of positive regulation of cell proliferation, and were highly associated with colon cancer. These results suggested that these genes might be the potential risk genes for colon cancer. Copyright © 2013. Published by Elsevier Inc.

  8. Bordetella pertussis modulates human macrophage defense gene expression.

    PubMed

    Valdez, Hugo Alberto; Oviedo, Juan Marcos; Gorgojo, Juan Pablo; Lamberti, Yanina; Rodriguez, Maria Eugenia

    2016-08-01

    Bordetella pertussis, the etiological agent of whooping cough, still causes outbreaks. We recently found evidence that B. pertussis can survive and even replicate inside human macrophages, indicating that this host cell might serve as a niche for persistence. In this work, we examined the interaction of B. pertussis with a human monocyte cell line (THP-1) that differentiates into macrophages in culture in order to investigate the host cell response to the infection and the mechanisms that promote that intracellular survival. To that end, we investigated the expression profile of a selected number of genes involved in cellular bactericidal activity and the inflammatory response during the early and late phases of infection. The bactericidal and inflammatory response of infected macrophages was progressively downregulated, while the number of THP-1 cells heavily loaded with live bacteria increased over time postinfection. Two of the main toxins of B. pertussis, pertussis toxin (Ptx) and adenylate cyclase (CyaA), were found to be involved in manipulating the host cell response. Therefore, failure to express either toxin proved detrimental to the development of intracellular infections by those bacteria. Taken together, these results support the relevance of host defense gene manipulation to the outcome of the interaction between B. pertussis and macrophages. © FEMS 2016. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  9. Valsalva maneuver: Insights into baroreflex modulation of human sympathetic activity

    NASA Technical Reports Server (NTRS)

    Smith, Michael L.; Eckberg, Dwain L.; Fritsch, Janice M.; Beightol, Larry A.; Ellenbogen, Kenneth A.

    1991-01-01

    Valsalva's maneuver, voluntary forced expiration against a closed glottis, is a well-characterized research tool, used to assess the integrity of human autonomic cardiovascular control. Valsalva straining provokes a stereotyped succession of alternating positive and negative arterial pressure and heart rate changes mediated in part by arterial baroreceptors. Arterial pressure changes result primarily from fluctuating levels of venous return to the heart and changes of sympathetic nerve activity. Muscle sympathetic activity was measured directly in nine volunteers to explore quantitatively the relation between arterial pressure and human sympathetic outflow during pressure transients provoked by controlled graded Valsalva maneuvers. Our results underscore several properties of sympathetic regulation during Valsalva straining. First, muscle sympathetic nerve activity changes as a mirror image of changes in arterial pressure. Second, the magnitude of sympathetic augmentation during Valsalva straining predicts phase 4 arterial pressure elevations. Third, post-Valsalva sympathetic inhibition persists beyond the return of arterial and right atrial pressures to baseline levels which reflects an alteration of the normal relation between arterial pressure and muscle sympathetic activity. Therefore, Valsalva straining may have some utility for investigating changes of reflex control of sympathetic activity after space flight; however, measurement of beat-to-beat arterial pressure is essential for this use. The utility of this technique in microgravity can not be determined from these data. Further investigations are necessary to determine whether these relations are affected by the expansion of intrathoracic blood volume associated with microgravity.

  10. Pentoxifylline modulation of plasma membrane functions in human polymorphonuclear leukocytes.

    PubMed Central

    Hand, W L; Butera, M L; King-Thompson, N L; Hand, D L

    1989-01-01

    Pentoxifylline is known to have major effects on cell membrane function in mammalian cells, including human leukocytes. The protective effects of this agent in animal models of infection and inflammation may be due to alterations in phagocyte (neutrophil and macrophage) function. However, the exact mechanism of action of pentoxifylline is unknown. In this study, we evaluated the effect of the drug on several membrane-associated activities in human polymorphonuclear neutrophils and investigated possible mechanisms for the observed changes in neutrophil function. Pentoxifylline inhibited ingestion of microbial particles (Staphylococcus aureus and zymosan); decreased superoxide generation activated by zymosan, formyl-methionyl-leucyl-phenylalanine, and concanavalin A (but not phorbol myristate acetate); and decreased uptake (transport) of adenosine stimulated by formyl-methionyl-leucyl-phenylalanine and zymosan. In contrast, pentoxifylline actually increased clindamycin uptake in zymosan-stimulated polymorphonuclear neutrophils. However, pentoxifylline had no effect on uptake of adenosine or clindamycin in unstimulated neutrophils. In comparison with known inhibitors of nucleoside transport (nitrobenzylthioinosine and dipyridamole), the results suggested that pentoxifylline does not bind to membrane nucleoside transport receptors. At concentrations which inhibit neutrophil function, pentoxifylline activity is not mediated through external membrane nucleoside regulatory sites. Thus, pentoxifylline affects the activation signal chain at a point beyond the membrane receptors. Whatever its precise mechanism of action, pentoxifylline has a striking modulatory effect on cell membrane-associated responses in stimulated leukocytes and may prove useful for control of injurious inflammatory states. PMID:2553608

  11. Functional modules, mutational load and human genetic disease

    PubMed Central

    Zaghloul, Norann A.; Katsanis, Nicholas

    2013-01-01

    The ability to generate a massive amount of sequencing and genotyping data is transforming the study of human genetic disorders. Driven by such innovation, it is likely that whole exome and whole-genome resequencing will replace regionally focused approaches for gene discovery and clinical testing in the next few years. However, this opportunity brings a significant interpretative challenge to assigning function and phenotypic variance to common and rare alleles. Understanding the effect of individual mutations in the context of the remaining genomic variation represents a major challenge to our interpretation of disease. Here, we discuss the challenges of assigning mutation functionality and, drawing from the examples of ciliopathies as well as cohesinopathies and channelopathies, discuss possibilities for the functional modularization of the human genome. Functional modularization in addition to the development of physiologically-relevant assays to test allele functionality will accelerate our understanding of disease architecture and enable the use of genome-wide sequence data for disease diagnosis and phenotypic prediction in individuals. PMID:20226561

  12. Oxytocin modulates human communication by enhancing cognitive exploration.

    PubMed

    de Boer, Miriam; Kokal, Idil; Blokpoel, Mark; Liu, Rui; Stolk, Arjen; Roelofs, Karin; van Rooij, Iris; Toni, Ivan

    2017-09-08

    Oxytocin is a neuropeptide known to influence how humans share material resources. Here we explore whether oxytocin influences how we share knowledge. We focus on two distinguishing features of human communication, namely the ability to select communicative signals that disambiguate the many-to-many mappings that exist between a signal's form and meaning, and adjustments of those signals to the presumed cognitive characteristics of the addressee ("audience design"). Fifty-five males participated in a randomized, double-blind, placebo controlled experiment involving the intranasal administration of oxytocin. The participants produced novel non-verbal communicative signals towards two different addressees, an adult or a child, in an experimentally-controlled live interactive setting. We found that oxytocin administration drives participants to generate signals of higher referential quality, i.e. signals that disambiguate more communicative problems; and to rapidly adjust those communicative signals to what the addressee understands. The combined effects of oxytocin on referential quality and audience design fit with the notion that oxytocin administration leads participants to explore more pervasively behaviors that can convey their intention, and diverse models of the addressees. These findings suggest that, besides affecting prosocial drive and salience of social cues, oxytocin influences how we share knowledge by promoting cognitive exploration. Copyright © 2017 Elsevier Ltd. All rights reserved.

  13. Oxygen-Sensitive K+ Channels Modulate Human Chorionic Gonadotropin Secretion from Human Placental Trophoblast

    PubMed Central

    Díaz, Paula; Sibley, Colin P.; Greenwood, Susan L.

    2016-01-01

    Human chorionic gonadotropin (hCG) is a key autocrine/paracrine regulator of placental syncytiotrophoblast, the transport epithelium of the human placenta. Syncytiotrophoblast hCG secretion is modulated by the partial pressure of oxygen (pO2), reactive oxygen species (ROS) and potassium (K+) channels. Here we test the hypothesis that K+ channels mediate the effects of pO2 and ROS on hCG secretion. Placental villous explants from normal term pregnancies were cultured for 6 days at 6% (normoxia), 21% (hyperoxia) or 1% (hypoxia) pO2. On days 3–5, explants were treated with 5mM 4-aminopyridine (4-AP) or tetraethylammonium (TEA), blockers of pO2-sensitive voltage-gated K+ (KV) channels, or ROS (10–1000μM H2O2). hCG secretion and lactate dehydrogenase (LDH) release, a marker of necrosis, were determined daily. At day 6, hCG and LDH were measured in tissue lysate and 86Rb (K+) efflux assessed to estimate syncytiotrophoblast K+ permeability. hCG secretion and 86Rb efflux were significantly greater in explants maintained in 21% pO2 than normoxia. 4-AP/TEA inhibited hCG secretion to a greater extent at 21% than 6% and 1% pO2, and reduced 86Rb efflux at 21% but not 6% pO2. LDH release and tissue LDH/hCG were similar in 6%, 21% and 1% pO2 and unaffected by 4-AP/TEA. H2O2 stimulated 86Rb efflux and hCG secretion at normoxia but decreased 86Rb efflux, without affecting hCG secretion, at 21% pO2. 4-AP/TEA-sensitive K+ channels participate in pO2-sensitive hCG secretion from syncytiotrophoblast. ROS effects on both hCG secretion and 86Rb efflux are pO2-dependent but causal links between the two remain to be established. PMID:26863525

  14. Oxygen-Sensitive K+ Channels Modulate Human Chorionic Gonadotropin Secretion from Human Placental Trophoblast.

    PubMed

    Díaz, Paula; Sibley, Colin P; Greenwood, Susan L

    2016-01-01

    Human chorionic gonadotropin (hCG) is a key autocrine/paracrine regulator of placental syncytiotrophoblast, the transport epithelium of the human placenta. Syncytiotrophoblast hCG secretion is modulated by the partial pressure of oxygen (pO2), reactive oxygen species (ROS) and potassium (K+) channels. Here we test the hypothesis that K+ channels mediate the effects of pO2 and ROS on hCG secretion. Placental villous explants from normal term pregnancies were cultured for 6 days at 6% (normoxia), 21% (hyperoxia) or 1% (hypoxia) pO2. On days 3-5, explants were treated with 5mM 4-aminopyridine (4-AP) or tetraethylammonium (TEA), blockers of pO2-sensitive voltage-gated K+ (KV) channels, or ROS (10-1000μM H2O2). hCG secretion and lactate dehydrogenase (LDH) release, a marker of necrosis, were determined daily. At day 6, hCG and LDH were measured in tissue lysate and 86Rb (K+) efflux assessed to estimate syncytiotrophoblast K+ permeability. hCG secretion and 86Rb efflux were significantly greater in explants maintained in 21% pO2 than normoxia. 4-AP/TEA inhibited hCG secretion to a greater extent at 21% than 6% and 1% pO2, and reduced 86Rb efflux at 21% but not 6% pO2. LDH release and tissue LDH/hCG were similar in 6%, 21% and 1% pO2 and unaffected by 4-AP/TEA. H2O2 stimulated 86Rb efflux and hCG secretion at normoxia but decreased 86Rb efflux, without affecting hCG secretion, at 21% pO2. 4-AP/TEA-sensitive K+ channels participate in pO2-sensitive hCG secretion from syncytiotrophoblast. ROS effects on both hCG secretion and 86Rb efflux are pO2-dependent but causal links between the two remain to be established.

  15. Oxygen modulates growth of human cells at physiologic partial pressures

    PubMed Central

    1984-01-01

    We have examined the growth of human diploid fibroblasts (WI-38 and IMR90) as a function of initial seeding density and oxygen tension. Cells at young and mid-passage levels were subcultivated in Dulbecco's modified Eagle's medium with 10% fetal bovine serum at 0.005, 0.01, 0.03, 0.1, 0.3, 1, and 2 X 10(4) cells/cm2. Flasks were equilibrated before and after seeding with 1 of 10 gas mixtures containing the desired oxygen tension (9-591 mm Hg) and placed in incubators that measure and maintain a preset oxygen tension. The partial pressure of oxygen (PO2) in media of all flasks was determined at harvest. Cells were shielded from light of wavelength less than 500 nm. Cell growth varied inversely with oxygen tension and seeding density. At 50 cells/cm2, growth was maximal at PO2 9 and 16 mm Hg. Growth was progressively inhibited as the oxygen tension was increased. The population doubling increase at 14 d was 8.6 for PO2 9 and 16 mm Hg, 5.8 for PO2 42 mm Hg, 3.8 for PO2 78 mm Hg, 3.8 for PO2 104 mm Hg, and 3 for PO2 138 mm Hg. As the seeding density was increased, the differences in growth at PO2 less than 140 mm Hg were progressively minimized, such that at seeding densities of 10(4) cells/cm2 there was little difference in the rate of exponential growth or the final saturation density of cells cultivated between PO2 9 and 96 mm Hg. At all seeding densities tested, growth was progressively inhibited when the PO2 was increased greater than 140 mm Hg. The seeding density dependence of oxygen's influence on cellular growth is not explained by oxygen consumption of higher density cultures. Oxygen acts directly on the cells and not by destroying some essential medium component. We have found that oxygen regulates the growth of human cells under pressures of oxygen physiologic to humans, and that oxygen toxicity contributes to the seeding density dependence of cellular growth commonly seen in cell culture. PMID:6736869

  16. Ulipristal acetate resembles mifepristone in modulating human fallopian tube function.

    PubMed

    Li, Hang Wun Raymond; Liao, Su-Bin; Yeung, William Shu-Biu; Ng, Ernest Hung-Yu; O, Wai-Sum; Ho, Pak-Chung

    2014-10-10

    Do ulipristal acetate (UPA) and mifepristone have an effect on ciliary beat frequency and muscular contractions in the human Fallopian tube? UPA, in resemblance to mifepristone, inhibits ciliary beat and muscular contraction of the human Fallopian tube, probably through an agonistic effect on the tubal progesterone receptor. UPA, like mifepristone, acts as an emergency contraceptive mainly by inhibiting ovulation. Little is known about its effects on tubal function. This was an in vitro experimental study using Fallopian tube samples collected from 11 women undergoing hysterectomy for benign non-tubal gynaecological conditions. The tubal epithelium and longitudinal smooth muscle fibres were isolated, cultured and treated with UPA at graded concentrations of 0, 20, 200 and 2000 ng/ml, and mifepristone at graded concentrations of 0, 300, 3000 and 30 000 ng/ml, respectively. After treatment, ciliary beat frequency was determined using a photometric method. Basal tone, amplitude and frequency of muscular contraction were recorded through a force transducer. The mRNA expression of progesterone receptor (total and PR-B isoform), glycodelin and adrenomedullin were determined by real-time quantitative PCR. There was an overall dose-dependent suppressive effect on ciliary beat frequency (P < 0.0001) after treatment with UPA at all concentrations and with mifepristone at 3000 ng/ml or above. The basal tone, amplitude and frequency of muscular contractions were significantly reduced (P < 0.05) after treatment with UPA at 200 ng/ml or above, and with mifepristone at 3000 ng/ml or above. UPA treatment at 200 ng/ml or above significantly up-regulated the mRNA expression of progesterone receptor and glycodelin and down-regulated the mRNA expression of adrenomedullin in Fallopian tube tissue (P < 0.05). Whether or not the tubal effect may translate into additional mechanisms for contraceptive action in vivo is uncertain. The clinical relevance of UPA with regard to contraceptive

  17. Human Driving Forces and Their Impacts on Land Use/Land Cover. Hands-On! Developing Active Learning Modules on the Human Dimensions of Global Change.

    ERIC Educational Resources Information Center

    Moser, Susanne

    This learning module aims to engage students in problem solving, critical thinking, scientific inquiry, and cooperative learning. The module is appropriate for use in any introductory or intermediate undergraduate course that focuses on human-environment relationships. The module explains that land use/cover change has occurred at all times in all…

  18. Modulation of human eosinophil polymorphonuclear leukocyte migration and function.

    PubMed Central

    Goetzl, E. J.

