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Sample records for agonist diethylstilbestrol des

  1. Diethylstilbestrol (DES) and Cancer

    MedlinePLUS

    ... Other Funding Find NCI funding for small business innovation, technology transfer, and contracts Training Cancer Training at ... following: Pelvic examination Pap test and colposcopy —A routine cervical Pap test is not adequate for DES ...

  2. Iron(II)-catalyzed enhancement of ultrasonic-induced degradation of diethylstilbestrol (DES)

    PubMed Central

    Ben Abderrazik, N.; Azmani, A.; R’kiek, C.; Song, Weihua; O’Shea, Kevin E.

    2015-01-01

    The oxidation of the endocrine disruptor, diethylstilbestrol (DES) in aqueous media by ultrasound is significantly enhanced by Fe(II) catalyst. The observed enhancement is likely the result of increased levels of hydroxyl radicals from the iron-promoted reduction of the hydrogen peroxide produced during ultrasonic irradiation. The degradation is effective over a range of concentrations and is consistent with pseudo first-order kinetics. Relatively high concentrations of hydrogen peroxide, ~450 mM, are present in solution under our experimental conditions after 1 h of ultrasonic irradiation (665 kHz). The concentration of H2O2 in solution decreased with the addition of Fe(II) along with an increase in the degradation of DES. Hydrogen peroxide alone does not appreciably degrade DES. Our results demonstrate ultrasonic-induced degradation of DES can be accelerated with the addition of Fe(II). The combination of ultrasonic irradiation and Fe(II)-promoted conversion of H2O2 to hydroxyl radical may provide a valuable strategy for the treatment of organic pollutants.

  3. Diethylstilbestrol (DES)-induced cell cycle delay and meiotic spindle disruption in mouse oocytes during in-vitro maturation.

    PubMed

    Can, A; Semiz, O

    2000-02-01

    Due to the growing amount of data related to the deleterious effects of the synthetic oestrogenic compound, diethylstilbestrol (DES), on the female reproductive system, we tested the potential effects of this compound on mouse oocytes. Controlled time- and dose-dependent in-vitro experiments were carried out on isolated cumulus-oocyte-complexes (COCs) to examine the meiotic spindle assembly and chromosome distribution. alpha-tubulin, chromosomes and F-actin were labelled and detected by confocal laser scanning microscope. COCs were exposed to varying doses of DES (5-30 micromol/l) from the germinal vesicle (GV) stage to the end of metaphase II (MII) when meiosis I and meiosis II is normally completed. Exposure to DES during meiosis I caused a dose-dependent inhibition of cell cycle progression. In comparison with controls, fewer oocytes reached metaphase I (MI) at low doses (5 micromol/l) of DES, while none of the oocytes reached MI in high doses (30 micromol/l). When COCs were exposed to high doses of DES during meiosis II, fragmentation of first meiotic spindle was detected, whereas lower doses caused loosening of the first and the second meiotic spindles. No microtubular abnormalities were detected either in GV-stage oocytes or in cumulus cells. The above data demonstrate that one mode of action of DES on mouse oocytes is a severe yet reversible deterioration of meiotic spindle microtubule organization during maturation. PMID:10655457

  4. In utero exposure to diethylstilbestrol (DES) or bisphenol-A (BPA) increases EZH2 expression in the mammary gland: an epigenetic mechanism linking endocrine disruptors to breast cancer.

    PubMed

    Doherty, Leo F; Bromer, Jason G; Zhou, Yuping; Aldad, Tamir S; Taylor, Hugh S

    2010-06-01

    Diethylstilbestrol (DES) and bisphenol-A (BPA) are estrogen-like endocrine-disrupting chemicals that induce persistent epigenetic changes in the developing uterus. However, DES exposure in utero is also associated with an increased risk of breast cancer in adult women. Similarly, fetal exposure to BPA induces neoplastic changes in mammary tissue of mice. We hypothesized that epigenetic alterations would precede the increased risk of breast neoplasia after in utero exposure to endocrine disruptors. Enhancer of Zeste Homolog 2 (EZH2) is a histone methyltransferase that has been linked to breast cancer risk and epigenetic regulation of tumorigenesis. We examined the effect of BPA and DES on EZH2 expression and function in MCF-7 cells and in mammary glands of mice exposed in utero. DES and BPA treatment approximated human exposure. EZH2 functional activity was assessed by measuring histone H3 trimethylation. Treatment of MCF-7 cells with DES or BPA led to a 3- and 2-fold increase in EZH2 mRNA expression, respectively (p?DES in utero showed a >2-fold increase in EZH2 expression in adult mammary tissue compared with controls (p?DES or BPA. Histone H3 trimethylation was increased in MCF-7 cells treated with BPA or DES. Similarly, mice exposed to BPA or DES in utero showed increased mammary histone H3 trimethylation. Developmental programming of EZH2 is a novel mechanism by which in utero exposure to endocrine disruptors leads to epigenetic regulation of the mammary gland. PMID:21761357

  5. Screening and Management of Diethylstilbestrol Exposed Offspring

    PubMed Central

    Malus, Michael; Ferenczy, Alex

    1984-01-01

    Prenatal diethylstilbestrol (DES) exposure in pregnancy has been associated with adenocarcinoma of the vagina and/or cervix as well as teratogenic abnormalities of the genital tract in both female and male offspring. DES Action groups are alerting the public to the dangers inherent in being a `DES daughter' or a `DES son'. Family physicians must be able to reassure those patients who are not DES offspring, manage those who are, and detect those who didn't know they were. The screening and management of DES problems, including history-taking, physical examination, relevant laboratory exams and consultation for diagnosis and treatment of both male and female patients are discussed. In addition, psychological support, patient education, longterm follow up, the management of contraception and pregnancy in DES daughters, and infertility in DES sons are considered. ImagesFig. 2 PMID:21278977

  6. Diethylstilbestrol metabolism by the fetal genital tract.

    PubMed

    Maydl, R; Newbold, R R; Metzler, M; McLachlan, J A

    1983-07-01

    Oxidative metabolism of diethylstilbestrol (DES) was measured in both the male and female genital tracts of the fetal mouse in organ culture. The major oxidative metabolite formed was Z,Z-dienestrol, whose formation appeared to be time dependent in the isolated fetal genital tract of both sexes. This peroxidative metabolite, which has been previously linked to bioactivation of DES in adult target tissues, was not detected in the fetal liver cultures. In addition, fetal genital tracts were capable of O-methylation of DES. In fact, a new metabolite, 4'-O-methyl-DES, was formed in fetal genital tissues but not in liver cultures. On the other hand, conjugation of DES occurred extensively in the fetal liver and placenta but not in the fetal genital tissues; conjugated DES was found primarily in the media. Thus, the fetal genital tract, which is the primary target for the transplacental carcinogenicity of DES, has the capacity to metabolize this compound. PMID:6861692

  7. Effect of prenatal and/or neonatal diethylstilbestrol (DES) or allylestrenol (AE) treatment on the postnatal development of the chicken ovary.

    PubMed

    Sótonyi, P T; Csaba, G

    1986-01-01

    Chickens treated with allylestrenol or diethylstilbestrol in the egg on 9th day of incubation, or one day after hatching, or on both occasions, equally showed histomorphological indications of a distinct ovarian activation at 5 days of age, which was most pronounced in the twice-treated birds. A single steroid exposure at one day of age accounted for inhibition of ovarian activity at 6 weeks, presumably owing to a long-term effect on the hypothalamo-hypophyseal system, which begins to function from the 12th day of incubation. PMID:3442171

  8. Diethylstilbestrol Exposure in Neonatal Mice Induces Changes in the Adulthood in the Immune Response to Taenia crassiceps without Modifications of Parasite Loads

    PubMed Central

    Nava-Castro, Karen E.; Morales-Montor, Jorge; Ortega-Hernando, Alejandra; Camacho-Arroyo, Ignacio

    2014-01-01

    Industrial growth has increased the exposition to endocrine disruptor compounds (EDC's), which are exogenous agents with agonist or antagonist action of endogenous steroid hormones that may affect the course of parasite infections. We wanted to determine if the exposure to diethylstilbestrol (DES), an estrogen agonist, to both male and female mice affected the immune response and their susceptibility to T. crassiceps cysticercosis. In all infected groups, females showed higher parasite loads than males, and neonatal DES administration did not modify this pattern. In the spleen, noninfected mice showed sex-related differences in the percentage of the CD8+ subpopulation, but DES decreased the percentage of CD3+, CD19+, and CD8+ subpopulations in infected mice. In the mesenteric lymphatic node (MNL), DES showed a dimorphic effect in the percentage of CD19+ cells. Regarding estrogen receptor alpha (ER-?) expression, DES treatment induced a reduction in the expression of this receptor in both noninfected female and male mice in the spleen, which was decreased only in males in CD3+ and CD8+ lymphocytes in MNL cell subpopulations. Our study is the first one to demonstrate that DES neonatal treatment in male and female mice affects the immune cell percentage, without effect on the susceptibility to T. crassiceps cysticercosis. PMID:25243144

  9. Effects of Diethylstilbestrol in Fathead Minnows: Part 1. Effects on Reproductive Endocrine Function

    EPA Science Inventory

    Diethylstilbestrol (DES), a synthetic nonsteroidal estrogen, was once widely prescribed to prevent miscarriages, and was used as a growth promoter in feed for beef and poultry production. After it was determined that DES caused significant adverse effects in the offspring of mo...

  10. Effects of Diethylstilbestrol in Fathead Minnows: Part 2. Concentrations in Water and Tissues

    EPA Science Inventory

    Diethylstilbestrol (DES), a synthetic nonsteroidal estrogen, was once widely prescribed to prevent miscarriages, and was used as a growth promoter in feed for beef and poultry production. After it was determined that DES caused significant adverse effects in the offspring of mot...

  11. Influence of neonatal steroid (diethylstilbestrol, allylestrenol) treatment on the sexual behaviour of the adult rat.

    PubMed

    Csaba, G; Dobozy, O; Dalló, J

    1986-01-01

    A single neonatal treatment with diethylstilbestrol (DES) or allylestrenol (AE) considerably depressed the sexual activity of male rats in adulthood. DES had a stronger depressive effect than AE. Though the adult sexual activity of intact female rats was also reduced by DES it was not influenced by AE. Ovariectomized females that had been hormone-treated before experimental mating showed reduced sexual activity under the influence of neonatal DES-treatment but increased sexual activity when treated neonatally with AE. PMID:3023767

  12. Changes of free histones in chick testicular and ovarian cells after embryonic and/or neonatal treatment with diethylstilbestrol (DES) or allyloestrenol (AE).

    PubMed

    Sótonyi, P T; Dobozy, O; Csaba, G

    1986-01-01

    DES and AE when injected into the yolk sac of chick embryos on the 9th day of incubation decreased the neonatal weight of the testis and the PMB-reaction of spermatogonia whereas they increased the neonatal weight and granulosa cell PMB-reaction of the ovary. In the ovary, embryonic treatment increased the efficiency of post-hatching hormone treatments. PMID:3105256

  13. Bioactivation of diethylstilbestrol by the Syrian hamster kidney

    SciTech Connect

    Adams, S.P.

    1987-01-01

    Male Syrian golden hamsters chronically exposed to diethylstilbestrol (DES) develop renal adenocarcinomas with an incidence approaching 100%. The ability of the hamster kidney to bioactivate DES was assessed using hamster kidney slices. The male hamster renal cortex has a 2- to 5-fold greater capacity to irreversibly bind ({sup 3}H)DES as compared with female hamster renal cortex and with male hamster renal medulla. Incubation of the tissue under anaerobic conditions inhibited the metabolism and irreversible binding of ({sup 3}H)DES. Gel electrophoresis analysis of covalently modified proteins revealed several radioactive peaks indicating that specific adduct formation had occurred. The cytochrome P-450 inhibitors SKF 525-A, metyrapone, carbon monoxide, butylated hydroxytoluene, and dicumarol decreased the irreversible binding of ({sup 3}H)DES to renal cortical protein by 38 to 72%.

  14. Sister chromatid exchanges and cell division delays induced by diethylstilbestrol, estradiol, and estriol in human lymphocytes

    SciTech Connect

    Hill, A.; Wolff, S.

    1983-09-01

    It had been found previously that exposure of human lymphocytes in vitro to diethylstilbestrol (DES), a synthetic estrogen and known human carcinogen, led to the induction of sister chromatid exchangers. More sister chromatid exchanges were induced in cells from pregnant women than from men. To see if the effects of DES could be induced by other estrogens, lymphocytes from a man and a pregnant woman were treated in vitro with the natural estrogens estradiol and estriol. These did not induce sister chromatid exchanges.

  15. Neonatal exposure to diethylstilbestrol causes granulomatous orchitis via epididymal inflammation.

    PubMed

    Miyaso, Hidenobu; Naito, Munekazu; Hirai, Shuichi; Matsuno, Yoshiharu; Komiyama, Masatoshi; Itoh, Masahiro; Mori, Chisato

    2014-09-01

    Diethylstilbestrol (DES), an endocrine-disrupting chemical, is an infamous artificial estrogenic compound. Although neonatal exposure to DES has been shown to result in inflammation of the male reproductive system, it has not, to our knowledge, been reported to induce testicular inflammation. Here we report that neonatal exposure to DES caused granulomatous orchitis with spermatogenic disturbance in 4 of 17 ICR male mice at 12weeks of age. In the animals with spermatogenic disturbance, we observed either seminiferous tubules containing only cells with Sertoli cell features (likely Sertoli cell syndrome), or tubule cells in maturation arrest that contained only spermatogonia and/or spermatocytes. Following neonatal DES exposure, 5-week-old mice exhibited inflammation in cauda epididymis; by 8weeks, the inflammation had spread to all segments of epididymis but not the testis; by 12weeks, inflammation of the epididymis was observed in all mice. These data indicated that cauda epididymis has increased sensitivity to neonatal DES exposure compared to other segments of epididymis and testis. The data also implied that neonatal DES exposure-induced inflammation in cauda epididymis extended gradually to the testis via corpus and caput during development. PMID:24449359

  16. Quantitative proteomic determination of diethylstilbestrol action on prostate cancer.

    PubMed

    Bigot, Pierre; Mouzat, Kevin; Lebdai, Souhil; Bahut, Muriel; Benhabiles, Nora; Tassin, Géraldine Cancel; Azzouzi, Abdel-Rahmène; Cussenot, Olivier

    2013-05-01

    Diethylstilbestrol (DES) has a direct cellular mechanism inhibition on prostate cancer. Its action is independent from the oestrogen receptors and is preserved after a first-line hormonal therapy. We aimed to identify proteins involved in the direct cellular inhibition effects of DES on prostate cancer. We used a clonogenic assay to establish the median lethal concentration of DES on 22RV1 cells. 22RV1 cells were exposed to standard and DES-enriched medium. After extraction, protein expression levels were obtained by two-dimensional differential in-gel electrophoresis (2D-DIGE) and isotope labelling tags for relative and absolute quantification (iTRAQ). Proteins of interest were analysed by quantitative RT-PCR and western blotting. The differentially regulated proteins (P<0.01) were interrogated against a global molecular network based on the ingenuity knowledge base. The 2D-DIGE analyses revealed DES-induced expression changes for 14 proteins (>1.3 fold; P<0.05). The iTRAQ analyses allowed the identification of 895 proteins. Among these proteins, 65 had a modified expression due to DES exposure (i.e., 23 overexpressed and 42 underexpressed). Most of these proteins were implicated in apoptosis and redox processes and had a predicted mitochondrial expression. Additionally, ingenuity pathway analysis placed the OAT and HSBP1 genes at the centre of a highly significant network. RT-PCR confirmed the overexpression of OAT (P=0.006) and HSPB1 (P=0.046). PMID:23435471

  17. Quantitative proteomic determination of diethylstilbestrol action on prostate cancer

    PubMed Central

    Bigot, Pierre; Mouzat, Kevin; Lebdai, Souhil; Bahut, Muriel; Benhabiles, Nora; Tassin, Géraldine Cancel; Azzouzi, Abdel-Rahmène; Cussenot, Olivier

    2013-01-01

    Diethylstilbestrol (DES) has a direct cellular mechanism inhibition on prostate cancer. Its action is independent from the oestrogen receptors and is preserved after a first-line hormonal therapy. We aimed to identify proteins involved in the direct cellular inhibition effects of DES on prostate cancer. We used a clonogenic assay to establish the median lethal concentration of DES on 22RV1 cells. 22RV1 cells were exposed to standard and DES-enriched medium. After extraction, protein expression levels were obtained by two-dimensional differential in-gel electrophoresis (2D-DIGE) and isotope labelling tags for relative and absolute quantification (iTRAQ). Proteins of interest were analysed by quantitative RT-PCR and western blotting. The differentially regulated proteins (P<0.01) were interrogated against a global molecular network based on the ingenuity knowledge base. The 2D-DIGE analyses revealed DES-induced expression changes for 14 proteins (>1.3 fold; P<0.05). The iTRAQ analyses allowed the identification of 895 proteins. Among these proteins, 65 had a modified expression due to DES exposure (i.e., 23 overexpressed and 42 underexpressed). Most of these proteins were implicated in apoptosis and redox processes and had a predicted mitochondrial expression. Additionally, ingenuity pathway analysis placed the OAT and HSBP1 genes at the centre of a highly significant network. RT-PCR confirmed the overexpression of OAT (P=0.006) and HSPB1 (P=0.046). PMID:23435471

  18. Diethylstilbestrol affects the expression of GPER in the gubernaculum testis.

    PubMed

    Zhang, Xuan; Ke, Song; Chen, Kai-Hong; Li, Jian-Hong; Ma, Lian; Jiang, Xue-Wu

    2015-01-01

    Recent evidence suggested a positive correlation between environmental estrogens (EEs) and high incidence of abnormalities in male urogenital system. EEs are known to cause the abnormalities of testes development and testicular descent. Diethylstilbestrol (DES) is a nonsteroidal synthetic estrogen that disrupts the morphology and proliferation of gubernacular cells, and its nongenomic effects on gubernaculum testis cells may be mediated by G protein-coupled estrogen receptor (GPER). In this study, we detected the expression of GPER in mouse gubernacular testis and investigated the effects of DES on the expression of GPER in gubernaculum testis cells. RT-PCR analysis revealed that GPER mRNA was expressed in the gubernaculum. GPER protein was detected in the parenchymal cells of the gubernaculum early in development. Furthermore, we demonstrate that GPER inhibitor G15 relieved DES-induced inhibition of GPER expression in gubernaculum testis cell, but ER inhibitor ICI 182780 had the converse effects on DES-induced inhibition of GPER expression in these cells. These data suggest that the effects of DES on mouse gubernaculum testis cells are mediated at least partially by the regulation of GPER expression. PMID:26261617

  19. Adrenal steroidogenesis disruption caused by HDL/cholesterol suppression in diethylstilbestrol-treated adult male rat.

    PubMed

    Haeno, Satoko; Maeda, Naoyuki; Yamaguchi, Kousuke; Sato, Michiko; Uto, Aika; Yokota, Hiroshi

    2016-04-01

    The synthetic estrogen diethylstilbestrol is used to prevent miscarriages and as a therapeutic treatment for prostate cancer, but it has been reported to have adverse effects on endocrine homeostasis. However, the toxicity mechanism is poorly understood. Recently, we reported that diethylstilbestrol impairs adrenal steroidogenesis via cholesterol insufficiency in adult male rats. In the present study, we found that the adrenal cholesterol level was significantly reduced without of the decrease in other precursors in the adrenal steroidogenesis 24 h after a single dose of diethylstilbestrol (0.33 μg/g body mass). The serum HDL/cholesterol level was also reduced only 12 h after the diethylstilbestrol exposure. The level of Apo E, which is indispensable for HDL/cholesterol maturation, was decreased in both the HDL and VLDL/LDL fractions, whereas the level of Apo A1, which is an essential constituent of HDL, was not altered in the HDL fraction. Because the liver is a major source of Apo E and Apo A1, the secretion rates of these proteins were examined using a liver perfusion experiment. The secretion rate of Apo A1 from the liver was consistent between DES-treated and control rats, but that of Apo E was comparatively suppressed in the DES-treated rats. The disruption of adrenal steroidogenesis by diethylstilbestrol was caused by a decrease in serum HDL/cholesterol, which is the main source of adrenal steroidogenesis, due to the inhibition of Apo E secretion from the liver. PMID:26349937

  20. Diethylstilbestrol Exposure in Utero and Depression in Women

    PubMed Central

    O'Reilly, ilis J.; Mirzaei, Fariba; Forman, Michele R.; Ascherio, Alberto

    2010-01-01

    Diethylstilbestrol (DES) is an estrogenic endocrine disruptor with long-term health effects, possibly including depression, following exposure in utero. Understanding the relation between in utero DES exposure and depression will provide insight to the potential adverse effects of bisphenol A, a functionally similar and ubiquitous endocrine disruptor. The association between in utero DES exposure and depression was assessed among participants in the Nurses Health Study II who first reported their history of antidepressant use in 1993 and lifetime history of depressive symptoms in 2001. DES exposure was reported by 1,612 (2.2%) women. A history of depression at baseline was higher among women exposed to DES in utero compared with those not exposed (age-adjusted odds ratio (OR) = 1.47, 95% confidence interval (CI): 1.26, 1.72) (P < 0.001). Incident depression (first use of antidepressants among women who also reported depressive symptoms) during follow-up (19952005) was reported by 19.7% of women exposed to DES and 15.9% unexposed (age-adjusted OR = 1.41, 95% CI: 1.22, 1.63) (P < 0.001). Adjustment for risk factors of depression and correlates of DES exposure moderately attenuated the association (multivariable-adjusted OR = 1.30, 95% CI: 1.13, 1.51) (P = 0.0004). These results suggest that the neurophysiologic effects of in utero exposure to DES could lead to an increased risk of depression in adult life. Further research should assess whether in utero exposure to bisphenol A has similar adverse effects. PMID:20332145

  1. Exposure to Diethylstilbestrol during Sensitive Life Stages: A legacy of heritable health effects

    PubMed Central

    Reed, Casey E.; Fenton, Suzanne E.

    2013-01-01

    Diethylstilbestrol (DES) is a potent estrogen mimic that was predominantly used from the 1940s to 1970s in hopes of preventing miscarriage in pregnant women. Decades later, DES is known to enhance breast cancer risk in exposed women, and cause a variety of birth related adverse outcomes in their daughters such as spontaneous abortion, second trimester pregnancy loss, preterm delivery, stillbirth, and neonatal death. Additionally, children exposed to DES in utero suffer from sub/infertility and cancer of reproductive tissues. DES is a pinnacle compound which demonstrates the fetal basis of adult disease. The mechanisms of cancer and endocrine disruption induced by DES are not fully understood. Future studies should focus on common target tissue pathways affected and the health of the DES grandchildren. PMID:23897597

  2. Exposure to diethylstilbestrol during sensitive life stages: a legacy of heritable health effects.

    PubMed

    Reed, Casey E; Fenton, Suzanne E

    2013-06-01

    Diethylstilbestrol (DES) is a potent estrogen mimic that was predominantly used from the 1940s to the 1970s by pregnant women in hopes of preventing miscarriage. Decades later, DES is known to enhance breast cancer risk in exposed women and cause a variety of birth-related adverse outcomes in their daughters such as spontaneous abortion, second trimester pregnancy loss, preterm delivery, stillbirth, and neonatal death. Additionally, children exposed to DES in utero suffer from sub/infertility and cancer of reproductive tissues. DES is a pinnacle compound that demonstrates the fetal basis of adult disease. The mechanisms of cancer and endocrine disruption induced by DES are not fully understood. Future studies should focus on common target tissue pathways affected and the health of the DES grandchildren. PMID:23897597

  3. Autoimmune disease incidence among women prenatally exposed to Diethylstilbestrol

    PubMed Central

    Strohsnitter, William C.; Noller, Kenneth L.; Troisi, Rebecca; Robboy, Stanley J.; Hatch, Elizabeth E.; Titus-Ernstoff, Linda; Kaufman, Raymond H.; Palmer, Julie R.; Anderson, Diane; Hoover, Robert N.

    2010-01-01

    Objective Animal studies have suggested that prenatal Diethylstilbestrol (DES) exposure may alter immune system development and function including antigen self-recognition. A cohort study was conducted to investigate whether prenatal DES exposure might influence the incidence of at least some specific autoimmune diseases in women. Methods Women who were and were not prenatally exposed to DES have been followed for more than 25 years for numerous health outcomes including autoimmune disease. To verify diagnoses, medical records or physician abstracts were requested for all women who reported a diagnosis of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), optic neuritis (ON) and idiopathic thrombocytopenic purpura (ITP). Incidence rates of these autoimmune diseases were compared between women who were or were not prenatally DES-exposed. Results Overall there was no increase in verified autoimmune disease among DES-exposed women relative to those who were not exposed (Relative Rate (RR) = 1.2; 95% Confidence Interval (CI): 0.7, 2.1). There was, however, a positive association between prenatal DES exposure and RA among women younger than 45 years (RR = 4.9; 95% CI: 1.1, 21.6) and an inverse association among women who were 45 years and older (RR = 0.1; 95% CI 0.01, 0.7). Conclusions Overall, these data provide little support for an association between prenatal DES exposure and development of autoimmune disease. The implication that such exposure may be related to RA in an unusual age-related manner is based on small numbers of cases and warrants further study. PMID:20634240

  4. Diethylstilbestrol Regulates the Expression of LGR8 in Mouse Gubernaculum Testis Cells

    PubMed Central

    Duan, Shouxing; Jiang, Xuewu; Zhang, Xuan; Xie, Lei; Sun, Zongbo; Ma, Shuhua; Li, Jianhong

    2016-01-01

    Background Hormonal effects on the gubernaculum can affect testicular descent. Diethylstilbestrol (DES) is a nonsteroidal synthetic estrogen that disrupts the outgrowth of gubernaculums, leading to testis maldescent. However, the underlying mechanisms remain elusive. Material/Methods The gubernaculum were removed from 3-day-old mice and cultured. The subcultured cells were randomly divided into a normal control group and experimental groups. The DES groups were administered 10 μg/ml, 1 μg/ml, 0.1 μg/ml, 0.01 μg/ml of diethylstilbestrol dissolved in dimethyl sulfoxide (DMSO) respectively. The cell morphology was observed under an inverted microscope, and leucine-rich repeat-containing G protein-coupled receptor 8 (LGR8) was localized by immunofluorescence. The expressions of LGR8 gene and protein in gubernaculum cells were quantified by RT-PCR and Flow Cytometer respectively. Results DES treatment converted cells from a normal fibroblast-like morphology into a more refractile, spindle-shaped morphology or irregular elliptical shapes along with cytoplasmic shrinkage. LGR8 was expressed in the cytoplasmic membrane, DES dose-dependently downregulated LGR8 expression at low doses (≤1.0 μg/ml), but upregulated LGR8 at high doses (10 μg/ml) at both the mRNA and protein levels. Conclusions These results suggest that DES causes testicular maldescent by altering the LGR8 pathway in mouse gubernaculum testis cells. PMID:26855023

  5. Diethylstilbestrol Regulates the Expression of LGR8 in Mouse Gubernaculum Testis Cells.

    PubMed

    Duan, Shouxing; Jiang, Xuewu; Zhang, Xuan; Xie, Lei; Sun, Zongbo; Ma, Shuhua; Li, Jianhong

    2016-01-01

    BACKGROUND Hormonal effects on the gubernaculum can affect testicular descent. Diethylstilbestrol (DES) is a nonsteroidal synthetic estrogen that disrupts the outgrowth of gubernaculums, leading to testis maldescent. However, the underlying mechanisms remain elusive. MATERIAL AND METHODS The gubernaculum were removed from 3-day-old mice and cultured. The subcultured cells were randomly divided into a normal control group and experimental groups. The DES groups were administered 10 μg/ml, 1 μg/ml, 0.1 μg/ml, 0.01 μg/ml of diethylstilbestrol dissolved in dimethyl sulfoxide (DMSO) respectively. The cell morphology was observed under an inverted microscope, and leucine-rich repeat-containing G protein-coupled receptor 8 (LGR8) was localized by immunofluorescence. The expressions of LGR8 gene and protein in gubernaculum cells were quantified by RT-PCR and Flow Cytometer respectively. RESULTS DES treatment converted cells from a normal fibroblast-like morphology into a more refractile, spindle-shaped morphology or irregular elliptical shapes along with cytoplasmic shrinkage. LGR8 was expressed in the cytoplasmic membrane, DES dose-dependently downregulated LGR8 expression at low doses (≤1.0 μg/ml), but upregulated LGR8 at high doses (10 μg/ml) at both the mRNA and protein levels. CONCLUSIONS These results suggest that DES causes testicular maldescent by altering the LGR8 pathway in mouse gubernaculum testis cells. PMID:26855023

  6. Effect of diethylstilbestrol on thyroid hormone binding to amphibian transthyretins.

    PubMed

    Yamauchi, K; Prapunpoj, P; Richardson, S J

    2000-09-01

    Transthyretin (TTR) is responsible for a major part of the binding of thyroid hormone to proteins in the plasma in amphibian tadpoles. To characterize the binding properties of amphibian TTRs, the effects of 17 hydrophobic signaling molecules, including 6 endocrine disruptors, on 3,5,3'-l-[(125)I]triiodothyronine ([(125)I]T(3)) binding to plasma proteins were examined in bullfrog Rana catesbeiana tadpoles. T(3) was the most potent competitive inhibitor among the 11 natural biological ligands studied, with an ID(50) of 8 nM. Diethylstilbestrol (DES) was the most powerful inhibitor among the 6 endocrine disruptors studied, with an ID(50) of 20 nM. Similar inhibitions of [(125)I]T(3) binding by these compounds were obtained when purified recombinant Xenopus and Rana TTRs were analyzed. Scatchard analysis revealed that Xenopus and Rana TTRs each possessed a single class of binding site for T(3), with a K(d) of 262 and 1.9 nM, respectively, at 0 degrees C. DES, at a concentration of 200 nM, induced the uptake of [(125)I]T(3) into Rana red blood cells suspended in Rana plasma from prometamorphic stages XIII-XV, when TTR is present in plasma. DES induced the uptake of [(125)I]T(3) into red blood cells to a lesser extent when they were suspended in Rana plasma from metamorphic climax stage XXIV, in which the level of TTR was lower than in plasma from the prometamorphic tadpoles. These results indicate that amphibian TTRs have the ability to bind DES with similar affinity to T(3), the natural ligand, and raise the possibility that DES binding to TTR might induce the temporary elevation of the free concentration of plasma T(3) followed by acceleration of cellular T(3) uptake. PMID:11017780

  7. [Isolation, identification and characterization of a diethylstilbestrol-degrading bacterial strain Serratia sp].

    PubMed

    Xu, Ran-Fang; Sun, Min-Xia; Liu, Juan; Wang, Hong; Li, Xin; Zhu, Xue-Zhu; Ling, Wan-Ting

    2014-08-01

    Utilizing the diethylstilbestrol (DES)-degrading bacteria to biodegrade DES is a most reliable technique for cleanup of DES pollutants from the environment. However, little information is available heretofore on the isolation of DES-degrading bacteria and their DES removal performance in the environment. A novel bacterium capable of degrading DES was isolated from the activated sludge of a wastewater treatment plant. According to its morphology, physiochemical characteristics, and 16S rDNA sequence analysis, this strain was identified as Serratia sp.. The strain was an aerobic bacterium, and it could degrade 68.3% of DES (50 mg x L(-1)) after culturing for 7 days at 30 degrees C, 150 r x min(-1) in shaking flasks. The optimal conditions for DES biodegradation by the obtained strain were 30 degrees C, 40-60 mg x L(-1) DES, pH 7.0, 5% of inoculation volume, 0 g x L(-1) of added NaCl, and 10 mL of liquid medium volume in 100 mL flask. PMID:25338395

  8. Oxidative metabolites of diethylstilbestrol in the fetal Syrian golden hamster

    SciTech Connect

    Maydl, R.; Metzler, M.

    1984-12-01

    /sup 14/C-Diethylstilbestrol was administered orally, intraperitoneally, and intrafetally to 15-day pregnant hamsters at a dose of 20 mg/kg body weight, and the radioactivity was determined in the fetus, placenta, and maternal liver after 6 hours. Significant amounts of radioactivity were found in these tissues in every case, indicating maternal-fetal and fetal-maternal transfer of diethylstilbestrol. Part of the radioactivity found in the tissues could not be extracted even after excessive washing. This implied the presence of reactive metabolites. In the fetal and placental extracts, eight oxidative metabolites of diethylstilbestrol were identified by mass fragmentography as hydroxy- and methoxy-derivatives of diethylstilbestrol, pseudodiethylstilbestrol, and dienestrol. The presence of oxidative metabolites in the hamster fetus and the covalent binding to tissue macromolecules are possibly associated with the fetotoxic effects of diethylstilbestrol.

  9. Structural insights into selective agonist actions of tamoxifen on human estrogen receptor alpha.

    PubMed

    Chakraborty, Sandipan; Biswas, Pradip Kumar

    2014-08-01

    Tamoxifen-an anti-estrogenic ligand in breast tissues used as a first-line treatment in estrogen receptor (ER)-positive breast cancers-is associated with the development of resistance followed by resumption of tumor growth in about 30 % of cases. Whether tamoxifen assists in proliferation in such cases or whether any ligand-independent pathway to transcription exists is not fully understood; also, no ERα mutants have been detected so far that could lead to tamoxifen resistance. Using in silico conformational analysis of the ERα ligand binding domain (LBD), in the absence and presence of selective agonist (diethylstilbestrol; DES), antagonist (Faslodex; ICI), and selective estrogen receptor modulator (SERM; 4-hydroxy tamoxifen; 4-OHT) ligands, we have elucidated ligand-responsive structural modulations of the ERα-LBD dimer in its agonist and antagonist complexes to address the issue of "tamoxifen resistance". DES and ICI were found to stabilize the dimer in their agonist and antagonist conformations, respectively. The ERα-LBD dimer without the presence of any bound ligand also led to a stable structure in agonist conformation. However, binding of 4-OHT to the antagonist structure led to a flexible conformation allowing the protein to visit conformations populated by agonists as was evident from principal component analysis and radius of gyration plots. Further, the relaxed conformations of the 4-OHT bound protein exhibited a diminished size of the co-repressor binding pocket in the LBD, thus signaling a partial blockage of the co-repressor binding motif. Thus, the ability of 4-OHT-bound ERα-LBD to assume flexible conformations visited by agonists and reduced co-repressor binding surface at the LBD provide crucial structural insights into tamoxifen-resistance that complement our existing understanding. PMID:25060147

  10. Structural insights into selective agonist actions of tamoxifen on human Estrogen Receptor alpha

    PubMed Central

    Chakraborty, Sandipan; Biswas, P. K.

    2014-01-01

    Tamoxifen, an anti-estrogenic ligand in breast tissues and being used as a first-line treatment in ER-positive breast cancers, is found to develop resistance followed by resumption of growth of the tumor in about 30% of cases. Whether tamoxifen starts assisting in proliferation in such cases or there exists any ligand-independent pathways to transcription is not fully understood; also, no ERα mutants have been detected so far which could lead to tamoxifen resistance. Performing in-silico conformational analysis of ERα ligand binding domain, in the absence and presence of selective agonist (Diethylstilbestrol; DES), antagonist (Faslodex; ICI), and SERM (4-hydroxy tamoxifen; 4-OHT) ligands, we elucidated ligand-responsive structural modulations of ERα-LBD dimer in their agonist and antagonist complexes and address the issue of “tamoxifen resistance”. We found DES and ICI to stabilize the dimer in their agonist and antagonist conformations, respectively. The ERα-LBD dimer without the presence of any bound ligand also leads to a stable structure in agonist conformation. However, the binding of 4-OHT to antagonist structure is found to lead to a flexible conformation allowing the protein visiting conformations populated by agonists as are evident from principal component analysis and radius of gyration plots. Further, the relaxed conformations of the 4-OHT bound protein is found to exhibit a diminished size of the co-repressor binding pocket at LBD, thus signaling a partial blockage of the co-repressor binding motif. Thus, the ability of 4-OHT bound ERα-LBD to assume flexible conformations visited by agonists and reduced co-repressor binding surface at LBD provide crucial structural insights into tamoxifen-resistance complementing our existing understanding. PMID:25060147

  11. The development of cervical and vaginal adenosis as a result of diethylstilbestrol exposure in utero.

    PubMed

    Laronda, Monica M; Unno, Kenji; Butler, Lindsey M; Kurita, Takeshi

    2012-10-01

    Exposure to exogenous hormones during development can result in permanent health problems. In utero exposure to diethylstilbestrol (DES) is probably the most well documented case in human history. DES, an orally active synthetic estrogen, was believed to prevent adverse pregnancy outcome and thus was routinely given to selected pregnant women from the 1940s to the 1960s. It has been estimated that 5 million pregnant women worldwide were prescribed DES during this period. In the early 1970s, vaginal clear cell adenocarcinomas (CCACs) were diagnosed in daughters whose mother took DES during pregnancy (known as DES daughters). Follow-up studies demonstrated that exposure to DES in utero causes a spectrum of congenital anomalies in female reproductive tracts and CCACs. Among those, cervical and vaginal adenoses are most commonly found, which are believed to be the precursors of CCACs. Transformation related protein 63 (TRP63/p63) marks the cell fate decision of Mllerian duct epithelium (MDE) to become squamous epithelium in the cervix and vagina. DES disrupts the TRP63 expression in mice and induces adenosis lesions in the cervix and vagina. This review describes mouse models that can be used to study the development of DES-induced anomalies, focusing on cervical and vaginal adenoses, and discusses their molecular pathogenesis. PMID:22682699

  12. Effects of Low-Dose Diethylstilbestrol Exposure on DNA Methylation in Mouse Spermatocytes

    PubMed Central

    Yin, Li; Zheng, Li-juan; Jiang, Xiao; Liu, Wen-bin; Han, Fei; Cao, Jia; Liu, Jin-yi

    2015-01-01

    Evidence from previous studies suggests that the male reproductive system can be disrupted by fetal or neonatal exposure to diethylstilbestrol (DES). However, the molecular basis for this effect remains unclear. To evaluate the effects of DES on mouse spermatocytes and to explore its potential mechanism of action, the levels of DNA methyltransferases (DNMTs) and DNA methylation induced by DES were detected. The results showed that low doses of DES inhibited cell proliferation and cell cycle progression and induced apoptosis in GC-2 cells, an immortalized mouse pachytene spermatocyte-derived cell line, which reproduces primary cells responses to E2. Furthermore, global DNA methylation levels were increased and the expression levels of DNMTs were altered in DES-treated GC-2 cells. A total of 141 differentially methylated DNA sites were detected by microarray analysis. Rxra, an important component of the retinoic acid signaling pathway, and mybph, a RhoA pathway-related protein, were found to be hypermethylated, and Prkcd, an apoptosis-related protein, was hypomethylated. These results showed that low-dose DES was toxic to spermatocytes and that DNMT expression and DNA methylation were altered in DES-exposed cells. Taken together, these data demonstrate that DNA methylation likely plays an important role in mediating DES-induced spermatocyte toxicity in vitro. PMID:26588706

  13. The Development of Cervical and Vaginal Adenosis as a Result of Diethylstilbestrol Exposure In Utero

    PubMed Central

    Laronda, Monica M.; Unno, Kenji; Butler, Lindsey M.; Kurita, Takeshi

    2012-01-01

    Exposure to exogenous hormones during development can result in permanent health problems. In utero exposure to diethylstilbestrol (DES) is probably the most well documented case in human history. DES, an orally active synthetic estrogen, was believed to prevent adverse pregnancy outcome and thus was routinely given to selected pregnant women from the 1940s to the 1960s. It has been estimated that 5 million pregnant women worldwide were prescribed with DES during this period. In the early 1970s, vaginal clear cell adenocarcinomas (CCACs) were diagnosed in daughters whose mother took DES during pregnancy (known as DES daughters). Follow up studies demonstrated that exposure to DES in utero causes a spectrum of congenital anomalies in female reproductive tracts and CCACs. Among those, cervical and vaginal adenoses are most commonly found, which are believed to be the precursors of CCACs. Transformation related protein 63 (TRP63/p63) marks the cell fate decision of Mllerian duct epithelium (MDE) to become squamous epithelium in the cervix and vagina. DES disrupts the TRP63 expression in mice and induces adenosis lesions in the cervix and vagina. This review describes mouse models can be used to study the development of DES-induced anomalies, focusing on cervical and vaginal adenoses, and discusses its molecular pathogenesis. PMID:22682699

  14. Histochemical Analysis of Laminin ? Chains in Diethylstilbestrol-Induced Prolactinoma in Rats

    PubMed Central

    Ramadhani, Dini; Tofrizal, Alimuddin; Tsukada, Takehiro; Yashiro, Takashi

    2015-01-01

    Laminin, a major basement membrane component, is important in structural support and cell proliferation and differentiation. Its 19 isoforms are assemblies of ?, ?, and ? chains, and the ? chains (?1-5) determine the isoform characteristics. Although our previous studies showed alterations in ? chain expressions during anterior pituitary development, their expressions in pituitary tumors yet to be determined. The present study used a rat model of diethylstilbestrol (DES)-induced prolactinoma to examine ? chain expressions during prolactinoma tumorigenesis (012 weeks of DES treatment) by in situ hybridization and immunohistochemistry. mRNA of ?1, ?3, and ?4 chains was detected in control and after 4 weeks of DES treatment. These expressions were undetectable after 8 weeks of DES treatment and in prolactinoma (12 weeks of DES treatment). Immunohistochemistry showed that the ?1 chain was localized in some anterior pituitary cells in control and after 4 weeks of treatment and in endothelial cells after 8 weeks of treatment. The ?3 and ?4 chains were expressed in endothelial cells, and immunoreactivity and the number of immunopositive cells decreased during DES treatment. These findings suggest that alteration of laminin ? chains is related to abnormal cell proliferation and neovascularization during development of DES-induced prolactinoma. PMID:26019376

  15. Structural insights into Resveratrol’s antagonist and partial agonist actions on estrogen receptor alpha

    PubMed Central

    2013-01-01

    Background Resveratrol, a naturally occurring stilbene, has been categorized as a phytoestrogen due to its ability to compete with natural estrogens for binding to estrogen receptor alpha (ERα) and modulate the biological responses exerted by the receptor. Biological effects of resveratrol (RES) on estrogen receptor alpha (ERα) remain highly controversial, since both estrogenic and anti-estrogenic properties were observed. Results Here, we provide insight into the structural basis of the agonist/antagonist effects of RES on ERα ligand binding domain (LBD). Using atomistic simulation, we found that RES bound ERα monomer in antagonist conformation, where Helix 12 moves away from the ligand pocket and orients into the co-activator binding groove of LBD, is more stable than RES bound ERα in agonist conformation, where Helix 12 lays over the ligand binding pocket. Upon dimerization, the agonistic conformation of RES-ERα dimer becomes more stable compared to the corresponding monomer but still remains less stable compared to the corresponding dimer in antagonist conformation. Interestingly, while the binding pocket and the binding contacts of RES to ERα are similar to those of pure agonist diethylstilbestrol (DES), the binding energy is much less and the hydrogen bonding contacts also differ providing clues for the partial agonistic character of RES on ERα. Conclusions Our Molecular Dynamics simulation of RES-ERα structures with agonist and antagonist orientations of Helix 12 suggests RES action is more similar to Selective Estrogen Receptor Modulator (SERM) opening up the importance of cellular environment and active roles of co-regulator proteins in a given system. Our study reveals that potential co-activators must compete with the Helix 12 and displace it away from the activator binding groove to enhance the agonistic activity. PMID:24160181

  16. The endocrine disruptor diethylstilbestrol induces adipocyte differentiation and promotes obesity in mice

    SciTech Connect

    Hao, Chan-Juan; Cheng, Xue-Jia; Xia, Hong-Fei Ma, Xu

    2012-08-15

    Epidemiology studies indicate that exposure to endocrine disruptors during developmental “window” contributes to adipogenesis and the development of obesity. Implication of endocrine disruptor such as diethylstilbestrol (DES) on adipose tissue development has been poorly investigated. Here we evaluated the effects of DES on adipocyte differentiation in vitro and in vivo, and explored potential mechanism involved in its action. DES induced 3T3-L1 preadipocyte differentiation in a dose-dependent manner, and activated the expression of estrogen receptor (ER) and peroxisome proliferator-acivated receptor (PPAR) γ as well as its target genes required for adipogenesis in vitro. ER mediated the enhancement of DES-induced PPARγ activity. Moreover, DES perturbed key regulators of adipogenesis and lipogenic pathway in vivo. In utero exposure to low dose of DES significantly increased body weight, liver weight and fat mass in female offspring at postnatal day (PND) 60. In addition, serum triglyceride and glucose levels were also significantly elevated. These results suggest that perinatal exposure to DES may be expected to increase the incidence of obesity in a sex-dependent manner and can act as a potential chemical stressor for obesity and obesity-related disorders. -- Highlights: ► DES induced adipocyte differentiation in a dose-dependent manner in 3T3-L1 cells. ► DES activated adipogenic critical regulators and markers in vitro and in vivo. ► Perinatal exposure to DES led to the obese phenotype in female offspring. ► DES might be a potential chemical stressor for obesity and obesity-related disorders.

  17. Switched impulsive control of the endocrine disruptor diethylstilbestrol singular model

    NASA Astrophysics Data System (ADS)

    Zamani, Iman; Shafiee, Masoud; Ibeas, Asier; de la Sen, M.

    2014-12-01

    In this work, a switched and impulsive controller is designed to control the Endocrine Disruptor Diethylstilbestrol mechanism which is usually modeled as a singular system. Then the exponential stabilization property of the proposed switched and impulsive singular model is discussed under matrix inequalities. A design algorithm is given and applied for the physiological process of endocrine disruptor diethylstilbestrol model to illustrate the effectiveness of the results.

  18. Model ecosystem evaluation of the environmental impacts of the veterinary drugs phenothiazine, sulfamethazine, clopidol, and diethylstilbestrol.

    PubMed Central

    Coats, J R; Metcalf, R L; Lu, P Y; Brown, D D; Williams, J F; Hansen, L G

    1976-01-01

    Four veterinary drugs of dissimilar chemical structures were evaluated for environmental stability and penchant for bioaccumulation. The techniques used were (1) a model aquatic ecosystem (3 days) and (2) a model feedlot ecosystem (33 days) in which the drugs were introduced via the excreta of chicks or mice. The model feedlot ecosystem was supported by metabolism cage studies to determine the amount and the form of the drug excreted by the chicks or mice. Considerable quantities of all the drugs were excreted intact or as environmentally short-lived conjugates. Diethylstilbestrol (DES) and Clopidol were the most persistent molecules, but only DES bioaccumulated to any appreciable degree. Phenothiazine was very biodegradable; sulfamethazine was relatively biodegradable and only accumulated in the organisms to very low levels. Data from the aquatic model ecosystem demonstrated a good correlation between the partition coefficients of the drugs and their accumulation in the fish. Images FIGURE 1. PMID:1037611

  19. Physiological and biochemical perturbations in Daphnia magna following exposure to the model environmental estrogen diethylstilbestrol

    SciTech Connect

    Baldwin, W.S.; Milam, D.L.; LeBlanc, G.A.

    1995-06-01

    The estrogenic properties of many environmental contaminants, such as DDE and PCBs, have been associated with reproductive failure in a variety of vertebrate species. While estrogens have been measured in many invertebrate species, the function of this hormone in invertebrates is controversial. The objective of the present study was to identify possible physiological and biochemical target sites for the estrogenic effects of some xenobiotics on the freshwater crustacean Daphnia magna using the model environmental estrogen diethylstilbestrol (DES). Chronic exposure of daphnids to 0.50 mg/L DES reduced molting frequency among first-generation juveniles and decreased fecundity of second-generation daphnids. Adult first-generation daphnids chronically exposed to DES, as well as adult daphnids acutely exposed to DES for only 48 h, were examined for steroid hormone metabolic capabilities using testosterone as the model steroid. The rate of elimination of two major hydroxylated metabolites of testosterone was significantly reduced, and elimination of glucose conjugates of testosterone was significantly elevated from exposure to 0.50 mg/L DES. These results demonstrate that multigeneration exposure of daphnids to DES results in reduced fecundity and altered steroid metabolic capabilities. Thus, some arthropods, like vertebrates, are sensitive to the effects of endocrine-disrupting chemicals.

  20. Effects of diethylstilbestrol on the proliferation and tyrosinase activity of cultured human melanocytes

    PubMed Central

    TANG, JIANBING; LI, QIN; CHENG, BIAO; HUANG, CHONG; CHEN, KUI

    2015-01-01

    The aim of the present study was to observe the effects of different exogenous estrogen diethylstilbestrol (DES) concentrations on the human melanocyte proliferation and tyrosinase activity. Skin specimens were obtained following blepharoplasty, and the melanocytes were primary cultured and passaged to the third generation. The melanocytes were seeded in 96-well plates, each well had 5103 cells. The medium was changed after 24 h, and contained 10?4-10?8 M DES. After the melanocytes were incubated, the proliferation and tyrosinase activity were detected by the MTT assay and L-DOPA reaction. DES (10?8-10?6 M) enhanced the proliferation of cultured melanocytes. The intensity was positively correlated with the concentration of drug. DES, >10?5 M, inhibited the melanocytes proliferation or even produced the toxicity effect. Following the addition of 10?6 M DES to the medium, the tyrosinase activity of melanocytes was significantly increased, with P<0.05. In conclusion, a certain concentration of DES promoted the proliferation of melanocytes, enhanced the activity of tyrosinase and promoted pigment synthesis of melanocytes, with the optimal concentration of 10?6 M. PMID:26171155

  1. [Immobilization of Estrogen-degrading Bacteria to Remove the 17?-estradiol and Diethylstilbestrol from Polluted Water and Cow Dung].

    PubMed

    Li, Xin; Ling, Wan-ting; Liu, Jing-xian; Sun, Min-xia; Gao, Yan-zheng; Liu, Juan

    2015-07-01

    Estradiol (E2) and diethylstilbestrol (DES) can be enriched in sewage and cow dung, posing serious threats to human and ecological health. Strain Rhodococcus sp. JX-2 and strain Serratia sp. S, which could degrade 17?-estradiol and diethylstilbestrol, respectively, were immobilized by alginate and then added into sewage and cow dung to remove E2 and DES. The immobilization was determined by orthogonal experiment, and the removal of E2 and DES from sewage and cow dung was compared between treatments of immobilized bacteria, free bacteria and control without bacteria. The influencing factors including inoculation amount, pH value, moisture content, turning time on the removal of E2 and DES were investigated. The optimal conditions of JX-2 and S immobilization were as follows: Strain JX-2: strain S (V/V) 1: 1, alginate concentration 5%, calcium chloride concentration 4%, bacteria-cement ratio 1 : 2. The immobilized strains removed 99. 42% and 84. 59% of the 2 mg.L-1 E2 and DES under laboratory conditions, respectively. The optimal conditions for E2 and DES removal from water by the immobilized strains were as follows: 300 g.L-1 inoculation volume of immobilized strains and pH 5. 0-6. 0. Immobilized bacteria could completely remove DES and remove 95. 85% of E2 from water. The optimal conditions for E2 and DES removal from cow dung by the immobilized strains were: inoculation volume 600 g.kg-1, moisture content 70% and pile turning time 12 h. The immobilized bacteria could completely remove E2 and remove 97. 41% of DES from cow dung. PMID:26489328

  2. Urogenital teratogenicity of synthetic and natural estrogens in the rat: diethylstilbestrol and estradiol

    SciTech Connect

    Henry, E.C.

    1984-01-01

    Diethylstilbestrol (DES), a synthetic estrogen and a carcinogen, is a potent urogenital teratogen in humans and rodents. The natural estrogen, estradiol (E/sub 2/), induces malformations in rats only at a maternal toxic dose. This difference in potency could result from differences in fetal sensitivity, or in the distribution and/or metabolism of the two compounds. The current studies tested the hypothesis that the teratogenicity of DES is mediated by its estrogenic activity (rather than its metabolic activation). The two estrogens were directly compared by injecting them into day 19 fetuses, bypassing any maternal modifying factors. Both DES (0.1, 1 or 10 ..mu..g/fetus) and E/sub 2/ (10 or 100 ..mu..g/fetus) caused dose-related incidences of urogenital malformations (diagnosed at 6-7 weeks), but DES was 10- to 100-fold more potent. Between 24 h and 9 days after DES or E/sub 2/ exposure, histologic evidence of estrogenic stimulation was observed, including premature myometrial growth and differentiation, and vaginal epithelial thickening. Thus, DES and E/sub 2/ act directly in the fetus, to produce similar teratogenic effects, without maternal mediation. Following both maternal and fetal administration of /sup 14/C-DES or /sup 3/H-E/sub 2/, the /sup 14/C (from DES) was concentrated in fetal tissues, whereas /sup 3/H (from E/sub 2/) was retained in fetal plasma (protein-bound). Fetal genital tract contained the largest proportion of unchanged E/sub 2/ (74%) or DES (86%). It was concluded that (1) the teratogenicity of DES reflects its estrogenic activity in the fetus; (2) the fetus is sensitive to a brief exposure to estrogens, including LY and (3) the synthetic estrogen is more potent that estradiol because of its greater availability to fetal genital tissues: protein binding and rapid metabolism reduce the teratogenicity of the natural estrogen.

  3. Determination of diethylstilbestrol in seawater by molecularly imprinted solid-phase extraction coupled with high-performance liquid chromatography.

    PubMed

    He, Xiuping; Mei, Xiaoqi; Wang, Jiangtao; Lian, Ziru; Tan, Liju; Wu, Wei

    2016-01-15

    An effective and highly selective molecularly imprinted material was prepared by suspension polymerization for the isolation and pre-concentration of synthetic estrogen diethylstilbestrol (DES) in seawater. The obtained MIPMs were proved to have more uniform size and porous structure, with maximum adsorption capacity of 8.43mgg(-1) almost two times more than NIPMs (4.43mgg(-1)). The MIPMs showed no significant deterioration of the adsorption capacity after five rounds of regeneration. An off-line molecularly imprinted solid phase extraction (MISPE) method followed by HPLC-DAD was proposed for the detection of DES in seawater, and recoveries were satisfactorily higher than 77%. Four seawater samples in aquaculture area were analyzed and 0.61ngmL(-1) DES was detected in one sample. The result demonstrated that this method can be used for the rapid separation and clean up of trace residual of DES in seawater. PMID:26646976

  4. Diethylstilbestrol, teratogenesis, and carcinogenesis: medical/legal implications of its long-term sequelae, including third generation effects.

    PubMed

    Lynch, H T; Quinn, T; Severin, M J

    1990-01-01

    The spectrum of teratogenic and carcinogenic effects which can be exerted when the unborn child is exposed to diethylstilbestrol (DES) has been shown to be broad. Animal work indicates the need for vigilance as regards genetic susceptibility to DES sequelae. The emergence of third generation sequelae has been demonstrated in mice, and has been postulated to occur in humans. Given the emergent data establishing problems of infertility in men and women and of relatively late onset cancer, and the possibility that in utero exposure to DES may prime a variety of tissues to noxious environmental influences there is an urgent need for measures to provide just coverage for those harmed by the drug. The DES disaster also raises important ethical and reserch questions which demand attention. PMID:23511655

  5. Waterborne exposure of zebrafish embryos to micromole concentrations of ioxynil and diethylstilbestrol disrupts thyrocyte development.

    PubMed

    Campinho, M A; Power, D M

    2013-09-15

    The herbicide ioxynil (IOX) and synthetic estrogen diethylstilbestrol (DES) are common aquatic contaminants with an endocrine disrupting action. In juvenile teleost fish IOX and DES disrupt the hypothalamic-pituitary-thyroid (HPT) axis. To assess how IOX and DES influence the developing HPT axis prior to establishment of central regulation of thyroid hormones, zebrafish embryos were exposed to low concentrations of the chemicals in water. IOX and DES (1 and 0.1 μM) exposure failed to modify hypothalamic development but had a negative effect on thyrocyte development. Specifically, IOX and DES caused a significant (p<0.05) reduction in the size of the thyroid anlagen by decreasing the mRNA expression field of both nk2.1a and thyroglobulin (Tg) genes. Inhibition of thyroid gland development by IOX and DES (0.1 μM) was strongly associated with altered heart morphology. To test if the effect of IOX and DES on the thyroid was a consequence of altered cardiac development a morpholino (MO) against zebrafish cardiac troponin I (zcTnI) was microinjected. The zcTnI morphants had modified heart function, a small thyroid anlagen and a reduction in the mRNA expression of nk2.1a and Tg genes similar to that of zebrafish exposed to IOX (1 and 0.1 μM) and DES (0.1 μM). Collectively the data indicate that IOX and DES alter thyroid development in zebrafish and chemicals that alter heart development and function can have an indirect endocrine disrupting action on the thyroid in teleosts. PMID:23851054

  6. Diethylstilbestrol-induced cervical and vaginal adenosis using the neonatal mouse model.

    PubMed

    Prahalada, S; Castracane, V D; Hendrickx, A G; Goldzieher, J W

    1988-05-01

    The relevance of diethylstilbestrol (DES) administration to neonatal mice as a model for human pathology attributed to the use of DES in high-risk pregnancies has been investigated, particularly with respect to cervical and vaginal changes in female offspring. Neonatal DES treatment of mice results in tonic pituitary gonadotropin release and continuous estrogen secretion by the ovary. Studies were designed to determine the effect of this altered ovarian endocrine activity on cervical and vaginal histopathology. Ovariectomy of DES-treated mice, with or without estradiol replacement, did not eliminate the lesions, nor did estrogen and progesterone administered in a regimen intended to mimic estrous cycle changes. Induction of the constant estrus state by neonatal estradiol benzoate or testosterone propionate administration or by exposure to constant light did not produce the type of vaginal or cervical changes seen in DES mice. Thus, altered ovarian function is apparently not required for the vaginal and cervical changes appearing in later life. A role for endogenous (or exogenous) ovarian hormones in the developmental progression toward normality is suggested. PMID:3401547

  7. Hormonal imprinting by steroids: a single neonatal treatment with diethylstilbestrol or allylestrenol gives rise to a lasting decrease in the number of rat uterine receptors.

    PubMed

    Csaba, G; Inczefi-Gonda, A; Dobozy, O

    1986-01-01

    Binding of hormone by the uterine receptors of 6 week old rats treated with diethylstilbestrol (DES) or allylestrenol (AE) in neonatal age differed considerably from the controls. Both pretreatments accounted for a decrease in the number of Type II binding sites for estradiol without altering receptor affinity. It follows that steroids, too, are able to induce a hormonal imprinting during the critical stage of receptor maturation. PMID:3739744

  8. Experimental electron density studies of non-steroidal synthetic estrogens: Diethylstilbestrol and dienestrol

    NASA Astrophysics Data System (ADS)

    Yearley, Eric J.; Zhurova, Elizabeth A.; Zhurov, Vladimir V.; Alan Pinkerton, A.

    2008-11-01

    An experimental charge density analysis has been carried out on two synthetic estrogens, diethylstilbestrol (DES) and dienestrol (DNS), to further investigate the alignment and binding of estrogenic compounds to the estrogen receptor, and to also establish a relationship between the biological function and the electronic properties of steroidal and non-steroidal estrogens by analysis of their electron density distribution. X-ray diffraction data for DES and DNS were obtained using a Rigaku R-Axis Rapid high-power rotating anode diffractometer with a curved image plate detector at 20(1) K. The total electron density was modeled using the Hansen-Coppens multipole model. Relatively strong OH sbnd O hydrogen bonds, weak OH sbnd C hydrogen bonds, and a number of intermolecular HH interactions were characterized from the topological analyses of the total electron density of DES and DNS. Mapping of the electrostatic potential onto the molecular surface revealed negative regions around all the hydroxyl oxygens, above and below the aromatic rings as expected from previous studies. A proposed alignment and binding of DES and DNS to the estrogen receptor is discussed in terms of the atomic charges and electrostatic potential derived from the electron density distribution.

  9. In utero exposure to the oestrogen mimic diethylstilbestrol disrupts gonadal development in a viviparous reptile.

    PubMed

    Parsley, Laura M; Wapstra, Erik; Jones, Susan M

    2014-04-10

    The ubiquitous presence of endocrine-disrupting chemicals (EDCs) in the environment is of major concern. Studies on oviparous reptiles have significantly advanced knowledge in this field; however, 30% of reptilian species are viviparous (live-bearing), a parity mode in which both yolk and a placenta support embryonic development, thus exposure to EDCs may occur via multiple routes. In this first study of endocrine disruption in a viviparous lizard (Niveoscincus metallicus), we aimed to identify effects of the oestrogen mimic diethylstilbestrol (DES) on gonadal development. At the initiation of sexual differentiation, pregnant N. metallicus were treated with a single dose of DES at 100 or 10gkg--1, a vehicle solvent or received no treatment. There was no dose-response effect, but the testes of male neonates born to DES-exposed mothers showed reduced organisation of seminiferous tubules and a lack of germ cells compared with those from control groups. The ovaries of female neonates born to DES-exposed mothers exhibited phenotypic abnormalities of ovarian structure, oocytes and follicles compared with controls. The results indicate that, in viviparous lizards, maternal exposure to oestrogenic EDCs during gestation may have profound consequences for offspring reproductive fitness. PMID:24718097

  10. Effect of in utero exposure to diethylstilbestrol on lumbar and femoral bone, articular cartilage, and the intervertebral disc in male and female adult mice progeny with and without swimming exercise

    PubMed Central

    2012-01-01

    Introduction Developmental exposure to estrogens has been shown to affect the musculoskeletal system. Furthermore, recent studies have shown that environmental exposure to estrogen-like compounds is much higher than originally anticipated. The aim of this study was to determine the effects of diethylstilbestrol (DES), a well-known estrogen agonist, on articular cartilage, intervertebral disc (IVD), and bone phenotype. Methods C57Bl/6 pregnant mice were dosed orally with vehicle (peanut oil) or 0.1, 1.0, and 10 ?g/kg/day of DES on gestational days 11 to 14. Male and female pups were allowed to mature without further treatment until 3 months of age, when swim and sedentary groups were formed. After euthanasia, bone mineral density (BMD), bone mineral content (BMC), bone area (BA), and trabecular bone area (TBA) of the lumbar vertebrae and femur were measured by using a PIXImus Bone Densitometer System. Intervertebral disc proteoglycan was measured with the DMMB assay. Histologic analysis of proteoglycan for IVD and articular cartilage was performed with safranin O staining, and degeneration parameters were scored. Results The lumbar BMC was significantly increased in female swimmers at both the highest and lowest dose of DES, whereas the femoral BMC was increased only at the highest. The males, conversely, showed a decreased BMC at the highest dose of DES for both lumbar and femoral bone. The female swim group had an increased BA at the highest dose of DES, whereas the male counterpart showed a decreased BA for femoral bone. The TBA showed a similar pattern. Proteoglycan analysis of lumbar IVDs showed a decrease at the lowest doses but a significant increase at the highest doses for both males and females. Histologic examination showed morphologic changes of the IVD and articular cartilage for all doses of DES. Conclusions DES significantly affected the musculoskeletal system of adult mice. Results suggest that environmental estrogen contaminants can have a detrimental effect on the developmental lumbar bone growth and mineralization in mice. Further studies measuring the impact of environmental estrogen mimics, such as bisphenol A, are then warranted. PMID:22269139

  11. Liver X receptors interfere with the deleterious effect of diethylstilbestrol on testicular physiology

    SciTech Connect

    Oumeddour, Abdelkader; Viennois, Emilie; Caira, Françoise; Decourbey, Clélia; Maqdasy, Salwan; and others

    2014-04-11

    Highlights: • Part of the neonatal effect of DES on testis needs the presence of Lxrα/β. • Some DES-induced pathways are blocked in Lxr-deficient mice. • Lxr-deficient mice analysis defines DES-target genes protected by Lxr. - Abstract: Liver X receptors LXRα (NR1H3) and LXRβ (NR1H2) are transcription factors belonging to the nuclear receptor superfamily, activated by specific oxysterols, oxidized derivatives of cholesterol. These receptors are involved in the regulation of testis physiology. Lxr-deficient mice pointed to the physiological roles of these nuclear receptors in steroid synthesis, lipid homeostasis and germ cell apoptosis and proliferation. Diethylstilbestrol (DES) is a synthetic estrogen considered as an endocrine disruptor that affects the functions of the testis. Various lines of evidences have made a clear link between estrogens, their nuclear receptors ERα (NR3A1) and ERβ (NR3A2), and Lxrα/β. As LXR activity could also be regulated by the nuclear receptor small heterodimer partner (SHP, NR0A2) and DES could act through SHP, we wondered whether LXR could be targeted by estrogen-like endocrine disruptors such as DES. For that purpose, wild-type and Lxr-deficient mice were daily treated with 0.75 μg DES from days 1 to 5 after birth. The effects of DES were investigated at 10 or 45 days of age. We demonstrated that DES induced a decrease of the body mass at 10 days only in the Lxr-deficient mice suggesting a protective effect of Lxr. We defined three categories of DES-target genes in testis: those whose accumulation is independent of Lxr; those whose accumulation is enhanced by the lack of both Lxrα/β; those whose accumulation is repressed by the absence of Lxrα/β. Lipid accumulation is also modified by neonatal DES injection. Lxr-deficient mice present different lipid profiles, demonstrating that DES could have its effects in part due to Lxrα/β. Altogether, our study shows that both nuclear receptors Lxrα and Lxrβ are not only basally important for testicular physiology but could also have a preventive effect against estrogen-like endocrine disruptors.

  12. Comparative effects of neonatal diethylstilbestrol on external genitalia development in adult males of two mouse strains with differential estrogen sensitivity

    PubMed Central

    Mahawong, Phitsanu; Sinclair, Adriane; Li, Yi; Schlomer, Bruce; Rodriguez, Esequiel; Ferretti, Max M.; Liu, Baomai; Baskin, Laurence S.; Cunha, Gerald R.

    2014-01-01

    The effect of neonatal exposure to diethylstilbestrol (DES), a potent synthetic estrogen, was examined to evaluate whether the CD-1 (estrogen insensitive, outbred) and C57 (estrogen sensitive, inbred) mouse strains differ in their response to estrogen disruption of male ExG differentiation. CD-1 and C57BL/6 litters were injected with sesame oil or DES (200 ng/g/5?l in sesame oil vehicle) every other day from birth to day 10. Animals were sacrificed at the following time points: birth, 5, 10 and 60 days postnatal. Neonatally DES-treated mice from both strains had many ExG abnormalities that included the following: (a) severe truncation of the prepuce and glans penis, (b) an abnormal urethral meatus, (c) ventral tethering of the penis, (d) reduced os penis length and glans width, (e) impaired differentiation of cartilage, (f) absence of urethral flaps, and (g) impaired differentiation of erectile bodies. Adverse effects of DES correlated with the expression of estrogen receptors within the affected tissues. While the effects of DES were similar in the more estrogen-sensitive C57BL/6 mice versus the less estrogen-sensitive CD-1 mice, the severity of DES effects was consistently greater in C57BL/6 mice. We suggest that many of the effects of DES, including the induction of hypospadias, are due to impaired growth and tissue fusion events during development. PMID:25449353

  13. In Utero Exposure to Diethylstilbestrol and Blood DNA Methylation in Women Ages 4059 Years from the Sister Study

    PubMed Central

    Harlid, Sophia; Xu, Zongli; Panduri, Vijayalakshmi; DAloisio, Aimee A.; DeRoo, Lisa A.; Sandler, Dale P.; Taylor, Jack A.

    2015-01-01

    In utero exposure to diethylstilbestrol (DES) has been associated with increased risk of adverse health outcomes such as fertility problems and vaginal as well as breast cancer. Animal studies have linked prenatal DES exposure to lasting DNA methylation changes. We investigated genome-wide DNA methylation and in utero DES exposure in a sample of non-Hispanic white women aged 4059 years from the Sister Study, a large United States cohort study of women with a family history of breast cancer. Using questionnaire information from women and their mothers, we selected 100 women whose mothers reported taking DES while pregnant and 100 control women whose mothers had not taken DES. DNA methylation in blood was measured at 485,577 CpG sites using the Illumina HumanMethylation450 BeadChip. Associations between CpG methylation and DES exposure status were analyzed using robust linear regression with adjustment for blood cell composition and multiple comparisons. Although four CpGs had p<105, after accounting for multiple comparisons using the false discovery rate (FDR), none reached genome-wide significance. In conclusion, adult women exposed to DES in utero had no evidence of large persistent changes in blood DNA methylation. PMID:25751399

  14. Comparative effects of neonatal diethylstilbestrol on external genitalia development in adult males of two mouse strains with differential estrogen sensitivity.