    1976-01-01

    Eosinophil migration toward a concentration gradient of a chemotactic factor is regulated at four levels. Diverse immunologic pathways generate stimuli with eosinophil chemotactic activity, including the complement products C5a and a fragment of C3a and the peptide products of mast cells and basophils activated by IgE-mediated reactions, such as eosinophil chemotactic factor of anaphylaxis (ECF-A) and other oligopeptides. The intrinsic preferential leukocyte activity of the chemotactic stimuli represents the second level of modulation, with ECF-A and other mast cell-derived peptides exhibiting the most selective action on eosinophils. The third level of control of eosinophil chemotaxis is composed of inactivators and inhibitors of chemotactic stimuli and is exemplified by degradation of C5a by anaphylatoxin inactivator or chemotactic factor inactivator and of ECF-A by carboxypeptidase-A or aminopeptidases. The activity of ECF-A is uniquely suppressed by equimolar quantities of its NH2- terminal tripeptide substituent, presumably by eosinophil membrane receptor competition. Factors comprising the fourth level of regulation, which alter eosinophil responsiveness to chemotactic stimuli, include the chemotactic factors themselves, through deactivation; nonchemotactic inhibitors such as the COOH-terminal tripeptide substituent of ECF-A, the neutrophil-immobilizing factor (NIF), the phagocytosis-enhancing factor Thr-Lys-Pro-Arg, and histamine at concentrations greater than 400 ng/ml; and nonchemotactic enhancing principles represented by ascorbate and by histamine at concentrations of 30 ng/ml or less. Local concentrations of eosinophils called to and immobilized at the site of a hypersenitivity reaction may express their regulatory functions by degrading the chemical mediators elaborated including histamine, slow-reacting substance of anaphylaxis (SRS-A), and platelet-activating factor (PAF) by way of their content of histaminase, arylsulfatase B, and phospholipase D

  19. Respiratory modulation of human autonomic function on Earth.

    PubMed

    Eckberg, Dwain L; Cooke, William H; Diedrich, André; Biaggioni, Italo; Buckey, Jay C; Pawelczyk, James A; Ertl, Andrew C; Cox, James F; Kuusela, Tom A; Tahvanainen, Kari U O; Mano, Tadaaki; Iwase, Satoshi; Baisch, Friedhelm J; Levine, Benjamin D; Adams-Huet, Beverley; Robertson, David; Blomqvist, C Gunnar

    2016-10-01

    We studied healthy supine astronauts on Earth with electrocardiogram, non-invasive arterial pressure, respiratory carbon dioxide concentrations, breathing depth and sympathetic nerve recordings. The null hypotheses were that heart beat interval fluctuations at usual breathing frequencies are baroreflex mediated, that they persist during apnoea, and that autonomic responses to apnoea result from changes of chemoreceptor, baroreceptor or lung stretch receptor inputs. R-R interval fluctuations at usual breathing frequencies are unlikely to be baroreflex mediated, and disappear during apnoea. The subjects' responses to apnoea could not be attributed to changes of central chemoreceptor activity (hypocapnia prevailed); altered arterial baroreceptor input (vagal baroreflex gain declined and muscle sympathetic nerve burst areas, frequencies and probabilities increased, even as arterial pressure climbed to new levels); or altered pulmonary stretch receptor activity (major breathing frequency and tidal volume changes did not alter vagal tone or sympathetic activity). Apnoea responses of healthy subjects may result from changes of central respiratory motoneurone activity. We studied eight healthy, supine astronauts on Earth, who followed a simple protocol: they breathed at fixed or random frequencies, hyperventilated and then stopped breathing, as a means to modulate and expose to view important, but obscure central neurophysiological mechanisms. Our recordings included the electrocardiogram, finger photoplethysmographic arterial pressure, tidal volume, respiratory carbon dioxide concentrations and peroneal nerve muscle sympathetic activity. Arterial pressure, vagal tone and muscle sympathetic outflow were comparable during spontaneous and controlled-frequency breathing. Compared with spontaneous, 0.1 and 0.05 Hz breathing, however, breathing at usual frequencies (∼0.25 Hz) lowered arterial baroreflex gain, and provoked smaller arterial pressure and R-R interval

  20. Serotonin selectively modulates reward value in human decision-making

    PubMed Central

    Seymour, Ben; Daw, Nathaniel D.; Roiser, Jonathan P; Dayan, Peter; Dolan, Ray

    2017-01-01

    Establishing a function for the neuromodulator serotonin in human decision-making has proved remarkably difficult, because if its complex role in reward and punishment processing. In a novel choice task where actions led concurrently and independently to the stochastic delivery of both money and pain, we studied the impact of decreased brain serotonin induced by acute dietary tryptophan depletion. Depletion selectively impaired both behavioural and neural representations of reward outcome value, and hence the effective exchange rate by which rewards and punishments were compared. This effect was computationally and anatomically distinct from a separate effect on increasing outcome-independent choice perseveration. Our results provide evidence for a surprising role for serotonin in reward processing, while illustrating its complex and multifarious effects. PMID:22539845

  1. Identification of Non-nucleoside Human Ribonucleotide Reductase Modulators

    DOE PAGES

    Ahmad, Md. Faiz; Huff, Sarah E.; Pink, John; ...

    2015-10-21

    Ribonucleotide reductase (RR) catalyzes the rate-limiting step of dNTP synthesis and is an established cancer target. Drugs targeting RR are mainly nucleoside in nature. In this study, we sought to identify non-nucleoside small-molecule inhibitors of RR. Using virtual screening, binding affinity, inhibition, and cell toxicity, we have discovered a class of small molecules that alter the equilibrium of inactive hexamers of RR, leading to its inhibition. Several unique chemical categories, including a phthalimide derivative, show micromolar IC50s and KDs while demonstrating cytotoxicity. A crystal structure of an active phthalimide binding at the targeted interface supports the noncompetitive mode of inhibitionmore » determined by kinetic studies. Furthermore, the phthalimide shifts the equilibrium from dimer to hexamer. Finally, together, these data identify several novel non-nucleoside inhibitors of human RR which act by stabilizing the inactive form of the enzyme.« less

  2. Identification of Non-nucleoside Human Ribonucleotide Reductase Modulators

    SciTech Connect

    Ahmad, Md. Faiz; Huff, Sarah E.; Pink, John; Alam, Intekhab; Zhang, Andrew; Perry, Kay; Harris, Michael E.; Misko, Tessianna; Porwal, Suheel K.; Oleinick, Nancy L.; Miyagi, Masaru; Viswanathan, Rajesh; Dealwis, Chris Godfrey

    2015-10-21

    Ribonucleotide reductase (RR) catalyzes the rate-limiting step of dNTP synthesis and is an established cancer target. Drugs targeting RR are mainly nucleoside in nature. In this study, we sought to identify non-nucleoside small-molecule inhibitors of RR. Using virtual screening, binding affinity, inhibition, and cell toxicity, we have discovered a class of small molecules that alter the equilibrium of inactive hexamers of RR, leading to its inhibition. Several unique chemical categories, including a phthalimide derivative, show micromolar IC50s and KDs while demonstrating cytotoxicity. A crystal structure of an active phthalimide binding at the targeted interface supports the noncompetitive mode of inhibition determined by kinetic studies. Furthermore, the phthalimide shifts the equilibrium from dimer to hexamer. Finally, together, these data identify several novel non-nucleoside inhibitors of human RR which act by stabilizing the inactive form of the enzyme.

  3. Preference for Sucrose Solutions Modulates Taste Cortical Activity in Humans.

    PubMed

    Jacquin-Piques, Agnès; Mouillot, Thomas; Gigot, Vincent; Meillon, Sophie; Leloup, Corinne; Penicaud, Luc; Brondel, Laurent

    2016-09-01

    High time resolution is required to reliably measure neuronal activity in the gustatory cortex in response to taste stimuli. Hedonic aspects of gustatory processing have never been explored using gustatory evoked potentials (GEPs), a high-time-resolution technique. Our aim was to study cerebral processing of hedonic taste in humans using GEPs in response to sucrose solutions in subjects with different ratings of pleasantness regarding sucrose. In this exploratory study, 30 healthy volunteers were randomly stimulated with 3 sucrose solutions. The sucrose stimulus was presented to the tongue for 1s 20 times. GEPs were recorded from 9 cortical sites with EEG sensors at Cz, Fz, Pz, C3, C4, F3, F4, Fp1, and Fp2 (10/20 system). The main result was that subjects who preferred the high-concentration (20g/100mL) sucrose solution had higher GEP amplitudes on the Pz, Cz, and Fz electrodes than did subjects who preferred the low-concentration (5g/100mL) or the moderate-concentration (10g/100mL) solutions regardless of stimulus intensity. The difference in P1N1 amplitude on the Pz, Cz, and Fz electrodes according to sucrose preference of the subjects was described with stronger significance with stimulation by the 20 g-sucrose solution than by the 5 and 10g sucrose solutions. Using the reliable and safe GEP technique, we provide an original demonstration of variability of the gustatory response on the Pz, Cz, and Fz electrodes according to a sweet preference in humans. Further studies are needed to correlate the electric signal recorded by surface electrodes to the neural generator. © The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  4. Extinction and Renewal of Pavlovian Modulation in Human Sequential Feature Positive Discrimination Learning

    ERIC Educational Resources Information Center

    Baeyens, Frank; Vansteenwegen, Debora; Beckers, Tom; Hermans, Dirk; Kerkhof, Ineke; De Ceulaer, Annick

    2005-01-01

    Using a conditioned suppression task, we investigated extinction and renewal of Pavlovian modulation in human sequential Feature Positive (FP) discrimination learning. In Experiment 1, in context a participants were first trained on two FP discriminations, X[right arrow]A+/A- and Y[right arrow]B+/B-. Extinction treatment was administered in the…

  5. Overcoming Masculine Bias in Introductory College Human Geography: A Module Approach.

    ERIC Educational Resources Information Center

    Rengert, Arlene; Monk, Janice J.

    This report describes a project launched under the auspices of the Association of American Geographers to produce a series of modules designed to increase and improve the representation of women in introductory college human geography courses. The project aimed to produce materials which could be used to supplement existing courses in diverse…

  6. Career Education for Mental Health Workers. Health Assessment. Human Service Instructional Series. Module No. 6.

    ERIC Educational Resources Information Center

    Redcay, Madeleine C.

    This module on health assessment is one of a set of six developed to prepare human services workers for the changing mental health service delivery system. A total of seven objectives are included to help students utilize knowledge of physical factors which may influence health and behavior in order to recognize signs and symptoms which indicate…

  7. Extinction and Renewal of Pavlovian Modulation in Human Sequential Feature Positive Discrimination Learning

    ERIC Educational Resources Information Center

    Baeyens, Frank; Vansteenwegen, Debora; Beckers, Tom; Hermans, Dirk; Kerkhof, Ineke; De Ceulaer, Annick

    2005-01-01

    Using a conditioned suppression task, we investigated extinction and renewal of Pavlovian modulation in human sequential Feature Positive (FP) discrimination learning. In Experiment 1, in context a participants were first trained on two FP discriminations, X[right arrow]A+/A- and Y[right arrow]B+/B-. Extinction treatment was administered in the…

  8. Overcoming Masculine Bias in Introductory College Human Geography: A Module Approach.

    ERIC Educational Resources Information Center

    Rengert, Arlene; Monk, Janice J.

    This report describes a project launched under the auspices of the Association of American Geographers to produce a series of modules designed to increase and improve the representation of women in introductory college human geography courses. The project aimed to produce materials which could be used to supplement existing courses in diverse…

  9. Melatonin and oestrogen treatments were able to improve neuroinflammation and apoptotic processes in dentate gyrus of old ovariectomized female rats.

    PubMed

    Kireev, Roman A; Vara, Elena; Viña, Jose; Tresguerres, Jesus A F

    2014-01-01

    The aim of this study was to determine the outcomes of oestrogen and melatonin treatments following long-term ovarian hormone depletion on neuroinflammation and apoptotic processes in dentate gyrus of hippocampi. Forty-six female Wistar rats of 22 months of age were used. Twelve of them remained intact, and the other 34 were ovariectomized at 12 months of age. Ovariectomized animals were divided into three groups and treated for 10 weeks with oestrogens, melatonin or saline. All rats were killed by decapitation at 24 months of age, and dentate gyri were collected. A group of 2 month-old intact female rats was used as young control. The levels of pro-inflammatory cytokines and heat shock protein 70 (HSP 70) were analysed by ELISA. The expressions of TNFα, IL1β, GFAP, nNOS, iNOS, HO-1, NFκB, Bax, Bad, AIF, Bcl2 and SIRT1 genes were detected by real-time (RT)-PCR. Western blots were used to measure the protein expression of NFκB p65, NFκB p50/105, IκBα, IκBβ, p38 MAPK, MAP-2 and synapsin I. We have assessed the ability of 17β-oestradiol and melatonin administration to downregulate markers of neuroinflammation in the dentate gyrus of ovariectomized female rats. Results indicated that 17β-oestradiol and melatonin treatments were able to significantly decrease expression of pro-inflammatory cytokines, iNOS and HO-1 in the hippocampus when compared to non-treated animals. A similar age- and long-term ovarian hormone depletion- related increase in GFAP was also attenuated after both melatonin and oestradiol treatments. In a similar way to oestradiol, melatonin decreased the activation of p38 MAPK and NFκB pathways. The treatments enhanced the levels of synaptic molecules synapsin I and MAP-2 and have been shown to modulate the pro-antiapoptotic ratio favouring the second and to increase SIRT1 expression. These findings support the potential therapeutic role of melatonin and oestradiol as protective anti-inflammatory agents for the central nervous system

  10. Production of Recombinant Polypeptides Containing One GA-Module and Analysis of Their Ability to Bind to Human Albumin.

    PubMed

    Bormotova, E A; Gupalova, T V

    2016-11-01

    Surface proteins of many bacterial species interact with human serum albumin (HSA) via a special region of amino acid sequence termed GA module. For instance, surface peptostreptococcal albumin-binding protein of anaerobic bacteria Peptostreptococcus magnus contains one HSA-binding GA-module. Protein G from group G and C Streptococcus strains isolated from humans has HSA-binding region consisting of three GA-modules. HSA-binding protein containing two GA-modules was found in strains of group G Streptococcus of animal origin. We obtained two recombinant polypeptides GA1 and GA2 congaing one GA-module each. Recombinant polypeptide with two GA-modules binds HSA with a much higher affinity than polypeptides GA1 and GA2 containing one GA-module. Polypeptide with the second GAmodule more effectively binds HSA than polypeptides with the GA-module.

  11. Influence of oestrogens on formation of reactive oxygen species in liver microsomes of differently aged male Wistar rats.

    PubMed

    Barth, A; Landmann, G; Liepold, K; Zapf, H; Müller, D; Karge, E; Klinger, W

    1999-07-01

    Metabolic pathways of oestrogens are the formation of catechol oestrogens (CE; 2- and 4-hydroxy-oestrogens), redox cycling of CE and free radical generation, mediated through cytochrome P450 (P450) oxidase/reductase activity. We checked the oestrogens oestradiol (E2), oestradiol valerate (E2V) and ethinyloestradiol (EE2) for formation of reactive oxygen species in vitro and ex vivo in male Wistar rats in dependence on age. In liver microsomes of 10-, 30-, 60- and 270-day-old rats the influence of E2, E2V and EE2 (10(-7)-10(-3) M) on NADPH-Fe(++)-stimulated lipid peroxidation (LPO), H2O2 generation and lucigenin (LUC) and luminol (LUM) amplified chemiluminescence (CL) was investigated. The same parameters, additionally P450 content and monooxygenase activities were measured in liver 9000 x g supernatants after subchronic administration of the oestrogens (1, 10 mg/kg b. wt. orally). The most important results are the strong inhibitory capacities of the oestrogens in vitro on LPO in the order of E2V < E2 < EE2, most pronounced in 10-, 60- and 270-day-old animals. In microsomes of 30-day-old rats with the highest control LPO the antioxidative effect of the oestrogens was lower. Whereas the H2O2 generation was not changed by E2, enhanced by E2V, but diminished by EE2 in all age groups, CL(LUC) and CL(LUM) were inhibited in the order of E2 < E2V < EE2. Also after subchronical treatment of the rats the antioxidative action of the oestrogens was evident, microsomal LPO was inhibited in the order of E2 < E2V < EE2. All oestrogens inhibited ethylmorphine N-demethylation. But enhanced H2O2 generation and increased CL(LUC) also indicate a formation of reactive oxygen species by these oestrogens. Obviously in vitro the antioxidative phenolic structure of the oestrogens dominates, whereas after in vivo administration the dose- and age-dependent biotransformation produces prooxidative in addition to antioxidative structures.

  12. Context modulates effects of nicotine abstinence on human cooperative responding.

    PubMed

    Spiga, R; Day, J D; Schmitz, J M; Broitman, M; Elk, R; Caperton-Brown, H

    1998-11-01

    The effects of ad libitum smoking, abstinence, and 0-, 2-, and 4-mg nicotine gum on human cooperative responding were examined. Participants were provided the opportunity to respond cooperatively or independently to episodes initiated by a computer-simulated other person. Participants could also initiate episodes that ostensibly provided the other person the opportunity to respond cooperatively or independently of the participant. Working cooperatively added points to both the participant's and other person's counters. Working independently added points only to the participant's counter. Results demonstrated that abstinence decreased cooperative responses during episodes initiated by the computer-stimulated other person. Relative to abstinence and placebo gum conditions, ad libitum smoking and administration of 2- and 4-mg nicotine gum increased these cooperative responses. No gender differences were observed. The number of cooperative episodes initiated by the participants was not affected significantly by the smoking or gum conditions. Nicotine increased reports of vigor and decreased abstinence-engendered reports of depression, anger, confusion, and tension. The difference in the effects of nicotine abstinence on the 2 classes of cooperative responding demonstrates that the social contingency mediates the behavioral effects of abstinence.

  13. Human Rap1 modulates TRF2 attraction to telomeric DNA

    PubMed Central

    Janoušková, Eliška; Nečasová, Ivona; Pavloušková, Jana; Zimmermann, Michal; Hluchý, Milan; Marini, Victoria; Nováková, Monika; Hofr, Ctirad

    2015-01-01

    More than two decades of genetic research have identified and assigned main biological functions of shelterin proteins that safeguard telomeres. However, a molecular mechanism of how each protein subunit contributes to the protecting function of the whole shelterin complex remains elusive. Human Repressor activator protein 1 (Rap1) forms a multifunctional complex with Telomeric Repeat binding Factor 2 (TRF2). Rap1–TRF2 complex is a critical part of shelterin as it suppresses homology-directed repair in Ku 70/80 heterodimer absence. To understand how Rap1 affects key functions of TRF2, we investigated full-length Rap1 binding to TRF2 and Rap1–TRF2 complex interactions with double-stranded DNA by quantitative biochemical approaches. We observed that Rap1 reduces the overall DNA duplex binding affinity of TRF2 but increases the selectivity of TRF2 to telomeric DNA. Additionally, we observed that Rap1 induces a partial release of TRF2 from DNA duplex. The improved TRF2 selectivity to telomeric DNA is caused by less pronounced electrostatic attractions between TRF2 and DNA in Rap1 presence. Thus, Rap1 prompts more accurate and selective TRF2 recognition of telomeric DNA and TRF2 localization on single/double-strand DNA junctions. These quantitative functional studies contribute to the understanding of the selective recognition of telomeric DNA by the whole shelterin complex. PMID:25675958

  14. Effects of soy isoflavone and endogenous oestrogen on breast cancer in MMTV-erbB2 transgenic mice.

    PubMed

    Zhang, G P; Han, D; Liu, G; Gao, S G; Cai, X Q; Duan, R H; Feng, X S

    2012-01-01

    Soy isoflavone is associated with modification of breast cancer risk. Effects of dietary isoflavone on breast tissue carcinogenesis under varying endogenous oestrogen contexts were investigated. Five-week-old mouse mammary tumour virus (MMTV)-erbB2 female transgenic mice (n = 180) were divided into three equal groups: low-, normal- and high-oestrogen groups. Each group was then subdivided into an experimental group (given soybean feed) and a control group (given control feed). In the high-oestrogen environment, breast cancer incidence was significantly lower in the experimental versus the control group, whereas in the low-oestrogen environment, breast cancer incidence was significantly higher in the experimental versus the control group. There were no between-group differences in mean breast tumour latency, mean largest tumour diameter and breast tumour tissue vascular endothelial growth factor levels. Dietary soy isoflavones promote breast cancer at low oestrogen levels but inhibit breast cancer at high oestrogen levels. This effect may only occur during the initiation stage of breast cancer.