    PubMed

    Mahawong, Phitsanu; Sinclair, Adriane; Li, Yi; Schlomer, Bruce; Rodriguez, Esequiel; Ferretti, Max M; Liu, Baomai; Baskin, Laurence S; Cunha, Gerald R

    2014-01-01

    The effect of neonatal exposure to diethylstilbestrol (DES), a potent synthetic estrogen, was examined to evaluate whether the CD-1 (estrogen insensitive, outbred) and C57 (estrogen sensitive, inbred) mouse strains differ in their response to estrogen disruption of male ExG differentiation. CD-1 and C57BL/6 litters were injected with sesame oil or DES (200 ng/g/5 ?l in sesame oil vehicle) every other day from birth to day 10. Animals were sacrificed at the following time points: birth, 5, 10 and 60 days postnatal. Neonatally DES-treated mice from both strains had many ExG abnormalities that included the following: (a) severe truncation of the prepuce and glans penis, (b) an abnormal urethral meatus, (c) ventral tethering of the penis, (d) reduced os penis length and glans width, (e) impaired differentiation of cartilage, (f) absence of urethral flaps, and (g) impaired differentiation of erectile bodies. Adverse effects of DES correlated with the expression of estrogen receptors within the affected tissues. While the effects of DES were similar in the more estrogen-sensitive C57BL/6 mice versus the less estrogen-sensitive CD-1 mice, the severity of DES effects was consistently greater in C57BL/6 mice. We suggest that many of the effects of DES, including the induction of hypospadias, are due to impaired growth and tissue fusion events during development. PMID:25449353

  15. Mechanism of metabolic activation and DNA adduct formation by the human carcinogen diethylstilbestrol: The defining link to natural estrogens

    PubMed Central

    Saeed, Muhammad; Rogan, Eleanor

    2009-01-01

    Diethylstilbestrol (DES) is a human carcinogen, based on sufficient epidemiological evidence. DES is mainly metabolized to its catechol, 3?-hydroxyDES (3?-OH-DES), which can further oxidize to DES-3?,4?-quinone (DES-3?,4?-Q). Similarly to estradiol-3,4-quinone, the reaction of DES-3?,4?-Q with DNA would form the depurinating 3?-OH-DES-6?-N3Ade and 3?-OH-DES-6?-N7Gua adducts. To prove this hypothesis, synthesis of DES-3?,4?-Q by oxidation of 3?-OH-DES with Ag2O was tried; this failed due to instantaneous formation of a spiro-quinone. Oxidation of 3?-OH-DES by lactoperoxidase or tyrosinase in the presence of DNA led to the formation of 3?-OH-DES-6?-N3Ade and 3?-OH-DES-6?-N7Gua adducts. These adducts were tentatively identified by LC-MS/MS as 3?-OH-DES-6?-N3Ade, m/z = 418 [M+H]+, and 3?-OH-DES-6?-N7Gua, m/z = 434 [M+H]+. Demonstration of their structures derived from their oxidation by MnO2 to the DES quinone adducts and subsequent tautomerization to the dienestrol (DIES) catechol adducts, which are identical to the standard 3?-OH-DIES-6?-N3Ade, m/z = 416 [M+H]+, and 3?-OH-DIES-6?-N7Gua, m/z = 432 [M+H]+, adducts. The reaction of DIES-3?,4?-Q or lactoperoxidase-activated 3?-OH-DIES with DNA did not produce any depurinating adducts, due to the dienic chain being perpendicular to the phenyl planes, which impedes the intercalation of DIES into the DNA. Enzymic oxidation of 3?-OH-DES suggests that the catechol of DES intercalates into DNA and is then oxidized to its quinone to yield N3Ade and N7Gua adducts. These results suggest that the common denominator of tumor initiation by the synthetic estrogen DES and the natural estrogen estradiol is formation of their catechol quinones, which react with DNA to afford the depurinating N3Ade and N7Gua adducts. PMID:19089919

  16. Effect of embryonic and/or neonatal diethylstilbestrol and allylestrenol treatment on postnatal development of the chick testis.

    PubMed

    Sótonyi, P T; Csaba, G

    1987-01-01

    The synthetic steroid diethylstilbestrol (DES) and the steroid-like allylestrenol (AE) have been used for years in human medicine for the protection of pregnancy. The hazards to the fetus of gestational DES treatment are well established [2, 17, 18]. Knowledge of a similar effect of AE is still fragmentary. Therefore, further studies are required of the after-effects of embryonic and perinatal AE exposure. In our earlier experiments with polypeptide hormones [4, 5, 6] we have observed that perinatal age is a critical period in the maturation of hormone receptors. In this period the presence of hormone induces the development of its specific receptors. The phenomenon is termed hormonal imprinting [4, 5, 6]. During its maturation the receptor is flexible and the presence of non-specific hormones capable of binding to it may alter its normal development Accordingly, even a single hormone injection in the perinatal period may alter the hormone-sensitivity of the target organ. PMID:3124504

  17. Maternal exposure to diethylstilbestrol during pregnancy and increased breast cancer risk in daughters

    PubMed Central

    2014-01-01

    The idea that susceptibility to breast cancer is determined not only through inherited germline mutations but also by epigenetic changes induced by alterations in hormonal environment during fetal development is gaining increasing support. Using findings obtained in human and animal studies, this review addresses the mechanisms that may explain why daughters of mothers who took synthetic estrogen diethylstilbestrol (DES) during pregnancy have two times higher breast cancer risk than women who were not exposed to it. The mechanisms likely involve epigenetic alterations, such as increased DNA methylation and modifications in histones and microRNA expression. Further, these alterations may target genes that regulate stem cells and prevent differentiation of their daughter cells. Recent findings in a preclinical model suggest that not only are women exposed to DES in utero at an increased risk of developing breast cancer, but this risk may extend to their daughters and granddaughters as well. It is critical, therefore, to determine if the increased risk is driven by epigenetic alterations in genes that increase susceptibility to breast cancer and if these alterations are reversible. PMID:25032259

  18. Disruption of the thyroid system by diethylstilbestrol and ioxynil in the sea bream (Sparus aurata).

    PubMed

    Morgado, Isabel; Campinho, Marco A; Costa, Rita; Jacinto, Rita; Power, Deborah M

    2009-05-17

    Some environmental contaminants are thought to cause disruption of the thyroid system in vertebrates acting as endocrine disrupting chemicals (EDCs). Such chemicals may affect synthesis, transport and metabolism of thyroid hormones (THs). Ioxynil (IOX) and diethylstilbestrol (DES) are potential EDCs with strong affinity in vitro for sea bream transthyretin (TTR), a TH distributor protein (THDP). The aim of the present study was to establish how such chemicals influence the thyroid axis in sea bream (Sparus aurata). DES, IOX and propilthyouracil (PTU, a goitrogen) were administered in the diet to sea bream juveniles at 1 mg/kg fish (n = 14/treatment) for 21 days. After exposure plasma TH levels, quantified by RIA, were similar to those of control fish (p > 0.05) in all treatment groups. Analysis by quantitative PCR revealed that all treatments down-regulated TSH gene transcription (p < 0.05) in the brain and pituitary and deiodinase II and III transcription in the brain (p < 0.001). In contrast, PTU caused DII up-regulation in the liver (p < 0.05). Thyroid receptor beta (TRbeta) transcription was down-regulated in the pituitary by PTU (p < 0.001) and DES (p < 0.05). TTR plasma levels, quantified by ELISA, were elevated by all the chemicals including PTU (p < 0.001) which also increased TTR gene transcription in the liver (p < 0.05). Thyroid histology indicated follicular hyperstimulation in all treatments with marked hyperplasia, hypertrophy and colloid depletion in the PTU group. It appears therefore, that in vitro TTR-binders, IOX and DES, can strongly influence several components of the fish thyroid system in vivo but that the thyroid axis may have the ability to maintain or re-establish plasma TH homeostasis. PMID:19375178

  19. The effects of diethylstilbestrol and medroxyprogesterone acetate on kinetics and production of testosterone and dihydrotestosterone in patients with prostatic carcinoma.

    PubMed

    Nolten, W E; Sholiton, L J; Srivastava, L S; Knowles, H C; Werk, E E

    1976-12-01

    Alterations in the metabolism of testosterone (T) and dihydrotestosterone (DHT) induced by diethylstilbestrol (DES) or medroxprogesterone acetate (MPA) could account for the beneficial therapeutic effect of these agents in prostatic carcinoma. To investigate this possibility we sutdied plasma kinetics of T and DHT in 17 elderly patients with prostatic carcinoma, before and after treatment with DES (1 or 5 mg/d) or MPA (10 or 30 mg/d) for 30 days. Metabolic clearance rates (MCR) were determined with the single injection technique and by use of two compartment model, plasma concentrations (PC) of T and DHT by radioimmunoassay, the per cent of T bound to plasma protein (T-binding) by charcoal adsorption of the unbound steroid. Production rate (PR) and PC of T were lower, PR and PC of DHT were higher in our patients than in normal men. With both DES regimens, PR, PC and MCR of either androgen declined; however, T was suppressed to a much greater extent than DHT. In either instance, the decrease may have been caused by direct suppression of testicular androgen synthesis and/or by decreased gonadotropin stimulation. Enhanced T-binding played an additional role in reducing the free testosterone index. High and low dose of DES were equally effective. The low dose regimen of MPA did not influence androgen metabolism. MPA in the higher dose suppressed PR and PC of T and DHT, possibly due to effects on testicular synthesis or by gonadotropin suppression as suggested for DES. In contrast to DES, MPA failed to cause profound changes in MCR of either androgen or in T-binding. When judged by its influence on the metabolism of T and DHT in prostatic carcinoma, MPA in higher doses is much less effective than either dose regimen of DES. PMID:1002814

  20. Diethylstilbestrol at environmental levels affects the development of early life stage and target gene expression in Japanese Medaka (Oryzias latipes).

    PubMed

    Lei, Bingli; Peng, Wei; Li, Wei; Yu, Yingxin; Xu, Jie; Wang, Yipei

    2016-04-01

    In this study, the biologic effects of DES on the early life and adult life stages of Japanese medaka (Oryzias latipes) were evaluated. At the early life stage, the fertilized eggs were exposed to 1-1000 ng/L diethylstilbestrol (DES) for 15 days and the hatched larvae were continually exposed to the same concentrations for an additional 25 days. Significant adverse effects on hatchability, time to hatching and mortality rate occurred at DES concentrations of 100 and 1000 ng/L, while the abnormality (scoliosis and abdominal swelling) rate was significantly increased at 10 ng/L and above. After exposure, the fish were maintained in charcoal-dechlorinated tap water for a further 30 days. Only the male gonadosomatic index (GSI) at 1000 ng/L was significantly increased. At concentrations greater than 1 ng/L, estrogen receptor α (ERα) mRNA in both sexes and vitellogenin-I (Vtg-I) mRNA in males were significantly down-regulated; while Vtg-I mRNA in females was significantly up-regulated. When sexually mature medaka were exposed to 10 and 1000 ng/L DES for 21 days, only the GSI in females was significantly decreased at 1000 ng/L. At 10 and 1000 ng/L, ERα mRNA in both sexes was significantly down-regulated, while Vtg-I mRNA in males was significantly up-regulated. These findings showed that DES at the environmental concentration of 10 ng/L can affect the early life stage development of medaka and alter liver ERα and Vtg-I gene expression. Therefore, if we only focused on these sensitive toxicity endpoints such as ERα and Vtg-I mRNA expression, DES has a strong estrogenic effect on Japanese medaka. PMID:26908245

  1. Gestational exposure to diethylstilbestrol alters cardiac structure/function, protein expression and DNA methylation in adult male mice progeny

    SciTech Connect

    Haddad, Rami; Division of Experimental Medicine, Department of Medicine, McGill University, 850 Sherbrooke Street, Montréal, Québec, Canada H3A 1A2 ; Kasneci, Amanda; Mepham, Kathryn; Division of Experimental Medicine, Department of Medicine, McGill University, 850 Sherbrooke Street, Montréal, Québec, Canada H3A 1A2 ; Sebag, Igal A.; and others

    2013-01-01

    Pregnant women, and thus their fetuses, are exposed to many endocrine disruptor compounds (EDCs). Fetal cardiomyocytes express sex hormone receptors making them potentially susceptible to re-programming by estrogenizing EDCs. Diethylstilbestrol (DES) is a proto-typical, non-steroidal estrogen. We hypothesized that changes in adult cardiac structure/function after gestational exposure to the test compound DES would be a proof in principle for the possibility of estrogenizing environmental EDCs to also alter the fetal heart. Vehicle (peanut oil) or DES (0.1, 1.0 and 10.0 μg/kg/da.) was orally delivered to pregnant C57bl/6n dams on gestation days 11.5–14.5. At 3 months, male progeny were left sedentary or were swim trained for 4 weeks. Echocardiography of isoflurane anesthetized mice revealed similar cardiac structure/function in all sedentary mice, but evidence of systolic dysfunction and increased diastolic relaxation after swim training at higher DES doses. The calcium homeostasis proteins, SERCA2a, phospholamban, phospho-serine 16 phospholamban and calsequestrin 2, are important for cardiac contraction and relaxation. Immunoblot analyses of ventricle homogenates showed increased expression of SERCA2a and calsequestrin 2 in DES mice and greater molecular remodeling of these proteins and phospho-serine 16 phospholamban in swim trained DES mice. DES increased cardiac DNA methyltransferase 3a expression and DNA methylation in the CpG island within the calsequestrin 2 promoter in heart. Thus, gestational DES epigenetically altered ventricular DNA, altered cardiac function and expression, and reduced the ability of adult progeny to cardiac remodel when physically challenged. We conclude that gestational exposure to estrogenizing EDCs may impact cardiac structure/function in adult males. -- Highlights: ► Gestational DES changes cardiac SERCA2a and CASQ2 expression. ► Echocardiography identified systolic dysfunction and increased diastolic relaxation. ► DES increased DNMT3a expression and increased CpG DNA methylation. ► DES impacts fetal heart reducing cardiac reserve on challenge in adulthood. ► Fetal heart can be re-programmed by a non-steroidal estrogen.

  2. Inhibition of XO or NOX attenuates diethylstilbestrol-induced endothelial nitric oxide deficiency without affecting its effects on LNCaP cell invasion and apoptosis.

    PubMed

    Youn, Ji-Youn; Nguyen, Andrew; Cai, Hua

    2012-10-01

    Oestrogen protects cardiovascular health partially via an up-regulation of NO (NO radical) production. Its synthetic analogue DES (diethylstilbestrol), used as a potent androgen deprivation therapy for patients with prostate cancer, is however associated with high incidence of thromboembolic events. Exposure of BAECs (bovine aortic endothelial cells) to pharmacologically relevant dosage (12.5 ?mol/l, 24 h) of DES resulted in a marked reduction in endothelial NO bioavailability determined by ESR (electron spin resonance), while 17?-oestradiol instead increased NO production as expected. Intriguingly, endothelial O(2)- (superoxide anion) production was up-regulated by DES in vitro and in vivo, which was, however, attenuated by the ER (oestrogen receptor) antagonist ICI 182780, the XO (xanthine oxidase) inhibitor oxypurinol or the NOX (NADPH oxidase) inhibitor NSC23766. These agents also restored NO production. DES alone in a cell-free system did not produce any ESR-sound O(2)- signal. Of note, eNOS (endothelial NO synthase) mRNA and protein remained unchanged in response to DES. These results suggest that receptor-dependent activation of XO or NOX, and subsequent production of O(2)-, mediate DES-induced NO deficiency. This could represent a previously unrecognized mechanism that is responsible for cardiovascular complications of DES administration. Importantly, DES-induced suppression of LNCaP cell invasion and apoptosis were not affected by XO or NOX inhibitor. Therefore combinatorial therapy of DES and XO/NOX inhibitor may prove to be an innovative and useful therapeutic option in eliminating cardiovascular complications of DES, while preserving its anti-cancer effects, benefiting patients with advanced cancer who do not respond well to any other treatments but DES. PMID:22568671

  3. Effect of perinatal synthetic steroid hormone (allylestrenol, diethylstilbestrol) treatment (hormonal imprinting) on the bone mineralization of the adult male and female rat.

    PubMed

    Karabélyos, C; Horváth, C; Holló, I; Csaba, G

    1999-01-01

    Neonatal treatment with allylestrenol or diethylstilbestrol (DES) reduced the bone mineral content (BMC/bw) of the adult (four months old) female rats, without influencing bone mineral density (BMD/bw). In males these neonatal treatments elevated BMC and BMD alike. Ovariectomy alone decreased BMC and BMD alike; however the neonatal hormone treatments did not influence this reduced value. Ovariectomy of two months old animals increased body weight without the influence of neonatal hormone treatments. In adult males, the body weight was reduced significantly by neonatal DES and non-significantly by neonatal allylestrenol treatment. The experiments call attention to the possible human bone-effects of allylestrenol, which was used in the last decades as medication protecting endangered pregnancies. PMID:10075115

  4. Prenatal diethylstilbestrol induces malformation of the external genitalia of male and female mice and persistent second-generation developmental abnormalities of the external genitalia in two mouse strains

    PubMed Central

    Mahawong, Phitsanu; Sinclair, Adriane; Li, Yi; Schlomer, Bruce; Rodriguez, Esequiel; Max, Ferretti M.; Liu, Baomei; Baskin, Laurence S.; Cunha, Gerald R.

    2014-01-01

    Potential trans-generational influence of diethylstilbestrol (DES) exposure emerged with reports of effects in grandchildren of DES-treated pregnant women and of reproductive tract tumors in offspring of mice exposed in utero to DES. Accordingly, we examined the trans-generational influence of DES on development of external genitalia (ExG) and compared effects of in utero DES exposure in CD-1 and C57BL/6 mice injected with oil or DES every other day from gestational days 12 to 18. Mice were examined at birth, and on 5 to 120 days postnatal to evaluate ExG malformations. Of 23 adult (≥60 days) prenatally DES-exposed males, features indicative of urethral meatal hypospadias (see text for definitions) ranged from 18 to 100% in prenatally DES-exposed CD-1 males and 31 to 100% in prenatally DES-exposed C57BL/6 males. Thus, the strains differed in the incidence of male urethral hypospadias. Ninety-one percent of DES-exposed CD-1 females and 100% of DES-exposed C57BL/6 females had urethral-vaginal fistula. All DES-exposed CD-1 and C57BL/6 females lacked an os clitoris. None of the prenatally oil-treated CD-1 and C57BL/6 male and female mice had ExG malformations. For the second-generation study, 10 adult CD-1 males and females, from oil- and DES-exposed groups, respectively, were paired with untreated CD-1 mice for 30 days, and their offspring evaluated for ExG malformations. None of the F1 DES-treated females were fertile. Nine of 10 prenatally DES-exposed CD-1 males sired offspring with untreated females, producing 55 male and 42 female pups. Of the F2 DES-lineage adult males, 20% had exposed urethral flaps, a criterion of urethral meatal hypospadias. Five of 42 (11.9%) F2 DES lineage females had urethral-vaginal fistula. In contrast, all F2 oil-lineage males and all oil-lineage females were normal. Thus, prenatal DES exposure induces malformations of ExG in both sexes and strains of mice, and certain malformations are transmitted to the second-generation. PMID:25449352

  5. Bisphenol-A and diethylstilbestrol exposure induces the expression of breast cancer associated long noncoding RNA HOTAIR in vitro and in vivo.

    PubMed

    Bhan, Arunoday; Hussain, Imran; Ansari, Khairul I; Bobzean, Samara A M; Perrotti, Linda I; Mandal, Subhrangsu S

    2014-05-01

    Antisense transcript, long non-coding RNA HOTAIR is a key player in gene silencing and breast cancer and is transcriptionally regulated by estradiol. Here, we have investigated if HOTAIR expression is misregulated by bisphenol-A (BPA) and diethylstilbestrol (DES). Our findings demonstrate BPA and DES induce HOTAIR expression in cultured human breast cancer cells (MCF7) as well as in vivo in the mammary glands of rat. Luciferase assay showed that HOTAIR promoter estrogen-response-elements (EREs) are induced by BPA and DES. Estrogen-receptors (ERs) and ER-coregulators such as MLL-histone methylases (MLL1 and MLL3) bind to the HOTAIR promoter EREs in the presence of BPA and DES, modify chromatin (histone methylation and acetylation) and lead to gene activation. Knockdown of ERs down-regulated the BPA and DES-induced expression of HOTAIR. In summary, our results demonstrate that BPA and DES exposure alters the epigenetic programming of the HOTAIR promoters leading to its endocrine disruption in vitro and in vivo. PMID:24533973

  6. G protein-coupled estrogen receptor-protein kinase A-ERK-CREB signaling pathway is involved in the regulation of mouse gubernaculum testis cells by diethylstilbestrol.

    PubMed

    Zhang, Xuan; Li, Jian-hong; Duan, Shou-xing; Lin, Qing-Jun; Ke, Song; Ma, Lian; Huang, Tian-hua; Jiang, Xue-wu

    2014-07-01

    The etiology of testicular dysgenesis syndrome is multifactorial and involves environmental factors, such as environmental estrogens. Several studies have shown that hormonal effects on the gubernaculum may affect testicular descent. Diethylstilbestrol (DES) is a nonsteroidal synthetic estrogen that disrupts the morphology and proliferation of gubernacular cells, but the underlying mechanisms remain elusive. In this study, we aimed to determine whether DES may regulate the function of gubernaculum testis cells by way of nongenomic effects mediated by G protein-coupled estrogen receptor (GPER). We used cultured mouse gubernacular testis cells to demonstrate that GPER is expressed in gubernaculum testis cells. Erk1/2 inhibitor PD98059, PKA inhibitor H89, and Src inhibitor PP2 relieved DES-induced inhibition of gubernaculum testis cell proliferation, but ER inhibitor ICI 182780 had no effects on DES-induced inhibition of gubernaculum testis cell proliferation. In addition, we found that DES induced the activation of CREB downstream of PKA, Src, and ERK1/2 in these cells. These data suggest that the effects of DES on mouse gubernaculum testis cells are mediated at least partially by GPER-protein kinase A-ERK-CREB signaling pathway. PMID:24306628

  7. Bisphenol-A and diethylstilbestrol exposure induces the expression of breast cancer associated long noncoding RNA HOTAIR in vitro and in vivo

    PubMed Central

    Bhan, Arunoday; Hussain, Imran; Ansari, Khairul I.; Bobzean, Samara A. M.; Perrotti, Linda I.; Mandal, Subhrangsu S.

    2014-01-01

    Antisense transcript, long non-coding RNA HOTAIR is a key player in gene silencing and breast cancer and is transcriptionally regulated by estradiol. Here, we have investigated if HOTAIR expression is misregulated by bisphenol-A (BPA) and diethylstilbestrol (DES). Our findings demonstrate BPA and DES induce HOTAIR expression in cultured human breast cancer cells (MCF7) as well as in vivo in the mammary glands of rat. Luciferase assay showed that HOTAIR promoter estrogen-response-elements (EREs) are induced by BPA and DES. Estrogen-receptors (ERs) and ER-coregulators such as MLL-histone methylases (MLL1 and MLL3) bind to the HOTAIR promoter EREs in the presence of BPA and DES, modify chromatin (histone methylation and acetylation) and lead to gene activation. Knockdown of ERs down-regulated the BPA and DES induced expression of HOTAIR. In summary, our results demonstrate that BPA and DES exposure alters the epigenetic programming of the HOTAIR promoters leading to its endocrine disruption in vitro and in vivo. PMID:24533973

  8. Histone methyltransferase EZH2 is transcriptionally induced by estradiol as well as estrogenic endocrine disruptors bisphenol-A and diethylstilbestrol.

    PubMed

    Bhan, Arunoday; Hussain, Imran; Ansari, Khairul I; Bobzean, Samara A M; Perrotti, Linda I; Mandal, Subhrangsu S

    2014-10-01

    Enhancer of Zeste homolog 2 (EZH2), a methyltransferase specific to histone 3 lysine 27, is a critical player in gene silencing and is overexpressed in breast cancer. Our studies demonstrate that EZH2 is transcriptionally induced by estradiol in cultured breast cancer cells and in the mammary glands of ovariectomized rats. EZH2 promoter contains multiple functional estrogen-response elements. Estrogen receptors (ERs) and ER coregulators such as mixed lineage leukemia (MLL) histone methylases (MLL2 and MLL3) and histone acetyltransferase CBP/P300 bind to the EZH2 promoter in the presence of estradiol and regulate estradiol-induced EZH2 expression. EZH2 expression is also increased upon exposure to estrogenic endocrine disrupting chemicals (EDCs) such as bisphenol-A (BPA) and diethylstilbestrol (DES). Similar to estradiol, BPA and DES-induced EZH2 expression is coordinated by ERs, MLLs and CBP/P300. In summary, we demonstrate that EZH2 is transcriptionally regulated by estradiol in vitro and in vivo, and its expression is potentially dysregulated upon exposure to estrogenic EDCs. PMID:25088689

  9. Neonatal diethylstilbestrol treatment alters aflatoxin B1-DNA adduct concentrations in adult rats.

    PubMed

    Lamartiniere, C A

    1990-01-01

    Aflatoxin B1-DNA adduct concentrations were measured in the livers of adult Sprague-Dawley CD rats treated on days 2, 4, and 6 postnatally with 1.45 mumols of diethylstilbestrol and in adulthood with phenobarbital, 3-methylcholanthrene, or vehicle prior to treatment with aflatoxin B1. Aflatoxin B1 (1 mg/kg) was injected 5 hr prior to killing the rats. Female rats exposed neonatally to diethylstilbestrol had significantly higher aflatoxin B1-DNA adduct concentrations (three- to sixfold) than adult female rats treated neonatally with propylene glycol. Liver aflatoxin B1-DNA adduct concentrations were slightly higher in control males as compared to adduct concentrations in neonatally diethylstilbestrol-treated males, as compared to adduct concentrations in control females (not significant [NS]). Phenobarbital and 3-methylcholanthrene treatment followed by aflatoxin B1 injection resulted in decreased aflatoxin B1-DNA adduct concentrations in all rats. Our results demonstrate that neonatal exposure to diethylstilbestrol alters the capacity of adult female rats to form and/or dispose of carcinogen-DNA adducts following a single dose of aflatoxin B1 (increased adduct concentration). This alteration may be a consequence of altered imprinting mechanisms with diethylstilbestrol causing developmental modifications early in life. The animals were, however, able to respond to cytochrome P-450 and P-448 inducers as evidenced by decreased aflatoxin B1-DNA adduct concentrations. PMID:2119435

  10. Comparison of Reductions in Adenosine Triphosphate Content, Plasma Membrane-associated Adenosine Triphosphatase Activity, and Potassium Absorption in Oat Roots by Diethylstilbestrol 1

    PubMed Central

    Balke, Nelson E.; Hodges, Thomas K.

    1979-01-01

    The possibility was investigated that diethylstilbestrol (DES) inhibits potassium absorption in oat (Avena sativa L. cv. Goodfield) roots by inhibiting mitochondrial functions in addition to inhibiting the plasma membrane ATPase. DES at 10−6 molar stimulated the mitochondrial ATPase slightly, but higher concentrations had no effect. Oxidative phosphorylation by isolated mitochondria was inhibited 50% by 2.6 × 10−5 molar DES; concentrations of 10−4 molar or greater were completely inhibitory. After a lag of about 2 minutes, 10−4 molar DES produced a linear decrease in ATP content of excised roots. After 20 minutes, the ATP content of the tissue was about 50% of the control and remained at that level after 30 minutes in DES. Comparison of changes in ATP content, plasma membrane ATPase activity, and K+ absorption rate with time in the presence of DES showed that the rapid decrease in K+ absorption rate corresponded more closely with the decrease in ATPase activity than the decrease in ATP content. Total inhibition of the ATPase was calculated by multiplying together the percentage decreases in ATPase activity and ATP content. At times greater than 10 minutes this “net” ATPase activity corresponded very closely with the K+ absorption rate. These results show that DES can inhibit potassium absorption by reducing mitochondrial ATP production in addition to inhibiting the plasma membrane ATPase. However, the rapid (less than 5 minutes) inhibition of absorption is caused by direct inhibition of the ATPase rather than a reduced ATP supply because the ATP content is lowered only slightly whereas the ATPase is inhibited dramatically in that time. The relationship between plasma membrane ATPase activity and K+ absorption rate as inhibited by DES supports the hypothesis that the ATPase is involved in cation absorption by plant roots. PMID:16660692

  11. Diethylstilbestrol alters positive and negative selection of T cells in the thymus and modulates T-cell repertoire in the periphery

    SciTech Connect

    Brown, Nicole; Nagarkatti, Mitzi; Nagarkatti, Prakash S. . E-mail: pnagark@hsc.vcu.edu

    2006-04-15

    Prenatal exposure to diethylstilbestrol (DES) is known to cause altered immune functions and increased susceptibility to autoimmune disease in humans. In the current study, we investigated the effects of DES on T-cell differentiation in the thymus using the HY-TCR transgenic (Tg) mouse model in which the female mice exhibit positive selection of T cells bearing the Tg TCR, while the male mice show negative selection of such T cells. In female HY-TCR-Tg mice, exposure to DES showed more pronounced decrease in thymic cellularity when compared to male mice. Additionally, female mice also showed a significant decrease in the proportion of double-positive (DP) T cells in the thymus and HY-TCR-specific CD8{sup +} T cells in the periphery. Male mice exhibiting negative selection also showed decreased thymic cellularity following DES exposure. Moreover, the male mice showed increased proportion of double-negative (DN) T cells in the thymus and decreased proportion of CD8{sup +} T cells. The density of expression of HY-TCR on CD8{sup +} cells was increased following DES exposure in both females and males. Finally, the proliferative response of thymocytes to mitogens and peripheral lymph node T cells to male H-Y antigen was significantly altered in female and male mice following DES treatment. Taken together, these data suggest that DES alters T-cell differentiation in the thymus by interfering with positive and negative selection processes, which in turn modulates the T-cell repertoire in the periphery.

  12. Enhanced urinary bladder and liver carcinogenesis in male CD1 mice exposed to transplacental inorganic arsenic and postnatal diethylstilbestrol or tamoxifen

    SciTech Connect

    Waalkes, Michael P. . E-mail: waalkes@niehs.nih.gov; Liu Jie; Ward, Jerrold M.; Diwan, Bhalchandra A.

    2006-09-15

    Pregnant CD1 mice received 85 ppm arsenite in the drinking water from gestation day 8 to 18, groups (n = 35) of male offspring were subsequently injected on postpartum days 1 through 5 with diethylstilbestrol (DES; 2 {mu}g/pup/day) or tamoxifen (TAM; 10 {mu}g/pup/day), and tumor formation was assessed over 90 weeks. Arsenic alone increased hepatocellular carcinoma (14%), adenoma (23%) and total tumors (31%) compared to control (0, 2 and 2%, respectively). Arsenic alone also increased lung adenocarcinoma, adrenal cortical adenoma and renal cystic tubular hyperplasia compared to control. Compared to arsenic alone, arsenic plus DES increased liver tumor incidence in mice at risk 2.2-fold and increased liver tumor multiplicity (tumors/liver) 1.8-fold. The treatments alone did not impact urinary bladder carcinogenesis, but arsenic plus TAM significantly increased formation of urinary bladder transitional cell tumors (papilloma and carcinoma; 13%) compared to control (0%). Urinary bladder proliferative lesions (combined tumors and hyperplasia) were also increased by arsenic plus TAM (40%) or arsenic plus DES (43%) compared to control (0%) or the treatments alone. Urinary bladder proliferative lesions occurred in the absence of any evidence of uroepithelial cytotoxic lesions. Urinary bladder lesions and hepatocellular carcinoma induced by arsenic plus TAM and/or DES overexpressed estrogen receptor-{alpha}, indicating that aberrant estrogen signaling may have been a factor in the enhanced carcinogenic response. Thus, in male CD1 mice, gestational arsenic exposure alone induced liver adenoma and carcinoma, lung adenocarcinoma, adrenal adenoma and renal cystic hyperplasia. Furthermore, DES enhanced transplacental arsenic-induced hepatocarcinogenesis. In utero arsenic also initiated urinary bladder tumor formation when followed by postnatal TAM and uroepithelial proliferative lesions when followed by TAM or DES.

  13. Altered Gene Expression Patterns During the Initiation and Promotion Stages of Neonatally Diethylstilbestrol-Induced Hyperplasia/Dysplasia/Neoplasia in the Hamster Uterus

    PubMed Central

    Hendry, William J.; Hariri, Hussam Y.; Alwis, Imala D.; Gunewardena, Sumedha S.; Hendry, Isabel R.

    2014-01-01

    Neonatal treatment of hamsters with diethylstilbestrol (DES) induces uterine hyperplasia/dysplasia/neoplasia (endometrial adenocarcinoma) in adult animals. We subsequently determined that the neonatal DES exposure event directly and permanently disrupts the developing hamster uterus (initiation stage) so that it responds abnormally when it is stimulated with estrogen in adulthood (promotion stage). To identify candidate molecular elements involved in progression of the disruption/neoplastic process, we performed: 1) immunoblot analyses and 2) microarray profiling (Affymetrix Gene Chip System) on sets of uterine protein and RNA extracts, respectively, and 3) immunohistochemical analysis on uterine sections; all from both initiation stage and promotion stage groups of animals. Here we report that: 1) progression of the neonatal DES-induced hyperplasia/dysplasia/neoplasia phenomenon in the hamster uterus involves a wide spectrum of specific gene expression alterations and 2) the gene products involved and their manner of altered expression differ dramatically during the initiation vs. promotion stages of the phenomenon. Particularly interesting changes included members in the functional categories of nuclear receptors (progesterone receptor), cell-cell interactions (E-cadherin, connexins), cytokine action (IRF-1, Stat5A), growth factor action (IRS-1), extracellular matrix component (tenascin-C), transcription factors (Nrf2, Sp1), and multi-functional nuclear protein (SAFB1). PMID:25242112

  14. Free histones in the cells of the rat uterus after neonatal treatment with diethylstilbestrol or allylestrenol.

    PubMed

    Sótonyi, P T; Csaba, G; Treit, P

    1986-01-01

    Neonatal diethylstilbestrol and allylestrenol treatments resulted in a prompt release of free histones that could be demonstrated histochemically by the phosphomolybdic-acid-benzidine reaction. This effect could not be observed in the uterus of 6-10-week old rats but reappeared between 11-14 weeks in the myometrium and uterine epithelium without any repeated treatment. This may be due to the increased production of endogenous steroids. The finding suggest caution when applying steroids to pregnants and neonates. PMID:3105260

  15. Towards functional glycomics by localization of binding sites for tissue lectins: lectin histochemical reactivity for galectins during diethylstilbestrol-induced kidney tumorigenesis in male Syrian hamster.

    PubMed

    Saussez, Sven; Lorfevre, Francois; Nonclercq, Denis; Laurent, Guy; Andr, Sabine; Journ, Fabrice; Kiss, Robert; Toubeau, Grard; Gabius, Hans-Joachim

    2006-07-01

    Endogenous lectins act as effectors of cellular activities such as growth regulation, migration, and adhesion. Following their immunohistochemical localization in our previous study (Saussez et al. in Histochem Cell Biol 123:29-41, 2005) we purified several galectins and used them as tools for monitoring accessible binding sites. Herein, we report the use of galectin histochemistry for the analysis of diethylstilbestrol (DES)-induced renal tumors in male Syrian hamster kidney (SHKT). Sections of normal kidney and DES-treated kidney were analyzed with biotinylated galectins-1, -3 (full-length and truncated), and -7. Accessible binding sites were detected, localization was predominantly extracellular and confined to medium-sized and large tumors. Monitoring the SHKT-derived HKT-1097 line, processed in vitro or as xenograft material, cytoplasmic and nuclear staining for galectins-1, -3, and -3tr could be observed. Adaptation of SHKT cells to long-term growth in culture is thus associated with emergence of this signal. Our data set illustrates the feasibility to complement immunohistochemical data by application of the tissue lectins as probes, and to detect regulation of galectin reactivity with differential characteristics within tumor progression in vivo and unique features of the tumor cell line in vitro and in vivo. PMID:16435123

  16. In vitro effects of diethylstilbestrol, genistein, 4-tert-butylphenol, and 4-tert-octylphenol on steroidogenic activity of isolated immature rat ovarian follicles

    SciTech Connect

    Myllymaeki, Sari . E-mail: saanmy@utu.fi; Haavisto, Tapio; Vainio, Minna; Toppari, Jorma; Paranko, Jorma

    2005-04-01

    Isolated rat ovarian follicles grow and produce steroid hormones in vitro and so provide a good model for studying the effects of hormonally active compounds on follicular steroidogenesis. We have evaluated the effects of diethylstilbestrol (DES), genistein (GEN) and two alkylphenols, 4-tert-butylphenol (BP) and 4-tert-octylphenol (OP) on the growth, survival, and steroid hormone and cAMP production by isolated 14-day-old rat (Sprague-Dawley) ovarian follicles. During a 5-day culture, FSH was obligatory for follicle growth and increased estradiol and testosterone secretion in a dose-dependent manner. DES (10{sup -6} M) caused the strongest decline in estradiol and testosterone levels but did not have detectable effects on either cAMP production or aromatase enzyme activity. GEN caused a prominent decrease in cAMP and testosterone levels without significant changes in secreted estradiol. The latter, apparently, was due to a dose-dependent stimulation of aromatase enzyme activity in the presence of genistein. Both BP and OP decreased estradiol and testosterone secretion in a dose-dependent manner while no effect on aromatase activity was observed. OP, unlike BP, decreased forskolin-induced cAMP levels. Xenoestrogens at the used concentrations did not interfere with the growth and survival of the follicles. The results indicate that isolated ovarian follicles representing intact morphological and functional units offer a sensitive model system for elucidating the female-specific reproductive effects of environmental chemicals.

  17. Prenatal Exposure of Mice to Diethylstilbestrol Disrupts T-Cell Differentiation by Regulating Fas/Fas Ligand Expression through Estrogen Receptor Element and Nuclear Factor-κB Motifs

    PubMed Central

    Singh, Narendra P.; Singh, Udai P.; Nagarkatti, Prakash S.

    2012-01-01

    Prenatal exposure to diethylstilbestrol (DES) is known to cause altered immune functions and increased susceptibility to autoimmune disease in humans. In the current study, we investigated the effect of prenatal exposure to DES on thymocyte differentiation involving apoptotic pathways. Prenatal DES exposure caused thymic atrophy, apoptosis, and up-regulation of Fas and Fas ligand (FasL) expression in thymocytes. To examine the mechanism underlying DES-mediated regulation of Fas and FasL, we performed luciferase assays using T cells transfected with luciferase reporter constructs containing full-length Fas or FasL promoters. There was significant luciferase induction in the presence of Fas or FasL promoters after DES exposure. Further analysis demonstrated the presence of several cis-regulatory motifs on both Fas and FasL promoters. When DES-induced transcription factors were analyzed, estrogen receptor element (ERE), nuclear factor κB (NF-κB), nuclear factor of activated T cells (NF-AT), and activator protein-1 motifs on the Fas promoter, as well as ERE, NF-κB, and NF-AT motifs on the FasL promoter, showed binding affinity with the transcription factors. Electrophoretic mobility-shift assays were performed to verify the binding affinity of cis-regulatory motifs of Fas or FasL promoters with transcription factors. There was shift in mobility of probes (ERE or NF-κB2) of both Fas and FasL in the presence of nuclear proteins from DES-treated cells, and the shift was specific to DES because these probes failed to shift their mobility in the presence of nuclear proteins from vehicle-treated cells. Together, the current study demonstrates that prenatal exposure to DES triggers significant alterations in apoptotic molecules expressed on thymocytes, which may affect T-cell differentiation and cause long-term effects on the immune functions. PMID:22888145

  18. The effect of neonatal exposure to diethylstilbestrol, genistein, and zearalenone on pituitary responsiveness and sexually dimorphic nucleus volume in the castrated adult rat.

    PubMed

    Faber, K A; Hughes, C L

    1991-10-01

    The neonatal hormone environment determines the sexually differentiated pattern of brain growth. Estrogens, derived from intracerebral aromatization of testosterone, promote male sexual central nervous system (CNS) development. Developing animals may also encounter estrogens from plant, fungal, and xenobiotic sources (environmental estrogens). The purpose of this study was to assess the effects of environmental estrogens on the physiology and morphology of the hypothalamus and pituitary. Neonatal rats received injections of either corn oil, 0.1 microgram diethylstilbestrol (DES), 100 micrograms genistein (G100), 1000 micrograms genistein (G1000), 100 micrograms zearalenone (Z100), or 1000 micrograms zearalenone (Z1000) on Days 1-10 of life and were castrated on Day 21. On Day 42, right heart catheters were placed, GnRH (50 ng/kg) was administered, and blood was sampled for LH at 0, 5, 10, 15, and 30 min. Females exposed neonatally to DES, G1000, Z100, and Z1000 showed significantly decreased pituitary responsiveness to GnRH, whereas G100 increased GnRH-induced LH secretion. Males exposed neonatally to G100 also showed increased pituitary response to GnRH, and the remaining estrogen-exposed groups of males exhibited either decreased tonic LH or attenuated GnRH-stimulated LH secretion. The animals were killed by decapitation on Day 49. Volumes of the sexually dimorphic nucleus of the preoptic area (SDN-POA) of the exposed groups were compared. In females, DES, G1000, and Z1000 increased SDN volume; Z100 and G100 had no effect. There was no difference in SDN size among the male groups. These data show that exposure to environmental estrogens early in development alters postpubertal pituitary response to GnRH and "androgenizes" the SDN-POA. PMID:1836392

  19. Lack of effects for low dose levels of bisphenol A and diethylstilbestrol on the prostate gland of CF1 mice exposed in utero.

    PubMed

    Ashby, J; Tinwell, H; Haseman, J

    1999-10-01

    vom Saal et al. (Proc. Natl. Acad. Sci. 94, 2056-2061, 1997) have reported that low dose exposure (0.02-2 microg/kg/day) of CF1 mice to diethylstilbestrol (DES) in utero led to increases in the prostate gland weight when the pups reached 8 months of age. Nagel et al. (Environ. Health Perspect. 105, 70-76, 1997) reported similar effects in CF1 mice at 6 months of age after exposure in utero to low dose levels (2 and 20 microg/kg/day) of bisphenol A (BPA). vom Saal et al. (Toxicol. Indust. Health 14(1/2) 239-260, 1998) subsequently reported reduced sperm efficiency (daily sperm production per gram testes) in a subset of the BPA animals for which enlarged prostates had been observed. These three experiments have been repeated in a single experiment that was terminated when the offspring reached 6 months of age. No statistically significant effects on prostate weight or sperm efficiency were recorded for offspring of animals exposed to either DES (0.2 microg/kg/day) or BPA (2 and 20 microg/kg/day) in utero. Significant dam effects were seen for several of the assay parameters indicating that the litter, as opposed to the individual, should be considered as the statistical unit in such experiments. A statistically significant increase in body weight was recorded for the low dose BPA male offspring. Females from the study underwent normal sexual maturation and showed no significant differences in reproductive tissue weights at termination and the mean day of vaginal opening. The possible reasons for this failure to confirm the earlier reported effects for DES and BPA at these low doses are discussed. PMID:10536110

  20. Metabolism of diethylstilbestrol by horseradish peroxidase and prostaglandin-H synthase. Generation of a free radical intermediate and its interaction with glutathione

    SciTech Connect

    Ross, D.; Mehlhorn, R.J.; Moldeus, P.; Smith, M.T.

    1985-12-25

    Diethylstilbestrol is carcinogenic in rodents and in humans and its peroxidatic oxidation in utero has been associated with its carcinogenic activity. Horseradish peroxidase-catalyzed oxidation of (14C)diethylstilbestrol and (14C)diethylstilbestrol analogs induced binding of radiolabel to DNA only when the compound contained a free hydroxy group (Metzler, M., and Epe, B. (1984) Chem. Biol. Interact. 50, 351-360). We have found that horseradish peroxidase or prostaglandin-H synthase-catalyzed oxidation of diethylstilbestrol in the presence of the spin trap 5,5-dimethyl-1-pyrroline-N-oxide caused the generation of an ESR signal indicative of a free radical intermediate (aN = 14.9 G, aH = 18.3 G). The identity of the trapped radical could not be identified on the basis of published hyperfine coupling constants, but the observation that horseradish peroxidase-catalyzed oxidation of 1-naphthol produced an identical ESR signal suggests that the radical was either a phenoxy or phenoxy-derived radical. During horseradish peroxidase-catalyzed oxidation of diethylstilbestrol in the presence of glutathione the thiol reduced the diethylstilbestrol radical to generate a thiyl radical. This was shown by a thiol-dependent oxygen uptake during horseradish peroxidase-catalyzed oxidation of diethylstilbestrol and the observation of an ESR signal consistent with 5,5-dimethylpyrroline-N-oxide-glutathionyl radical adduct formation. A diethylstilbestrol analog devoid of free hydroxy groups, namely diethylstilbestrol dipropionate, did not produce an ESR signal above control levels during horseradish peroxidase-catalyzed metabolism in the presence of 5,5-dimethylpyrroline-N-oxide. Thus, free radicals are formed during peroxidatic oxidation of diethylstilbestrol and must be considered as possible determinants of the genotoxic activity of this compound.

  1. Hormonal imprinting and damages caused by fetal steroid treatment. Influence of fetal treatment with pregnancy-protecting steroids (allylestrenol, diethylstilbestrol) on the effect of gonadotropin administered to cockerels perinatally and at the age of six weeks.

    PubMed

    Sótonyi, P T; Csaba, G

    1988-01-01

    Single fetal (9th day) treatment with either diethylstilbestrol (DES) or allylestrenol (AE) caused a considerable decrease, both at the age of five days and six weeks, in the weight of the testicles and the diameter of the seminiferous cords, while the ratio of spermatogonia to primary spermatocytes increased. When measured either at the age of five days or six weeks, gonadotropin treatment [a combination of follicle stimulating hormone (FSH) and luteinizing hormone (LH)], administered twice daily for three days after the hatching, led to an increase in the above-mentioned parameter and to a shift in the cell ratio towards the control value. However, the absolute value of the controls treated with FSH-LH was by far not reached. The effect of perinatal treatment could be detected even in adulthood, namely, at the age of five days the response capability was relatively weak in the cockerels treated with DES and AE, while high responsiveness was observed at the age of six weeks. In some cases the relative value of the increment exceeded even that of the control; however in absolute term it was well below the control. On the basis of these experiments it might be concluded that hormonal imprinting evoked by FSH-LH treatment also occurs in the gonad damaged by DES and AE. The setting in of imprinting ameliorates the damages caused by DES and AE and increases the response capability of the cells. PMID:3133925

  2. Influence of single neonatal treatment with allylestrenol or diethylstilbestrol on microsomal enzyme activity of rat liver in adulthood.

    PubMed

    Csaba, G; Szeberényi, S; Dobozy, O

    1986-01-01

    A single neonatal treatment of rats with a steroid (allylestrenol or diethylstilbestrol) did not alter the later activity of the hepatic microsomal (cytochrome P-450) enzyme system, but inhibited the inducer action of another steroid (testosterone) administered at the age of six weeks. This suggests that a hormonal imprinting-like mechanism also operates in the case of enzymes. PMID:3784633

  3. [Diethylstilbestrol story].

    PubMed

    Tournaire, Michel; Epelboin, Sylvie; Devouche, Emmanuel

    2014-01-01

    This story, that has been going on for 75 years begins with an infatuation for a "miraculous" drug supposed to, according to a theory and without scientific proof of effectiveness, reduce the pregnancy complications, especially the number of miscarriages. The next steps are painful with the discovery during the seventies, for the in utero exposed daughters, of particular cancers (clear cells adenocarcinoma) of the uterus cervix or the vagina, then during the eighties infertility and pregnancy accidents. This story is exemplary because it involves the different society actors whose roles will be analysed: health professionals, health authorities, patients associations, media and pharmaceutical companies. We will propose lessons for the future. PMID:24698194

  4. [New dopaminergic agonists].

    PubMed

    de Mattos, J P; Mattos, V M

    1999-06-01

    We present a brief review of the literature about dopaminergic agonists. We report the five known dopaminergic receptors, where they are located, the advantages and disadvantages of the employment in parkinsonian patients. The dopaminergic agonists were introduced to control the limitations of levodopa-increasing the therapeutic window. We analyse the pharmacocynetic efficacy and the side effects of cabergoline, ropinirole and pramipexole. PMID:10412541

  5. Gynaecomastia linked to the intake of a herbal supplement fortified with diethylstilbestrol.

    PubMed

    Toorians, A W F T; Bovee, T F H; De Rooy, J; Stolker, L A A M; Hoogenboom, R L A P

    2010-07-01

    This study reports the findings of a supplement marketed on the Internet for prostate problems. The supplement was orally taken by a 60-year-old man with divergent hormonal levels and who was surgically treated for gynaecomastia: development of abnormally large mammary glands in males. The supplement showed a strong effect in a yeast oestrogen bioassay, expressing a yeast-enhanced green fluorescent protein (yEGFP) upon exposure to oestrogens. Using both nuclear magnetic resonance (NMR) and a gradient liquid chromatographic time-of-flight mass spectrometric (LC/TOF-MS) method, the response was shown to be caused by very high levels of diethylstilbestrol, known for causing gynaecomastia. The gynaecomastia was most probably caused by this orally taken 'natural' herbal supplement, as the patient's hormonal levels also returned to normal again when stopping the use of it. This case demonstrates that physicians need to be aware of the use of supplements with illegal components that may be responsible for unwanted side-effects. PMID:20432093

  6. The effect of diethylstilbestrol as measured by host resistance and tumor susceptibility assays in mice.

    PubMed

    Fugmann, R A; Aranyi, C; Barbera, P W; Bradof, J N; Gibbons, R D; Fenters, J D

    1983-01-01

    As part of a program to develop and validate methodology to measure chemically induced immunotoxicity, the effect of DES on resistance of adult B6C3F1 female mice to various microorganisms and to challenge with syngeneic tumor cells was evaluated. The mice received sc injections of 50 microliter corn oil alone or of corn oil containing the equivalent of 0.2, 1, and 4 mg DES/kg X d for 14 d. Three days later they were challenged with Listeria monocytogenes, Streptococcus sp. influenza virus, herpes virus, Trichinella spiralis, or B16-F10 tumor cells. Host resistance parameters were mortality for the bacterial and viral systems, expulsion of adult parasites from the gut for T. spiralis, and lung weights for the B16-F10 tumor-cell model. Host resistance to L. monocytogenes, herpes virus, and T. spiralis was significantly decreased following DES exposure. Resistance to Streptococcus sp. was decreased, but not at a statistically significant level following these doses of DES. However a dose of DES at 8 mg/kg X d resulted in a highly significant decrease in resistance to the organism. Resistance to influenza virus was unaffected by the DES. In contrast to the above, host resistance to iv-administered B16-F10 tumor cells was significantly increased as a consequence of DES exposure. These model systems for measuring alterations in host resistance have been indicated to hold potential for the routine screening of drugs, chemicals, and environmental agents for their possible immune effects, both adverse and potentiating. The results indicate the importance of selecting the appropriate assay for evaluating a particular agent. They also stress the necessity for including host resistance assays along with assays to measure specific immune aspects, in order to assess in the intact animal the overall effect of complex immune interactions following exposure to a test agent. PMID:6620414

  7. Induction at high incidence of ductal prostate adenocarcinomas in NBL/Cr and Sprague-Dawley Hsd:SD rats treated with a combination of testosterone and estradiol-17 beta or diethylstilbestrol.

    PubMed

    Bosland, M C; Ford, H; Horton, L

    1995-06-01

    This study determined the incidence of prostate adenocarcinoma following long-term treatment of NBL and Sprague-Dawley rats with estradiol-17 beta or diethylstilbestrol (DES) plus testosterone and it defined the origin of these tumors. NBL and Sprague-Dawley rats were treated with two Silastic tubing implants (i.d. 1.6 mm, o.d. 3.2 mm) containing a 2 cm long filling of testosterone and one implant containing a 1 cm long filling of estradiol-17 beta or DES. Control animals received empty implants. Treated animals were killed when moribund and controls were killed at 91 (NBL) or 75 (Sprague-Dawley) weeks after initiation of treatment and accessory sex glands were sampled for histopathological examination of multiple step sections. Prostatic adenocarcinoma occurred in 100% of NBL rats after treatment with estradiol-17 beta or DES plus testosterone for 44 and 59 weeks (group means) respectively. Adenocarcinoma incidences were lower in Sprague-Dawley rats. The adenocarcinomas were small, microscopic, invasive tumors and they were spatially closely associated with the periurethral ducts of the dorsal, lateral and/or anterior (= coagulating gland) prostate, but never with the ducts of the ventral lobe and seminal vesicles. One adenocarcinoma was of uncertain origin. Duct-acinar dysplastic lesions occurred in the periphery of the dorsal and lateral prostate of all hormone-treated NBL and many Sprague-Dawley rats, but did not appear to give rise to carcinoma. Although some adenocarcinomas were contiguous with dysplastic ducts of the peripheral dorsolateral prostate, the main mass of these neoplasms was located in the periurethral area. Also, most adenocarcinomas were only connected with the periurethral ducts, in which atypical hyperplasia occurred following hormone treatment for 36 weeks or longer. Thus atypical hyperplasia of the periurethral prostate ducts, but not peripheral duct-acinar dysplasia, appeared to be the likely precursor of the induced carcinomas. Testosterone plus DES, but not estradiol-17 beta, induced marked dysplasia-like lesions in the acini of the ventral prostate of all NBL and many Sprague-Dawley rats. These lesions had progressed to carcinoma in situ (or adenoma) in 46% of NBL rats. PMID:7788848

  8. Beta-Adrenergic Agonists

    PubMed Central

    Barisione, Giovanni; Baroffio, Michele; Crimi, Emanuele; Brusasco, Vito

    2010-01-01

    Inhaled ?2-adrenoceptor (?2-AR) agonists are considered essential bronchodilator drugs in the treatment of bronchial asthma, both as symptoms-relievers and, in combination with inhaled corticosteroids, as disease-controllers. In this article, we first review the basic mechanisms by which the ?2-adrenergic system contributes to the control of airway smooth muscle tone. Then, we go on describing the structural characteristics of ?2-AR and the molecular basis of G-protein-coupled receptor signaling and mechanisms of its desensitization/ dysfunction. In particular, phosphorylation mediated by protein kinase A and ?-adrenergic receptor kinase are examined in detail. Finally, we discuss the pivotal role of inhaled ?2-AR agonists in the treatment of asthma and the concerns about their safety that have been recently raised.

  9. Neuroprotection and dopamine agonists.

    PubMed

    Schapira, Anthony H V

    2002-02-26

    Several factors are known to be capable of inducing relatively selective dopaminergic cell death in the substantia nigra and inducing the clinical features that characterize Parkinson's disease (PD). Neuronal toxins such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) can induce parkinsonism in human and animal models, and rotenone, another specific mitochondrial complex I inhibitor, can induce similar effects in rodents to produce a model for PD. Studies in twins suggest a significant genetic component to young-onset PD, and several gene mutations have now been identified as causing familial autosomal dominant or autosomal recessive PD. Etiologic factors including free radical-mediated damage (including excitotoxicity), mitochondrial dysfunction, and inflammation-mediated cell damage can contribute to pathogenesis. In addition, the recent interest in protein misfolding, aggregation, and proteosomal activity has provided further insight into potential pathogenetic pathways in PD. Against this background there has been increasing interest in the development of drugs to modify these biochemical abnormalities and thus alter the course of PD, either by retarding the rate of cell death or by restoring function to neurons that are likely to be damaged but not dead. In this context, dopamine agonists have shown significant promise. Not only do these drugs provide symptomatic relief of PD but they also appear to be associated with a significant decrease in the rate of motor complications and to be capable of protecting against some of the adverse consequences of levodopa use. However, evidence is now emerging that dopamine agonists may have additional neuroprotective properties. As a group, they have antioxidant actions in vitro and in vivo. More specifically, the D(2)/D(3) dopamine agonist pramipexole may have neuroprotective activity that is, at least in part, unrelated to its dopamine agonist action. Protection in cell and animal models against a variety of toxins, including MPTP and 6-hydroxydopamine, confirms that this agonist has in vitro and in vivo neuroprotective action. Evidence is now emerging that some of this may be mediated by direct action on mitochondrial membrane potential and the inhibition of apoptosis. If the neuroprotective action of this drug is confirmed in patients with PD, this will have important implications for its early use in patients. PMID:11909981

  10. [Biological activity of surfagon--a synthetic luliberin agonist].

    PubMed

    Krivosheev, O G; Nabatchikova, N A; Pozdniakova, G I; Siutkin, E A; Vinogradov, V A

    1988-01-01

    The biological activity of surfagon (D-Ala6-desGly10-Pro9-ethylamide), a synthetic LH-RH agonist, is dozens of times higher than that of LH-RH in the test of rat hypophyseal stimulation of gonadotropin secretion in vivo and in vitro and in the ovulation induction test. A dose of surfagon required for the stimulation of LH secretion was considerably lower than that for the stimulation of FSH secretion. It may permit the use of surfagon in clinical practice for selective stimulation of secretion either of LH or total gonadotropins--LH and FSH. PMID:3148928

  11. ?2-AGONISTS IN CHILDHOOD ASTHMA.

    PubMed

    Miraglia Del Giudice, M; Campana, G; Galdo, F; De Vivo, D; Cuppari, C; Coronella, A; Maiello, N

    2015-01-01

    ?2-agonists reduce airflow limitation by improving airway diameter as a consequence of a direct action on airway smooth muscle. ?;2-agonists can be broadly classified according to their duration of action: short-acting ?2-agonists (SABAs), including albuterol, terbutaline and fenoterol, have pharmacodynamics half?lives between 2 and 6 h and long-acting ?2-agonists (LABAs), including salmeterol and formoterol, require twice daily treatment. SABAs are often used ?as needed? for asthma exacerbations and before exercise in the presence of exercise-induced bronchospasm. LABAs provide longer symptom control, which is a particularly useful feature for preventing night-time symptoms. There are two main LABAs, salmeterol and formoterol. This review focused on the recent data published on this topic. PMID:26634602

  12. Influence of neonatal and postnatal administration of diethylstilbestrol on hepatic monooxygenase activities and lipid peroxidation in adult rats.

    PubMed

    Jahn, F; Karge, E; Klinger, W

    1991-01-01

    Treatment of adult male and female rats with DES caused a significant reduction of cytochrome P450 concentration, ethylmorphine N-demethylation and ethoxycoumarin O-deethylation. These decreases are not modified by a neonatal treatment with this hormone. In contrast to monooxygenase activities the NADPH-induced lipid peroxidation shows only a tendency to decrease if animals received DES as adults. But a decrease of about 50% is observed after "neonatal plus treatment of adults" with DES. The role of formation of reactive oxygen species characterized by chemiluminescence methods in connection with lipid peroxidation is discussed. PMID:1814470

  13. Diethylstilbestrol regulates expression of avian apolipoprotein D during regression and recrudescence of the oviduct and epithelial-derived ovarian carcinogenesis.

    PubMed

    Jeong, J; Bae, H; Lim, W; Bazer, F W; Song, G

    2015-07-01

    Apolipoprotein D (APOD) is a glycoprotein which is widely expressed in mammalian tissues. It is structurally and functionally similar to the lipocalins which are multiple lipid-binding proteins that transport hydrophobic ligands and other small hydrophobic molecules, including cholesterol and several steroid hormones. Although multiple functions for APOD in various tissues have been reported, its expression, biological function, and hormonal regulation in the female reproductive system are not known. Thus, in this study, we focused on correlations between APOD and estrogen during development, differentiation, regression, and regeneration of the oviduct in chickens and in the development of ovarian carcinogenesis in laying hens. Results of the present study indicated that APOD messenger RNA (mRNA) expression increased (P < 0.001) in the luminal and glandular (GE) epithelia of the chicken oviduct in response to diethylstilbestrol (a nonsteroidal synthetic estrogen). In addition, the expression of APOD mRNA and protein decreased (P < 0.001) as the oviduct regressed during induced molting, and gradually increased (P < 0.001) with abundant expression in GE of the oviduct during recrudescence after molting. Furthermore, APOD mRNA and protein were predominantly localized in GE of cancerous, but not normal ovaries from laying hens. Collectively, results of the present study suggest that APOD is a novel estrogen-stimulated gene in the chicken oviduct which likely regulates growth, differentiation, and remodeling of the oviduct during oviposition cycles. Moreover, up-regulated expression of APOD in epithelial cell-derived ovarian cancerous tissue suggests that it could be a candidate biomarker for early detection and treatment of ovarian cancer in laying hens and in women. PMID:25929245

  14. Diethylstilbestrol 1 mg in the Treatment of Acute Urinary Retention due to Prostatic Obstruction in the Elderly: A Preliminary Study

    PubMed Central

    Reis, Leonardo Oliveira; De Mendonça, Gustavo Borges; Carneiro, Bruno D.; Schneider, Edson; Gewehr, Eduardo Varella; Meirelles, André; Denardi, Fernandes; Gugliotta, Antonio

    2014-01-01

    Patients who failed a catheter-free trial after acute urinary retention and one week of full dose alpha-blocker and 5-alpha-reductase inhibitor were offered Diethylstilbestrol 1 mg plus Aspirin 100 mg over 4 weeks. Prostate volume, age, serum creatinine, and initial retention drained urine volume were recorded. After excluding cardiovascular morbidity (n = 7), upper urinary tract dilation (n = 3), compromised renal function (n = 2), urinary tract infection (n = 2), neurological diagnosis (n = 2), or preferred immediate channel transurethral resection of prostate (n = 5), 48 of 69 consecutive patients ≥70 years were included. Mean age was 76.6 years (70–84), mean prostate volume 90 cm3 (42–128), and mean follow-up 204 days; 58% (28/48) were passing urine and 42% (20/48) were catheter dependent after 4 weeks Diethylstilbestrol trial. Mean age and drained urine volume of catheter dependent patients were 82.4 years and 850 mL compared with 74.6 years and 530 mL in catheter-free men, respectively. Age and drained urine volume were independent predictors of catheter-free trial (both P < 0.01). Seventy-five percent (6/8) of patients 80 years and older were catheter dependent. Transient nipple/breast tenderness and gynecomastia were the only adverse effects reported by 21% (10/48) and 4% (2/48), respectively. No patient presented severe complications. PMID:24575128

  15. An optimised method for the accurate determination of zeranol and diethylstilbestrol in animal tissues using isotope dilution-liquid chromatography/mass spectrometry.

    PubMed

    Han, Hyesun; Kim, Byungjoo; Lee, Sueg Geun; Kim, Jeongkwon

    2013-09-01

    Isotope dilution-liquid chromatography/mass spectrometry (ID-LC/MS) has been established as a candidate reference method for the accurate determination of growth promoters (zeranol, taleranol, and diethylstilbesterol) in raw meat samples. Sample preparation processes including an enzymatic hydrolysis, extraction, and SPE clean-up were optimised. The sensitivity difference of trans- and cis-diethylstilbestrol (isomerizing in sample preparation processes) by the LC/MS was measured by running a trans/cis mixture (ratio measured by a quantitative NMR) with and without sample matrices, and applied for the determination of total diethylstilbestrol. Validity, repeatability, and reproducibility of the analytical method were tested by measuring gravimetrically fortified samples (chicken breast, bovine muscles, and porcine muscle) in a number of different time periods. Measurement results agreed with the fortified values within their uncertainties. The method provided accurate results of the target analytes in the range of 0.05-15 ?g/kg with the relative expanded uncertainty of 2-15%. PMID:23578613

  16. Histamine H3 receptor agonists.

    PubMed

    De Esch, I J P; Belzar, K J

    2004-11-01

    The SAR of H3 ligands has been difficult to evaluate because of species differences, multiple isoforms and constitutive activity, among other complicating factors. A review is given of the sometimes-conflicting affinity, activity and efficacy data of H3 agonists that has been described in literature to date. PMID:15544556

  17. Des Moines.

    ERIC Educational Resources Information Center

    Gore, Deborah, Ed.

    1988-01-01

    This document, intended for elementary students, contains articles and activities designed to acquaint young people with the history of Des Moines, Iowa. The articles are short, and new or difficult words are highlighted and defined for young readers. "The Raccoon River Indian Agency" discusses the archeological exploration of the indian

  18. Hormonal imprinting of the microsomal enzyme system in adults. Microsomal activity change in response to estrogen (DES, AE) treatment during liver regeneration.

    PubMed

    Csaba, G; Szeberényi, S Z; Dobozy, O

    1987-10-01

    Estrogen (diethylstilbestrol-DES or allylestrenol-AE) treatment applied to rats of both sexes during liver regeneration following subtotal hepatectomy had a long lasting influence on the inducibility by phenobarbital of the hepatic microsomal enzyme system of the females. The enzyme activities of the DES-treated females differed hardly from the baseline two weeks after treatment, but increased almost two-fold over control on induction with phenobarbital 5 and 7 weeks later. The AE-treated females showed a smaller although yet significant, enzyme activity increase only at 7 weeks. The influence of estrogens was negligible, and inhibitory rather than stimulatory, in the males. It appears that, in appropriate conditions, enzyme imprinting can also be induced in adult organisms, since, in all probability, availability for imprinting depends not so much on the age of the organism, as on the developmental state of the target cell. PMID:3428868

  19. Novel diazabicycloalkane delta opioid agonists.

    PubMed

    Loriga, Giovanni; Lazzari, Paolo; Manca, Ilaria; Ruiu, Stefania; Falzoi, Matteo; Murineddu, Gabriele; Bottazzi, Mirko Emilio Heiner; Pinna, Giovanni; Pinna, Grard Aim

    2015-09-01

    Here we report the investigation of diazabicycloalkane cores as potential new scaffolds for the development of novel analogues of the previously reported diazatricyclodecane selective delta (?) opioid agonists, as conformationally constrained homologues of the reference ? agonist (+)-4-[(?R)-?((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC80). In particular, we have simplified the diazatricyclodecane motif of ? opioid agonist prototype 1a with bridged bicyclic cores. 3,6-diazabicyclo[3.1.1]heptane, 3,8-diazabicyclo[3.2.1]octane, 3,9-diazabicyclo[3.3.1]nonane, 3,9-diazabicyclo[4.2.1]nonane, and 3,10-diazabicyclo[4.3.1]decane were adopted as core motifs of the novel derivatives. The compounds were synthesized and biologically assayed as racemic (3-5) or diastereoisomeric (6,7) mixtures. All the novel compounds 3-7 showed ? agonism behaviour and remarkable affinity to ? receptors. Amongst the novel derivatives, 3,8-diazabicyclo[3.2.1]octane based compound 4 evidenced improved ? affinity and selectivity relative to SNC80. PMID:26252963

  20. Association between fetal DES-exposure and psychiatric disorders in adolescence/adulthood: evidence from a French cohort of 1002 prenatally exposed children.

    PubMed

    Soyer-Gobillard, Marie-Odile; Paris, Franoise; Gaspari, Laura; Courtet, Philippe; Sultan, Charles

    2016-01-01

    In utero diethylstilbestrol (DES) exposure has been demonstrated to be associated with somatic abnormalities in adult men and women. Conversely, the data are contradictory regarding the association with psychological or psychiatric disorders during adolescence and adulthood. This work was designed to determine whether prenatal exposure to DES affects brain development and whether it is associated with psychiatric disorders in male and female adolescents and young adults. HHORAGES Association, a national patient support group, has assembled a cohort of 1280 women who took DES during pregnancy. We obtained questionnaire responses from 529 families, corresponding to 1182 children divided into three groups: Group 1 (n?=?180): firstborn children without DES treatment, Group 2 (n?=?740): exposed children, and Group 3 (n?=?262): children born after a previous pregnancy treated by DES. No psychiatric disorders were reported in Group 1. In Group 2, the incidence of disorders was drastically elevated (83.8%), and in Group 3, the incidence was still elevated (6.1%) compared with the general population. This work demonstrates that prenatal exposure to DES is associated with a high risk of psychiatric disorders in adolescence and adulthood. PMID:26172930

  1. Effect of PCB and DES on rat monoamine oxidase, acetylcholinesterase, testosterone, and estradiol ontogeny

    SciTech Connect

    Vincent, D.R.; Bradshaw, W.S.; Booth, G.M.; Seegmiller, R.E.; Allen, S.D.

    1992-06-01

    Diethylstilbestrol (DES) and polychlorinated biphenyl (PCB) have been documented as potentially hazardous environmental agents. In utero exposure to DES produces human vaginal adenocarcinoma, male reproductive tract lesions in mice, and has been correlated with personality changes in human males. PCB (Kanechlor) was found to be the major toxin in the {open_quotes}Yusho{close_quotes} rice oil poisoning in Japan in 1968. Other investigators have shown in rats that PCB (Arochlor) causes liver adenofibrosis, thyroid dysfunction, atypical mitochondria, and dilation of both smooth and rough endoplasmic reticulum. Matthews et al. (1978) also reported that 4, 4{prime} chlorinated biphenyl was the most potent inducer of monooxygenases, irrespective of chlorination at other sites. Although these compounds have been studied extensively in mammals, there is a paucity of data examining their effects when non-fetotoxic amounts are administered chronically and orally during gestation. The present study is part of a larger effort designed to establish a protocol for testing the developmental effects of xenobiotics such as DES and PCB. Levels of acetylcholinesterase (AChE) were measured as an indicator of the integrity of nerve transmission in the central nervous system. Monoamine oxidase (MAO) is a marker for the outer mitochondrial membrane and is an important amine metabolizing enzyme. Testosterone and estradiol are important sex steroids in mammals, and effects upon levels of the two hormones may signal anomalies in development of sex characteristics. 35 refs., 3 figs., 1 tab.

  2. Kappa Opioid Receptor Agonist and Brain Ischemia

    PubMed Central

    Chunhua, Chen; Chunhua, Xi; Megumi, Sugita; Renyu, Liu

    2014-01-01

    Opioid receptors, especially Kappa opioid receptor (KOR) play an important role in the pathophysiological process of cerebral ischemia reperfusion injury. Previously accepted KOR agonists activity has included anti-nociception, cardiovascular, anti-pruritic, diuretic, and antitussive effects, while compelling evidence from various ischemic animal models indicate that KOR agonist have neuroprotective effects through various mechanisms. In this review, we aimed to demonstrate the property of KOR agonist and its role in global and focal cerebral ischemia. Based on current preclinical research, the KOR agonists may be useful as a neuroprotective agent. The recent discovery of salvinorin A, highly selective non-opioid KOR agonist, offers a new tool to study the role of KOR in brain HI injury and the protective effects of KOR agonist. The unique pharmacological profile of salvinorin A along with the long history of human usage provides its high candidacy as a potential alternative medication for brain HI injury. PMID:25574482

  3. TRPV4 agonists and antagonists.

    PubMed

    Vincent, Fabien; Duncton, Matthew A J

    2011-01-01

    TRPV4 belongs to the TRPV subfamily of Transient Receptor Potential (TRP) ion channels. This year marks the 10 year anniversary of the discovery of this polymodal ion channel which is activated by a variety of stimuli including warm temperatures, hypotonicity and endogenous lipids. Coupled with a widespread tissue distribution, this activation profile has resulted in a large number of disparate physiological functions for TRPV4. These range from temperature monitoring in skin keratinocytes to osmolarity sensing in kidneys, sheer stress detection in blood vessels and osteoclast differentiation control in bone. As knowledge of its physiological roles has expanded, interest in targeting TRPV4 modulation for therapeutic purposes has arisen and is now focused on several areas. First, as with related TRP channels TRPV1, TRPV3, TRPM8 and TRPA1, TRPV4 antagonism is being considered for inflammatory and neuropathic pain treatment. Recent work conducted using KO mice and agonists 4?PDD and GSK1016790A suggests bladder dysfunctions may also be targeted. Additionally, ventilator-induced lung injury has emerged as another potential indication for TRPV4 antagonists. Herein we review the known small molecule modulators of TRPV4 and relate progress made in identifying potent, selective and bioavailable agonists and antagonists to interrogate this ion channel in vivo. PMID:21671873

  4. Dopamine receptor agonists, partial agonists and psychostimulant addiction.

    PubMed

    Pulvirenti, L; Koob, G F

    1994-10-01

    Despite the epidemic growth of psychostimulant addiction over the past years, few pharmacological means of intervention are available to date for clinical treatment. This is of importance since the withdrawal syndrome that follows abstinence from drugs such as cocaine and the amphetamines is characterized, among other symptoms, by intense craving for the abused drug, and this is considered a critical factor leading into relapse of drug use. In this article, Luigi Pulvirenti and George Koob focus on the modulatory role shown by drugs acting at the dopamine receptor on the various phases of psychostimulant dependence in preclinical models and in human studies, and suggest that a class of compounds with partial agonist properties at the dopamine receptor may have therapeutic potential. PMID:7809953

  5. Beta-agonists and animal welfare

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The use of beta-agonists in animal feed is a high profile topic within the U.S. as consumers and activist groups continue to question its safety. The only beta-agonist currently available for use in swine is ractopamine hydrochloride (RAC). This is available as Paylean™ (Elanco Animal Health – FDA a...

  6. Purine Receptors: GPCR Structure and Agonist Design

    PubMed Central

    Jacobson, Kenneth A.; Kim, Soo-Kyung; Costanzi, Stefano; Gao, Zhan-Guo

    2012-01-01

    An integrated approach to the study of drug-receptor interactions has been applied to adenosine receptors (ARs) and P2Y nucleotide receptors. This approach includes probing the receptor structure through site-directed mutagenesis and molecular modeling, in concert with altering the structure of the agonist ligands. Goals of this structural approach are to generate a testable hypothesis for location of the binding site and subsequently to enable the rational design of new agonists and antagonists. In this manner, receptor subtype selectivity has been increased, and agonists have been converted into partial agonists and antagonists. An approach to receptor engineering (neoceptors) has been explored, in which synthetic small molecule agonists (neoligands) are specifically tailored to activate only receptors in which the putative binding sites have been modified. This orthogonal approach to receptor activation, intended for eventual gene therapy, has been demonstrated for A3 and A2A ARs. PMID:15616163

  7. The cannabinoid receptor inverse agonist AM251 regulates the expression of the EGF receptor and its ligands via destabilization of oestrogen-related receptor ? protein

    PubMed Central

    Fiori, JL; Sanghvi, M; O'Connell, MP; Krzysik-Walker, SM; Moaddel, R; Bernier, M

    2011-01-01

    BACKGROUND AND PURPOSE AM251 is an inverse agonist of the cannabinoid 1 receptor (CB1R) that can exert off-target effects in vitro and in CB1R knock-out mice. AM251 is also potent at modulating tumour cell growth, suggesting that growth factor-mediated oncogenic signalling could be regulated by AM251. Since dysregulation of the EGF receptor has been associated with carcinogenesis, we examined AM251 regulation of EGF receptor (EGFR) expression and function. EXPERIMENTAL APPROACH The various biological functions of AM251 were measured in CB1R-negative human cancer cells. Pharmacological and genetic approaches were used to validate the data. KEY RESULTS The mRNA levels for EGFR and its associated ligands, including HB-EGF, were induced several fold in PANC-1 and HCT116 cells in response to AM251. This event was associated with enhanced expression of EGFR on the cell surface with concomitant increase in EGF-induced cellular responses in AM251-treated cells. Exposure to XCT790, a synthetic inverse agonist of the orphan nuclear oestrogen-related receptor ? (ERR?), also induced EGFR and HB-EGF expression to the same extent as AM251, whereas pretreatment with the ERR?-selective agonist, biochanin A, blunted AM251 actions. AM251 promoted the degradation of ERR? protein without loss of the corresponding mRNA. Knock-down of ERR? by siRNA-based approach led to constitutive induction of EGFR and HB-EGF levels, and eliminated the biological responses of AM251 and XCT790. Finally, AM251 displaced diethylstilbestrol prebound to the ligand-binding domain of ERR?. CONCLUSIONS AND IMPLICATIONS AM251 up-regulates EGFR expression and signalling via a novel non-CB1R-mediated pathway involving destabilization of ERR? protein in selected cancer cell lines. PMID:21449913

  8. [Adrenergic beta-agonist intoxication].

    PubMed

    Carrola, Paulo; Devesa, Nuno; Silva, Jos Manuel; Ramos, Fernando; Alexandrino, Mrio B; Moura, Jos J

    2003-01-01

    The authors describe two clinical cases (father and daughter), observed in the Hospital Urgency with distal tremors, anxiety, palpitations, nausea, headaches and dizziness, two hours after ingestin of cow liver. They also had leucocytosis (with neutrophylia), hypokalemia and hyperglycaemia. After treatment with potassium i.v. and propranolol, the symptoms disappeared. The symptoms recurred at home because the patients didn't take the prescribed medication and persisted for five days, with spontaneous disappearance. The serum of both patients revealed the presence of clenbuterol (65 hg/ml - father and 58 hg/ml - daughter). The animal's liver had a concentration of 1,42 mg/kg. Clenbuterol is a -adrenergic agonist with low specificity, with some veterinary indications. However, this substance has been illegally used as a growth's promotor. We intend to alert doctors for this problem, particularly those that work in the Urgency. PMID:22226216

  9. Small Molecule Fluoride Toxicity Agonists

    PubMed Central

    Nelson1, James W.; Plummer, Mark S.; Blount, Kenneth F.; Ames, Tyler D.; Breaker, Ronald R.

    2015-01-01

    SUMMARY Fluoride is a ubiquitous anion that inhibits a wide variety of metabolic processes. Here we report the identification of a series of compounds that enhance fluoride toxicity in Escherichia coli and Streptococcus mutans. These molecules were isolated by using a high-throughput screen (HTS) for compounds that increase intracellular fluoride levels as determined via a fluoride riboswitch-reporter fusion construct. A series of derivatives were synthesized to examine structure-activity relationships, leading to the identification of compounds with improved activity. Thus, we demonstrate that small molecule fluoride toxicity agonists can be identified by HTS from existing chemical libraries by exploiting a natural fluoride riboswitch. In addition, our findings suggest that some molecules might be further optimized to function as binary antibacterial agents when combined with fluoride. PMID:25910244

  10. Monoterpenoid agonists of TRPV3

    PubMed Central

    Vogt-Eisele, A K; Weber, K; Sherkheli, M A; Vielhaber, G; Panten, J; Gisselmann, G; Hatt, H

    2007-01-01

    Background and purpose: Transient receptor potential (TRP) V3 is a thermosensitive ion channel expressed predominantly in the skin and neural tissues. It is activated by warmth and the monoterpene camphor and has been hypothesized to be involved in skin sensitization. A selection of monoterpenoid compounds was tested for TRPV3 activation to establish a structure-function relationship. The related channel TRPM8 is activated by cool temperatures and a number of chemicals, among them the monoterpene (-)-menthol. The overlap of the receptor pharmacology between the two channels was investigated. Experimental approach: Transfected HEK293 cells were superfused with the test substances. Evoked currents were measured in whole cell patch clamp measurements. Dose-response curves for the most potent agonists were obtained in Xenopus laevis oocytes. Key results: Six monoterpenes significantly more potent than camphor were identified: 6-tert-butyl-m-cresol, carvacrol, dihydrocarveol, thymol, carveol and (+)-borneol. Their EC50 is up to 16 times lower than that of camphor. All of these compounds carry a ring-located hydroxyl group and neither activates TRPM8 to a major extent. Conclusions and implications: Terpenoids have long been recognized as medically and pharmacologically active compounds, although their molecular targets have only partially been identified. TRPV3 activation may be responsible for several of the described effects of terpenoids. We show here that TRPV3 is activated by a number of monoterpenes and that a secondary hydroxyl-group is a structural requirement. PMID:17420775

  11. Rheologie des Polymeres Charges

    NASA Astrophysics Data System (ADS)

    Lepez, Olivier

    Une etude des proprietes rheologiques en ecoulement oscillatoire et en ecoulement transitoire a ete realisee sur des suspensions de particules spheriques dans des solutions de polymere d'une part et dans des polymeres a l'etat fondu d'autre part. Une attention particuliere a ete portee sur l'influence des parametres suivants sur les proprietes en ecoulement de ces fluides complexes: nature du fluide suspendant, fraction volumique en particule, temperature. Apres analyse des resultats, de nouveaux modeles empiriques ont ete proposes afin de predire l'allure des courbes d'ecoulement de ces suspensions en cisaillement oscillatoire. Enfin, certaines analogies entre les proprietes visqueuses et viscoelastiques des suspensions dans les deux milieux mentionnes precedemment ont ete discutees.

  12. Long-acting beta2 agonists.

    PubMed

    Norman, Peter

    2006-01-01

    Two applications claim very closely related arylsulfonamide beta(2)-agonists. The basic generic claim is the same in both cases with subsidiary claims covering different permutations of the same Markush structure. The claimed compounds are potent beta(2)-agonists whose structures suggest that they would have a long duration of action. These applications represent part of what is now a significant chemical programme at Pfizer. PMID:20141509

  13. Des ballons pour demain

    NASA Astrophysics Data System (ADS)

    Rgipa, R.

    A partir d'une thorie sur la dtermination des formes et des contraintes globales d'un ballon de rvolution, ou s'en rapprochant, une nouvelle famille de ballons a t dfinie. Les ballons actuels, dits de ``forme naturelle'', sont calculs en gnral pour une tension circonfrencielle nulle. Ainsi, pour une mission donne, la tension longitudinale et la forme de l'enveloppe sont strictement imposes. Les ballons de la nouvelle gnration sont globalement cylindriques et leurs ples sont runis par un cble axial, charg de transmettre une partie des efforts depuis le crochet (ple infrieur), directement au ple suprieur. De plus, la zone latrale cylindrique est soumise un faible champ de tensions circonfrencielles. Ainsi, deux paramtres permettent de faire voluer la distribution des tensions et la forme de l'enveloppe: - la tension du cble de liaison entre ples (ou la longueur de ce cble) - la tension circonfrencielle moyenne dsire (ou le rayon du ballon). On peut donc calculer et raliser: - soit des ballons de forme adapte, comme les ballons fond plat pour le bon fonctionnement des montgolfires infrarouge (projet MIR); - soit des ballons optimiss pour une bonne rpartition des contraintes et une meilleure utilisation des matriaux d'enveloppe, pour l'ensemble des programmes stratosphriques. Il s'ensuit une conomie sensible des cots de fabrication, une fiabilit accrue du fonctionnement de ces ballons et une rendement oprationnel bien suprieur, permettant entre autres, d'envisager des vols trs haute altitude en matriaux trs lgers.

  14. Dopamine receptor partial agonists and addiction.

    PubMed

    Moreira, Fabricio A; Dalley, Jeffrey W

    2015-04-01

    Many drugs abused by humans acutely facilitate, either directly or indirectly, dopamine neurotransmission in the mesolimbic pathway. As a consequence dopamine receptor agonists and antagonists have been widely investigated as putative pharmacological therapies for addiction. This general strategy, however, has had only limited success due in part to poor treatment adherence and efficacy and the significant adverse effects of dopaminergic medications. In this perspective, we discuss the potential therapeutic use of dopamine receptor partial agonists in addiction, developed initially as antipsychotic agents. Recent research indicates that the dopamine D2 receptor partial agonists, such as aripiprazole, also shows useful ancillary efficacy in several animal models of psychostimulant and opioid addiction. Notably, these findings suggest that unlike full dopamine receptor agonists and antagonists these compounds have low abuse liability and are generally well tolerated. Indeed, partial dopamine agonists attenuate the rewarding properties of opioids without interfering with their analgesic effects. Herein we discuss the utility and potential of dopamine receptor partial agonists as treatments for both stimulant and non-stimulant drug addiction. PMID:25724788

  15. Receptor agonists of macrophage migration inhibitory factor

    PubMed Central

    Jorgensen, William L.; Gandavadi, Sunilkumar; Du, Xin; Hare, Alissa A.; Trofimov, Alexander; Leng, Lin; Bucala, Richard

    2010-01-01

    The cytokine MIF is involved in inflammation and cell proliferation via pathways initiated by its binding to the transmembrane receptor CD74. MIF also promotes AMPK activation with potential benefits for response to myocardial infarction and ischaemia-reperfusion. Structure-based molecular design has led to the discovery of not only antagonists, but also the first agonists of MIF-CD74 binding. The compounds contain a triazole core that is readily assembled via Cu-catalyzed click chemistry. The agonist and antagonist behaviors were confirmed via study of MIF-dependent ERK1/2 phosphorylation in human fibroblasts. PMID:20971005

  16. Muscimol as an ionotropic GABA receptor agonist.

    PubMed

    Johnston, Graham A R

    2014-10-01

    Muscimol, a psychoactive isoxazole from Amanita muscaria and related mushrooms, has proved to be a remarkably selective agonist at ionotropic receptors for the inhibitory neurotransmitter GABA. This historic overview highlights the discovery and development of muscimol and related compounds as a GABA agonist by Danish and Australian neurochemists. Muscimol is widely used as a ligand to probe GABA receptors and was the lead compound in the development of a range of GABAergic agents including nipecotic acid, tiagabine, 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol, (Gaboxadol(®)) and 4-PIOL. PMID:24473816

  17. Emerging adenosine receptor agonistsan update

    PubMed Central

    Gao, Zhan-Guo; Jacobson, Kenneth A

    2012-01-01

    Adenosine receptors (ARs), the major targets of caffeine and theophylline, comprise four receptor subtypes designated as A1, A2A, A2B and A3. Over a dozen AR agonists are currently in clinical trials for various conditions, including cardiac arrhythmias, neuropathic pain, myocardial perfusion imaging, cardiac ischemia, inflammatory diseases and cancer. Adenosine (non-selective), regadenoson (A2A) and dipyridamole (act indirectly via ARs) have received regulatory approval for clinical use. The present editorial will give a brief update on the current status of AR agonists in clinical trials. PMID:22148938

  18. Amputation des quatre membres

    PubMed Central

    Feruzi, Maruis Kitembo; Milindi, Cdrick Sangwa; Zabibu, Mireille Kakinga; Mulefu, Jules Panda; Katombe, Francois Tshilombo

    2014-01-01

    Les auteurs prsentent les cas d'amputation des quatre membres ralise chez trois patients diffrents. Ce sont des amputations ralises pour chaque patient au cours d'une seule hospitalisation et en un seul temps opratoire. Deux patients pour gangrne sche infecte et un pour amputation traumatique des quatre membres. L'amputation d'urgence a t pratique en premier temps suivie de remodelage des moignons d'amputation en second temps. Lvolution de tous les patients a t bonne. PMID:25469177

  19. Identification of potent and selective neuropeptide Y Y(1) receptor agonists with orexigenic activity in vivo.

    PubMed

    Mullins, D; Kirby, D; Hwa, J; Guzzi, M; Rivier, J; Parker, E

    2001-09-01

    Neuropeptide Y (NPY) binds to a family of G-protein coupled receptors termed Y(1), Y(2), Y(3), Y(4), Y(5), and y(6). The use of various receptor subtype-selective agonists and antagonists has facilitated identification of the receptor subtypes responsible for mediating many of the biological effects of NPY. For example, the potent orexigenic activity of NPY is believed to be mediated by both the Y(1) and Y(5) receptor subtypes. Several selective Y(5) receptor agonists that stimulate food intake in rodents are available, but no selective Y(1) receptor agonist has been reported. We have identified several NPY analogs that bind the NPY Y(1) receptor with high affinity and exhibit full agonist activity, measured as inhibition of forskolin-stimulated cAMP production in cells expressing the cloned NPY Y(1) receptor. [D-Arg(25)]-NPY, [D-His(26)]-NPY, Des-AA(10--17)[Cys(7,21),Pro(34)]-NPY, Des-AA(11--18)[Cys(7,21),D-Lys(9)(Ac)]-NPY, Des-AA(11--18)[Cys(7,21),D-Lys(9)(Ac),Pro(34)]-NPY, Des-AA(11--18)[Cys(7,21),D-Lys(9)(Ac),D-His(26)]-NPY and Des-AA(11--18)[Cys(7,21),D-Lys(9)(Ac),D-His(26), Pro(34)]-NPY bind the NPY Y(1) receptor with K(i) values of 0.9 +/- 0.2, 2.0 +/- 0.3, 0.2 +/- 0.05, 0.7 +/- 0.1, 0.2 +/- 0.01, 2.2 +/- 0.3, and 1.2 +/- 0.3 nM, respectively, and inhibit forskolin-stimulated cAMP production with EC(50) values of 0.2 +/- 0.02, 0.5 +/- 0.04, 0.3 +/- 0.03, 0.5 +/- 0.05, 0.4 +/- 0.16, 5.3 +/- 0.32, and 5.1 +/- 0.97 nM, respectively. These peptides are highly selective for the NPY Y(1) receptor relative to the NPY Y(2), Y(4), and Y(5) receptors. [D-Arg(25)]-NPY, [D-His(26)]-NPY and Des-AA(11--18)[Cys(7,21), D-Lys(9)(Ac),D-His(26),Pro(34)]-NPY stimulate food intake dose-responsively in Long-Evans rats for at least 4 h after intracerebroventricular administration. Although the involvement of Y(1) receptors in several physiological activities, such as vasoconstriction and anxiolysis, remains to be investigated, adequate tools are now available. PMID:11502885

  20. Early exposure of 17α-ethynylestradiol and diethylstilbestrol induces morphological changes and alters ovarian steroidogenic pathway enzyme gene expression in catfish, Clarias gariepinus.

    PubMed

    Sridevi, P; Chaitanya, R K; Prathibha, Y; Balakrishna, S L; Dutta-Gupta, A; Senthilkumaran, B

    2015-04-01

    Environmental estrogens are major cause of endocrine disruption in vertebrates, including aquatic organisms. Teleosts are valuable and popular models for studying the effects of endocrine disrupting chemicals (EDCs) in the environment. In the present study, we investigated the changes caused by exposure to the synthetic estrogens 17α-ethynylestradiol (EE2 ) and diethylstilbesterol (DES) during early stages of growth and sex differentiation of air-breathing catfish, Clarias gariepinus, at the morphological, histological, and molecular levels. Catfish hatchlings, 0 day post hatch (dph) were exposed continuously to sublethal doses of EE2 (50 ng/L) and DES (10 ng/L) until 50 dph and subsequently monitored for ovarian structural changes and alteration in the gene expression of steroidogenic enzymes till adulthood. Treated fish exhibited morphological deformities such as spinal curvature, stunted growth, and yolk-sac fluid retention. In addition to ovarian atrophy, DES-treated fish showed either rudimentary or malformed ovaries. Detailed histological studies revealed precocious oocyte development as well as follicular atresia. Further, transcript levels of various steroidogenic enzyme and transcription factor genes were altered in response to EE2 and DES. Activity of the rate-limiting enzyme of estrogen biosynthesis, aromatase, in the ovary as well as the brain of treated fish was in accordance with transcript level changes. These developmental and molecular effects imparted by EE2 and DES during early life stages of catfish could demonstrate the deleterious effects of estrogen exposure and provide reliable markers for estrogenic EDCs exposure in the environment. PMID:24273110

  1. FXR agonist activity of conformationally constrained analogs of GW 4064

    SciTech Connect

    Akwabi-Ameyaw, Adwoa; Bass, Jonathan Y.; Caldwell, Richard D.; Caravella, Justin A.; Chen, Lihong; Creech, Katrina L.; Deaton, David N.; Madauss, Kevin P.; Marr, Harry B.; McFadyen, Robert B.; Miller, Aaron B.; Navas, III, Frank; Parks, Derek J.; Spearing, Paul K.; Todd, Dan; Williams, Shawn P.; Wisely, G. Bruce

    2010-09-27

    Two series of conformationally constrained analogs of the FXR agonist GW 4064 1 were prepared. Replacement of the metabolically labile stilbene with either benzothiophene or naphthalene rings led to the identification of potent full agonists 2a and 2g.

  2. Identification of Selective ERR? Inverse Agonists.

    PubMed

    Kim, Jina; Im, Chun Young; Yoo, Eun Kyung; Ma, Min Jung; Kim, Sang-Bum; Hong, Eunmi; Chin, Jungwook; Hwang, Hayoung; Lee, Sungwoo; Kim, Nam Doo; Jeon, Jae-Han; Lee, In-Kyu; Jeon, Yong Hyun; Choi, Hueng-Sik; Kim, Seong Heon; Cho, Sung Jin

    2016-01-01

    GSK5182 (4) is currently one of the lead compounds for the development of estrogen-related receptor gamma (ERR?) inverse agonists. Here, we report the design, synthesis, pharmacological and in vitro absorption, distribution, metabolism, excretion, toxicity (ADMET) properties of a series of compounds related to 4. Starting from 4, a series of analogs were structurally modified and their ERR? inverse agonist activity was measured. A key pharmacophore feature of this novel class of ligands is the introduction of a heterocyclic group for A-ring substitution in the core scaffold. Among the tested compounds, several of them are potent ERR? inverse agonists as determined by binding and functional assays. The most promising compound, 15g, had excellent binding selectivity over related subtypes (IC50 = 0.44, >10, >10, and 10 ?M at the ERR?, ERR?, ERR?, and ER? subtypes, respectively). Compound 15g also resulted in 95% transcriptional repression at a concentration of 10 ?M, while still maintaining an acceptable in vitro ADMET profile. This novel class of ERR? inverse agonists shows promise in the development of drugs targeting ERR?-related diseases. PMID:26771593

  3. Corepressors of agonist-bound nuclear receptors

    SciTech Connect

    Gurevich, Igor; Aneskievich, Brian J.

    2007-09-15

    Nuclear receptors (NRs) rely on coregulator proteins to modulate transcription of target genes. NR coregulators can be broadly subdivided into coactivators which potentiate transcription and corepressors which silence gene expression. The prevailing view of coregulator action holds that in the absence of agonist the receptor interacts with a corepressor via the corepressor nuclear receptor (CoRNR, 'corner') box motifs within the corepressor. Upon agonist binding, a conformational change in the receptor causes the shedding of corepressor and the binding of a coactivator which interacts with the receptor via NR boxes within the coregulator. This view was challenged with the discovery of RIP140 which acts as a NR corepressor in the presence of agonist and utilizes NR boxes. Since then a number of other corepressors of agonist-bound NRs have been discovered. Among them are LCoR, PRAME, REA, MTA1, NSD1, and COPR1 Although they exhibit a great diversity of structure, mechanism of repression and pathophysiological function, these corepressors frequently have one or more NR boxes and often recruit histone deacetylases to exert their repressive effects. This review highlights these more recently discovered corepressors and addresses their potential functions in transcription regulation, disease pharmacologic responses and xenobiotic metabolism.

  4. Agonistic CD40 antibodies and cancer therapy

    PubMed Central

    Vonderheide, Robert H.; Glennie, Martin J.

    2013-01-01

    Recent success in cancer immunotherapy has reinvigorated the hypothesis that the immune system can control many if not most cancers, in some cases producing durable responses in a way not seen with many small molecule drugs. Agonistic CD40 monoclonal antibodies (mAb) offer a new therapeutic option which has the potential to generate anti-cancer immunity by various mechanisms. CD40 is a tumor necrosis factor receptor superfamily member expressed broadly on antigen-presenting cells (APC) such as dendritic cells, B cells, and monocytes as well as many non-immune cells and a range of tumors. Agonistic CD40 mAb have been shown to activate APC and promote anti-tumor T cell responses and to foster cytotoxic myeloid cells with the potential to control cancer in the absence of T-cell immunity. Thus, agonistic CD40 mAb are fundamentally different from mAb which block negative immune checkpoint such as anti-CTLA-4 or anti-PD-1. Initial clinical trials of agonistic CD40 mAb have shown highly promising results in the absence of disabling toxicity, both in single-agent studies and in combination with chemotherapy; however, numerous questions remain regarding dose, schedule, route of administration, and formulation. Recent findings regarding the role played by the IgG isotype and the Fc gamma receptor (Fc?R) in mAb crosslinking, together with insights into mechanisms of action, particularly with regards to the role of myeloid cells, are predicted to help design next-generation CD40 agonistic reagents with greater efficacy. Here, we will review the preclinical and clinical data and discuss the major issues facing the field. PMID:23460534

  5. Anti-nociception mediated by a ? opioid receptor agonist is blocked by a ? receptor agonist

    PubMed Central

    Taylor, A M W; Roberts, K W; Pradhan, A A; Akbari, H A; Walwyn, W; Lutfy, K; Carroll, F I; Cahill, C M; Evans, C J

    2015-01-01

    BACKGROUND AND PURPOSE The opioid receptor family comprises four structurally homologous but functionally distinct sub-groups, the ? (MOP), ? (DOP), ? (KOP) and nociceptin (NOP) receptors. As most opioid agonists are selective but not specific, a broad spectrum of behaviours due to activation of different opioid receptors is expected. In this study, we examine whether other opioid receptor systems influenced KOP-mediated antinociception. EXPERIMENTAL APPROACH We used a tail withdrawal assay in C57Bl/6 mice to assay the antinociceptive effect of systemically administered opioid agonists with varying selectivity at KOP receptors. Pharmacological and genetic approaches were used to analyse the interactions of the other opioid receptors in modulating KOP-mediated antinociception. KEY RESULTS Etorphine, a potent agonist at all four opioid receptors, was not anti-nociceptive in MOP knockout (KO) mice, although etorphine is an efficacious KOP receptor agonist and specific KOP receptor agonists remain analgesic in MOP KO mice. As KOP receptor agonists are aversive, we considered KOP-mediated antinociception might be a form of stress-induced analgesia that is blocked by the anxiolytic effects of DOP receptor agonists. In support of this hypothesis, pretreatment with the DOP antagonist, naltrindole (10 mgkg?1), unmasked etorphine (3 mgkg?1) antinociception in MOP KO mice. Further, in wild-type mice, KOP-mediated antinociception by systemic U50,488H (10 mgkg?1) was blocked by pretreatment with the DOP agonist SNC80 (5 mgkg?1) and diazepam (1 mgkg?1). CONCLUSIONS AND IMPLICATIONS Systemic DOP receptor agonists blocked systemic KOP antinociception, and these results identify DOP receptor agonists as potential agents for reversing stress-driven addictive and depressive behaviours mediated through KOP receptor activation. LINKED ARTICLES This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2 PMID:24923251

  6. Agonistic and reproductive interactions in Betta splendens.

    PubMed

    Bronstein, P M

    1984-12-01

    Reproductive and agonistic behaviors in Siamese fighting fish were investigated in eight experiments, and some consequences and determinants of these sequences were isolated. First, fights and the formation of dominance-subordinancy relations were studied. Second, it was determined that large body size as well as males' prior residency in a tank produced an agonistic advantage; the magnitude of this advantage was positively related to the duration of residency. Third, the prior-residency effect in Bettas was determined by males' familiarity with visual and/or tactile cues in their home tanks. Fourth, dominant males had greater access to living space and were more likely to display at a mirror, build nests, and approach females than were subordinates. Finally, it was discovered that chemical cues associated with presumedly inert plastic tank dividers influence Bettas' social behavior. PMID:6542479

  7. Theories of recovery for DES damage. Is tort liability the answer?

    PubMed

    Downey, A H; Gulley, K G

    1983-06-01

    An estimated 1000 individual or class action products liability lawsuits have been filed against the pharmaceutical manufacturers of diethylstilbestrol (DES). The field of potential plaintiffs is estimated at 500,000-6,000,000 and there are 150-300 potential defendant manufacturers. This article addresses the question of whether the current system of tort liability dispenses fair, timely, and uniform justice both to DES claimants and manufacturers and presents a historical perspective on the basis for liability. Traditional theories of tort recovery are based on negligence, breach of warranty, and strict liability. They place the burden of proof on the claimant to specifically identify the product manufacturer and establish proximate causation. Novel theories of recovery have had to be applied in DES lawsuits, including concert of action and alternative liability. Most of these theories have been unaccepted by trial and appellate courts because of the inability to identify the manufacturer. Even if DES manufacturers were to be held liable under a theory of industry-wide or market share liability, defendants would be called upon to allocate liability among themselves. Many believe that any departure from traditional tort principles should be accomplished by the legislature, not the judiciary. There is not currently a bill before the US Congress dealing specifically with compensation for damages to DES victims. Any model toxic tort legislation should aim to eliminate the benefit inequities as between claimants and the cost inequities in delivering benefits to qualified recipients by the responsible parties. The claimant's burden of establishing fault should be eliminated in exchange for a claimant's surrender of a right to sue a third party, and a standardization of compensatory damages. The requirements of specific product identification, duration of exposure, and degree of fault would be eliminated. Jurisdictional requirements and statues of limitation must be drafted to permit recovery for previously unknown injuries. Finally, there should be an overall goal of promptness in recovery. The most equitable solution to problems with the tort system is legislation which deals with the toxic tort problem as a whole and not just on a case-by-case basis. PMID:6604118

  8. Radiolabelled D2 agonists as prolactinoma imaging agents

    SciTech Connect

    Otto, C.A.

    1989-08-01

    During the past year, further studies on mAChR were conducted. These studies included verification of the difference in pituitary distribution based on ligand charge. The pituitary localization of TRB. A neutral mAChR ligand, was verified. The lack of QNB blockade of TRB uptake was tested by blockage with scopolamine, another mAChR antagonist and by testing the effect in a different strain of rat. Neither scopolamine or change of rat strain had any effect. We concluded that TRB uptake in pituitary is not a receptor-mediated process. Further studies were conducted with an additional quaternized mAChR ligand: MQNB. Pituitary localization of MQNB, like MTRB, could be blocked by pretreatment with QNB. We have tentatively concluded that permanent charge on a mAChR antagonist changes the mechanism of uptake in the pituitary. Time course studies and the effects of DES on myocardial uptake are reported. A brief report on preliminary results of evaluation of quaternized mAChR ligands in the heart is included. In a limited series of such ligands, we have observed a single binding site and a difference in B{sub max} values: QNB competition studies yield larger B{sub max} values than studies with {sup 3}H-NMS. Progress in the synthesis of D{sub 2} agonists includes solving a synthetic problem and preparation of the cold'' analogue of N-0437 using procedures applicable to eventual synthesis with {sup 11}C-CH{sub 3}I. 2 refs., 5 figs., 1 tab.

  9. Pentapeptides displaying mu opioid receptor agonist and delta opioid receptor partial agonist/antagonist properties

    PubMed Central

    Purington, Lauren C.; Pogozheva, Irina D.; Traynor, John R.; Mosberg, Henry I.

    2009-01-01

    Chronic use of mu-opioid agonists has been shown to cause neurochemical adaptations resulting in tolerance and dependence. While the analgesic effects of these drugs are mediated by mu-opioid receptors (MOR), several studies have shown that antagonism or knockdown of delta-opioid receptors (DOR) can lessen or prevent development of tolerance and dependence. Based on computational modeling of putative active and inactive conformations of MOR and DOR, we have synthesized a series of pentapeptides with the goal of developing a MOR agonist/DOR antagonist peptide with similar affinity at both receptors as a tool to probe functional opioid receptor interaction(s). The eight resulting naphthylalanine-substituted cyclic pentapeptides displayed variable mixed-efficacy profiles. The most promising peptide (9; Tyr-c(S-CH2-S)[D-Cys-Phe-2-Nal-Cys]NH2) displayed a MOR agonist and DOR partial agonist/antagonist profile and bound with equipotent affinity (Ki ~ 0.5 nM) to both receptors, but also showed kappa opioid receptor (KOR) agonist activity. PMID:19788201

  10. Note des diteurs scientifiques

    NASA Astrophysics Data System (ADS)

    Averbuch, P.

    Cette srie d'articles est une revue de rsultats exprimentaux sur diffrents "fluides" molculaires, dans lesquels la cohsion est due des forces de Van der Waals et des liaisons hydrogne, l'eau tant un de ces fluides. Ces rsultats sont prsents de faon justifier exprimentalement un modle original, non extensif, des proprits de ces fluides, et l'ensemble se prsente sous la forme de trois articles dcrivant le modle, suivis chacun par un article le comparant aux rsultats exprimentaux publis par de nombreux auteurs. Le caractre non extensif des proprits physiques des fluides est choquant, contraire beaucoup d'ides tablies, il semble n'avoir en sa faveur qu'un argument, la comparaison avec un nombre de rsultats exprimentaux assez grand pour que l'effet du hasard soit difficilement souponnable. En particulier, les carts entre des rsultats de mesures faits par des auteurs diffrents dans des conditions diffrentes sont expliqus, le srieux et la comptence des diffrents exprimentateurs ne sont plus mis en doute : mais l'interprtation de ces rsultats avec un modle extensif non adapt est seule mise en cause. Les modles extensifs tant utiliss systmatiquement, au del des expriences de physiciens, dans les calculs d'ingnieurs, et dans la modlisation d'appareils qui fonctionnent et de phnomnes naturels observs par tout le monde, il fallait expliquer pourquoi on pouvait renoncer l'extensivit. Les raisons du succs pratique des modles extensifs sont donnes, d'abord dans le cas des nmatiques, puis dans celui des liquides ordinaires, et c'est ce qui rend l'ensemble cohrent, tant avec les mesures physiques fines qu'avec les observations quotidiennes. Il n'en reste pas moins que si l'interprtation donne dans cette srie d'articles est gnralisable, une justification thorique du modle utilis devient ncessaire. Pour ce qui est des proprits d'quilibre, une sparation de l'nergie libre en nergie libre de volume et en nergie libre de surface devrait donner les mmes rsultats ; par contre les choses deviennent troublantes ds que l'on passe aux coefficients de transport, c'est--dire l'aspect macroscopique de la dynamique molculaire. Il y a l un cart notable avec les conceptions courantes, ce qui rend trs surprenante la lecture de ces articles. On peut mentionner la liste des problmes thoriques poss par la description phnomnologique qui est celle de cette srie d'articles : la gnralisation de lois d'chelle en dehors de zones critiques n'est pas absolument nouvelle, par contre la simplicit des lois reliant l'exposant v la temprature pose problme ; le sens des temps de relaxation utiliss est sans doute galement prciser. Enfin les modes considrs semblent n'intervenir dans les proprits thermodynamiques que par un facteur par mode, comme si seulement l'nergie potentielle devait intervenir, les termes cintiques ne participant pas vraiment aux transitions de phase. Tout cela pose donc problme, et l'on peut se demander si un pareil modle peut tre compatible avec tout ce qui est connu par ailleurs en physique statistique. Mais s'il rend bien compte de beaucoup de rsultats exprimentaux, ce sont ces derniers qui seraient en difficult avec la mcanique statistique. Il a donc sembl prfrable de publier le modle, sa justification exprimentale et de poser quelques problmes, tant aux thoriciens, qui pourraient expliquer pourquoi un tel modle rend compte de rsultats observs, qu'aux exprimentateurs, qui pourraient reprendre certaines mesures, et dlimiter le caractre plus ou moins gnral du modle.

  11. Synergistic antinociception by the cannabinoid receptor agonist anandamide and the PPAR-? receptor agonist GW7647

    PubMed Central

    Russo, Roberto; LoVerme, Jesse; La Rana, Giovanna; D'Agostino, Giuseppe; Sasso, Oscar; Calignano, Antonio; Piomelli, Daniele

    2007-01-01

    The analgesic properties of cannabinoid receptor agonists are well characterized. However, numerous side effects limit the therapeutic potential of these agents. Here we report a synergistic antinociceptive interaction between the endogenous cannabinoid receptor agonist anandamide and the synthetic peroxisome proliferator-activated receptor-? (PPAR-?) agonist 2-(4-(2-(1-Cyclohexanebutyl)-3-cyclohexylureido)ethyl)phenylthio)-2-methylpropionic acid (GW7647) in a model of acute chemical-induced pain. Moreover, we show that anandamide synergistically interacts with the large-conductance potassium channel (KCa1.1, BK) activator isopimaric acid. These findings reveal a synergistic interaction between the endocannabinoid and PPAR-? systems that might be exploited clinically and identify a new pharmacological effect of the BK channel activator isopimaric acid. PMID:17434479

  12. Binding ability of impromidine, a potent H2 agonist of histamine

    NASA Astrophysics Data System (ADS)

    Anouar, A.; Lhadi, E.; Decock, P.; Kozlowskyinst4, H.

    1999-09-01

    Impromidine (fig.1) is a potent and selective histamine H2 receptor agonist and its structure comprises a strongly basic guanidine group containing two different imidazole-containing side chains. The present work deals with the study of coordination equilibria between impromidine and Cu(II) and Ni(II) in aqueous solution at 25 circC. Potentiometric, UV-Visible and EPR studies on Cu(II) complexes with impromidine have shown that this anti-ulcerogenic drug is a very potent chelating agent. This drug is found to be a very effective ligand for Ni(II) ions also. The effective coordination of impromidine to metal ions may have significant biological implications. L'impromidine est un agoniste H2 de l'histamine, sa structure possède un groupement guanidinique de forte basicité et dont l'environne ment des deux groupements imidazoliques est différent. Le présent travail consiste en l'étude de la coordination de l'impromidine avec le Cu(II) et le Ni(II) en milieu aqueux à 25 circC. La potentiométrie, LíUV-Visible et la RPE montrent que le cuivre se coordine très fortement avec l'impromidine. Nous avons trouvé que ce médicament se coordine aussi fortement avec le nickel(II). La coordination de l'impromidine avec les métaux pourrait avoir des applications importantes en médecine.

  13. Signal Use by Octopuses in Agonistic Interactions.

    PubMed

    Scheel, David; Godfrey-Smith, Peter; Lawrence, Matthew

    2016-02-01

    Cephalopods show behavioral parallels to birds and mammals despite considerable evolutionary distance [1, 2]. Many cephalopods produce complex body patterns and visual signals, documented especially in cuttlefish and squid, where they are used both in camouflage and a range of interspecific interactions [1, 3-5]. Octopuses, in contrast, are usually seen as solitary and asocial [6, 7]; their body patterns and color changes have primarily been interpreted as camouflage and anti-predator tactics [8-12], though the familiar view of the solitary octopus faces a growing list of exceptions. Here, we show by field observation that in a shallow-water octopus, Octopus tetricus, a range of visible displays are produced during agonistic interactions, and these displays correlate with the outcome of those interactions. Interactions in which dark body color by an approaching octopus was matched by similar color in the reacting octopus were more likely to escalate to grappling. Darkness in an approaching octopus met by paler color in the reacting octopus accompanied retreat of the paler octopus. Octopuses also displayed on high ground and stood with spread web and elevated mantle, often producing these behaviors in combinations. This study is the first to document the systematic use of signals during agonistic interactions among octopuses. We show prima facie conformity of our results to an influential model of agonistic signaling [13]. These results suggest that interactions have a greater influence on octopus evolution than has been recognized and show the importance of convergent evolution in behavioral traits. VIDEO ABSTRACT. PMID:26832440

  14. Modulation of Innate Immune Responses via Covalently Linked TLR Agonists

    PubMed Central

    2015-01-01

    We present the synthesis of novel adjuvants for vaccine development using multivalent scaffolds and bioconjugation chemistry to spatially manipulate Toll-like receptor (TLR) agonists. TLRs are primary receptors for activation of the innate immune system during vaccination. Vaccines that contain a combination of small and macromolecule TLR agonists elicit more directed immune responses and prolong responses against foreign pathogens. In addition, immune activation is enhanced upon stimulation of two distinct TLRs. Here, we synthesized combinations of TLR agonists as spatially defined tri- and di-agonists to understand how specific TLR agonist combinations contribute to the overall immune response. We covalently conjugated three TLR agonists (TLR4, 7, and 9) to a small molecule core to probe the spatial arrangement of the agonists. Treating immune cells with the linked agonists increased activation of the transcription factor NF-κB and enhanced and directed immune related cytokine production and gene expression beyond cells treated with an unconjugated mixture of the same three agonists. The use of TLR signaling inhibitors and knockout studies confirmed that the tri-agonist molecule activated multiple signaling pathways leading to the observed higher activity. To validate that the TLR4, 7, and 9 agonist combination would activate the immune response to a greater extent, we performed in vivo studies using a vaccinia vaccination model. Mice vaccinated with the linked TLR agonists showed an increase in antibody depth and breadth compared to mice vaccinated with the unconjugated mixture. These studies demonstrate how activation of multiple TLRs through chemically and spatially defined organization assists in guiding immune responses, providing the potential to use chemical tools to design and develop more effective vaccines. PMID:26640818

  15. Reticulation des fibres lignocellulosiques

    NASA Astrophysics Data System (ADS)

    Landrevy, Christel

    Pour faire face la crise conomique la conception de papier valeur ajoute est dveloppe par les industries papetires. Le but de se projet est l'amlioration des techniques actuelles de rticulation des fibres lignocellulosiques de la pte papier visant produire un papier plus rsistant. En effet, lors des ractions de rticulation traditionnelles, de nombreuses liaisons intra-fibres se forment ce qui affecte ngativement l'amlioration anticipe des proprits physiques du papier ou du matriau produit. Pour viter la formation de ces liaisons intra-fibres, un greffage sur les fibres de groupements ne pouvant pas ragir entre eux est ncessaire. La rticulation des fibres par une raction de click chemistry appele cycloaddition de Huisgen entre un azide et un alcyne vrai, catalyse par du cuivre (CuAAC) a t l'une des solutions trouve pour remdier ce problme. De plus, une adaptation de cette raction en milieux aqueux pourrait favoriser son utilisation en milieu industriel. L'tude que nous dsirons entreprendre lors de ce projet vise optimiser la raction de CuAAC et les ractions intermdiaires (propargylation, tosylation et azidation) sur la pte kraft, en milieu aqueux. Pour cela, les ractions ont t adaptes en milieu aqueux sur la cellulose microcristalline afin de vrifier sa faisabilit, puis transfre la pte kraft et l'influence de diffrents paramtres comme le temps de raction ou la quantit de ractifs utilise a t tudie. Dans un second temps, une tude des diffrentes proprits confres au papier par les ractions a t ralise partir d'une srie de tests papetiers optiques et physiques. Mots Cls Click chemistry, Huisgen, CuAAC, propargylation, tosylation, azidation, cellulose, pte kraft, milieu aqueux, papier.

  16. IL-15 Agonists: The Cancer Cure Cytokine.

    PubMed

    Wu, Jennifer

    2013-10-28

    The immune stimulatory cytokine interleukin-15 was recognized as one of the most promising cancer cure drug in an NIH guided review and is currently in clinical trial alone or as an adjuvant for certain types of metastatic solid tumors. IL-15 is an essential survival factor for natural killer (NK), natural killer-like T (NKT), and CD44(hi) memory CD8 T cells. The bioactivity of IL-15 in vivo is conferred mainly through a trans-presentation mechanism in which IL-15 is presented in complex with the ?-subunit of soluble IL-15 receptor (IL-15R) to NK, NKT or T cells rather than directly interacts with membrane-bound IL-15R. With these understandings, recent studies have been focused on generating IL-15 agonists which consist of IL-15 and partial or whole of soluble IL-15R to improve its in vivo bioactivity. This minireview will summarize the key features of IL-15 as a potential cancer treatment cytokine and the most recent development of IL-15 agonists and preclinical studies. Critical milestones to translate the pre-clinical development to in-patients treatment are emphasized. PMID:24587813

  17. D-Cycloserine: Agonist turned antagonist.

    PubMed

    Lanthorn, T H

    1994-10-01

    D-Cycloserine can enhance activation of the NMDA receptor complex and could enhance the induction of long-term potentiation (LTP). In animals and humans, D-cycloserine can enhance performance in learning and memory tasks. This enhancing effect can disappear during repeated administration. The enhancing effects are also lost when higher doses are used, and replaced by behavioral and biochemical effects like those produced by NMDA antagonists. It has been reported that NMDA agonists, applied before or after tetanic stimulation, can block the induction of LTP. This may be the result of feedback inhibition of second messenger pathways stimulated by receptor activation. This may explain the antagonist-like effects of glycine partial agonists like D-cycloserine. In clinical trials of D-cycloserine in age-associated memory impairment (AAMI) and Alzheimer's disease, chronic treatment provided few positive effects on learning and memory. This may be due to inhibition of second messenger pathways following chronic stimulation of the receptor complex. PMID:24189733

  18. Therapeutic perspectives for melatonin agonists and antagonists.

    PubMed

    Delagrange, P; Atkinson, J; Boutin, J A; Casteilla, L; Lesieur, D; Misslin, R; Pellissier, S; Pnicaud, L; Renard, P

    2003-04-01

    Melatonin is a neurohormone synthesized in the pineal gland during the dark period in all species, including humans. The diversity and differences in melatonin receptor distribution in the brain and extracerebral organs suggest multiple functional roles for melatonin. Administration of melatonin agonists reduces neophobia and treatment with a melatonin antagonist during the dark period reverses the anxiolytic-like effect of endogenous melatonin. Chronic treatment with agonists prevents various perturbations induced by chronic mild stress. Melatonin in vivo directly constricts cerebral arterioles in rats and decreases the lower limit of cerebral blood flow autoregulation, suggesting that melatonin may diminish the risk of hypoperfusion-induced cerebral ischemia. At the extracerebral level, melatonin regulates intestinal motility in rats. The intestinal postprandial motor response is shorter in the dark phase than in the light phase and this reduction is reversed in animals pretreated with a melatonin antagonist. Moreover, melatonin reduces the duration of cholecystokinin excitomotor effect. Endogenous melatonin may modulate intestinal motility to coordinate intestinal functions such as digestion and transit and control the metabolism of the animal. An adipocyte melatonin binding site may also participate in this control. Melatonin is involved in a wide range of physiological functions. The question remains as to whether evolution, adaptation and diurnal life have modified the physiological role of melatonin in humans. Moreover, the functional role of each of the receptor subtypes has to be characterized to design selective ligands to treat specific diseases. PMID:12622848

  19. Beta-2-agonists of third generation.

    PubMed

    Palma-Carlos, A G; Palma-Carlos, G S

    1986-04-01

    Beta-adrenergic agents have been used for a long time in the treatment of asthma. For the purpose of bronchodilation the better results would be attained with the increase in Beta-2-selectivity. From the newer Beta-agonists the mot currently used are TERBUTALINE, FENOTEROL, SALBUTAMOL, CLEMBUTEROL, TOLBUTEROL, CARBUTEROL, PROCATEROL, RIMITEROL and REPROTEROL, this last combining in its molecule the structure of a beta-agonist with a Xanthine group. These agents could be used in different ways, by mouth, injection and inhalation (with a exception of Clembuterol which is effective only by oral route). The authors have, some years ago, comparatively studied the bronchodilating effect of Salbutamol and Fenoterol including 18 patients. The main increase of PFR was slightly higher after FENOTEROL but this difference was not significant. The authors have studied REPROTEROL by inhalation and oral routes in 11 asthmatic patients. After inhalation of 400 mcg of REPROTEROL the bronchodilator effect was comparable to others inhaled bronchodilators. However they could not confirm that REPROTEROL acts also as a Xanthine and only traces of Theophylline have been detected in blood of subjects taking it. These data seem to indicate that REPROTEROL do not release Theophylline in the body or only release a Xanthine like compound not detected by "EMIT" of high pressure liquid chromatography. PMID:2899434

  20. Physical Chemistry to the Rescue: Differentiating Nicotinic and Cholinergic Agonists

    ERIC Educational Resources Information Center

    King, Angela G.

    2005-01-01

    Researches suggest that two agonists can bind to the same binding site of an important transmembrane protein and elicit a biological response through strikingly different binding interactions. Evidence is provided which suggests two possible types of nicotinic acetylcholine receptor agonist binding like acetlycholine (cholinergic) or like nicotine

  1. TOXICITY OF AHR AGONISTS TO FISH EARLY LIFE STAGES

    EPA Science Inventory

    Fish early life stages are exceptionally sensitive to the lethal toxicity of chemicals that act as arylhydrocarbon receptor (AhR) agonists. Toxicity characterizations based on 2,3,7,8-tetrachlorodibenzo-p-dioxin, generally the most potent AhR agonist, support the toxicity equiva...

  2. Discovery of the First Selective, Nonpeptidic Orexin 2 Receptor Agonists.

    PubMed

    Heifetz, Alexander; Bodkin, Mike J; Biggin, Philip C

    2015-10-22

    In this issue, Nagase and colleagues report the discovery of the first selective nonpeptidic orexin 2 receptor (OX2R) agonists. The discovery of these OX2R selective agonists opens up new avenues for therapies related to the activation of the orexin system, especially with respect to the treatment of sleep disorders such as narcolepsy. PMID:26375584

  3. Physical Chemistry to the Rescue: Differentiating Nicotinic and Cholinergic Agonists

    ERIC Educational Resources Information Center

    King, Angela G.

    2005-01-01

    Researches suggest that two agonists can bind to the same binding site of an important transmembrane protein and elicit a biological response through strikingly different binding interactions. Evidence is provided which suggests two possible types of nicotinic acetylcholine receptor agonist binding like acetlycholine (cholinergic) or like nicotine…

  4. Estrogen receptor agonists for attenuation of neuroinflammation and neurodegeneration

    PubMed Central

    Chakrabarti, Mrinmay; Haque, Azizul; Banik, Naren L.; Nagarkatti, Prakash; Nagarkatti, Mitzi; Ray, Swapan K.

    2014-01-01

    Recent results from laboratory investigations and clinical trials indicate important roles for estrogen receptor (ER) agonists in protecting the central nervous system (CNS) from noxious consequences of neuroinflammation and neurodegeneration. Neurodegenerative processes in several CNS disorders including spinal cord injury (SCI), multiple sclerosis (MS), Parkinson's disease (PD), and Alzheimer's disease (AD) are associated with activation of microglia and astrocytes, which drive the resident neuroinflammatory response. During neurodegenerative processes, activated microglia and astrocytes cause deleterious effects on surrounding neurons. The inhibitory activity of ER agonists on microglia activation might be a beneficial therapeutic option for delaying the onset or progression of neurodegenerative injuries and diseases. Recent studies suggest that ER agonists can provide neuroprotection by modulation of cell survival mechanisms, synaptic reorganization, regenerative responses to axonal injury, and neurogenesis process. The anti-inflammatory and neuroprotective actions of ER agonists are mediated mainly via two ERs known as ERα and ERβ. Although some studies have suggested that ER agonists may be deleterious to some neuronal populations, the potential clinical benefits of ER agonists for augmenting cognitive function may triumph over the associated side effects. Also, understanding the modulatory activities of ER agonists on inflammatory pathways will possibly lead to the development of selective anti-inflammatory molecules with neuroprotective roles in different CNS disorders such as SCI, MS, PD, and AD in humans. Future studies should be concentrated on finding the most plausible molecular pathways for enhancing protective functions of ER agonists in treating neuroinflammatory and neurodegenerative injuries and diseases in the CNS. PMID:25245209

  5. [Pathological gambling induced by dopamine agonists].

    PubMed

    Gahr, M; Connemann, B J; Schnfeldt-Lecuona, C J

    2011-08-01

    Problems with impulse control and pathological gambling are known as possible side effects of dopaminergic therapy in patients with Parkinson's disease. We report 2 cases of pathological gambling induced by dopamine agonists in patients without Parkinson's disease. The first patient, a 46-year-old man, was treated with ropinirole for restless legs syndrome and had lost huge amounts of money in the context of internet-based poker game. Another 46-year-old male patient developed pathological gambling under treatment with cabergoline administered for prolactinoma. The two cases implicate pathological gambling as a possible consequence of dopaminergic treatment and support the increasing evidence regarding pathological gambling as an adverse drug reaction of dopaminergic treatment, also in patients who do not suffer from Parkinson's disease. PMID:21809260

  6. TLR AGONISTS: Are They Good Adjuvants?

    PubMed Central

    Bhardwaj, Nina; Gnjatic, Sacha; Sawhney, Nikhil B.

    2010-01-01

    Therapeutic immunization leading to cancer regression remains a significant challenge. Successful immunization requires activation of adaptive immunity, including tumor specific CD4 + T cells and CD8+ T cells. Generally speaking, the activation of T cells is compromised in patients with cancer due to immune suppression, loss of tumor antigen expression, and dysfunction of antigen presenting cells (APC). APC such as dendritic cells (DC) are key for the induction of adaptive anti-tumor immune responses. Recently, attention has focused on novel adjuvants that enhance DC function and their ability to prime T cells. Agonists that target toll-like receptors (TLR) are being used clinically either alone or in combination with tumor antigens and showing initial success both in terms of enhancing immune responses and eliciting anti-tumor activity. This review summarizes the application of these adjuvants to treat cancer and the potential for boosting responses in vivo. PMID:20693851

  7. Des Vents et des Jets Astrophysiques

    NASA Astrophysics Data System (ADS)

    Sauty, C.

    Plasma outflows from a central gravitating object are a widespread phenomenon in astrophysics. They include the solar and stellar winds, jets from Young Stellar Objects, jets from compact stellar objects and extra-galactic jets associated with Active Galactic Nuclei and quasars. Beyond this huge zoology, a common theoretical ground exists. The aim of this review is to present qualitatively the various theories of winds (Part 1) and how different astrophysical domains interplay. A more or less complete catalog of the ideas proposed for explaining the acceleration and the morphologies of winds and jets is intended. All this part avoids getting into any mathematical formalism. Some macroscopic properties of such outflows may be described by solving the time-independent and axisymmetric magnetohydrodynamic equations. This formalism, underlying most of the theories, is presented in Part 2. It helps to introduce quantitatively the free integrals that such systems possess. Those integrals play an important role in the basic physics of acceleration and collimation, in particular the mass loss rate, the angular momentum loss rate and the energy of the magnetic rotator. Most of the difficulty in modelling flows lies in the necessity to cross critical points, characteristic of non linear equations. The physical nature and the location of such critical points is debated because they are the clue towards the resolution. We thus introduce the notions of topology and critical points (Parts 3 and 4) from the simplest hydrodynamic and spherically symmetric case to the most sophisticated, MHD and axisymmetric cases. Particular attention is given to self-similar models which allows to give some general and simple ideas on the problem due to their semi-analytical treatment. With the use of these notions, a more quantitative comparison of the various models is given (Parts 3 and 4), especially on the shape of the flows. It is thus shown that magnetic collimation of winds into jets is a well expected result from the theory. Although, collimation may be conical, paraboloidal or cylindrical (Part 4), cylindrical collimation is the more likely to occur. The shape of outflows may then be used as a tool to predict physical conditions on the flows or on their source. L'jection continue de plasma autour d'objets massifs est un phnomne largement rpandu en astrophysique, que ce soit sous la forme du vent solaire, de vents stellaires, de jets d'toiles en formation, de jets stellaires autour d'objets compacts ou de jets extra-galactiques. Cette zoologie diversifie fait pourtant l'objet d'un commun effort de modlisation. Le but de cette revue est d'abord de prsenter qualitativement le dveloppement, depuis leur origine, des diverses thories de vents (Partie 1) et l'inter disciplinarit dans ce domaine. Il s'agit d'une numration, plus ou moins exhaustive, des ides proposes pour expliquer l'acclration et la morphologie des vents et des jets, accompagne d'une prsentation sommaire des aspects observationnels. Cette partie s'abstient de tout aspect faisant appel au formalisme mathmatique. Ces coulements peuvent tre dcrits, au moins partiellement, en rsolvant les quations magntohydrodynamiques, axisymtriques et stationnaires. Ce formalisme, la base de la plupart des thories, est expos dans la Partie 2. Il permet d'introduire quantitativement les intgrales premires qu'un tel systme possde. Ces dernires sont amenes jouer un rle important dans la comprhension des phnomnes d'acclration ou de collimation, en particulier le taux de perte de masse, le taux de perte de moment angulaire ou l'nergie du rotateur magntique. La difficult de modlisation rside dans l'existence de points critiques, propres aux quations non linaires, qu'il faut franchir. La nature physique et la localisation de ces points critiques fait l'objet d'un dbat important car ils sont la clef de voute de la rsolution. Nous introduisons donc la notion de topologie des points critiques (Parties 3 et 4

  8. Additive antinociceptive effects of mixtures of the ?-opioid receptor agonist spiradoline and the cannabinoid receptor agonist CP55940 in rats.

    PubMed

    Maguire, David R; France, Charles P

    2016-02-01

    Pain is a significant clinical problem, and there is a need for pharmacotherapies that are more effective with fewer adverse effects than currently available medications. Cannabinoid receptor agonists enhance the antinociceptive effects of ?-opioid receptor agonists; it is unclear whether they impact the effects of agonists acting at other opioid receptors. ?-Opioid receptor agonists have antinociceptive effects, but their clinical use is precluded by adverse effects; however, their therapeutic potential might be realized if antinociceptive effects could be selectively enhanced. In this study, the antinociceptive effects of the cannabinoid receptor agonist CP55940 and the ?-opioid receptor agonist spiradoline, alone and in combination, were studied in rats (n=7) using a warm water tail-withdrawal procedure. When administered alone, CP55940 (0.032-1.0?mg/kg) and spiradoline (1.0-32.0?mg/kg) increased tail-withdrawal latency, and mixtures of CP55940 and spiradoline (ratios of 1?:?3, 1?:?1, and 3?:?1) produced additive effects. It remains to be determined whether this additive interaction between a ?-opioid receptor agonist and a cannabinoid receptor agonist is selective for antinociception and whether it can be generalized to other drugs. PMID:26292184

  9. Cartographie des disques

    NASA Astrophysics Data System (ADS)

    Hameury, Jean-Marie

    2001-01-01

    Two techniques are frequently used to produce images of the accretion disc in an eclipsing binary: eclipse mapping and Doppler tomography. From the light curve, one can deduce the radial distribution of the effective temperature, assuming axial symmetry. On the other hand, from the variation of the line profile one can reconstruct an image in the velocity space, which can be converted into a real image if one knows the kinematics of the system. Deux techniques sont couramment utilisées pour obtenir des images des disques dans les systèmes binaires à éclipses. En utilisant la courbe de lumière, on peut remonter à la distribution radiale de la brillance de surface, en supposant que celle-ci a une symètrie axiale. D'autre part, les profils de raies renseignent sur la distribution de vitesse des régions émissives leur variation temporelle permet de réaliser une image dans l'espace des vitesses, que l'on peut ensuite transformer en carte dans l'espace (x,y) si on connaît la cinématique du système.

  10. In vitro and in vivo effects of kinin B1 and B2 receptor agonists and antagonists in inbred control and cardiomyopathic hamsters

    PubMed Central

    Hall, S; Gobeil, F; Ouellette, J; Lambert, C; Regoli, D

    2000-01-01

    The aims of this study were to examine the possible alterations occurring in the effects of kinins on isolated aortae of inbred control (CHF 148) and cardiomyopathic (CHF 146) hamsters of 150175 and 350375 days of age.Bradykinin (BK) and desArg9BK contracted isolated aortae (with or without endothelium) of hamsters of both strains and ages. After tissue equilibration (90?min), responses elicited by both kinin agonists were stable over the time of experiments. The patterns of isometric contractions of BK and desArg9BK were however found to be different; desArg9BK had a slower onset and a longer duration of action than BK.Potencies (pEC50 values) of BK in all groups of hamsters were significantly increased by preincubating the tissues with captopril (10?5?M).No differences in the pEC50 values and the Emax values for BK or desArg9BK were seen between isolated vessels from inbred control and cardiomyopathic hamsters.The myotropic effect of BK was inhibited by the selective non peptide antagonist, FR 173657 (pIC50 7.250.12 at the bradykinin B2 receptor subtype (B2 receptor)). Those of desArg9BK, at the bradykinin B1 receptor subtype (B1 receptor) were abolished by either R 715 (pIC50 of 7.550.05; ?E=0), Lys[Leu8]desArg9BK (pIC50 of 7.210.01; ?E=0.22) or [Leu8]desArg9BK (pIC50 of 7.250.02; ?E=0.18).FR 173657 had no agonistic activity, exerted a non competitive type of antagonism and was poorly reversible (lasting more than 5?h) from B2 receptor. In vivo, FR 173657 (given per os at 1 and 5?mg?kg?1, 1?h before the experiment) antagonized the acute hypotensive effect of BK in anaesthetized hamsters.It is concluded that aging and/or the presence of a congenital cardiovascular disorder in hamsters are not associated with changes in the in vitro aortic responses to either BK or desArg9BK. PMID:10780969

  11. Non-equivalent ligand selectivity of agonist sites in (?4?2)2?4 nicotinic acetylcholine receptors: a key determinant of agonist efficacy.

    PubMed

    Mazzaferro, Simone; Gasparri, Federica; New, Karina; Alcaino, Constanza; Faundez, Manuel; Iturriaga Vasquez, Patricio; Vijayan, Ranjit; Biggin, Philip C; Bermudez, Isabel

    2014-08-01

    The ?4?2 nicotinic acetylcholine receptor (nAChR) is the most abundant nAChR type in the brain, and this receptor type exists in alternate (?4?2)2?4 and (?4?2)2?2 forms, which are activated by agonists with strikingly differing efficacies. Recent breakthroughs have identified an additional operational agonist binding site in the (?4?2)2?4 nAChR that is responsible for the signature sensitivity of this receptor to activation by agonists, yet the structural mechanisms determining agonist efficacy at this receptor type are not yet fully understood. In this study, we characterized the ligand selectivity of the individual agonist sites of the (?4?2)2?4 nAChR to determine whether differences in agonist selectivity influence agonist efficacy. Applying the substituted cysteine accessibility method to individual agonist sites in concatenated (?4?2)2?4 receptors, we determined the agonist selectivity of the agonist sites of the (?4?2)2?4 receptor. We show that (a) accessibility of substituted cysteines to covalent modification by methanesulfonate reagent depends on the agonist site at which the modification occurs and (b) that agonists such as sazetidine-A and TC-2559 are excluded from the site at the ?4/?4 interface. Given that additional binding to the agonist site in the ?4/?4 interface increases acetylcholine efficacy and that agonists excluded from the agonist site at the ?4/?4 interface behave as partial agonists, we conclude that the ability to engage all agonist sites in (?4?2)2?4 nAChRs is a key determinant of agonist efficacy. The findings add another level of complexity to the structural mechanisms that govern agonist efficacy in heteromeric nAChRs and related ligand-gated ion channels. PMID:24936069

  12. [PPAR receptors and insulin sensitivity: new agonists in development].

    PubMed

    Pgorier, J-P

    2005-04-01

    Thiazolidinediones (or glitazones) are synthetic PPARgamma (Peroxisome Proliferator-Activated Receptors gamma) ligands with well recognized effects on glucose and lipid metabolism. The clinical use of these PPARgamma agonists in type 2 diabetic patients leads to an improved glycemic control and an inhanced insulin sensitivity, and at least in animal models, to a protective effect on pancreatic beta-cell function. However, they can produce adverse effects, generally mild or moderate, but some of them (mainly peripheral edema and weight gain) may conduct to treatment cessation. Several pharmacological classes are currently in pre-clinical or clinical development, with the objective to retain the beneficial metabolic properties of PPARgamma agonists, either alone or in association with the PPARalpha agonists (fibrates) benefit on lipid profile, but devoid of the side-effects on weight gain and fluid retention. These new pharmacological classes: partial PPARgamma agonists, PPARgamma antagonists, dual PPARalpha/PPARgamma agonists, pan PPARalpha/beta(delta)/gamma agonists, RXR receptor agonists (rexinoids), are presented in this review. Main results from in vitro cell experiments and animal model studies are discussed, as well as the few published short-term studies in type 2 diabetic patients. PMID:15959400

  13. Toll-like receptor 2 agonists inhibit human fibrocyte differentiation

    PubMed Central

    2010-01-01

    Background In healing wounds, some monocytes enter the wound and differentiate into fibroblast-like cells called fibrocytes. Since Toll-like receptors (TLRs) are present on monocytes, and pathogens that can infect a wound have and/or release TLR agonists, we examined whether TLR agonists affect fibrocyte differentiation. Results When human peripheral blood mononuclear cells (PBMCs) were cultured with TLR3, TLR4, TLR5, TLR7, TLR8 or TLR9 agonists, there was no significant effect on fibrocyte differentiation, even though enhanced extracellular tumor necrosis factor (TNF)-? accumulation and/or increased cell surface CD86 or major histocompatibility complex (MHC) class II levels were observed. However, all TLR2 agonists tested inhibited fibrocyte differentiation without any significant effect on cell survival. Adding TLR2 agonists to purified monocytes had no effect on fibrocyte differentiation. However, some TLR2 agonists caused PBMCs to secrete a factor that inhibits the differentiation of purified monocytes into fibrocytes. This factor is not interferon (IFN)-?, IFN-?, interleukin (IL)-12, aggregated immunoglobulin G (IgG) or serum amyloid P (SAP), factors known to inhibit fibrocyte differentiation. TLR2 agonist-treated PBMCs secrete low levels of IL-6, TNF-?, IFN-?, granulocyte colony-stimulating factor and tumor growth factor ?1, but combinations of these factors had no effect on fibrocyte differentiation from purified monocytes. Conclusions Our results indicate that TLR2 agonists indirectly inhibit fibrocyte differentiation and that, for some TLR2 agonists, this inhibition involves other cell types in the PBMC population secreting an unknown factor that inhibits fibrocyte differentiation. Together, these data suggest that the presence of some bacterial signals can inhibit fibrocyte differentiation and may thus slow wound closure. PMID:21106092

  14. Relamorelin: A Novel Gastrocolokinetic Synthetic Ghrelin Agonist

    PubMed Central

    Camilleri, Michael; Acosta, Andres

    2015-01-01

    Synthetic ghrelin agonists, predominantly small molecules, are being developed as prokinetic agents that may prove useful in the treatment of gastrointestinal motility disorders. Relamorelin (RM-131) is a pentapeptide synthetic ghrelin analog that activates the growth hormone secretagogue (GHS)-1a (also called the ghrelin) receptor with approximately 6-fold greater potency than natural ghrelin. The ability of relamorelin to stimulate growth hormone (GH) release is comparable to that of native ghrelin. Relamorelin has enhanced efficacy and plasma stability compared to native ghrelin. In this review, we discuss the pharmacokinetics, pharmacodynamics and potential indications for relamorelin. Relamorelin is administered subcutaneously, dosed daily or twice daily. Relamorelin is being studied for the treatment of patients with gastrointestinal motility disorders. Phase IIA pharmacodynamic studies have demonstrated acceleration of gastric emptying in patients with type 1 diabetes mellitus (T1DM) and type 2 DM (T2DM) and upper gastrointestinal symptoms. In a phase IIA study in patients with diabetic gastroparesis, relamorelin accelerated gastric emptying and significantly improved vomiting frequency compared to placebo and improved other symptoms of gastroparesis in a pre-specified subgroup of patients with vomiting at baseline. In patients with chronic idiopathic constipation with defined transit profile at baseline, relamorelin relieved constipation and accelerated colonic transit compared to placebo. These characteristics suggest that this new ghrelin analog shows great promise to relieve patients with upper or lower gastrointestinal motility disorders. PMID:25545036

  15. [Choosing a dopamine agonist in Parkinson's disease].

    PubMed

    Bogucki, Andrzej; Gajos, Agata

    2007-01-01

    The number of dopamine agonists (DA) used in Parkinson's disease (PD) is gradually increasing. They have different affinity to the dopamine receptor subtypes. When choosing one of these drugs one should consider its efficacy in monotherapy in early phase and in combined therapy with levodopa in advanced PD, side effects profile, effectiveness in non-motor symptoms of PD, dosing and route of administration. The efficacy of new DA (pramipexol, ropinirol, cabergoline) is probably higher than bromocriptine and comparable to pergolide with similar profile of the most common side effects (headache, vertigo, nausea, somnolence, oedema). However, fibrosis of the pleura, peritoneum and pericardium as well as valvular heart disease (caused by noninflammatory fibrotic degeneration) are significantly more common after ergoline DA (pergolide, cabergoline). Pramipexol shows antidepressant activity. Ropinirol is metabolised by the liver and can be safely administered in renal insufficiency. Pramipexol is excreted in urine and the risk of interaction with other drugs metabolised in the liver is reduced. Rotigotine is the only DA available as skin patches. Whenever necessary, one DA agent can be changed safely overnight to another one. PMID:17941454

  16. Psychotogenic properties of benzodiazepine receptor inverse agonists.

    PubMed

    Sarter, M; Bruno, J P; Berntson, G G

    2001-06-01

    The neurochemical, behavioral, and cognitive effects of the benzodiazepine receptor partial inverse agonist beta-carboline FG 7142 (FG), a drug traditionally described as exhibiting 'anxiogenic' effects, are proposed to model core components of present theories of the neuronal mechanisms of schizophrenia. FG activates the mesolimbic dopaminergic system and, via increases in dopaminergic activity in the nucleus accumbens, disinhibits corticopetal cholinergic projections. The latter effect of FG is hypothesized to mediate the hyperattentional impairments that contribute to the development of psychotic cognition. Furthermore, the FG-induced abnormal overprocessing of conditioned stimuli and contexts provides an explanation of the 'anxiogenic' effects of FG. The FG-induced increases in the activity of cortical cholinergic inputs and the FG-induced cognitive impairments in rats and monkeys were demonstrated to be attenuated by the administration of typical and atypical antipsychotic drugs. Compared to the classic psychotogenic drugs amphetamine and phencyclidine, the effects of FG serve as an alternative psychotogenic manipulation in research focusing on the cortical and cognitive aspects of current theories of schizophrenia. PMID:11465627

  17. Grundlagen des Tissue Engineering

    NASA Astrophysics Data System (ADS)

    Mayer, Jrg; Blum, Janaki; Wintermantel, Erich

    Die Organtransplantation stellt eine verbreitete Therapie dar, um bei krankheitsoder unfallbedingter Schdigung eines Organs die Gesamtheit seiner Funktionen wieder herzustellen, indem es durch ein Spenderorgan ersetzt wird. Organtransplantationen werden fr die Leber, die Niere, die Lunge, das Herz oder bei schweren grossflchigen Verbrennungen der Haut vorgenommen. Der grosse apparative, personelle und logistische Aufwand und die Risiken der Transplantationschirurgie (Abstossungsreaktionen) sowie die mangelnde Verfgbarkeit von immunologisch kompatiblen Spenderorganen fhren jedoch dazu, dass der Bedarf an Organtransplantaten nur zu einem sehr geringen Teil gedeckt werden kann. Sind Spenderorgane nicht verfgbar, knnen in einzelnen Fllen lebenswichtige Teilfunktionen, wie beispielsweise die Filtrationsfunktion der Niere durch die Blutreinigung mittels Dialyse ersetzt oder, bei mangelnder Funktion der Bauchspeicheldrse (Diabetes), durch die Verabreichung von Insulin ein normaler Zustand des Gesamtorganismus auch ber Jahre hinweg erhalten werden. Bei der notwendigen lebenslangen Anwendung apparativer oder medikamentser Therapie knnen fr den Patienten jedoch hufig schwerwiegende, mglicherweise lebensverkrzende Nebenwirkungen entstehen. Daher werden in der Forschung Alternativen gesucht, um die Funktionen des ausgefallenen Organs durch die Implantation von Zellen oder in vitro gezchteten Geweben mglichst umfassend wieder herzustellen. Dies erfordert biologisch aktive Implantate, welche die fr den Stoffwechsel des Organs wichtigen Zellen enthalten und einen organtypischen Stoffwechsel entfalten.