  15. Oestrogen-induced androgen insufficiency results in a reduction of proliferation and differentiation of spermatogonia in the zebrafish testis.

    PubMed

    de Waal, Paul P; Leal, Marcelo C; García-López, Angel; Liarte, Sergio; de Jonge, Hugo; Hinfray, Nathalie; Brion, François; Schulz, Rüdiger W; Bogerd, Jan

    2009-08-01

    Androgens can induce complete spermatogenesis in immature or prepubertal teleost fish. However, many aspects of the role of androgens in adult teleost spermatogenesis have remained elusive. Since oestrogens inhibit androgen synthesis, we used an oestrogen-induced androgen depletion model to identify androgen-dependent stages during adult zebrafish spermatogenesis. Exposure to 10 nM 17beta-oestradiol (E(2)) in vivo at least halved the mass of differentiating germ cells (from type B spermatogonia to spermatids), while type A spermatogonia accumulated. Studies on the cellular dynamics revealed that a reduction of spermatogonial proliferation together with an inhibition of their differentiation to type B spermatogonia were the basis for the oestrogen-mediated disturbance of spermatogenesis. The capacity of the zebrafish testis to produce 11-ketotestosterone as well as the expression of steroidogenesis-related genes was markedly decreased after in vivo oestrogen exposure. Moreover, the androgen-release response to recombinant zebrafish Lh was lost after oestrogen exposure. We conclude that oestrogen exposure caused a state of androgen insufficiency in adult male zebrafish. Since the downregulation of the steroidogenic system as well as the disturbance of spermatogenesis in testicular explants exposed to E(2) ex vivo was much less severe than after in vivo exposure, the main inhibitory effect appears to be exerted via feedback inhibition of gonadotropin release. This experimental set-up helped to identify spermatogonial proliferation and their differentiation as androgen targets in adult zebrafish spermatogenesis.

  16. Modulation of human corticospinal excitability by paired associative stimulation

    PubMed Central

    Carson, Richard G.; Kennedy, Niamh C.

    2013-01-01

    Paired Associative Stimulation (PAS) has come to prominence as a potential therapeutic intervention for the treatment of brain injury/disease, and as an experimental method with which to investigate Hebbian principles of neural plasticity in humans. Prototypically, a single electrical stimulus is directed to a peripheral nerve in advance of transcranial magnetic stimulation (TMS) delivered to the contralateral primary motor cortex (M1). Repeated pairing of the stimuli (i.e., association) over an extended period may increase or decrease the excitability of corticospinal projections from M1, in manner that depends on the interstimulus interval (ISI). It has been suggested that these effects represent a form of associative long-term potentiation (LTP) and depression (LTD) that bears resemblance to spike-timing dependent plasticity (STDP) as it has been elaborated in animal models. With a large body of empirical evidence having emerged since the cardinal features of PAS were first described, and in light of the variations from the original protocols that have been implemented, it is opportune to consider whether the phenomenology of PAS remains consistent with the characteristic features that were initially disclosed. This assessment necessarily has bearing upon interpretation of the effects of PAS in relation to the specific cellular pathways that are putatively engaged, including those that adhere to the rules of STDP. The balance of evidence suggests that the mechanisms that contribute to the LTP- and LTD-type responses to PAS differ depending on the precise nature of the induction protocol that is used. In addition to emphasizing the requirement for additional explanatory models, in the present analysis we highlight the key features of the PAS phenomenology that require interpretation. PMID:24348369

  17. Calcium pantothenate modulates gene expression in proliferating human dermal fibroblasts.

    PubMed

    Wiederholt, Tonio; Heise, Ruth; Skazik, Claudia; Marquardt, Yvonne; Joussen, Sylvia; Erdmann, Kati; Schröder, Henning; Merk, Hans F; Baron, Jens Malte

    2009-11-01

    Topical application of pantothenate is widely used in clinical practice for wound healing. Previous studies identified a positive effect of pantothenate on migration and proliferation of cultured fibroblasts. However, these studies were mainly descriptive with no molecular data supporting a possible model of its action. In this study, we first established conditions for an in vitro model of pantothenate wound healing and then analysed the molecular effects of pantothenate. To test the functional effect of pantothenate on dermal fibroblasts, cells were cultured and in vitro proliferation tests were performed using a standardized scratch test procedure. For all three donors analysed, a strong stimulatory effect of pantothenate at a concentration of 20 microg/ml on the proliferation of cultivated dermal fibroblasts was observed. To study the molecular mechanisms resulting in the proliferative effect of pantothenate, gene expression was analysed in dermal fibroblasts cultivated with 20 microg/ml of pantothenate compared with untreated cells using the GeneChip Human Exon 1.0 ST Array. A number of significantly regulated genes were identified including genes coding for interleukin (IL)-6, IL-8, Id1, HMOX-1, HspB7, CYP1B1 and MARCH-II. Regulation of these genes was subsequently verified by quantitative real-time polymerase chain reaction analysis. Induction of HMOX-1 expression by pantothenol and pantothenic acid in dermal cells was confirmed on the protein level using immunoblots. Functional studies revealed the enhanced suppression of free radical formation in skin fibroblasts cultured with panthenol. In conclusion, these studies provided new insight in the molecular mechanisms linked to the stimulatory effect of pantothenate and panthenol on the proliferation of dermal fibroblasts.

  18. Oleaster oil positively modulates plasma lipids in humans.

    PubMed

    Belarbi, Meriem; Bendimerad, Soraya; Sour, Souad; Soualem, Zoubida; Baghdad, Choukri; Hmimed, Sara; Chemat, Farid; Visioli, Francesco

    2011-08-24

    The olive tree had been domesticated during the early Neolithic in the Near East, and more than 1000 different cultivars have been identified to date. However, examples of wild olive trees (Olea europaea oleaster) can still be found in the Mediterranean basin. Evidence of oleaster use for oil production can be found in historical and sacred texts, such as the Odyssey, the Holey Koran, and the Holey Bible. While the nutritional and healthful properties of olive oil are actively being explored, there are no data on the human actions of oleaster oil. Therefore, we investigated the effect of prolonged, i.e., 1 month, consumption of oleaster oil on the lipid profile of a 40 healthy Algerian subjects (aged 27.9 ± 3.85 years), as compared to nonconsumers from the same area. Plasma urea, creatinine, and uric acid concentrations and glycemia did not significantly differ, at the end of the study, between controls and oleaster-oil-supplemented subjects. Conversely, we recorded significant decreases of plasma triglyceride concentration (-24.8%; p < 0.05), total cholesterol (-12.13%; p < 0.05), and low-density lipoprotein-cholesterol (LDL-C) (-24.39%; p < 0.05) in oleaster-oil-treated subjects. Concomitantly, high-density lipoprotein-cholesterol (HDL-C) concentrations were significantly increased (17.94%; p < 0.05) by oleaster oil administration. In conclusion, we show that oil obtained from feral olive trees, i.e., oleasters, improves the plasma lipid profile of healthy volunteers.

  19. Sensitivity to temporal modulation rate and spectral bandwidth in the human auditory system: MEG evidence.

    PubMed

    Wang, Yadong; Ding, Nai; Ahmar, Nayef; Xiang, Juanjuan; Poeppel, David; Simon, Jonathan Z

    2012-04-01

    Slow acoustic modulations below 20 Hz, of varying bandwidths, are dominant components of speech and many other natural sounds. The dynamic neural representations of these modulations are difficult to study through noninvasive neural-recording methods, however, because of the omnipresent background of slow neural oscillations throughout the brain. We recorded the auditory steady-state responses (aSSR) to slow amplitude modulations (AM) from 14 human subjects using magnetoencephalography. The responses to five AM rates (1.5, 3.5, 7.5, 15.5, and 31.5 Hz) and four types of carrier (pure tone and 1/3-, 2-, and 5-octave pink noise) were investigated. The phase-locked aSSR was detected reliably in all conditions. The response power generally decreases with increasing modulation rate, and the response latency is between 100 and 150 ms for all but the highest rates. Response properties depend only weakly on the bandwidth. Analysis of the complex-valued aSSR magnetic fields in the Fourier domain reveals several neural sources with different response phases. These neural sources of the aSSR, when approximated by a single equivalent current dipole (ECD), are distinct from and medial to the ECD location of the N1m response. These results demonstrate that the globally synchronized activity in the human auditory cortex is phase locked to slow temporal modulations below 30 Hz, and the neural sensitivity decreases with an increasing AM rate, with relative insensitivity to bandwidth.

  20. Independent component analysis: mining microarray data for fundamental human gene expression modules

    PubMed Central

    Engreitz, Jesse M.; Daigle, Bernie J.; Marshall, Jonathan J.; Altman, Russ B.

    2010-01-01

    As public microarray repositories rapidly accumulate gene expression data, these resources contain increasingly valuable information about cellular processes in human biology. This presents a unique opportunity for intelligent data mining methods to extract information about the transcriptional modules underlying these biological processes. Modeling cellular gene expression as a combination of functional modules, we use independent component analysis (ICA) to derive 423 fundamental components of human biology from a 9,395-array compendium of heterogeneous expression data. Annotation using the Gene Ontology (GO) suggests that while some of these components represent known biological modules, others may describe biology not well characterized by existing manually-curated ontologies. In order to understand the biological functions represented by these modules, we investigate the mechanism of the preclinical anticancer drug parthenolide (PTL) by analyzing the differential expression of our fundamental components. Our method correctly identifies known pathways and predicts that N-glycan biosynthesis and T-cell receptor signaling may contribute to PTL response. The fundamental gene modules we describe have the potential to provide pathway-level insight into new gene expression datasets. PMID:20619355

  1. Long-term topical oestrogen treatment of sun-exposed facial skin in post-menopausal women does not improve facial wrinkles or skin elasticity, but induces matrix metalloproteinase-1 expression.

    PubMed

    Yoon, Hyun-Sun; Lee, Se-Rah; Chung, Jin Ho

    2014-01-01

    It is controversial whether treatment with oestrogen stimulates collagen production or accumulation in sun-exposed skin. The aim of this study was to determine the effect of long-term treatment with topical oestrogen on photoaged facial skin, with regard to wrinkle severity, and expression of procollagen and matrix metalloproteinase-1 enzyme. Two groups of 40 post-menopausal women applied either 1 g of 1% oestrone or vehicle cream once daily to the face for 24 weeks. Visiometer R1-R5 values (skin wrinkles) and Cutometer values (skin elasticity) were not significantly improved in the oestrone group after 24 weeks of treatment. Type I procollagen immunostaining did not increase in the oestrone group compared with the control group. However, levels of matrix metalloproteinase-1 mRNA increased robustly (10.3 times) in oestrone-treated skin compared with vehicle-treated skin. Thus, treatment with topical oestrogen may be deleterious in ultraviolet-induced skin ageing, at least in part, through induction of matrix metalloproteinase-1 (MMP-1) expression in human skin.

  2. Role of oestrogen in the regulation of bone turnover at the menarche.

    PubMed

    Eastell, Richard

    2005-05-01

    The rise in oestrogen levels at menarche in girls is associated with a large reduction in bone turnover markers. This reduction reflects the closure of the epiphyseal growth plates, the reduction in periosteal apposition and endosteal resorption within cortical bone, and in bone remodelling within cortical and cancellous bone. Oestrogen promotes these changes, in part, by promoting apoptosis of chondrocytes in the growth plate and osteoclasts within cortical and cancellous bone. The period of early puberty is associated with an increased risk of fracture, particularly of the distal forearm, and this may be related to the high rate of bone turnover. A late menarche is a consistent risk factor for fracture and low bone mineral density in the postmenopausal period; models that might explain this association are considered.

  3. A clinical trial of adjunctive oestrogen treatment in women with schizophrenia.

    PubMed

    Kulkarni, J; Riedel, A; de Castella, A R; Fitzgerald, P B; Rolfe, T J; Taffe, J; Burger, H

    2002-11-01

    A double-blind, 28-day, placebo-controlled study was conducted with three groups of women of child-bearing age (N = 12 in each group) who received standardised antipsychotic medication plus a) 50 microg transdermal estradiol or b) 100 microg transdermal estradiol or c) transdermal placebo. Preliminary analyses show that women receiving 100 microg of estradiol made greater improvements in the symptoms of schizophrenia than either the 50 microg estradiol or placebo groups. The addition of 100 microg adjunctive transdermal oestrogen significantly enhanced treatment responsivity of acute, severe psychotic symptoms in women with schizophrenia. The positive impact of oestrogen treatment on psychotic symptoms via a multiplicity of possible actions (see accompanying articles in this issue) may prove clinically useful in the overall treatment of women with schizophrenia.

  4. First report of vaginal prolapse in a bitch treated with oestrogen.

    PubMed

    Sarrafzadeh-Rezaei, F; Saifzadeh, S; Mazaheri, R; Behfar, M

    2008-06-01

    Vaginal prolapse is the protrusion of edematous vaginal tissue into and through the opening of the vulva occurring during the pro-oestrus and oestrus stages of the sexual cycle. True vaginal prolapse may occur near parturition, as the concentration of serum progesterone declines and the concentration of serum oestrogen increases. In a bitch, true vaginal prolapse is a very rare condition. This case report describes an 18-month-old crossbreed bitch, weighing 40 kg presented with type III vaginal prolapse. The patient had developed vaginal prolapse after receiving oestrogen in order to oestrus induction. Subsequent to unsuccessful attempts for repositioning, ovariohysterectomy (OHE), circumferential excision of the prolapsed tissue and finally vulvoplasty were performed. There was no evidence of recurrence of the prolapse during 30 days after surgery. This case report describes type III vaginal prolapse as an unusual side effect of oestrus induction hormonal therapy in the bitch.

  5. Selective attention modulates human auditory brainstem responses: relative contributions of frequency and spatial cues.

    PubMed

    Lehmann, Alexandre; Schönwiesner, Marc

    2014-01-01

    Selective attention is the mechanism that allows focusing one's attention on a particular stimulus while filtering out a range of other stimuli, for instance, on a single conversation in a noisy room. Attending to one sound source rather than another changes activity in the human auditory cortex, but it is unclear whether attention to different acoustic features, such as voice pitch and speaker location, modulates subcortical activity. Studies using a dichotic listening paradigm indicated that auditory brainstem processing may be modulated by the direction of attention. We investigated whether endogenous selective attention to one of two speech signals affects amplitude and phase locking in auditory brainstem responses when the signals were either discriminable by frequency content alone, or by frequency content and spatial location. Frequency-following responses to the speech sounds were significantly modulated in both conditions. The modulation was specific to the task-relevant frequency band. The effect was stronger when both frequency and spatial information were available. Patterns of response were variable between participants, and were correlated with psychophysical discriminability of the stimuli, suggesting that the modulation was biologically relevant. Our results demonstrate that auditory brainstem responses are susceptible to efferent modulation related to behavioral goals. Furthermore they suggest that mechanisms of selective attention actively shape activity at early subcortical processing stages according to task relevance and based on frequency and spatial cues.

  6. Hydroxytyrosol supplementation modulates the expression of miRNAs in rodents and in humans.

    PubMed

    Tomé-Carneiro, Joao; Crespo, María Carmen; Iglesias-Gutierrez, Eduardo; Martín, Roberto; Gil-Zamorano, Judit; Tomas-Zapico, Cristina; Burgos-Ramos, Emma; Correa, Carlos; Gómez-Coronado, Diego; Lasunción, Miguel A; Herrera, Emilio; Visioli, Francesco; Dávalos, Alberto

    2016-08-01

    Dietary microRNAs (miRNAs) modulation could be important for health and wellbeing. Part of the healthful activities of polyphenols might be due to a modulation of miRNAs' expression. Among the most biologically active polyphenols, hydroxytyrosol (HT) has never been studied for its actions on miRNAs. We investigated whether HT could modulate the expression of miRNAs in vivo. We performed an unbiased intestinal miRNA screening in mice supplemented (for 8 weeks) with nutritionally relevant amounts of HT. HT modulated the expression of several miRNAs. Analysis of other tissues revealed consistent HT-induced modulation of only few miRNAs. Also, HT administration increased triglycerides levels. Acute treatment with HT and in vitro experiments provided mechanistic insights. The HT-induced expression of one miRNA was confirmed in healthy volunteers supplemented with HT in a randomized, double-blind and placebo-controlled trial. HT consumption affects specific miRNAs' expression in rodents and humans. Our findings suggest that the modulation of miRNAs' action through HT consumption might partially explain its healthful activities and might be pharmanutritionally exploited in current therapies targeting endogenous miRNAs. However, the effects of HT on triglycerides warrant further investigations.

  7. Activation of IFN/STAT1 signalling predicts response to chemotherapy in oestrogen receptor-negative breast cancer

    PubMed Central

    Legrier, Marie-Emmanuelle; Bièche, Ivan; Gaston, Julie; Beurdeley, Arnaud; Yvonnet, Vanessa; Déas, Olivier; Thuleau, Aurélie; Château-Joubert, Sophie; Servely, Jean-Luc; Vacher, Sophie; Lassalle, Myriam; Depil, Stéphane; C Tucker, Gordon; Fontaine, Jean-Jacques; Poupon, Marie-France; Roman-Roman, Sergio; Judde, Jean-Gabriel; Decaudin, Didier; Cairo, Stefano; Marangoni, Elisabetta

    2016-01-01

    Background: Oestrogen receptor-negative (ER−) breast cancer is intrinsically sensitive to chemotherapy. However, tumour response is often incomplete, and relapse occurs with high frequency. The aim of this work was to analyse the molecular characteristics of residual tumours and early response to chemotherapy in patient-derived xenografts (PDXs) of breast cancer. Methods: Gene and protein expression profiles were analysed in a panel of ER− breast cancer PDXs before and after chemotherapy treatment. Tumour and stromal interferon-gamma expression was measured in xenografts lysates by human and mouse cytokine arrays, respectively. Results: The analysis of residual tumour cells in chemo-responder PDX revealed a strong overexpression of IFN-inducible genes, induced early after AC treatment and associated with increased STAT1 phosphorylation, DNA-damage and apoptosis. No increase in IFN-inducible gene expression was observed in chemo-resistant PDXs upon chemotherapy. Overexpression of IFN-related genes was associated with human IFN-γ secretion by tumour cells. Conclusions: Treatment-induced activation of the IFN/STAT1 pathway in tumour cells is associated with chemotherapy response in ER− breast cancer. Further validations in prospective clinical trials will aim to evaluate the usefulness of this signature to assist therapeutic strategies in the clinical setting. PMID:26695443

  8. Experiment on parallel correlated recognition of 2030 human faces based on speckle modulation.

    PubMed

    Liao, Yi; Guo, Yunbo; Cao, Liangcai; Ma, Xiaosu; He, Qingsheng; Jin, Guofan

    2004-08-23

    In this paper, the experiment on parallel correlated recognition of 2030 human faces in Fe:LiNbO(3) crystal is detailedly presented, a very clear correlation spots array was achieved and the recognition accuracy is better than 95%. According to the experiment, it is proved that speckle modulation on the object beam of volume holographic correlators can well suppress the crosstalk, so that the multiplexing spacing is markedly reduced and the channel density is increased 10 times compared with the traditional holographic correlators without speckle modulation.