  18. Agonist Replacement for Stimulant Dependence: A Review of Clinical Research

    PubMed Central

    Stoops, William W.; Rush, Craig R.

    2013-01-01

    Stimulant use disorders are an unrelenting public health concern worldwide. Agonist replacement therapy is among the most effective strategies for managing substance use disorders including nicotine and opioid dependence. The present paper reviewed clinical data from human laboratory self-administration studies and clinical trials to determine whether agonist replacement therapy is a viable strategy for managing cocaine and/or amphetamine use disorders. The extant literature suggests that agonist replacement therapy may be effective for managing stimulant use disorders, however, the clinical selection of an agonist replacement medication likely needs to be based on the pharmacological mechanism of the medication and the stimulant abused by patients. Specifically, dopamine releasers appear most effective for reducing cocaine use whereas dopamine reuptake inhibitors appear most effective for reducing amphetamine use. PMID:23574440

  19. Agonist pharmacology of two Drosophila GABA receptor splice variants.

    PubMed Central

    Hosie, A. M.; Sattelle, D. B.

    1996-01-01

    1. The Drosophila melanogaster gamma-aminobutyric acid (GABA) receptor subunits, RDLac and DRC 17-1-2, form functional homo-oligomeric receptors when heterologously expressed in Xenopus laevis oocytes. The subunits differ in only 17 amino acids, principally in regions of the N-terminal domain which determine agonist pharmacology in vertebrate ionotropic neurotransmitter receptors. A range of conformationally restricted GABA analogues were tested on the two homo-oligomers and their agonists pharmacology compared with that of insect and vertebrate iontropic GABA receptors. 2. The actions of GABA, isoguvacine and isonipecotic acid on RDLac and DRC 17-1-2 homo-oligomers were compared, by use of two-electrode voltage-clamp. All three compounds were full agonists of both receptors, but were 4-6 fold less potent agonists of DRC 17-1-2 homo-oligomers than of RDLac. However, the relative potencies of these agonists on each receptor were very similar. 3. A more complete agonist profile was established for RDLac homo-oligomers. The most potent agonists of these receptors were GABA, muscimol and trans-aminocrotonic acid (TACA), which were approximately equipotent. RDLac homo-oligomers were fully activated by a range of GABA analogues, with the order of potency: GABA > ZAPA ((Z)-3-[(aminoiminomethyl)thio]prop-2-enoic acid) > isoguvacine > imidazole-4-acetic acid > or = isonipecotic acid > or = cis-aminocrotonic acid (CACA) > beta-alanine. 3-Aminopropane sulphonic acid (3-APS), a partial agonist of RDLac homo-oligomers, was the weakest agonist tested and 100 fold less potent than GABA. 4. SR95531, an antagonist of vertebrate GABAA receptors, competitively inhibited the GABA responses of RDLac homo-oligomers, which have previously been found to insensitive to bicuculline. However, its potency (IC50 500 microM) was much reduced when compared to GABAA receptors. 5. The agonist pharmacology of Drosophila RDLac homo-oligomers exhibits aspects of the characteristic pharmacology of certain native insect GABA receptors which distinguish them from vertebrate GABA receptors. The high potency and efficacy of isoguvacine and ZAPA distinguishes RDLac homo-oligomers from bicuculline-insensitive vertebrate GABAC receptors, while the low potency of SR95531 and 3-APS distinguishes them from GABAA receptors. The differences in the potency of agonists on RDLac and DRC 17-1-2 homo-oligomers observed in the present study may assist in identification of further molecular determinants of GABA receptor function. PMID:8982504

  20. 5-HT4 receptor agonists: similar but not the same.

    PubMed

    De Maeyer, J H; Lefebvre, R A; Schuurkes, J A J

    2008-02-01

    5-Hydroxytryptamine(4) (5-HT(4)) receptors are an interesting target for the management of patients in need of gastrointestinal (GI) promotility treatment. They have proven therapeutic potential to treat patients with GI motility disorders. Lack of selectivity for the 5-HT(4) receptor has limited the clinical success of the agonists used until now. For instance, next to their affinity for 5-HT(4) receptors, both cisapride and tegaserod have appreciable affinity for other receptors, channels or transporters [e.g. cisapride: human ether-a-go-go-related gene (hERG) is K(+) channel and tegaserod: 5-HT(1) and 5-HT(2) receptors]. Adverse cardiovascular events observed with these compounds are not 5-HT(4) receptor-related. Recent efforts have led to the discovery of a series of selective 5-HT(4) receptor ligands, with prucalopride being the most advanced in clinical development. The selectivity of these new compounds clearly differentiates them from the older generation compounds by minimizing the potential of target-unrelated side effects. The availability of selective agonists enables the focus to shift to the exploration of 5-HT(4) receptor-related differences between agonists. Based on drug- and tissue-related properties (e.g. differences in receptor binding, receptor density, effectors, coupling efficiency), 5-HT(4) receptor agonists are able to express tissue selectivity, i.e. behave as a partial agonist in some and as a full agonist in other tissues. Furthermore, the concept of ligand-directed signalling offers great opportunities for future drug development by enlarging the scientific basis for the generation of agonist-specific effects in different cell types, tissues or organs. Selective 5-HT(4) receptor agonists might thus prove to be innovative drugs with an attractive safety profile for better treatment of patients suffering from hypomotility disorders. PMID:18199093

  1. [Effects of GLP-1 receptor agonists on carbohydrate metabolism control].

    PubMed

    Fernndez-Garca, Jos Carlos; Colomo, Natalia; Tinahones, Francisco Jos

    2014-09-01

    Glucagon-like peptide-1 (GLP-1) receptor agonists are a new group of drugs for the treatment of type 2 diabetes mellitus (DM2). In the present article, we review the available evidence on the efficacy of GLP-1 receptor agonists as glucose-lowering agents, their place in therapeutic algorithms, and the clinical factors associated with a favorable treatment response. Finally, we describe the clinical characteristics of patients who may benefit from these drugs. PMID:25437461

  2. [Effects of GLP-1 receptor agonists on carbohydrate metabolism control].

    PubMed

    Fernndez-Garca, Jos Carlos; Colomo, Natalia; Tinahones, Francisco Jos

    2014-01-01

    Glucagon-like peptide-1 (GLP-1) receptor agonists are a new group of drugs for the treatment of type 2 diabetes mellitus (DM2). In the present article, we review the available evidence on the efficacy of GLP-1 receptor agonists as glucose-lowering agents, their place in therapeutic algorithms, and the clinical factors associated with a favorable treatment response. Finally, we describe the clinical characteristics of patients who may benefit from these drugs. PMID:25326839

  3. Identification of M-CSF agonists and antagonists

    DOEpatents

    Pandit, Jayvardhan; Jancarik, Jarmila; Kim, Sung-Hou; Koths, Kirston; Halenbeck, Robert; Fear, Anna Lisa; Taylor, Eric; Yamamoto, Ralph; Bohm, Andrew

    2000-02-15

    The present invention is directed to methods for crystallizing macrophage colony stimulating factor. The present invention is also directed to methods for designing and producing M-CSF agonists and antagonists using information derived from the crystallographic structure of M-CSF. The invention is also directed to methods for screening M-CSF agonists and antagonists. In addition, the present invention is directed to an isolated, purified, soluble and functional M-CSF receptor.

  4. The Cardiovascular Effects of GLP-1 Receptor Agonists

    PubMed Central

    Okerson, Theodore; Chilton, Robert J

    2012-01-01

    Glucagon-like peptide-1 receptor (GLP-1R) agonists have been shown to regulate blood glucose concentrations by mechanisms including enhanced insulin synthesis/secretion, suppressed glucagon secretion, slowed gastric emptying, and enhanced satiety. GLP-1 receptors have also been identified in the heart, kidneys, and blood vessels, leading to the hypothesis that GLP-1R agonists may affect cardiovascular function or cardiovascular disease (CVD). The aim of this literature review was to assemble and assess preclinical and clinical data of potential medical importance regarding the cardiovascular effects of GLP-1R agonists. Preclinical studies with the GLP-1R agonists GLP-1, exenatide, or liraglutide provided evidence that GLP-1R stimulation favorably affects endothelial function, sodium excretion, recovery from ischemic injury, and myocardial function in animals. Similar observations have been made in exploratory studies on GLP-1 infusion in normal subjects and patients with type 2 diabetes. Post hoc analyses of phase III studies of patients with type 2 diabetes treated with exenatide(bid or qw) or liraglutide(qd) showed that these GLP-1R agonists reduced blood pressure, an effect largely independent of weight loss, and that liraglutide slightly increased heart rate. Preliminary data also indicated that GLP-1R agonists reduced markers of CVD risk such as C-reactive protein and plasminogen activator inhibitor-1. Ongoing studies are examining the effects of administering GLP-1R agonists to patients at risk of CVD, postangioplasty patients, post-CABG patients, and patients with heart failure. Additional studies should provide meaningful data to determine whether GLP-1R agonists provide unique treatment benefits to patients at risk for or with established CVD. PMID:21167014

  5. The cardiovascular effects of GLP-1 receptor agonists.

    PubMed

    Okerson, Theodore; Chilton, Robert J

    2012-06-01

    Glucagon-like peptide-1 receptor (GLP-1R) agonists have been shown to regulate blood glucose concentrations by mechanisms including enhanced insulin synthesis/secretion, suppressed glucagon secretion, slowed gastric emptying, and enhanced satiety. GLP-1 receptors have also been identified in the heart, kidneys, and blood vessels, leading to the hypothesis that GLP-1R agonists may affect cardiovascular function or cardiovascular disease (CVD). The aim of this literature review was to assemble and assess preclinical and clinical data of potential medical importance regarding the cardiovascular effects of GLP-1R agonists. Preclinical studies with the GLP-1R agonists GLP-1, exenatide, or liraglutide provided evidence that GLP-1R stimulation favorably affects endothelial function, sodium excretion, recovery from ischemic injury, and myocardial function in animals. Similar observations have been made in exploratory studies on GLP-1 infusion in normal subjects and patients with type 2 diabetes. Post hoc analyses of phase III studies of patients with type 2 diabetes treated with exenatide(bid or qw) or liraglutide(qd) showed that these GLP-1R agonists reduced blood pressure, an effect largely independent of weight loss, and that liraglutide slightly increased heart rate. Preliminary data also indicated that GLP-1R agonists reduced markers of CVD risk such as C-reactive protein and plasminogen activator inhibitor-1. Ongoing studies are examining the effects of administering GLP-1R agonists to patients at risk of CVD, postangioplasty patients, post-CABG patients, and patients with heart failure. Additional studies should provide meaningful data to determine whether GLP-1R agonists provide unique treatment benefits to patients at risk for or with established CVD. PMID:21167014

  6. Differential effects of AMPK agonists on cell growth and metabolism.

    PubMed

    Vincent, E E; Coelho, P P; Blagih, J; Griss, T; Viollet, B; Jones, R G

    2015-07-01

    As a sensor of cellular energy status, the AMP-activated protein kinase (AMPK) is believed to act in opposition to the metabolic phenotypes favored by proliferating tumor cells. Consequently, compounds known to activate AMPK have been proposed as cancer therapeutics. However, the extent to which the anti-neoplastic properties of these agonists are mediated by AMPK is unclear. Here we examined the AMPK dependence of six commonly used AMPK agonists (metformin, phenformin, 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), 2-deoxy-D-glucose (2DG), salicylate and A-769662) and their influence on cellular processes often deregulated in tumor cells. We demonstrate that the majority of these agonists display AMPK-independent effects on cell proliferation and metabolism with only the synthetic activator, A-769662, exerting AMPK-dependent effects on these processes. We find that A-769662 promotes an AMPK-dependent increase in mitochondrial spare respiratory capacity. Finally, contrary to the view of AMPK activity being tumor suppressive, we find that A-769662 confers a selective proliferative advantage to tumor cells growing under nutrient deprivation. Our results indicate that many of the antigrowth properties of these agonists cannot be attributed to AMPK activity in cells, and thus any observed effects using these agonists should be confirmed using AMPK-deficient cells. Ultimately, our data urge caution not only regarding the type of AMPK agonist proposed for cancer treatment but also the context in which they are used. PMID:25241895

  7. Analyse des intensits et filtrage des nergies en mission lectronique

    NASA Astrophysics Data System (ADS)

    Duval, P.; Blaise, G.; Henry, L.

    1991-10-01

    A different method for using a dispersive system consisting of a magnetic prism and an electrostatic mirror is proposed. This method allows one to study electron intensities and energies coming from the surface of a sample which has been bombarded by an electron beam of a given energy. Le systme dispersif constitu d'un prisme magntique et d'un miroir lectrostatique, utilis jusqu' prsent en microscopie lectronique par transmission pour l'analyse et le filtrage des nergies des lectrons transmis travers une couche mince, peut tre adapt pour constituer une nouvelle mthode d'tude des intensits et des nergies des lectrons diffuss par la surface d'un chantillon bombard par un faisceau d'lectrons d'nergie choisie.

  8. Dihydrocodeine/Agonists for Alcohol Dependents

    PubMed Central

    Ulmer, Albrecht; Mller, Markus; Frietsch, Bernhard

    2012-01-01

    Objective: Alcohol addiction too often remains insufficiently treated. It shows the same profile as severe chronic diseases, but no comparable, effective basic treatment has been established up to now. Especially patients with repeated relapses, despite all therapeutic approaches, and patients who are not able to attain an essential abstinence to alcohol, need a basic medication. It seems necessary to acknowledge that parts of them need any agonistic substance, for years, possibly lifelong. For >14?years, we have prescribed such substances with own addictive character for these patients. Methods: We present a documented best possible practice, no designed study. Since 1997, we prescribed Dihydrocodeine (DHC) to 102 heavily alcohol addicted patients, later, also Buprenorphine, Clomethiazole (>6?weeks), Baclofen, and in one case Amphetamine, each on individual indication. This paper focuses on the data with DHC, especially. The Clomethiazole-data has been submitted to a German journal. The number of treatments with the other substances is still low. Results: The 102 patients with the DHC treatment had 1367 medically assisted detoxifications and specialized therapies before! The 4?years-retention rate was 26.4%, including 2.8% successfully terminated treatments. In our 12-steps scale on clinical impression, we noticed a significant improvement from mean 3.7 to 8.4 after 2?years. The demand for medically assisted detoxifications in the 2?years remaining patients was reduced by 65.5%. Mean GGT improved from 206.6?U/l at baseline to 66.8?U/l after 2?years. Experiences with the other substances are similar but different in details. Conclusion: Similar to the Italian studies with GHB and Baclofen, we present a new approach, not only with new substances, but also with a new setting and much more trusting attitude. We observe a huge improvement, reaching an almost optimal, stable, long term status in around 1/4 of the patients already. Many further optimizations are possible. PMID:22470353

  9. Impact of Efficacy at the ?-Opioid Receptor on Antinociceptive Effects of Combinations of ?-Opioid Receptor Agonists and Cannabinoid Receptor Agonists

    PubMed Central

    Maguire, David R.

    2014-01-01

    Cannabinoid receptor agonists, such as ?9-tetrahydrocannabinol (?9-THC), enhance the antinociceptive effects of ?-opioid receptor agonists, which suggests that combining cannabinoids with opioids would improve pain treatment. Combinations with lower efficacy agonists might be preferred and could avoid adverse effects associated with large doses; however, it is unclear whether interactions between opioids and cannabinoids vary across drugs with different efficacy. The antinociceptive effects of ?-opioid receptor agonists alone and in combination with cannabinoid receptor agonists were studied in rhesus monkeys (n = 4) using a warm water tail withdrawal procedure. Etorphine, fentanyl, morphine, buprenorphine, nalbuphine, ?9-THC, and CP 55,940 (2-[(1R,2R,5R)-5-hydroxy-2-(3-hydroxypropyl) cyclohexyl]-5-(2-methyloctan-2-yl)phenol) each increased tail withdrawal latency. Pretreatment with doses of ?9-THC (1.0 mg/kg) or CP 55,940 (0.032 mg/kg) that were ineffective alone shifted the fentanyl dose-effect curve leftward 20.6- and 52.9-fold, respectively, and the etorphine dose-effect curve leftward 12.4- and 19.6-fold, respectively. ?9-THC and CP 55,940 shifted the morphine dose-effect curve leftward only 3.4- and 7.9-fold, respectively, and the buprenorphine curve only 5.4- and 4.1-fold, respectively. Neither ?9-THC nor CP 55,940 significantly altered the effects of nalbuphine. Cannabinoid receptor agonists increase the antinociceptive potency of higher efficacy opioid receptor agonists more than lower efficacy agonists; however, because much smaller doses of each drug can be administered in combinations while achieving adequate pain relief and that other (e.g., abuse-related) effects of opioids do not appear to be enhanced by cannabinoids, these results provide additional support for combining opioids with cannabinoids to treat pain. PMID:25194020

  10. Impact of efficacy at the ?-opioid receptor on antinociceptive effects of combinations of ?-opioid receptor agonists and cannabinoid receptor agonists.

    PubMed

    Maguire, David R; France, Charles P

    2014-11-01

    Cannabinoid receptor agonists, such as ?(9)-tetrahydrocannabinol (?(9)-THC), enhance the antinociceptive effects of ?-opioid receptor agonists, which suggests that combining cannabinoids with opioids would improve pain treatment. Combinations with lower efficacy agonists might be preferred and could avoid adverse effects associated with large doses; however, it is unclear whether interactions between opioids and cannabinoids vary across drugs with different efficacy. The antinociceptive effects of ?-opioid receptor agonists alone and in combination with cannabinoid receptor agonists were studied in rhesus monkeys (n = 4) using a warm water tail withdrawal procedure. Etorphine, fentanyl, morphine, buprenorphine, nalbuphine, ?(9)-THC, and CP 55,940 (2-[(1R,2R,5R)-5-hydroxy-2-(3-hydroxypropyl) cyclohexyl]-5-(2-methyloctan-2-yl)phenol) each increased tail withdrawal latency. Pretreatment with doses of ?(9)-THC (1.0 mg/kg) or CP 55,940 (0.032 mg/kg) that were ineffective alone shifted the fentanyl dose-effect curve leftward 20.6- and 52.9-fold, respectively, and the etorphine dose-effect curve leftward 12.4- and 19.6-fold, respectively. ?(9)-THC and CP 55,940 shifted the morphine dose-effect curve leftward only 3.4- and 7.9-fold, respectively, and the buprenorphine curve only 5.4- and 4.1-fold, respectively. Neither ?(9)-THC nor CP 55,940 significantly altered the effects of nalbuphine. Cannabinoid receptor agonists increase the antinociceptive potency of higher efficacy opioid receptor agonists more than lower efficacy agonists; however, because much smaller doses of each drug can be administered in combinations while achieving adequate pain relief and that other (e.g., abuse-related) effects of opioids do not appear to be enhanced by cannabinoids, these results provide additional support for combining opioids with cannabinoids to treat pain. PMID:25194020

  11. Cloning and functional characterization of the ornithokinin receptor. Recognition of the major kinin receptor antagonist, HOE140, as a full agonist.

    PubMed

    Schroeder, C; Beug, H; Mller-Esterl, W

    1997-05-01

    Kinins are proinflammatory peptides that dilate vessels, increase vascular permeability, contract smooth muscles, and provoke pain. The known mammalian kinin receptors are classified as two subtypes, i.e. the B1 receptor triggered by [des-Arg9]bradykinin and inhibited by [des-Arg9,Leu8]bradykinin, and the B2 receptor stimulated by bradykinin and antagonized by HOE140. Here we report the cloning of a non-mammalian kinin receptor gene amplified from genomic chicken DNA. The protein predicted from the open reading frame shows 31 and 49% sequence identity to the human B1 and B2 receptors, respectively, suggesting that it represents a G protein-coupled receptor of the kinin receptor family. The recombinantly expressed chicken receptor had IC50 values of 4.7 nM for the authentic ligand, ornithokinin ([Thr6,Leu8]bradykinin), 3.8 nM for HOE140, and >/=10 microM for bradykinin, [des-Arg9]bradykinin, and [des-Arg9,Leu8]bradykinin. Ornithokinin and HOE140 at nanomolar concentrations stimulated intracellular inositol phosphate accumulation and induced a significant transient rise in intracelluar free Ca2+, whereas bradykinin was ineffective even at 100 nM. Hence the principal B2 receptor antagonist HOE140 is a potent agonist of the chicken kinin receptor. This unique pharmacological profile classifies the ornithokinin receptor as a novel subtype among kinin receptors and will facilitate further molecular studies on ligand binding and receptor activation. PMID:9139696

  12. Radiolabelled D/sub 2/ agonists as prolactinoma imaging agents: Progress report for period February 1, 1987-January 31, 1988

    SciTech Connect

    Otto, C.A.

    1987-11-07

    Three D/sub 2/ agonists, /sup 3/H-DHEC, /sup 3/H-BrCr and /sup 3/H-ADTN, were evaluated with /sup 3/H-DHEC showing the most promise as a potential prolactinoma imaging agent. Concentration vs time plots for all three compounds in normal and in DES-treated pituitary tissue are reported. The exceptional D/sub 2/ receptor affinity of N-0437 has prompted synthetic efforts towards preparation of iodo-N-0437 in spite of a lack of preliminary tissue distribution data. An evaluation of /sup 18/F-FDG uptake in the prolactinoma model and as a muscarinic ligand in control animals were evaluated. 2 refs., 3 figs.

  13. RXR Partial Agonist CBt-PMN Exerts Therapeutic Effects on Type 2 Diabetes without the Side Effects of RXR Full Agonists

    PubMed Central

    2012-01-01

    Treating insulin resistance and type 2 diabetes in rodents, currently known retinoid X receptor (RXR) agonists induce significant adverse effects. Here we introduce a novel RXR partial agonist CBt-PMN (11b), which shows a potent glucose-lowering effect and improvements of insulin secretion and glucose tolerance without the serious adverse effects caused by RXR full agonists. We suggest that RXR partial agonists may be a new class of antitype 2 diabetes drug candidates. PMID:24900488

  14. Methamphetamine-like discriminative-stimulus effects of nicotinic agonists.

    PubMed

    Desai, Rajeev I; Bergman, Jack

    2014-03-01

    Nicotine was recently shown to engender d-methamphetamine (MA)-like discriminative-stimulus effects in rats, which may be indicative of shared psychomotor stimulant properties. To further investigate such overlapping discriminative-stimulus effects, nicotinic agonists varying in efficacy and selectivity were studied in squirrel monkeys that discriminated a moderate intramuscular dose of MA (0.1 mg/kg) from vehicle. These included ?4?2-selective ligands that may vary in efficacy from relatively high [nicotine, (+)- and (-)-epibatidine] to relatively low [isoarecolone, varenicline, (-)-cytisine, (-)-lobeline] and the ?7-selective ligands anabaseine and anabasine. Results show that nicotine, (+)-epibatidine, and (-)-epibatidine substituted fully for MA, whereas the highest doses of other nicotinic agonists produced intermediate levels of MA-like effects (isoarecolone, anabaseine, anabasine, and varenicline) or did not substitute for MA [(-)-cytisine and (-)-lobeline]. The relative potencies of nicotinic agonists, based on effective dose50 (ED50) values, corresponded more closely with their relative affinities at ?4?2 than at ?7 receptors. Regardless of selectivity or efficacy, nicotinic agonists also were observed to produce untoward effects, including salivation and emesis during or after experimental sessions. In pretreatment studies, the ?4?2-selective antagonist dihydro-?-erythroidine hydrobromide (DH?E) (0.032 and 0.1 mg/kg) and the partial agonists varenicline (0.0032-0.1 mg/kg) and (-)-cytisine (0.032 and 0.1 mg/kg) surmountably antagonized (>10-fold rightward shift) nicotine's MA-like effects but were ineffective in blocking nicotine's emetic effects. Overall, our results show that 1) MA-like discriminative-stimulus effects of nicotinic agonists likely are mediated through ?4?2 nicotinic acetylcholine receptor actions, and 2) nicotinic ?4?2 partial agonists, like the nicotinic antagonist DH?E, can reduce MA-like behavioral effects of nicotine. PMID:24389640

  15. La participation des enfants et des adolescents la boxe

    PubMed Central

    Purcell, Laura K; LeBlanc, Claire MA

    2012-01-01

    RSUM Des milliers de garons et de filles de moins de 19 ans font de la boxe en Amrique du Nord. Mme si la boxe comporte des avantages pour ceux qui y participent, y compris lexercice, lautodiscipline et la confiance en soi, le sport lui-mme favorise et rcompense des coups dlibrs la tte et au visage. Les personnes qui font de la boxe risquent de subir des blessures la tte, au visage et au cou, y compris des traumatismes neurologiques chroniques et mme fatals. Les commotions crbrales sont lune des principales blessures causes par la boxe. En raison du risque de blessures crniennes et faciales, la Socit canadienne de pdiatrie et lAmerican Academy of Pediatrics sopposent vigoureusement la boxe comme activit sportive pour les enfants et les adolescents. Ces organismes recommandent que les mdecins slvent contre la boxe auprs des jeunes et les encouragent participer dautres activits dans lesquelles les coups intentionnels la tte ne constituent pas un lment essentiel du sport.

  16. March 2012 Timeline

    Cancer.gov

    DES Timeline Year Event 1938 Diethylstilbestrol (DES) was produced for use in pregnancy. 1940 DES was widely prescribed to women for use in threatened miscarriages and was promoted to physicians through medical publications and other communications.

  17. A propos des divergences en thorie des champs quantifis [83

    NASA Astrophysics Data System (ADS)

    Comme nous le montrons ailleurs1), la causalit impose la matrice S qui dcrit l'volution d'un systme une structure bien dtermine : lorsqu'on dveloppe celle-ci suivant les oprateurs de translation dans l'espace des quanta, les coefficients S^{(i)} left[ {tau ''; u''../tau '; u' \\cdot \\cdot } right] sont des intgrales multiples o n'apparaissent, cOt des champs lis un seul point de l'espace temps, que les functions*): D^c (x/y) = D^s (x/y) + _2^i D^1 (x/y) x ne y

  18. Benzodiazepine agonist and inverse agonist actions on GABAA receptor-operated chloride channels. II. Chronic effects of ethanol

    SciTech Connect

    Buck, K.J.; Harris, R.A. )

    1990-05-01

    Mice were made tolerant to and dependent on ethanol by administration of a liquid diet. Gamma-aminobutyric acid (GABA) receptor-dependent uptake of 36Cl- by mouse cortical microsacs was used to study the actions of benzodiazepine (BZ) agonists and inverse agonists. Chronic exposure to ethanol attenuated the ability of a BZ agonist, flunitrazepam, to augment muscimol-stimulated uptake of 36Cl- and enhanced the actions of BZ inverse agonists, Ro15-4513 (ethyl-8-azido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo(1,4)-benzodiazepine - 3-carboxylate) and DMCM (methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate), to inhibit GABAA receptor-operated chloride channels. Augmentation of chloride flux by pentobarbital was not reduced by chronic ethanol exposure. Attenuation of flunitrazepam efficacy was transient and returned to control levels within 6 to 24 hr after withdrawal from ethanol, but increased sensitivity to Ro15-4513 was observed as long as 8 days after withdrawal. Chronic exposure to ethanol did not alter (3H)SR 95531 (2-(3'-carbethoxy-2'propyl)-3-amino-6-p-methoxyphenylpyridazinium bromide) binding to low-affinity GABAA receptors or muscimol stimulation of chloride flux; and did not alter (3H)Ro15-4513 or (3H)flunitrazepam binding to central BZ receptors or allosteric modulation of this binding by muscimol (i.e., muscimol-shift). These results suggest that chronic exposure to ethanol reduces coupling between BZ agonist sites and the chloride channel, and may be responsible for the development of cross-tolerance between ethanol and BZ agonists. In contrast, coupling between BZ inverse agonist sites and the chloride channel is increased.

  19. Modification of opiate agonist binding by pertussis toxin

    SciTech Connect

    Abood, M.E.; Lee, N.M.; Loh, H.H.

    1986-03-05

    Opiate agonist binding is decreased by GTP, suggesting the possible involvement of GTP binding proteins in regulation of opiate receptor binding. This possibility was addressed by asking whether pertussis toxin treatment, which results in ADP-ribosylation and modification of G proteins, would alter opiate agonist binding. The striatum was chosen for the initial brain area to be studied, since regulation of opiate action in this area had been shown to be modified by pertussis toxin. Treatment of striatal membranes with pertussis toxin results in up to a 55% decrease in /sup 3/(H)-DADLE binding as compared with membranes treated identically without toxin. This corresponds to a near complete ADP-ribosylation of both G proteins in the striatal membrane. The decrease in agonist binding appears to be due to an altered affinity of the receptor for agonist as opposed to a decrease in the number of sites. This effect of pertussis toxin on opiate agonist binding demonstrates the actual involvement of G proteins in regulation of opiate receptor binding.

  20. Tolerance with beta 2-adrenoceptor agonists: time for reappraisal.

    PubMed Central

    Grove, A; Lipworth, B J

    1995-01-01

    1. In spite of the widespread use of beta 2-adrenoceptor agonists in the treatment of asthma controversy continues regarding their possible role in increasing asthma mortality and morbidity. There is however no evidence available to suggest that tolerance to the bronchodilator or anti-bronchoconstrictor effects of these drugs is responsible for the deleterious effects reported with the regular use of bronchodilators. 2. There is no conclusive evidence to suggest that tolerance develops to the bronchodilator effects of short-acting beta 2-adrenoceptor agonists. Tolerance does however appear to develop to the anti-bronchoconstrictor effects of these drugs. 3. With regard to the long-acting beta 2-adrenoceptor agonists, there is evidence to suggest that tolerance develops both to their anti-bronchoconstrictor, and bronchodilator effects. Tolerance was however demonstrated in the presence of improved symptom control, therefore the clinical relevance of this phenomenon is uncertain. 4. Systemic corticosteroids can modulate lymphocyte beta 2-adrenoceptor function both preventing, and reversing tolerance. The situation regarding the effects of systemic or inhaled corticosteroids on modulating bronchodilator responses in asthmatics is less clear. There is some evidence to suggest that inhaled corticosteroids are unable to prevent bronchodilator or systemic tolerance to long-acting beta 2-adrenoceptor agonists. 5. On the basis of the current evidence, the British Thoracic Society guidelines for the management of asthma appear appropriate with regard to their recommendations for the use of long-acting beta 2-adrenoceptor agonists. PMID:7742147

  1. Honokiol: A non-adipogenic PPARγ agonist from nature☆

    PubMed Central

    Atanasov, Atanas G.; Wang, Jian N.; Gu, Shi P.; Bu, Jing; Kramer, Matthias P.; Baumgartner, Lisa; Fakhrudin, Nanang; Ladurner, Angela; Malainer, Clemens; Vuorinen, Anna; Noha, Stefan M.; Schwaiger, Stefan; Rollinger, Judith M.; Schuster, Daniela; Stuppner, Hermann; Dirsch, Verena M.; Heiss, Elke H.

    2013-01-01

    Background Peroxisome proliferator-activated receptor gamma (PPARγ) agonists are clinically used to counteract hyperglycemia. However, so far experienced unwanted side effects, such as weight gain, promote the search for new PPARγ activators. Methods We used a combination of in silico, in vitro, cell-based and in vivo models to identify and validate natural products as promising leads for partial novel PPARγ agonists. Results The natural product honokiol from the traditional Chinese herbal drug Magnolia bark was in silico predicted to bind into the PPARγ ligand binding pocket as dimer. Honokiol indeed directly bound to purified PPARγ ligand-binding domain (LBD) and acted as partial agonist in a PPARγ-mediated luciferase reporter assay. Honokiol was then directly compared to the clinically used full agonist pioglitazone with regard to stimulation of glucose uptake in adipocytes as well as adipogenic differentiation in 3T3-L1 pre-adipocytes and mouse embryonic fibroblasts. While honokiol stimulated basal glucose uptake to a similar extent as pioglitazone, it did not induce adipogenesis in contrast to pioglitazone. In diabetic KKAy mice oral application of honokiol prevented hyperglycemia and suppressed weight gain. Conclusion We identified honokiol as a partial non-adipogenic PPARγ agonist in vitro which prevented hyperglycemia and weight gain in vivo. General significance This observed activity profile suggests honokiol as promising new pharmaceutical lead or dietary supplement to combat metabolic disease, and provides a molecular explanation for the use of Magnolia in traditional medicine. PMID:23811337

  2. Les Applications Therapeutiques Des Lasers

    NASA Astrophysics Data System (ADS)

    Brunetaud, J. M.; Mordon, S.; Bourez, J.; Mosquet, L.; Moschetto, Y.

    1984-03-01

    C'est de tres loin le mecanisme predominant dans les applications therapeutiques du laser. En concentrant le flux lumineux sur une surface redui-te, le laser chauffe localement les tissus qui se retractent (coagulation) pour etre elimines ensuite (detersion) ; si on chauffe plus intensement, les tissus peuvent etre volatilises. La coagulation est utilisee soit pour detruire de petits phenomenes tumoraux qui seront elimines lors du processus de detersion, soit pour arreter une hemorragie (hemo-stase) ; dans ce cas la retraction thermique des tissus va provoquer la fermeture de la lumiere des vaisseaux qui seront secondairement obliteres par des caillots formes sur place (thrombose). Par volatilisation it est possible de detruire des phenomenes tumoraux plus importants que ceux at-teints lors d'une simple coagulation. Si la zone volatilisee est tres etroite (de 0,1 a 1 mm) on obtient un effet de coupe avec une excellente hemostase au niveau des berges. Certes ces deux processus - coagulation et volatilisation - peuvent etre obtenus par d'autres procedes : echauffement par contact (sonde thermique) ou effet Joule (courant electrique haute frequence). Le laser a l'avantage de ne necessiter aucun contact mecanique entre le vecteur d'energie et les tissus ; on peut alors predire correctement la repartition d'energie au niveau des tissus et les effets sont tres repro-ductibles. Par ailleurs, l'absorption tissulaire variant considerablement avec la longueur d'onde on peut choisir la source laser en fonction des effets desires.

  3. Médecine des voyages

    PubMed Central

    Aw, Brian; Boraston, Suni; Botten, David; Cherniwchan, Darin; Fazal, Hyder; Kelton, Timothy; Libman, Michael; Saldanha, Colin; Scappatura, Philip; Stowe, Brian

    2014-01-01

    Résumé Objectif Définir la pratique de la médecine des voyages, présenter les éléments fondamentaux d’une consultation complète préalable aux voyages à des voyageurs internationaux et aider à identifier les patients qu’il vaudrait mieux envoyer en consultation auprès de professionnels de la médecine des voyages. Sources des données Les lignes directrices et les recommandations sur la médecine des voyages et les maladies liées aux voyages publiées par les autorités sanitaires nationales et internationales ont fait l’objet d’un examen. Une recension des ouvrages connexes dans MEDLINE et EMBASE a aussi été effectuée. Message principal La médecine des voyages est une spécialité très dynamique qui se concentre sur les soins préventifs avant un voyage. Une évaluation exhaustive du risque pour chaque voyageur est essentielle pour mesurer avec exactitude les risques particuliers au voyageur, à son itinéraire et à sa destination et pour offrir des conseils sur les interventions les plus appropriées en gestion du risque afin de promouvoir la santé et prévenir les problèmes médicaux indésirables durant le voyage. Des vaccins peuvent aussi être nécessaires et doivent être personnalisés en fonction des antécédents d’immunisation du voyageur, de son itinéraire et du temps qu’il reste avant son départ. Conclusion La santé et la sécurité d’un voyageur dépendent du degré d’expertise du médecin qui offre le counseling préalable à son voyage et les vaccins, au besoin. On recommande à ceux qui donnent des conseils aux voyageurs d’être conscients de l’ampleur de cette responsabilité et de demander si possible une consultation auprès de professionnels de la médecine des voyages pour tous les voyageurs à risque élevé.

  4. Principles of agonist recognition in Cys-loop receptors

    PubMed Central

    Lynagh, Timothy; Pless, Stephan A.

    2014-01-01

    Cys-loop receptors are ligand-gated ion channels that are activated by a structurally diverse array of neurotransmitters, including acetylcholine, serotonin, glycine, and GABA. After the term chemoreceptor emerged over 100 years ago, there was some wait until affinity labeling, molecular cloning, functional studies, and X-ray crystallography experiments identified the extracellular interface of adjacent subunits as the principal site of agonist binding. The question of how subtle differences at and around agonist-binding sites of different Cys-loop receptors can accommodate transmitters as chemically diverse as glycine and serotonin has been subject to intense research over the last three decades. This review outlines the functional diversity and current structural understanding of agonist-binding sites, including those of invertebrate Cys-loop receptors. Together, this provides a framework to understand the atomic determinants involved in how these valuable therapeutic targets recognize and bind their ligands. PMID:24795655

  5. Identification and quantification of estrogen receptor agonists in wastewater effluents.

    PubMed

    Snyder, S A; Villeneuve, D L; Snyder, E M; Giesy, J P

    2001-09-15

    Total concentrations of several known xenobiotic estrogen receptor (ER) agonists and natural and synthetic estrogen were measured in water by use of a combination of instrumental and bioanalytical approaches. Samples from 3 municipal wastewater treatment plants (WWTPs) in south central Michigan (upstream and effluent); 4 point source locations on the Trenton Channel of the Detroit River, MI; and 5 locations in Lake Mead, NV were analyzed. Organic compounds were extracted from 5 L water samples using solid-phase extraction disks and separated into three fractions based on polarity. Whole extracts and fractions were tested for ER agonist potency using the MVLN in vitro bioassay. ER agonist potency was characterized by comparing the magnitude of induction elicited by the extract or fraction to the maximum induction caused by 17beta-estradiol (E2). The greatest concentrations of ER agonists were associated with the most polar fraction (F3). Instrumental analyses and further fractionation were used to identify specific ER agonists associated with bioassay responses. Bioassay data were compared to extract concentrations in order minimize variability associated with the extraction procedure. Concentrations of endogenous estrogen, E2, and the synthetic estrogen ethynylestradiol (EE2) ranged from nondetectable to 14.6 ng/mL extract (nondetectable to 3.66 ng/L water) and represented from 88 to 99.5% of the total estrogen equivalents in the water samples analyzed. Concentrations of alkylphenols (APs) ranged from nondetectable to 148 microg/mL extract (nondetectable to 37,000 ng/L water). In general, alkylphenols contributed less than 0.5% of the total estrogen equivalents in the water samples. Both bioassay-directed fractionation results and comparison of ER agonist concentrations, adjusted for their known relative potencies, support the conclusion that E2 and EE2 were the dominant environmental estrogens in water samples from mid-Michigan and Lake Mead, NV. PMID:11783637

  6. Insect Nicotinic Receptor Agonists as Flea Adulticides in Small Animals

    PubMed Central

    Vo, Dai Tan; Hsu, Walter H.; Martin, Richard J.

    2013-01-01

    Fleas are significant ectoparasites of small animals. They can be a severe irritant to animals and serve as a vector for a number of infectious diseases. In this article, we discuss the pharmacological characteristics of four insect nicotinic acetylcholine receptor (nAChR) agonists used as fleacides in dogs and cats, which include three neonicotinoids (imidacloprid, nitenpyram, and dinotefuran) and spinosad. Insect nAChR agonists are one of the most important new classes of insecticides, which are used to control sucking insects both on plants and on companion animals. These new compounds provide a new approach for practitioners to safely and effectively eliminate fleas. PMID:20646191

  7. Identification of N-sulfonyl-tetrahydroquinolines as RORc inverse agonists.

    PubMed

    Fauber, Benjamin P; Gobbi, Alberto; Savy, Pascal; Burton, Brenda; Deng, Yuzhong; Everett, Christine; La, Hank; Johnson, Adam R; Lockey, Peter; Norman, Maxine; Wong, Harvey

    2015-10-01

    A high-throughput screen of the Genentech/Roche compound collection using a retinoic acid receptor-related orphan receptor C (RORc, ROR?, or NR1F3) biochemical assay revealed a N-sulfonyl-tetrahydroquinoline hit. Herein, we describe the hit-to-lead optimization and structure-activity relationships of these tetrahydroquinoline RORc inverse agonists. Through iterative synthesis and analog design, we identified compounds with improved biochemical RORc inverse agonist activity and RORc cellular potencies. These improved N-sulfonyl-tetrahydroquinoline compounds also exhibited selectivity for RORc over other nuclear receptors. PMID:26321361

  8. Beta2-agonist extraction procedures for chromatographic analysis.

    PubMed

    dos Ramos, F J

    2000-06-01

    Normally, different procedures were necessary to prepare sample matrices for chromatographic determination of beta2-agonists. The present review includes sampling, pre-treatment and extraction/purification for urine, plasma, liver, meat, feeds, hair and milk powder, as previous steps for chromatographic analysis of beta2-agonists. Six methodologies were especially revised for extraction/purification namely, liquid-liquid extraction, solid-phase extraction (SPE), matrix solid-phase dispersion, immunoaffinity chromatography, dialysis and supercritical fluid extraction. SPE was discussed in detail and five mechanisms were described: adsorption, apolar, polar, ion-exchange and mixed phase. A brief conclusion in this field was also outlined. PMID:10890511

  9. Nicotine enhances murine airway contractile responses to kinin receptor agonists via activation of JNK- and PDE4-related intracellular pathways

    PubMed Central

    2010-01-01

    Background Nicotine plays an important role in cigarette-smoke-associated airway disease. The present study was designed to examine if nicotine could induce airway hyperresponsiveness through kinin receptors, and if so, explore the underlying mechanisms involved. Methods Murine tracheal segments were cultured for 1, 2 or 4 days in serum-free DMEM medium in presence of nicotine (1 and 10 μM) or vehicle (DMSO). Contractile responses induced by kinin B1 receptor agonist, des-Arg9-bradykinin, and B2 receptor agonist, bradykinin, were monitored with myographs. The B1 and B2 receptor mRNA expressions were semi-quantified using real-time PCR and their corresponding protein expressions assessed with confocal-microscopy-based immunohistochemistry. Various pharmacological inhibitors were used for studying intracellular signaling pathways. Results Four days of organ culture with nicotine concentration-dependently increased kinin B1 and B2 receptor-mediated airway contractions, without altering the kinin receptor-mediated relaxations. No such increase was seen at day 1 or day 2. The airway contractile responses to 5-HT, acetylcholine and endothelin receptor agonists remained unaffected by nicotine. Two different neuronal nicotinic receptor antagonists MG624 and hexamethonium blocked the nicotine-induced effects. The enhanced contractile responses were accompanied by increased mRNA and protein expression for both kinin receptors, suggesting the involvement of transcriptional mechanisms. Confocal-microscopy-based immunohistochemistry showed that 4 days of nicotine treatment induced activation (phosphorylation) of c-Jun N-terminal kinase (JNK), but not extracellular signal-regulated kinase 1 and 2 (ERK1/2) and p38. Inhibition of JNK with its specific inhibitor SP600125 abolished the nicotine-induced effects on kinin receptor-mediated contractions and reverted the enhanced receptor mRNA expression. Administration of phosphodiesterase inhibitors (YM976 and theophylline), glucocorticoid (dexamethasone) or adenylcyclase activator (forskolin) suppressed the nicotine-enhanced airway contractile response to des-Arg9-bradykinin and bradykinin. Conclusions Nicotine induces airway hyperresponsiveness via transcriptional up-regulation of airway kinin B1 and B2 receptors, an effect mediated via neuronal nicotinic receptors. The underlying molecular mechanisms involve activation of JNK- and PDE4-mediated intracellular inflammatory signal pathways. Our results might be relevant to active and passive smokers suffering from airway hyperresponsiveness, and suggest new therapeutic targets for the treatment of smoke-associated airway disease. PMID:20113502

  10. Pyrrolo- and pyridomorphinans: non-selective opioid antagonists and delta opioid agonists/mu opioid partial agonists.

    PubMed

    Kumar, V; Clark, M J; Traynor, J R; Lewis, J W; Husbands, S M

    2014-08-01

    Opioid ligands have found use in a number of therapeutic areas, including for the treatment of pain and opiate addiction (using agonists) and alcohol addiction (using antagonists such as naltrexone and nalmefene). The reaction of imines, derived from the opioid ligands oxymorphone and naltrexone, with Michael acceptors leads to pyridomorphinans with structures similar to known pyrrolo- and indolomorphinans. One of the synthesized compounds, 5e, derived from oxymorphone had substantial agonist activity at delta opioid receptors but not at mu and/or kappa opioid receptors and in that sense profiled as a selective delta opioid receptor agonist. The pyridomorphinans derived from naltrexone and naloxone were all found to be non-selective potent antagonists and as such could have utility as treatments for alcohol abuse. PMID:24973818

  11. Synergistic antinociception by the cannabinoid receptor agonist anandamide and the PPAR-alpha receptor agonist GW7647.

    PubMed

    Russo, Roberto; LoVerme, Jesse; La Rana, Giovanna; D'Agostino, Giuseppe; Sasso, Oscar; Calignano, Antonio; Piomelli, Daniele

    2007-07-01

    The analgesic properties of cannabinoid receptor agonists are well characterized. However, numerous side effects limit the therapeutic potential of these agents. Here we report a synergistic antinociceptive interaction between the endogenous cannabinoid receptor agonist anandamide and the synthetic peroxisome proliferator-activated receptor-alpha (PPAR-alpha) agonist 2-(4-(2-(1-Cyclohexanebutyl)-3-cyclohexylureido)ethyl)phenylthio)-2-methylpropionic acid (GW7647) in a model of acute chemical-induced pain. Moreover, we show that anandamide synergistically interacts with the large-conductance potassium channel (KCa1.1, BK) activator isopimaric acid. These findings reveal a synergistic interaction between the endocannabinoid and PPAR-alpha systems that might be exploited clinically and identify a new pharmacological effect of the BK channel activator isopimaric acid. PMID:17434479

  12. Vecteurs Singuliers des Theories des Champs Conformes Minimales

    NASA Astrophysics Data System (ADS)

    Benoit, Louis

    En 1984 Belavin, Polyakov et Zamolodchikov revolutionnent la theorie des champs en explicitant une nouvelle gamme de theories, les theories quantiques des champs bidimensionnelles invariantes sous les transformations conformes. L'algebre des transformations conformes de l'espace-temps presente une caracteristique remarquable: en deux dimensions elle possede un nombre infini de generateurs. Cette propriete impose de telles conditions aux fonctions de correlations qu'il est possible de les evaluer sans aucune approximation. Les champs des theories conformes appartiennent a des representations de plus haut poids de l'algebre de Virasoro, une extension centrale de l'algebre conforme du plan. Ces representations sont etiquetees par h, le poids conforme de leur vecteur de plus haut poids, et par la charge centrale c, le facteur de l'extension centrale, commune a toutes les representations d'une meme theorie. Les theories conformes minimales sont constituees d'un nombre fini de representations. Parmi celles-ci se trouvent des theories unitaires dont les representation forment la serie discrete de l'algebre de Virasoro; leur poids h a la forme h_{p,q}(m)=[ (p(m+1) -qm)^2-1] (4m(m+1)), ou p,q et m sont des entiers positifs et p+q<= m+1. L'entier m parametrise la charge centrale: c(m)=1 -{6over m(m+1)} avec n>= 2. Ces representations possedent un sous-espace invariant engendre par deux sous-representations avec h_1=h_{p,q} + pq et h_2=h_{p,q} + (m-p)(m+1-q) dont chacun des vecteurs de plus haut poids portent le nom de vecteur singulier et sont notes respectivement |Psi _{p,q}> et |Psi_{m-p,m+1-q}>. . Les theories super-conformes sont une version super-symetrique des theories conformes. Leurs champs appartiennent a des representation de plus haut poids de l'algebre de Neveu-Schwarz, une des deux extensions super -symetriques de l'algebre de Virasoro. Les theories super -conformes minimales possedent la meme structure que les theories conformes minimales. Les representations sont elements de la serie h_{p,q}= [ (p(m+2)-qm)^2-4] /(8m(m+2)) ou p,q et m sont des entiers positifs, p et q etant de meme parite, et p+q<= m+2. La charge centrale est donnee par c(m)={3over 2}-{12over m(m+2)} avec m >= 2. Les vecteurs singuliers | Psi_{p,q}> et |Psi_{m-p,m+2-q} > sont respectivement de poids h _{p,q}+pq/2 et h_ {p,q}+(m-p)(m+2-q)/2.. Les vecteurs singuliers ont une norme nulle et on doit les eliminer des representations pour que celles -ci soient unitaires. Cette elimination engendrent des equations (super-)differentielles qui dependent directement de la forme explicite des vecteurs singuliers et auxquelles doivent obeir les fonctions de correlations de la theorie. Ainsi la connaissance de ces vecteurs singuliers est intimement reliee au calcul des fonctions de correlation. Les equations definissant les vecteurs singuliers forment un systeme lineaire surdetermine dont le nombre d'equations est de l'ordre de N(pq), le nombre de partitions de l'entier pq. Puisque les vecteurs singuliers jouent un role capital en theorie conforme, il est naturel de chercher des formes explicites pour les vecteurs (ou pour des familles infinies de ceux -ci). Nous donnons ici la forme explicite pour la famille infinie de vecteurs singuliers ayant un de ses indices egal a 1, pour les algebres de Virasoro et de Neveu-Schwarz. Depuis ces decouvertes, d'autres techniques de construction des vecteurs singuliers ont ete developpees, dont celle de Bauer, Di Francesco, Itzykson et Zuber pour l'algebre de Virasoro qui reproduit directement l'expression explicite des vecteurs singuliers |Psi _{1,q}> et |Psi_{p,1}>. Ils ont utilise l'algebre des produits d'operateurs et la fusion entre representations irreductibles pour engendrer des relations de recurence produisant les vecteurs singuliers. Dans le dernier chapitre de cette these nous adaptons cet algorithme a la construction des vecteurs singuliers de l'algebre de Neveu-Schwarz.

  13. Potent Agonists of the Protease Activated Receptor 2 (PAR2)

    PubMed Central

    Boitano, Scott; Flynn, Andrea N.; Schulz, Stephanie M.; Hoffman, Justin; Price, Theodore J.; Vagner, Josef

    2011-01-01

    Novel peptidomimetic pharmacophores to PAR2 were designed based on the known activating peptide SLIGRL-NH2. A set of 15 analogues was evaluated with a model cell line (16HBE14o-) that highly expresses PAR2. Cells exposed to the PAR2 activating peptide with N-terminal 2-furoyl modification (2-furoyl-LIGRLO-NH2) initiated increases in intracellular calcium concentration ([Ca2+]i EC50 = 0.84 ?M) and in vitro physiological responses as measured by the xCELLigence real time cell analyzer (RTCA EC50 = 138 nM). We discovered two selective PAR2 agonists with comparable potency: compound 1 (2-aminothiazol-4-yl; Ca2+ EC50 = 1.77 ?M, RTCA EC50 = 142 nM) and compound 2 (6-aminonicotinyl; Ca2+ EC50 = 2.60 ?M, RTCA EC50 = 311 nM). Unlike the previously described agonist, these novel agonists are devoid of the metabolically unstable 2-furoyl modification and thus provide potential advantages for PAR2 peptide design for in vitro and in vivo studies. The novel compounds described herein also serve as a starting point for structureactivity relationship (SAR) design and are, for the first time, evaluated via a unique high throughput in vitro physiological assay. Together these will lead to discovery of more potent agonists and antagonists of PAR2. PMID:21294569

  14. Once-weekly glucagon-like peptide 1 receptor agonists.

    PubMed

    Kalra, Sanjay; Gupta, Yashdeep

    2015-07-01

    The once-weekly glucagon-like peptide 1 receptor agonists (QW GLP1RA) represent a major advancement in diabetes pharmaco-therapeutics. This review describes the basic, clinical, and comparative pharmacology of this novel class of drugs. It highlights the clinical placement and posology of these drugs. PMID:26160096

  15. Therapeutic strategies in Alzheimer's disease: M1 muscarinic agonists.

    PubMed

    Fisher, A

    2000-10-01

    The cholinergic hypofunction in Alzheimer's disease (AD) appears to be linked with two other major hallmarks of this disease, beta-amyloid and hyperphosphorylated tau protein. Formation of beta-amyloids might impair the coupling of M1 muscarinic acetylcholine receptors (mAChR) with G-proteins. This can lead to decreased signal transduction, a decrease of trophic and non-amyloidogenic amyloid precursor protein (APPs) and generation of more beta-amyloids, aggravating further the cholinergic deficiency. This review is an attempt to explore the M1 mAChR regulation of beta-amyloid metabolism, tau hyperphosphorylation and cognitive functions. The therapeutic potential of M1-selective muscarinic agonists including AF102B, AF150(S), AF267B (the AF series) is evaluated and compared, when possible, with several FDA-approved acetylcholinesterase inhibitors. These M1 agonists can elevate APPs, decrease tau protein phosphorylation/hyperphosphorylation in vitro and in vivo and restore cognitive impairments in several animal models for AD. Except for the M1 agonists, no other compounds were reported yet with combined effects; e.g., amelioration of cognition dysfunction and beneficial modulation of APPs/beta-amyloid together with tau hyperphosphorylation/phosphorylation. This property of M1 agonists to alter different aspects associated with AD pathogenesis could represent the most remarkable clinical value of such drugs. PMID:11128032

  16. Elastic, Agonistic Publics: John Dewey's Call for a Third Party.

    ERIC Educational Resources Information Center

    Finnegan, Cara A.

    2003-01-01

    Notes that John Dewey committed to the construction of an "elastic" social imaginary responsive to the rhetorical needs of a public in crisis. Explains that Dewey argued that a new third party must adopt an agonistic style of communication. Suggests that Dewey described the role of a third party in ways that might prove productive for scholars

  17. Taranabant, a novel cannabinoid type 1 receptor inverse agonist.

    PubMed

    Fremming, Bradley A; Boyd, Steven T

    2008-10-01

    Merck & Co Inc is developing the cannabinoid receptor type 1 inverse agonist taranabant for the potential treatment of obesity and nicotine dependence. By October 2006, the drug had entered phase III trials for obesity, and by May 2008, a phase II study of taranabant as an aid to smoking cessation in chronic cigarette smokers had been completed. PMID:18821475

  18. Amylin and Amylin Agonists for Treating Psychiatric Diseases and Disorders

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Methods and compositions for treating psychiatric diseases and disorders are disclosed. The methods provided generally involve the administration of an amylin or an amylin agonist to a subject in order to treat psychiatric diseases and disorders, and conditions associated with psychiatric diseases a...

  19. Partial Agonists Activate PPARgamma Using a Helix 12 Independent Mechanism

    SciTech Connect

    Bruning, J.B.; Chalmers, M.J.; Prasad, S.; Bushby, S.A.; Kamenecka, T.A.; He, Y.; Nettles, K.W.; Griffin, P.R.

    2009-05-28

    Binding to helix 12 of the ligand-binding domain of PPAR{gamma} is required for full agonist activity. Previously, the degree of stabilization of the activation function 2 (AF-2) surface was thought to correlate with the degree of agonism and transactivation. To examine this mechanism, we probed structural dynamics of PPAR{gamma} with agonists that induced graded transcriptional responses. Here we present crystal structures and amide H/D exchange (HDX) kinetics for six of these complexes. Amide HDX revealed each ligand induced unique changes to the dynamics of the ligand-binding domain (LBD). Full agonists stabilized helix 12, whereas intermediate and partial agonists did not at all, and rather differentially stabilized other regions of the binding pocket. The gradient of PPAR{gamma} transactivation cannot be accounted for solely through changes to the dynamics of AF-2. Thus, our understanding of allosteric signaling must be extended beyond the idea of a dynamic helix 12 acting as a molecular switch.

  20. Dopamine partial receptor agonists reduce ethanol intake in the rat.

    PubMed

    Bono, G; Balducci, C; Richelmi, P; Koob, G F; Pulvirenti, L

    1996-02-01

    Dopamine neurotransmission is an important neuropharmacological component of ethanol reinforcement in rodents. A recently characterized class of compounds, dopamine partial receptor agonists, appears to possess a unique pharmacological profile on dopamine neurotransmission. The aim of the present study was to test the effects of systemic administration of terguride and SDZ 208-911 (N-[(8 alpha)-2,6-dimethylergoline-8-yl]-2,2-diethylpropanamide), two prototype dopamine partial receptor agonists, in free-feeding, non-deprived rats trained to drink ethanol (10% w/v) and water in 'free-choice' limited access conditions. Both acute and chronic administration of terguride and SDZ 208-911 significantly reduced ethanol intake while water intake was not significantly affected, thus ruling out possible non-specific effects of these drugs on fluid intake. These results suggest that dopamine partial receptor agonists reduce the reinforcing properties of ethanol in the rat, an effect similar to that previously observed with cocaine. Therefore, the pharmacological profile of dopamine partial receptor agonists and their effects in animal models of dependence provide preclinical support to the hypothesis that these compounds may represent a novel pharmacological strategy for intervention in various forms of drug addiction. PMID:8904074

  1. Activation of endplate nicotinic acetylcholine receptors by agonists.

    PubMed

    Auerbach, Anthony

    2015-10-15

    The interaction of a small molecule made in one cell with a large receptor made in another is the signature event of cell signaling. Understanding the structure and energy changes associated with agonist activation is important for engineering drugs, receptors and synapses. The nicotinic acetylcholine receptor (AChR) is a ∼300kD ion channel that binds the neurotransmitter acetylcholine (ACh) and other cholinergic agonists to elicit electrical responses in the central and peripheral nervous systems. This mini-review is in two sections. First, general concepts of skeletal muscle AChR operation are discussed in terms of energy landscapes for conformational change. Second, adult vs. fetal AChRs are compared with regard to interaction energies between ACh and agonist-site side chains, measured by single-channel electrophysiology and molecular dynamics simulations. The five aromatic residues that form the core of each agonist binding site can be divided into two working groups, a triad (led by αY190) that behaves similarly at all sites and a coupled pair (led by γW55) that has a large influence on affinity only in fetal AChRs. Each endplate AChR has 5 homologous subunits, two of α(1) and one each of β, δ, and either γ (fetal) or ϵ (adult). These nicotinic AChRs have only 2 functional agonist binding sites located in the extracellular domain, at αδ and either αγ or αϵ subunit interfaces. The receptor undergoes a reversible, global isomerization between structures called C and O. The C shape does not conduct ions and has a relatively low affinity for ACh, whereas O conducts cations and has a higher affinity. When both agonist sites are empty (filled only with water) the probability of taking on the O conformation (PO) is low, <10(-6). When ACh molecules occupy the agonist sites the C→O opening rate constant and C↔O gating equilibrium constant increase dramatically. Following a pulse of ACh at the nerve-muscle synapse, the endplate current rises rapidly to reach a peak that corresponds to PO ∼0.96. PMID:26206191

  2. Melatonin receptor agonists: new options for insomnia and depression treatment.

    PubMed

    Spadoni, Gilberto; Bedini, Annalida; Rivara, Silvia; Mor, Marco

    2011-12-01

    The circadian nature of melatonin (MLT) secretion, coupled with the localization of MLT receptors to the suprachiasmatic nucleus, has led to numerous studies of the role of MLT in modulation of the sleep-wake cycle and circadian rhythms in humans. Although much more needs to be understood about the various functions exerted by MLT and its mechanisms of action, three therapeutic agents (ramelteon, prolonged-release MLT, and agomelatine) are already in use, and MLT receptor agonists are now appearing as new promising treatment options for sleep and circadian-rhythm related disorders. In this review, emphasis has been placed on medicinal chemistry strategies leading to MLT receptor agonists, and on the evidence supporting therapeutic efficacy of compounds undergoing clinical evaluation. A wide range of clinical trials demonstrated that ramelteon, prolonged-release MLT and tasimelteon have sleep-promoting effects, providing an important treatment option for insomnia and transient insomnia, even if the improvements of sleep maintenance appear moderate. Well-documented effects of agomelatine suggest that this MLT agonist offers an attractive alternative for the treatment of depression, combining efficacy with a favorable side effect profile. Despite a large number of high affinity nonselective MLT receptor agonists, only limited data on MT? or MT? subtype-selective compounds are available up to now. Administration of the MT?-selective agonist IIK7 to rats has proved to decrease NREM sleep onset latency, suggesting that MT? receptor subtype is involved in the acute sleep-promoting action of MLT; rigorous clinical studies are needed to demonstrate this hypothesis. Further clinical candidates based on selective activation of MT? or MT? receptors are expected in coming years. PMID:21554566

  3. Effects of adenosine agonists on consumptive behaviour and body temperature.

    PubMed

    Coupar, Ian M; Tran, Binh L T

    2002-02-01

    This study was designed to determine the effects of the A1-receptor selective agonist N6-cyclopentyladenosine (CPA), and the A2-selective agonist, 2-p-(2-carboxyethyl)-phenethylamino-5'-N-ethylcarboxamidoadenosine-hydrochloride (CGS-21680) on consumptive behaviour and body temperature in rats in relation to the non-selective A1/A2 adenosine agonist, N-ethylcarboxamidoadenosine (NECA), and to morphine. It was shown that two subcutaneous injections of 0.1 and 0.3 mg kg(-1) CPA caused a similar decrease in food consumption to NECA (2 x 0.03 mg kg(-1)) and morphine (2 x 10 mg kg(-1)). However, two doses of 0.03 mg kg(-1) CPA and 0.1 and 0.3 mg kg(-1)CGS-21680 enhanced feeding. These effects were not directly correlated to faecal output at all doses of the selective agonists, as NECA and morphine induced constipation. The doses of CPA and 0.1 and 0.3 mg kg(-1) of CGS-21680 enhanced water consumption, as did NECA, but not morphine. The stimulation of drinking by CPA was not absolutely associated with diuresis. Instead, urine output was reduced by 0.03 and 0.1 mg kg(-1) and increased by 0.3 mg kg(-1). CGS-21680 at 0.1 and 0.3 mg kg(-1) and NECA also induced diuresis, which was opposite to the effect of morphine. CPA and CGS-21680 both caused significant dose-dependent decreases in body temperature after the two-injection treatment, but their effects were significantly less after 36 h when four doses had been administered. The study indicates that highly selective A1 and A2A adenosine agonists might have the ability to interfere with consumptive behaviour, induce constipation, affect renal function and to lower body temperature. PMID:11858214

  4. Synthesis and SAR of potent LXR agonists containing an indole pharmacophore

    SciTech Connect

    Washburn, David G.; Hoang, Tram H.; Campobasso, Nino; Smallwood, Angela; Parks, Derek J.; Webb, Christine L.; Frank, Kelly A.; Nord, Melanie; Duraiswami, Chaya; Evans, Christopher; Jaye, Michael; Thompson, Scott K.

    2009-03-27

    A novel series of 1H-indol-1-yl tertiary amine LXR agonists has been designed. Compounds from this series were potent agonists with good rat pharmacokinetic parameters. In addition, the crystal structure of an LXR agonist bound to LXR{alpha} will be disclosed.

  5. Cytokine-induced loss of glucocorticoid function: effect of kinase inhibitors, long-acting β(2)-adrenoceptor [corrected] agonist and glucocorticoid receptor ligands.

    PubMed

    Rider, Christopher F; Shah, Suharsh; Miller-Larsson, Anna; Giembycz, Mark A; Newton, Robert

    2015-01-01

    Acting on the glucocorticoid receptor (NR3C1), glucocorticoids are widely used to treat inflammatory diseases. However, glucocorticoid resistance often leads to suboptimal asthma control. Since glucocorticoid-induced gene expression contributes to glucocorticoid activity, the aim of this study was to use a 2 × glucocorticoid response element (GRE) reporter and glucocorticoid-induced gene expression to investigate approaches to combat cytokine-induced glucocorticoid resistance. Pre-treatment with tumor necrosis factor-α (TNF) or interleukin-1β inhibited dexamethasone-induced mRNA expression of the putative anti-inflammatory genes RGS2 and TSC22D3, or just TSC22D3, in primary human airway epithelial and smooth muscle cells, respectively. Dexamethasone-induced DUSP1 mRNA was unaffected. In human bronchial epithelial BEAS-2B cells, dexamethasone-induced TSC22D3 and CDKN1C expression (at 6 h) was reduced by TNF pre-treatment, whereas DUSP1 and RGS2 mRNAs were unaffected. TNF pre-treatment also reduced dexamethasone-dependent 2×GRE reporter activation. This was partially reversed by PS-1145 and c-jun N-terminal kinase (JNK) inhibitor VIII, inhibitors of IKK2 and JNK, respectively. However, neither inhibitor affected TNF-dependent loss of dexamethasone-induced CDKN1C or TSC22D3 mRNA. Similarly, inhibitors of the extracellular signal-regulated kinase, p38, phosphoinositide 3-kinase or protein kinase C pathways failed to attenuate TNF-dependent repression of the 2×GRE reporter. Fluticasone furoate, fluticasone propionate and budesonide were full agonists relative to dexamethasone, while GSK9027, RU24858, des-ciclesonide and GW870086X were partial agonists on the 2×GRE reporter. TNF reduced reporter activity in proportion with agonist efficacy. Full and partial agonists showed various degrees of agonism on RGS2 and TSC22D3 expression, but were equally effective at inducing CDKN1C and DUSP1, and did not affect the repression of CDKN1C or TSC22D3 expression by TNF. Finally, formoterol-enhanced 2×GRE reporter activity was also proportional to agonist efficacy and functionally reversed repression by TNF. As similar effects were apparent on glucocorticoid-induced gene expression, the most effective strategy to overcome glucocorticoid resistance in this model was addition of formoterol to high efficacy NR3C1 agonists. PMID:25625944

  6. Cytokine-Induced Loss of Glucocorticoid Function: Effect of Kinase Inhibitors, Long-Acting ?2-Adrenoceptor Agonist and Glucocorticoid Receptor Ligands

    PubMed Central

    Rider, Christopher F.; Shah, Suharsh; Miller-Larsson, Anna; Giembycz, Mark A.; Newton, Robert

    2015-01-01

    Acting on the glucocorticoid receptor (NR3C1), glucocorticoids are widely used to treat inflammatory diseases. However, glucocorticoid resistance often leads to suboptimal asthma control. Since glucocorticoid-induced gene expression contributes to glucocorticoid activity, the aim of this study was to use a 2glucocorticoid response element (GRE) reporter and glucocorticoid-induced gene expression to investigate approaches to combat cytokine-induced glucocorticoid resistance. Pre-treatment with tumor necrosis factor-? (TNF) or interleukin-1? inhibited dexamethasone-induced mRNA expression of the putative anti-inflammatory genes RGS2 and TSC22D3, or just TSC22D3, in primary human airway epithelial and smooth muscle cells, respectively. Dexamethasone-induced DUSP1 mRNA was unaffected. In human bronchial epithelial BEAS-2B cells, dexamethasone-induced TSC22D3 and CDKN1C expression (at 6 h) was reduced by TNF pre-treatment, whereas DUSP1 and RGS2 mRNAs were unaffected. TNF pre-treatment also reduced dexamethasone-dependent 2GRE reporter activation. This was partially reversed by PS-1145 and c-jun N-terminal kinase (JNK) inhibitor VIII, inhibitors of IKK2 and JNK, respectively. However, neither inhibitor affected TNF-dependent loss of dexamethasone-induced CDKN1C or TSC22D3 mRNA. Similarly, inhibitors of the extracellular signal-regulated kinase, p38, phosphoinositide 3-kinase or protein kinase C pathways failed to attenuate TNF-dependent repression of the 2GRE reporter. Fluticasone furoate, fluticasone propionate and budesonide were full agonists relative to dexamethasone, while GSK9027, RU24858, des-ciclesonide and GW870086X were partial agonists on the 2GRE reporter. TNF reduced reporter activity in proportion with agonist efficacy. Full and partial agonists showed various degrees of agonism on RGS2 and TSC22D3 expression, but were equally effective at inducing CDKN1C and DUSP1, and did not affect the repression of CDKN1C or TSC22D3 expression by TNF. Finally, formoterol-enhanced 2GRE reporter activity was also proportional to agonist efficacy and functionally reversed repression by TNF. As similar effects were apparent on glucocorticoid-induced gene expression, the most effective strategy to overcome glucocorticoid resistance in this model was addition of formoterol to high efficacy NR3C1 agonists. PMID:25625944

  7. Peste des petits ruminants.

    PubMed

    Parida, S; Muniraju, M; Mahapatra, M; Muthuchelvan, D; Buczkowski, H; Banyard, A C

    2015-12-14

    Peste des petits ruminants virus causes a highly infectious disease of small ruminants that is endemic across Africa, the Middle East and large regions of Asia. The virus is considered to be a major obstacle to the development of sustainable agriculture across the developing world and has recently been targeted by the World Organisation for Animal Health (OIE) and the Food and Agriculture Organisation (FAO) for eradication with the aim of global elimination of the disease by 2030. Fundamentally, the vaccines required to successfully achieve this goal are currently available, but the availability of novel vaccine preparations to also fulfill the requisite for differentiation between infected and vaccinated animals (DIVA) may reduce the time taken and the financial costs of serological surveillance in the later stages of any eradication campaign. Here, we overview what is currently known about the virus, with reference to its origin, updated global circulation, molecular evolution, diagnostic tools and vaccines currently available to combat the disease. Further, we comment on recent developments in our knowledge of various recombinant vaccines and on the potential for the development of novel multivalent vaccines for small ruminants. PMID:26443889

  8. Peste des petits ruminants

    PubMed Central

    Parida, S.; Muniraju, M.; Mahapatra, M.; Muthuchelvan, D.; Buczkowski, H.; Banyard, A.C.