  9. Roles of Oestrogen Receptors α and β in Behavioural Neuroendocrinology: Beyond Yin/Yang

    PubMed Central

    Rissman, E. F.

    2009-01-01

    Oestrogen receptor β (ERβ) was discovered more than 10 years ago. It is widely distributed in the brain. In some areas, such as the entorhinal cortex, it is present as the only ER, whereas in other regions, such as the bed nucleus of the stria terminalis and preoptic area, it can be found co-expressed with ERα, often within the same neurones. These ERs share ligands, and there are several complex relationships between the two receptors. Initially, the relationship between them was labelled as ‘yin/yang’, meaning that the actions of each complemented those of the other, but now, years later, other relationships have been described. Based on evidence from neuroendocrine and behavioural studies, three types of interactions between the two oestrogen receptors are described in this review. The first relationship is antagonistic; this is evident from studies on the role of oestrogen in spatial learning. When oestradiol is given in a high, chronic dose, spatial learning is impaired. This action of oestradiol requires ERα, and when ERβ is not functional, lower doses of oestradiol have this negative effect on behaviour. The second relationship between the two receptors is one that is synergistic, and this is illustrated in the combined effects of the two receptors on the production of the neuropeptide oxytocin and its receptor. The third relationship is sequential; separate actions of the two receptors are postulated in activation and organisation of sexually dimorphic reproductive behaviours. Future studies on all of these topics will inform us about how ER selective ligands might affect oestrogen functions at the organismal level. PMID:18601711

  10. Does Human Milk Modulate Body Composition in Late Preterm Infants at Term-Corrected Age?

    PubMed

    Giannì, Maria Lorella; Consonni, Dario; Liotto, Nadia; Roggero, Paola; Morlacchi, Laura; Piemontese, Pasqua; Menis, Camilla; Mosca, Fabio

    2016-10-23

    (1) Background: Late preterm infants account for the majority of preterm births and are at risk of altered body composition. Because body composition modulates later health outcomes and human milk is recommended as the normal method for infant feeding, we sought to investigate whether human milk feeding in early life can modulate body composition development in late preterm infants; (2) Methods: Neonatal, anthropometric and feeding data of 284 late preterm infants were collected. Body composition was evaluated at term-corrected age by air displacement plethysmography. The effect of human milk feeding on fat-free mass and fat mass content was evaluated using multiple linear regression analysis; (3) Results: Human milk was fed to 68% of the infants. According to multiple regression analysis, being fed any human milk at discharge and at  term-corrected and being fed exclusively human milk at term-corrected age were positively associated with fat-free mass content(β = -47.9, 95% confidence interval (CI) = -95.7; -0.18; p = 0.049; β = -89.6, 95% CI = -131.5; -47.7; p < 0.0001; β = -104.1, 95% CI = -151.4; -56.7, p < 0.0001); (4) Conclusion: Human milk feeding appears to be associated with fat-free mass deposition in late preterm infants. Healthcare professionals should direct efforts toward promoting and supporting breastfeeding in these vulnerable infants.

  11. Does Human Milk Modulate Body Composition in Late Preterm Infants at Term-Corrected Age?

    PubMed Central

    Giannì, Maria Lorella; Consonni, Dario; Liotto, Nadia; Roggero, Paola; Morlacchi, Laura; Piemontese, Pasqua; Menis, Camilla; Mosca, Fabio

    2016-01-01

    (1) Background: Late preterm infants account for the majority of preterm births and are at risk of altered body composition. Because body composition modulates later health outcomes and human milk is recommended as the normal method for infant feeding, we sought to investigate whether human milk feeding in early life can modulate body composition development in late preterm infants; (2) Methods: Neonatal, anthropometric and feeding data of 284 late preterm infants were collected. Body composition was evaluated at term-corrected age by air displacement plethysmography. The effect of human milk feeding on fat-free mass and fat mass content was evaluated using multiple linear regression analysis; (3) Results: Human milk was fed to 68% of the infants. According to multiple regression analysis, being fed any human milk at discharge and at  term-corrected and being fed exclusively human milk at term-corrected age were positively associated with fat-free mass content(β = −47.9, 95% confidence interval (CI) = −95.7; −0.18; p = 0.049; β = −89.6, 95% CI = −131.5; −47.7; p < 0.0001; β = −104.1, 95% CI = −151.4; −56.7, p < 0.0001); (4) Conclusion: Human milk feeding appears to be associated with fat-free mass deposition in late preterm infants. Healthcare professionals should direct efforts toward promoting and supporting breastfeeding in these vulnerable infants. PMID:27782098

  12. Effects of a diet rich in sesame ( Sesamum indicum) pericarp on the expression of oestrogen receptor alpha and oestrogen receptor beta in rat prostate and uterus.

    PubMed

    Anagnostis, Aristotelis; Papadopoulos, Athanasios I

    2009-09-01

    The expression of oestrogen receptors (ERalpha and ERbeta) in the prostate and uterus tissues of Wistar rats supplied for 8 weeks with a diet rich in sesame (Sesamum indicum) pericarp (30 %) was monitored. Eight male rats, aged 6 weeks, were divided into a control group fed on a normal diet, and an experimental one, provided with the normal diet enriched with 30 % sesame pericarp. A similar experiment was performed with female rats. At the end of the experiment, the prostate and uterus tissues were surgically removed and kept at - 80 degrees C for up to 2 months. Western blotting and quantitative real-time PCR (qRT-PCR) methods were used in order to investigate the levels of receptor proteins and mRNA. Significant increase in the expression of ERbeta in prostate and uterus was evident in both methods, while the magnitude of the observed alteration depended on the applied method. No statistically significant change was observed in the expression of ERalpha in uterus. In prostate, although the increase was more evident when investigated by means of qRT-PCR, the difference in expression of ERalpha was not statistically significant. In both tissues, a shift of the ratio of ERalpha:ERbeta in favour of ERbeta was evident, indicating, according to existing literature, a beneficial effect of the diet provided upon the health status of the organisms. It is suggested that this effect is attributed to the lignans present in the pericarp which exert phyto-oestrogenic activity.

  13. Altered burst swimming in rainbow trout Oncorhynchus mykiss exposed to natural and synthetic oestrogens.

    PubMed

    Osachoff, H L; Osachoff, K N; Wickramaratne, A E; Gunawardane, E K; Venturini, F P; Kennedy, C J

    2014-08-01

    Juvenile rainbow trout Oncorhynchus mykiss were exposed to two concentrations each of 17β-oestradiol (E2; natural oestrogen hormone) or 17α-ethinyl oestradiol (EE2; a potent synthetic oestrogen hormone) to evaluate their potential effects on burst-swimming performance. In each of six successive burst-swimming assays, burst-swimming speed (Uburst ) was lower in fish exposed to 0.5 and 1 µg l(-1) E2 and EE2 for four days compared with control fish. A practice swim (2 days prior to exposure initiation) in control fish elevated initial Uburst values, but this training effect was not evident in the 1 µg l(-1) EE2-exposed fish. Several potential oestrogen-mediated mechanisms for Uburst reductions were investigated, including effects on metabolic products, osmoregulation and blood oxygen-carrying capacity. Prior to burst-swimming trials, fish exposed to E2 and EE2 for 4 days had significantly reduced erythrocyte numbers and lower plasma glucose concentrations. After six repeated burst-swimming trials, plasma glucose, lactate and creatinine concentrations were not significantly different among treatment groups; however, plasma Cl(-) concentrations were significantly reduced in E2- and EE2-treated fish. In summary, E2 and EE2 exposure altered oxygen-carrying capacity ([erythrocytes]) and an osmoregulatory-related variable ([Cl(-) ]), effects that may underlie reductions in burst-swimming speed, which will have implications for fish performance in the wild.

  14. Subcellular localisation of VEGF in different pituitary cells. Changes of its expression in oestrogen induced prolactinomas.

    PubMed

    Mukdsi, Jorge Humberto; De Paul, Ana Lucía; Gutiérrez, Silvina; Roth, Félix Daniel; Aoki, Agustín; Torres, Alicia Inés

    2005-10-01

    Vascular endothelial growth factor (VEGF) is an important angiogenic factor in the pituitary gland. The objective of this study was to unveil the VEGF subcellular localisation in different pituitary cell types and to evaluate changes in its expression at different time intervals after oestrogen stimulation. A relevant feature demonstrated was the identification of this cytokine in the nucleus and cytoplasm of lactotrophs, somatotrophs and gonadotrophs, as well as in follicle-stellate cells of male rats. Oestrogen treatment increased the number of VEGF immunopositive cells and its expression detected differentially by western blot in both nucleus and cytoplasm of pituitary cells when compared to the control. At ultrastructural level VEGF appeared associated with nucleolus and euchromatin involving a possible internal autocrine loop. In lactotrophs, the predominant cell of the tumour, VEGF was immunodetected in RER, Golgi complex, and vesicular organelles, supporting further the association with an auto-paracrine effect exerted by VEGF. The nucleus/cytoplasm ratio of VEGF revealed a prevalent accumulation of VEGF in the cytoplasm. The presence of VEGF in the nucleus may probably be associated with a translocation to this cell compartment. This study demonstrated a cytoplasmic and nuclear immunolocalisation of VEGF in normal and tumoural adenohypophyseal cells. In the course of prolactinoma development, the oestrogen stimulated VEGF expression in tumoural cells, promoting a vascular adaptation which contributes to growth and progression of the tumour.

  15. Oestradiol rapidly inhibits Ca2+ signals in ciliary neurons through classical oestrogen receptors in cytoplasm.

    PubMed

    Viso-León, M Carmen; Ripoll, Cristina; Nadal, Angel

    2004-10-01

    Oestrogen plays a key role in a great variety of actions in the nervous system, either through classical or alternative pathways. The classical pathways are initiated after oestrogen binding to the oestrogen receptors ERalpha or ERbeta, which translocate from the cytoplasm to the nucleus and act there as transcription factors. Alternative pathways are initiated at the plasma membrane and cytoplasm, via binding to classical or non-classical ERs. Using isolated ciliary ganglion neurons from the chick embryo and Ca2+ imaging, we demonstrated that a 10-min exposure to 17beta-oestradiol reduces Ca2+ influx through the plasma membrane. This effect was not reproduced by oestradiol conjugated to bovine serum albumin, which does not cross the plasma membrane, indicating that 17beta-oestradiol was acting intracellularly. ERalpha was detected in the cytoplasm by immunostaining and its involvement in the regulation of Ca2+ influx by ICI182,780 inhibition. The phosphatidylinositol-3 kinase (Pi3-kinase) inhibitor wortmannin and the nitric oxide synthase (NOS) inhibitor Nomega-nitro-L-arginine methyl ester (L-NAME) both blocked the oestradiol effect. The oestradiol effect was reproduced by 8Br-cGMP and abolished in the presence of the cGMP-dependent protein kinase (PKG) inhibitor KT5823. Our study indicates that 17beta-oestradiol can regulate Ca2+ influx via PI3-kinase, NOS and PKG after activation of cytoplasmic ER.

  16. The effect of Ramadan fasting on LH, FSH, oestrogen, progesterone and leptin in pregnant women.

    PubMed

    Khoshdel, A; Kheiri, S; Hashemi-Dehkordi, E; Nasiri, J; Shabanian-Borujeni, S; Saedi, E

    2014-10-01

    Many pregnant Muslim women fast during Ramadan. Leptin has an important role in the reproductive system and hormones. In this study, FSH, LH, oestrogen, progesterone and leptin were measured in the first, second and fourth week of Ramadan and the second week post-Ramadan, in 30 fasting pregnant women. Data were analysed using repeated measures ANOVA by SPSS. The weight and BMI did not change during the study. A significant change in FSH, oestrogen, progesterone and leptin was observed (p < 0.05). The lowest value of FSH was in the second week of Ramadan. Progesterone increased at the end of Ramadan and the second week after. Oestrogen increased significantly during Ramadan and decreased after Ramadan. A decreasing trend was seen in LH during the Ramadan and 2 weeks after (p < 0.1). Leptin decreased significantly 2 weeks after Ramadan. We found poor weight gain and hypoleptinaemia in pregnant fasted women during the study. Food restriction in pregnant fasted women during Ramadan may induce poor weight gain during pregnancy. These data confirm that Ramadan fasting by pregnant women may have potential risks during pregnancy. We recommend further study to evaluate long-term effects of Ramadan fasting during pregnancy in different countries with different food habits and traditions, to obtain reliable and documented data.

  17. D-003 does not possess oestrogenic potential in-vivo: findings of the uterotrophic assay.

    PubMed

    Noa, Miriam; Mendoza, Sarahí; Mas, Rosa; Gámez, Rafael; Valle, Maikel; Pardo, Balia; Gutiérrez, Ariadne; Mendoza, Nilda

    2007-10-01

    D-003 is a mixture of long-chain fatty acids purified from sugarcane wax that inhibits both cholesterol synthesis prior to mevalonate formation, and lipid peroxidation. D-003 has been shown to prevent bone loss and bone resorption in ovariectomized rats, and significantly improves bone resorption markers in postmenopausal women with reduced bone mineral density. As hormone-replacement therapy, D-003 displays cholesterol-lowering and anti-resorptive effects. We have studied its potential oestrogenic activity in-vivo using the uterotrophic assay. Rats were randomly distributed into five groups: a sham-operated group and four groups of ovariectomized rats, one treated with vehicle, one with D-003 (50 mg kg(-1)), one with oestradiol benzoate (30 microg kg(-1)) and one with D-003 (50 mg kg(-1)) plus oestradiol benzoate (30 microg kg(-1)). Treatments were administered for 14 days. Ovariectomy decreased the values of relative uterus weight, epithelium cell height and endometrial thickness compared with sham-operated rats, and these effects were all significantly reduced with oestradiol benzoate, but not with D-003. Concurrent administration of D-003 and oestradiol benzoate had statistically similar effects on all variables as oestradiol benzoate alone. In conclusions, D-003 orally given at 50 mg kg(-1), a dose that prevents bone loss and bone resorption in ovariectomized rats, did not display oestrogenic/anti-oestrogenic activity in-vivo, as assessed in the uterotrophic assay.

  18. Efficient specification of interneurons from human pluripotent stem cells by dorsoventral and rostrocaudal modulation.

    PubMed

    Kim, Tae-Gon; Yao, Ruiqin; Monnell, Travis; Cho, Jun-Hyeong; Vasudevan, Anju; Koh, Alice; Peeyush, Kumar T; Moon, Minho; Datta, Debkanya; Bolshakov, Vadim Y; Kim, Kwang-Soo; Chung, Sangmi

    2014-07-01

    GABAergic interneurons regulate cortical neural networks by providing inhibitory inputs, and their malfunction, resulting in failure to intricately regulate neural circuit balance, is implicated in brain diseases such as Schizophrenia, Autism, and Epilepsy. During early development, GABAergic interneuron progenitors arise from the ventral telencephalic area such as medial ganglionic eminence (MGE) and caudal ganglionic eminence (CGE) by the actions of secreted signaling molecules from nearby organizers, and migrate to their target sites where they form local synaptic connections. In this study, using combinatorial and temporal modulation of developmentally relevant dorsoventral and rostrocaudal signaling pathways (SHH, Wnt, and FGF8), we efficiently generated MGE cells from multiple human pluripotent stem cells. Most importantly, modulation of FGF8/FGF19 signaling efficiently directed MGE versus CGE differentiation. Human MGE cells spontaneously differentiated into Lhx6-expressing GABAergic interneurons and showed migratory properties. These human MGE-derived neurons generated GABA, fired action potentials, and displayed robust GABAergic postsynaptic activity. Transplantation into rodent brains results in well-contained neural grafts enriched with GABAergic interneurons that migrate in the host and mature to express somatostatin or parvalbumin. Thus, we propose that signaling modulation recapitulating normal developmental patterns efficiently generate human GABAergic interneurons. This strategy represents a novel tool in regenerative medicine, developmental studies, disease modeling, bioassay, and drug screening.

  19. HEMD: An Integrated Tool of Human Epigenetic Enzymes and Chemical Modulators for Therapeutics

    PubMed Central

    Chen, Yingyi; Wong, Jiemin; Wang, Qi; Huang, Wenkang; Shi, Ting; Zhang, Jian

    2012-01-01

    Background Epigenetic mechanisms mainly include DNA methylation, post-translational modifications of histones, chromatin remodeling and non-coding RNAs. All of these processes are mediated and controlled by enzymes. Abnormalities of the enzymes are involved in a variety of complex human diseases. Recently, potent natural or synthetic chemicals are utilized to establish the quantitative contributions of epigenetic regulation through the enzymes and provide novel insight for developing new therapeutics. However, the development of more specific and effective epigenetic therapeutics requires a more complete understanding of the chemical epigenomic landscape. Description Here, we present a human epigenetic enzyme and modulator database (HEMD), the database which provides a central resource for the display, search, and analysis of the structure, function, and related annotation for human epigenetic enzymes and chemical modulators focused on epigenetic therapeutics. Currently, HEMD contains 269 epigenetic enzymes and 4377 modulators in three categories (activators, inhibitors, and regulators). Enzymes are annotated with detailed description of epigenetic mechanisms, catalytic processes, and related diseases, and chemical modulators with binding sites, pharmacological effect, and therapeutic uses. Integrating the information of epigenetic enzymes in HEMD should allow for the prediction of conserved features for proteins and could potentially classify them as ideal targets for experimental validation. In addition, modulators curated in HEMD can be used to investigate potent epigenetic targets for the query compound and also help chemists to implement structural modifications for the design of novel epigenetic drugs. Conclusions HEMD could be a platform and a starting point for biologists and medicinal chemists for furthering research on epigenetic therapeutics. HEMD is freely available at http://mdl.shsmu.edu.cn/HEMD/. PMID:22761927

  20. Vestibular Modulation of Sympathetic Nerve Activity to Muscle and Skin in Humans

    PubMed Central

    Hammam, Elie; Macefield, Vaughan G.