    2015-01-01

    Peste des petits ruminants virus causes a highly infectious disease of small ruminants that is endemic across Africa, the Middle East and large regions of Asia. The virus is considered to be a major obstacle to the development of sustainable agriculture across the developing world and has recently been targeted by the World Organisation for Animal Health (OIE) and the Food and Agriculture Organisation (FAO) for eradication with the aim of global elimination of the disease by 2030. Fundamentally, the vaccines required to successfully achieve this goal are currently available, but the availability of novel vaccine preparations to also fulfill the requisite for differentiation between infected and vaccinated animals (DIVA) may reduce the time taken and the financial costs of serological surveillance in the later stages of any eradication campaign. Here, we overview what is currently known about the virus, with reference to its origin, updated global circulation, molecular evolution, diagnostic tools and vaccines currently available to combat the disease. Further, we comment on recent developments in our knowledge of various recombinant vaccines and on the potential for the development of novel multivalent vaccines for small ruminants. PMID:26443889

  9. Diffusion incohrente des neutrons : modles analytiques pour la dynamique interne des protines

    NASA Astrophysics Data System (ADS)

    Bicout, D. J.

    2005-11-01

    La dynamique interne des protines joue un rle central dans la stabilit, la fonction et l'activit biologique de ces biomolcules. Il est maintenant tabli que les fluctuations d'tats conformationnels des protines influencent fortement la plupart des ractions biochimiques et s'accompagnent d'une augmentation brutale des dplacements carrs moyens des atomes au dessus de la temprature de la transition dynamique. Dans cette contribution, nous prsentons une revue critique de quelques modles thoriques couramment utiliss dans la littrature pour l'analyse des mouvements internes des protines et la description de la transition dynamique.

  10. Exploration des mcanismes de repliement des protines par dynamique molculaire

    NASA Astrophysics Data System (ADS)

    Gilquin, B.

    2005-11-01

    Comment se replient les protines? Cette question est ancienne. En introduction nous rappellerons ce qu'est le paradoxe de Levinthal et comment on est pass de la notion de chemin de repliement la notion de paysage nergtique. Les simulations de dynamique molculaire ont permis d'aborder la comprhension du processus de repliement au niveau atomique. Cependant l'chelle de temps des processus de repliement (de l'ordre de la milliseconde) n'est pas accessible aux simulations numriques (de l'ordre de la nanoseconde). Plusieurs auteurs ont donc propos de simuler le dpliement des protines par dynamique molculaire. En admettant le principe de micro-rversibilit l'tude du processus de dpliement renseigne sur celui de repliement. Cependant, il est ncessaire d'acclrer le dpliement en introduisant un biais afin que les tats dplies soient accessibles aux chelles de temps des simulations. Nous prsenterons un exemple de ce qui a t ralise dans le cas de l'tude de protines de petite taille suivant un repliement simple, globalement deux tats. Nous prsenterons ensuite ce que nous avons ralis dans le cas d'une protine de taille plus importante et pour laquelle le processus de repliement est plus complexe car il existe un intermdiaire transitoire de repliement. C'est le cas du lysozyme pour lequel les simulations de dpliement permettent d'accder au mcanisme atomique de repliement et de comprendre pourquoi des mutants de cette protine se replient plus lentement et forment des fibres amylodiques. Ainsi les intermdiaires de repliement seraient l'origine de formes pathognes des protines observes dans les maladies neuro-dgneratives. Enfin nous montrerons comment partir de plusieurs simulations longues de dynamique molculaire, le paysage nergtique pour de petites protines peut tre calcul.

  11. Ephmrides astronomiques 2011 : Connaissance des Temps

    NASA Astrophysics Data System (ADS)

    Bureau Des Longitudes (Bdl); Institut de Mcanique Cleste Et de Calcul Des Ephmrides (Imcce); Observatoire de Paris

    2011-12-01

    Cet ouvrage d'phmrides destin aux astronomes, aux professeurs et aux tudiants est divis en deux parties. Il donne les positions des astres pour l'anne 2011. Le livre prsente l'tat actuel des connaissances sur les bases et les explications de calculs des phmrides puis donne sous forme d'phmrides tabules les donnes permettant d'obtenir la position des astres observer. En utilisant le CD-ROM, l'utilisateur peut prparer ses observations.

  12. Illegal use of beta-adrenergic agonists: European Community.

    PubMed

    Kuiper, H A; Noordam, M Y; van Dooren-Flipsen, M M; Schilt, R; Roos, A H

    1998-01-01

    The use of veterinary medicinal products within the European Community is governed by a series of directives and regulations that describe the requirements for safety, quality, and efficacy of these products. Veterinary therapeutic use of beta-agonists has only been approved in the case of clenbuterol for bronchodilatation in horses and calves and for tocolysis in cows. No beta-agonists have been permitted in the European Community for growth-promoting purposes in farm animals. Surveillance for the presence of residues of veterinary agents in food-producing animals and meat is regulated by the Directive 86/469/EEC containing specific guidelines for sampling procedures on farms and in slaughterhouses. The level and frequency of sampling is dependent on the category of compounds and animal species. When positive samples have been identified (above certain action levels), sampling intensity is increased. Results of monitoring programs in EU member states during 1992 and 1993 for the occurrence of residues of beta-agonists in food-producing animals vary substantially with respect to the percentages of positive samples, ranging from 0 to 7%. The variability is partly explained by differences in sampling strategies, detection methods, and action levels applied. Identification of the proper matrices for sampling and detection of beta-agonists is important. In the case of clenbuterol, hair and choroid retinal tissue are appropriate tissues because clenbuterol accumulates in these matrices. A clear decrease in the use of clenbuterol in cattle has been observed in The Netherlands, Germany, Northern Ireland, and Spanish Basque Country over the last 3 yr. This is partly due to intensified surveillance activities at farms and slaughterhouses by governmental agencies and production sector organizations. There are data on human intoxication following consumption of liver or meat from cattle treated with beta-agonists. At the concentrations of clenbuterol measured in contaminated liver and meat samples, pharmacological effects may be expected in humans after consuming 100 to 200 g of product. The use of highly active beta-agonists as growth promoters is not appropriate because of the potential hazard for human and animal health, as was recently concluded at the scientific Conference on Growth Promotion in Meat Production (Nov. 1995, Brussels). PMID:9464899

  13. A Potent and Site-Selective Agonist of TRPA1.

    PubMed

    Takaya, Junichiro; Mio, Kazuhiro; Shiraishi, Takuya; Kurokawa, Tatsuki; Otsuka, Shinya; Mori, Yasuo; Uesugi, Motonari

    2015-12-23

    TRPA1 is a member of the transient receptor potential (TRP) cation channel family that is expressed primarily on sensory neurons. This chemosensor is activated through covalent modification of multiple cysteine residues with a wide range of reactive compounds including allyl isothiocyanate (AITC), a spicy component of wasabi. The present study reports on potent and selective agonists of TRPA1, discovered through screening 1657 electrophilic molecules. In an effort to validate the mode of action of hit molecules, we noted a new TRPA1-selective agonist, JT010 (molecule 1), which opens the TRPA1 channel by covalently and site-selectively binding to Cys621 (EC50 = 0.65 nM). The results suggest that a single modification of Cys621 is sufficient to open the TRPA1 channel. The TRPA1-selective probe described herein might be useful for further mechanistic studies of TRPA1 activation. PMID:26630251

  14. Cardiometabolic Effects of Glucagon-Like Peptide-1 Agonists.

    PubMed

    Sarraju, Ashish; Kim, Sun H; Knowles, Joshua W

    2016-02-01

    Cardiovascular disease is the leading cause of death among adults in the USA. Both type 1 (T1DM) and type 2 diabetes mellitus (T2DM) are known risk factors for cardiovascular disease. Despite the development of numerous effective anti-glycemic therapies, we have been unable to completely mitigate cardiovascular risk with glucose lowering alone, and prevention of cardiovascular disease in patients with diabetes is primarily achieved with the use of medications that address other risk factors such as anti-hypertensives or statins. Glucagon-like peptide-1 (GLP-1) is a key hormone in the pathophysiology of diabetes. GLP-1 agonists have been recently approved for the treatment of T2DM as well as for chronic weight management. In this review, we aim to explore the effects of GLP-1 agonists on cardiovascular health with a focus on cardiometabolic variables and cardiac function. PMID:26782825

  15. Orvinols with Mixed Kappa/Mu Opioid Receptor Agonist Activity

    PubMed Central

    2013-01-01

    Dual-acting kappa opioid receptor (KOR) agonist and mu opioid receptor (MOR) partial agonist ligands have been put forward as potential treatment agents for cocaine and other psychostimulant abuse. Members of the orvinol series of ligands are known for their high binding affinity to both KOR and MOR, but efficacy at the individual receptors has not been thoroughly evaluated. In this study, it is shown that a predictive model for efficacy at KOR can be derived, with efficacy being controlled by the length of the group attached to C20 and by the introduction of branching into the side chain. In vivo evaluation of two ligands with the desired in vitro profile confirms both display KOR, and to a lesser extent MOR, activity in an analgesic assay suggesting that, in this series, in vitro measures of efficacy using the [35S]GTP?S assay are predictive of the in vivo profile. PMID:23438330

  16. Safety and tolerability of TRAIL receptor agonists in cancer treatment.

    PubMed

    Fulda, Simone

    2015-05-01

    Targeting the death receptor pathway of apoptosis represents a promising approach for the development of novel cancer therapeutics, since death receptors on the cell surface are directly linked to the apoptotic machinery. The tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) receptor/ligand system is of particular interest among the death receptor superfamily for therapeutic targeting in cancer, since TRAIL has been reported to preferentially induce apoptosis in cancer cells, while sparing non-malignant cells. Evaluation of TRAIL receptor agonists in clinical trials has revealed that they are, in principle, well-tolerated but exert limited efficacy in unselective patient populations. Currently, the challenge resides in the development of rational TRAIL-based combination therapies with potent TRAIL receptor agonists in order to exploit the potential of death receptor targeting for cancer therapy. PMID:25704217

  17. ?2-adrenoceptor agonists in the regulation of mitochondrial biogenesis

    PubMed Central

    Peterson, Yuri K.; Cameron, Robert B.; Wills, Lauren P.; Trager, Richard E.; Lindsey, Chris C.; Beeson, Craig C.; Schnellmann, Rick G.

    2014-01-01

    The stimulation of mitochondrial biogenesis (MB) via cell surface G-protein coupled receptors is a promising strategy for cell repair and regeneration. Here we report the specificity and chemical rationale of a panel of ?2-adrenoceptor agonists with regards to MB. Using primary cultures of renal cells, a diverse panel of ?2-adrenoceptor agonists elicited three distinct phenotypes: full MB, partial MB, and non-MB. Full MB compounds had efficacy in the low nanomolar range and represent two chemical scaffolds containing three distinct chemical clusters. Interestingly, the MB phenotype did not correlate with reported receptor affinity or chemical similarity. Chemical clusters were then subjected to pharmacophore modeling creating two models with unique and distinct features, consisting of five conserved amongst full MB compounds were identified. The two discrete pharmacophore models were coalesced into a consensus pharmacophore with four unique features elucidating the spatial and chemical characteristics required to stimulate MB. PMID:23954364

  18. Protein structure based rational design of ecdysone agonists.

    PubMed

    Holmwood, Graham; Schindler, Michael

    2009-06-15

    We review the impact of protein X-ray crystallography on the rational design of insecticides that act as agonists of the ligand-binding domain of the Ecdysone receptor (EcR). As the EcR is a target specific to insects, these compounds potentially constitute new chemical classes of safe insecticides. The increased insight relative to that from ligand-only based (Quantitative) Structure-Activity Relations (QSARs), classical 2D-Hansch type or 3D-CoMFA/CoMSIA (Comparative Molecular Field/Similarity Analysis), is discussed. The importance of protein X-ray structure determination in support of the discovery process is stressed as the simplistic lock-and-key picture fails due to the remarkable flexibility of the EcR ligand binding site. Several new non-steroidal chemical classes of ecdysone agonists, designed by guidance from protein X-ray studies, are described. PMID:19168365

  19. Clinical use of GLP-1 agonists and DPP4 inhibitors.

    PubMed

    Tuch, Bernard E

    2016-01-01

    Type 2 diabetes is a growing problem, with 387 million people currently affected, and 592 million by 2035. Whilst diet and exercise are the corner stones of treatment, oral hypoglycaemic agents are often needed to achieve glycaemic control, thereby reducing the chance of long term diabetic complications. Biguanides and sulfonylureas have been the standard tablets used for this disorder, until 2005-7 when glucagon-like peptide-1 (GLP-1) agonists and dipeptidyl peptidase-4 (DPP4) inhibitors became available. Their major advantage over sulfonylureas is that they are weight lowering or weight neutral, and have a very low incidence of hypoglycaemia. GLP-1 agonists are injectables, whereas the DPP4 inhibitors are administered orally. Both agents are best used in combination with other hypoglycaemic medication, especially metformin and sodium glucose co-transporter 2 (SGLT2) inhibtors. Usage is increasing, being roughly equal to that of sulfonylureas, but less than that of metformin. Side effects appear to be minimal. PMID:26138513

  20. [Indications of GnRH agonist therapy during childhood].

    PubMed

    Carel, Jean-Claude

    2012-02-01

    Precocious pubertal development is frequent and requires rigorous investigations to avoid unnecessary treatment. Central precocious puberty is by far the most frequent form and raises the issue of GnRH agonist therapy. It is essential first to determine if pubertal development is truly precocious, as there is currently a downwards trend in the average age of normal onset. The mechanism needs to be identified In particular, increased gonadotropin secretion must be documented in central precocious puberty. It is also essential to recognize non progressive forms of precocious puberty, which have an excellent prognosis and should not be treated. Long-acting GnRH agonists are indicated for proven central precocious puberty. Their use and long-term results are discussed. PMID:23420954

  1. [GnRH agonists versus antagonists during in vitro fertilization].

    PubMed

    Frydman, Ren

    2005-10-01

    During in vitro fertilization (IVF) GnRH antagonists or agonists are used to optimize the control of organization of oocyte collection. The choice of stimulation protocol also takes into account the ovulatory, clinical, biological and ultrasound characteristics of the FIV candidate, as well as any stimulation measures already taken. Age appears to be the major predictive factor of oocyte response to stimulation and ultrasonography on the 3rd day is a predictive element of the success of oocyte collection. Determination of hormonal parameters on the 3rd day of the cycle (FSH, oestradiol, inhibin B, anti-mullerian hormone) makes it possible to refine the choice of therapy. All these elements are used to define various categories of patients in terms of response to hormonal stimulation. Agonists induce a suppression of pituitary secretion which inhibits the preovulatory LH peak and blocks natural ovulation. Nevertheless, there is an initial transient stimulating effect (flare-up) for a few days and a risk of prolonged ovarian desensitization responsible for side effects. The antagonists, administered just before the supposed ovulatory phase, provoke a rapid diminution in LH while avoiding the flare-up and prolonged ovarian desensitization. Various meta-analyses to compare both types of treatments currently suggest that agonists are superior in terms of number of oocytes produced, though the percentage of mature oocytes obtained as well as the levels of fertility are comparable whatever the type of treatment. In practice, organization of stimulation protocols using agonists is easier especially for teams working in a sequential manner. However, protocols using antagonists may be particularly useful in poor responders and are globally better tolerated. PMID:16302711

  2. Improving the developability profile of pyrrolidine progesterone receptor partial agonists

    SciTech Connect

    Kallander, Lara S.; Washburn, David G.; Hoang, Tram H.; Frazee, James S.; Stoy, Patrick; Johnson, Latisha; Lu, Qing; Hammond, Marlys; Barton, Linda S.; Patterson, Jaclyn R.; Azzarano, Leonard M.; Nagilla, Rakesh; Madauss, Kevin P.; Williams, Shawn P.; Stewart, Eugene L.; Duraiswami, Chaya; Grygielko, Eugene T.; Xu, Xiaoping; Laping, Nicholas J.; Bray, Jeffrey D.; Thompson, Scott K.

    2010-09-17

    The previously reported pyrrolidine class of progesterone receptor partial agonists demonstrated excellent potency but suffered from serious liabilities including hERG blockade and high volume of distribution in the rat. The basic pyrrolidine amine was intentionally converted to a sulfonamide, carbamate, or amide to address these liabilities. The evaluation of the degree of partial agonism for these non-basic pyrrolidine derivatives and demonstration of their efficacy in an in vivo model of endometriosis is disclosed herein.

  3. Octopaminergic agonists for the cockroach neuronal octopamine receptor

    PubMed Central

    Hirashima, Akinori; Morimoto, Masako; Kuwano, Eiichi; Eto, Morifusa

    2003-01-01

    The compounds 1-(2,6-diethylphenyl)imidazolidine-2-thione and 2-(2,6-diethylphenyl)imidazolidine showed the almost same activity as octopamine in stimulating adenylate cyclase of cockroach thoracic nervous system among 70 octopamine agonists, suggesting that only these compounds are full octopamine agonists and other compounds are partial octopamine agonists. The quantitative structure-activity relationship of a set of 22 octopamine agonists against receptor 2 in cockroach nervous tissue, was analyzed using receptor surface modeling. Three-dimensional energetics descriptors were calculated from receptor surface model/ligand interaction and these three-dimensional descriptors were used in quantitative structure-activity relationship analysis. A receptor surface model was generated using some subset of the most active structures and the results provided useful information in the characterization and differentiation of octopaminergic receptor. Abbreviation: AEA arylethanolamine AII 2-(arylimino)imidazolidine AIO 2-(arylimino)oxazolidine AIT 2-(arylimino)thiazolidine APAT 2-(α-phenylethylamino)-2-thiazoline BPAT 2-(β-phenylethylamino)-2-thiazoline CAO 2-(3-chlorobenzylamino)-2-oxazoline DCAO 2-(3,5-dichlorobenzylamino)-2-oxazoline DET5 2-(2,6-diethylphenylimino)-5-methylthiazolidine DET6 2-(2,6-diethylphenylimino)thiazine EGTA ethylene glycol bis(β-aminoethyl ether)-N,N,N′,N′-tetraacetic acid GFA genetic function approximation G/PLS genetic partial least squares IND 2-aminomethyl-2-indanol LAH lithium aluminum hydride MCSG maximum common subgroup MCT6 2-(2-methyl-4-chlorophenylimino)thiazine OA octopamine PLS partial least squares QSAR quantitative structure-activity relationship SBAT 2-(substituted benzylamino)-2-thiazoline SD the sum of squared deviations of the dependent variable values from their mean SPIT 3-(substituted phenyl)imidazolidine-2-thione THI 2-amino-1-(2-thiazoyl)ethanol TMS tetramethyl silane PMID:15841226

  4. Classification of 20 DES Supernova with OzDES

    NASA Astrophysics Data System (ADS)

    Davis, T. M.; Kim, A. G.; Macualay, E.; Lidman, C.; Sharp, R.; Tucker, B. E.; Yuan, F.; Zhang, B.; Lewis, G. F.; Sommer, N. E.; Martini, P.; Mould, J.; Ahn, E.; Finley, D. A.; Frieman, J.; Marriner, J.; Wester, W.; Aldering, G.; Thomas, R. C.; Barbary, K.; Bloom, J. S.; Goldstein, D.; Nugent, P.; Perlmutter, S.; Foley, R. J.; Pan, Y.-C.; Casas, R.; Castander, F. J.; Desai, S.; Paech, K.; Smith, R. C.; Schubnell, M.; Kessler, R.; Lasker, J.; Scolnic, D.; Brout, D. J.; Gladney, L.; Sako, M.; Wolf, R. C.; Brown, P. J.; Krisciunas, K.; Suntzeff, N.; Nichol, R.; Papadopoulos, A.; Childress, M.; D'Andrea, C.; Smith, M.; Sullivan, M.; Maartens, R.; Gupta, R.; Kovacs, E.; Kuhlmann, S.; Spinka, H.

    2015-12-01

    We report new spectroscopic classifications by OzDES of supernovae discovered by the Dark Energy Survey (ATEL #4668). The spectra (370-885nm) were obtained with the AAOmega Spectrograph (Saunders et al. 2004, SPIE, 5492, 389) and the 2dF fibre positioner at the Anglo-Australian Telescope (AAT).

  5. Classification of 4 DES supernovae by OzDES

    NASA Astrophysics Data System (ADS)

    Glazebrook, K.; Amon, A.; Lidman, C.; Martini, P.; Tucker, B. E.; Yuan, F.; Aldering, G.; Kim, A. G.; Thomas, R. C.; Barbary, K.; Bloom, J. S.; Goldstein, D.; Nugent, P.; Perlmutter, S.; Foley, R. J.; Pan, Y.-C.; Casas, R.; Castander, F. J.; Desai, S.; Paech, K.; Smith, R. C.; Schubnell, M.; Kessler, R.; Lasker, J.; Scolnic, D.; Brout, D. J.; Gladney, L.; Sako, M.; Wolf, R. C.; Brown, P. J.; Krisciunas, K.; Suntzeff, N.; Nichol, R.; Papadopoulos, A.; Childress, M.; D'Andrea, C.; Smith, M.; Sullivan, M.; Maartens, R.; Gupta, R.; Kovacs, E.; Kuhlmann, S.; Spinka, H.; Ahn, E.; Finley, D. A.; Frieman, J.; Marriner, J.; Wester, W.

    2015-12-01

    We report new spectroscopic classifications by OzDES of supernovae discovered by the Dark Energy Survey (ATEL #4668). The spectra (370-885nm) were obtained with the AAOmega Spectrograph (Saunders et al. 2004, SPIE, 5492, 389) and the 2dF fibre positioner at the Anglo-Australian Telescope (AAT).

  6. Classification of 15 DES supernovae by OzDES

    NASA Astrophysics Data System (ADS)

    Yuan, F.; Tucker, B. E.; Lidman, C.; Martini, P.; Gshwend, Julia; Moller, A.; Zhang, B.; Smith, R. C.; Schubnell, M.; Kessler, R.; Lasker, J.; Scolnic, D.; Brout, D. J.; Gladney, L.; Sako, M.; Wolf, R. C.; Brown, P. J.; Krisciunas, K.; Suntzeff, N.; Nichol, R.; Papadopoulos, A.; Childress, M.; D'Andrea, C.; Smith, M.; Sullivan, M.; Maartens, R.; Gupta, R.; Kovacs, E.; Kuhlmann, S.; Spinka, H.; Ahn, E.; Finley, D. A.; Frieman, J.; Marriner, J.; Wester, W.; Aldering, G.; Kim, A. G.; Thomas, R. C.; Barbary, K.; Bloom, J. S.; Goldstein, D.; Nugent, P.; Perlmutter, S.; Foley, R. J.; Pan, Y.-C.; Casas, R.; Castander, F. J.; Desai, S.; Paech, K.

    2015-12-01

    We report new spectroscopic classifications by OzDES of supernovae discovered by the Dark Energy Survey (ATEL #4668). The spectra (370-885nm) were obtained with the AAOmega Spectrograph (Saunders et al. 2004, SPIE, 5492, 389) and the 2dF fibre positioner at the Anglo-Australian Telescope (AAT).

  7. Classification of 3 DES Supernovae with OzDES

    NASA Astrophysics Data System (ADS)

    Moller, A.; Tucker, B. E.; Yuan, F.; Lewis, G.; Lidman, C.; Macaulay, E.; Nichol, R.; Papadopoulos, A.; Childress, M.; D'Andrea, C.; Smith, M.; Sullivan, M.; Maartens, R.; Gupta, R.; Kovacs, E.; Kuhlmann, S.; Spinka, H.; Ahn, E.; Finley, D. A.; Frieman, J.; Marriner, J.; Wester, W.; Aldering, G.; Kim, A. G.; Thomas, R. C.; Barbary, K.; Bloom, J. S.; Goldstein, D.; Nugent, P.; Perlmutter, S.; Foley, R. J.; Pan, Y.-C.; Casas, R.; Castander, F. J.; Desai, S.; Paech, K.; Smith, R. C.; Schubnell, M.; Kessler, R.; Lasker, J.; Scolnic, D.; Brout, D. J.; Gladney, L.; Sako, M.; Wolf, R. C.; Brown, P. J.; Krisciunas, K.; Suntzeff, N.

    2016-02-01

    We report new spectroscopic classifications by OzDES of supernovae discovered by the Dark Energy Survey (ATEL #4668). The spectra (370-885nm) were obtained with the AAOmega Spectrograph (Saunders et al. 2004, SPIE, 5492, 389) and the 2dF fibre positioner at the Anglo-Australian Telescope (AAT).

  8. Classification of 14 DES Supernova with OzDES

    NASA Astrophysics Data System (ADS)

    Tucker, B. E.; Sharp, R.; Yuan, F.; Zhang, B.; Lidman, C.; Davis, T. M.; Hinton, S.; Mould, J.; Smith, R. C.; Schubnell, M.; Kessler, R.; Scolnic, D.; Covarrubias, R. A.; Brout, D. J.; Fischer, J. A.; Gladney, L.; March, M.; Sako, M.; Wolf, R. C.; Brown, P. J.; Krisciunas, K.; Suntzeff, N.; Nichol, R.; Papadopoulos, A.; D'Andrea, C.; Smith, M.; Sullivan, M.; Childress, M.; Maartens, R.; Gupta, R.; Kovacs, E.; Kuhlmann, S.; Spinka, H.; Ahn, E.; Finley, D. A.; Frieman, J.; Marriner, J.; Wester, W.; Aldering, G.; Kim, A. G.; Thomas, R. C.; Barbary, K.; Bloom, J. S.; Goldstein, D.; Nugent, P.; Perlmutter, S.; Foley, R. J.; Castander, F. J.; Desai, S.; Paech, K.

    2015-10-01

    We report new spectroscopic classifications by OzDES of supernovae discovered by the Dark Energy Survey. The spectra (370-885nm) were obtained with the AAOmega Spectrograph (Saunders et al. 2004, SPIE, 5492, 389) and the 2dF fibre positioner at the Anglo-Australian Telescope (AAT).

  9. Classification of 6 DES Supernova with OzDES

    NASA Astrophysics Data System (ADS)

    Lewis, G. F.; Mould, J.; Lidman, C.; Tucker, B. E.; Sharp, R.; Yuan, F.; Martini, P.; Kessler, R.; Scolnic, D.; Covarrubias, R. A.; Brout, D. J.; Fischer, J. A.; Gladney, L.; March, M.; Sako, M.; Wolf, R. C.; Brown, P. J.; Krisciunas, K.; Suntzeff, N.; Nichol, R.; Papadopoulos, A.; D'Andrea, C.; Smith, M.; Sullivan, M.; Childress, M.; Maartens, R.; Gupta, R.; Kovacs, E.; Kuhlmann, S.; Spinka, H.; Ahn, E.; Finley, D. A.; Frieman, J.; Marriner, J.; Wester, W.; Aldering, G.; Kim, A. G.; Thomas, R. C.; Barbary, K.; Bloom, J. S.; Goldstein, D.; Nugent, P.; Perlmutter, S.; Foley, R. J.; Casas, R.; Castander, F. J.; Desai, S.; Paech, K.; Smith, R. C.; Schubnell, M.

    2015-10-01

    We report new spectroscopic classifications by OzDES of supernovae discovered by the Dark Energy Survey (ATEL #4668). The spectra (370-885nm) were obtained with the AAOmega Spectrograph (Saunders et al. 2004, SPIE, 5492, 389) and the 2dF fibre positioner at the Anglo-Australian Telescope (AAT).

  10. Emerging strategies for exploiting cannabinoid receptor agonists as medicines.

    PubMed

    Pertwee, Roger G

    2009-02-01

    Medicines that activate cannabinoid CB(1) and CB(2) receptor are already in the clinic. These are Cesamet (nabilone), Marinol (dronabinol; Delta(9)-tetrahydrocannabinol) and Sativex (Delta(9)-tetrahydrocannabinol with cannabidiol). The first two of these medicines can be prescribed to reduce chemotherapy-induced nausea and vomiting. Marinol can also be prescribed to stimulate appetite, while Sativex is prescribed for the symptomatic relief of neuropathic pain in adults with multiple sclerosis and as an adjunctive analgesic treatment for adult patients with advanced cancer. One challenge now is to identify additional therapeutic targets for cannabinoid receptor agonists, and a number of potential clinical applications for such agonists are mentioned in this review. A second challenge is to develop strategies that will improve the efficacy and/or the benefit-to-risk ratio of a cannabinoid receptor agonist. This review focuses on five strategies that have the potential to meet either or both of these objectives. These are strategies that involve: (i) targeting cannabinoid receptors located outside the blood-brain barrier; (ii) targeting cannabinoid receptors expressed by a particular tissue; (iii) targeting up-regulated cannabinoid receptors; (iv) targeting cannabinoid CB(2) receptors; or (v) 'multi-targeting'. Preclinical data that justify additional research directed at evaluating the clinical importance of each of these strategies are also discussed. PMID:19226257

  11. Molecular impact of juvenile hormone agonists on neonatal Daphnia magna.

    PubMed

    Toyota, Kenji; Kato, Yasuhiko; Miyakawa, Hitoshi; Yatsu, Ryohei; Mizutani, Takeshi; Ogino, Yukiko; Miyagawa, Shinichi; Watanabe, Hajime; Nishide, Hiroyo; Uchiyama, Ikuo; Tatarazako, Norihisa; Iguchi, Taisen

    2014-05-01

    Daphnia magna has been used extensively to evaluate organism- and population-level responses to pollutants in acute toxicity and reproductive toxicity tests. We have previously reported that exposure to juvenile hormone (JH) agonists results in a reduction of reproductive function and production of male offspring in a cyclic parthenogenesis, D. magna. Recent advances in molecular techniques have provided tools to understand better the responses to pollutants in aquatic organisms, including D. magna. DNA microarray was used to evaluate gene expression profiles of neonatal daphnids exposed to JH agonists: methoprene (125, 250 and 500 ppb), fenoxycarb (0.5, 1 and 2 ppb) and epofenonane (50, 100 and 200 ppb). Exposure to these JH analogs resulted in chemical-specific patterns of gene expression. The heat map analyses based on hierarchical clustering revealed a similar pattern between treatments with a high dose of methoprene and with epofenonane. In contrast, treatment with low to middle doses of methoprene resulted in similar profiles to fenoxycarb treatments. Hemoglobin and JH epoxide hydrolase genes were clustered as JH-responsive genes. These data suggest that fenoxycarb has high activity as a JH agonist, methoprene shows high toxicity and epofenonane works through a different mechanism compared with other JH analogs, agreeing with data of previously reported toxicity tests. In conclusion, D. magna DNA microarray is useful for the classification of JH analogs and identification of JH-responsive genes. PMID:24038158

  12. Cryptochinones from Cryptocarya chinensis act as farnesoid X receptor agonists.

    PubMed

    Lin, Hsiang-Ru; Chou, Tsung-Hsien; Huang, Din-Wen; Chen, Ih-Sheng

    2014-09-01

    Cryptochinones A-D are tetrahydroflavanones isolated from the leaves of Cryptocarya chinensis, an evergreen tree whose extracts are believed to have a variety of health benefits. The origin of their possible bioactivity is unclear. The farnesoid X receptor (FXR) is a member of nuclear receptor superfamily that has been widely targeted for developing treatments for chronic liver disease and for hyperglycemia. We studied whether cryptochinones A-D, which are structurally similar to known FXR ligands, may act at this target. Indeed, in mammalian one-hybrid and transient transfection reporter assays, cryptochinones A-D transactivated FXR to modulate promoter action including GAL4, SHP, CYP7A1, and PLTP promoters in dose-dependent manner, while they exhibited similar agonistic activity as chenodeoxycholic acid (CDCA), an endogenous FXR agonist. Through molecular modeling docking studies we evaluated their ability to bind to the FXR ligand binding pocket. Our results indicate that cryptochinones A-D can behave as FXR agonists. PMID:25127166

  13. Temperature Dependence of Acetylcholine Receptor Channels Activated by Different Agonists

    PubMed Central

    Gupta, Shaweta; Auerbach, Anthony

    2011-01-01

    The temperature dependence of agonist binding and channel gating were measured for wild-type adult neuromuscular acetylcholine receptors activated by acetylcholine, carbamylcholine, or choline. With acetylcholine, temperature changed the gating rate constants (Q10 ? 3.2) but had almost no effect on the equilibrium constant. The enthalpy change associated with gating was agonist-dependent, but for all three ligands it was approximately equal to the corresponding free-energy change. The equilibrium dissociation constant of the resting conformation (Kd), the slope of the rate-equilibrium free-energy relationship (?), and the acetylcholine association and dissociation rate constants were approximately temperature-independent. In the mutant ?G153S, the choline association and dissociation rate constants were temperature-dependent (Q10 ? 7.4) but Kd was not. By combining two independent mutations, we were able to compensate for the catalytic effect of temperature on the decay time constant of a synaptic current. At mouse body temperature, the channel-opening and -closing rate constants are ?400 and 16ms?1. We hypothesize that the agonist dependence of the gating enthalpy change is associated with differences in ligand binding, specifically to the open-channel conformation of the protein. PMID:21320433

  14. Pharmacophore-driven identification of PPAR? agonists from natural sources.

    PubMed

    Petersen, Rasmus K; Christensen, Kathrine B; Assimopoulou, Andreana N; Frett, Xavier; Papageorgiou, Vassilios P; Kristiansen, Karsten; Kouskoumvekaki, Irene

    2011-02-01

    In a search for more effective and safe anti-diabetic compounds, we developed a pharmacophore model based on partial agonists of PPAR?. The model was used for the virtual screening of the Chinese Natural Product Database (CNPD), a library of plant-derived natural products primarily used in folk medicine. From the resulting hits, we selected methyl oleanonate, a compound found, among others, in Pistacia lentiscus var. Chia oleoresin (Chios mastic gum). The acid of methyl oleanonate, oleanonic acid, was identified as a PPAR? agonist through bioassay-guided chromatographic fractionations of Chios mastic gum fractions, whereas some other sub-fractions exhibited also biological activity towards PPAR?. The results from the present work are two-fold: on the one hand we demonstrate that the pharmacophore model we developed is able to select novel ligand scaffolds that act as PPAR? agonists; while at the same time it manifests that natural products are highly relevant for use in virtual screening-based drug discovery. PMID:21069556

  15. Microbial TLR Agonists and Humoral Immunopathogenesis in HIV Disease

    PubMed Central

    Yu, Xiaocong; Li, Zihai; Zhou, Zhenxian; Kilby, J Michael; Jiang, Wei

    2014-01-01

    Although T cells are the primary and most-studied targets of the Human Immunodeficiency Virus (HIV), B cells, especially memory B lymphocytes, are also chronically depleted in the course of HIV disease. Although the lack of CD4+ T cell help may explain these deficiencies, intrinsic defects in B lymphocytes appear to contribute to B cell depletion and reduced antibody (Ab) production in the setting of HIV, especially of some antigens eliciting T cell-independent responses. The gut mucosal barrier is disrupted in HIV disease, resulting in increased systemic exposure to microbial products such as Toll-Like Receptor (TLR) agonists. The association of enhanced systemic levels of TLR agonists and B cell dysfunction in HIV disease is not understood. This review discusses the potential role of microbial TLR agonists in the B cell depletion, enhanced autoantibody production and impaired responses to vaccination observed in HIV-infected hosts. Increased microbial translocation in HIV infection may drive B cells to produce autoantibodies and increase susceptibilities of B cells to apoptosis through activation-induced cell death. Determining the mechanisms of B cell perturbations in HIV disease will inform the design of novel strategies of improve immune responses to vaccines, reduce opportunistic infections and slow disease progression. PMID:24795844

  16. TLR agonists: our best frenemy in cancer immunotherapy

    PubMed Central

    Kaczanowska, Sabina; Joseph, Ann Mary; Davila, Eduardo

    2013-01-01

    Various TLR agonists are currently under investigation in clinical trials for their ability to orchestrate antitumor immunity. The antitumor responses are largely attributed to their aptitude to stimulate APCs such as DCs which in turn, activate tumor-specific T cell responses. However, there is a potential for TLR signaling to occur on cells other than professional APCs that could negate antitumor responses or even worse, promote tumor growth. The impetus for this review is twofold. First, there is accumulating data demonstrating that the engagement of TLRs on different T cell subsets and different cancer types could promote tumor growth or conversely, contribute to antitumor responses. Second, the efficacy of TLR agonists as monotherapies to treat cancer patients has been limited. In this review, we discuss how TLR signaling within different T cell subsets and cancer cells can potentially impact the generation of antitumor responses. Based on evidence from preclinical models and clinical trials, we draw attention to several criteria that we believe must be considered when selecting TLR agonists for developing effective immunotherapeutic strategies against cancer. PMID:23475577

  17. Benzocyclobutane, benzocycloheptane and heptene derivatives as melatonin agonists and antagonists.

    PubMed

    Tsotinis, Andrew; Afroudakis, Pandelis A; Garratt, Peter J; Bocianowska-Zbrog, Alina; Sugden, David

    2014-10-01

    Two series of analogues were designed, synthesised and evaluated as potential human melatonin type?1 and?2 receptor (hMT1 and hMT2 ) ligands. Their biological effects were assessed by a well-established, specific model of melatonin action, the pigment response of Xenopus laevis melanophores. Compounds containing a benzocyclobutane scaffold and a methoxy group in the "melatonin" orientation were found to be potent agonists, with one of the analogues exhibiting activity comparable to melatonin. In contrast, analogues with a methoxy group in non-melatonin positions or with multiple methoxy groups showed either weaker agonist activity or were antagonists. Benzocycloheptene derivatives with one methoxy group are found to be weak agonists, whereas those with two methoxy groups were found to be antagonists, as were all of the benzocycloheptane derivatives evaluated. The most active compounds were assessed in a human receptor radio ligand binding assay but showed little discrimination between MT1 and MT2 . These results again show that the indole nitrogen of melatonin is not a necessary component for analogue activity and also illustrate that replacement of the indole ring with a 4-membered carbocycle can provide highly active compounds when the methoxy group is in the melatonin position. PMID:25044938

  18. Agonist versus antagonist binding to alpha-adrenergic receptors.

    PubMed Central

    Hoffman, B B; Michel, T; Kilpatrick, D M; Lefkowitz, R J; Tolbert, M E; Gilman, H; Fain, J N

    1980-01-01

    The binding properties of two alpha-adrenergic radioligands, [3H]epinephrine (an agonist) and [3H]dihydroergocryptine (an antagonist), were compared in two model systems--membranes derived from human platelets and membranes from rat liver. The platelet contains exclusively alpha 2 and the liver mostly (approximately 80%) alpha 1 receptors. Agonists induce the formation of a guanine nucleotide-sensitive high-affinity state of alpha 2 but not alpha 1 receptors. [3H]Dihydroergocryptine labels all the alpha receptors, whereas [3H]epinephrine at low concentrations labels predominantly the high-affinity form of the alpha 2 receptor in both platelet and liver. However, in the liver, alpha-adrenergic effects such as glycogen phosphorylase activation are shown to be mediated via alpha 1 receptors. Thus, in liver membranes the endogenous "physiological" agonist may not label the physiologically relevant alpha 1 receptors in typical radioligand binding assays using low concentrations of [3H]epinephrine. PMID:6107908

  19. LHRH Agonists for the Treatment of Prostate Cancer: 2012

    PubMed Central

    Lepor, Herbert; Shore, Neal D

    2012-01-01

    The most recent guidelines on prostate cancer screening from the American Urological Association (2009), the National Comprehensive Cancer Network (2011), and the European Association of Urology (2011), as well as treatment and advances in disease monitoring, have increased the androgen deprivation therapy (ADT) population and the duration of ADT usage as the first-line treatment for metastatic prostate cancer. According to the European Association of Urology, gonadotropin-releasing hormone (GnRH) agonists have become the leading therapeutic option for ADT because they avoid the physical and psychological discomforts associated with orchiectomy. However, GnRH agonists display several shortcomings, including testosterone (T) surge (“clinical flare”) and microsurges. T surge delays the intended serologic endpoint of T suppression and may exacerbate clinical symptoms. Furthermore, ADT manifests an adverse-event spectrum that can impact quality of life with its attendant well-documented morbidities. Strategies to improve ADT tolerability include a holistic management approach, improved diet and exercise, and more specific monitoring to detect and prevent T depletion toxicities. Intermittent ADT, which allows hormonal recovery between treatment periods, has become increasingly utilized as a methodology for improving quality of life while not diminishing chronic ADT efficacy, and may also provide healthcare cost savings. This review assesses the present and potential future role of GnRH agonists in prostate cancer and explores strategies to minimize the adverse-event profile for patients receiving ADT. PMID:23172994

  20. Science gone translational: the OX40 agonist story

    PubMed Central

    Weinberg, Andrew D.; Morris, Nicholas P.; Kovacsovics-Bankowski, Magdalena; Urba, Walter J.; Curti, Brendan D.

    2013-01-01

    Summary OX40 (CD134) is a tumor necrosis factor (TNF) receptor expressed primarily on activated CD4+ and CD8+ T cells and transmits a potent costimulatory signal when engaged. OX40 is transiently expressed after T-cell receptor engagement and is upregulated on the most recently antigen-activated T cells within inflammatory lesions (e.g. sites of autoimmune destruction and on tumor-infiltrating lymphocytes). Hence, it is an attractive target to modulate immune responses: OX40 blocking agents to inhibit undesirable inflammation or OX40 agonists to enhance immune responses. In regards to this review, OX40 agonists enhance anti-tumor immunity, which leads to therapeutic effects in mouse tumor models. A team of laboratory and clinical scientists at the Providence Cancer Center has collaborated to bring the preclinical observations in cancer models from the bench to the bedside. This review describes the journey from in vitro experiments through preclinical mouse models to the successful translation of the first OX40 agonist to the clinic for the treatment of patients with cancer. PMID:22017441

  1. Vitamin D receptor agonists' anti-inflammatory properties.

    PubMed

    Vojinovic, Jelena

    2014-05-01

    One century after its discovery, vitamin D has been shown to be, in fact, a pleiotropic steroid hormone, which, besides regulation of calcium homeostasis and bone turnover, has antiproliferative, prodifferentiation, antibacterial, immunomodulatory, and anti-inflammatory properties in various cells and tissues. D hormone (1?,25(OH)2 D), regulated in an endocrine, autocrine, and paracrine manner, must be bound to the specific nuclear vitamin D receptor (VDR) to exert epigenetic and genetic effects, acting as a connection between extracellular stimuli and genomic responses of the cells. Since only high doses of hormone, provoking hypercalcemia, can achieve immunomodulatory effects, more than 3000 VDR agonists have been synthesized. Numerous experimental trials have been performed in animal models, evidencing the preventive and therapeutic potential of VDR agonists for chronic inflammatory diseases and cancer. Considering the selective anti-inflammatory effects of VDR agonists compared to glucocorticoids, sparing microbicidal functions, the fear of hypercalcemia as their only frequent side effect becomes a questionable reason for the lack of clinical studies. PMID:24754474

  2. Lipopolysaccharide is a Direct Agonist for Platelet RNA Splicing

    PubMed Central

    Shashkin, Pavel N.; Brown, G. Thomas; Ghosh, Arundhati; Marathe, Gopal K.; McIntyre, Thomas M.

    2008-01-01

    Platelets express TLR4 receptors, but its ligand lipopolysaccharide (LPS) does not directly activate thrombotic functions nor, obviously, transcription by these anucleate cells. Platelets, however, store information that changes their phenotype over a few hours in the form of unprocessed RNA transcripts. We show even low concentrations of LPS in the presence of soluble CD14 initiated splicing of unprocessed IL-1? RNA, with translation and accumulation of IL-1? protein. LPS was a more robust agonist for this response than thrombin. Platelets also contained cyclooxygenase-2 pre-mRNA, which also was spliced and translated after LPS stimulation. Flow cytometry and immunocytochemistry of platelets extensively purified by negative immunodepletion showed platelets contained IL-1?, and quantitative assessment of white blood cell contamination by CD14 real time PCR confirms that leukocytes were not the IL-1? source, nor were they required for platelet stimulation. LPS did not initiate rapid platelet responses, but over time did prime platelet aggregation to soluble agonists, induced actin rearrangement, and initiated granule secretion with P-selectin expression that resulted the coating of quiescent leukocytes with activated platelets. LPS is a direct agonist for platelets that allows these cells to directly participate in the innate immune response to bacteria. PMID:18714022

  3. Highly selective agonists for substance P receptor subtypes.

    PubMed Central

    Wormser, U; Laufer, R; Hart, Y; Chorev, M; Gilon, C; Selinger, Z

    1986-01-01

    The existence of a third tachykinin receptor (SP-N) in the mammalian nervous system was demonstrated by development of highly selective agonists. Systematic N-methylation of individual peptide bonds in the C-terminal hexapeptide of substance P gave rise to agonists which specifically act on different receptor subtypes. The most selective analog of this series, succinyl-[Asp6,Me-Phe8]SP6-11, elicits half-maximal contraction of the guinea pig ileum through the neuronal SP-N receptor at a concentration of 0.5 nM. At least 60,000-fold higher concentrations of this peptide are required to stimulate the other two tachykinin receptors (SP-P and SP-E). The action of selective SP-N agonists in the guinea pig ileum is antagonized by opioid peptides, suggesting a functional counteraction between opiate and SP-N receptors. These results indicate that the tachykinin receptors are distinct entities which may mediate different physiological functions. PMID:2431898

  4. Transport quantique dans des nanostructures

    NASA Astrophysics Data System (ADS)

    Naud, C.

    2002-09-01

    Quantum transport in nanostructures This work is devoted to the design, fabrication and magnetotransport investigations of mesoscopic devices. The sample are obtain by e-beam lithography and the measurements are performed at low temperature in a dilution refrigerator in the presence of a magnetic field. We have used MBE grown AlGaAs/GaAs heterojonctions as starting material to fabricate a bipartite tiling of rhombus called mathcal{T}3 lattice. We observe for the first time large amplitude h/e oscillations in this network as compared to the one measured in square lattices of similar size. These oscillations are the signature of a recently predited localization phenomenon induced by Aharonov-Bohm interferences on this peculiar topology. For particular values of the magnetic field the propagation of the electron wave function is bounded in a small number of cells, called Aharonov-Bohm cages. More strikingly, at high magnetic field, h/2e oscillations appear whose amplitude can be much higher than the fundamental period. Their temperature dependence is similar to that of the h/e signal. These observations withdraw a simple interpretation in terms of harmonics generation. The origin of this phenomenon is still unclear and needs more investigations. The influence electrical width of the wire defining the network and so the rule of the number of channels can be studied using a gate deposited over the lattice. In particular we have measured the amplitude dependence of the h/e and h/2e signal versus the gate voltage. Ce travail est consacr la ralisation d'chantillons msoscopiques partir de la lithographie lectronique ainsi qu' leur caractrisation trs basse temprature en magntotransport. Nous avons pour cela exploit le gaz bidimensionnel d'lectrons situ l'interface d'une htrojonction AlGaAs/GaAs pour raliser un rseau de boucle d'une gomtrie particulire baptise la gomtrie mathcal{T}3. Nous avons observ sur cette structure des oscillations de conductance en fonction du flux du champ magntique de priode h/e dont l'amplitude est beaucoup plus importante que celle mesure sur un rseau carr de mme dimension. Cette diffrence constitue une signature d'un effet de localisation induit par le champ magntique sur la topologie mathcal{T}3. Pour des valeurs spcifiques du champ magntique, du fait des interfrences destructives Aharonov-Bohm, la propagation des fonctions d'ondes est limite un ensemble fini de cellule du rseau appel cage. De la dpendance en temprature des oscillations de priode h/e mesures sur le rseau mathcal{T}3 nous avons tir une longueur caractristique qui peut tre rattache au primtre des cages. Un phnomne inattendu fut l'observation, pour des champs magntiques plus importants, d'un doublement de frquence des oscillations. Ces oscillations de priode h/2e pouvant avoir une amplitude suprieure aux oscillations de priode h/e, une interprtation en terme d'harmonique n'est pas possible. Enfin, l'influence de la largeur lectrique des fils constituant le rseau et donc celle du nombre de canaux par brin a t tudie en ralisant des grilles lectrostatique. Les variations de l'amplitude des signaux en h/e et h/2e en fonction de la tension de grille ont t mesurs.

  5. Switching from ergot to nonergot dopamine agonists in Parkinson's disease: a clinical series and five-drug dose conversion table.

    PubMed

    Grosset, Katherine; Needleman, Fiona; Macphee, Graeme; Grosset, Donald

    2004-11-01

    Of 99 patients on ergot-derived dopamine agonists informed about possible long-term side effects, switching to a nonergot was undertaken in 88 (89%). There were adverse events in 26%. After 11 months, 82% were on their switch agonist and 93% were on any agonist. Switching dopamine agonists is feasible in this population. PMID:15389984

  6. Safety and pharmacokinetics of a kinin B1 receptor peptide agonist produced with different counter-ions.

    PubMed

    Savard, Martin; Côté, Jérôme; Tremblay, Luc; Neugebauer, Witold; Regoli, Domenico; Gariépy, Sébastien; Hébert, Nathalie; Gobeil, Fernand

    2016-04-01

    Several studies have shown the potential therapeutic utility of kinin B1 receptor (B1R) peptide agonists in neurological and ischemic cardiovascular diseases and brain cancer. Preclinical safety studies are a prerequisite for further drug development. The objectives of this study were to determine the acute toxicity and pharmacokinetics of the peptide B1R agonist, SarLys[dPhe8]desArg9-bradykinin (NG29), as trifluoroacetate (TFacetate) or acetate salt form, following intravenous injection in rats. A maximum tolerated dose (MTD) of NG29-TFacetate was established at 75 mg/kg from the results of a dose range-finding study (up to 200 mg/kg). The short-term (4-day) repeat-dose toxicity study of NG29, using its MTD value, showed that NG29-acetate exhibited minimal non-adverse clinical pathology changes in hematology, coagulation, clinical chemistry and urine parameters and severe kidney histopathological changes characterized by renal tubular degeneration. No such effects were observed with NG29-TFacetate. At the injection site, NG29-TFacetate was considered to be more locally irritating when compared to the acetate form. The extent of exposure and half-life values of NG29-TFacetate were comparable to the acetate form (AUC0-α of 10.2 mg/l*h vs. 9.9 mg/l*h; T1/2 of 2.3 h vs. 2.4 h). This study shows that in rats NG29-TFacetate exhibits a superior tolerability profile compared with the peptide acetate form. PMID:26565554

  7. Annuaire du Bureau des longitudes - 2006

    NASA Astrophysics Data System (ADS)

    Imcce; Bureau Des Longitudes

    2005-07-01

    This annual publication provides ephemerides and data to the use of professionnal and amateur astronomers. Divided in 11 chapters it covers concordance of various calendars, explanation of fondamental astronomy and various time scales, explanation for the use of ephemerides; tables provide ephemerides (positions, rise/set/passage) of the Sun and the Moon, planets, planetary satellites, asteroids, comets, bright stars; data and explanation for the physical observation of the surface of the Sun, the Moon, and planets; chart of the sky and a list of constellations and galaxies; prediction and ephemerides for astronomical phenomenon: occultation by the moon, stellar occultations by asteroids and appulses, solar eclipses and lunar eclipses; and an additional review about a hot scientific topic, this year: "Legendre et le mridien terrestre, 200 ans aprs". Cette publication annuelle fournit des phmrides et des donnes l'usage des astronomes professionnels et des astronomes amateurs. Compose de 11 chapitres elle comprend les rubriques sur les diffrents calendriers et leurs concordance, les ftes lgales en France, les dates et dcrets sur les heures lgales en France mtropolitaine ; une introduction l'astronomie fondamentale et aux diffrentes chelles de temps, des explications sur l'utilisation des phmrides ; des tables fournissent les phmrides (positions, heures de lever/coucher/passage) du Soleil et de la Lune, de plantes, de satellites naturels, d'astrodes, de comtes, d'toiles brillantes ; des donnes pour l'observation de la surface du Soleil, de la Lune, et des plantes ; des cartes du ciel ainsi qu'une liste de constellations et de galaxies ; des prdictions des phnomnes astronomiques : occultation par la Lune, occultation stellaires par des astrodes et appulses, clipses de Soleil et de la Lune; la liste et les coordonnes des observatoires astronomiques les plus connus ; et enfin un cahier thmatique sur un sujet d'actulait, pour cette anne : "Legendre et le mridien terrestre, 200 ans aprs".

  8. L'astronomie des Anciens

    NASA Astrophysics Data System (ADS)

    Nazé, Yaël

    2009-04-01

    Quelle que soit la civilisation à laquelle il appartient, l'être humain cherche dans le ciel des réponses aux questions qu'il se pose sur son origine, son avenir et sa finalité. Le premier mérite de ce livre est de nous rappeler que l'astronomie a commencé ainsi à travers les mythes célestes imaginés par les Anciens pour expliquer l'ordre du monde et la place qu'ils y occupaient. Mais les savoirs astronomiques passés étaient loin d'être négligeables et certainement pas limités aux seuls travaux des Grecs : c'est ce que l'auteur montre à travers une passionnante enquête, de Stonehenge à Gizeh en passant par Pékin et Mexico, fondée sur l'étude des monuments anciens et des sources écrites encore accessibles. Les tablettes mésopotamiennes, les annales chinoises, les chroniques médiévales, etc. sont en outre d'une singulière utilité pour les astronomes modernes : comment sinon remonter aux variations de la durée du jour au cours des siècles, ou percer la nature de l'explosion qui a frappé tant d'observateurs en 1054 ? Ce livre offre un voyage magnifiquement illustré à travers les âges, entre astronomie et archéologie.

  9. Specificity of the thrombin receptor for agonist peptide is defined by its extracellular surface

    NASA Astrophysics Data System (ADS)

    Gerszten, Robert E.; Chen, Ji; Ishli, Maki; Ishil, Kenji; Wang, Ling; Nanevicz, Tania; Turck, Christoph W.; Vu, Thien-Khai H.; Coughlin, Shaun R.

    1994-04-01

    G-PROTEIN-COUPLED receptors for catecholamines and some other small ligands are activated when agonists bind to the transmem-brane region of the receptor1. The docking interactions through which peptide agonists activate their receptors are less well characterized2-7. The thrombin receptor is a specialized peptide receptor. It is activated by binding its tethered ligand domain, which is unmasked upon receptor cleavage by thrombin8,9. Human and Xenopus thrombin receptor homologues are each selectively activated by the agonist peptide representing their respective tethered ligand domains. Here we identify receptor domains that confer this agonist specificity by replacing the Xenopus receptor's amino-terminal exodomain and three extracellular loops with the corresponding human structures. This switches receptor specificity from Xenopus to human. The specificity of these thrombin receptors for their respective peptide agonists is thus determined by their extracellular surfaces. Our results indicate that agonist interaction with extracellular domains is important for thrombin receptor activation.

  10. Classification of DES15S2myz and DES15S2mwz by GTC

    NASA Astrophysics Data System (ADS)

    Casas, R.; Castander, F. J.; Desai, S.; Paech, K.; Smith, R. C.; Schubnell, M.; Kessler, R.; Lasker, J.; Scolnic, D.; Brout, D. J.; Gladney, L.; Sako, M.; Wolf, R. C.; Brown, P. J.; Krisciunas, K.; Suntzeff, N.; Nichol, R.; Papadopoulos, A.; Childress, M.; D'Andrea, C.; Smith, M.; Sullivan, M.; Maartens, R.; Gupta, R.; Kovacs, E.; Kuhlmann, S.; Spinka, H.; Ahn, E.; Finley, D. A.; Frieman, J.; Marriner, J.; Wester, W.; Aldering, G.; Kim, A. G.; Thomas, R. C.; Barbary, K.; Bloom, J. S.; Goldstein, D.; Nugent, P.; Perlmutter, S.; Foley, R. J.; Pan, Y.-C.

    2015-12-01

    We report optical spectroscopy of DES15S2myz and DES15S2mwz discovered by the Dark Energy Survey (ATel #4668). The spectra (495-920nm) were obtained using OSIRIS on the Gran Telescopio CANARIAS (GTC).

  11. Heritable victimization and the benefits of agonistic relationships

    PubMed Central

    Lea, Amanda J.; Blumstein, Daniel T.; Wey, Tina W.; Martin, Julien G. A.

    2010-01-01

    Here, we present estimates of heritability and selection on network traits in a single population, allowing us to address the evolutionary potential of social behavior and the poorly understood link between sociality and fitness. To evolve, sociality must have some heritable basis, yet the heritability of social relationships is largely unknown. Recent advances in both social network analyses and quantitative genetics allow us to quantify attributes of social relationships and estimate their heritability in free-living populations. Our analyses addressed a variety of measures (in-degree, out-degree, attractiveness, expansiveness, embeddedness, and betweenness), and we hypothesized that traits reflecting relationships controlled by an individual (i.e., those that the individual initiated or were directly involved in) would be more heritable than those based largely on the behavior of conspecifics. Identifying patterns of heritability and selection among related traits may provide insight into which types of relationships are important in animal societies. As expected, we found that variation in indirect measures was largely explained by nongenetic variation. Yet, surprisingly, traits capturing initiated interactions do not possess significant additive genetic variation, whereas measures of received interactions are heritable. Measures describing initiated aggression and position in an agonistic network are under selection (0.3 < |S| < 0.4), although advantageous trait values are not inherited by offspring. It appears that agonistic relationships positively influence fitness and seemingly costly or harmful ties may, in fact, be beneficial. Our study highlights the importance of studying agonistic as well as affiliative relationships to understand fully the connections between sociality and fitness. PMID:21115836

  12. Pharmacological properties of acid N-thiazolylamide FFA2 agonists

    PubMed Central

    Brown, Andrew J; Tsoulou, Christina; Ward, Emma; Gower, Elaine; Bhudia, Nisha; Chowdhury, Forhad; Dean, Tony W; Faucher, Nicolas; Gangar, Akanksha; Dowell, Simon J

    2015-01-01

    FFA2 is a receptor for short-chain fatty acids. Propionate (C3) and 4-chloro-?-(1-methylethyl)-N-2-thiazolyl-benzeneacetamide (4-CMTB), the prototypical synthetic FFA2 agonist, evoke calcium mobilization in neutrophils and inhibit lipolysis in adipocytes via this G-protein-coupled receptor. 4-CMTB contains an N-thiazolylamide motif but no acid group, and 4-CMTB and C3 bind to different sites on FFA2 and show allosteric cooperativity. Recently, FFA2 agonists have been described that contain both N-thiazolylamide and carboxylate groups, reminiscent of bitopic ligands. These are thought to engage the carboxylate-binding site on FFA2, but preliminary evidence suggests they do not bind to the same site as 4-CMTB even though both contain N-thiazolylamide. Here, we describe the characterization of four FFA2 ligands containing both N-thiazolylamide and carboxylate. (R)-3-benzyl-4-((4-(2-chlorophenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid (compound 14) exhibits allosteric agonism with 4-CMTB but not C3. Three other compounds agonize FFA2 in [35S]GTP?S-incorporation or cAMP assays but behave as inverse agonists in yeast-based gene-reporter assays, showing orthosteric antagonism of C3 responses but allosteric antagonism of 4-CMTB responses. Thus, the bitopic-like FFA2 ligands engage the orthosteric site but do not compete at the site of 4-CMTB binding on an FFA2 receptor molecule. Compound 14 activates FFA2 on human neutrophils and mouse adipocytes, but appears not to inhibit lipolysis upon treatment of human primary adipocytes in spite of the presence of a functional FFA2 receptor in these cells. Hence, these new ligands may reveal differences in coupling of FFA2 between human and rodent adipose tissues. PMID:26236484

  13. Defining Nicotinic Agonist Binding Surfaces through Photoaffinity Labeling†

    PubMed Central

    Tomizawa, Motohiro; Maltby, David; Medzihradszky, Katalin F.; Zhang, Nanjing; Durkin, Kathleen A.; Presley, Jack; Talley, Todd T.; Taylor, Palmer; Burlingame, Alma L.; Casida, John E.

    2016-01-01

    Nicotinic acetylcholine (ACh) receptor (nAChR) agonists are potential therapeutic agents for neurological dysfunction. In the present study, the homopentameric mollusk ACh binding protein (AChBP), used as a surrogate for the extracellular ligand-binding domain of the nAChR, was specifically derivatized by the highly potent agonist azidoepibatidine (AzEPI) prepared as a photoaffinity probe and radioligand. One EPI-nitrene photoactivated molecule was incorporated in each subunit interface binding site based on analysis of the intact derivatized protein. Tryptic fragments of the modified AChBP were analyzed by collision-induced dissociation and Edman sequencing of radiolabeled peptides. Each specific EPI-nitrene-modified site involved either Tyr195 of loop C on the principal or (+)-face or Met116 of loop E on the complementary or (−)-face. The two derivatization sites were observed in similar frequency, providing evidence of the reactivity of the azido/nitrene probe substituent and close proximity to both residues. [3H]AzEPI binds to the α4β2 nAChR at a single high-affinity site and photoaffinity-labels only the α4 subunit, presumably modifying Tyr225 spatially corresponding to Tyr195 of AChBP. Phe137 of the β2 nAChR subunit, equivalent to Met116 of AChBP, conceivably lacks sufficient reactivity with the nitrene generated from the probe. The present photoaffinity labeling in a physiologically relevant condition combined with the crystal structure of AChBP allows development of precise structural models for the AzEPI interactions with AChBP and α4β2 nAChR. These findings enabled us to use AChBP as a structural surrogate to define the nAChR agonist site. PMID:17614369

  14. Antinociceptive properties of selective MT(2) melatonin receptor partial agonists.

    PubMed

    Lpez-Canul, Martha; Comai, Stefano; Domnguez-Lpez, Sergio; Granados-Soto, Vinicio; Gobbi, Gabriella

    2015-10-01

    Melatonin is a neurohormone involved in the regulation of both acute and chronic pain whose mechanism is still not completely understood. We have recently demonstrated that selective MT2 melatonin receptor partial agonists have antiallodynic properties in animal models of chronic neuropathic pain by modulating ON/OFF cells of the descending antinociceptive system. Here, we examined the antinociceptive properties of the selective MT2 melatonin receptor partial agonists N-{2-[(3-methoxyphenyl)phenylamino]ethyl}acetamide (UCM765) and N-{2-[(3-bromophenyl)-(4-fluorophenyl)amino]ethyl}acetamide (UCM924) in two animal models of acute and inflammatory pain: the hot-plate and formalin tests. UCM765 and UCM924 (5-40 mg/kg, s.c.) dose-dependently increased the temperature of the first hind paw lick in the hot-plate test, and decreased the total time spent licking the injected hind paw in the formalin test. Antinociceptive effects of UCM765 and UCM924 were maximal at the dose of 20mg/kg. At this dose, the effects of UCM765 and UCM924 were similar to those produced by 200 mg/kg acetaminophen in the hot-plate test, and by 3 mg/kg ketorolac or 150 mg/kg MLT in the formalin test. Notably, antinociceptive effects of the two MT2 partial agonists were blocked by the pre-treatment with the MT2 antagonist 4-phenyl-2-propionamidotetralin (4P-PDOT, 10 mg/kg) in both paradigms. These results demonstrate the antinociceptive properties of UCM765 and UCM924 in acute and inflammatory pain models and corroborate the concept that MT2 melatonin receptor may be a novel target for analgesic drug development. PMID:26162699

  15. Adjunctive ?2-agonists reverse neuromuscular involvement in murine Pompe disease

    PubMed Central

    Li, Songtao; Sun, Baodong; Nilsson, Mats I.; Bird, Andrew; Tarnopolsky, Mark A.; Thurberg, Beth L.; Bali, Deeksha; Koeberl, Dwight D.

    2013-01-01

    Pompe disease has resisted enzyme replacement therapy with acid ?-glucosidase (GAA), which has been attributed to inefficient cation-independent mannose-6-phosphate receptor (CI-MPR) mediated uptake. We evaluated ?2-agonist drugs, which increased CI-MPR expression in GAA knockout (KO) mice. Clenbuterol along with a low-dose adeno-associated virus vector increased Rotarod latency by 75% at 4 wk, in comparison with vector alone (P<210?5). Glycogen content was lower in skeletal muscles, including soleus (P<0.01), extensor digitorum longus (EDL; P<0.001), and tibialis anterior (P<0.05) following combination therapy, in comparison with vector alone. Glycogen remained elevated in the muscles following clenbuterol alone, indicating an adjunctive effect with gene therapy. Elderly GAA-KO mice treated with combination therapy demonstrated 2-fold increased wirehang latency, in comparison with vector or clenbuterol alone (P<0.001). The glycogen content of skeletal muscle decreased following combination therapy in elderly mice (P<0.05). Finally, CI-MPR-KO/GAA-KO mice did not respond to combination therapy, indicating that clenbuterol's effect depended on CI-MPR expression. In summary, adjunctive ?2-agonist treatment increased CI-MPR expression and enhanced efficacy from gene therapy in Pompe disease, which has implications for other lysosomal storage disorders that involve primarily the brain.Li, S., Sun, B., Nilsson, M. I., Bird, A., Tarnopolsky, M. A., Thurberg, B. L., Bali, D., Koeberl, D. D. Adjunctive ?2-agonists reverse neuromuscular involvement in murine Pompe disease. PMID:22993195

  16. Thiazolidinediones are Partial Agonists for the Glucocorticoid Receptor

    PubMed Central

    Matthews, L; Berry, A; Tersigni, M; DAcquisto, F; Ianaro, A; Ray, D

    2014-01-01

    Although thiazolidinediones were designed as specific PPAR?-ligands there is evidence for some off-target effects mediated by a non-PPAR? mechanism. Previously we have shown that Rosiglitazone has anti-inflammatory actions not explicable by activation of PPAR?, but possibly by the glucocorticoid receptor (GR). Rosiglitazone induces nuclear translocation both of GR-GFP, and endogenous GR in HeLa and U20S cells but with slower kinetics than Dexamethasone. Rosiglitazone also induces GR phosphorylation (Ser211), a GR ligand-binding specific effect. Rosiglitazone drives luciferase expression from a simple GRE containing reporter gene in a GR-dependent manner (EC50 4?M), with a similar amplitude response to the partial GR agonist RU486. Rosiglitazone also inhibits Dexamethasone driven reporter gene activity (IC50 2.9?M) in a similar fashion to RU486, suggesting partial agonist activity. Importantly we demonstrate a similar effect in PPAR?-null cells suggesting both GR-dependence and PPAR?-independence. Rosiglitazone also activates a GAL4-GR chimera, driving a UAS promoter, demonstrating DNA template sequence independence, and furthermore enhanced SRC1-GR interaction, measured by a mammalian two-hybrid assay. Both Ciglitazone and Pioglitazone, structurally related to Rosiglitazone, show similar effects on the GR. The antiproliferative effect of Rosiglitazone is increased in U20S cells that overexpress GR, suggesting a biologically important GR-dependent component of Rosiglitazone action. Rosiglitazone is a partial GR agonist, affecting GR activation and trafficking to influence engagement of target genes and affect cell function. This novel mode of action may explain some off-target effects observed in vivo. Additionally, antagonism of glucocorticoid action may contribute to the anti-diabetic actions of Rosiglitazone. PMID:18801908

  17. PPARgamma agonist pioglitazone does not enhance performance in mice.

    PubMed

    Sanchis-Gomar, Fabian; Pareja-Galeano, Helios; Martinez-Bello, Vladimir E

    2014-09-01

    Peroxisome-proliferator-activated receptor (PPAR) delta and adenosine monophosphate (AMP)-activated protein kinases (AMPKs) regulate the metabolic and contractile characteristics of myofibres. PPAR proteins are nuclear receptors that function as transcription factors and regulate the expression of multiple genes. AMPK has been described as a master metabolic regulator which also controls gene expression through the direct phosphorylation of some nuclear proteins. Since it was discovered that both PPARdelta agonists (GW1516) and AMPK activators (5-aminoimidazole-4-carboxamide-1-?-D-ribofuranoside, known as AICAR) are very effective performance-enhancing substances in sedentary mice, the World Anti-doping Agency (WADA) included AICAR and GW1516 in the prohibited list of substances as metabolic modulators in the class 'Hormone and metabolic modulators'. Thiazolidinediones are PPARgamma agonists that can induce similar biological effects to those of PPARdelta and PPARdelta-AMPK agonists. Thus in this study, the effects of pioglitazone on mitochondrial biogenesis and performance were evaluated. Blood glucose levels and the protein expression of the intermediates involved in the mitochondrial biogenesis pathway and the citrate synthase activity were determined in both gastrocnemius and soleus muscles. Maximal aerobic velocity (MAV), endurance capacity, and grip strength before and after the training period were also determined. The MAV endurance capacity and grip strength of trained animals significantly increased. We found that the peroxisome proliferator-activated receptor-? coactivator-1? (PGC-1?) and the nuclear respiratory factor-1 (NRF-1) protein content and citrate synthase activity significantly increased in the soleus muscle of trained animals. No effect of treatment was found. Therefore in our study, pioglitazone administration did not affect mitochondrial biogenesis signaling pathway. PMID:24259440

  18. Estrogen Receptor Agonists and Antagonists in the Yeast Estrogen Bioassay.

    PubMed

    Wang, Si; Bovee, Toine F H

    2016-01-01

    Cell-based bioassays can be used to predict the eventual biological activity of a substance on a living organism. In vitro reporter gene bioassays are based on recombinant vertebrate cell lines or yeast strains and especially the latter are easy-to-handle, cheap, and fast. Moreover, yeast cells do not express estrogen, androgen, progesterone or glucocorticoid receptors, and are thus powerful tools in the development of specific reporter gene systems that are devoid of crosstalk from other hormone pathways. This chapter describes our experience with an in-house developed RIKILT yeast estrogen bioassay for testing estrogen receptor agonists and antagonists, focusing on the applicability of the latter. PMID:26585147

  19. Clenbuterol, a beta(2)-agonist, retards atrophy in denervated muscles

    NASA Technical Reports Server (NTRS)

    Zeman, Richard J.; Ludemann, Robert; Etlinger, Joseph D.

    1987-01-01

    The effects of a beta(2) agonist, clenbuterol, on the protein content as well as on the contractile strength and the muscle fiber cross-sectional area of various denervated muscles from rats were investigated. It was found that denervated soleus, anterior tibialis, and gastrocnemius muscles, but not the extensor digitorum longus, of rats treated for 2-3 weeks with clenbuterol contained 95-110 percent more protein than denervated controls. The twofold difference in the protein content of denervated solei was paralleled by similar changes in contractile strength and muscle fiber cross-sectional area.