    2017-01-01

    We review the existence of vestibulosympathetic reflexes in humans. While several methods to activate the human vestibular apparatus have been used, galvanic vestibular stimulation (GVS) is a means of selectively modulating vestibular afferent activity via electrodes over the mastoid processes, causing robust vestibular illusions of side-to-side movement. Sinusoidal GVS (sGVS) causes partial entrainment of sympathetic outflow to muscle and skin. Modulation of muscle sympathetic nerve activity (MSNA) from vestibular inputs competes with baroreceptor inputs, with stronger temporal coupling to the vestibular stimulus being observed at frequencies remote from the cardiac frequency; “super entrainment” was observed in some individuals. Low-frequency (<0.2 Hz) sGVS revealed two peaks of modulation per cycle, with bilateral recordings of MSNA or skin sympathetic nerve activity, providing evidence of lateralization of sympathetic outflow during vestibular stimulation. However, it should be noted that GVS influences the firing of afferents from the entire vestibular apparatus, including the semicircular canals. To identify the specific source of vestibular input responsible for the generation of vestibulosympathetic reflexes, we used low-frequency (<0.2 Hz) sinusoidal linear acceleration of seated or supine subjects to, respectively, target the utricular or saccular components of the otoliths. While others had discounted the semicircular canals, we showed that the contributions of the utricle and saccule to the vestibular modulation of MSNA are very similar. Moreover, that modulation of MSNA occurs at accelerations well below levels at which subjects are able to perceive any motion indicates that, like vestibulospinal control of posture, the vestibular system contributes to the control of blood pressure through potent reflexes in humans. PMID:28798718

  1. Vestibular Activation Differentially Modulates Human Early Visual Cortex and V5/MT Excitability and Response Entropy

    PubMed Central

    Guzman-Lopez, Jessica; Arshad, Qadeer; Schultz, Simon R; Walsh, Vincent; Yousif, Nada

    2013-01-01

    Head movement imposes the additional burdens on the visual system of maintaining visual acuity and determining the origin of retinal image motion (i.e., self-motion vs. object-motion). Although maintaining visual acuity during self-motion is effected by minimizing retinal slip via the brainstem vestibular-ocular reflex, higher order visuovestibular mechanisms also contribute. Disambiguating self-motion versus object-motion also invokes higher order mechanisms, and a cortical visuovestibular reciprocal antagonism is propounded. Hence, one prediction is of a vestibular modulation of visual cortical excitability and indirect measures have variously suggested none, focal or global effects of activation or suppression in human visual cortex. Using transcranial magnetic stimulation-induced phosphenes to probe cortical excitability, we observed decreased V5/MT excitability versus increased early visual cortex (EVC) excitability, during vestibular activation. In order to exclude nonspecific effects (e.g., arousal) on cortical excitability, response specificity was assessed using information theory, specifically response entropy. Vestibular activation significantly modulated phosphene response entropy for V5/MT but not EVC, implying a specific vestibular effect on V5/MT responses. This is the first demonstration that vestibular activation modulates human visual cortex excitability. Furthermore, using information theory, not previously used in phosphene response analysis, we could distinguish between a specific vestibular modulation of V5/MT excitability from a nonspecific effect at EVC. PMID:22291031

  2. Movement-related frequency modulation of beta oscillatory activity in the human subthalamic nucleus.

    PubMed

    Foffani, G; Bianchi, A M; Baselli, G; Priori, A

    2005-10-15

    Event-related changes of brain electrical rhythms are typically analysed as amplitude modulations of local field potential (LFP) oscillations, like radio amplitude modulation broadcasting. In telecommunications, frequency modulation (FM) is less susceptible to interference than amplitude modulation (AM) and is therefore preferred for high-fidelity transmissions. Here we hypothesized that LFP rhythms detected from deep brain stimulation (DBS) electrodes implanted in the subthalamic nucleus (STN) in patients with Parkinson's disease could represent movement-related activity not only in AM but also in FM. By combining adaptive autoregressive identification with spectral power decomposition, we were able to show that FM of low-beta (13-20 Hz) and high-beta (20-35 Hz) rhythms significantly contributes to the involvement of the human STN in movement preparation, execution and recovery, and that the FM patterns are regulated by the dopamine levels in the system. Movement-related FM of beta oscillatory activity in the human subthalamic nucleus therefore provides a novel informational domain for rhythm-based pathophysiological models of cortico-basal ganglia processing.

  3. Vestibular activation differentially modulates human early visual cortex and V5/MT excitability and response entropy.

    PubMed

    Seemungal, Barry M; Guzman-Lopez, Jessica; Arshad, Qadeer; Schultz, Simon R; Walsh, Vincent; Yousif, Nada

    2013-01-01

    Head movement imposes the additional burdens on the visual system of maintaining visual acuity and determining the origin of retinal image motion (i.e., self-motion vs. object-motion). Although maintaining visual acuity during self-motion is effected by minimizing retinal slip via the brainstem vestibular-ocular reflex, higher order visuovestibular mechanisms also contribute. Disambiguating self-motion versus object-motion also invokes higher order mechanisms, and a cortical visuovestibular reciprocal antagonism is propounded. Hence, one prediction is of a vestibular modulation of visual cortical excitability and indirect measures have variously suggested none, focal or global effects of activation or suppression in human visual cortex. Using transcranial magnetic stimulation-induced phosphenes to probe cortical excitability, we observed decreased V5/MT excitability versus increased early visual cortex (EVC) excitability, during vestibular activation. In order to exclude nonspecific effects (e.g., arousal) on cortical excitability, response specificity was assessed using information theory, specifically response entropy. Vestibular activation significantly modulated phosphene response entropy for V5/MT but not EVC, implying a specific vestibular effect on V5/MT responses. This is the first demonstration that vestibular activation modulates human visual cortex excitability. Furthermore, using information theory, not previously used in phosphene response analysis, we could distinguish between a specific vestibular modulation of V5/MT excitability from a nonspecific effect at EVC.

  4. Movement-related frequency modulation of beta oscillatory activity in the human subthalamic nucleus

    PubMed Central

    Foffani, G; Bianchi, AM; Baselli, G; Priori, A

    2005-01-01

    Event-related changes of brain electrical rhythms are typically analysed as amplitude modulations of local field potential (LFP) oscillations, like radio amplitude modulation broadcasting. In telecommunications, frequency modulation (FM) is less susceptible to interference than amplitude modulation (AM) and is therefore preferred for high-fidelity transmissions. Here we hypothesized that LFP rhythms detected from deep brain stimulation (DBS) electrodes implanted in the subthalamic nucleus (STN) in patients with Parkinson's disease could represent movement-related activity not only in AM but also in FM. By combining adaptive autoregressive identification with spectral power decomposition, we were able to show that FM of low-beta (13–20 Hz) and high-beta (20–35 Hz) rhythms significantly contributes to the involvement of the human STN in movement preparation, execution and recovery, and that the FM patterns are regulated by the dopamine levels in the system. Movement-related FM of beta oscillatory activity in the human subthalamic nucleus therefore provides a novel informational domain for rhythm-based pathophysiological models of cortico-basal ganglia processing. PMID:16123109

  5. H-reflex modulation in the human medial and lateral gastrocnemii during standing and walking

    PubMed Central

    Makihara, Yukiko; Segal, Richard L.; Wolpaw, Jonathan R.; Thompson, Aiko K.

    2011-01-01

    Introduction The soleus H-reflex is dynamically modulated during walking. However, modulation of the gastrocnemii H-reflexes has not been studied systematically. Methods The medial and lateral gastrocnemii (MG and LG) and soleus H-reflexes were measured during standing and walking in humans. Results Maximum H-reflex amplitude was significantly smaller in MG (mean 1.1 mV) or LG (1.1 mV) than in soleus (3.3 mV). Despite these size differences, the reflex amplitudes of the three muscles were positively correlated. The MG and LG H-reflexes were phase- and task-dependently modulated in ways similar to the soleus H-reflex. Discussion Although there are anatomical and physiological differences between the soleus and gastrocnemii muscles, the reflexes of the three muscles are similarly modulated during walking and between standing and walking. The findings support the hypothesis that these reflexes are synergistically modulated during walking to facilitate ongoing movement. PMID:22190317

  6. Mifepristone treatment demonstrates the participation of adrenal glucocorticoids in the regulation of oestrogen-induced prolactin secretion in ovariectomized rats.

    PubMed

    Carón, R W; Salicioni, A M; Deis, R P

    1994-03-01

    Accumulated evidence indicates that the adrenal cortex is able to regulate prolactin (PRL) secretion in rats. The aim of this study was to determine the participation of adrenal steroids on the regulation of PRL release in ovariectomized (OVX) and oestrogen-treated rats, by using mifepristone or a specific progesterone antiserum. Blood samples were obtained at 13:00 and 18:00 h 3 days after priming with oestradiol benzoate (OB). A significant increase in serum PRL at 13:00 and 18:00 h was induced by OB treatment. The administration of mifepristone to OVX and oestrogen-primed rats enhanced serum PRL increase at 13:00 h, without modifying the values at 18:00 h; while the administration of progesterone antiserum did not modify PRL levels, indicating that the effect of mifepristone on PRL secretion is due to its antiglucocorticoid action. Adrenalectomy induced a release of PRL at 13:00 h similar to that observed in the OVX and oestrogen-primed rats after mifepristone administration. Treatment with a low dose of progesterone (0.1 mg/rat) to OVX, adrenalectomized and oestrogen-primed rats did not modify the effect of adrenalectomy in serum PRL. Progesterone (2 mg/rat) given at 08:00 h to OVX and oestrogen-primed rats increased serum PRL 5 h later. Mifepristone treatment partially reverted the PRL increase induced by progesterone. These results suggest that after a previous sensitization of the pituitary by oestrogen, circulating glucocorticoids may exert a direct inhibitory effect on PRL release. This inhibition takes place at 13:00 h on day 3. On the other hand, the lack of effect of mifepristone or adrenalectomy on the PRL release at 18:00 h may also indicate that neither progesterone nor glucocorticoids modify PRL release induced by oestrogen at this time.

  7. Effects of oestrogen and exercise on caspase-3 activity in primary and secondary lymphoid compartments in ovariectomized mice.

    PubMed

    Patel, H; Hoffman-Goetz, L

    2002-11-01

    This study investigated the effect of oestrogen exposure and exercise on caspase-3 activity, a measure of apoptosis, in lymphocytes from the thymus, spleen, and lymph nodes in ovariectomized mice. Fifty-nine female B6D2F1 mice were randomized to hormone and exercise conditions. Hormone treatment consisted of implantation with oestradiol pellets (0.72 mg oestradiol) or placebo pellets (0 mg) for 21 days following bilateral ovariectomy (OVX). Exercise consisted of a single treadmill exercise bout (26 m min(-1), 6 degrees slope, 90-min) or sedentary condition. Mice were killed and the thymus, spleen and lymph nodes were removed for the determination of caspase-3 expression by enzyme-linked immunosorbent assay (ELISA), serum oestrogen levels by RIA, and tissue weights. Body weights were monitored throughout the study. In the thymus, oestrogen exposure, exercise and both treatments together were associated with higher caspase-3 activity (P < 0.05) and lower thymus weights (P < 0.05). In contrast, oestrogen exposure and exercise treatment were not associated with greater caspase-3 activity or change in tissue weight in secondary lymphoid tissues (spleen, lymph nodes). Oestrogen-replaced OVX mice had a higher concentration of plasma oestradiol than placebo OVX mice (P < 0.05). The results suggest that oestrogen and treadmill exercise are associated with greater apoptosis, as measured by caspase-3 activity, in the thymus but not in the spleen or lymph nodes. Clinical studies will be necessary to determine if women who take oestrogen have higher rates of apoptosis in primary lymphoid tissues and the significance of thymocyte apoptosis for maintenance of cellular immune function during the post-menopausal years.

  8. Acute administration of conjugated equine oestrogen does not improve exercise-induced myocardial ischaemia in men with coronary artery disease.

    PubMed

    Davis, S R; Bradbury, J; Bell, R; Johns, J A

    2003-01-01

    The parenteral administration of oestradiol acutely protects against exercise-induced myocardial ischaemia in women, but whether this effect is sex-specific is not known. The effects of acutely administered conjugated equine oestrogen on exercise-induced myocardial ischaemia in men with established coronary heart disease were investigated in a randomized, placebo-controlled, double-blind cross-over trial. Twenty men, aged 62 +/- 11.6 years, with reproducible exercise-induced myocardial ischaemia were treated with either intravenous conjugated equine oestrogen (25 mg) or saline prior to undergoing an exercise stress test. Primary end-points were total exercise time and time to 1 mm ST-segment depression. All participants completed the protocol. Total exercise time exceeded the baseline value in 17 of the 20 men following saline, and in 17 of the 20 men following oestrogen pretreatment. Time to 1 mm ST-segment depression exceeded the baseline value in 14 of the 19 men following saline, and following oestrogen administration, exceeded baseline in 13 of the 19 men. There was no significant difference between the two treatments in either time to 1 mm ST-segment depression or total exercise time. A period effect was apparent for total exercise time (P = 0.05) but not for time to ST-segment depression. Acute parenteral oestrogen therapy did not increase total exercise time or time to the onset of electrocardiographic changes of ischaemia in men with chronic stable coronary artery disease. These findings contrast the favourable effects of oestrogen in women in comparable studies and indicate a sex specificity for the acute cardiovascular effects of oestrogen.

  9. You Look Human, But Act Like a Machine: Agent Appearance and Behavior Modulate Different Aspects of Human-Robot Interaction.

    PubMed

    Abubshait, Abdulaziz; Wiese, Eva

    2017-01-01

    Gaze following occurs automatically in social interactions, but the degree to which gaze is followed depends on whether an agent is perceived to have a mind, making its behavior socially more relevant for the interaction. Mind perception also modulates the attitudes we have toward others, and determines the degree of empathy, prosociality, and morality invested in social interactions. Seeing mind in others is not exclusive to human agents, but mind can also be ascribed to non-human agents like robots, as long as their appearance and/or behavior allows them to be perceived as intentional beings. Previous studies have shown that human appearance and reliable behavior induce mind perception to robot agents, and positively affect attitudes and performance in human-robot interaction. What has not been investigated so far is whether different triggers of mind perception have an independent or interactive effect on attitudes and performance in human-robot interaction. We examine this question by manipulating agent appearance (human vs. robot) and behavior (reliable vs. random) within the same paradigm and examine how congruent (human/reliable vs. robot/random) versus incongruent (human/random vs. robot/reliable) combinations of these triggers affect performance (i.e., gaze following) and attitudes (i.e., agent ratings) in human-robot interaction. The results show that both appearance and behavior affect human-robot interaction but that the two triggers seem to operate in isolation, with appearance more strongly impacting attitudes, and behavior more strongly affecting performance. The implications of these findings for human-robot interaction are discussed.

  10. Human Superior Temporal Gyrus Organization of Spectrotemporal Modulation Tuning Derived from Speech Stimuli

    PubMed Central

    Hullett, Patrick W.; Hamilton, Liberty S.; Mesgarani, Nima; Schreiner, Christoph E.

    2016-01-01

    The human superior temporal gyrus (STG) is critical for speech perception, yet the organization of spectrotemporal processing of speech within the STG is not well understood. Here, to characterize the spatial organization of spectrotemporal processing of speech across human STG, we use high-density cortical surface field potential recordings while participants listened to natural continuous speech. While synthetic broad-band stimuli did not yield sustained activation of the STG, spectrotemporal receptive fields could be reconstructed from vigorous responses to speech stimuli. We find that the human STG displays a robust anterior–posterior spatial distribution of spectrotemporal tuning in which the posterior STG is tuned for temporally fast varying speech sounds that have relatively constant energy across the frequency axis (low spectral modulation) while the anterior STG is tuned for temporally slow varying speech sounds that have a high degree of spectral variation across the frequency axis (high spectral modulation). This work illustrates organization of spectrotemporal processing in the human STG, and illuminates processing of ethologically relevant speech signals in a region of the brain specialized for speech perception. SIGNIFICANCE STATEMENT Considerable evidence has implicated the human superior temporal gyrus (STG) in speech processing. However, the gross organization of spectrotemporal processing of speech within the STG is not well characterized. Here we use natural speech stimuli and advanced receptive field characterization methods to show that spectrotemporal features within speech are well organized along the posterior-to-anterior axis of the human STG. These findings demonstrate robust functional organization based on spectrotemporal modulation content, and illustrate that much of the encoded information in the STG represents the physical acoustic properties of speech stimuli. PMID:26865624

  11. Proliferative activity, apoptosis and expression of oestrogen receptor and Bcl-2 oncoprotein in canine mammary gland tumours.

    PubMed

    Yang, W-Y; Liu, C-H; Chang, C-J; Lee, C-C; Chang, K-J; Lin, C-T

    2006-01-01

    Samples of 39 canine mammary gland tumours (MGTs) were examined immunohistochemically for oestrogen receptor (ER-alpha), Bcl-2 protein and Ki67 antigen, and by TUNEL assay for apoptosis. ER-alpha was expressed by 80% (31/39) of the tumours, including all of the 15 benign tumours and 67% (16/42) of the malignant tumours. ER-alpha expression was greater in the benign than in the malignant tumours (P<0.01). Bcl-2 protein was detected in 62% (24/39) of the MGTs, of which 67% (10/15) were benign and 58% (14/24) malignant. No significant difference in Bcl-2 expression between benign and malignant tumours was detected. The Ki67 and TUNEL indices were greater in malignant than in benign tumours (P<0.01). Correlation analysis suggested that ER-alpha and Bcl-2 expression were related, but this observation lacked statistical significance. The levels of cell proliferation and apoptosis did not appear to be significantly correlated with the expression of Bcl-2. A positive relationship was apparent between cell proliferation and apoptosis, whilst a negative correlation between ER-alpha and cell proliferation was demonstrated. In conclusion, the suggestion of a positive correlation between ER-alpha and Bcl-2 in canine MGTs indicates that ER may be the regulator of Bcl-2 protein, as in human breast cancer. In contrast to cell proliferation and apoptosis, ER-alpha and Bcl-2 expression were greater in benign MGTs than in their malignant counterparts.