  20. Dopamine agonists suppress visual-cortical reflex myoclonus.

    PubMed Central

    Obeso, J A; Artieda, J; Tun, T; Luquin, M R; Martnez Lage, J M

    1985-01-01

    Two patients with a diagnosis of olivo-ponto-cerebellar atrophy developed cortical reflex myoclonus to visual (flash) and somaesthetic stimuli. Oral treatment with levodopacarbidopa (1000/100 mg) or subcutaneous administration of apomorphine (1 mg) abolished the visually-triggered myoclonus, without modifying reflex myoclonus to electrical or tactile stimulation. Intravenous administration of lisuride (0.1 mg) produced a marked reduction in both types of reflex myoclonus. These results indicate a selective inhibitory effect of dopamine agonist drugs on visual reflex myoclonus of cortical origin. Images PMID:3936901

  1. Discovery of benzamides as potent human ?3 adrenergic receptor agonists.

    PubMed

    Zhu, Cheng; Kar, Nam F; Li, Bing; Costa, Melissa; Dingley, Karen H; Di Salvo, Jerry; Ha, Sookhee N; Hurley, Amanda L; Li, Xiaofang; Miller, Randy R; Salituro, Gino M; Struthers, Mary; Weber, Ann E; Hale, Jeffrey J; Edmondson, Scott D

    2016-01-01

    The paper will describe the synthesis and SAR studies that led to the discovery of benzamide (reverse amide) as potent and selective human ?3-adrenergic receptor agonist. Based on conformationally restricted pyrrolidine scaffold we discovered earlier, pyrrolidine benzoic acid intermediate 22 was synthesized. From library synthesis and further optimization efforts, several structurally diverse reverse amides such as 24c and 24i were found to have excellent human ?3-adrenergic potency and good selectivity over the ?1 and ?2 receptors. In addition to human ?1, ?2, ?3 and hERG data, PK of selected compounds will be described. PMID:26590100

  2. Treating prolactinomas with dopamine agonists: always worth the gamble?

    PubMed

    Noronha, Sean; Stokes, Victoria; Karavitaki, Niki; Grossman, Ashley

    2016-02-01

    Dopamine agonists are the treatment of choice for all patients with prolactinomas. They are generally safe, effective, and well-tolerated. However, a link between their use and the development of impulse control disorders has been well recognized in the field of neurology for some time, and evidence for a similar effect in endocrine patients is emerging. This has mainly been revealed through clinical case reports, plus a small number of comparative studies of varying robustness. We review the current available literature and discuss the implications for clinical practice, in particular emphasizing the need for clinicians to be alert to these uncommon but serious adverse effects. PMID:26336835

  3. INSIGHT AGONISTES: A READING OF SOPHOCLES'S OEDIPUS THE KING.

    PubMed

    Mahon, Eugene J

    2015-07-01

    In this reading of Sophocles's Oedipus the King, the author suggests that insight can be thought of as the main protagonist of the tragedy. He personifies this depiction of insight, calling it Insight Agonistes, as if it were the sole conflicted character on the stage, albeit masquerading at times as several other characters, including gods, sphinxes, and oracles. This psychoanalytic reading of the text lends itself to an analogy between psychoanalytic process and Sophocles's tragic hero. The author views insight as always transgressing against, always at war with a conservative, societal, or intrapsychic chorus of structured elements. A clinical vignette is presented to illustrate this view of insight. PMID:26198605

  4. Substituted isoxazole analogs of farnesoid X receptor (FXR) agonist GW4064

    SciTech Connect

    Bass, Jonathan Y.; Caldwell, Richard D.; Caravella, Justin A.; Chen, Lihong; Creech, Katrina L.; Deaton, David N.; Madauss, Kevin P.; Marr, Harry B.; McFadyen, Robert B.; Miller, Aaron B.; Parks, Derek J.; Todd, Dan; Williams, Shawn P.; Wisely, G. Bruce

    2010-09-27

    Starting from the known FXR agonist GW 4064 1a, a series of alternately 3,5-substituted isoxazoles was prepared. Several of these analogs were potent full FXR agonists. A subset of this series, with a tether between the isoxazole ring and the 3-position aryl substituent, were equipotent FXR agonists to GW 4064 1a, with the 2,6-dimethyl phenol analog 1t having greater FRET FXR potency than GW 4064 1a.

  5. Fine tuning of agonistic/antagonistic activity for vitamin D receptor by 22-alkyl chain length of ligands: 22S-Hexyl compound unexpectedly restored agonistic activity.

    PubMed

    Anami, Yasuaki; Sakamaki, Yuta; Itoh, Toshimasa; Inaba, Yuka; Nakabayashi, Makoto; Ikura, Teikichi; Ito, Nobutoshi; Yamamoto, Keiko

    2015-11-15

    1?,25-Dihydroxyvitamin D3 exerts its actions by binding to vitamin D receptor (VDR). We are continuing the study related to the alteration of pocket structure of VDR by 22-alkyl substituent of ligands and the relationships between the alteration and agonistic/antagonistic activity. Previously we reported that compounds 2 (22-H), 3 (22S-Et), and 4 (22S-Bu) are VDR agonist, partial agonist and antagonist, respectively. Here, we describe the synthesis and biological evaluation of 22S-hexyl analog 5 (22S-Hex), which was designed to be a stronger VDR antagonist than 4. Unexpectedly, 5 showed partial agonistic but not antagonistic activity when bound to VDR, indicating that it is not necessarily true that the bulkier the side chain is, the stronger the antagonistic activity will be. X-ray crystallographic analysis of the VDR-ligand-binding domain (VDR-LBD) accommodating compound 5 indicated that the partial agonist activity of 5 is dependent on the mixed population of the agonistic and antagonistic conformations. Binding of compound 5 may not bring the complex into the only antagonistic conformation due to the large conformational change of the VDR-LBD. From this study it was found that fine tuning of agonistic/antagonistic activity for VDR is possible by 22-alkyl chain length of ligands. PMID:26515040

  6. Two distinct classes of novel pyrazolinecarboxamides as potent cannabinoid CB1 receptor agonists.

    PubMed

    Lange, Jos H M; Attali, Amos; van der Neut, Martina A W; Wals, Henri C; Mulder, Arie; Zilaout, Hicham; Duursma, Ate; van Aken, Hans H M; van Vliet, Bernard J

    2010-09-01

    The synthesis and SAR of 3-alkyl-4-aryl-4,5-dihydropyrazole-1-carboxamides 1-23 and 1-alkyl-5-aryl-4,5-dihydropyrazole-3-carboxamides 24-27 as two novel cannabinoid CB(1) receptor agonist classes were described. The target compounds elicited high affinities to the CB(1) as well as the CB(2) receptor and were found to act as CB(1) receptor agonists. The key compound 19 elicited potent CB(1) agonistic and CB(2) inverse agonistic properties in vitro and showed in vivo activity in a rodent model for multiple sclerosis after oral administration. PMID:20688519

  7. Profil pidemio-clinique et radiologique des atteintes osto-articulaires des hmophiles Madagascar

    PubMed Central

    Narindra, Lova Hasina Rajaonarison Ny Ony; Rabemanorintsoa, Feno Hasina; Randrianantenaina, Faralahy Ravelonarivo; Rakoto, Olivat Alson Aime; Ahmad, Ahmad

    2014-01-01

    Introduction Dterminer le profil pidmio-clinique et radiologique des atteintes osto-articulaires des hmophiles malagasy. Mthodes Une tude prospective, descriptive portant sur 25 patients hmophiles venant de tout Madagascar a t ralise. Des radiographies numrises des genoux, des chevilles et des coudes en incidence de face et de profil ainsi qu'une chographie des hanches, des genoux, des chevilles et des coudes ont t ralises chez ces patients. Le type et la svrit de la maladie ainsi que l'aspect de la cavit articulaire, la synoviale, les noyaux piphysaires et les surfaces articulaires ont t analyss. Rsultats Soixante-huit pourcent des patients taient hmophiles de type A et 32 % de type B. Quarante pourcent taient classs svres, 28 % modrs et 32 % mineurs. Les atteintes osto-articulaires ont t retrouves chez 56 % des patients. Il n'existait pas de prdominance d'atteinte selon le type ni la svrit de la maladie. Les plus jeunes taient les plus atteints et l'articulation du genou et de la cheville taient les plus touches. Conclusion Les complications osto-articulaire de l'hmophilie sont graves et ne dpendent pas du type ni de la svrit de l'affection. Elles touchent surtout les enfants d'ge scolaire. Le couple radiographie-chographie permet de diagnostiquer et de surveiller ces lsions. PMID:25870742

  8. Benzodiazepine agonist and inverse agonist actions on GABAA receptor-operated chloride channels. I. Acute effects of ethanol

    SciTech Connect

    Buck, K.J.; Harris, R.A. )

    1990-05-01

    Acute exposure to ethanol was found to enhance the ability of a benzodiazepine (BZ) inverse agonist, methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM), to reduce muscimol-activated 36Cl- uptake by membranes isolated from mouse cerebral cortex. Pretreatment in vivo with a hypnotic dose of ethanol (but not a subhypnotic dose), or exposure to a corresponding concentration in vitro, was effective. This increase in sensitivity of gamma-aminobutyric acid receptor-operated chloride channels to the actions of DMCM was due to an increase in both the potency and efficacy of DMCM. Sensitization to DMCM was reversible and was not observed 24 hr after a single injection of ethanol. Pretreatment with ethanol (10, 50 and 100 mM) in vitro produced sensitization to DMCM in a concentration-dependent manner, similar to that produced by in vivo exposure; this increase in sensitivity did not develop if the membranes were pretreated with ethanol at 0 degrees C. Similarly, in vitro exposure to pentobarbital (200 microM) or flunitrazepam (1 microM) enhanced the actions of the inverse agonist Ro15-4513 (ethyl-8-azido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo(1,5a)(1,4)BZ-3- carboxylate). Acute ethanol exposure did not alter low-affinity gamma-aminobutyric acidA receptor binding or muscimol action, or the ability of a BZ agonist, flunitrazepam, to augment muscimol-activated chloride flux. Ethanol exposure did not alter (3H)flumazenil (Ro15-1788) binding to central BZ receptors, its displacement by DMCM or allosteric modulation of DMCM binding by muscimol (muscimol-shift).

  9. Acceptation et tolrance des allogreffes : nouveau concept

    PubMed Central

    STARZL, Thomas E.

    2010-01-01

    RSUM La dcouverte du microchimrisme dans la transplantation de rein et de foie a permis de mieux comprendre lacceptation des allogreffes, lanalyse des problmes de conditionnement et la recherche de nouvelles orientations dans le traitement des greffes. En fonction de ce nouveau concept, seront ici discutes les relations avec les maladies infectieuses provoques par des micro-organismes non cytopathologiques, les rponses aux questions autrefois poses, la raction immunologique et les implications dans le domaine de limmunologie gnrale. PMID:9622934

  10. Behavioural determinants of agonistic success in invasive crayfish.

    PubMed

    Hudina, Sandra; Hock, Karlo

    2012-09-01

    Ecosystems today increasingly suffer invasions by multiple invasive species, some of which may share similar advantageous life history traits and ecological niche. In such cases, direct competition can influence invasion success of both species, and provide insights into competition without co-evolution in species equally novel to the environment. We used two widespread crayfish invaders of freshwater ecosystems of Europe, signal crayfish (Pacifastacus leniusculus) and spiny cheek crayfish (Orconectes limosus), to investigate how behavioural decisions in agonistic encounters contribute to competitive advantages in the absence of adaptation to either opponents or an environment. In direct competition against novel but comparable opponents, the key factor for establishing clear dominance of P. leniusculus in interspecific bouts was its greater tendency towards continued engagement in high-intensity fights. With O. limosus individuals consistently retreating from staged bouts as fights became more intense, P. leniusculus individuals did not need to adapt their strategy to be successful, suggesting that their agonistic behaviour intrinsically predisposed them to win. While both species are detrimental to invaded ecosystems, our results indicate that aggressive behaviour of P. leniusculus against unfamiliar opponents could allow it to more easily outcompete other comparable species and consequently present a potentially greater threat for native ecosystems. PMID:22688078

  11. Antidiabetic Actions of an Estrogen Receptor β Selective Agonist

    PubMed Central

    Alonso-Magdalena, Paloma; Ropero, Ana B.; García-Arévalo, Marta; Soriano, Sergi; Quesada, Iván; Muhammed, Sarheed J.; Salehi, Albert; Gustafsson, Jan-Ake; Nadal, Ángel

    2013-01-01

    The estrogen receptor β (ERβ) is emerging as an important player in the physiology of the endocrine pancreas. We evaluated the role and antidiabetic actions of the ERβ selective agonist WAY200070 as an insulinotropic molecule. We demonstrate that WAY200070 enhances glucose-stimulated insulin secretion both in mouse and human islets. In vivo experiments showed that a single administration of WAY200070 leads to an increase in plasma insulin levels with a concomitant improved response to a glucose load. Two-week treatment administration increased glucose-induced insulin release and pancreatic β-cell mass and improved glucose and insulin sensitivity. In addition, streptozotocin-nicotinamide–induced diabetic mice treated with WAY200070 exhibited a significant improvement in plasma insulin levels and glucose tolerance as well as a regeneration of pancreatic β-cell mass. Studies performed in db/db mice demonstrated that this compound restored first-phase insulin secretion and enhanced pancreatic β-cell mass. We conclude that ERβ agonists should be considered as new targets for the treatment of diabetes. PMID:23349481

  12. Mood Disorders, Circadian Rhythms, Melatonin and Melatonin Agonists

    PubMed Central

    Quera Salva, M.A.; Hartley, S.

    2012-01-01

    Recent advances in the understanding of circadian rhythms have led to an interest in the treatment of major depressive disorder with chronobiotic agents. Many tissues have autonomous circadian rhythms, which are orchestrated by the master clock, situated in the suprachiasmatic nucleus (SNC). Melatonin (N-acetyl-5-hydroxytryptamine) is secreted from the pineal gland during darkness. Melatonin acts mainly on MT1 and MT2 receptors, which are present in the SNC, regulating physiological and neuroendocrine functions, including circadian entrainment, referred to as the chronobiotic effet. Circadian rhythms has been shown to be either misaligned or phase shifted or decreased in amplitude in both acute episodes and relapse of major depressive disorder (MDD) and bipolar disorder. Manipulation of circadian rhythms either using physical treatments (such as high intensity light) or behavioral therapy has shown promise in improving symptoms. Pharmacotherapy using melatonin and pure melatonin receptor agonists, while improving sleep, has not been shown to improve symptoms of depression. A novel antidepressant, agomelatine, combines 5HT2c antagonist and melatonin agonist action, and has shown promise in both acute treatment of MDD and in preventing relapse. PMID:23650464

  13. Identification of agonists for a group of human odorant receptors

    PubMed Central

    Gonzalez-Kristeller, Daniela C.; do Nascimento, Joo B. P.; Galante, Pedro A. F.; Malnic, Bettina

    2015-01-01

    Olfaction plays a critical role in several aspects of the human life. Odorants are detected by hundreds of odorant receptors (ORs) which belong to the superfamily of G protein-coupled receptors. These receptors are expressed in the olfactory sensory neurons of the nose. The information provided by the activation of different combinations of ORs in the nose is transmitted to the brain, leading to odorant perception and emotional and behavioral responses. There are ~400 intact human ORs, and to date only a small percentage of these receptors (~10%) have known agonists. The determination of the specificity of the human ORs will contribute to a better understanding of how odorants are discriminated by the olfactory system. In this work, we aimed to identify human specific ORs, that is, ORs that are present in humans but absent from other species, and their corresponding agonists. To do this, we first selected 22 OR gene sequences from the human genome with no counterparts in the mouse, rat or dog genomes. Then we used a heterologous expression system to screen a subset of these human ORs against a panel of odorants of biological relevance, including foodborne aroma volatiles. We found that different types of odorants are able to activate some of these previously uncharacterized human ORs. PMID:25784876

  14. Long-Acting Beta Agonists Enhance Allergic Airway Disease

    PubMed Central

    Knight, John M.; Mak, Garbo; Shaw, Joanne; Porter, Paul; McDermott, Catherine; Roberts, Luz; You, Ran; Yuan, Xiaoyi; Millien, Valentine O.; Qian, Yuping; Song, Li-Zhen; Frazier, Vincent; Kim, Choel; Kim, Jeong Joo; Bond, Richard A.; Milner, Joshua D.; Zhang, Yuan; Mandal, Pijus K.; Luong, Amber; Kheradmand, Farrah

    2015-01-01

    Asthma is one of the most common of medical illnesses and is treated in part by drugs that activate the beta-2-adrenoceptor (β2-AR) to dilate obstructed airways. Such drugs include long acting beta agonists (LABAs) that are paradoxically linked to excess asthma-related mortality. Here we show that LABAs such as salmeterol and structurally related β2-AR drugs such as formoterol and carvedilol, but not short-acting agonists (SABAs) such as albuterol, promote exaggerated asthma-like allergic airway disease and enhanced airway constriction in mice. We demonstrate that salmeterol aberrantly promotes activation of the allergic disease-related transcription factor signal transducer and activator of transcription 6 (STAT6) in multiple mouse and human cells. A novel inhibitor of STAT6, PM-242H, inhibited initiation of allergic disease induced by airway fungal challenge, reversed established allergic airway disease in mice, and blocked salmeterol-dependent enhanced allergic airway disease. Thus, structurally related β2-AR ligands aberrantly activate STAT6 and promote allergic airway disease. This untoward pharmacological property likely explains adverse outcomes observed with LABAs, which may be overcome by agents that antagonize STAT6. PMID:26605551

  15. Serotonergic agonists stimulate inositol lipid metabolism in rabbit platelets

    SciTech Connect

    Schaechter, M.; Godfrey, P.P.; Minchin, M.C.W.; McClue, S.J.; Young, M.M.

    1985-10-28

    The metabolism of inositol phospholipids in response to serotonergic agonists was investigated in rabbit platelets. In platelets prelabelled with (/sup 3/H)-inositol, in a medium containing 10 mM LiCl which blocks the enzyme inositol-1-phosphatase, 5-hydroxytryptamine (5-HT) caused a dose-dependent accumulation of inositol phosphates (IP). This suggests a phospholipase-C-mediated breakdown of phosphoinositides. Ketanserin, a selective 5-HT/sub 2/ antagonist, was a potent inhibitor of the 5-HT response, with a Ki of 28 nM, indicating that 5-HT is activating receptors of the 5-HT/sub 2/ type in the platelet. Lysergic acid diethylamide (LSD) and quipazine also caused dose-related increases in inositol phosphate levels, though these were considerably less than those produced by 5-HT. These results show that relatively small changes in phosphoinositide metabolism induced by serotonergic agonists can be investigated in the rabbit platelet, and this cell may therefore be a useful model for the study of some 5-HT receptors. 30 references, 4 figures.

  16. A Sphingosine 1-phosphate receptor 2 selective allosteric agonist

    PubMed Central

    Satsu, Hideo; Schaeffer, Marie-Therese; Guerrero, Miguel; Saldana, Adrian; Eberhart, Christina; Hodder, Peter; Cayanan, Charmagne; Schrer, Stephan; Bhhatarai, Barun; Roberts, Ed; Rosen, Hugh; Brown, Steven J.

    2013-01-01

    Molecular probe tool compounds for the Sphingosine 1-phosphate receptor 2 (S1PR2) are important for investigating the multiple biological processes in which the S1PR2 receptor has been implicated. Amongst these are NF-?B-mediated tumor cell survival and fibroblast chemotaxis to fibronectin. Here we report our efforts to identify selective chemical probes for S1PR2 and their characterization. We employed high throughput screening to identify two compounds which activate the S1PR2 receptor. SAR optimization led to compounds with high nanomolar potency. These compounds, XAX-162 and CYM-5520, are highly selective and do not activate other S1P receptors. Binding of CYM-5520 is not competitive with the antagonist JTE-013. Mutation of receptor residues responsible for binding to the zwitterionic headgroup of sphingosine 1-phosphate (S1P) abolishes S1P activation of the receptor, but not activation by CYM-5520. Competitive binding experiments with radiolabeled S1P demonstrate that CYM-5520 is an allosteric agonist and does not displace the native ligand. Computational modeling suggests that CYM-5520 binds lower in the orthosteric binding pocket, and that co-binding with S1P is energetically well tolerated. In summary, we have identified an allosteric S1PR2 selective agonist compound. PMID:23849205

  17. Adjunctive ?2-agonists reverse neuromuscular involvement in murine Pompe disease.

    PubMed

    Li, Songtao; Sun, Baodong; Nilsson, Mats I; Bird, Andrew; Tarnopolsky, Mark A; Thurberg, Beth L; Bali, Deeksha; Koeberl, Dwight D

    2013-01-01

    Pompe disease has resisted enzyme replacement therapy with acid ?-glucosidase (GAA), which has been attributed to inefficient cation-independent mannose-6-phosphate receptor (CI-MPR) mediated uptake. We evaluated ?2-agonist drugs, which increased CI-MPR expression in GAA knockout (KO) mice. Clenbuterol along with a low-dose adeno-associated virus vector increased Rotarod latency by 75% at 4 wk, in comparison with vector alone (P<210(-5)). Glycogen content was lower in skeletal muscles, including soleus (P<0.01), extensor digitorum longus (EDL; P<0.001), and tibialis anterior (P<0.05) following combination therapy, in comparison with vector alone. Glycogen remained elevated in the muscles following clenbuterol alone, indicating an adjunctive effect with gene therapy. Elderly GAA-KO mice treated with combination therapy demonstrated 2-fold increased wirehang latency, in comparison with vector or clenbuterol alone (P<0.001). The glycogen content of skeletal muscle decreased following combination therapy in elderly mice (P<0.05). Finally, CI-MPR-KO/GAA-KO mice did not respond to combination therapy, indicating that clenbuterol's effect depended on CI-MPR expression. In summary, adjunctive ?2-agonist treatment increased CI-MPR expression and enhanced efficacy from gene therapy in Pompe disease, which has implications for other lysosomal storage disorders that involve primarily the brain. PMID:22993195

  18. Nicotinic acetylcholine receptor agonists: a milestone for modern crop protection.

    PubMed

    Jeschke, Peter; Nauen, Ralf; Beck, Michael Edmund

    2013-09-01

    The destruction of crops by invertebrate pests is a major threat against a background of a continuously rising demand in food supply for a growing world population. Therefore, efficient crop protection measures in a vast range of agricultural settings are of utmost importance to guarantee sustainable yields. The discovery of synthetic agonists selectively addressing the nicotinic acetylcholine receptors (nAChRs), located in the central nervous system of insects, for use as insecticides was a major milestone in applied crop protection research. These compounds, as a result of their high target specificity and versatility in application methods, opened a new innovative era in the control of some of the world's most devastating insect pests. These insecticides also contributed massively to extending our knowledge of the biochemistry of insect nicotinic acetylcholine receptors. The global economic success of synthetic nAChR agonists as insecticides renders the nicotinic acetylcholine receptor still one of the most attractive target sites for exploration in insecticide discovery. PMID:23934864

  19. Opioid agonist and antagonist behavioural effects of buprenorphine.

    PubMed Central

    Leander, J. D.

    1983-01-01

    1 The agonist and antagonist effects of a range of buprenorphine doses (0.08-20 mg/kg) were studied on the responding of pigeons under a multiple fixed-ratio, fixed-interval schedule of grain presentation. Various doses (0.02-10 mg/kg) of buprenorphine were also tested in pigeons trained to discriminate between injections of 0.05 mg/kg of fentanyl and injections of distilled water. 2 Buprenorphine, over a broad dose range (0.08-5 mg/kg), increased the rates of responding in the fixed-interval component of the multiple schedule and disrupted patterning of responding within the fixed-interval, without affecting fixed-ratio responding even at a dose of 40 mg/kg. The effects of some of the high doses on fixed-interval responding were still evident one and two days after buprenorphine injection. 3 Doses of buprenorphine which produced increases in fixed-interval responding were also effective as antagonists of the behavioural depression produced by 40 mg/kg of morphine, and were discriminated as fentanyl-like by pigeons trained to discriminate between injections of fentanyl and injections of water. 4 These results show that buprenorphine produces marked agonist and antagonist effects over an extremely broad dose range without producing behavioural depressant effects. PMID:6850163

  20. Dopamine D3 agonists in the treatment of Parkinson's disease.

    PubMed

    Das, Banibrata; Modi, Gyan; Dutta, Aloke

    2015-01-01

    Parkinson's disease (PD) is t he second most common form of neurodegenerative disorders that results from the progressive loss of dopaminergic neurons in the midbrain substantia nigra pars compacta (SNpc) triggering profound motor perturbation, as well as cognitive, sensory and mood deficits. Although these symptoms can be improved using currently available dopamine replacement strategies, they are not able to slow the neurodegenerative process that underlies PD progression. Following the discovery of the D3 receptor from molecular cloning, it has gained much attention as a potential therapeutic target for the treatment of PD due to their localization in the limbic regions of the brain as well as pharmacologic similarity to the D2 receptor subtype. Of particular interest, D3 receptor-selective agonists appear to have neuroprotective effects apart from their ability to relieve PD symptoms. Owing to the distinct significance of D3 receptor in mediating diverse neurological effects, it represents a unique target for therapeutic intervention in PD with much less undesirable side effects. Herein, we review progress in the development of D3 receptor-selective agonist molecules having a broad spectrum of affinities, selectivities as well as unique pharmacological properties directed at slowing the neurodegeneration process. PMID:25832718

  1. A novel PPARgamma agonist monascin's potential application in diabetes prevention.

    PubMed

    Hsu, Wei-Hsuan; Pan, Tzu-Ming

    2014-07-25

    Edible fungi of the Monascus species have been used as traditional Chinese medicine in eastern Asia for several centuries. Monascus-fermented products possess a number of functional secondary metabolites, including the anti-inflammatory pigments monascin and ankaflavin. Monascin has been shown to prevent or ameliorate several conditions, including hypercholesterolemia, hyperlipidemia, diabetes, and obesity. Recently, monascin has been shown to improve hyperglycemia, attenuate oxidative stress, inhibit insulin resistance, and suppress inflammatory cytokine production. In our recent study, we have found that monascin is a peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist. The PPARgamma agonist activity had been investigated and its exerted benefits are inhibition of inflammation in methylglyoxal (MG)-treated rats, prevention of pancreas impairment causing advanced glycation endproducts (AGEs), promotion of insulin expression in vivo and in vitro, and attenuated carboxymethyllysine (CML)-induced hepatic stellate cell (HSC) activation in the past several years. Moreover, our studies also demonstrated that monascin also activated nuclear factor-erythroid 2-related factor 2 (Nrf2) in pancreatic RIN-m5F cell line thereby invading methylglyoxal induced pancreas dysfunction. In this review, we focus on the chemo-preventive properties of monascin against metabolic syndrome through PPARgamma and Nrf2 pathways. PMID:24752777

  2. Aging changes agonist induced contractile responses in permeabilized rat bladder.

    PubMed

    Durlu-Kandilci, N Tugba; Denizalti, Merve; Sahin-Erdemli, Inci

    2015-08-01

    Aging alters bladder functions where a decrease in filling, storage and emptying is observed. These changes cause urinary incontinence, especially in women. The aim of this study is to examine how aging affects the intracellular calcium movements due to agonist-induced contractions in permeabilized female rat bladder. Urinary bladder isolated from young and old female Sprague-Dawley rats were used. Small detrusor strips were permeabilized with ?-escin. The contractile responses induced with agonists were compared between young and old groups. Carbachol-induced contractions were decreased in permeabilized detrusor from old rats compared to young group. Heparin and ryanodine decreased carbachol-induced contractions in young rats where only heparin inhibited these contractions in olds. Caffeine-induced contractions but not inositol triphosphate (IP3)-induced contractions were decreased in old group compared to youngs. The cumulative calcium response curves (pCa 8-4) were also decreased in old rats. Carbachol-induced calcium sensitization responses did not alter by age where GTP-?-S and GF-109203X but not Y-27632 inhibited these responses. Carbachol-induced contractions decrease with aging in rat bladder detrusor. It can be postulated as IP3-induced calcium release (IICR) is primarily responsible for the contractions in older rats where the decrease in carbachol contractions in aging may be as a result of a decrease in calcium-induced calcium release (CICR), rather than carbachol-induced calcium sensitization. PMID:26153091

  3. Characterization of unconditioned behavioral effects of dopamine D3/D2 receptor agonists.

    PubMed

    Geter-Douglass, B; Katz, J L; Alling, K; Acri, J B; Witkin, J M

    1997-10-01

    A series of experiments examined the ability of dopamine D3/D2 receptor agonists [(+)-(4aR,10bR)-3,4,4a,10b-tetrahydro-4-propyl-2H,5H-[1]b enzopyrano-[4,3-b]-1,4-oxazin-9-ol hydrochloride (PD 128,907), (+/-)-7-hydroxy-dipropylaminotetralin hydrobromide (7-OH-DPAT), quinpirole and bromocriptine] to produce a variety of dopaminergically mediated behaviors. The effects of these drugs with selectivity for D3/D2 receptors over D1 receptors were compared with those produced by the selective D1 agonists [(+/-)-Phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrochloride (SKF 38393), (+/-)-6-Chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-be nzazepine hydrobromide (SKF 82958)], a nonselective dopaminergic agonist (apomorphine), and an indirect dopamine agonist (cocaine). The D3/D2 agonists decreased locomotor activity, had no effect on gnawing and only inconsistently induced climbing in mice. Further, these agonists dose-dependently produced scratching in squirrel monkeys. In contrast, the D1 agonists, SKF 82958 and SKF 38393, did not produce scratching in squirrel monkeys. Whereas the full D1 agonist, SKF 82958, produced increases in locomotor activity and in climbing and gnawing, the partial D1 agonist, SKF 38393, did not increase the frequencies of these behaviors. The nonselective dopamine agonist, apomorphine, produced decreases in locomotor activity and increases in climbing and gnawing in mice. Apomorphine dose-dependently produced scratching in squirrel monkeys. The indirect dopamine agonist, cocaine, produced increases in locomotor activity and climbing, but had no effect on climbing or gnawing in mice and did not produce scratching in squirrel monkeys. These findings suggest that D3/D2 agonists can be distinguished on various behavioral measures from the nonselective agonist, apomorphine (gnawing), D1 agonists (scratching) and the indirect agonist, cocaine (locomotor activity and scratching). Behaviors once attributed to stimulation of D2 (locomotor activity and scratching) or D1/D2 (climbing and gnawing) receptors may also involve dopamine D3 receptors. PMID:9336302

  4. Using XML to encode TMA DES metadata

    PubMed Central

    Lyttleton, Oliver; Wright, Alexander; Treanor, Darren; Lewis, Paul

    2011-01-01

    Background: The Tissue Microarray Data Exchange Specification (TMA DES) is an XML specification for encoding TMA experiment data. While TMA DES data is encoded in XML, the files that describe its syntax, structure, and semantics are not. The DTD format is used to describe the syntax and structure of TMA DES, and the ISO 11179 format is used to define the semantics of TMA DES. However, XML Schema can be used in place of DTDs, and another XML encoded format, RDF, can be used in place of ISO 11179. Encoding all TMA DES data and metadata in XML would simplify the development and usage of programs which validate and parse TMA DES data. XML Schema has advantages over DTDs such as support for data types, and a more powerful means of specifying constraints on data values. An advantage of RDF encoded in XML over ISO 11179 is that XML defines rules for encoding data, whereas ISO 11179 does not. Materials and Methods: We created an XML Schema version of the TMA DES DTD. We wrote a program that converted ISO 11179 definitions to RDF encoded in XML, and used it to convert the TMA DES ISO 11179 definitions to RDF. Results: We validated a sample TMA DES XML file that was supplied with the publication that originally specified TMA DES using our XML Schema. We successfully validated the RDF produced by our ISO 11179 converter with the W3C RDF validation service. Conclusions: All TMA DES data could be encoded using XML, which simplifies its processing. XML Schema allows datatypes and valid value ranges to be specified for CDEs, which enables a wider range of error checking to be performed using XML Schemas than could be performed using DTDs. PMID:21969921

  5. Effects of ?-opioid receptor agonists in assays of acute pain-stimulated and pain-depressed behavior in male rats: role of ?-agonist efficacy and noxious stimulus intensity.

    PubMed

    Altarifi, Ahmad A; Rice, Kenner C; Negus, S Stevens

    2015-02-01

    Pain is associated with stimulation of some behaviors and depression of others, and ?-opioid receptor agonists are among the most widely used analgesics. This study used parallel assays of pain-stimulated and pain-depressed behavior in male Sprague-Dawley rats to compare antinociception profiles for six ?-agonists that varied in efficacy at ?-opioid receptors (from highest to lowest: methadone, fentanyl, morphine, hydrocodone, buprenorphine, and nalbuphine). Intraperitoneal injection of diluted lactic acid served as an acute noxious stimulus to either stimulate stretching or depress operant responding maintained by electrical stimulation in an intracranial self-stimulation (ICSS). All ?-agonists blocked both stimulation of stretching and depression of ICSS produced by 1.8% lactic acid. The high-efficacy agonists methadone and fentanyl were more potent at blocking acid-induced depression of ICSS than acid-stimulated stretching, whereas lower-efficacy agonists displayed similar potency across assays. All ?-agonists except morphine also facilitated ICSS in the absence of the noxious stimulus at doses similar to those that blocked acid-induced depression of ICSS. The potency of the low-efficacy ?-agonist nalbuphine, but not the high-efficacy ?-agonist methadone, to block acid-induced depression of ICSS was significantly reduced by increasing the intensity of the noxious stimulus to 5.6% acid. These results demonstrate sensitivity of acid-induced depression of ICSS to a range of clinically effective ?-opioid analgesics and reveal distinctions between opioids based on efficacy at the ?-receptor. These results also support the use of parallel assays of pain-stimulated and -depressed behaviors to evaluate analgesic efficacy of candidate drugs. PMID:25406170

  6. Effects of ?-Opioid Receptor Agonists in Assays of Acute Pain-Stimulated and Pain-Depressed Behavior in Male Rats: Role of ?-Agonist Efficacy and Noxious Stimulus Intensity

    PubMed Central

    Rice, Kenner C.; Negus, S. Stevens

    2015-01-01

    Pain is associated with stimulation of some behaviors and depression of others, and ?-opioid receptor agonists are among the most widely used analgesics. This study used parallel assays of pain-stimulated and pain-depressed behavior in male Sprague-Dawley rats to compare antinociception profiles for six ?-agonists that varied in efficacy at ?-opioid receptors (from highest to lowest: methadone, fentanyl, morphine, hydrocodone, buprenorphine, and nalbuphine). Intraperitoneal injection of diluted lactic acid served as an acute noxious stimulus to either stimulate stretching or depress operant responding maintained by electrical stimulation in an intracranial self-stimulation (ICSS). All ?-agonists blocked both stimulation of stretching and depression of ICSS produced by 1.8% lactic acid. The high-efficacy agonists methadone and fentanyl were more potent at blocking acid-induced depression of ICSS than acid-stimulated stretching, whereas lower-efficacy agonists displayed similar potency across assays. All ?-agonists except morphine also facilitated ICSS in the absence of the noxious stimulus at doses similar to those that blocked acid-induced depression of ICSS. The potency of the low-efficacy ?-agonist nalbuphine, but not the high-efficacy ?-agonist methadone, to block acid-induced depression of ICSS was significantly reduced by increasing the intensity of the noxious stimulus to 5.6% acid. These results demonstrate sensitivity of acid-induced depression of ICSS to a range of clinically effective ?-opioid analgesics and reveal distinctions between opioids based on efficacy at the ?-receptor. These results also support the use of parallel assays of pain-stimulated and -depressed behaviors to evaluate analgesic efficacy of candidate drugs. PMID:25406170

  7. Discriminative stimulus properties of indorenate, a serotonin agonist.

    PubMed Central

    Velzquez-Martnez, D N; Lpez Cabrera, M; Snchez, H; Ramrez, J I; Hong, E

    1999-01-01

    OBJECTIVE: To determine whether indorenate, a serotonin-receptor agonist, can exert discriminative control over operant responses, to establish the temporal course of discriminative control and to compare its stimulus properties to a (5-HT)IA receptor agonist. [3H]-8-hydroxy-2-(di-N-propylamino) tetralin (8-OH-DPAT). DESIGN: Prospective animal study. ANIMALS: Ten male Wistar rats. INTERVENTIONS: Rats were trained to press either of 2 levers for sucrose solution according to a fixed ratio schedule, which was gradually increased. Rats were given injections of either indorenate or saline solution during discrimination training. Once they had achieved an 83% accuracy rate, rats underwent generalization tests after having received a different dose of indorenate, the training dose of indorenate at various intervals before the test, various doses of 8-OH-DPT, or NAN-190 administered before indorenate or 8-OH-DPAT. OUTCOME MEASURES: Distribution of responses between the 2 levers before the first reinforcer of the session, response rate for all the responses in the session, and a discrimination index that expressed the drug-appropriate responses as a proportion of the total responses. RESULTS: Indorenate administration resulted in discriminative control over operant responses, maintained at fixed ratio 10, at a dose of 10.0 mg/kg (but not 3.0 mg/kg). When the interval between the administration of indorenate and the start of the session was varied, the time course of its cue properties followed that of its described effects on 5-HT turnover. In generalization tests, the discrimination index was a function of the dose of indorenate employed; moreover, administration of 8-OH-DPAT (from 0.1 to 1.0 mg/kg) fully mimicked the stimulus properties of indorenate in a dose-dependent way. The (5-HT)IA antagonist NAN-190 prevented the stimulus generalization from indorenate to 8-OH-DPAT. Also, NAN-190 antagonized the stimulus control of indorenate when administered 45 minutes before the session, but not when administered 105 minutes before the session (i.e., 15 minutes before the administration of indorenate). CONCLUSION: (5-HT)IA receptors are of relevance to the stimulus function of indorenate. However, other receptor subtypes may also be involved. Hence, other agonists and specific antagonists should be studied before definite conclusions are drawn. PMID:10212554

  8. High-affinity partial agonists of the vanilloid receptor.

    PubMed

    Wang, Yun; Toth, Attila; Tran, Richard; Szabo, Tamas; Welter, Jacqueline D; Blumberg, Peter M; Lee, Jiyoun; Kang, Sang-Uk; Lim, Ju-Ok; Lee, Jeewoo

    2003-08-01

    The vanilloid receptor VR1 is a polymodal nociceptor sensitive to capsaicin, protons, and heat. Because VR1 represents an attractive therapeutic target for conditions ranging from long-term pain to bladder hyperreflexia, we and other groups have sought to develop novel ligands with enhanced potencies and novel pharmacological properties. Here, we characterize two compounds, N-[2-(3,4-dimethylbenzyl)-3-(pivaloyloxy)propyl]-N'-[4-(methylsulfonylamino)benzyl]thiourea (JYL827) and N-(4-tert-butylbenzyl)-N'-[3-methoxy-4-(methylsulfonylamino)benzyl]thiourea (JYL1511), that function as partial agonists for rat VR1 heterologously expressed in Chinese hamster ovary cells. Both compounds showed substantially enhanced potency, inhibiting [3H] resiniferatoxin binding with Ki values of 29.3 +/- 7.6 and 50.4 +/- 16.5 nM, respectively, compared with 1810 +/- 270 nM for capsaicin. The compounds showed different extents of partial agonism, 6.8 +/- 0.7% and 17.4 +/- 0.6%, respectively, and the expected corresponding degrees of partial antagonism (93.9 +/- 0.9 and 84.1 +/- 3.2%, respectively). Their IC50 values for antagonism of 45Ca2+ uptake in response to capsaicin were 67.3 +/- 24.9 nM and 3.4 +/- 0.5 nM, respectively. Protons, temperature, and protein kinase C all function as coactivators/modulators of rVR1. All enhanced the extent of partial agonism of JYL827 and JYL1511. Thus, at pH 5.5, for example, the extents of partial agonism increased to 54.9 +/- 2.5% and to 90.7 +/- 1.7%, respectively, relative to the response elicited by 300 nM capsaicin. The extents of partial antagonism decreased correspondingly. Compounds such as JYL827 and JYL1511 now permit exploration of the potential utility of partial agonists of rVR1 in animal models. Our results emphasize, moreover, the strong dependence of such partial agonists on other modulators of rVR1 and predict that their biological behavior will depend strongly on biological context. PMID:12869637

  9. New Small Molecule Agonists to the Thyrotropin Receptor

    PubMed Central

    Ali, M. Rejwan; Ma, Risheng; David, Martine; Morshed, Syed A.; Ohlmeyer, Michael; Felsenfeld, Dan P.; Lau, Zerlina; Mezei, Mihaly; Davies, Terry F.

    2015-01-01

    Background Novel small molecular ligands (SMLs) to the thyrotropin receptor (TSHR) have potential as improved molecular probes and as therapeutic agents for the treatment of thyroid dysfunction and thyroid cancer. Methods To identify novel SMLs to the TSHR, we developed a transcription-based luciferase-cAMP high-throughput screening system and we screened 48,224 compounds from a 100K library in duplicate. Results We obtained 62 hits using the cut-off criteria of the meanthree standard deviations above the baseline. Twenty molecules with the greatest activity were rescreened against the parent CHO-luciferase cell for nonspecific activation, and we selected two molecules (MS437 and MS438) with the highest potency for further study. These lead molecules demonstrated no detectible cross-reactivity with homologous receptors when tested against luteinizing hormone (LH)/human chorionic gonadotropin receptor and follicle stimulating hormone receptorexpressing cells. Molecule MS437 had a TSHR-stimulating potency with an EC50 of 1310?8 M, and molecule MS438 had an EC50 of 5.310?8 M. The ability of these small molecule agonists to bind to the transmembrane domain of the receptor and initiate signal transduction was suggested by their activation of a chimeric receptor consisting of an LHR ectodomain and a TSHR transmembrane. Molecular modeling demonstrated that these molecules bound to residues S505 and E506 for MS438 and T501 for MS437 in the intrahelical region of transmembrane helix 3. We also examined the G protein activating ability of these molecules using CHO cells co-expressing TSHRs transfected with luciferase reporter vectors in order to measure Gs?, G??, G?q, and G?12 activation quantitatively. The MS437 and MS438 molecules showed potent activation of Gs?, G?q, and G?12 similar to TSH, but neither the small molecule agonists nor TSH showed activation of the G?? pathway. The small molecules MS437 and MS438 also showed upregulation of thyroglobulin (Tg), sodium iodine symporter (NIS), and TSHR gene expression. Conclusions Pharmacokinetic analysis of MS437 and MS438 indicated their pharmacotherapeutic potential, and their intraperitoneal administration to normal female mice resulted in significantly increased serum thyroxine levels, which could be maintained by repeated treatments. These molecules can therefore serve as lead molecules for further development of powerful TSH agonists. PMID:25333622

  10. μ-opioid receptors: correlation of agonist efficacy for signalling with ability to activate internalization.

    PubMed

    McPherson, Jamie; Rivero, Guadalupe; Baptist, Myma; Llorente, Javier; Al-Sabah, Suleiman; Krasel, Cornelius; Dewey, William L; Bailey, Chris P; Rosethorne, Elizabeth M; Charlton, Steven J; Henderson, Graeme; Kelly, Eamonn

    2010-10-01

    We have compared the ability of a number of μ-opioid receptor (MOPr) ligands to activate G proteins with their abilities to induce MOPr phosphorylation, to promote association of arrestin-3 and to cause MOPr internalization. For a model of G protein-coupled receptor (GPCR) activation where all agonists stabilize a single active conformation of the receptor, a close correlation between signaling outputs might be expected. Our results show that overall there is a very good correlation between efficacy for G protein activation and arrestin-3 recruitment, whereas a few agonists, in particular endomorphins 1 and 2, display apparent bias toward arrestin recruitment. The agonist-induced phosphorylation of MOPr at Ser(375), considered a key step in MOPr regulation, and agonist-induced internalization of MOPr were each found to correlate well with arrestin-3 recruitment. These data indicate that for the majority of MOPr agonists the ability to induce receptor phosphorylation, arrestin-3 recruitment, and internalization can be predicted from their ability as agonists to activate G proteins. For the prototypic MOPr agonist morphine, its relatively weak ability to induce MOPr internalization can be explained by its low agonist efficacy. PMID:20647394

  11. Classical and atypical agonists activate M1 muscarinic acetylcholine receptors through common mechanisms.

    PubMed

    Randkov, Alena; Dolej, Eva; Rudajev, Vladimr; Zim?k, Pavel; Doleal, Vladimr; El-Fakahany, Esam E; Jakubk, Jan

    2015-07-01

    We mutated key amino acids of the human variant of the M1 muscarinic receptor that target ligand binding, receptor activation, and receptor-G protein interaction. We compared the effects of these mutations on the action of two atypical M1 functionally preferring agonists (N-desmethylclozapine and xanomeline) and two classical non-selective orthosteric agonists (carbachol and oxotremorine). Mutations of D105 in the orthosteric binding site and mutation of D99 located out of the orthosteric binding site decreased affinity of all tested agonists that was translated as a decrease in potency in accumulation of inositol phosphates and intracellular calcium mobilization. Mutation of D105 decreased the potency of the atypical agonist xanomeline more than that of the classical agonists carbachol and oxotremorine. Mutation of the residues involved in receptor activation (D71) and coupling to G-proteins (R123) completely abolished the functional responses to both classical and atypical agonists. Our data show that both classical and atypical agonists activate hM1 receptors by the same molecular switch that involves D71 in the second transmembrane helix. The principal difference among the studied agonists is rather in the way they interact with D105 in the orthosteric binding site. Furthermore, our data demonstrate a key role of D105 in xanomeline wash-resistant binding and persistent activation of hM1 by wash-resistant xanomeline. PMID:25882246

  12. Functional desensitization of the ?2 adrenoceptor is not dependent on agonist efficacy

    PubMed Central

    Rosethorne, Elizabeth M; Bradley, Michelle E; Kent, Toby C; Charlton, Steven J

    2015-01-01

    Chronic treatment with ?2 adrenoceptor agonists is recommended as a first-line maintenance therapy for chronic obstructive pulmonary disease (COPD). However, a potential consequence of long-term treatment may be the loss of functional response (tachyphylaxis) over time. In this study, we have investigated the tendency of such agonists, with a range of efficacies, to develop functional desensitization to cAMP responses in primary human bronchial smooth muscle cells following prolonged agonist exposure. The data show that upon repeat exposure, all agonists produced functional desensitization to the same degree and rate. In addition, ?2 adrenoceptor internalization and ?-arrestin-2 recruitment were monitored using ?2eGFP visualization and the PathHunter ?-arrestin-2 assay, respectively. All agonists were capable of causing robust receptor internalization and ?-arrestin-2 recruitment, the rate of which was influenced by agonist efficacy, as measured in those assays. In summary, although a relationship exists between agonist efficacy and the rate of both receptor internalization and ?-arrestin-2 recruitment, there is no correlation between agonist efficacy and the rate or extent of functional desensitization. PMID:25692019

  13. Identification of diarylsulfonamides as agonists of the free fatty acid receptor 4 (FFA4/GPR120).

    PubMed

    Sparks, Steven M; Chen, Grace; Collins, Jon L; Danger, Dana; Dock, Steven T; Jayawickreme, Channa; Jenkinson, Stephen; Laudeman, Christopher; Leesnitzer, M Anthony; Liang, Xi; Maloney, Patrick; McCoy, David C; Moncol, David; Rash, Vincent; Rimele, Thomas; Vulimiri, Padmaja; Way, James M; Ross, Sean

    2014-07-15

    The exploration of a diarylsulfonamide series of free fatty acid receptor 4 (FFA4/GPR120) agonists is described. This work led to the identification of selective FFA4 agonist 8 (GSK137647A) and selective FFA4 antagonist 39. The in vitro profile of compounds 8 and 39 is presented herein. PMID:24881566

  14. Agonist-induced platelet procoagulant activity requires shear and a Rac1-dependent signaling mechanism.

    PubMed

    Delaney, Michael Keegan; Liu, Junling; Kim, Kyungho; Shen, Bo; Stojanovic-Terpo, Aleksandra; Zheng, Yi; Cho, Jaehyung; Du, Xiaoping

    2014-09-18

    Activated platelets facilitate blood coagulation by exposing phosphatidylserine (PS) and releasing microvesicles (MVs). However, the potent physiological agonists thrombin and collagen poorly induce PS exposure when a single agonist is used. To obtain a greater procoagulant response, thrombin is commonly used in combination with glycoprotein VI agonists. However, even under these conditions, only a percentage of platelets express procoagulant activity. To date, it remains unclear why platelets poorly expose PS even when stimulated with multiple agonists and what the signaling pathways are of soluble agonist-induced platelet procoagulant activity. Here we show that physiological levels of shear present in blood significantly enhance agonist-induced platelet PS exposure and MV release, enabling low doses of a single agonist to induce full-scale platelet procoagulant activity. PS exposed on the platelet surface was immediately released as MVs, revealing a tight coupling between the 2 processes under shear. Using platelet-specific Rac1(-/-) mice, we discovered that Rac1 plays a common role in mediating the low-dose agonist-induced procoagulant response independent of platelet aggregation, secretion, and the apoptosis pathway. Platelet-specific Rac1 function was not only important for coagulation in vitro but also for fibrin accumulation in vivo following laser-induced arteriolar injury. PMID:25079357

  15. The dopamine D1 receptor agonist SKF-82958 effectively increases eye blinking count in common marmosets.

    PubMed

    Kotani, Manato; Kiyoshi, Akihiko; Murai, Takeshi; Nakako, Tomokazu; Matsumoto, Kenji; Matsumoto, Atsushi; Ikejiri, Masaru; Ogi, Yuji; Ikeda, Kazuhito

    2016-03-01

    Eye blinking is a spontaneous behavior observed in all mammals, and has been used as a well-established clinical indicator for dopamine production in neuropsychiatric disorders, including Parkinson's disease and Tourette syndrome [1,2]. Pharmacological studies in humans and non-human primates have shown that dopamine agonists/antagonists increase/decrease eye blinking rate. Common marmosets (Callithrix jacchus) have recently attracted a great deal of attention as suitable experimental animals in the psychoneurological field due to their more developed prefrontal cortex than rodents, easy handling compare to other non-human primates, and requirement for small amounts of test drugs. In this study, we evaluated the effects of dopamine D1-4 receptors agonists on eye blinking in common marmosets. Our results show that the dopamine D1 receptor agonist SKF-82958 and the non-selective dopamine receptor agonist apomorphine significantly increased common marmosets eye blinking count, whereas the dopamine D2 agonist (+)-PHNO and the dopamine D3 receptor agonist (+)-PD-128907 produced somnolence in common marmosets resulting in a decrease in eye blinking count. The dopamine D4 receptor agonists PD-168077 and A-41297 had no effect on common marmosets' eye blinking count. Finally, the dopamine D1 receptor antagonist SCH 39166 completely blocked apomorphine-induced increase in eye blinking count. These results indicate that eye blinking in common marmosets may be a useful tool for in vivo screening of novel dopamine D1 receptor agonists as antipsychotics. PMID:26675887

  16. Des Lacs River and Souris River

    USGS Multimedia Gallery

     The Des Lacs River coming in to the Souris River. Des Lacs River is the darker water, which is sediment and the Souris River is the lighter water. >Photo taken by USGS personnel on a Civil Air Patrol flight....

  17. Copernic: la piste des influences arabes

    NASA Astrophysics Data System (ADS)

    Khalatbari, A.; Bonnet-Bidaud, J. M.

    2004-10-01

    Copernic a-t-il connu le travail des astronomes du Moyen-Orient ? S'en est-il inspir pour laborer sa thorie de l'hliocentrisme ? C'est l'hypothse avance par certains historiens des sciences pour comprendre le gnie de celui qui, le premier, a plac le Soleil au centre du monde. Enqute.

  18. Major drawbacks and additional benefits of agonist trigger--not ovarian hyperstimulation syndrome related.

    PubMed

    Shapiro, Bruce S; Andersen, Claus Yding

    2015-04-01

    The GnRH agonist trigger alters traditional IVF paradigms when compared with hCG-only triggers. The agonist trigger induces rapid luteolysis and therefore separates the oocyte maturation aspect of LH from the luteal support previously afforded by lingering hCG. This might allow customized and more optimal luteal support. The agonist trigger option also allows continued stimulation and subsequent trigger of high responders with reasonable safety, potentially leading to retrievals of larger cohorts of mature oocytes. It may also reduce the number of retrievals needed to achieve a large family. The agonist trigger might alter other paradigms as well, such as making oocyte donation more efficient per stimulation by virtually eliminating follicular-phase cycle cancellation, coasting, and premature triggering. There are both corresponding potential benefits and drawbacks of using the agonist trigger and the shifting paradigms it allows. PMID:25707333

  19. Rate constants of agonist binding to muscarinic receptors in rat brain medulla. Evaluation by competition kinetics

    SciTech Connect

    Schreiber, G.; Henis, Y.I.; Sokolovsky, M.

    1985-07-25

    The method of competition kinetics, which measures the binding kinetics of an unlabeled ligand through its effect on the binding kinetics of a labeled ligand, was employed to investigate the kinetics of muscarinic agonist binding to rat brain medulla pons homogenates. The agonists studied were acetylcholine, carbamylcholine, and oxotremorine, with N-methyl-4-(TH)piperidyl benzilate employed as the radiolabeled ligand. Our results suggested that the binding of muscarinic agonists to the high affinity sites is characterized by dissociation rate constants higher by 2 orders of magnitude than those of antagonists, with rather similar association rate constants. Our findings also suggest that isomerization of the muscarinic receptors following ligand binding is significant in the case of antagonists, but not of agonists. Moreover, it is demonstrated that in the medulla pons preparation, agonist-induced interconversion between high and low affinity bindings sites does not occur to an appreciable extent.

  20. La rfrigration des grandes machines supraconductrices

    NASA Astrophysics Data System (ADS)

    Gistau, Guy

    1991-02-01

    The large scale superconducting devices which are now in operation for deviation of heavy particles, acceleration of light particles or plasma confinement need very large powers of refrigeration. After a short survewing of the different functions of refrigerators and the special requirements for large units, the paper describes some existing or envisaged cooling systems which have an equivalent cooling power in the range of 5 kW at 4.5 K. Les grands appareils de physique utilisant les supraconducteurs demandent des puissances cryogniques de plus en plus importantes. Aprs un examen des fonctions lmentaires assures par un rfrigrateur lies au cahier des charges spcifique chaque utilisation, les spcificits des grosses units de rfrigration (fiabilit, efficacit, flexibilit, automatisme) sont mises en vidence. Les solutions proposes dans plusieurs grands projets ncessitant des puissances froides suprieures 5 kW 4,5 K sont discutes.

  1. TLR9 agonists as adjuvants for prophylactic and therapeutic vaccines.

    PubMed

    Daubenberger, Claudia A

    2007-02-01

    Distinct immune responses are required for efficient elimination of different pathogens. Programming of the desired type of immune response by safe non-replicating vaccines requires suitable vaccine adjuvants that determine the magnitude and quality of immune responses elicited. Unfortunately, rational vaccine design with a logical choice of adjuvants is hampered by a lack of knowledge about the mechanism(s) of adjuvant activity. Synthetic natural and non-natural oligodeoxynucleotides containing specific motifs centered on a CpG dinucleotide are potent immunostimulatory agents through their binding to toll-like receptor 9 (TLR9). The evolutionary conservation of TLR9 function and the broad therapeutic potential of CpG oligodeoxynucleotides make them of considerable interest for use in human and veterinary medicine. Recent advances in the development and utility of TLR9 agonists in prophylactic or therapeutic vaccines against infectious diseases are focused on. PMID:17330401

  2. TSH and Thyrotropic Agonists: Key Actors in Thyroid Homeostasis

    PubMed Central

    Dietrich, Johannes W.; Landgrafe, Gabi; Fotiadou, Elisavet H.

    2012-01-01

    This paper provides the reader with an overview of our current knowledge of hypothalamic-pituitary-thyroid feedback from a cybernetic standpoint. Over the past decades we have gained a plethora of information from biochemical, clinical, and epidemiological investigation, especially on the role of TSH and other thyrotropic agonists as critical components of this complex relationship. Integrating these data into a systems perspective delivers new insights into static and dynamic behaviour of thyroid homeostasis. Explicit usage of this information with mathematical methods promises to deliver a better understanding of thyrotropic feedback control and new options for personalised diagnosis of thyroid dysfunction and targeted therapy, also by permitting a new perspective on the conundrum of the TSH reference range. PMID:23365787

  3. Are GLP-1 receptor agonists useful against traumatic brain injury?

    PubMed

    Combs, Colin K

    2015-12-01

    This Editorial highlights a study by Li etal. (2015) in the current issue of J. Neurochem. The image depicts the hypothesized neuroprotective pathway that is proposed by the authors. Using a combination of SH-SY5Y and primary rat neuron cultures the GLP-1R agonist, Liraglutide, was shown to increase SH-SY5Y proliferation and CREB phosphorylation correlating with reduced toxicity, preservation of Bcl2 protein levels, and decreased caspase 3 activity following glutamate or H2 O2 stimulations. These invitro observations correlated with a Liraglutide-dependent improvement in memory performance in mice subjected to a mild TBI. Bcl2, B-cell lymphoma 2; CREB, cAMP-response element binding protein; GLP-1R, glucagon-like peptide 1 receptor; TBI, traumatic brain injury; PKA, protein kinase A. PMID:26234912

  4. Medical Treatment of Acromegaly with Dopamine Agonists or Somatostatin Analogs.

    PubMed

    Chanson, Philippe

    2016-01-01

    Treatment of acromegaly aims to correct (or prevent) tumor compression of surrounding tissues by excising the disease-causing lesion and reduce growth hormone (GH) and IGF-1 levels to normal values. When surgery (the usual first-line treatment) fails to correct GH/IGF-1 hypersecretion, medical treatment with dopamine agonists (DAs; particularly cabergoline) or somatostatin analogs (SAs) can be used. The GH receptor antagonist pegvisomant is helpful in patients who are totally or partially resistant to SAs and can be given in association with both SAs and/or DAs. Thanks to this multistep therapeutic strategy, adequate hormonal disease control is achieved in most patients, giving them normal life expectancy. Comorbidities associated with acromegaly generally improve after treatment, but persistent sequelae may nonetheless impair quality of life. PMID:25677539

  5. The GLP-1 agonist, liraglutide, as a pharmacotherapy for obesity

    PubMed Central

    Crane, James; McGowan, Barbara

    2015-01-01

    There is a global obesity epidemic that will continue to be a financial burden on healthcare systems around the world. Tackling obesity through diet and exercise should always be the first intervention, but this has not proved to be effective for a large number of patients. Pharmacotherapeutic options have been limited and many previously available drugs have been withdrawn due to safety concerns. Currently, only bariatric surgery has the capability to induce both substantial and durable weight loss. This article briefly reviews the history of pharmacotherapy for obesity before focusing on the clinical trial evidence for the use of the GLP-1 agonist liraglutide as a weight loss agent and comparing its efficacy with other emerging drug therapies for obesity. PMID:26977279

  6. Alternation of Agonists and Antagonists During Turtle Hindlimb Motor Rhythms

    PubMed Central

    Stein, Paul S.G.

    2010-01-01

    In a variety of vertebrates, including turtle, many classical and contemporary studies of spinal cord neuronal networks generating rhythmic motor behaviors emphasize a Reciprocal Model with alternation of agonists and antagonists, alternation of excitatory and inhibitory postsynaptic potentials, and reciprocal inhibition. Some studies of spinal cord neuronal networks, including those in turtle during scratch motor rhythms, describe a Balanced Model with concurrent excitatory and inhibitory postsynaptic potentials. The present report reviews turtle spinal cord studies and concludes that there is support for a Combined Model with both alternating and concurrent excitation and inhibition, i.e., characteristics of both the Reciprocal and the Balanced Models, in the same spinal cord neuronal network for scratch reflex in turtle. Studies of spinal cord neuronal networks for locomotion in a variety of vertebrates also support a Combined Model. PMID:20536925

  7. Peripheral GABAB agonists stimulate gastric acid secretion in mice

    PubMed Central

    Piqueras, Laura; Martinez, Vicente

    2004-01-01

    We characterized the effects of intravenous GABA and preferential GABAA (muscimol), GABAB (R-baclofen and SKF-97541) and GABAC agonists (imidazole-4-acetic acid) on gastric acid secretion in urethane-anesthetized mice implanted with a gastric cannula, and determined the role of vagal cholinergic mechanisms, and gastrin and somatostatin by using peptide immunoneutralization, the SSTR2 antgonist, PRL-2903, and SSTR2 knockout mice. The selective GABAB agonists R-baclofen (0.13 mg kg?1, i.v.) and SKF-97541 (0.010.3 mg kg?1, i.v.) induced a dose-related stimulation of gastric acid secretion. SKF-97541 was about 10 times more potent than R-baclofen stimulating gastric acid secretion. Neither GABA (0.1100 mg kg?1, i.v.) nor muscimol (0.13 mg kg?1) nor imidazole-4-acetic acid (0.110 mg kg?1) affected basal gastric acid secretion. Stimulatory effects of SKF-97541 (0.1 mg kg?1, i.v.) were blocked by the selective GABAB antagonist, 2-hydroxysaclofen, cholinergic blockade with atropine, subdiaphragmatic vagotomy or gastrin immunoneutralization. Somatostatin immunoneutralization or SSTR2 blockade with PRL-2903 enhanced the secretory response to SKF-97541 (0.1 mg kg?1, i.v.) by 78 and 105%, respectively. In SSTR2 knockout mice, SKF-97541 (0.1 mg kg?1, i.v.) increased basal gastric acid secretion by 48%. Neither GABA nor muscimol nor imidazole-4-acetic acid modified basal gastric acid secretion in SSTR2 knockout mice. These results indicate that, in mice, stimulation of GABAB receptors increases gastric acid secretion through vagal- and gastrin-dependent mechanisms. Somatostatin implication might be secondary to the release of gastrin and the increase in gastric luminal acidity. PMID:15210585

  8. Agonist and antagonist effects of cytisine in vivo.

    PubMed

    Radchenko, Elena V; Dravolina, Olga A; Bespalov, Anton Y

    2015-08-01

    Varenicline, the most successful smoking cessation aid, is a selective partial agonists at α4β2* nicotinic receptors. Its efficacy is likely to be shared by other drugs with similar receptor action, including cytisine. The present study aimed to characterize behavioral effects of cytisine compared with nicotine using locomotor activity tests, intracranial self-stimulation of ventral tegmental area (discrete-trial threshold current intensity titration procedure), drug discrimination (0.6 mg/kg nicotine from vehicle), physical dependence (osmotic minipumps delivering 6 mg/kg/day of nicotine) and intravenous nicotine self-administration (0.01 mg/kg per infusion) in adult Wistar rats. Cytisine (1-3 mg/kg) partially substituted for nicotine and at the highest dose tended to antagonize nicotine's discriminative stimulus effects. Nicotine (0.05-0.4 mg/kg), but not cytisine (0.3-3 mg/kg), lowered ICSS thresholds and cytisine dose-dependently reversed effects of nicotine. Nicotine (0.15-0.6 mg/kg), but not cytisine (0.3-3 mg/kg), stimulated locomotor activity and cytisine (3 mg/kg) fully reversed these effects of nicotine. Acute pretreatment with nicotine (0.15-0.6 mg/kg), but not cytisine (0.3-3 mg/kg), reinstated extinguished nicotine self-administration. Continuous infusion of nicotine induced physical dependence, as indicated by reduced rates of food-reinforced responding induced by a challenge dose of mecamylamine. At the highest tested dose (3 mg/kg), cytisine tended to reduce response rates irrespective of whether the rats were continuously exposed to nicotine or saline. Cytisine behaves like a weak partial agonist, mimicking effects of nicotine to a limited degree. Although cytisine reversed several effects of nicotine, it seemed to have a reduced potential to produce withdrawal signs in nicotine-dependent subjects. PMID:25839895

  9. Recent advances in the development of farnesoid X receptor agonists.

    PubMed

    Ali, Ahmad H; Carey, Elizabeth J; Lindor, Keith D

    2015-01-01

    Farnesoid X receptors (FXRs) are nuclear hormone receptors expressed in high amounts in body tissues that participate in bilirubin metabolism including the liver, intestines, and kidneys. Bile acids (BAs) are the natural ligands of the FXRs. FXRs regulate the expression of the gene encoding for cholesterol 7 alpha-hydroxylase, which is the rate-limiting enzyme in BA synthesis. In addition, FXRs play a critical role in carbohydrate and lipid metabolism and regulation of insulin sensitivity. FXRs also modulate live growth and regeneration during liver injury. Preclinical studies have shown that FXR activation protects against cholestasis-induced liver injury. Moreover, FXR activation protects against fatty liver injury in animal models of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), and improved hyperlipidemia, glucose intolerance, and insulin sensitivity. Obeticholic acid (OCA), a 6?-ethyl derivative of the natural human BA chenodeoxycholic acid (CDCA) is the first-in-class selective FXR agonist that is ~100-fold more potent than CDCA. Preliminary human clinical trials have shown that OCA is safe and effective. In a phase II clinical trial, administration of OCA was well-tolerated, increased insulin sensitivity and reduced markers of liver inflammation and fibrosis in patients with type II diabetes mellitus and NAFLD. In two clinical trials of OCA in patients with primary biliary cirrhosis (PBC), a progressive cholestatic liver disease, OCA significantly reduced serum alkaline phosphatase (ALP) levels, an important disease marker that correlates well with clinical outcomes of patients with PBC. Together, these studies suggest that FXR agonists could potentially be used as therapeutic tools in patients suffering from nonalcoholic fatty and cholestatic liver diseases. Larger and Longer-term studies are currently ongoing. PMID:25705637

  10. RS 30026: a potent and effective calcium channel agonist.

    PubMed Central

    Patmore, L.; Duncan, G. P.; Clarke, B.; Anderson, A. J.; Greenhouse, R.; Pfister, J. R.

    1990-01-01

    1. A series of dihydropyridine derivatives has been evaluated for calcium channel agonist activity using reversal of nisoldipine-induced inhibition of beating of aggregates of embryonic chick myocytes. This test appears to be specific for calcium channel agonists since isoprenaline and cardiac glycosides are inactive. 2. RS 30026 was the most potent of the series, was significantly more potent than CGP 28392 and of similar potency to Bay K 8644 (pEC50 = 7.45, 6.16 and 7.20, respectively). RS 30026 increased edge movement of individual aggregates, in the absence of nisoldipine, by 50% at 2 nM. 3. Compounds were also evaluated for their effects on guinea-pig papillary muscle and porcine coronary artery rings. RS 30026 displayed positive inotropism at concentrations between 10(-9) and 10(-6) M (pEC200 = 8.21), but was a much more powerful inotrope than Bay K 8644, increasing contractility to 1300% of control at 10(-6) M (compared to 350% of control for Bay K 8644). RS 30026 caused vasoconstriction at concentrations between 10(-10) and 10(-7) M. 4. Calcium channel currents in single embryonic chick myocytes were recorded by whole-cell voltage clamp techniques. RS 30026 (100 nM-500 nM) produced large increases in peak current amplitude and shifted the voltage for threshold and maximal currents to more negative values. RS 30026 (500 nM) also produced large increases in the inward tail currents evoked upon repolarization. The effects of Bay K 8644 (50 and 500 nM) were much less marked.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1694461

  11. Could Dopamine Agonists Aid in Drug Development for Anorexia Nervosa?

    PubMed Central

    Frank, Guido K. W.

    2014-01-01

    Anorexia nervosa is a severe psychiatric disorder most commonly starting during the teenage-years and associated with food refusal and low body weight. Typically there is a loss of menses, intense fear of gaining weight, and an often delusional quality of altered body perception. Anorexia nervosa is also associated with a pattern of high cognitive rigidity, which may contribute to treatment resistance and relapse. The complex interplay of state and trait biological, psychological, and social factors has complicated identifying neurobiological mechanisms that contribute to the illness. The dopamine D1 and D2 neurotransmitter receptors are involved in motivational aspects of food approach, fear extinction, and cognitive flexibility. They could therefore be important targets to improve core and associated behaviors in anorexia nervosa. Treatment with dopamine antagonists has shown little benefit, and it is possible that antagonists over time increase an already hypersensitive dopamine pathway activity in anorexia nervosa. On the contrary, application of dopamine receptor agonists could reduce circuit responsiveness, facilitate fear extinction, and improve cognitive flexibility in anorexia nervosa, as they may be particularly effective during underweight and low gonadal hormone states. This article provides evidence that the dopamine receptor system could be a key factor in the pathophysiology of anorexia nervosa and dopamine agonists could be helpful in reducing core symptoms of the disorder. This review is a theoretical approach that primarily focuses on dopamine receptor function as this system has been mechanistically better described than other neurotransmitters that are altered in anorexia nervosa. However, those proposed dopamine mechanisms in anorexia nervosa also warrant further study with respect to their interaction with other neurotransmitter systems, such as serotonin pathways. PMID:25988121

  12. Agonistic and antagonistic estrogens in licorice root (Glycyrrhiza glabra).

    PubMed

    Simons, Rudy; Vincken, Jean-Paul; Mol, Loes A M; The, Susan A M; Bovee, Toine F H; Luijendijk, Teus J C; Verbruggen, Marian A; Gruppen, Harry

    2011-07-01

    The roots of licorice (Glycyrrhiza glabra) are a rich source of flavonoids, in particular, prenylated flavonoids, such as the isoflavan glabridin and the isoflavene glabrene. Fractionation of an ethyl acetate extract from licorice root by centrifugal partitioning chromatography yielded 51 fractions, which were characterized by liquid chromatography-mass spectrometry and screened for activity in yeast estrogen bioassays. One third of the fractions displayed estrogenic activity towards either one or both estrogen receptors (ERs; ER? and ER?). Glabrene-rich fractions displayed an estrogenic response, predominantly to the ER?. Surprisingly, glabridin did not exert agonistic activity to both ER subtypes. Several fractions displayed higher responses than the maximum response obtained with the reference compound, the natural hormone 17?-estradiol (E(2)). The estrogenic activities of all fractions, including this so-called superinduction, were clearly ER-mediated, as the estrogenic response was inhibited by 20-60% by known ER antagonists, and no activity was found in yeast cells that did not express the ER? or ER? subtype. Prolonged exposure of the yeast to the estrogenic fractions that showed superinduction did, contrary to E(2), not result in a decrease of the fluorescent response. Therefore, the superinduction was most likely the result of stabilization of the ER, yeast-enhanced green fluorescent protein, or a combination of both. Most fractions displaying superinduction were rich in flavonoids with single prenylation. Glabridin displayed ER?-selective antagonism, similar to the ER?-selective antagonist RU 58668. Whereas glabridin was able to reduce the estrogenic response of E(2) by approximately 80% at 6??10(-6) M, glabrene-rich fractions only exhibited agonistic responses, preferentially on ER?. PMID:21573846

  13. Recent advances in the development of farnesoid X receptor agonists

    PubMed Central

    Carey, Elizabeth J.; Lindor, Keith D.