  12. 2q36.3 is associated with prognosis for oestrogen receptor-negative breast cancer patients treated with chemotherapy.

    PubMed

    Li, Jingmei; Lindström, Linda S; Foo, Jia N; Rafiq, Sajjad; Schmidt, Marjanka K; Pharoah, Paul D P; Michailidou, Kyriaki; Dennis, Joe; Bolla, Manjeet K; Wang, Qin; Van 't Veer, Laura J; Cornelissen, Sten; Rutgers, Emiel; Southey, Melissa C; Apicella, Carmel; Dite, Gillian S; Hopper, John L; Fasching, Peter A; Haeberle, Lothar; Ekici, Arif B; Beckmann, Matthias W; Blomqvist, Carl; Muranen, Taru A; Aittomäki, Kristiina; Lindblom, Annika; Margolin, Sara; Mannermaa, Arto; Kosma, Veli-Matti; Hartikainen, Jaana M; Kataja, Vesa; Chenevix-Trench, Georgia; Phillips, Kelly-Anne; McLachlan, Sue-Anne; Lambrechts, Diether; Thienpont, Bernard; Smeets, Ann; Wildiers, Hans; Chang-Claude, Jenny; Flesch-Janys, Dieter; Seibold, Petra; Rudolph, Anja; Giles, Graham G; Baglietto, Laura; Severi, Gianluca; Haiman, Christopher A; Henderson, Brian E; Schumacher, Fredrick; Le Marchand, Loic; Kristensen, Vessela; Alnæs, Grethe I Grenaker; Borresen-Dale, Anne-Lise; Nord, Silje; Winqvist, Robert; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Grip, Mervi; Andrulis, Irene L; Knight, Julia A; Glendon, Gord; Tchatchou, Sandrine; Devilee, Peter; Tollenaar, Robert; Seynaeve, Caroline; Hooning, Maartje; Kriege, Mieke; Hollestelle, Antoinette; van den Ouweland, Ans; Li, Yi; Hamann, Ute; Torres, Diana; Ulmer, Hans U; Rüdiger, Thomas; Shen, Chen-Yang; Hsiung, Chia-Ni; Wu, Pei-Ei; Chen, Shou-Tung; Teo, Soo Hwang; Taib, Nur Aishah Mohd; Har Yip, Cheng; Fuang Ho, Gwo; Matsuo, Keitaro; Ito, Hidemi; Iwata, Hiroji; Tajima, Kazuo; Kang, Daehee; Choi, Ji-Yeob; Park, Sue K; Yoo, Keun-Young; Maishman, Tom; Tapper, William J; Dunning, Alison; Shah, Mitul; Luben, Robert; Brown, Judith; Khor, Chiea Chuen; Eccles, Diana M; Nevanlinna, Heli; Easton, Douglas; Humphreys, Keith; Liu, Jianjun; Hall, Per; Czene, Kamila

    2014-06-17

    Large population-based registry studies have shown that breast cancer prognosis is inherited. Here we analyse single-nucleotide polymorphisms (SNPs) of genes implicated in human immunology and inflammation as candidates for prognostic markers of breast cancer survival involving 1,804 oestrogen receptor (ER)-negative patients treated with chemotherapy (279 events) from 14 European studies in a prior large-scale genotyping experiment, which is part of the Collaborative Oncological Gene-environment Study (COGS) initiative. We carry out replication using Asian COGS samples (n=522, 53 events) and the Prospective Study of Outcomes in Sporadic versus Hereditary breast cancer (POSH) study (n=315, 108 events). Rs4458204_A near CCL20 (2q36.3) is found to be associated with breast cancer-specific death at a genome-wide significant level (n=2,641, 440 events, combined allelic hazard ratio (HR)=1.81 (1.49-2.19); P for trend=1.90 × 10(-9)). Such survival-associated variants can represent ideal targets for tailored therapeutics, and may also enhance our current prognostic prediction capabilities.

  13. 2q36.3 is associated with prognosis for oestrogen receptor-negative breast cancer patients treated with chemotherapy

    PubMed Central

    Li, Jingmei; Lindström, Linda S.; Foo, Jia N.; Rafiq, Sajjad; Schmidt, Marjanka K.; Pharoah, Paul D. P.; Michailidou, Kyriaki; Dennis, Joe; Bolla, Manjeet K.; Wang, Qin; Van ‘t Veer, Laura J.; Cornelissen, Sten; Rutgers, Emiel; Southey, Melissa C.; Apicella, Carmel; Dite, Gillian S.; Hopper, John L.; Fasching, Peter A.; Haeberle, Lothar; Ekici, Arif B.; Beckmann, Matthias W.; Blomqvist, Carl; Muranen, Taru A.; Aittomäki, Kristiina; Lindblom, Annika; Margolin, Sara; Mannermaa, Arto; Kosma, Veli-Matti; Hartikainen, Jaana M.; Kataja, Vesa; Chenevix-Trench, Georgia; Investigators, kConFab; Phillips, Kelly-Anne; McLachlan, Sue-Anne; Lambrechts, Diether; Thienpont, Bernard; Smeets, Ann; Wildiers, Hans; Chang-Claude, Jenny; Flesch-Janys, Dieter; Seibold, Petra; Rudolph, Anja; Giles, Graham G.; Baglietto, Laura; Severi, Gianluca; Haiman, Christopher A.; Henderson, Brian E.; Schumacher, Fredrick; Le Marchand, Loic; Kristensen, Vessela; Alnæs, Grethe I. Grenaker; Borresen-Dale, Anne-Lise; Nord, Silje; Winqvist, Robert; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Grip, Mervi; Andrulis, Irene L.; Knight, Julia A.; Glendon, Gord; Tchatchou, Sandrine; Devilee, Peter; Tollenaar, Robert; Seynaeve, Caroline; Hooning, Maartje; Kriege, Mieke; Hollestelle, Antoinette; van den Ouweland, Ans; Li, Yi; Hamann, Ute; Torres, Diana; Ulmer, Hans U.; Rüdiger, Thomas; Shen, Chen-Yang; Hsiung, Chia-Ni; Wu, Pei-Ei; Chen, Shou-Tung; Teo, Soo Hwang; Taib, Nur Aishah Mohd; Har Yip, Cheng; Fuang Ho, Gwo; Matsuo, Keitaro; Ito, Hidemi; Iwata, Hiroji; Tajima, Kazuo; Kang, Daehee; Choi, Ji-Yeob; Park, Sue K.; Yoo, Keun-Young; Maishman, Tom; Tapper, William J.; Dunning, Alison; Shah, Mitul; Luben, Robert; Brown, Judith; Chuen Khor, Chiea; Eccles, Diana M.; Nevanlinna, Heli; Easton, Douglas; Humphreys, Keith; Liu, Jianjun; Hall, Per; Czene, Kamila

    2014-01-01

    Large population-based registry studies have shown that breast cancer prognosis is inherited. Here we analyse single-nucleotide polymorphisms (SNPs) of genes implicated in human immunology and inflammation as candidates for prognostic markers of breast cancer survival involving 1,804 oestrogen receptor (ER)-negative patients treated with chemotherapy (279 events) from 14 European studies in a prior large-scale genotyping experiment, which is part of the Collaborative Oncological Gene-environment Study (COGS) initiative. We carry out replication using Asian COGS samples (n=522, 53 events) and the Prospective Study of Outcomes in Sporadic versus Hereditary breast cancer (POSH) study (n=315, 108 events). Rs4458204_A near CCL20 (2q36.3) is found to be associated with breast cancer-specific death at a genome-wide significant level (n=2,641, 440 events, combined allelic hazard ratio (HR)=1.81 (1.49–2.19); P for trend=1.90 × 10−9). Such survival-associated variants can represent ideal targets for tailored therapeutics, and may also enhance our current prognostic prediction capabilities. PMID:24937182

  14. Transcriptional burst frequency and burst size are equally modulated across the human genome

    PubMed Central

    Dar, Roy D.; Razooky, Brandon S.; Singh, Abhyudai; Trimeloni, Thomas V.; McCollum, James M.; Cox, Chris D.; Simpson, Michael L.; Weinberger, Leor S.

    2012-01-01

    Gene expression occurs either as an episodic process, characterized by pulsatile bursts, or as a constitutive process, characterized by a Poisson-like accumulation of gene products. It is not clear which mode of gene expression (constitutive versus bursty) predominates across a genome or how transcriptional dynamics are influenced by genomic position and promoter sequence. Here, we use time-lapse fluorescence microscopy to analyze 8,000 individual human genomic loci and find that at virtually all loci, episodic bursting—as opposed to constitutive expression—is the predominant mode of expression. Quantitative analysis of the expression dynamics at these 8,000 loci indicates that both the frequency and size of the transcriptional bursts varies equally across the human genome, independent of promoter sequence. Strikingly, weaker expression loci modulate burst frequency to increase activity, whereas stronger expression loci modulate burst size to increase activity. Transcriptional activators such as trichostatin A (TSA) and tumor necrosis factor α (TNF) only modulate burst size and frequency along a constrained trend line governed by the promoter. In summary, transcriptional bursting dominates across the human genome, both burst frequency and burst size vary by chromosomal location, and transcriptional activators alter burst frequency and burst size, depending on the expression level of the locus. PMID:23064634

  15. Discovery of Small-Molecule Modulators of the Human Y4 Receptor

    PubMed Central

    Weaver, David; Beck-Sickinger, Annette G.; Meiler, Jens

    2016-01-01

    The human neuropeptide Y4 receptor (Y4R) and its native ligand, pancreatic polypeptide, are critically involved in the regulation of human metabolism by signaling satiety and regulating food intake, as well as increasing energy expenditure. Thus, this receptor represents a putative target for treatment of obesity. With respect to new approaches to treat complex metabolic disorders, especially in multi-receptor systems, small molecule allosteric modulators have been in the focus of research in the last years. However, no positive allosteric modulators or agonists of the Y4R have been described so far. In this study, small molecule compounds derived from the Niclosamide scaffold were identified by high-throughput screening to increase Y4R activity. Compounds were characterized for their potency and their effects at the human Y4R and as well as their selectivity towards Y1R, Y2R and Y5R. These compounds provide a structure-activity relationship profile around this common scaffold and lay the groundwork for hit-to-lead optimization and characterization of positive allosteric modulators of the Y4R. PMID:27294784

  16. Characterization of Bitter Compounds via Modulation of Proton Secretion in Human Gastric Parietal Cells in Culture.

    PubMed

    Liszt, Kathrin I; Hans, Joachim; Ley, Jakob P; Köck, Elke; Somoza, Veronika

    2017-05-26

    Humans perceive bitterness via around 25 different bitter receptors. Therefore, the identification of antagonists remains a complex challenge. We previously demonstrated several bitter-tasting compounds such as caffeine to induce acid secretion in the stomach and in a human gastric tumor cell line (HGT-1). Here, the results of a fluorescent-based in vitro assay using HGT-1 cells and a human sensory panel testing nine selected potential bitter modulators, with or without the bitter compounds caffeine or theobromine, were compared. Of the bitter-modulating compounds tested, eriodictyol, matairesinol, enterolacton, lariciresinol, and homoeriodictyol reduced the effect of caffeine on proton secretion by -163 ± 14.0, -152 ± 12.4, -74 ± 16.4, -58 ± 7.2, and -44.6 ± 16.5%, respectively, and reduced the bitter intensity of caffeine in the human sensory panel. In contrast, naringenin and 5,7-dihydroxy-4(4-hydroxyphenyl)chroman-2-one neither reduced the caffeine-induced proton secretion in HGT-1 cells nor showed an effect on bitter intensity perceived by the sensory panel. Results for theobromine were not as pronounced as those for caffeine, but followed a similar trend. The results demonstrate that the HGT-1 in vitro assay is a useful tool to identify potential bitter-masking compounds. Nevertheless, a sensory human panel is necessary to quantify the bitter-masking potency.

  17. Experimental study on trace chemical contaminant generation rates of human metabolism in spacecraft crew module

    NASA Astrophysics Data System (ADS)

    Lihua, Guo; Xinxing, He; Guoxin, Xu; Xin, Qi

    2012-12-01

    Trace chemical contaminants generated by human metabolism is a major source of contamination in spacecraft crew module. In this research, types and generation rates of pollutants from human metabolism were determined in the Chinese diets. Expired air, skin gas, and sweat of 20 subjects were analyzed at different exercise states in a simulated module. The exercise states were designed according to the basic activities in the orbit of astronauts. Qualitative and quantitative analyses of contaminants generated by human metabolic were performed with gas chromatography/mass spectrometry, gas chromatography and UV spectrophotometer. Sixteen chemical compounds from metabolic sources were found. With the increase in physical load, the concentrations of chemical compounds from human skin and expired air correspondingly increased. The species and the offgassing rates of pollutants from human metabolism are different among the Chinese, Americans and the Russians due to differences in ethnicity and dietary customs. This research provides data to aid in the design, development and operation of China's long duration space mission.

  18. Adult female wildtype, but not oestrogen receptor β knockout, mice have decreased depression-like behaviour during pro-oestrus and following administration of oestradiol or diarylpropionitrile

    PubMed Central

    Walf, AA; Koonce, CJ; Frye, CA

    2013-01-01

    Studies in people and animal models suggest that depression is influenced by natural, fluctuations in the levels of 17β-oestradiol (E2), as well as administration of E2-based therapies, such as selective oestrogen receptor modulators (SERMs). Elucidating the effects and mechanisms of E2 is important to improve future E2-based therapeutics. An important question is whether effects of E2 or SERMs for mood regulation act at the α or β isoform of the oestrogen receptor (ER) because some of the unwanted trophic effects of E2-based therapies may involve actions at ERα, rather than ERβ. In the present study, whether there are sex differences in depression-like behaviour of adult mice (experiment 1), and the effects of natural fluctuations in E2 (experiment 2), or administration of E2 or a SERM that has higher affinity for ERβ than for ERα (diarylpropionitrile; DPN) to ovariectomised (experiment 3) wildtype and ERβ knockout (βERKO) mice were investigated. Results of this study supported our hypotheses that: there would be sex differences favouring males for depression-like behaviour and endogenous increases in, or exogenous administration of, E2 or administration of an ERβ SERM would decrease depression-like behaviour in wildtype, but not βERKO, mice. In experiment 1, adult male mice spent less time immobile in the forced swim test (i.e., showed less depression-like behaviour) compared with female mice. In experiment 2, pro-oestrous (higher circulating E2 levels), compared with dioestrous (lower circulating E2 levels), mice had reduced immobility in the forced swim test; this effect was not observed in βERKO mice. In experiment 3, administration of E2 or DPN to ovariectomised wildtype, but not βERKO, mice decreased immobility compared with vehicle administration, these data suggest that ERβ may be required for some of the anti–depressant-like effects of E2. PMID:18562442

  19. Repurposing Resveratrol and Fluconazole To Modulate Human Cytochrome P450-Mediated Arachidonic Acid Metabolism.

    PubMed

    El-Sherbeni, Ahmed A; El-Kadi, Ayman O S

    2016-04-04

    Cytochrome P450 (P450) enzymes metabolize arachidonic acid (AA) to several biologically active epoxyeicosatrienoic acids (EETs) and hydroxyeicosatetraenoic acids (HETEs). Repurposing clinically-approved drugs could provide safe and readily available means to control EETs and HETEs levels in humans. Our aim was to determine how to significantly and selectively modulate P450-AA metabolism in humans by clinically-approved drugs. Liquid chromatography-mass spectrometry was used to determine the formation of 15 AA metabolites by human recombinant P450 enzymes, as well as human liver and kidney microsomes. CYP2C19 showed the highest EET-forming activity, while CYP1B1 and CYP2C8 showed the highest midchain HETE-forming activities. CYP1A1 and CYP4 showed the highest subterminal- and 20-HETE-forming activity, respectively. Resveratrol and fluconazole produced the most selective and significant modulation of hepatic P450-AA metabolism, comparable to investigational agents. Monte Carlo simulations showed that 90% of human population would experience a decrease by 6-22%, 16-39%, and 16-35% in 16-, 18-, and 20-HETE formation, respectively, after 2.5 g daily of resveratrol, and by 22-31% and 14-23% in 8,9- and 14,15-EET formation after 50 mg of fluconazole. In conclusion, clinically-approved drugs can provide selective and effective means to modulate P450-AA metabolism, comparable to investigational drugs. Resveratrol and fluconazole are good candidates to be repurposed as new P450-based treatments.

  20. Modulation of human muscle spindle discharge by arterial pulsations--functional effects and consequences.

    PubMed

    Birznieks, Ingvars; Boonstra, Tjeerd W; Macefield, Vaughan G

    2012-01-01

    Arterial pulsations are known to modulate muscle spindle firing; however, the physiological significance of such synchronised modulation has not been investigated. Unitary recordings were made from 75 human muscle spindle afferents innervating the pretibial muscles. The modulation of muscle spindle discharge by arterial pulsations was evaluated by R-wave triggered averaging and power spectral analysis. We describe various effects arterial pulsations may have on muscle spindle afferent discharge. Afferents could be "driven" by arterial pulsations, e.g., showing no other spontaneous activity than spikes generated with cardiac rhythmicity. Among afferents showing ongoing discharge that was not primarily related to cardiac rhythmicity we illustrate several mechanisms by which individual spikes may become phase-locked. However, in the majority of afferents the discharge rate was modulated by the pulse wave without spikes being phase locked. Then we assessed whether these influences changed in two physiological conditions in which a sustained increase in muscle sympathetic nerve activity was observed without activation of fusimotor neurones: a maximal inspiratory breath-hold, which causes a fall in systolic pressure, and acute muscle pain, which causes an increase in systolic pressure. The majority of primary muscle spindle afferents displayed pulse-wave modulation, but neither apnoea nor pain had any significant effect on the strength of this modulation, suggesting that the physiological noise injected by the arterial pulsations is robust and relatively insensitive to fluctuations in blood pressure. Within the afferent population there was a similar number of muscle spindles that were inhibited and that were excited by the arterial pulse wave, indicating that after signal integration at the population level, arterial pulsations of opposite polarity would cancel each other out. We speculate that with close-to-threshold stimuli the arterial pulsations may serve as an

  1. Light Modulates Metabolic Pathways and Other Novel Physiological Traits in the Human Pathogen Acinetobacter baumannii.

    PubMed

    Müller, Gabriela L; Tuttobene, Marisel; Altilio, Matías; Martínez Amezaga, Maitena; Nguyen, Meaghan; Cribb, Pamela; Cybulski, Larisa E; Ramírez, María Soledad; Altabe, Silvia; Mussi, María Alejandra

    2017-05-15

    Light sensing in chemotrophic bacteria has been relatively recently ascertained. In the human pathogen Acinetobacter baumannii, light modulates motility, biofilm formation, and virulence through the blue-light-sensing-using flavin (BLUF) photoreceptor BlsA. In addition, light can induce a reduction in susceptibility to certain antibiotics, such as minocycline and tigecycline, in a photoreceptor-independent manner. In this work, we identified new traits whose expression levels are modulated by light in this pathogen, which comprise not only important determinants related to pathogenicity and antibiotic resistance but also metabolic pathways, which represents a novel concept for chemotrophic bacteria. Indeed, the phenylacetic acid catabolic pathway and trehalose biosynthesis were modulated by light, responses that completely depend on BlsA. We further show that tolerance to some antibiotics and modulation of antioxidant enzyme levels are also influenced by light, likely contributing to bacterial persistence in adverse environments. Also, we present evidence indicating that surfactant production is modulated by light. Finally, the expression of whole pathways and gene clusters, such as genes involved in lipid metabolism and genes encoding components of the type VI secretion system, as well as efflux pumps related to antibiotic resistance, was differentially induced by light. Overall, our results indicate that light modulates global features of the A. baumannii lifestyle.IMPORTANCE The discovery that nonphototrophic bacteria respond to light constituted a novel concept in microbiology. In this context, we demonstrated that light could modulate aspects related to bacterial virulence, persistence, and resistance to antibiotics in the human pathogen Acinetobacter baumannii In this work, we present the novel finding that light directly regulates metabolism in this chemotrophic bacterium. Insights into the mechanism show the involvement of the photoreceptor BlsA. In

  2. Comparison between novel steroid-like and conventional nonsteroidal antioestrogens in inhibiting oestradiol- and IGF-I-induced proliferation of human breast cancer-derived cells.

    PubMed Central

    de Cupis, A.; Noonan, D.; Pirani, P.; Ferrera, A.; Clerico, L.; Favoni, R. E.

    1995-01-01

    1. This study has two specific aims: (a) to compare the antioestrogenic activity of two steroidal analogues of 17 beta-oestradiol, the 7 alpha-alkylamide, ICI 164,384 and the 7 alpha-alkylsulphinylamide, ICI 182,780, with that of the triphenylethylene-derived compound 4OH-tamoxifen on a pool of human breast cancer cell lines (HBCCL) with a range of hormonal responsiveness and acquired anti-oestrogen resistance and (b) to investigate the ability of such antioestrogens to modulate the potent breast carcinoma growth-stimulatory activity of the 'IGF-I system'. 2. For the chemosensitivity investigations we used a long-term colorimetric and the short-term thymidine incorporation assay; we analysed IGF-I in conditioned media by a radioimmunoassay, IGF-I mRNA in the cells by RT-PCR and molecular species of IGF-I-binding proteins, secreted in conditioned media, by Western ligand blot. IGF-I receptors were assayed on cell monolayers by binding studies and by Scatchard analysis, we calculated KD, Bmax and sites/cell. 3. Our results indicate that ICI 182,780 and ICI 164,384 are 1.5-5.5 fold more potent than 4OH-tamoxifen in inhibiting the basal proliferation of oestrogen-receptor positive (ER+) breast cancer cell lines. Moreover we demonstrate the capacity of ICI 182,780 and ICI 164,384 to reduce, in a time-dependent fashion, oestrogen- and/or IGF-I-stimulated growth of ER+cell lines, possibly by negatively interfering with an IGF-I-like material secretion and IGF-I-receptor number. 4. Our data provide the first evidence that, on ER+human breast carcinoma cell lines, steroidal antioestrogens inhibit cell growth and modulate the IGF-I mitogenic system. The mechanism of this latter effect has yet to be identified. Images Figure 1 Figure 2 Figure 3 Figure 4 PMID:8581274

  3. Sequence learning modulates neural responses and oscillatory coupling in human and monkey auditory cortex

    PubMed Central

    Attaheri, Adam; Wilson, Benjamin; Rhone, Ariane E.; Nourski, Kirill V.; Gander, Phillip E.; Kovach, Christopher K.; Kawasaki, Hiroto; Griffiths, Timothy D.; Howard, Matthew A.; Petkov, Christopher I.

    2017-01-01

    Learning complex ordering relationships between sensory events in a sequence is fundamental for animal perception and human communication. While it is known that rhythmic sensory events can entrain brain oscillations at different frequencies, how learning and prior experience with sequencing relationships affect neocortical oscillations and neuronal responses is poorly understood. We used an implicit sequence learning paradigm (an “artificial grammar”) in which humans and monkeys were exposed to sequences of nonsense words with regularities in the ordering relationships between the words. We then recorded neural responses directly from the auditory cortex in both species in response to novel legal sequences or ones violating specific ordering relationships. Neural oscillations in both monkeys and humans in response to the nonsense word sequences show strikingly similar hierarchically nested low-frequency phase and high-gamma amplitude coupling, establishing this form of oscillatory coupling—previously associated with speech processing in the human auditory cortex—as an evolutionarily conserved biological process. Moreover, learned ordering relationships modulate the observed form of neural oscillatory coupling in both species, with temporally distinct neural oscillatory effects that appear to coordinate neuronal responses in the monkeys. This study identifies the conserved auditory cortical neural signatures involved in monitoring learned sequencing operations, evident as modulations of transient coupling and neuronal responses to temporally structured sensory input. PMID:28441393

  4. A new hexapeptide from the leader peptide of rMnSOD enters cells through the oestrogen receptor to deliver therapeutic molecules

    PubMed Central

    Borrelli, Antonella; Schiattarella, Antonietta; Mancini, Roberto; Pica, Alessandra; Pollio, Maria Laura; Ruggiero, Maria Grazia; Bonelli, Patrizia; De Luca, Viviana; Tuccillo, Franca Maria; Capasso, Clemente; Gori, Enrico; Sanseverino, Marina; Carpentieri, Andrea; Birolo, Leila; Pucci, Piero; Rommelaere, Jean; Mancini, Aldo

    2016-01-01

    A 24-amino acid leader peptide of a new human recombinant manganese superoxide dismutase can enter cells and carry molecules. Here, we demonstrated that six of the 24 amino acids penetrate cells through a particular gate represented by a specific amino acid sequence of the oestrogen receptor (ER). We analysed the internalization of the synthetic hexapeptide and the cytotoxic activity of the hexapeptide conjugated to cisplatin on a cell line panel. In most cell lines, the hexapeptide delivered an amount of cisplatin that was 2 to 8 times greater than that released by cisplatin when the drug was used alone. This increased delivery increases the therapeutic index of cisplatin and reduces side effects caused by a high dosage or long-term treatment times. We may consider this hexapeptide a new molecular carrier to deliver molecules with therapeutic activity into ER+ cells for diagnostic purposes and clinical or immune therapy. PMID:26725847

  5. Pupil size directly modulates the feedforward response in human primary visual cortex independently of attention.

    PubMed

    Bombeke, Klaas; Duthoo, Wout; Mueller, Sven C; Hopf, Jens-Max; Boehler, C Nico

    2016-02-15

    Controversy revolves around the question of whether psychological factors like attention and emotion can influence the initial feedforward response in primary visual cortex (V1). Although traditionally, the electrophysiological correlate of this response in humans (the C1 component) has been found to be unaltered by psychological influences, a number of recent studies have described attentional and emotional modulations. Yet, research into psychological effects on the feedforward V1 response has neglected possible direct contributions of concomitant pupil-size modulations, which are known to also occur under various conditions of attentional load and emotional state. Here we tested the hypothesis that such pupil-size differences themselves directly affect the feedforward V1 response. We report data from two complementary experiments, in which we used procedures that modulate pupil size without differences in attentional load or emotion while simultaneously recording pupil-size and EEG data. Our results confirm that pupil size indeed directly influences the feedforward V1 response, showing an inverse relationship between pupil size and early V1 activity. While it is unclear in how far this effect represents a functionally-relevant adaptation, it identifies pupil-size differences as an important modulating factor of the feedforward response of V1 and could hence represent a confounding variable in research investigating the neural influence of psychological factors on early visual processing. Copyright © 2015 Elsevier Inc. All rights reserved.

  6. LinkNMF: identification of histone modification modules in the human genome using nonnegative matrix factorization.

    PubMed

    Jung, Inkyung; Kim, Dongsup

    2013-04-10

    Histone modifications are ubiquitous processes involved in various cellular mechanisms. Systemic analysis of multiple chromatin modifications has been used to characterize various chromatin states associated with functional DNA elements, gene expression, and specific biological functions. However, identification of modular modification patterns is still required to understand the functional associations between histone modification patterns and specific chromatin/DNA binding factors. To recognize modular modification patterns, we developed a novel algorithm that combines nonnegative matrix factorization (NMF) and a clique-detection algorithm. We applied it, called LinkNMF, to generate a comprehensive modification map in human CD4+ T cell promoter regions. Initially, we identified 11 modules not recognized by conventional approaches. The modules were grouped into two major classes: gene activation and repression. We found that genes targeted by each module were enriched with distinguishable biological functions, suggesting that each modular pattern plays a unique functional role. To explain the formation of modular patterns, we investigated the module-specific binding patterns of chromatin regulators. Application of LinkNMF to histone modification maps of diverse cells and developmental stages will be helpful for understanding how histone modifications regulate gene expression. The algorithm is available on our website at biodb.kaist.ac.kr/LinkNMF. Copyright © 2012 Elsevier B.V. All rights reserved.

  7. Procyanidin A2 Modulates IL-4-Induced CCL26 Production in Human Alveolar Epithelial Cells

    PubMed Central

    Coleman, Sara L.; Kruger, Marlena C.; Sawyer, Gregory M.; Hurst, Roger D.

    2016-01-01

    Allergic asthma is an inflammatory lung disease that is partly sustained by the chemokine eotaxin-3 (CCL26), which extends eosinophil migration into tissues long after allergen exposure. Modulation of CCL26 could represent a means to mitigate airway inflammation. Here we evaluated procyanidin A2 as a means of modulating CCL26 production and investigated interactions with the known inflammation modulator, Interferon γ (IFNγ). We used the human lung epithelial cell line A549 and optimized the conditions for inducing CCL26. Cells were exposed to a range of procyanidin A2 or IFNγ concentrations for varied lengths of time prior to an inflammatory insult of interleukin-4 (IL-4) for 24 h. An enzyme-linked immunosorbent assay was used to measure CCL26 production. Exposing cells to 5 μM procyanidin A2 (prior to IL-4) reduced CCL26 production by 35% compared with control. Greatest inhibition by procyanidin A2 was seen with a 2 h exposure prior to IL-4, whereas IFNγ inhibition was greatest at 24 h. Concomitant incubation of procyanidin A2 and IFNγ did not extend the inhibitory efficacy of procyanidin A2. These data provide evidence that procyanidin A2 can modulate IL-4-induced CCL26 production by A549 lung epithelial cells and that it does so in a manner that is different from IFNγ. PMID:27845745

  8. Phenotypic modulations of human umbilical vein endothelial cells and human dermal fibroblasts using two angiogenic assays.

    PubMed

    Bikfalvi, A; Cramer, E M; Tenza, D; Tobelem, G

    1991-01-01

    Different angiogenic assays in vitro have helped to define various events underlying angiogenesis. In this report we have compared the phenotypic modifications of human umbilical vein endothelial cells (HUVE cells) and human dermal fibroblasts using Matrigel and collagen gels. Both HUVE cells and human dermal fibroblasts form a network of anastomosing cords that apparently resemble blood capillaries when grown on Matrigel. The whole network was formed by several cellular aggregates joined to each other by cellular cords. Lumen formation was not observed in this angiogenic system. In opposite, considerable differences between HUVE cells and human dermal fibroblasts were observed in the three-dimensional angiogenic assay on collagen gels described by Montesano et al [14]. These results indicate that data obtained with angiogenic systems using Matrigel must be interpreted with caution and that the assay described by Montesano et al [14], is more reliable to describe angiogenesis.

  9. Characterization of human septic sera induced gene expression modulation in human myocytes

    PubMed Central

    Hussein, Shaimaa; Michael, Paul; Brabant, Danielle; Omri, Abdelwahab; Narain, Ravin; Passi, Kalpdrum; Ramana, Chilakamarti V.; Parrillo, Joseph E.; Kumar, Anand; Parissenti, Amadeo; Kumar, Aseem

    2009-01-01

    To gain a better understanding of the gene expression changes that occurs during sepsis, we have performed a cDNA microarray study utilizing a tissue culture model that mimics human sepsis. This study utilized an in vitro model of cultured human fetal cardiac myocytes treated with 10% sera from septic patients or 10% sera from healthy volunteers. A 1700 cDNA expression microarray was used to compare the transcription profile from human cardiac myocytes treated with septic sera vs normal sera. Septic sera treatment of myocytes resulted in the down-regulation of 178 genes and the up-regulation of 4 genes. Our data indicate that septic sera induced cell cycle, metabolic, transcription factor and apoptotic gene expression changes in human myocytes. Identification and characterization of gene expression changes that occur during sepsis may lead to the development of novel therapeutics and diagnostics. PMID:19684886

  10. Quantitative High-Throughput Identification of Drugs as Modulators of Human Constitutive Androstane Receptor

    PubMed Central

    Lynch, Caitlin; Zhao, Jinghua; Huang, Ruili; Xiao, Jingwei; Li, Linhao; Heyward, Scott; Xia, Menghang; Wang, Hongbing

    2015-01-01

    The constitutive androstane receptor (CAR, NR1I3) plays a key role in governing the transcription of numerous hepatic genes that involve xenobiotic metabolism/clearance, energy homeostasis, and cell proliferation. Thus, identification of novel human CAR (hCAR) modulators may not only enhance early prediction of drug-drug interactions but also offer potentially novel therapeutics for diseases such as metabolic disorders and cancer. In this study, we have generated a double stable cell line expressing both hCAR and a CYP2B6-driven luciferase reporter for quantitative high-throughput screening (qHTS) of hCAR modulators. Approximately 2800 compounds from the NIH Chemical Genomics Center Pharmaceutical Collection were screened employing both the activation and deactivation modes of the qHTS. Activators (115) and deactivators (152) of hCAR were identified from the primary qHTS, among which 10 agonists and 10 antagonists were further validated in the physiologically relevant human primary hepatocytes for compound-mediated hCAR nuclear translocation and target gene expression. Collectively, our results reveal that hCAR modulators can be efficiently identified through this newly established qHTS assay. Profiling drug collections for hCAR activity would facilitate the prediction of metabolism-based drug-drug interactions, and may lead to the identification of potential novel therapeutics. PMID:25993555

  11. Preexisting antigen-specific immune responses are modulated by oral KLH feeding in humans.

    PubMed

    Hostmann, Arwed; Meyer, Tim; Maul, Jochen; Preiss, Jan; Boortz, Bertram; Thiel, Andreas; Duchmann, Rainer; Ullrich, Reiner

    2015-07-01

    Oral tolerance is the antigen-specific inhibition of a systemic immune response after oral antigen uptake and well established in animal models. We recently showed that keyhole limpet hemocyanin (KLH) feeding modulates subsequently induced systemic immune responses in humans as well. In the present study, we investigated whether oral KLH can also modulate preexisting antigen-specific systemic B- and T-cell responses. We induced delayed-type hypersensitivity (DTH) reactions as well as systemic KLH-specific B- and T-cell responses by subcutaneous KLH injections. Subsequent oral KLH administration decreased the small proportion of antigen-specific CD4(+) T cells positive for the cytokine IL-17 at the end of the feeding regimen even further. After reimmunization, there was no difference in DTH reactions and the KLH-specific B-cell responses, but KLH-fed volunteers had an increased proportion of antigen-specific CD4(+) T cells positive for IL-10 and a reduced proportion of antigen-specific CD4(+) T cells positive for the skin-homing receptor cutaneous lymphocyte antigen and IL-2 and IFN-γ. Taken together, oral KLH can modulate a preexisting systemic KLH-specific immune response. These results suggest that feeding antigen may offer therapeutic strategies for the suppression of unwanted immune reactions in humans.

  12. Quantitative high-throughput identification of drugs as modulators of human constitutive androstane receptor.

    PubMed

    Lynch, Caitlin; Zhao, Jinghua; Huang, Ruili; Xiao, Jingwei; Li, Linhao; Heyward, Scott; Xia, Menghang; Wang, Hongbing

    2015-05-20

    The constitutive androstane receptor (CAR, NR1I3) plays a key role in governing the transcription of numerous hepatic genes that involve xenobiotic metabolism/clearance, energy homeostasis, and cell proliferation. Thus, identification of novel human CAR (hCAR) modulators may not only enhance early prediction of drug-drug interactions but also offer potentially novel therapeutics for diseases such as metabolic disorders and cancer. In this study, we have generated a double stable cell line expressing both hCAR and a CYP2B6-driven luciferase reporter for quantitative high-throughput screening (qHTS) of hCAR modulators. Approximately 2800 compounds from the NIH Chemical Genomics Center Pharmaceutical Collection were screened employing both the activation and deactivation modes of the qHTS. Activators (115) and deactivators (152) of hCAR were identified from the primary qHTS, among which 10 agonists and 10 antagonists were further validated in the physiologically relevant human primary hepatocytes for compound-mediated hCAR nuclear translocation and target gene expression. Collectively, our results reveal that hCAR modulators can be efficiently identified through this newly established qHTS assay. Profiling drug collections for hCAR activity would facilitate the prediction of metabolism-based drug-drug interactions, and may lead to the identification of potential novel therapeutics.