    2015-01-01

    Farnesoid X receptors (FXRs) are nuclear hormone receptors expressed in high amounts in body tissues that participate in bilirubin metabolism including the liver, intestines, and kidneys. Bile acids (BAs) are the natural ligands of the FXRs. FXRs regulate the expression of the gene encoding for cholesterol 7 alpha-hydroxylase, which is the rate-limiting enzyme in BA synthesis. In addition, FXRs play a critical role in carbohydrate and lipid metabolism and regulation of insulin sensitivity. FXRs also modulate live growth and regeneration during liver injury. Preclinical studies have shown that FXR activation protects against cholestasis-induced liver injury. Moreover, FXR activation protects against fatty liver injury in animal models of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), and improved hyperlipidemia, glucose intolerance, and insulin sensitivity. Obeticholic acid (OCA), a 6α-ethyl derivative of the natural human BA chenodeoxycholic acid (CDCA) is the first-in-class selective FXR agonist that is ~100-fold more potent than CDCA. Preliminary human clinical trials have shown that OCA is safe and effective. In a phase II clinical trial, administration of OCA was well-tolerated, increased insulin sensitivity and reduced markers of liver inflammation and fibrosis in patients with type II diabetes mellitus and NAFLD. In two clinical trials of OCA in patients with primary biliary cirrhosis (PBC), a progressive cholestatic liver disease, OCA significantly reduced serum alkaline phosphatase (ALP) levels, an important disease marker that correlates well with clinical outcomes of patients with PBC. Together, these studies suggest that FXR agonists could potentially be used as therapeutic tools in patients suffering from nonalcoholic fatty and cholestatic liver diseases. Larger and Longer-term studies are currently ongoing. PMID:25705637

  14. Cardiovascular selectivity of adenosine receptor agonists in anaesthetized dogs.

    PubMed Central

    Gerencer, R. Z.; Finegan, B. A.; Clanachan, A. S.

    1992-01-01

    1. In order to determine the relevance of adenosine (Ado) receptor classification obtained from in vitro methods to the cardiovascular actions of Ado agonists in vivo, the cardiovascular effects of adenosine 5'-monophosphate (AMP), N6-cyclohexyladenosine (CHA, 400 fold A1-selective), 5'-N-ethyl-carboxamidoadenosine (NECA, A1 approximately A2) and 2-phenylaminoadenosine (PAA, 5 fold A2-selective) were compared in open-chest, fentanyl-pentobarbitone anaesthetized dogs. 2. Graded doses of CHA (10 to 1000 micrograms kg-1), NECA (0.5 to 100 micrograms kg-1) or PAA (0.1 to 20 micrograms kg-1) were administered intravenously and changes in haemodynamics and myocardial contractility were assessed 10 min following each dose. The effects of graded infusions of AMP (200 to 1000 micrograms kg-1 min-1) were also evaluated. 3. AMP and each of the Ado analogues (NECA > PAA > CHA) increased the systemic vascular conductance index (SVCI) in a dose-dependent manner and reduced mean arterial pressure (MAP). At doses causing similar increases in SVCI, these agonists caused (i) similar reflex increases in heart rate (HR) and cardiac index (CI) and decreases in AV conduction interval (AVi) and (ii) similar increases in coronary vascular conductance (CVC). 4. After cardiac autonomic blockade with atropine (0.2 mg kg-1) and propranolol (1 mg kg-1), AMP, CHA and PAA still increased SVCI and CVC and decreased MAP. CHA and PAA had no marked effects on HR, CI or AVi. As in the absence of cardiac autonomic blockade, equieffective vasodilator doses of CHA and PAA had identical effects on CVC, CI and AVi.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1467827

  15. Interaction of a radiolabeled agonist with cardiac muscarinic cholinergic receptors

    SciTech Connect

    Harden, T.K.; Meeker, R.B.; Martin, M.W.

    1983-12-01

    The interaction of a radiolabeled muscarinic cholinergic receptor agonist, (methyl-/sup 3/H)oxotremorine acetate ((/sup 3/H)OXO), with a washed membrane preparation derived from rat heart, has been studied. In binding assays at 4 degrees C, the rate constants for association and dissociation of (/sup 3/H)OXO were 2 X 10(7) M-1 min-1 and 5 X 10(-3) min-1, respectively, Saturation binding isotherms indicated that binding was to a single population of sites with a Kd of approximately 300 pM. The density of (/sup 3/H)OXO binding sites (90-100 fmol/mg of protein) was approximately 75% of that determined for the radiolabeled receptor antagonist (/sup 3/H)quinuclidinyl benzilate. Both muscarinic receptor agonists and antagonists inhibited the binding of (/sup 3/H)OXO with high affinity and Hill slopes of approximately one. Guanine nucleotides completely inhibited the binding of (/sup 3/H)OXO. This effect was on the maximum binding (Bmax) of (/sup 3/H)OXO with no change occurring in the Kd; the order of potency for five nucleotides was guanosine 5'-O-(3-thio-triphosphate) greater than 5'-guanylylimidodiphosphate greater than GTP greater than or equal to guanosine/diphosphate greater than GMP. The (/sup 3/H)OXO-induced interaction of muscarinic receptors with a guanine nucleotide binding protein was stable to solubilization. That is, membrane receptors that were prelabeled with (/sup 3/H)OXO could be solubilized with digitonin, and the addition of guanine nucleotides to the soluble, (/sup 3/H)OXO-labeled complex resulted in dissociation of (/sup 3/H)OXO from the receptor. Pretreatment of membranes with relatively low concentrations of N-ethylmaleimide inhibited (/sup 3/H)OXO binding by 85% with no change in the Kd of (/sup 3/H)OXO, and with no effect on (/sup 3/H)quinuclidinyl benzilate binding.

  16. Early Life Stress in Depressive Patients: HPA Axis Response to GR and MR Agonist

    PubMed Central

    Baes, Cristiane von Werne; Martins, Camila Maria Severi; Tofoli, Sandra Mrcia de Carvalho; Juruena, Mrio Francisco

    2014-01-01

    Background: Evidence indicates that early life stress (ELS) can induce persistent changes in the hypothalamic-pituitary-adrenal (HPA) axis to respond to stress in the adult life that leads to depression. These appear to be related to the impairment of HPA hormones through binding to glucocorticoid (GR) and mineralocorticoid receptors (MR). The aim of this study was to evaluate the impact of ELS in HPA axis response to challenges with GR and MR agonists in depressed patients. Methods: We included 30 subjects, 20 patients with current major depression (HAM-D21???17). Patients were recruited into two groups according to ELS history assessed by the Childhood Trauma Questionnaire (CTQ). The cortisol measures in the saliva and plasma were evaluated after using (at 10:00 p.m.) placebo, fludrocortisone (MR agonist), or dexamethasone (GR agonist). Results: Depressed patients showed a significantly lower salivary cortisol upon waking after placebo compared with controls. Moreover, cortisol awakening responses (CAR) after MR agonist were found to be lower in depressed patients than in controls. With CTQ scores, HAM-D21, body mass index and CAR after placebo, GR agonist, MR agonist we found in a Linear Regression model that depressive patients with ELS (p?=?0.028) show differences between placebo vs. MR agonist (R?=?0.51; p?agonist; in depressive patients, without ELS the data show differences between placebo vs. MR agonist (R?=?0.69; p?agonist (R?=?0.53; p?agonist, indicating that patients with ELS are sensitive to MR agonists. In contrast with depressed patients without ELS, we find suppression after both MR and GR agonist. These data suggested that in ELS an imbalance exists between MR and GR with MR dysfunction. PMID:24478730

  17. Use of β2 agonists and risk of acute myocardial infarction in patients with hypertension

    PubMed Central

    de Vries, Frank; Pouwels, Sander; Bracke, Madelon; Lammers, Jan-Willem; Klungel, Olaf; Leufkens, Hubert; van Staa, Tjeerd

    2008-01-01

    AIM Observational retrospective studies of the association between use of β2 agonists and the risk of acute myocardial infarction (MI) have demonstrated conflicting results, particularly among first-time users. The aim of this study was to examine the association between β2 agonist use and first nonfatal acute MI. METHODS We conducted a case–control study (2476 cases) nested in a cohort of antihypertensive drug users in the Dutch PHARMO RLS database. PHARMO RLS consists of drug dispensing linked to the national hospitalizations register. Each case of nonfatal acute MI was matched with up to 12 control patients by gender, age and region. Drug and disease history and the severity of the underlying respiratory disease were adjusted for. RESULTS Risk of acute MI was increased in current β2 agonist users [crude odds ratio (OR) 1.36, 95% confidence interval (CI) 1.15, 1.61]. However, this excess risk was reduced after adjustment for severity of asthma and chronic obstructive pulmonary disease (adjusted OR 1.18, 95% CI 0.93, 1.49). The risk was highest in patients with ischaemic heart disease and low cumulative dose of β2 agonists (adjusted OR 2.47, 95% CI 1.60, 3.82). CONCLUSION Most users of β2 agonists did not have an increased risk of acute MI. Only patients with ischaemic heart disease with low cumulative exposure to β2 agonists had an increased risk of acute MI. It is likely that this increased risk was related to latent cardiovascular disease rather than to the direct effects of β2 agonists. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT Use of β2 agonists has been associated with tachycardia, an abnormal ECG and atrial fibrillation.Previous observational studies of the association between use of β2 agonists and the risk of acute myocardial infarction (MI) have demonstrated conflicting results.Instead of a causal effect, the positive association between β2 agonist use and MI may be explained by latent ischaemic heart disease, which has symptoms that appear similar to respiratory complaints in chronic obstructive pulmonary disease. WHAT THIS STUDY ADDS The majority of β2 agonist users in our study population did not have an increased risk of nonfatal acute MI.Only patients with ischaemic heart disease and who had recently started β2 agonists had an increased risk of acute MI.It is likely that this increased risk was related to latent cardiovascular disease rather than direct effects of β2 agonists. PMID:18279472

  18. Repliement des protines : exemple de l'?-lactalbumine

    NASA Astrophysics Data System (ADS)

    Bushmarina, N. A.; Blanchet, C.; Vernier, G.; Forge, V.

    2005-11-01

    Cette revue sur le repliement des protines ne fait appel aucune exprience propre de diffusion de neutrons. Elle dcrit les aspects cintiques et thermodynamiques de la structuration des protines sur leur chemin de repliement, en faisant rfrence des techniques biophysiques varies permettant d'chantillonner des changements conformationnels sur des chelles de temps longues (ms. s.). Les neutrons constituent une sonde videmment complmentaire des techniques usuellement employes pour l'tude du repliement des protines. Nous avons choisi un modle d'tude, l'?-lactalbumine, pour donner un tat de l'art des connaissances acquises ce jour dans le domaine, et pour ainsi inciter biophysiciens et spectroscopistes dvelopper des techniques en temps rsolu sur des chelles plus rapides, afin de pouvoir dtecter les tapes prcoces du repliement. Les neutrons doivent trouver une place logique dans de tels dveloppements.

  19. Effects of dopamine indirect agonists and selective D1-like and D2-like agonists and antagonists on cocaine self-administration and food maintained responding in rats.

    PubMed

    Barrett, Andrew C; Miller, John R; Dohrmann, Jennifer M; Caine, S Barak

    2004-01-01

    A procedure is described for comprehensive evaluation of the effects of acute drug pretreatments on the reinforcing effects of cocaine using the rat self-administration assay in combination with a novel control assay of liquid-food maintained responding. In sessions comprised of five 20-min components, either complete dose-effect functions for cocaine self-administration or complete concentration-effect functions for liquid-food maintained responding were evaluated. The schedule of reinforcement (FR 5 TO 20-s), drug pretreatment doses and time intervals (0-30 min), and duration of sessions (108 min) were identical for cocaine- and food-reinforced test sessions. Whereas acute pretreatment with indirect dopamine agonists (D-amphetamine, GBR 12909) and D2-like agonists (7-OH-DPAT, quinelorane) produced dose-dependent leftward shifts in dose-effect functions for cocaine self-administration, D1-like agonists (SKF 82958, R-6-Br-APB) and dopamine antagonists (D1-like, SCH 39166; D2-like, eticlopride) shifted dose-effect functions for cocaine downward and rightward, respectively. Interestingly, with the indirect dopamine agonists but not the D2-like agonists, increased responding maintained by low cocaine doses was paralleled by increased responding maintained by low food concentrations. Moreover, three of the four direct agonists were moderately selective (< or =5-fold more potent) in decreasing cocaine self-administration relative to food maintained responding. When data were analyzed according to alterations in total cocaine intake, all of the agonists uniformly decreased total cocaine intake, whereas both antagonists increased total cocaine intake. Overall, this procedure was sensitive to leftward, downward and rightward shifts in cocaine dose-effect functions and should be useful for evaluating the nature of pharmacological interactions between novel compounds and self-administered cocaine, as well as the potential for altering cocaine self-administration selectively with candidate treatments for cocaine abuse and dependence. PMID:15464142

  20. Medications for stimulant abuse: agonist-based strategies and preclinical evaluation of the mixed-action D-sub-2 partial agonist aripiprazole (Abilify).

    PubMed

    Bergman, Jack

    2008-12-01

    The utility of full and partial agonists for the management of opioid addiction and smoking behavior has encouraged the development of dopamine partial agonist-based medications for treating monoaminergic stimulant abuse and addiction. Aripiprazole, a recently introduced atypical antipsychotic with D-sub-2 partial agonist actions, has been studied in mice, rats, and man, but its ability to attenuate abuse- and addiction-related effects of cocaine or methamphetamine remains controversial. The present studies in monkeys were conducted to further evaluate aripiprazole as a candidate medication. The effects of aripiprazole on overt behavior were first compared with those of other dopamine-related drugs. In contrast to D-sub-2 full agonists, aripiprazole did not induce self-scratching. Like D-sub-2 receptor blockers, however, aripiprazole occasioned dose-related increases in catalepsy-associated behavior that, at the highest doses, were characterized most prominently by periods of stillness and immobility. In methamphetamine-discrimination experiments, aripiprazole did not engender responding on the methamphetamine-associated lever; rather, aripiprazole antagonized the discriminative-stimulus effects of methamphetamine by shifting its dose-effect function rightward. In self-administration "choice" experiments, acute or chronic treatment with aripiprazole did not attenuate the reinforcing strength of intravenous cocaine relative to food delivery. However, like D-sub-2 full agonists, priming injections of aripiprazole prior to sessions of intravenous saline availability engendered comparable levels of responding on levers leading to food delivery and intravenous injections. The present findings indicate that agonist and antagonist effects of aripiprazole are evident under different experimental conditions and that, like D-sub-2 full agonists, aripiprazole may have limited value for treating monoaminergic stimulant abuse and addiction. PMID:19086768

  1. Effets perturbateurs endocriniens des pesticides organochlores.

    PubMed

    Charlier, C; Plomteux, G

    2002-01-01

    Xenoestrogens such organochlorine pesticides are known to induce changes in reproductive development, function or behaviour in wildlife. Because these compounds are able to modify the estrogens metabolism, or to compete with estradiol for binding to the estrogen receptor, it may be possible that these products affect the risk of developing impaired fertility, precocious puberty or some kinds of cancer in man. Le plus ancien rcit de lutte contre la pollution remonte une lgende indienne racontant que la divinit Sing-bonga tait incommode par les manations des fours dans lesquels les Asuras fondaient leurs mtaux (1). Evidemment depuis, la problmatique n-a cess de s-accrotre et la contamination de la Terre par de nombreux polluants est devenue aujourd-hui un problme majeur de notre Socit. La protection de notre environnement est une question capitale qui doit tre respecte malgr la pression conomique actuelle et qui ne cessera de crotre au cours des prochaines annes mme si l-identification objective et indiscutable de ce qui est essentiel - donc devant tre prioritairement garanti sur la plante - est difficile cerner (2). Un oiseau en mauvais tat ne pond pas de bons oeufs disait un proverbe grec. Mais ce n-est qu- partir de la seconde moiti du XXme sicle que les toxicologues ont commenc identifier les effets qu-avaient entrans l-chelle mondiale les pollutions mises aux XIXme sicle sur la faune sauvage et sur le cheptel (3). L-histoire contemporaine des pesticides industriels commence vers 1874 (synthse des organochlors) et se poursuit tout au long de ces 2 sicles en passant par la synthse des organophosphors (1950), des carbamates (1970) et des pyrthrodes (1975) (4). Le dichlorodiphnyltrichlorothane (DDT) a t synthtis pour la premire fois par un tudiant en cours de prparation de sa thse de doctorat : Othmer Zeidler. La production, reprise par les entreprises F.Mayo puis par la Geigy Co. a d-abord intress l-arme, puis l-agriculture. Ds la fin de la 2(me) guerre mondiale, des mises en garde furent lances propos des effets nocifs du produit (4). Un dclin des populations de grives, d-aigles chauves, d-orfaies et de mammifres consommateurs de poissons fut constat partir des annes 50 et dnonc par Rachel Carson dans son clbre appel du Silent Spring de 1962. Bien qu-il soit interdit en Occident depuis les annes 70, ce produit a t tellement utilis et prsente une rmanence si longue qu-une contamination ubiquitaire existe aujourd-hui encore. De plus, ce produit continue tre produit aux USA pour tre utilis des fins de dmoustification dans les pays en voie de dveloppement. Il en va de mme de l-Hexachlorobenzne (HCB), un autre organochlor dont l-usage est interdit sous nos latitudes, mais reste frquent dans d-autres pays. Ces deux exemples indiquent que le problme de la contamination continue nous concerner, mme pour des produits dont l-usage est aujourd-hui strictement rglement ou interdit. Des effets sur la faune semblent encore actuellement devoir tre attribus ces produits. La diminution de la population des phoques dans la mer de Wadden pourrait tre due la forte contamination en composants organochlors des poissons dont ces phoques se nourrissent (5). Expos au DDT et son mtabolite dichlorodiphenyldichlorothylne (DDE), le Seratherodon mossambicus prsente une rduction de la scrtion de cortisol par une action toxique cytospcifique sur l-axe hypothalamo-hypophysaire (6). Des travaux rcents ont montr que le DDT et le DDE se lient chez les oiseaux et les mammifres au moyen de liaisons covalentes aux cellules de la zona fasciculata - homologue du tissu interrnal du poisson - induisant des microhmorragies. Cette dfaillance cortisolique peut s-accompagner d-une perturbation du mtabolisme glucidique et notamment d-un taux lev de glycogne hpatique (7). Les pesticides organochlors (DDT, DDE) entranent galement des perturbations d-ordre mtabolique chez certaines espces d-oiseaux, notamment le faucon plerin en Grande Bretagne et les oiseaux piscivores des grands lacs nord amricains o l-on a constat au cours des annes 1960 que leur reproduction tait menace et qu-une des manifestations les plus videntes des perturbations observes tait le taux lev de malformations (8). Des mortalits leves de poissons ou de coquillages ont t rapportes dans des levages situs proximit des zones d-pandage de pesticides organophosphors et de carbamates. En 1991, la dispersion arienne de fenitrothion dans le but de provoquer la dmoustication en Languedoc a t l-origine de la perte de plusieurs tonnes de crevettes japonaises. L-utilisation de trichlorfon et de dichlorvos comme antiparasitaires dans des fermes d-levages de saumons a provoqu des pisodes de mortalit importante (9). PMID:24862516

  2. Structure et dynamique des systmes dsordonns

    NASA Astrophysics Data System (ADS)

    Damay, P.

    2003-09-01

    Dfinis par leur absence d'ordre, les systmes dsordonns ne forment pas proprement parler une famille. La notion de dsordre est elle-mme assez difficile dfinir. Aussi, dans ce type d'tude, le type de systmes, les techniques et les concepts sont-ils particulirement diversifis. Aprs avoir nonc quelques grandes gnralits sur la dfinition du dsordre et fait une tentative de classification des systmes dsordonns, cette revue a t principalement oriente sur les moyens d'tudes de la structure et de la dynamique des fluides et des verres. Une insistance particulire est mise sur les moyens mis disposition par la physique statistique aussi bien pour laborer des modles que pour analyser les rsultats d'expriences spectroscopiques ou de diffraction. En effet, le nombre de configurations locales des atomes et molcules dans ces systmes est tellement important que les rsultats exprimentaux et les modles ne dcrivent en gnral que des moyennes d'ensemble qui n'apportent que des informations partielles sur la ralit microscopique.

  3. Ascorbic acid enables reversible dopamine receptor /sup 3/H-agonist binding

    SciTech Connect

    Leff, S.; Sibley, D.R.; Hamblin, M.; Creese, I.

    1981-11-16

    The effects of ascorbic acid on dopaminergic /sup 3/H-agonist receptor binding were studied in membrane homogenates of bovine anterior pituitary and caudate, and rat striatum. In all tissues virtually no stereospecific binding (defined using 1uM (+)butaclamol) of the /sup 3/H-agonists N-propylnorapomorphine (NPA), apomorphine, or dopamine could be demonstrated in the absence of ascorbic acid. Although levels of total /sup 3/H-agonist binding were three to five times greater in the absence than in the presence of 0.1% ascorbic acid, the increased binding was entirely non-stereospecific. Greater amounts of dopamine-inhibitable /sup 3/H-NPA binding could be demonstrated in the absence of 0.1% ascorbic acid, but this measure of ''specific binding'' was demonstrated not to represent dopamine receptor binding since several other catecholamines and catechol were equipotent with dopamine and more potent than the dopamine agonist (+/-)amino-6,7-dihydroxy-1,2,3,4-tetrahydronapthalene (ADTN) in inhibiting this binding. High levels of dopamine-displaceable /sup 3/H-agonist binding were detected in fresh and boiled homogenates of cerebellum, an area of brain which receives no dopaminergic innervation, further demonstrating the non-specific nature of /sup 3/H-agonist binding in the absence of ascorbic acid. These studies emphasize that under typical assay conditions ascorbic acid is required in order to demonstrate reversible and specific /sup 3/H-agonist binding to dopamine receptors.

  4. Effects of yohimbine on the antinociceptive and place conditioning effects of opioid agonists in rodents

    PubMed Central

    Morales, Lydia; Perez-Garcia, Carmen; Alguacil, Luis F

    2001-01-01

    The pharmacological modulation of opioid actions by drugs acting on heterologous mechanisms could be useful to overcome some of the main problems associated with the use of opiate agonists. Based on previous findings on the interactions between yohimbine and opioid drugs, we have further studied the effects of yohimbine on the antinociceptive and positive-negative reinforcing effects of morphine (? opioid receptor-preferring agonist), U-50,488 (? agonist) and SNC80 (? agonist). Pretreatment with yohimbine completely blocked the antinociception provided by the three opioid agonists in the mouse tail-immersion test. A similar blockade of SNC80 and U-50,488-induced antinociception was observed with yohimbine in the mouse hot plate test at the same doses. In this paradigm, the effect of the ? agonist was very slight and the actions of yohimbine rather variable. In place conditioning experiments with SD (Sprague??Dawley) male rats, yohimbine alone was inactive but it limited the preference induced by morphine and SNC80 and the aversive effect of U-50,488. Impaired novelty preference was also observed with the combination of yohimbine and U-50,488. It is concluded that yohimbine tends to limit opioid antinociception and the addictive potential of ? and ? opioid agonists. More selective drugs could help to understand the mechanisms involved in these actions. PMID:11325807

  5. The beta 2-agonist controversy. Observations, explanations and relationship to asthma epidemiology.

    PubMed

    Sears, M R; Taylor, D R

    1994-10-01

    Links between frequent use of inhaled beta 2-agonists and morbidity and mortality from asthma appear probable. Two mortality epidemics followed the marketing of potent inhaled adrenergic agents. Case-control studies in New Zealand linked mortality with prescription of fenoterol, especially in severe asthma. A Saskatchewan case-control study confirmed an association of mortality with fenoterol, and also with frequent use of salbutamol (albuterol). Cardiac effects of beta 2-agonists do not cause mortality, but frequent use of these agents may increase the chronic severity of asthma, hence increasing the number of asthmatic patients at risk of death in an acute attack. Frequent use of beta 2-agonists may reduce lung function, increasing airway responsiveness, and impair control of asthma, despite use of inhaled corticosteroids. Mechanisms for this effect may include tachyphylaxis to nonbronchodilator effects, increased responsiveness to allergen, interaction with corticosteroid receptors, altered mucociliary function, differential effects of enantiomers, and masking of symptoms by beta 2-agonist use. The withdrawal of fenoterol from New Zealand in 1990 was associated with a substantial decline in morbidity and mortality. Overall, the evidence suggests that frequent use of inhaled beta 2-agonists has a deleterious effect on the control of asthma. Epidemics of mortality are explained by an increase in chronic severity of asthma following introduction of more potent beta 2-agonists. While beta 2-agonists remain essential for relief of breakthrough symptoms, long term use, particularly with high doses of potent agents, appears to be detrimental. PMID:7848546

  6. The pharmacokinetics, metabolism, and tissue residues of beta-adrenergic agonists in livestock.

    PubMed

    Smith, D J

    1998-01-01

    Since the early 1980s the usefulness of dietary beta-agonists to improve the efficiency of feed utilization and(or) to enhance carcass leanness in livestock species has been well documented. Less well documented are the pharmacokinetic properties, biotransformation pathways, and tissue residue profiles of beta-agonists used to enhance leanness in experimentally or illegally treated animals. Pharmacokinetic data for clenbuterol, cimaterol, fenoterol, L-644,969, ractopamine, salbutamol, and terbutaline have been published but biotransformation and tissue residue studies for these compounds in livestock species are sparse. In general, beta-agonists having halogenated aromatic ring systems are metabolized by oxidative and conjugative pathways and have long plasma half-lives, whereas beta-agonists having hydroxylated aromatic rings are metabolized solely by conjugation and have relatively short plasma half-lives. Beta-Agonists having high oral bioavailabilities, long plasma half-lives, and relatively slow rates of elimination have high oral potencies in humans. Residues of such illegally used compounds in edible tissues of livestock represent a genuine risk to consumers. Conversely, beta-agonists having low oral bioavailabilities, short plasma half-lives, and rapid rates of elimination have low oral potencies in humans. Residues of such compounds in edible tissues of properly treated animals would not likely represent a credible risk to consumers of such products. The reviewed data indicate that the development of a safe and effective beta-agonist for use in livestock is possible. PMID:9464898

  7. PPARgamma agonists inhibit vasopressin-mediated anion transport in the MDCK-C7 cell line.

    PubMed

    Nofziger, Charity; Brown, Kathleen K; Smith, Chari D; Harrington, Wallace; Murray, David; Bisi, John; Ashton, Thalia T; Maurio, Frank P; Kalsi, Kameljit; West, T Aaron; Baines, Deborah; Blazer-Yost, Bonnie L

    2009-07-01

    PPARgamma agonists are synthetic ligands for the peroxisome proliferator-activated receptor-gamma (PPARgamma). These agents have insulin-sensitizing properties but can cause fluid retention, thereby limiting their usefulness in patients at risk for cardiovascular disease. The side effect etiology is unknown, but the nature of presentation suggests modulation of renal salt and water homeostasis. In a well-characterized cell culture model of the principal cell type [Madin-Darby canine kidney (MDCK)-C7], PPARgamma agonists inhibit vasopressin-stimulated Cl(-) secretion with agonist dose-response relationships that mirror receptor transactivation profiles. Analyses of the components of the vasopressin-stimulated intracellular signaling pathway indicated no PPARgamma agonist-induced changes in basolateral membrane conductances, intracellular cAMP, protein kinase A, or total cellular adenine nucleotides. The PPARgamma agonist-induced decrease in anion secretion is the result of decreased mRNA of the final effector in the pathway, the apically located cystic fibrosis transmembrane regulator (CFTR). These data showing that CFTR is a target for PPARgamma agonists may provide new insights into the physiology of PPARgamma agonist-induced fluid retention. PMID:19403648

  8. Inhibition by TRPA1 agonists of compound action potentials in the frog sciatic nerve

    SciTech Connect

    Matsushita, Akitomo; Ohtsubo, Sena; Fujita, Tsugumi; Kumamoto, Eiichi

    2013-04-26

    Highlights: •TRPA1 agonists inhibited compound action potentials in frog sciatic nerves. •This inhibition was not mediated by TRPA1 channels. •This efficacy was comparable to those of lidocaine and cocaine. •We found for the first time an ability of TRPA1 agonists to inhibit nerve conduction. -- Abstract: Although TRPV1 and TRPM8 agonists (vanilloid capsaicin and menthol, respectively) at high concentrations inhibit action potential conduction, it remains to be unknown whether TRPA1 agonists have a similar action. The present study examined the actions of TRPA1 agonists, cinnamaldehyde (CA) and allyl isothiocyanate (AITC), which differ in chemical structure from each other, on compound action potentials (CAPs) recorded from the frog sciatic nerve by using the air-gap method. CA and AITC concentration-dependently reduced the peak amplitude of the CAP with the IC{sub 50} values of 1.2 and 1.5 mM, respectively; these activities were resistant to a non-selective TRP antagonist ruthenium red or a selective TRPA1 antagonist HC-030031. The CA and AITC actions were distinct in property; the latter but not former action was delayed in onset and partially reversible, and CA but not AITC increased thresholds to elicit CAPs. A CAP inhibition was seen by hydroxy-α-sanshool (by 60% at 0.05 mM), which activates both TRPA1 and TRPV1 channels, a non-vanilloid TRPV1 agonist piperine (by 20% at 0.07 mM) and tetrahydrolavandulol (where the six-membered ring of menthol is opened; IC{sub 50} = 0.38 mM). It is suggested that TRPA1 agonists as well as TRPV1 and TRPM8 agonists have an ability to inhibit nerve conduction without TRP activation, although their agonists are quite different in chemical structure from each other.

  9. Kinetic determinants of agonist action at the recombinant human glycine receptor

    PubMed Central

    Lewis, Trevor M; Schofield, Peter R; McClellan, Annette M L

    2003-01-01

    The amino acids glycine, β-alanine and taurine are all endogenous agonists of the glycine receptor. In this study, a combination of rapid agonist application onto macropatches and steady-state single-channel recordings was used to compare the actions of glycine, β-alanine and taurine upon homomeric α1 human glycine receptors transiently expressed in human embryonic kidney (HEK 293) cells. The 10–90 % rise times determined from rapid application of 100 μm of each agonist were indistinguishable, indicating each agonist has a similar association rate. At saturating concentrations (30 mm) the rise time for glycine (0.26 ms) was 1.8-fold faster than that for β-alanine (0.47 ms) and 3.9-fold faster than that for taurine (1.01 ms), indicating clear differences in the maximum opening rate between agonists. The relaxation following rapid removal of agonist was fitted with a single exponential for β-alanine (3.0 ms) and taurine (2.2 ms), and two exponential components for glycine with a weighted mean time constant of 27.1 ms. This was consistent with differences in dissociation rates estimated from analysis of bursts, with taurine > β-alanine > glycine. Exponential fits to the open period distributions gave time constants that did not differ between agonists and the geometric distribution for the number of openings per burst indicated that all three agonists had a significant component of single-opening bursts. Based upon these data, we propose a kinetic scheme with three independent open states, where the opening rates are dependent upon the activating agonist, while the closing rates are an intrinsic characteristic of the receptor. PMID:12679369

  10. CB(1) receptor allosteric modulators display both agonist and signaling pathway specificity.

    PubMed

    Baillie, Gemma L; Horswill, James G; Anavi-Goffer, Sharon; Reggio, Patricia H; Bolognini, Daniele; Abood, Mary E; McAllister, Sean; Strange, Phillip G; Stephens, Gary J; Pertwee, Roger G; Ross, Ruth A

    2013-02-01

    We have previously identified allosteric modulators of the cannabinoid CB(1) receptor (Org 27569, PSNCBAM-1) that display a contradictory pharmacological profile: increasing the specific binding of the CB(1) receptor agonist [(3)H]CP55940 but producing a decrease in CB(1) receptor agonist efficacy. Here we investigated the effect one or both compounds in a broad range of signaling endpoints linked to CB(1) receptor activation. We assessed the effect of these compounds on CB(1) receptor agonist-induced [(35)S]GTP?S binding, inhibition, and stimulation of forskolin-stimulated cAMP production, phosphorylation of extracellular signal-regulated kinases (ERK), and ?-arrestin recruitment. We also investigated the effect of these allosteric modulators on CB(1) agonist binding kinetics. Both compounds display ligand dependence, being significantly more potent as modulators of CP55940 signaling as compared with WIN55212 and having little effect on [(3)H]WIN55212 binding. Org 27569 displays biased antagonism whereby it inhibits: agonist-induced guanosine 5'-O-(3-[(35)S]thio)triphosphate ([(35)S]GTP?S) binding, simulation (G?(s)-mediated), and inhibition (G?(i)-mediated) of cAMP production and ?-arrestin recruitment. In contrast, it acts as an enhancer of agonist-induced ERK phosphorylation. Alone, the compound can act also as an allosteric agonist, increasing cAMP production and ERK phosphorylation. We find that in both saturation and kinetic-binding experiments, the Org 27569 and PSNCBAM-1 appeared to influence only orthosteric ligand maximum occupancy rather than affinity. The data indicate that the allosteric modulators share a common mechanism whereby they increase available high-affinity CB(1) agonist binding sites. The receptor conformation stabilized by the allosterics appears to induce signaling and also selectively traffics orthosteric agonist signaling via the ERK phosphorylation pathway. PMID:23160940

  11. Pairwise agonist scanning-flow cytometry (PAS-FC) measures inside-out signaling and patient-specific response to combinatorial platelet agonists

    PubMed Central

    Jaeger, Daniel T. L.; Diamond, Scott L.

    2014-01-01

    Understanding the response of cells to multiple stimuli is vital for predicting donor specific responses and better understanding the signaling pathways involved. This is of particular importance in platelets because exposure of phosphatidylserine (PS) occurs upon costimulation but not with a single agonist. Here, we describe a multiplexed pairwise agonist scanning flow cytometry (PAS-FC) method of measuring platelet inside-out responses to all pairs of six platelet agonists (convulxin, SFLLRN, AYPGKF, ADP, U46619, and PGE2) used at their EC50 concentrations. These agonists allowed exploration of platelet signaling downstream of GPVI, PAR-1, PAR-4, P2Y1, P2Y12, TP, and IP receptors. The three-color flow cytometry method simultaneously measured integrin αIIbβ3 activation with PAC-1 antibody, P-selectin exposure (via α granule release) with anti-P-selectin, and PS exposure with annexin V. These responses were consistent across a healthy male donor pool. In duplicate measurements with each donor, 4 of the 10 donors had a sufficiently unique 45-parameter (15 pairs × 3 colors) phenotype to self-cluster (P < 0.001). This method has the potential for efficiently scanning for patient specific responses across a broad agonist-receptor space. PMID:23662898

  12. Discovery of 2-Pyridylpyrimidines as the First Orally Bioavailable GPR39 Agonists

    PubMed Central

    2014-01-01

    The identification of highly potent and orally bioavailable GPR39 agonists is reported. Compound 1, found in a phenotypic screening campaign, was transformed into compound 2 with good activity on both the rat and human GPR39 receptor. This compound was further optimized to improve ligand efficiency and pharmacokinetic properties to yield GPR39 agonists for the potential oral treatment of type 2 diabetes. Thus, compound 3 is the first potent GPR39 agonist (EC50s ? 1 nM for human and rat receptor) that is orally bioavailable in mice and robustly induced acute GLP-1 levels. PMID:25313322

  13. Cannabinoid agonist rescues learning and memory after a traumatic brain injury

    PubMed Central

    Arain, Marium; Khan, Maida; Craig, Laura; Nakanishi, Stan T

    2015-01-01

    Traumatic brain injury can cause persistent challenges including problems with learning and memory. Previous studies suggest that the activation of the cannabinoid 1 receptor after a traumatic brain injury could be beneficial. We tested the hypothesis that posttraumatic brain injury administration of a cannabinoid 1 receptor agonist can rescue deficits in learning and memory. Young adult male rats were subjected to a moderately severe controlled cortical impact brain injury, with a subset given postinjury i.p. injections of a cannabinoid receptor agonist. Utilizing novel object recognition and the morris water task, we found that the brain-injured animals treated with the agonist showed a marked recovery. PMID:25815355

  14. Anaphylactic reaction to different gonadotropin-releasing hormone agonists for the treatment of endometriosis.

    PubMed

    Lchinger, Annemarie B; Mijatovic, Velja; Rustemeyer, Thomas; Hompes, Peter G A

    2011-03-01

    Anaphylactic reactions to gonadotropin-releasing hormone (GnRH) agonists are exceedingly rare, but if they occur, they can be life threatening. This case describes a 33-year-old patient with endometriosis who developed an acute allergic reaction on leuprolide (Lucrin) administration. Although skin tests with the replacement goserelin (Zoladex) were negative, usage of this medication resulted in a similar allergic reaction. This is the first case report that shows that, in case of a proven allergy to one GnRH agonist, a switch to another GnRH agonist should not be made even if allergy tests are negative for this medication. PMID:21233692

  15. Pharmacophore-based discovery of FXR agonists. Part I: Model development and experimental validation

    PubMed Central

    Schuster, Daniela; Markt, Patrick; Grienke, Ulrike; Mihaly-Bison, Judit; Binder, Markus; Noha, Stefan M.; Rollinger, Judith M.; Stuppner, Hermann; Bochkov, Valery N.; Wolber, Gerhard

    2011-01-01

    The farnesoid X receptor (FXR) is involved in glucose and lipid metabolism regulation, which makes it an attractive target for the metabolic syndrome, dyslipidemia, atherosclerosis, and type 2 diabetes. In order to find novel FXR agonists, a structure-based pharmacophore model collection was developed and theoretically evaluated against virtual databases including the ChEMBL database. The most suitable models were used to screen the National Cancer Institute (NCI) database. Biological evaluation of virtual hits led to the discovery of a novel FXR agonist with a piperazine scaffold (compound 19) that shows comparable activity as the endogenous FXR agonist chenodeoxycholic acid (CDCA, compound 2). PMID:22018919

  16. Gonadotropin-releasing hormone agonist testing of pituitary-gonadal function.

    PubMed

    Ehrmann, D A; Rosenfield, R L

    1991-01-01

    The development of gonadotropin-releasing hormone (GnRH) agonists has provided a unique means to functionally assess the pituitary-gonadal axis in both males and females. These agonists, when given in a dose sufficient to stimulate the gonadotropes and induce a gonadal steroid response, have provided insights into normal reproductive physiology, hyperandrogenic conditions such as the polycystic ovary syndrome (PCOS), and disorders of pubertal development. This review provides an overview of the use of such agonists as probes of the functional status of the pituitary-gonadal axis in both normal and abnormal reproductive states. PMID:18411171

  17. Agouti signalling protein is an inverse agonist to the wildtype and agonist to the melanic variant of the melanocortin-1 receptor in the grey squirrel (Sciurus carolinensis).

    PubMed

    McRobie, Helen R; King, Linda M; Fanutti, Cristina; Symmons, Martyn F; Coussons, Peter J

    2014-06-27

    The melanocortin-1 receptor (MC1R) is a key regulator of mammalian pigmentation. Melanism in the grey squirrel is associated with an eight amino acid deletion in the mutant melanocortin-1 receptor with 24 base pair deletion (MC1R?24) variant. We demonstrate that the MC1R?24 exhibits a higher basal activity than the wildtype MC1R (MC1R-wt). We demonstrate that agouti signalling protein (ASIP) is an inverse agonist to the MC1R-wt but is an agonist to the MC1R?24. We conclude that the deletion in the MC1R?24 leads to a receptor with a high basal activity which is further activated by ASIP. This is the first report of ASIP acting as an agonist to MC1R. PMID:24879893

  18. The enhancement of existing DES Maplet interface

    NASA Astrophysics Data System (ADS)

    Abdullah, Nur Lina; Mutalip, Rasidah Abdull; Abdullah, Kamilah

    2014-07-01

    This study pertains to the process of Data Encryption Standard, DES. DES consists of encryption and decryption processes linked with mathematical elements such as algebra and number theory. Preliminary, studies revealed that most of mathematics students face a problem in understanding the complicated process of DES. In modern learning methods, learning environment becomes more interesting with the use of computer and a variety of mathematical software packages. Several mathematical softwares such as Maple, Mathematica, Mathlab and Sage were developed in order to fulfill the specific calculation requirements. Correspondingly, motivated from that, this study incorporated with Maple to enhance the existing DES Maplet interface to be more interactive and user-friendly compared to the original version.

  19. Agonist photoaffinity label for the. beta. -adrenergic receptor

    SciTech Connect

    Resek, J.F.; Ruoho, A.E.

    1987-05-01

    An iodinated photosensitive derivative of norepinephrine, N-(p-azido-m-iodophenethylamidoisobutyryl)norepinephrine (NAIN), has been synthesized and characterized. Carrier-free radioiodinated NAIN ((/sup 125/I)-NAIN) was used at 1-2 x 10/sup -9/ M to photoaffinity label the ..beta..-adrenergic receptor in guinea pig lung membranes. SDS-PAGE analysis of (-)-alprenolol (10/sup -5/M) protectable (/sup 125/I)-NAIN labeling showed the same molecular weight polypeptide (65 kDa) that was specifically derivatized with the antagonist photolabel, (/sup 125/I)-IABP. Specific labeling of the ..beta..-adrenergic receptor with (/sup 125/I)-NAIN was dependent on the presence of MgCl/sub 2/ and the absence of guanyl nucleotide. GTP..gamma..S (10/sup -4/ M) abolished specific receptor labeling by (/sup 125/I)-NAIN. N-ethylmaleimide (2 mm) in the presence of (/sup 125/I)-NAIN protected against the guanyl nucleotide effect. These data are consistent with photolabeling by (/sup 125/I)-NAIN while the agonist, receptor, and GTP binding protein are in a high affinity complex.

  20. Object-horning in goitered gazelle: agonistic or marking behaviour?

    PubMed

    Blank, David; Yang, Weikang

    2014-03-01

    We studied object-horning behaviour in goitered gazelles in the natural, arid environment of Kazakhstan over a 6-year period. We found that object-horning was used by adult males mostly as a threat display during territorial conflicts. Therefore object-horning was observed most frequently in territorial single males during the rut in November-December. Object-horning, though, also had a marking effect, with the males' use of this behaviour leaving visible traces that advertized the location of preorbital and urination-defecation scent marks. Therefore, this pattern also was observed linked with preorbital marking and urination-defecation marking behaviours, especially during the rut. Goitered gazelle males chose the most abundant and eatable shrubs for object horning. In contrast to other gazelle species, object-horning in goitered gazelle was observed much more frequently and at the same rate as preorbital and urination-defecation scent markings. This, then, proved a more vigorous and aggressive level of rutting behaviour of the goitered gazelle compared to tropical gazelles, and most likely connected to the short rutting period in the studied species. We concluded, therefore, that object-horning was a manifold phenomenon that played a very important role in goitered gazelle agonistic displays, but without loosing the marking intention of this behaviour. PMID:24365541

  1. Combined modality therapy with TRAIL or agonistic death receptor antibodies

    PubMed Central

    Amm, Hope M; Oliver, Patsy G; Lee, Choo Hyung; Li, Yufeng

    2011-01-01

    Molecularly targeted therapies, such as antibodies and small molecule inhibitors have emerged as an important breakthrough in the treatment of many human cancers. One targeted therapy under development is tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) due to its ability to induce apoptosis in a variety of human cancer cell lines and xenografts, while lacking toxicity in most normal cells. TRAIL and apoptosis-inducing agonistic antibodies to the TRAIL death receptors have been the subject of many preclinical and clinical studies in the past decade. However, the sensitivity of individual cancer cell lines of a particular tumor type to these agents varies from highly sensitive to resistant. Various chemotherapy agents have been shown to enhance the apoptosis-inducing capacity of TRAIL receptor-targeted therapies and induce sensitization of TRAIL-resistant cells. This review provides an overview of the mechanisms associated with chemotherapy enhancement of TRAIL receptor-targeted therapies including modulation of the apoptotic (death receptor expression, FLIP and Bcl-2 or inhibitors of apoptosis [IAP] families) as well as cell signaling (NF?B, Akt, p53) pathways. These mechanisms will be important in establishing effective combinations to pursue clinically and in determining relevant targets for future cancer therapies. PMID:21263219

  2. Carba-Analogues of Fentanyl are Opioid Receptor Agonists

    PubMed Central

    Weltrowska, Grazyna; Chung, Nga N.; Lemieux, Carole; Guo, Jianxin; Lu, Yixin; Wilkes, Brian C.; Schiller, Peter W.

    2010-01-01

    There is evidence to indicate that the Asp residue in the third transmembrane helix (TMH) of opioid receptors forms a salt bridge with the positively charged nitrogen of endogenous and exogenous opioid ligands. To further examine the role of this electrostatic interaction in receptor binding and activation, we synthesized carba-analogues of a published fentanyl analogue containing a 3-(guanidinomethyl)-benzyl group in place of the phenyl moiety attached to the ethylamido group (C. Dardonville et al., Bioorg. Med. Chem. 2006, 14, 65706580 (1)), in which the piperidine ring nitrogen was replaced with a carbon. As expected, the resulting cis and trans isomers (8a and 8b) showed reduced ? and ? opioid receptor binding affinities as compared to 1, but surprisingly, retained opioid full agonist activity with about half the potency of leucine-enkephalin in the guinea pig ileum assay. In conjunction with performed receptor docking studies, these results indicate that the electrostatic interaction of the protonated nitrogen in the piperidine ring of fentanyl analogues with the Asp residue in the third TMH is not a conditio sine qua non for opioid receptor activation. PMID:20218625

  3. Thromboxane agonist (U46619) potentiates norepinephrine efflux from adrenergic nerves

    SciTech Connect

    Trachte, G.J.

    1986-05-01

    The effect of the synthetic thromboxane/prostaglandin (PG) H2 agonist U46619 on the electrically stimulated rabbit isolated vas deferens was examined to test for thromboxane influences on adrenergic nerves. U46619 effects on force generation, (/sup 3/H) norepinephrine release and norepinephrine-induced contractions were assessed to determine the mechanism of action. U46619 maximally enhanced adrenergic force generation 135 +/- 24% at a concentration of 100 nM. U46619 potentiated maximal contractile effects of exogenously administered norepinephrine 16 +/- 4% and augmented (/sup 3/H)norepinephrine release from electrically stimulated preparations 142 +/- 44%. A competitive thromboxane/PGH2 receptor antagonist, SQ29548, significantly shifted the concentration-response curve for U46619 to the right in a concentration-dependent manner and blocked U46619-induced tritium release. Thus, U46619 appears to potentiate neurotransmitter release by interacting with thromboxane/PGH2 receptors. Because SQ29548 did not prevent the potentiation of norepinephrine contractions by U46619, the postjunctional effect may be independent of thromboxane/PGH2 receptors. We interpret these results to be indicative of both pre- and postjunctional sites of action of U46619. The physiological importance of these thromboxane effects is unknown currently.

  4. Glyoxalase 1 increases anxiety by reducing GABAA receptor agonist methylglyoxal

    PubMed Central

    Distler, Margaret G.; Plant, Leigh D.; Sokoloff, Greta; Hawk, Andrew J.; Aneas, Ivy; Wuenschell, Gerald E.; Termini, John; Meredith, Stephen C.; Nobrega, Marcelo A.; Palmer, Abraham A.

    2012-01-01

    Glyoxalase 1 (Glo1) expression has previously been associated with anxiety in mice; however, its role in anxiety is controversial, and the underlying mechanism is unknown. Here, we demonstrate that GLO1 increases anxiety by reducing levels of methylglyoxal (MG), a GABAA receptor agonist. Mice overexpressing Glo1 on a Tg bacterial artificial chromosome displayed increased anxiety-like behavior and reduced brain MG concentrations. Treatment with low doses of MG reduced anxiety-like behavior, while higher doses caused locomotor depression, ataxia, and hypothermia, which are characteristic effects of GABAA receptor activation. Consistent with these data, we found that physiological concentrations of MG selectively activated GABAA receptors in primary neurons. These data indicate that GLO1 increases anxiety by reducing levels of MG, thereby decreasing GABAA receptor activation. More broadly, our findings potentially link metabolic state, neuronal inhibitory tone, and behavior. Finally, we demonstrated that pharmacological inhibition of GLO1 reduced anxiety, suggesting that GLO1 is a possible target for the treatment of anxiety disorders. PMID:22585572

  5. In silico exploration for agonists/antagonists of brassinolide.

    PubMed

    Takimoto, Seisuke; Sugiura, Airi; Minami, Saki; Tasaka, Tomohiko; Nakagawa, Yoshiaki; Miyagawa, Hisashi

    2016-04-01

    Brassinolide (BL) is a plant steroid hormone that is necessary for stem elongation and cell division. To date more than 70 steroidal BL-like compounds, which are collectively named as brassinosteroids, have been identified. However, non-steroidal compounds that mimic BL have not been reported yet, which can be used as plant growth regulators. Twenty-two non-steroidal compounds were screened from the database containing about 5 million compound structures using a pharmacophore-based in silico screening method. The crystal structure (PDB: 4LSX) of the BL receptor was used to generate a pharmacophore model required for in silico screening. Among 22 hit compounds, 15 compounds that are thought to be physicochemically acceptable were submitted to the in vivo rice lamina inclination assay. Although no compound showed BL like activity, three compounds were detected as BL antagonist. The most potent compound was an ester derivative of 1,4-diphenlenedimethanol and isoxazole-4-carboxylic acid, and the other two compounds contain 2-phenylfuran and pyrimidin-2(1H)-one moieties bridged by an ethenyl substructure. The 50% effective doses (ED50) for the antagonistic activity were in a range of 0.6-5nmol per plant. The inhibition of the lamina inclination by the most potent agonist was recovered by the co-application of BL in a dose-dependent manner. PMID:26935445

  6. New, potent, and selective peptidic oxytocin receptor agonists.

    PubMed

    Wi?niewski, Kazimierz; Alagarsamy, Sudarkodi; Galyean, Robert; Tariga, Hiroe; Thompson, Dorain; Ly, Brian; Wi?niewska, Halina; Qi, Steve; Croston, Glenn; Laporte, Regent; Rivire, Pierre J-M; Schteingart, Claudio D

    2014-06-26

    Mothers of preterm babies frequently have difficulty establishing or maintaining lactation, thought to be due to interference with the milk ejection reflex. Administration of exogenous oxytocin can produce alveolar contraction and adequate breast emptying resulting in establishment of successful lactation. The natural hormone oxytocin is not receptor-selective and may cause hyponatremia via V2 receptor mediated antidiuresis. We have designed a series of potent oxytocin analogues containing N-alkylglycines in position 7 with excellent selectivity versus the related V1a, V1b, and V2 vasopressin receptors and short half-life: agonists 31 ([2-ThiMeGly(7)]dOT), 47 (carba-6-[Phe(2),BuGly(7)]dOT), 55 (carba-6-[3-MeBzlGly(7)]dOT), and 57 (carba-1-[4-FBzlGly(7)]dOT) have EC50 values at hOTR < 0.1 nM, selectivity ratios versus related human vasopressin receptors of >2000, IC50 at hV1aR > 500 nM, and total clearance in rats in the range of 60-80 mL min(-1) kg(-1). Compound 57 (FE 202767) is currently in clinical development for the treatment of preterm mothers requiring lactation support. PMID:24874785

  7. cologie des soins de sant au Canada

    PubMed Central

    Stewart, Moira; Ryan, Bridget

    2015-01-01

    Rsum Objectif Prsenter un profil populationnel pancanadien des besoins en soins de sant et de leur utilisation, facile daccs et permettant des comparaisons entre les provinces et avec dautres instances internationales. Conception Une comparaison des taux dutilisation des soins de sant entre les provinces en utilisant des donnes denqutes et des renseignements administratifs sur la sant. Contexte Les provinces du Canada. Principaux paramtres ltude Les taux canadiens et provinciaux de personnes en mauvaise sant (prsence de problmes chroniques) et dutilisation des soins de sant (contacts avec des mdecins de famille, avec dautres mdecins spcialistes, avec des infirmires et hospitalisations) sous forme de proportions mensuelles par 1000 habitants normalises en fonction de lge et du genre. Rsultats La proportion mensuelle par 1000 habitants de personnes souffrant dau moins 1 problme chronique variait de 524 au Qubec 638 en Nouvelle-cosse; les contacts avec un mdecin de famille se situaient entre 158 au Qubec et 295 en Colombie-Britannique; les contacts avec dautres mdecins spcialistes variaient entre 53 en Saskatchewan et 79 en Ontario; et le nombre de contacts avec des infirmires se situait entre 23 en Colombie-Britannique et 41 au Qubec. Le nombre de sjours lhpital variait entre 8 et 11 par 1000 habitants et les proportions taient semblables dune province lautre. Conclusion Il est essentiel de reconnatre les distinctions entre les provinces pour clairer les politiques sur la sant dans lensemble du pays. Les diffrences persistaient lorsque les taux taient normaliss en fonction de la composition dmographique variable selon lge et le genre dans les provinces. Cet article prsente une mthodologie simple laide de donnes publiquement accessibles qui peut servir dans chaque province examiner, lavenir, lvolution avec le temps de lutilisation des soins de sant par les instances provinciales.

  8. Specific delta-opioid antagonists exert an agonist-independent inhibitory effect, similar to the agonist, on the release of GnRH in vitro.

    PubMed

    Dragatsis, I; Zioudrou, C; Gerozissis, K

    1995-08-01

    1. In in vitro studies with adult male rats we have recently shown that the delta-opioid agonist DTLET inhibits the release of the Gonadotropin-Releasing Hormone (GnRH) from hypothalamic fragments containing the arcuate nucleus and the median eminence. This effect is receptor mediated and eicosanoid dependent (Gerozissis et al., 1993). 2. In the present study we report that the delta-opioid antagonists with negative intrinsic activity, Diallyl-G and ICI 174864, applied under the same experimental conditions (30 min static incubations at 37 degrees C, in a potassium rich milieu), in the absence of the agonist DTLET, also exert a similar to the agonist inhibitory effect on the release of GnRH. 3. The dose-dependent inhibitory effect of Diallyl-G on GnRH release is reversed by increasing concentrations of DTLET. The mu and delta opioid antagonist, naloxone is without effect in the absence of DTLET. However, naloxone acts as an antagonist on the Diallyl-G-induced inhibition of GnRH release. 4. Diallyl-G also inhibits the release of prostaglandin E2 (PGE2). In the presence of indomethacin or nordihydroguaiaretic acid, Diallyl-G is ineffective to further inhibit the release of GnRH. These latter observations taken together with the results of eicosanoid estimation suggest that PGE2 but not leukotrienes participate in the agonist-independent effects of Diallyl-G on GnRH release. 5. Therefore these results support the hypothesis that delta-opioid antagonists with negative intrinsic activity exert agonist-independent biological responses similar to those of the agonists. PMID:8565043

  9. gamma-Aminobutyric acidA agonists differentially augment gnawing induced by indirect-acting dopamine agonists in C57BL/6J mice.

    PubMed

    Tirelli, E; Geter-Douglass, B; Witkin, J M

    1998-01-01

    Evidence from structure-activity, molecular biology, ligand binding and behavioral studies has suggested potential differences in the pharmacological effects of indirect dopamine agonists. Striatal dopaminergic neurotransmission is under the regulatory control of GABAergic inputs. The ability of agonists of gamma-aminobutyric acidA (GABAA) receptors to enhance stereotyped gnawing was used as a method for dissociating the pharmacological effects of indirect-acting dopamine agonists. Gnawing on corrugated cardboard was studied in C57BL/6J mice. The GABAA agonists, gaboxadol HCl (THIP) and muscimol, were not effective in augmenting gnawing in the presence of the direct-acting dopamine agonists, apomorphine, pergolide, RU 24213 or SKF 38393. In addition, THIP did not enhance the gnawing produced by cocaine, bupropion, GBR 12909 or WIN 35428. In contrast, THIP produced marked augmentation of the gnawing induced by methylphenidate, (+)-amphetamine, methamphetamine, amfonelic acid, indatraline, nomifensine, diclofensine, mazindol and GBR 12935. The qualitative differences in potentiation were not caused by differences in the maximal effect of the drugs alone, inadequate dose or routes of administration, or by differences in duration of action. Neither can the absence of potentiation be accounted for by unique effects of THIP; muscimol was only marginally effective in potentiating the effects of WIN 35428 and bupropion but completely inactive in augmenting the effects of cocaine and GBR 12909. Muscimol was efficacious in augmenting the effects of the drugs for which THIP was active. These results add to a small but growing literature that demonstrates differences in the in vitro and in vivo pharmacological effects of indirect dopamine agonists. The methods used here may help in defining the molecular and neural substrates of these differential effects. PMID:9435169

  10. Characterization of active and inactive states of CB1 receptor and the differential binding state modulation by cannabinoid agonists, antagonists and inverse agonists.

    PubMed

    Gullapalli, Srinivas; Amrutkar, Dipak; Gupta, Sangeetha; Kandadi, Machender R; Kumar, Hemant; Gandhi, Maulik; Karande, Vikas; Narayanan, Shridhar

    2010-06-01

    Cannabinoid 1 (CB1) receptors have the ability to change conformation between active (R*) and inactive (R) receptor states. Herein, we further characterize these receptor states using series of saturation radioligand binding studies and their differential displacement binding by various CB1 receptor ligands. Binding experiments were carried out in nave rat/dog whole brain membranes using radioligands [(3)H]CP55,940 (for R* state) & [(3)H]SR141716A (both R* and R states) and various agonist, antagonist & inverse agonist ligands at CB1 receptors. In the saturation binding experiments, of the total number of CB1 receptor binding sites (R* + R) in the rat and dog whole brain membranes, only about 18.3 and 11.6% were in the active (R*) state recognized by [(3)H]CP55,940, respectively. In the competitive binding studies, all the CB1 receptor agonists investigated had significantly very high affinity for the active R* state recognized by [(3)H]CP55,940 and lower affinity for the inactive R state mainly recognized by [(3)H]SR141716A in the presence of a non-hydrolyzable analogue of GTP [Gpp(NH)p]. In contrast, various CB1 receptor antagonists/inverse agonists had similar nanomolar affinities at both [(3)H]CP55,940 and [(3)H]SR141716A recognized binding states. These results clearly characterize the significant differences between the active R* and inactive R binding states of CB1 receptors in naive rat and dog brain. In addition, these results also demonstrates that the CB1 agonists and antagonists/inverse agonists can be differentiated by their relative affinities at active (R*) and inactive (R) binding states of the CB1 receptor. PMID:20214912

  11. Caracterisation des proprietes acoustiques des materiaux poreux a cellules ouvertes et a matrice rigide ou souple

    NASA Astrophysics Data System (ADS)

    Salissou, Yacoubou

    L'objectif global vise par les travaux de cette these est d'ameliorer la caracterisation des proprietes macroscopiques des materiaux poreux a structure rigide ou souple par des approches inverses et indirectes basees sur des mesures acoustiques faites en tube d'impedance. La precision des approches inverses et indirectes utilisees aujourd'hui est principalement limitee par la qualite des mesures acoustiques obtenues en tube d'impedance. En consequence, cette these se penche sur quatre problemes qui aideront a l'atteinte de l'objectif global precite. Le premier probleme porte sur une caracterisation precise de la porosite ouverte des materiaux poreux. Cette propriete en est une de passage permettant de lier la mesure des proprietes dynamiques acoustiques d'un materiau poreux aux proprietes effectives de sa phase fluide decrite par les modeles semi-phenomenologiques. Le deuxieme probleme traite de l'hypothese de symetrie des materiaux poreux selon leur epaisseur ou un index et un critere sont proposes pour quantifier l'asymetrie d'un materiau. Cette hypothese est souvent source d'imprecision des methodes de caracterisation inverses et indirectes en tube d'impedance. Le critere d'asymetrie propose permet ainsi de s'assurer de l'applicabilite et de la precision de ces methodes pour un materiau donne. Le troisieme probleme vise a mieux comprendre le probleme de transmission sonore en tube d'impedance en presentant pour la premiere fois un developpement exact du probleme par decomposition d'ondes. Ce developpement permet d'etablir clairement les limites des nombreuses methodes existantes basees sur des tubes de transmission a 2, 3 ou 4 microphones. La meilleure comprehension de ce probleme de transmission est importante puisque c'est par ce type de mesures que des methodes permettent d'extraire successivement la matrice de transfert d'un materiau poreux et ses proprietes dynamiques intrinseques comme son impedance caracteristique et son nombre d'onde complexe. Enfin, le quatrieme probleme porte sur le developpement d'une nouvelle methode de transmission exacte a 3 microphones applicable a des materiaux ou systemes symetriques ou non. Dans le cas symetrique, on montre que cette approche permet une nette amelioration de la caracterisation des proprietes dynamiques intrinseques d'un materiau. Mots cles. materiaux poreux, tube d'impedance, transmission sonore, absorption sonore, impedance acoustique, symetrie, porosite, matrice de transfert.

  12. Profil pidmiologique des tumeurs malignes primitives des glandes salivaires : propos de 154 cas

    PubMed Central

    Setti, Khadija; Mouanis, Mohamed; Moumni, Abdelmounim; Maher, Mostafa; Harmouch, Amal

    2014-01-01

    Introduction Les tumeurs des glandes salivaires sont des tumeurs rares reprsentant 3 5% des tumeurs de la tte et du cou. La classification de l'OMS 2005 distingue les tumeurs pithliales, les tumeurs msenchymateuses, les tumeurs hmatologiques et les tumeurs secondaires. Mthodes Notre travail consiste en une tude rtrospective ralise sur une priode de 10 ans allant de janvier 2002 janvier 2012. Les critres d'inclusion taient: l'ge, le sexe, le sige de la tumeur et le type histologique. Rsultats L'incidence annuelle des tumeurs malignes primitives des glandes salivaires dans notre srie tait de 15 cas par an. Cent cinquante quatre cas de tumeurs malignes primitives des glandes salivaires ont t colligs sans prdominance de sexe (78 femmes (50,6%) et 76 hommes (49,4%)). La moyenne d'ge tait de 60 ans avec des extrmes de 4 et 83 ans et un pic de frquence entre 51et 70 ans. Deux tiers des cas (65%) avaient une localisation au niveau des glandes principales avec 66 cas au niveau de la parotide (43%) et 34 cas au niveau de la glande sous maxillaire (22%). Cinquante quatre patients avaient une tumeur maligne des glandes salivaires accessoires (35%) dont 61% au niveau du palais. Aucun cas de tumeur maligne de la glande sublinguale n'a t recens dans notre tude. Le type histologique prdominant dans notre srie tait le carcinome adnode kystique et retrouv chez 43 patients (27,9%), suivi de l'adnocarcinome sans autre indication chez 37 patients (24%) puis du carcinome mucopidermode chez 16 patients (10,4%) et de l'adnocarcinome polymorphe de bas grade galement chez 16 patients (10. 4%). Conclusion Les tumeurs malignes des glandes salivaires reprsentent un ensemble htrogne de maladies de caractrisation complexe et de frquence variable. PMID:25120861

  13. Increasing Potential Access to Opioid Agonist Treatment in U.S. Treatment Shortage Areas

    PubMed Central

    Dick, Andrew W.; Pacula, Rosalie Liccardo; Gordon, Adam J.; Sorbero, Mark; Burns, Rachel M.; Leslie, Douglas L.; Stein, Bradley D.

    2015-01-01

    Opioid use disorders are a significant public health problem, affecting over 2 million individuals in the US. Although opioid agonist treatment, predominantly offered in licensed methadone clinics, is both effective and cost-effective, many individuals do not receive it. Buprenorphine, approved in 2002 for prescription by waivered physicians, could improve opioid agonist treatment access for individuals unable or unwilling to receive methadone. We examine the extent to which the geographic distribution of waivered physicians has enhanced potential opioid agonist treatment access, particularly in non-metropolitan areas with fewer methadone clinics. We found that while the approximately 90% of counties classified as methadone clinic shortage areas remained constant, buprenorphine shortage areas fell from 99% of counties in 2002 to 51% in 2011, lowering the US population percentage residing in opioid treatment shortage counties to approximately 10%. The increase in buprenorphine-waivered physicians has dramatically increased potential access to opioid agonist treatment, especially in non-metropolitan counties. PMID:26056209

  14. Lepidozenolide from the liverwort Lepidozia fauriana acts as a farnesoid X receptor agonist.

    PubMed

    Lin, Hsiang-Ru

    2015-01-01

    Lepidozenolide is a sesquiterpenoid isolated from the liverwort Lepidozia fauriana and its possible bioactivity is unclear. The farnesoid X receptor (FXR) is a member of nuclear receptor superfamily that has been widely targeted for developing treatments for chronic liver disease and hyperglycemia. In this study, whether lepidozenolide may act as a FXR agonist was determined. Indeed, in mammalian one-hybrid and transient transfection reporter assays, lepidozenolide transactivated FXR to modulate promoter action including GAL4, CYP7A1, and PLTP promoters in a dose-dependent manner, while it exhibited slightly less agonistic activity than chenodeoxycholic acid, an endogenous FXR agonist. Through the molecular modeling docking studies lepidozenolide was shown to bind to FXR ligand binding pocket fairly well. All these results indicate that lepidozenolide acts as a FXR agonist. PMID:25315435

  15. Innate immune responses to microbial agonist stimulations in heterophils and monocytes from young commercial turkeys

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The innate immune system recognizes microbial pathogens and pathogen associated molecular patterns and incites inflammatory immune responses to control the infection. Here, we examined functional innate immune responses of turkey heterophils and monocytes to microbial agonist stimulations by measur...

  16. Access to 7?-analogs of codeine with mixed ?/? agonist activity via 6,7-?-epoxide opening.

    PubMed

    Magnus, Philip; Ghavimi, Bahman; Coe, Jotham W

    2013-09-01

    (-)-Codeine 1 was converted into previously unknown 7?-methyl-7,8-dihydrocodeine/morphine derivatives such as 13 via classical diaxial opening of ?-epoxide 3. Several analogs exhibited dual ?/?-agonist activity. PMID:23880538

  17. Structure-based Ligand Design of Novel Human Toll-like Receptor 8 Agonists

    PubMed Central

    Kokatla, Hari Prasad; Sil, Diptesh; Tanji, Hiromi; Ohto, Umeharu; Malladi, Subbalakshmi S.; Fox, Lauren M.; Shimizu, Toshiyoki; David, Sunil A.

    2014-01-01

    Toll-like receptor (TLR)-8 agonists activate adaptive immune responses by inducing robust production of T helper 1-polarizing cytokines, suggesting that TLR8-active compounds may be promising candidate adjuvants. We recently reported pure TLR8 agonistic activity in a C2-butyl furo[2,3-c]quinoline. We have obtained the structure of human TLR8 ectodomain co-crystallized with the furoquinoline compound, which indicates ligand-induced reorganization of the binding pocket of TLR8. The loss of a key H-bond between the oxygen atom of the furanyl ring of the agonist and Thr574 in TLR8 suggested that the furan ring was dispensable. We employed a disconnection strategy and examined 3- and 4-substituted aminoquinolines. Focused structure-based ligand design studies led to the identification of 3-pentyl-quinoline-2-amine as a novel, structurally simple, and highly potent human TLR8-specific agonist. PMID:24474703

  18. Introduction: Gonadotropin-releasing hormone agonist triggering of final follicular maturation for in vitro fertilization.

    PubMed

    Casper, Robert F

    2015-04-01

    These Views and Reviews articles examine the use of GnRH agonist for triggering the final stage of follicular maturation in IVF, resulting in excellent follicle maturation. An advantage of the GnRH agonist trigger is the ability to retrieve oocytes in high responders, yet markedly reducing the risk of ovarian hyperstimulation syndrome (OHSS). However, the induction of early luteolysis after the GnRH agonist trigger requires the use of aggressive steroidal luteal support or low-dose hCG to allow successful fresh ET and live birth. With the enhanced effectiveness of vitrification, segmentation in GnRH agonist-triggered cycles with freezing all embryos for transfer in subsequent cycles may be the optimal strategy for eliminating OHSS. PMID:25681856

  19. Discovery of novel acetanilide derivatives as potent and selective beta3-adrenergic receptor agonists.

    PubMed

    Maruyama, Tatsuya; Onda, Kenichi; Hayakawa, Masahiko; Matsui, Tetsuo; Takasu, Toshiyuki; Ohta, Mitsuaki

    2009-06-01

    In the search for potent and selective human beta3-adrenergic receptor (AR) agonists as potential drugs for the treatment of obesity and noninsulin-dependent (type II) diabetes, a novel series of acetanilide-based analogues were prepared and their biological activities were evaluated at the human beta3-, beta2-, and beta1-ARs. Among these compounds, 2-pyridylacetanilide (2f), pyrimidin-2-ylacetanilide (2u), and pyrazin-2-ylacetanilide (2v) derivatives exhibited potent agonistic activity at the beta3-AR with functional selectivity over the beta1- and beta2-ARs. In particular, compound 2u was found to be the most potent and selective beta3-AR agonist with an EC(50) value of 0.11 microM and no agonistic activity for either the beta1- or beta2-AR. In addition, 2f, 2u, and 2v showed significant hypoglycemic activity in a rodent diabetic model. PMID:19232786

  20. Agonist binding to the NMDA receptor drives movement of its cytoplasmic domain without ion flow.

    PubMed

    Dore, Kim; Aow, Jonathan; Malinow, Roberto

    2015-11-24

    The NMDA receptor (R) plays important roles in brain physiology and pathology as an ion channel. Here we examine the ion flow-independent coupling of agonist to the NMDAR cytoplasmic domain (cd). We measure FRET between fluorescently tagged cytoplasmic domains of GluN1 subunits of NMDARs expressed in neurons. Different neuronal compartments display varying levels of FRET, consistent with different NMDARcd conformations. Agonist binding drives a rapid and transient ion flow-independent reduction in FRET between GluN1 subunits within individual NMDARs. Intracellular infusion of an antibody targeting the GluN1 cytoplasmic domain blocks agonist-driven FRET changes in the absence of ion flow, supporting agonist-driven movement of the NMDARcd. These studies indicate that extracellular ligand binding to the NMDAR can transmit conformational information into the cell in the absence of ion flow. PMID:26553997

  1. The Renoprotective Actions of Peroxisome Proliferator-Activated Receptors Agonists in Diabetes

    PubMed Central

    Thomas, M. C.; Jandeleit-Dahm, K. A.; Tikellis, C.