  13. Modulation of the human nociceptive flexion reflex by pleasant and unpleasant odors.

    PubMed

    Bartolo, Michelangelo; Serrao, Mariano; Gamgebeli, Zurab; Alpaidze, Marina; Perrotta, Armando; Padua, Luca; Pierelli, Francesco; Nappi, Giuseppe; Sandrini, Giorgio

    2013-10-01

    The nociceptive withdrawal reflex (NWR), a defensive response that allows withdrawal from a noxious stimulus, is a reliable index of spinal nociception in humans. It has been shown that various kinds of stimuli (emotional, visual, auditory) can modulate the transmission and perception of pain. The aim of the present study was to evaluate, by means of the NWR, the modulatory effect on the spinal circuitry of olfactory stimuli with different emotional valence. The magnitude of the NWR elicited by electrical stimulation of the sural nerve was measured while 18 subjects (9 women, 9 men) smelled pleasant, unpleasant, or neutral odors. The NWR was conditioned by odor probe with interstimulus intervals (ISIs) of 500 ms and 1,500 ms. The magnitude of NWR was significantly greater after the unpleasant odor probe (P <.001) and reduced following the pleasant odor probe (P<.001) at both ISIs. A significant effect of olfactory stimuli on subjective pain ratings were found at both ISIs for pleasant vs unpleasant odors (P<.000), and for both pleasant and unpleasant odors vs neutral and basal conditions (P<.000). No statistical differences in subjective pain ratings at different ISIs were found. Consistent with the notion that NWR magnitude and pain perception can be modulated by stimuli with different emotional valence, these results show that olfactory stimuli, too, can modulate spinal nociception in humans.

  14. Sex differences and effects of oestrogen in rat gastric mucosal defence.

    PubMed

    Shore, Richard; Björne, Håkan; Omoto, Yoko; Siemiatkowska, Anna; Gustafsson, Jan-Åke; Lindblad, Mats; Holm, Lena

    2017-01-21

    To evaluate sex differences and the effects of oestrogen administration in rat gastric mucosal defence. Sex differences in gastric mucus thickness and accumulation rate, absolute gastric mucosal blood flow using microspheres, the integrity of the gastric mucosal epithelium in response to a chemical irritant and the effects of oestrogen administration on relative gastric mucosal blood flow in an acute setting was assessed in an in vivo rat experimental model. Subsequently, sex differences in the distribution of oestrogen receptors and calcitonin gene related peptide in the gastric mucosa of animals exposed to oestrogen in the above experiments was evaluated using immunohistochemistry. The absolute blood flow in the GI-tract was generally higher in males, but only significantly different in the corpus part of the stomach (1.12 ± 0.12 mL/min•g in males and 0.51 ± 0.03 mL/min•g in females) (P = 0.002). After removal of the loosely adherent mucus layer the thickness of the firmly adherent mucus layer in males and females was 79 ± 1 µm and 80 ± 3 µm respectively. After 60 min the mucus thickness increased to 113 ± 3 µm in males and 121 ± 3 µm in females with no statistically significant difference seen between the sexes. Following oestrogen administration (0.1 followed by 1 µg/kg•min), mean blood flow in the gastric mucosa decreased by 31% [68 ± 13 perfusion units (PFU)] in males which was significantly different compared to baseline (P = 0.02). In females however, mean blood flow remained largely unchanged with a 4% (5 ± 33 PFU) reduction. The permeability of the gastric mucosa increased to a higher level in females than in males (P = 0.01) after taurocholate challenge. However, the calculated mean clearance increase did not significantly differ between the sexes [0.1 ± 0.04 to 1.1 ± 0.1 mL/min•100 g in males and 0.4 ± 0.3 to 2.1 ± 0.3 mL/min•100 g in females (P = 0.065)]. There were no significant differences between 17β-Estradiol treated

  15. Sex differences and effects of oestrogen in rat gastric mucosal defence

    PubMed Central

    Shore, Richard; Björne, Håkan; Omoto, Yoko; Siemiatkowska, Anna; Gustafsson, Jan-Åke; Lindblad, Mats; Holm, Lena

    2017-01-01

    AIM To evaluate sex differences and the effects of oestrogen administration in rat gastric mucosal defence. METHODS Sex differences in gastric mucus thickness and accumulation rate, absolute gastric mucosal blood flow using microspheres, the integrity of the gastric mucosal epithelium in response to a chemical irritant and the effects of oestrogen administration on relative gastric mucosal blood flow in an acute setting was assessed in an in vivo rat experimental model. Subsequently, sex differences in the distribution of oestrogen receptors and calcitonin gene related peptide in the gastric mucosa of animals exposed to oestrogen in the above experiments was evaluated using immunohistochemistry. RESULTS The absolute blood flow in the GI-tract was generally higher in males, but only significantly different in the corpus part of the stomach (1.12 ± 0.12 mL/min•g in males and 0.51 ± 0.03 mL/min•g in females) (P = 0.002). After removal of the loosely adherent mucus layer the thickness of the firmly adherent mucus layer in males and females was 79 ± 1 µm and 80 ± 3 µm respectively. After 60 min the mucus thickness increased to 113 ± 3 µm in males and 121 ± 3 µm in females with no statistically significant difference seen between the sexes. Following oestrogen administration (0.1 followed by 1 µg/kg•min), mean blood flow in the gastric mucosa decreased by 31% [68 ± 13 perfusion units (PFU)] in males which was significantly different compared to baseline (P = 0.02). In females however, mean blood flow remained largely unchanged with a 4% (5 ± 33 PFU) reduction. The permeability of the gastric mucosa increased to a higher level in females than in males (P = 0.01) after taurocholate challenge. However, the calculated mean clearance increase did not significantly differ between the sexes [0.1 ± 0.04 to 1.1 ± 0.1 mL/min•100 g in males and 0.4 ± 0.3 to 2.1 ± 0.3 mL/min•100 g in females (P = 0.065)]. There were no significant differences between 17

  16. TASK-1 channels may modulate action potential duration of human atrial cardiomyocytes.

    PubMed

    Limberg, Sven H; Netter, Michael F; Rolfes, Caroline; Rinné, Susanne; Schlichthörl, Günter; Zuzarte, Marylou; Vassiliou, Timon; Moosdorf, Rainer; Wulf, Hinnerk; Daut, Jürgen; Sachse, Frank B; Decher, Niels

    2011-01-01

    Atrial fibrillation is the most common arrhythmia in the elderly, and potassium channels with atrium-specific expression have been discussed as targets to treat atrial fibrillation. Our aim was to characterize TASK-1 channels in human heart and to functionally describe the role of the atrial whole cell current I(TASK-1). Using quantitative PCR, we show that TASK-1 is predominantly expressed in the atria, auricles and atrio-ventricular node of the human heart. Single channel recordings show the functional expression of TASK-1 in right human auricles. In addition, we describe for the first time the whole cell current carried by TASK-1 channels (I(TASK-1)) in human atrial tissue. We show that I(TASK-1) contributes to the sustained outward current I(Ksus) and that I(TASK-1) is a major component of the background conductance in human atrial cardiomyocytes. Using patch clamp recordings and mathematical modeling of action potentials, we demonstrate that modulation of I(TASK-1) can alter human atrial action potential duration. Due to the lack of ventricular expression and the ability to alter human atrial action potential duration, TASK-1 might be a drug target for the treatment of atrial fibrillation. Copyright © 2011 S. Karger AG, Basel.

  17. TASK-1 Channels May Modulate Action Potential Duration of Human Atrial Cardiomyocytes

    PubMed Central

    Limberg, Sven H.; Netter, Michael F.; Rolfes, Caroline; Rinné, Susanne; Schlichthörl, Günter; Zuzarte, Marylou; Vassiliou, Timon; Moosdorf, Rainer; Wulf, Hinnerk; Daut, Jürgen; Sachse, Frank B.; Decher, Niels

    2011-01-01

    Background/Aims: Atrial fibrillation is the most common arrhythmia in the elderly, and potassium channels with atrium-specific expression have been discussed as targets to treat atrial fibrillation. Our aim was to characterize TASK-1 channels in human heart and to functionally describe the role of the atrial whole cell current ITASK-1. Methods and Results: Using quantitative PCR, we show that TASK-1 is predominantly expressed in the atria, auricles and atrio-ventricular node of the human heart. Single channel recordings show the functional expression of TASK-1 in right human auricles. In addition, we describe for the first time the whole cell current carried by TASK-1 channels (ITASK-1) in human atrial tissue. We show that ITASK-1 contributes to the sustained outward current IKsus and that ITASK-1 is a major component of the background conductance in human atrial cardiomyocytes. Using patch clamp recordings and mathematical modeling of action potentials, we demonstrate that modulation of ITASK-1 can alter human atrial action potential duration. Conclusion: Due to the lack of ventricular expression and the ability to alter human atrial action potential duration, TASK-1 might be a drug target for the treatment of atrial fibrillation. PMID:22178873

  18. α-Fetoprotein as a modulator of the pro-inflammatory response of human keratinocytes

    PubMed Central

    Potapovich, AI; Pastore, S; Kostyuk, VA; Lulli, D; Mariani, V; De Luca, C; Dudich, EI; Korkina, LG

    2009-01-01

    Background and purpose: The immunomodulatory effects of α-fetoprotein (AFP) on lymphocytes and macrophages have been described in vitro and in vivo. Recombinant forms of human AFP have been proposed as potential therapeutic entities for the treatment of autoimmune diseases. We examined the effects of embryonic and recombinant human AFP on the spontaneous, UVA- and cytokine-induced pro-inflammatory responses of human keratinocytes. Experimental approach: Cultures of primary and immortalized human keratinocytes (HaCaT) and human blood T lymphocytes were used. The effects of AFP on cytokine expression were studied by bioplexed elisa and quantitative reverse transcriptase polymerase chain reaction assay. Kinase and nuclear factor kappa B (NFκB) phosphorylation were quantified by intracellular elisa. Nuclear activator protein 1 and NFκB DNA binding activity was measured by specific assays. Nitric oxide and H2O2 production and redox status were assessed by fluorescent probe and biochemical methods. Key results: All forms of AFP enhanced baseline expression of cytokines, chemokines and growth factors. AFP dose-dependently increased tumour necrosis factor alpha-stimulated granulocyte macrophage colony stimulating factor and interleukin 8 expression and decreased tumour necrosis factor alpha-induced monocyte chemotactic protein 1 and IP-10 (interferon gamma-produced protein of 10 kDa) expression. AFP induced a marked activator protein 1 activation in human keratinocytes. AFP also increased H2O2 and modulated nitrite/nitrate levels in non-stimulated keratinocytes whereas it did not affect these parameters or cytokine release from UVA-stimulated cells. Phosphorylation of extracellular signal-regulated kinase (ERK1/2) and Akt1 but not NFκB was activated by AFP alone or by its combination with UVA. Conclusions and implications: Exogenous AFP induces activation of human keratinocytes, with de novo expression of a number of pro-inflammatory mediators and modulation of their

  19. Cerium dioxide nanoparticles do not modulate the lipopolysaccharide-induced inflammatory response in human monocytes

    PubMed Central

    Hussain, Salik; Al-Nsour, Faris; Rice, Annette B; Marshburn, Jamie; Ji, Zhaoxia; Zink, Jeffery I; Yingling, Brenda; Walker, Nigel J; Garantziotis, Stavros

    2012-01-01

    Background Cerium dioxide (CeO2) nanoparticles have potential therapeutic applications and are widely used for industrial purposes. However, the effects of these nanoparticles on primary human cells are largely unknown. The ability of nanoparticles to exacerbate pre-existing inflammatory disorders is not well documented for engineered nanoparticles, and is certainly lacking for CeO2 nanoparticles. We investigated the inflammation-modulating effects of CeO2 nanoparticles at noncytotoxic concentrations in human peripheral blood monocytes. Methods CD14+ cells were isolated from peripheral blood samples of human volunteers. Cells were exposed to either 0.5 or 1 μg/mL of CeO2 nanoparticles over a period of 24 or 48 hours with or without lipopolysaccharide (10 ng/mL) prestimulation. Modulation of the inflammatory response was studied by measuring secreted tumor necrosis factor-alpha, interleukin-1beta, macrophage chemotactic protein-1, interferon-gamma, and interferon gamma-induced protein 10. Results CeO2 nanoparticle suspensions were thoroughly characterized using dynamic light scattering analysis (194 nm hydrodynamic diameter), zeta potential analysis (−14 mV), and transmission electron microscopy (irregular-shaped particles). Transmission electron microscopy of CD14+ cells exposed to CeO2 nanoparticles revealed that these nanoparticles were efficiently internalized by monocytes and were found either in vesicles or free in the cytoplasm. However, no significant differences in secreted cytokine profiles were observed between CeO2 nanoparticle-treated cells and control cells at noncytotoxic doses. No significant effects of CeO2 nanoparticle exposure subsequent to lipopolysaccharide priming was observed on cytokine secretion. Moreover, no significant difference in lipopolysaccharide-induced cytokine production was observed after exposure to CeO2 nanoparticles followed by lipopolysaccharide exposure. Conclusion CeO2 nanoparticles at noncytotoxic concentrations neither

  20. Oestrogen receptor-beta and neurohypophysial hormones: functional interaction and neuroanatomical localisation.

    PubMed

    Forsling, M L; Kalló, I; Hartley, D E; Heinze, L; Ladek, R; Coen, C W; File, S E

    2003-12-01

    Oestrogens affect fluid balance, influencing both ingestive behaviour and renal excretion. The renal effects are partly due to altered release of vasopressin and oxytocin. This study was designed to explore the role of oestrogen receptor-beta (ERbeta) in neurohypophysial hormonal function. Following dietary administration, soya isoflavones reach the brain in sufficient concentration to activate ERbeta, but not oestrogen receptor-alpha (ERalpha). ERbeta function was therefore manipulated by feeding rat diets differing in soya isoflavone content. Fluid balance and neurohypophysial hormone release were measured in male rats maintained for 14 days on a soya isoflavone-free diet or one containing 150 microg/g genistein+daidzein. Food and water intake, body weight, urine flow, osmolality and sodium concentrations were determined daily. After 14 days, plasma and urine osmolality and sodium, vasopressin and oxytocin concentrations were determined. There was no significant difference in weight gain between the two groups or in their excretion of sodium and water or plasma sodium and plasma oxytocin. However, plasma vasopressin was significantly lower in the iso-free group. Double-label immunocytochemistry was used to assess colocalisation of ERbeta with the neurohypophysial hormones in male rats. Cell nuclei showing ERbeta immunoreactivity were abundant in the posterior magnocellular paraventricular nucleus (PVNpm) and in the supraoptic nucleus (SON). Vasopressin-immunoreactive neurones were similarly distributed, forming the core of the PVNpm and the ventral portion of the SON; majority were positive for ERbeta. Cells with oxytocin immunoreactivity were located mainly at the periphery of the PVNpm and in the dorsal SON; only approximately a quarter of these cells showed ERbeta immunoreactivity. Thus, the difference in the effects of the soya diet on vasopressin and oxytocin release may be related to the ERbeta-activating properties of this diet and to the preponderance of

  1. Non-contraceptive oestrogen-containing preparations for controlling symptoms of premenstrual syndrome.

    PubMed

    Naheed, Bushra; Kuiper, Jan Herman; Uthman, Olalekan A; O'Mahony, Fidelma; O'Brien, Patrick Michael Shaughn

    2017-03-03

    Premenstrual syndrome (PMS) is a psychological and somatic disorder of unknown aetiology, with symptoms typically including irritability, depression, mood swings, bloating, breast tenderness and sleep disturbances. About 3% to 10% of women who experience these symptoms may also meet criteria for premenstrual dysphoric disorder (PMDD). PMS symptoms recur during the luteal phase of the menstrual cycle and reduce by the end of menstruation. PMS results from ovulation and may be due to ovarian steroid interactions relating to neurotransmitter dysfunction. Premenstrual disorders have a devastating effect on women, their families and their work.Several treatment options have been suggested for PMS, including pharmacological and surgical interventions. The treatments thought to be most effective tend to fall into one of two categories: suppressing ovulation or correcting a speculated neuroendocrine anomaly.Transdermal oestradiol by patch, gel or implant effectively stops ovulation and the cyclical hormonal changes which produce the cyclical symptoms. These preparations are normally used for hormone therapy and contain lower doses of oestrogen than found in oral contraceptive pills. A shortened seven-day course of a progestogen is required each month for endometrial protection but can reproduce premenstrual syndrome-type symptoms in these women. To determine the effectiveness and safety of non-contraceptive oestrogen-containing preparations in the management of PMS. On 14 March 2016, we searched the following databases: the Cochrane Gynaecology and Fertility Group (CGF) Specialised Register; Cochrane Central Register of Studies (CRSO); MEDLINE; Embase; PsycINFO; CINAHL; ClinicalTrials.gov; metaRegister of Controlled trials (mRCT); and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) Search Portal. In addition, we checked the reference lists of articles retrieved. We included published and unpublished randomized placebo or active

  2. Oestrogen exhibits type II collagen protective effects and attenuates collagen-induced arthritis in rats.

    PubMed

    Nielsen, R H; Christiansen, C; Stolina, M; Karsdal, M A

    2008-04-01

    As anti-inflammatory treatments used in rheumatoid arthritis, such as glucocorticoids, often result in secondary detrimental effects on bone health, the objective of this study was to investigate the effects of oestrogen therapy (ET) on the development and activity of collagen-induced arthritis (CIA) in rats, with a focus on assessment of chondroprotective effects using biomarkers of type II collagen degradation. Forty female Lewis rats were allocated into four intervention groups: (i) control + vehicle; (ii) CIA + vehicle; (iii) CIA + ET; and (iv) CIA + prednisolone. During the 28-day intervention period we monitored body weight, time-point of disease onset, incidence of manifest disease and paw volume. Levels of the type II collagen degradation marker (CTX-II) were measured in serum. At euthanasia, hind paws were isolated, extracted for proteins and measured for the concentration of CTX-II. Matrix metalloproteinase (MMP) activity was evaluated using gelatinase zymography. Oestrogen treatment delayed the time-point of disease onset and reduced the incidence and degree of manifest immunoarthritis significantly, assessed by macroscopic evaluation of hind paw inflammation and paw volume. Measures of serum or tissue levels of CTX-II showed significantly reduced type II collagen degradation