    2012-01-01

    Pharmaceutical agonists of peroxisome proliferator-activated receptors (PPARs) are widely used in the management of type 2 diabetes, chiefly as lipid-lowering agents and oral hypoglycaemic agents. Although most of the focus has been placed on their cardiovascular effects, both positive and negative, these agents also have significant renoprotective actions in the diabetic kidney. Over and above action on metabolic control and effects on blood pressure, PPAR agonists also appear to have independent effects on a number of critical pathways that are implicated in the development and progression of diabetic kidney disease, including oxidative stress, inflammation, hypertrophy, and podocyte function. This review will examine these direct and indirect actions of PPAR agonists in the diabetic kidney and explore recent findings of clinical trials of PPAR agonists in patients with diabetes. PMID:22448165

  2. Potent achiral agonists of the ghrelin (growth hormone secretagogue) receptor. Part I: Lead identification.

    PubMed

    Heightman, Tom D; Scott, Jackie S; Longley, Mark; Bordas, Vincent; Dean, David K; Elliott, Richard; Hutley, Gail; Witherington, Jason; Abberley, Lee; Passingham, Barry; Berlanga, Manuela; de Los Frailes, Maite; Wise, Alan; Powney, Ben; Muir, Alison; McKay, Fiona; Butler, Sharon; Winborn, Kim; Gardner, Christopher; Darton, Jill; Campbell, Colin; Sanger, Gareth

    2007-12-01

    High throughput screening combined with efficient datamining and parallel synthesis led to the discovery of a novel series of indolines showing potent in vitro ghrelin receptor agonist activity and acceleration of gastric emptying in rats. PMID:17942309

  3. INFLAMMATORY AGONIST STIMULATION AND SIGNAL PATHWAY OF OXIDATIVE BURST IN NEONATAL CHICKEN HETEROPHILS

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A fluorescence microplate assay was adapted to examine the oxidative response by heterophils from neonatal chicks following in vitro stimulation with various inflammatory agonists. Both nonopsonized formalin-killed Salmonella enteritidis and Staphylococcus aureus stimulated significant heterophil o...

  4. Investigation of D1 Receptor–Agonist Interactions and D1/D2 Agonist Selectivity Using a Combination of Pharmacophore and Receptor Homology Modeling

    PubMed Central

    Malo, Marcus; Brive, Lars; Luthman, Kristina; Svensson, Peder

    2012-01-01

    The aim of this study was to use a combined structure and pharmacophore modeling approach to extract information regarding dopamine D1 receptor agonism and D1/D2 agonist selectivity. A 3D structure model of the D1 receptor in its agonist-bound state was constructed with a full D1 agonist present in the binding site. Two different binding modes were identified using (+)-doxanthrine or SKF89626 in the modeling procedure. The 3D model was further compared with a selective D1 agonist pharmacophore model. The pharmacophore feature arrangement was found to be in good agreement with the binding site composition of the receptor model, but the excluded volumes did not fully reflect the shape of the agonist binding pocket. A new receptor-based pharmacophore model was developed with forbidden volumes centered on atom positions of amino acids in the binding site. The new pharmacophore model showed a similar ability to discriminate as the previous model. A comparison of the 3D structures and pharmacophore models of D1 and D2 receptors revealed differences in shape and ligand-interacting features that determine selectivity of D1 and D2 receptor agonists. A hydrogen bond pharmacophoric feature (Ser-TM5) was shown to contribute most to the selectivity. Non-conserved residues in the binding pocket that strongly contribute to D1/D2 receptor agonist selectivity were also identified; those were Ser/Cys3.36, Tyr/Phe5.38, Ser/Tyr5.41, and Asn/His6.55 in the transmembrane (TM) helix region, together with Ser/Ile and Leu/Asn in the second extracellular loop (EC2). This work provides useful information for the design of new selective D1 and D2 agonists. The combined receptor structure and pharmacophore modeling approach is considered to be general, and could therefore be applied to other ligand–protein interactions for which experimental information is limited. PMID:22315216

  5. Competitive molecular docking approach for predicting estrogen receptor subtype α agonists and antagonists

    PubMed Central

    2014-01-01

    Background Endocrine disrupting chemicals (EDCs) are exogenous compounds that interfere with the endocrine system of vertebrates, often through direct or indirect interactions with nuclear receptor proteins. Estrogen receptors (ERs) are particularly important protein targets and many EDCs are ER binders, capable of altering normal homeostatic transcription and signaling pathways. An estrogenic xenobiotic can bind ER as either an agonist or antagonist to increase or inhibit transcription, respectively. The receptor conformations in the complexes of ER bound with agonists and antagonists are different and dependent on interactions with co-regulator proteins that vary across tissue type. Assessment of chemical endocrine disruption potential depends not only on binding affinity to ERs, but also on changes that may alter the receptor conformation and its ability to subsequently bind DNA response elements and initiate transcription. Using both agonist and antagonist conformations of the ERα, we developed an in silico approach that can be used to differentiate agonist versus antagonist status of potential binders. Methods The approach combined separate molecular docking models for ER agonist and antagonist conformations. The ability of this approach to differentiate agonists and antagonists was first evaluated using true agonists and antagonists extracted from the crystal structures available in the protein data bank (PDB), and then further validated using a larger set of ligands from the literature. The usefulness of the approach was demonstrated with enrichment analysis in data sets with a large number of decoy ligands. Results The performance of individual agonist and antagonist docking models was found comparable to similar models in the literature. When combined in a competitive docking approach, they provided the ability to discriminate agonists from antagonists with good accuracy, as well as the ability to efficiently select true agonists and antagonists from decoys during enrichment analysis. Conclusion This approach enables evaluation of potential ER biological function changes caused by chemicals bound to the receptor which, in turn, allows the assessment of a chemical's endocrine disrupting potential. The approach can be used not only by regulatory authorities to perform risk assessments on potential EDCs but also by the industry in drug discovery projects to screen for potential agonists and antagonists. PMID:25349983

  6. Agonist-induced desensitization and phosphorylation of m1-muscarinic receptors.

    PubMed Central

    Waugh, M G; Challiss, R A; Berstein, G; Nahorski, S R; Tobin, A B

    1999-01-01

    Pre-stimulation of Chinese hamster ovary (CHO) cells expressing the human m1-muscarinic receptor (CHO-m1 cells) with a maximally effective concentration of the muscarinic agonist methacholine resulted in desensitization of Ins(1,4,5)P3 accumulation, apparent as a approximately 4-fold shift in the agonist dose-response curve. Agonist-induced desensitization was rapid (detectable by 10 s) and concentration dependent (EC50=8.2+/-2.2 microM) and resulted in a complete loss of receptor reserve for the agonist-stimulated Ins(1,4, 5)P3 response. An investigation of the possible mechanisms involved in m1-muscarinic receptor desensitization indicated that agonist-induced receptor internalization, PtdIns-(4,5)P2 depletion or an increased rate of Ins(1,4,5)P3 metabolism were not involved. m1-Muscarinic receptors did, however, undergo rapid agonist-induced phosphorylation with a time course that was consistent with an involvement in receptor desensitization. Characterization studies indicated that the receptor-specific kinase involved was distinct from protein kinase C and other second-messenger-dependent protein kinases. Since previous studies have suggested that the m3-muscarinic receptor subtype undergoes agonist-dependent phosphorylation via casein kinase 1alpha (CK1alpha) [Tobin, Totty, Sterlin and Nahorski (1997) J. Biol. Chem. 272, 20844-20849], we examined the ability of m1-muscarinic receptors to be phosphorylated by this kinase. In reconstitution experiments, CK1alpha was able to phosphorylate purified, soluble m1-muscarinic receptors in an agonist-dependent manner. PMID:9931314

  7. Systematic review: cardiovascular safety profile of 5-HT4 agonists developed for gastrointestinal disorders

    PubMed Central

    Tack, J; Camilleri, M; Chang, L; Chey, W D; Galligan, J J; Lacy, B E; Mller-Lissner, S; Quigley, E M M; Schuurkes, J; Maeyer, J H; Stanghellini, V

    2012-01-01

    Summary Background The nonselective 5-HT4 receptor agonists, cisapride and tegaserod have been associated with cardiovascular adverse events (AEs). Aim To perform a systematic review of the safety profile, particularly cardiovascular, of 5-HT4 agonists developed for gastrointestinal disorders, and a nonsystematic summary of their pharmacology and clinical efficacy. Methods Articles reporting data on cisapride, clebopride, prucalopride, mosapride, renzapride, tegaserod, TD-5108 (velusetrag) and ATI-7505 (naronapride) were identified through a systematic search of the Cochrane Library, Medline, Embase and Toxfile. Abstracts from UEGW 20062008 and DDW 20082010 were searched for these drug names, and pharmaceutical companies approached to provide unpublished data. Results Retrieved articles on pharmacokinetics, human pharmacodynamics and clinical data with these 5-HT4 agonists, are reviewed and summarised nonsystematically. Articles relating to cardiac safety and tolerability of these agents, including any relevant case reports, are reported systematically. Two nonselective 5-HT4 agonists had reports of cardiovascular AEs: cisapride (QT prolongation) and tegaserod (ischaemia). Interactions with, respectively, the hERG cardiac potassium channel and 5-HT1 receptor subtypes have been suggested to account for these effects. No cardiovascular safety concerns were reported for the newer, selective 5-HT4 agonists prucalopride, velusetrag, naronapride, or for nonselective 5-HT4 agonists with no hERG or 5-HT1 affinity (renzapride, clebopride, mosapride). Conclusions 5-HT4 agonists for GI disorders differ in chemical structure and selectivity for 5-HT4 receptors. Selectivity for 5-HT4 over non-5-HT4 receptors may influence the agent's safety and overall riskbenefit profile. Based on available evidence, highly selective 5-HT4 agonists may offer improved safety to treat patients with impaired GI motility. PMID:22356640

  8. Molecular basis for benzodiazepine agonist action at the type 1 cholecystokinin receptor.

    PubMed

    Harikumar, Kaleeckal G; Cawston, Erin E; Lam, Polo C H; Patil, Achyut; Orry, Andrew; Henke, Brad R; Abagyan, Ruben; Christopoulos, Arthur; Sexton, Patrick M; Miller, Laurence J

    2013-07-19

    Understanding the molecular basis of drug action can facilitate development of more potent and selective drugs. Here, we explore the molecular basis for action of a unique small molecule ligand that is a type 1 cholecystokinin (CCK) receptor agonist and type 2 CCK receptor antagonist, GI181771X. We characterize its binding utilizing structurally related radioiodinated ligands selective for CCK receptor subtypes that utilize the same allosteric ligand-binding pocket, using wild-type receptors and chimeric constructs exchanging the distinct residues lining this pocket. Intracellular calcium assays were performed to determine biological activity. Molecular models for docking small molecule agonists to the type 1 CCK receptor were developed using a ligand-guided refinement approach. The optimal model was distinct from the previous antagonist model for the same receptor and was mechanistically consistent with the current mutagenesis data. This study revealed a key role for Leu(7.39) that was predicted to interact with the isopropyl group in the N1 position of the benzodiazepine that acts as a "trigger" for biological activity. The molecular model was predictive of binding of other small molecule agonists, effectively distinguishing these from 1065 approved drug decoys with an area under curve value of 99%. The model also selectively enriched for agonist compounds, with 130 agonists identified by ROC analysis when seeded in 2175 non-agonist ligands of the type 1 CCK receptor (area under curve 78%). Benzodiazepine agonists in this series docked in consistent pose within this pocket, with a key role played by Leu(7.39), whereas the role of this residue was less clear for chemically distinct agonists. PMID:23754289

  9. Rational design of orally-active, pyrrolidine-based progesterone receptor partial agonists

    SciTech Connect

    Thompson, Scott K.; Washburn, David G.; Frazee, James S.; Madauss, Kevin P.; Hoang, Tram H.; Lapinski, Leahann; Grygielko, Eugene T.; Glace, Lindsay E.; Trizna, Walter; Williams, Shawn P.; Duraiswami, Chaya; Bray, Jeffrey D.; Laping, Nicholas J.

    2010-09-03

    Using the X-ray crystal structure of an amide-based progesterone receptor (PR) partial agonist bound to the PR ligand binding domain, a novel PR partial agonist class containing a pyrrolidine ring was designed. Members of this class of N-alkylpyrrolidines demonstrate potent and highly selective partial agonism of the progesterone receptor, and one of these analogs was shown to be efficacious upon oral dosing in the OVX rat model of estrogen opposition.

  10. Discovery of GSK1997132B a novel centrally penetrant benzimidazole PPAR? partial agonist.

    PubMed

    Sime, Mairi; Allan, Amanda C; Chapman, Paul; Fieldhouse, Charlotte; Giblin, Gerard M P; Healy, Mark P; Lambert, Millard H; Leesnitzer, Lisa M; Lewis, Ann; Merrihew, Raymond V; Rutter, Richard A; Sasse, Rosemary; Shearer, Barry G; Willson, Timothy M; Wilson, Timothy M; Xu, Robert X; Virley, David J

    2011-09-15

    The peroxisome proliferator-activated receptor ? (PPAR?) is a ligand-activated nuclear receptor, thought to play a role in energy metabolism, glucose homeostasis and microglia-mediated neuroinflammation. A novel benzimidazole series of centrally penetrant PPAR? partial agonists has been identified. The optimization of PPAR? activity and in vivo pharmacokinetics leading to the identification of GSK1997132B a potent, metabolically stable and centrally penetrant PPAR? partial agonist, is described. PMID:21798739

  11. The SAR analysis of TRPV1 agonists with the ?-methylated B-region

    PubMed Central

    Cho, Yongsung; Kim, Myeong Seop; Kim, Ho Shin; Ann, Ji Hyae; Lee, Jiyoun; Pearce, Larry V.; Pavlyukovets, Vladimir A.; Morgan, Matthew A.; Blumberg, Peter M.; Lee, Jeewoo

    2013-01-01

    A series of TRPV1 agonists with amide, reverse amide, and thiourea groups in the B-region and their corresponding ?-methylated analogues were investigated. Whereas the ?methylation of the amide B-region enhanced the binding affinities and potencies as agonists, that of the reverse amide and thiourea led to a reduction in receptor affinity. The analysis indicated that proper hydrogen bonding as well as steric effects in the B-region are critical for receptor binding. PMID:22796184

  12. Stereochemistry-activity relationship of orally active tetralin S1P agonist prodrugs.

    PubMed

    Ma, Bin; Guckian, Kevin M; Lin, Edward Yin-Shiang; Lee, Wen-Cherng; Scott, Daniel; Kumaravel, Gnanasambandam; Macdonald, Timothy L; Lynch, Kevin R; Black, Cheryl; Chollate, Sowmya; Hahm, Kyungmin; Hetu, Gregg; Jin, Ping; Luo, Yi; Rohde, Ellen; Rossomando, Anthony; Scannevin, Robert; Wang, Joy; Yang, Chunhua

    2010-04-01

    Modifying FTY720, an immunosuppressant modulator, led to a new series of well phosphorylated tetralin analogs as potent S1P1 receptor agonists. The stereochemistry effect of tetralin ring was probed, and (-)-(R)-2-amino-2-((S)-6-octyl-1,2,3,4-tetrahydronaphthalen-2-yl)propan-1-ol was identified as a good SphK2 substrate and potent S1P1 agonist with good oral bioavailability. PMID:20188554

  13. Discovery of Azetidinone Acids as Conformationally-Constrained Dual PPARalpha/gamma Agonists

    SciTech Connect

    Wang, W.; Devasthale, P; Farrelly, D; Gu, L; Harrity, T; Cap, M; Chu, C; Kunselman, L; Morgan, N; et. al.

    2008-01-01

    A novel class of azetidinone acid-derived dual PPAR{alpha}/{gamma} agonists has been synthesized for the treatment of diabetes and dyslipidemia. The preferred stereochemistry in this series for binding and functional agonist activity against both PPARa and PPAR? receptors was shown to be 3S,4S. Synthesis, in vitro and in vivo activities of compounds in this series are described. A high-yielding method for N-arylation of azetidinone esters is also described.

  14. Discovery of a novel series of potent S1P1 agonists.

    PubMed

    Crosignani, Stefano; Bombrun, Agnes; Covini, David; Maio, Maurizio; Marin, Delphine; Quattropani, Anna; Swinnen, Dominique; Simpson, Don; Sauer, Wolfgang; Franon, Bernard; Martin, Thierry; Cambet, Yves; Nichols, Anthony; Martinou, Isabelle; Burgat-Charvillon, Fabienne; Rivron, Delphine; Donini, Cristina; Schott, Olivier; Eligert, Valerie; Novo-Perez, Laurence; Vitte, Pierre-Alain; Arrighi, Jean-Franois

    2010-03-01

    The discovery of a novel series of S1P1 agonists is described. Starting from a micromolar HTS positive, iterative optimization gave rise to several single-digit nanomolar S1P1 agonists. The compounds were able to induce internalization of the S1P1 receptor, and a selected compound was shown to be able to induce lymphopenia in mice after oral dosing. PMID:20149651

  15. Wnt Agonist Attenuates Liver Injury and Improves Survival after Hepatic Ischemia/Reperfusion

    PubMed Central

    Kuncewitch, Michael; Yang, Weng-Lang; Molmenti, Ernesto; Nicastro, Jeffrey; Coppa, Gene F.; Wang, Ping

    2012-01-01

    The Wnt/β-catenin signaling pathway is well characterized in stem cell biology and plays a critical role in liver development, regeneration, and homeostasis. We hypothesized that pharmacological activation of Wnt signaling protects against hepatic ischemia/reperfusion (I/R) injury through its known proliferative and anti-apoptotic properties. Sprague-Dawley rats underwent 70% hepatic ischemia by microvascular clamping of the hilum of the left and median lobes of the liver for 90 min, followed by reperfusion. Wnt agonist (2-amino-4-[3,4-(methylenedioxy)benzylamino]-6-(3-methoxyphenyl)pyrimidine, 5 mg/kg BW) or vehicle (20% DMSO in saline) in 0.5 ml was injected intraperitoneally (i.p.) 1 h prior to ischemia or infused intravenously over 30 min right after ischemia. Blood and tissue samples from the pre-treated groups were collected 24 h after reperfusion, and a survival study was performed. Hepatic expression of β-catenin and its downstream target gene Axin2 were decreased after I/R while Wnt agonist restored their expression to sham levels. Wnt agonist blunted I/R-induced elevations of AST, ALT, and LDH and significantly improved the microarchitecture of the liver. The cell proliferation determined by Ki67 immunostaining significantly increased with Wnt agonist treatment and inflammatory cascades were dampened in Wnt agonist-treated animals, as demonstrated by attenuations in IL-6, myeloperoxdase, iNOS and nitrotyrosine. Wnt agonist also significantly decreased the amount of apoptosis, as evidenced by decreases in both TUNEL staining as well as caspase-3 activity levels. Finally, the 10-day survival rate was increased from 27% in the vehicle group to 73% in the pre-treated Wnt agonist group and 55% in the Wnt agonist post-ischemia treatment group. Thus, we propose that direct Wnt/β-catenin stimulation may represent a novel therapeutic approach in the treatment of hepatic I/R. PMID:23143067

  16. Do inhaled beta(2)-agonists have an ergogenic potential in non-asthmatic competitive athletes?

    PubMed

    Kindermann, Wilfried

    2007-01-01

    The prevalence of asthma is higher in elite athletes than in the general population. The risk of developing asthmatic symptoms is the highest in endurance athletes and swimmers. Asthma seems particularly widespread in winter-sport athletes such as cross-country skiers. Asthmatic athletes commonly use inhaled beta(2)-agonists to prevent and treat asthmatic symptoms. However, beta(2)-agonists are prohibited according to the Prohibited List of the World Anti-Doping Agency. An exception can be made only for the substances formoterol, salbutamol, salmeterol and terbutaline by inhalation, as long as a therapeutic use exemption has been applied for and granted. In this context, the question arises of whether beta(2)-agonists have ergogenic benefits justifying the prohibition of these substances. In 17 of 19 randomised placebo-controlled trials in non-asthmatic competitive athletes, performance-enhancing effects of the inhaled beta(2)-agonists formoterol, salbutamol, salmeterol and terbutaline could not be proved. This is particularly true for endurance performance, anaerobic power and strength performance. In three of four studies, even supratherapeutic doses of salbutamol (800-1200 microg) had no ergogenic effect. In contrast to inhaled beta(2)-agonists, oral administration of salbutamol seems to be able to improve the muscle strength and the endurance performance. There appears to be no justification to prohibit inhaled beta(2)-agonists from the point of view of the ergogenic effects. PMID:17241101

  17. GLP-1 receptor agonists or DPP-4 inhibitors: how to guide the clinician?

    PubMed

    Scheen, Andr J

    2013-12-01

    Pharmacological treatment of type 2 diabetes has been enriched during recent years, with the launch of incretin therapies targeting glucagon-like peptide-1 (GLP-1). Such medications comprise either GLP-1 receptor agonists, with short (one or two daily injections: exenatide, liraglutide, lixisenatide) or long duration (one injection once weekly: extended-released exenatide, albiglutide, dulaglutide, taspoglutide); or oral compounds inhibiting dipeptidyl peptidase-4 (DPP-4), the enzyme that inactives GLP-1, also called gliptins (sitagliptin, vildagliptin, saxagliptin, linagliptin, alogliptin). Although both pharmacological approaches target GLP-1, important differences exist concerning the mode of administration (subcutaneous injection versus oral ingestion), the efficacy (better with GLP-1 agonists), the effects on body weight and systolic blood pressure (diminution with agonists versus neutrality with gliptins), the tolerance profile (nausea and possibly vomiting with agonists) and the cost (higher with GLP-1 receptor agonists). Both agents may exert favourable cardiovascular effects. Gliptins may represent a valuable alternative to a sulfonylurea or a glitazone after failure of monotherapy with metformin while GLP-1 receptor agonists may be considered as a good alternative to insulin (especially in obese patients) after failure of a dual oral therapy. However, this scheme is probably too restrictive and modalities of using incretins are numerous, in almost all stages of type 2 diabetes. Physicians may guide the pharmacological choice based on clinical characteristics, therapeutic goals and patient's preference. PMID:23570814

  18. Proteasome involvement in agonist-induced down-regulation of mu and delta opioid receptors.

    PubMed

    Chaturvedi, K; Bandari, P; Chinen, N; Howells, R D

    2001-04-13

    This study investigated the mechanism of agonist-induced opioid receptor down-regulation. Incubation of HEK 293 cells expressing FLAG-tagged delta and mu receptors with agonists caused a time-dependent decrease in opioid receptor levels assayed by immunoblotting. Pulse-chase experiments using [(35)S]methionine metabolic labeling indicated that the turnover rate of delta receptors was accelerated 5-fold following agonist stimulation. Inactivation of functional G(i) and G(o) proteins by pertussis toxin-attenuated down-regulation of the mu opioid receptor, while down-regulation of the delta opioid receptor was unaffected. Pretreatment of cells with inhibitors of lysosomal proteases, calpain, and caspases had little effect on mu and delta opioid receptor down-regulation. In marked contrast, pretreatment with proteasome inhibitors attenuated agonist-induced mu and delta receptor down-regulation. In addition, incubation of cells with proteasome inhibitors in the absence of agonists increased steady-state mu and delta opioid receptor levels. Immunoprecipitation of mu and delta opioid receptors followed by immunoblotting with ubiquitin antibodies suggested that preincubation with proteasome inhibitors promoted accumulation of polyubiquitinated receptors. These data provide evidence that the ubiquitin/proteasome pathway plays a role in agonist-induced down-regulation and basal turnover of opioid receptors. PMID:11152677

  19. The good, the bad, and the ugly: agonistic behaviour in juvenile crocodilians.

    PubMed

    Brien, Matthew L; Lang, Jeffrey W; Webb, Grahame J; Stevenson, Colin; Christian, Keith A

    2013-01-01

    We examined agonistic behaviour in seven species of hatchling and juvenile crocodilians held in small groups (N?=?4) under similar laboratory conditions. Agonistic interactions occurred in all seven species, typically involved two individuals, were short in duration (5-15 seconds), and occurred between 1600-2200 h in open water. The nature and extent of agonistic interactions, the behaviours displayed, and the level of conspecific tolerance varied among species. Discrete postures, non-contact and contact movements are described. Three of these were species-specific: push downs by C. johnstoni; inflated tail sweeping by C. novaeguineae; and, side head striking combined with tail wagging by C. porosus. The two long-snouted species (C. johnstoni and G. gangeticus) avoided contact involving the head and often raised the head up out of the way during agonistic interactions. Several behaviours not associated with aggression are also described, including snout rubbing, raising the head up high while at rest, and the use of vocalizations. The two most aggressive species (C. porosus, C. novaeguineae) appeared to form dominance hierarchies, whereas the less aggressive species did not. Interspecific differences in agonistic behaviour may reflect evolutionary divergence associated with morphology, ecology, general life history and responses to interspecific conflict in areas where multiple species have co-existed. Understanding species-specific traits in agonistic behaviour and social tolerance has implications for the controlled raising of different species of hatchlings for conservation, management or production purposes. PMID:24349018

  20. Regulation of lateral mobility and cellular trafficking of the CCK receptor by a partial agonist.

    PubMed

    Roettger, B F; Pinon, D I; Burghardt, T P; Miller, L J

    1999-03-01

    Partial agonists are effective tools for advancing development of highly selective drugs and providing insights into molecular regulation of cellular functions. Here, we explore the impact of a partial agonist on key aspects of cholecystokinin (CCK) receptor regulation, its lateral mobility and cellular trafficking, in native pancreatic acinar cells and Chinese hamster ovary cells expressing CCK receptor (CHO-CCKR). We developed and characterized a novel fluorescent partial agonist, rhodamine-Gly-[(Nle28, 31)CCK-26-32]-phenethyl ester, that binds specifically and with high affinity to CCK receptors. Such analogs are fully efficacious pancreatic acinar cell secretagogues without supramaximal inhibition that mobilize intracellular calcium with little or no increase in phospholipase C (PLC) activity. Despite minimal phosphorylation of CCK receptors in response to this partial agonist, receptor trafficking was the same as that observed with full agonist (CCK). This included normal internalization via clathrin-dependent endocytosis in CHO-CCKR cells and insulation on the surface of pancreatic acinar cells. Also, as with CCK-occupied receptor, fluorescence recovery after photobleaching of partial agonist-occupied receptor on the acinar cell surface demonstrated a marked temperature-dependent slowing of its rate of diffusion. This was similarly associated with resistance to acid-induced dissociation of ligand. Thus some key molecular regulatory mechanisms for CCK receptor internalization and insulation may be initiated by cellular signaling cascades that are not dependent on PLC activation or receptor phosphorylation. PMID:10069980

  1. Targeted Delivery of LXR Agonist Using a Site-Specific Antibody-Drug Conjugate.

    PubMed

    Lim, Reyna K V; Yu, Shan; Cheng, Bo; Li, Sijia; Kim, Nam-Jung; Cao, Yu; Chi, Victor; Kim, Ji Young; Chatterjee, Arnab K; Schultz, Peter G; Tremblay, Matthew S; Kazane, Stephanie A

    2015-11-18

    Liver X receptor (LXR) agonists have been explored as potential treatments for atherosclerosis and other diseases based on their ability to induce reverse cholesterol transport and suppress inflammation. However, this therapeutic potential has been hindered by on-target adverse effects in the liver mediated by excessive lipogenesis. Herein, we report a novel site-specific antibody-drug conjugate (ADC) that selectively delivers a LXR agonist to monocytes/macrophages while sparing hepatocytes. The unnatural amino acid para-acetylphenylalanine (pAcF) was site-specifically incorporated into anti-CD11a IgG, which binds the ?-chain component of the lymphocyte function-associated antigen 1 (LFA-1) expressed on nearly all monocytes and macrophages. An aminooxy-modified LXR agonist was conjugated to anti-CD11a IgG through a stable, cathepsin B cleavable oxime linkage to afford a chemically defined ADC. The anti-CD11a IgG-LXR agonist ADC induced LXR activation specifically in human THP-1 monocyte/macrophage cells in vitro (EC50-27 nM), but had no significant effect in hepatocytes, indicating that payload delivery is CD11a-mediated. Moreover, the ADC exhibited higher-fold activation compared to a conventional synthetic LXR agonist T0901317 (Tularik) (3-fold). This novel ADC represents a fundamentally different strategy that uses tissue targeting to overcome the limitations of LXR agonists for potential use in treating atherosclerosis. PMID:25945727

  2. How neighborhood disorder increases blood pressure in youth: agonistic striving and subordination

    PubMed Central

    Elder, Gavin J.; Smyth, Joshua M.

    2012-01-01

    Growing evidence links perceptions of neighborhood disorder to adverse health outcomes but little is known about psychological processes that may mediate this association. We tested the hypothesis that two psychological mechanisms—agonistic striving and subordination—mediate the link between perceived neighborhood disorder and hypertension risk in youth. Perceived neighborhood disorder, agonistic striving, subordination experiences, negative affect, obesity, and ambulatory blood pressure during daily activities (48 h) were assessed in a multiethnic sample of 167 low- to middle-income urban adolescents. Path analyses revealed that agonistic striving, subordination, and obesity each independently mediated the association between neighborhood disorder and blood pressure; these variables accounted for 73 % of the shared variance, 42 % of which was explained by agonistic striving. The direct relationship between perceived neighborhood disorder and blood pressure was no longer significant in the presence of these mediators. Negative affect was associated with neighborhood disorder and subordination, but not blood pressure. Agonistic striving proved to be a significant and substantial mediator of the association between perceived neighborhood disorder, blood pressure, and future hypertension risk. New research should seek to clarify the processes by which stressful neighborhoods induce persistent agonistic motives and perceptions of subordination in adolescents. PMID:23229689

  3. Three-dimensional common-feature hypotheses for octopamine agonist 2-(arylimino)imidazolidines.

    PubMed

    Hirashima, Akinori; Morimoto, Masako; Kuwano, Eiichi; Taniguchi, Eiji; Eto, Morifusa

    2002-01-01

    Three-dimensional pharmacophore hypotheses were built from a set of 10 octopamine (OA) agonist 2-(Arylimino)imidazolidines (AIIs), 2-(Arylimino)thiazolidines (AITs) and 2-(Arylimino)oxazolidines (AIOs). Among the 10 common-featured models generated by program Catalyst/HipHop, a hypothesis including a ring aromatic (RA), a positive ionizable (PI) and three hydrophobic aliphatic (HpAl) features was considered to be important in evaluating the OA-agonist activity. Active OA agonist 2,6-Et2 AII mapped well onto all the RA, PI and HpAl features of the hypothesis. On the other hand, less active compounds were shown to be difficult to achieve the energetically favorable conformation which is found in the active molecules in order to fit the 3-D common-feature pharmacophore models. Taken together, 2,6-Et2-Ph and foramidine structures are important as OA agonists. The present studies on OA agonists demonstrate that a RA, a PI and three HpAl sites located on the molecule seem to be essential for OA-agonist activity. PMID:11738614

  4. In Vitro Effects of Beta-2 Agonists on Skeletal Muscle Differentiation, Hypertrophy, and Atrophy

    PubMed Central

    2012-01-01

    Background Beta-2 agonists are widely used in the treatment of asthma and chronic obstructive pulmonary disease for their effect on airway smooth muscle relaxation. They also act on skeletal muscle, although their reported ergogenic effect is controversial. Aim To evaluate the in vitro effects of short-acting and long-acting beta-2 agonists on adrenergic receptor (ADR) expression, hypertrophy, and atrophy markers, in a skeletal muscle cell line. Methods The C2C12 cell line was used as a model of skeletal muscle differentiation. ADR messenger RNA expression was evaluated in proliferating myoblasts, committed cells, and differentiated myotubes, in basal conditions and after treatment with 10-6 M clenbuterol, salbutamol, salmeterol, and formoterol. Effect of beta-2 agonists on gene and protein expression of hypertrophy and atrophy markers was assessed in differentiated myotubes. Results Our study shows that beta-2 ADR messenger RNA was expressed and progressively increased during cell differentiation. Beta-2 agonist treatment did not affect its expression. Skeletal muscle hypertrophy markers (fast and slow myosin, myogenin) were not modulated by any of the beta-2 agonists evaluated. However, clenbuterol induced a significant, dose-dependent downregulation of skeletal muscle atrophy genes (atrogin-1, MuRF-1, and cathepsin L). Conclusions The reported ergogenic effect of beta-2 agonists, if any, should be considered as drug-specific and not class-specific and that of clenbuterol is mediated by the inhibition of the atrophic pathway. PMID:23283108

  5. The actions of prolonged exposure to cholinergic agonists on isolated bladder strips from the rat.

    PubMed

    Gillespie, James I; Rouget, Celine; Palea, Stefano; Korstanje, Cees

    2015-07-01

    The present study was done to explore the cholinergic systems operating in the wall of the isolated rat bladder. In a first set of experiments, bladder strips in vitro were subjected to cumulative concentration-response curve (CRC) to non-selective muscarine agonist carbachol or the partially M2>M3 selective agonist arecaidine to establish optimal concentration to be used thereafter. In a second set of experiments, the effects of drugs (solifenacin, isoproterenol, and mirabegron) were tested on urinary bladder contraction induced by the non-selective muscarinergic agonist carbachol. For both agonists, the contractile responses are qualitatively similar: an initial transient rise in tension followed by complex bursts of high-frequency small 'micro'-contractions superposed on a tonic contraction, with immediate transient 'rebound' contraction after the agonist is washed from the preparation. This rebound contraction is greater with carbachol than arecaidine. Components of the responses to cholinergic stimulation, notably the micro-contractions, were found to be differently stimulated and inhibited by the M3>M2 selective antagonist solifenacin and by the β-adrenoceptor agonists isoprenaline and mirabegron. A physiological role for the muscarinic dependent phasic contractions and the micro-anatomical elements that might be involved are not known but may be related to non-voiding activity observed during filling cystometry in conscious animals related to afferent discharge and possibly sensation. Furthermore, suggestions for the potential impact of these findings and design of further studies in relation to bladder physiology, pharmacology, and pathology are discussed. PMID:25980359

  6. Substrate specificity of the agonist-stimulated release of polyunsaturated fatty acids from vascular endothelial cells

    SciTech Connect

    Rosenthal, M.D.; Garcia, M.C.; Sprecher, H. )

    1989-11-01

    Stimulation of vascular endothelial cells with agonists such as histamine and thrombin results in release of arachidonic acid from membrane lipids and subsequent eicosanoid synthesis. As shown previously, the agonist-stimulated deacylation is specific for arachidonate, eicosapentaenoate, and 5,8,11-eicosatrienoate. This study has utilized radiolabeled fatty acids differing in chain length and position of double bonds to further elucidate the fatty acyl specificity of agonist-stimulated deacylation. Replicate wells of confluent human umbilical vein endothelial cells were incubated with 14C-labeled fatty acids and then challenged with histamine, thrombin, or the calcium ionophore A23187. Comparison of the results obtained with isomeric eicosatetraenoic fatty acids with initial double bonds at carbons 4, 5, or 6 indicated that the deacylation induced by all three agonists exhibited marked specificity for the cis-5 double bond. Lack of stringent chain length specificity was indicated by agonist-stimulated release of 5,8,11,14- tetraenoic fatty acids with 18, 19, 20, and 21 carbons. Release of 5,8,14-(14C)eicosatrienoate was two-to threefold that of 5,11,14-(14C)eicosatrienoate, thus indicating that the cis-8 double bond may also contribute to the stringent recognition by the agonist-sensitive phospholipase. The present study has also demonstrated that histamine, thrombin, and A23187 do not stimulate release of docosahexaenoate from endothelial cells.

  7. The Good, the Bad, and the Ugly: Agonistic Behaviour in Juvenile Crocodilians

    PubMed Central

    Brien, Matthew L.; Lang, Jeffrey W.; Webb, Grahame J.; Stevenson, Colin; Christian, Keith A.

    2013-01-01

    We examined agonistic behaviour in seven species of hatchling and juvenile crocodilians held in small groups (N = 4) under similar laboratory conditions. Agonistic interactions occurred in all seven species, typically involved two individuals, were short in duration (5–15 seconds), and occurred between 1600–2200 h in open water. The nature and extent of agonistic interactions, the behaviours displayed, and the level of conspecific tolerance varied among species. Discrete postures, non-contact and contact movements are described. Three of these were species-specific: push downs by C. johnstoni; inflated tail sweeping by C. novaeguineae; and, side head striking combined with tail wagging by C. porosus. The two long-snouted species (C. johnstoni and G. gangeticus) avoided contact involving the head and often raised the head up out of the way during agonistic interactions. Several behaviours not associated with aggression are also described, including snout rubbing, raising the head up high while at rest, and the use of vocalizations. The two most aggressive species (C. porosus, C. novaeguineae) appeared to form dominance hierarchies, whereas the less aggressive species did not. Interspecific differences in agonistic behaviour may reflect evolutionary divergence associated with morphology, ecology, general life history and responses to interspecific conflict in areas where multiple species have co-existed. Understanding species-specific traits in agonistic behaviour and social tolerance has implications for the controlled raising of different species of hatchlings for conservation, management or production purposes. PMID:24349018

  8. Structural Requirements of N-Substituted Spiropiperidine Analogues as Agonists of Nociceptin/Orphanin FQ Receptor

    PubMed Central

    Bao, Pingping; Zhang, Xiaole; Ren, Hong; Li, Yan; Mu, Zulin; Zhang, Shuwei; Li, Guohui; Yang, Ling

    2011-01-01

    The nociceptin/orphanin FQ (NOP) receptor is involved in a wide range of biological functions, including pain, anxiety, depression and drug abuse. Especially, its agonists have great potential to be developed into anxiolytics. In this work, both the ligand- and receptor-based three-dimensional quantitative structureactivity relationship (3D-QSAR) studies were carried out using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques on 103 N-substituted spiropiperidine analogues as NOP agonists. The resultant optimal ligand-based CoMSIA model exhibited Q2 of 0.501, R2ncv of 0.912 and its predictive ability was validated by using an independent test set of 26 compounds which gave R2pred value of 0.818. In addition, docking analysis and molecular dynamics simulation (MD) were also applied to elucidate the probable binding modes of these agonists. Interpretation of the 3D contour maps, in the context of the topology of the active site of NOP, provided insight into the NOP-agonist interactions. The information obtained from this work can be used to accurately predict the binding affinity of related agonists and also facilitate the future rational design of novel agonists with improved activity. PMID:22272114

  9. Inhibitory effects of peroxisome proliferator-activated receptor ? agonists on collagen IV production in podocytes.

    PubMed

    Li, Yanjiao; Shen, Yachen; Li, Min; Su, Dongming; Xu, Weifeng; Liang, Xiubin; Li, Rongshan

    2015-07-01

    Peroxisome proliferator-activated receptor-? (PPAR-?) agonists have beneficial effects on the kidney diseases through preventing microalbuminuria and glomerulosclerosis. However, the mechanisms underlying these effects remain to be fully understood. In this study, we investigate the effects of PPAR-? agonist, rosiglitazone (Rosi) and pioglitazone (Pio), on collagen IV production in mouse podocytes. The endogenous expression of PPAR-? was found in the primary podocytes and can be upregulated by Rosi and Pio, respectively, detected by RT-PCR and Western blot. PPAR-? agonist markedly blunted the increasing of collagen IV expression and extraction in podocytes induced by TGF-?. In contrast, adding PPAR-? antagonist, GW9662, to podocytes largely prevented the inhibition of collagen IV expression from Pio treatment. Our data also showed that phosphorylation of Smad2/3 enhanced by TGF-? in a time-dependent manner was significantly attenuated by adding Pio. The promoter region of collagen IV gene contains one putative consensus sequence of Smad-binding element (SBE) by promoter analysis, Rosi and Pio significantly ameliorated TGF-?-induced SBE4-luciferase activity. In conclusion, PPAR-? activation by its agonist, Rosi or Pio, in vitro directly inhibits collagen IV expression and synthesis in primary mouse podocytes. The suppression of collagen IV production was related to the inhibition of TGF-?-driven phosphorylation of Smad2/3 and decreased response activity of SBEs of collagen IV in PPAR-? agonist-treated mouse podocytes. This represents a novel mechanistic support regarding PPAR-? agonists as podocyte protective agents. PMID:25920446

  10. Alpha/sub 1/ receptor coupling events initiated by methoxy-substituted tolazoline partial agonists

    SciTech Connect

    Wick, P.; Keung, A.; Deth, R.

    1986-03-01

    A series of mono- and dimethyoxy substituted tolazoline derivatives, known to be partial agonists at the alpha/sub 1/ receptor, were compared with the ..cap alpha../sub 1/ selective full agonist phenylephrine (PE) on isolated strips of rabbit aorta Agonist activity was evaluated in contraction, /sup 45/Ca influx, /sup 45/Ca efflux, and /sup 32/P-Phospholipid labelling studies. Maximum contractile responses for the 2-, 3-, and 3, 5- methoxy substituted tolazoline derivatives (10/sup -5/M) were 53.8, 67.6 and 99.7% of the PE (10/sup -5/M) response respectively. These same partial agonists caused a stimulation of /sup 45/Ca influx to the extent of 64, 86, and 95% of the PE response respectively. In /sup 45/Ca efflux studies, (a measure of the intracellular Ca/sup +2/ release) the tolazolines caused: 30%, 63%, and 78% of the PE stimulated level. /sup 32/P-Phosphatidic acid (PA) labelling was measured as an index of PI turnover after ..cap alpha../sub 1/ receptor stimulation. Compared to PE, the 2-, 3-, and 3,5- methoxy substituted tolazoline derivatives caused 22, 46, and 72% PA labelling. The above values are all in reasonable accord with the rank order or agonist activity shown in maximum contractile responses. The results of this investigation suggest that partial agonists stimulate ..cap alpha.. receptor coupling events at a level which is quantitatively comparable to their potencies in causing contraction of arterial smooth muscle.

  11. Predicting selective liver X receptor β agonists using multiple machine learning methods.

    PubMed

    Li, Yali; Wang, Ling; Liu, Zhihong; Li, Chanjuan; Xu, Jiake; Gu, Qiong; Xu, Jun

    2015-05-01

    Liver X receptor (LXR) α and β are cholesterol sensors; they respond to excess cholesterol and stimulate reverse cholesterol transport. Activating LXRs represents a promising therapeutic option for dyslipidemia. However, activating LXRα may cause unwanted lipogenicity. A better anti-dyslipidemia strategy would be to develop selective LXRβ agonists that do not activate LXRα. In this paper, a data set of 234 selective and non-selective LXRβ agonists was collected from the literature. For the first time, we derived the classification models from the data set to predict selective LXRβ agonists using multiple machine learning methods (naïve Bayesian (NB), Recursive Partitioning (RP), Support Vector Machine (SVM), and k-Nearest Neighbors (kNN) methods) with optimized property descriptors and structural fingerprints. The models were optimized from 324 multiple machine learning models, and most of the models showed high predictive abilities (overall predictive accuracies of >80%) for both training and test sets. The top 15 models were evaluated using an external test set of 76 compounds (all containing new scaffolds), and 10 of them displayed overall predictive accuracies exceeding 90%. The top models can be used for the virtual screening of selective LXRβ agonists. The NB models can identify privileged and unprivileged fragments for selective LXRβ agonists, and the fragments can be used to guide the design of new selective LXRβ agonists. PMID:25734698

  12. How neighborhood disorder increases blood pressure in youth: agonistic striving and subordination.

    PubMed

    Ewart, Craig K; Elder, Gavin J; Smyth, Joshua M

    2014-02-01

    Growing evidence links perceptions of neighborhood disorder to adverse health outcomes but little is known about psychological processes that may mediate this association. We tested the hypothesis that two psychological mechanisms-agonistic striving and subordination-mediate the link between perceived neighborhood disorder and hypertension risk in youth. Perceived neighborhood disorder, agonistic striving, subordination experiences, negative affect, obesity, and ambulatory blood pressure during daily activities (48h) were assessed in a multiethnic sample of 167 low- to middle-income urban adolescents. Path analyses revealed that agonistic striving, subordination, and obesity each independently mediated the association between neighborhood disorder and blood pressure; these variables accounted for 73% of the shared variance, 42% of which was explained by agonistic striving. The direct relationship between perceived neighborhood disorder and blood pressure was no longer significant in the presence of these mediators. Negative affect was associated with neighborhood disorder and subordination, but not blood pressure. Agonistic striving proved to be a significant and substantial mediator of the association between perceived neighborhood disorder, blood pressure, and future hypertension risk. New research should seek to clarify the processes by which stressful neighborhoods induce persistent agonistic motives and perceptions of subordination in adolescents. PMID:23229689

  13. Influence de la dpendance en temprature des proprits optiques des matriaux sur la force de Casimir

    NASA Astrophysics Data System (ADS)

    Joulain, K.; Henkel, C.; Greffet, J.-J.

    2006-10-01

    Nous valuons la force de Casimir entre deux surfaces planes mtalliques constitues d'argent. Nous prenons, pour effectuer cette valuation, des proprits optiques de l'argent diffrentes tempratures [1]. Nous montrons que cette dpendance en temprature modifie la force de Casimir (de 0.2%) y compris des distances infrieures la longueur d'onde thermique.

  14. Induction of Selective Blood-Tumor Barrier Permeability and Macromolecular Transport by a Biostable Kinin B1 Receptor Agonist in a Glioma Rat Model

    PubMed Central

    Côté, Jérôme; Bovenzi, Veronica; Savard, Martin; Dubuc, Céléna; Fortier, Audrey; Neugebauer, Witold; Tremblay, Luc; Müller-Esterl, Werner; Tsanaclis, Ana-Maria; Lepage, Martin; Fortin, David; Gobeil, Fernand

    2012-01-01

    Treatment of malignant glioma with chemotherapy is limited mostly because of delivery impediment related to the blood-brain tumor barrier (BTB). B1 receptors (B1R), inducible prototypical G-protein coupled receptors (GPCR) can regulate permeability of vessels including possibly that of brain tumors. Here, we determine the extent of BTB permeability induced by the natural and synthetic peptide B1R agonists, LysdesArg9BK (LDBK) and SarLys[dPhe8]desArg9BK (NG29), in syngeneic F98 glioma-implanted Fischer rats. Ten days after tumor inoculation, we detected the presence of B1R on tumor cells and associated vasculature. NG29 infusion increased brain distribution volume and uptake profiles of paramagnetic probes (Magnevist and Gadomer) at tumoral sites (T1-weighted imaging). These effects were blocked by B1R antagonist and non-selective cyclooxygenase inhibitors, but not by B2R antagonist and non-selective nitric oxide synthase inhibitors. Consistent with MRI data, systemic co-administration of NG29 improved brain tumor delivery of Carboplatin chemotherapy (ICP-Mass spectrometry). We also detected elevated B1R expression in clinical samples of high-grade glioma. Our results documented a novel GPCR-signaling mechanism for promoting transient BTB disruption, involving activation of B1R and ensuing production of COX metabolites. They also underlined the potential value of synthetic biostable B1R agonists as selective BTB modulators for local delivery of different sized-therapeutics at (peri)tumoral sites. PMID:22629405

  15. Evolution structurale et nature des liaisons de quelques composs polyanioniques des systmes IIB-V-VII

    NASA Astrophysics Data System (ADS)

    Rebbah, H.; Rebbah, A.

    1994-11-01

    The structural data for known cadmium and mercury polyanionic compounds are reported and classified with respect to the coordination of these atoms with elements of group V. These data are discussed according to the particular characteristics of elements IIB as well as the size of associated halogens. The character of IIB-V, V-V, and IIB-VII bonds in these compounds is also analyzed. Les donnes structurales des composs polyanioniques connus du cadmium et du mercure sont rassembles d'aprs les motifs de coordination prsents par ces atomes vis vis des lments V. Ces donnes sont discutes en fonction des caractristiques propres des lments IIB ainsi qu'en fonction de la dimension de l'halogne associ. Le caractre des liaisons IIB-V, V-V, et IIB-VII prsentes dans ces composs est galement analys.

  16. Metabolic mapping of A3 adenosine receptor agonist MRS5980.

    PubMed

    Fang, Zhong-Ze; Tosh, Dilip K; Tanaka, Naoki; Wang, Haina; Krausz, Kristopher W; O'Connor, Robert; Jacobson, Kenneth A; Gonzalez, Frank J

    2015-09-15

    (1S,2R,3S,4R,5S)-4-(2-((5-Chlorothiophen-2-yl)ethynyl)-6-(methylamino)-9H-purin-9-yl)-2,3-dihydroxy-N-methylbicyclo[3.1.0]hexane-1-carboxamide (MRS5980) is an A3AR selective agonist containing multiple receptor affinity- and selectivity-enhancing modifications and a therapeutic candidate drug for many inflammatory diseases. Metabolism-related poor pharmacokinetic behavior and toxicities are a major reason for drug R&D failure. Metabolomics with UPLC-MS was employed to profile the metabolism of MRS5980 and MRS5980-induced disruption of endogenous compounds. Recombinant drug-metabolizing enzymes screening experiment were used to determine the enzymes involved in MRS5980 metabolism. Analysis of lipid metabolism-related genes was performed to investigate the reason for MRS5980-induced lipid metabolic disorders. Unsupervised principal components analysis separated the control and MRS5980 treatment groups in feces, urine, and liver samples, but not in bile and serum. The major ions mainly contributing to the separation of feces and urine were oxidized MRS5980, glutathione (GSH) conjugates and cysteine conjugate (degradation product of the GSH conjugates) of MRS5980. The major ions contributing to the group separation of liver samples were phosphatidylcholines. In vitro incubation experiments showed the involvement of CYP3A enzymes in the oxidative metabolism of MRS5980 and direct GSH reactivity of MRS5980. The electrophilic attack by MRS5980 is a minor pathway and did not alter GSH levels in liver or liver histology, and thus may be of minor clinical consequence. Gene expression analysis further showed decreased expression of PC biosynthetic genes choline kinase a and b, which further accelerated conversion of lysophosphatidylcholine to phosphatidylcholines through increasing the expression of lysophosphatidylcholine acyltransferase 3. These data will be useful to guide rational design of drugs targeting A3AR, considering efficacy, metabolic elimination, and electrophilic reactivity. PMID:26212548

  17. Agonistic TAM-163 antibody targeting tyrosine kinase receptor-B

    PubMed Central

    Vugmeyster, Yulia; Rohde, Cynthia; Perreault, Mylene; Gimeno, Ruth E.; Singh, Pratap

    2013-01-01

    TAM-163, an agonist monoclonal antibody targeting tyrosine receptor kinase-B (TrkB), is currently being investigated as a potential body weight modulatory agent in humans. To support the selection of the dose range for the first-in-human (FIH) trial of TAM-163, we conducted a mechanistic analysis of the pharmacokinetic (PK) and pharmacodynamic (PD) data (e.g., body weight gain) obtained in lean cynomolgus and obese rhesus monkeys following single doses ranging from 0.3 to 60 mg/kg. A target-mediated drug disposition (TMDD) model was used to describe the observed nonlinear PK and Emax approach was used to describe the observed dose-dependent PD effect. The TMDD model development was supported by the experimental determination of the binding affinity constant (9.4 nM) and internalization rate of the drug-target complex (2.08 h?1). These mechanistic analyses enabled linking of exposure, target (TrkB) coverage, and pharmacological activity (e.g., PD) in monkeys, and indicated that ? 38% target coverage (time-average) was required to achieve significant body weight gain in monkeys. Based on the scaling of the TMDD model from monkeys to humans and assuming similar relationship between the target coverage and pharmacological activity between monkey and humans, subcutaneous (SC) doses of 1 and 15 mg/kg in humans were projected to be the minimally and the fully pharmacologically active doses, respectively. Based on the minimal anticipated biological effect level (MABEL) approach for starting dose selection, the dose of 0.05 mg/kg (3 mg for a 60 kg human) SC was recommended as the starting dose for FIH trials, because at this dose level < 10% target coverage was projected at Cmax (and all other time points). This study illustrates a rational mechanistic approach for the selection of FIH dose range for a therapeutic protein with a complex model of action. PMID:23529133

  18. GABAA agonist reduces visual awareness: a masking-EEG experiment.

    PubMed

    van Loon, Anouk M; Scholte, H Steven; van Gaal, Simon; van der Hoort, Björn J J; Lamme, Victor A F

    2012-04-01

    Consciousness can be manipulated in many ways. Here, we seek to understand whether two such ways, visual masking and pharmacological intervention, share a common pathway in manipulating visual consciousness. We recorded EEG from human participants who performed a backward-masking task in which they had to detect a masked figure form its background (masking strength was varied across trials). In a within-subject design, participants received dextromethorphan (a N-methyl-d-aspartate receptor antagonist), lorazepam (LZP; a GABA(A) receptor agonist), scopolamine (a muscarine receptor antagonist), or placebo. The behavioral results show that detection rate decreased with increasing masking strength and that of all the drugs, only LZP induced a further decrease in detection rate. Figure-related ERP signals showed three neural events of interest: (1) an early posterior occipital and temporal generator (94-121 msec) that was not influenced by any pharmacological manipulation nor by masking, (2) a later bilateral perioccipital generator (156-211 msec) that was reduced by masking as well as LZP (but not by any other drugs), and (3) a late bilateral occipital temporal generator (293-387 msec) that was mainly affected by masking. Crucially, only the intermediate neural event correlated with detection performance. In combination with previous findings, these results suggest that LZP and masking both reduce visual awareness by means of modulating late activity in the visual cortex but leave early activation intact. These findings provide the first evidence for a common mechanism for these two distinct ways of manipulating consciousness. PMID:22264199

  19. Farnesyl pyrophosphate regulates adipocyte functions as an endogenous PPAR? agonist

    PubMed Central

    Goto, Tsuyoshi; Nagai, Hiroyuki; Egawa, Kahori; Kim, Young-Il; Kato, Sota; Taimatsu, Aki; Sakamoto, Tomoya; Ebisu, Shogo; Hohsaka, Takahiro; Miyagawa, Hiroh; Murakami, Shigeru; Takahashi, Nobuyuki; Kawada, Teruo

    2011-01-01

    The cholesterol biosynthetic pathway produces not only sterols but also non-sterol mevalonate metabolites involved in isoprenoid synthesis. Mevalonate metabolites affect transcriptional and post-transcriptional events that in turn affect various biological processes including energy metabolism. In the present study, we examine whether mevalonate metabolites activate PPAR? (peroxisome-proliferator-activated receptor ?), a ligand-dependent transcription factor playing a central role in adipocyte differentiation. In the luciferase reporter assay using both GAL4 chimaera and full-length PPAR? systems, a mevalonate metabolite, FPP (farnesyl pyrophosphate), which is the precursor of almost all isoprenoids and is positioned at branch points leading to the synthesis of other longer-chain isoprenoids, activated PPAR? in a dose-dependent manner. FPP induced the in vitro binding of a co-activator, SRC-1 (steroid receptor co-activator-1), to GST (glutathione transferase)PPAR?. Direct binding of FPP to PPAR? was also indicated by docking simulation studies. Moreover, the addition of FPP up-regulated the mRNA expression levels of PPAR? target genes during adipocyte differentiation induction. In the presence of lovastatin, an HMG-CoA (3-hydroxy-3-methylglutaryl-CoA) reductase inhibitor, both intracellular FPP levels and PPAR?-target gene expressions were decreased. In contrast, the increase in intracellular FPP level after the addition of zaragozic acid, a squalene synthase inhibitor, induced PPAR?-target gene expression. The addition of FPP and zaragozic acid promotes lipid accumulation during adipocyte differentiation. These findings indicated that FPP might function as an endogenous PPAR? agonist and regulate gene expression in adipocytes. PMID:21605082

  20. Agonist-induced Ca2+ Sensitization in Smooth Muscle

    PubMed Central

    Artamonov, Mykhaylo V.; Momotani, Ko; Stevenson, Andra; Trentham, David R.; Derewenda, Urszula; Derewenda, Zygmunt S.; Read, Paul W.; Gutkind, J. Silvio; Somlyo, Avril V.

    2013-01-01

    Many agonists, acting through G-protein-coupled receptors and G? subunits of the heterotrimeric G-proteins, induce contraction of smooth muscle through an increase of [Ca2+]i as well as activation of the RhoA/RhoA-activated kinase pathway that amplifies the contractile force, a phenomenon known as Ca2+ sensitization. G?12/13 subunits are known to activate the regulator of G-protein signaling-like family of guanine nucleotide exchange factors (RhoGEFs), which includes PDZ-RhoGEF (PRG) and leukemia-associated RhoGEF (LARG). However, their contributions to Ca2+-sensitized force are not well understood. Using permeabilized blood vessels from PRG(?/?) mice and a new method to silence LARG in organ-cultured blood vessels, we show that both RhoGEFs are activated by the physiologically and pathophysiologically important thromboxane A2 and endothelin-1 receptors. The co-activation is the result of direct and independent activation of both RhoGEFs as well as their co-recruitment due to heterodimerization. The isolated recombinant C-terminal domain of PRG, which is responsible for heterodimerization with LARG, strongly inhibited Ca2+-sensitized force. We used photolysis of caged phenylephrine, caged guanosine 5?-O-(thiotriphosphate) (GTP?S) in solution, and caged GTP?S or caged GTP loaded on the RhoARhoGDI complex to show that the recruitment and activation of RhoGEFs is the cause of a significant time lag between the initial Ca2+ transient and phasic force components and the onset of Ca2+-sensitized force. PMID:24106280

  1. Prendre le virage des partenariats.

    PubMed

    Sebestyen, Norma; Sulatycky, Ron; Rondos, Spyro; Davis, Sheila

    2015-11-01

    Deux projets démontrent que la mise en œuvre de données colligées sur le terrain peut contribuer à régler des problèmes dans le milieu de la santé pour favoriser de meilleurs résultats et de plus grandes efficiences. Dans le premier exemple, une vaste coalition de partenaires publics et privés de l'Alberta recourt aux techniques de mesures améliorées et à la méthodologie du Triple objectif pour améliorer les résultats cliniques de populations de cas complexes et lourds du quartier Eastwood d'Edmonton. On espère que les conclusions novatrices qui en sont tirées seront adaptées à d'autres régions de la province. Dans le deuxième exemple, la Childhood Obesity Foundation s'associe à Merck au Canada et à Ayogo (une société de thérapies numériques située à Vancouver) et utilise le concept novateur de la « ludification » pour mobiliser les jeunes de plus en plus sédentaires du Canada et modifier leurs comportements. PMID:26482219

  2. Systemtherapie des metastasierten malignen Melanoms.

    PubMed

    Rauschenberg, Ricarda; Garzarolli, Marlene; Dietrich, Ursula; Beissert, Stefan; Meier, Friedegund

    2015-12-01

    Fr Patienten mit metastasiertem Melanom stehen aktuell mehrere wirksame Therapieoptionen zur Verfgung. Die BRAF-Inhibitoren Vemurafenib und Dabrafenib zeichnen sich durch eine rasche Tumorkontrolle und hohe Ansprechraten aus. In Kombination mit den MEK-Inhibitoren Trametinib bzw. Cobimetinib erreichen sie Ansprechraten (CR + PR, komplette plus partielle Remissionen) von 70%, wobei die Entwicklung einer Therapieresistenz verzgert wird, sowie ein medianes Gesamtberleben von >2 Jahren bei tolerablen Nebenwirkungen. Der CTLA-4-Antikrper Ipilimumab erzielte fr Patienten mit metastasiertem Melanom als erste Substanz eine signifikante Verlngerung des Gesamtberlebens (Langzeitberlebensrate: 20-26%). Verzgertes Therapieansprechen und schwere immunvermittelte Nebenwirkungen knnen den therapeutischen Benefit einschrnken. Die Monotherapie mit den PD-1-Antikrpern Nivolumab oder Pembrolizumab erreicht Ansprechraten (CR + PR) bis zu 45% und 1-Jahres-berlebensraten von >70% bei meist guter Vertrglichkeit. Die Kombination Ipilimumab plus Nivolumab zeigte Ansprechraten bis zu 58% und ein medianes progressionsfreies berleben von >11 Monaten. Von dieser Kombination wird ein zeitnahes und lang anhaltendes Ansprechen erwartet. Dieser potenzielle Benefit wird durch eine hohe Toxizitt erkauft. Aktuell werden in klinischen Studien Strategien fr Therapiesequenz und -kombinationen geprft. Insgesamt hat sich die Prognose fr Patienten mit metastasiertem Melanom signifikant verbessert. In Anbetracht eines mglichen Langzeitberlebens mssen neben akuten Nebenwirkungen auch die Langzeit-Nebenwirkungen einer Behandlung bercksichtigt werden. PMID:26612790

  3. Le contrle des infections au cabinet du pdiatre

    PubMed Central

    2008-01-01

    RSUM La transmission des infections au cabinet du pdiatre est de plus en plus proccupante. Le prsent document expose les voies de transmission des infections et les principes sous-jacents aux mesures actuelles pour contrler les infections. Pour prvenir les infections, il faut bien concevoir le cabinet et adopter des politiques administratives et de triage convenables, de mme que des pratiques de base pour les soins de tous les patients (p. ex., hygine des mains, port de gants, de masques, de lunettes de protection et dune blouse dhpital pour des interventions prcises; nettoyage, dsinfection et strilisation convenables des surfaces et du matriel, y compris les jouets, et techniques dasepsie en cas dinterventions effractives) et des prcautions additionnelles en cas dinfections prcises. Le personnel doit avoir reu les vaccins pertinents, et les personnes infectes doivent respecter les politiques de restriction au travail.

  4. Dopamine agonists, anti-progestins, anti-androgens, long-term-release GnRH agonists and anti-estrogens in canine reproduction: a review.

    PubMed

    Gobello, C

    2006-10-01

    Over the last 10 years, new drugs have been applied to canine reproduction, widening the spectrum of therapeutic possibilities for diseases that were previously surgically treated, and facilitating better control of the estrous cycle and fertility. Some are not approved for use in dogs; their use is experimental and further clinical trials are necessary. Dopamine agonists such as cabergoline, bromocriptine or metergoline are ergoderivative alkaloids that exert an anti-prolactinergic effect via stimulation of D2 pituitary receptors or inhibition of central serotoninergic ones. Their main indication is suppression of lactation. Anti-prolactinergic compounds have also been successfully used for pregnancy termination and shortening of interestrous intervals. Anti-progestins, (e.g. mifepristone and aglepristone) are synthetic steroids that bind with high affinity to progesterone (P4) receptors, preventing P4 from exerting its biological effects. Anti-progestins have been indicated in P4-dependent conditions, such as pregnancy termination, induction of parturition and the medical treatment of pyometra. Several groups of drugs have been described to have anti-androgenic properties through different mechanisms of action: progestins, receptor binding anti-androgens (e.g. flutamide), competitive enzyme inhibitors (e.g. finasteride), aromatase inhibitors, and GnRH agonists. Their main application is medical treatment of benign prostatic hyperplasia. Long-term release formulations of GnRH agonists (e.g. leuprolide or deslorelin acetate) postponed puberty and reversibly suppressed reproductive function in male and female dogs for periods exceeding 1 year. Anti-estrogens (e.g. clomiphene and tamoxifen citrate) are synthetic non-steroidal type I anti-estrogenic compounds that competitively block estrogen receptors with a combined antagonist-agonistic effect. In dogs, their action is more agonistic than antagonistic. PMID:16542717

  5. Specific Activation of Estrogen Receptor Alpha and Beta Enhances Male Sexual Behavior and Neuroplasticity in Male Japanese Quail

    PubMed Central

    Seredynski, Aurore L.; Ball, Gregory F.; Balthazart, Jacques; Charlier, Thierry D.

    2011-01-01

    Two subtypes of estrogen receptors (ER), ERα and ERβ, have been identified in humans and numerous vertebrates, including the Japanese quail. We investigated in this species the specific role(s) of each receptor in the activation of male sexual behavior and the underlying estrogen-dependent neural plasticity. Castrated male Japanese quail received empty (CX) or testosterone-filled (T) implants or were daily injected with the ER general agonist diethylstilbestrol (DES), the ERα-specific agonist PPT, the ERβ-specific agonist DPN or the vehicle, propylene glycol. Three days after receiving the first treatment, subjects were alternatively tested for appetitive (rhythmic cloacal sphincter movements, RCSM) and consummatory aspects (copulatory behavior) of male sexual behavior. 24 hours after the last behavioral testing, brains were collected and analyzed for aromatase expression and vasotocinergic innervation in the medial preoptic nucleus. The expression of RCSM was activated by T and to a lesser extent by DES and PPT but not by the ERβagonist DPN. In parallel, T fully restored the complete sequence of copulation, DES was partially active and the specific activation of ERα or ERβ only resulted in a very low frequency of mount attempts in few subjects. T increased the volume of the medial preoptic nucleus as measured by the dense cluster of aromatase-immunoreactive cells and the density of the vasotocinergic innervation within this nucleus. DES had only a weak action on vasotocinergic fibers and the two specific ER agonists did not affect these neural responses. Simultaneous activation of both receptors or treatments with higher doses may be required to fully activate sexual behavior and the associated neurochemical events. PMID:21533185

  6. β2-Adrenoceptor agonists as novel, safe and potentially effective therapies for Amyotrophic lateral sclerosis (ALS).

    PubMed

    Bartus, Raymond T; Bétourné, Alexandre; Basile, Anthony; Peterson, Bethany L; Glass, Jonathan; Boulis, Nicholas M

    2016-01-01

    Amyotrophic lateral sclerosis (ALS) is a chronic and progressive neuromuscular disease for which no cure exists and better treatment options are desperately needed. We hypothesize that currently approved β2-adrenoceptor agonists may effectively treat the symptoms and possibly slow the progression of ALS. Although β2-agonists are primarily used to treat asthma, pharmacologic data from animal models of neuromuscular diseases suggest that these agents may have pharmacologic effects of benefit in treating ALS. These include inhibiting protein degradation, stimulating protein synthesis, inducing neurotrophic factor synthesis and release, positively modulating microglial and systemic immune function, maintaining the structural and functional integrity of motor endplates, and improving energy metabolism. Moreover, stimulation of β2-adrenoceptors can activate a range of downstream signaling events in many different cell types that could account for the diverse array of effects of these agents. The evidence supporting the possible therapeutic benefits of β2-agonists is briefly reviewed, followed by a more detailed review of clinical trials testing the efficacy of β-agonists in a variety of human neuromuscular maladies. The weight of evidence of the potential benefits from treating these diseases supports the hypothesis that β2-agonists may be efficacious in ALS. Finally, ways to monitor and manage the side effects that may arise with chronic administration of β2-agonists are evaluated. In sum, effective, safe and orally-active β2-agonists may provide a novel and convenient means to reduce the symptoms of ALS and possibly delay disease progression, affording a unique opportunity to repurpose these approved drugs for treating ALS, and rapidly transforming the management of this serious, unmet medical need. PMID:26459114

  7. Retinoid X receptor agonists impair arterial mononuclear cell recruitment through peroxisome proliferator-activated receptor-? activation.

    PubMed

    Sanz, Maria-Jesus; Albertos, Fernando; Otero, Eduardo; Juez, Marina; Morcillo, Esteban J; Piqueras, Laura

    2012-07-01

    Mononuclear cell migration into the vascular subendothelium constitutes an early event of the atherogenic process. Because the effect of retinoid X receptor (RXR)? on arterial mononuclear leukocyte recruitment is poorly understood, this study investigated whether RXR agonists can affect this response and the underlying mechanisms involved. Decreased RXR? expression was detected after 4 h stimulation of human umbilical arterial endothelial cells with TNF-?. Interestingly, under physiological flow conditions, TNF-?-induced endothelial adhesion of human mononuclear cells was concentration-dependently inhibited by preincubation of the human umbilical arterial endothelial cells with RXR agonists such as bexarotene or 9-cis-retinoid acid. RXR agonists also prevented TNF-?-induced VCAM-1 and ICAM-1 expression, as well as endothelial growth-related oncogene-? and MCP-1 release. Suppression of RXR? expression with a small interfering RNA abrogated these responses. Furthermore, inhibition of MAPKs and NF-?B pathways were involved in these events. RXR agonist-induced antileukocyte adhesive effects seemed to be mediated via RXR?/peroxisome proliferator-activated receptor (PPAR)? interaction, since endothelial PPAR? silencing abolished their inhibitory responses. Furthermore, RXR agonists increased RXR/PPAR? interaction, and combinations of suboptimal concentrations of both nuclear receptor ligands inhibited TNF-?-induced mononuclear leukocyte arrest by 60-65%. In vivo, bexarotene dose-dependently inhibited TNF-?-induced leukocyte adhesion to the murine cremasteric arterioles and decreased VCAM-1 and ICAM-1 expression. Therefore, these results reveal that RXR agonists can inhibit the initial inflammatory response that precedes the atherogenic process by targeting different steps of the mononuclear recruitment cascade. Thus, RXR agonists may constitute a new therapeutic tool in the control of the inflammatory process associated with cardiovascular disease. PMID:22661092

  8. PPAR agonists regulate brain gene expression: Relationship to their effects on ethanol consumption

    PubMed Central

    Ferguson, Laura B.; Most, Dana; Blednov, Yuri A.; Harris, R. Adron

    2014-01-01

    Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that act as ligand-activated transcription factors. Although prescribed for dyslipidemia and type-II diabetes, PPAR agonists also possess anti-addictive characteristics. PPAR agonists decrease ethanol consumption and reduce withdrawal severity and susceptibility to stress-induced relapse in rodents. However, the cellular and molecular mechanisms facilitating these properties have yet to be investigated. We tested three PPAR agonists in a continuous access two-bottle choice (2BC) drinking paradigm and found that tesaglitazar (PPARα/γ; 1.5 mg/kg) and fenofibrate (PPARα; 150 mg/kg) decreased ethanol consumption in male C57BL/6J mice while bezafibrate (PPARα/γ/β; 75 mg/kg) did not. We hypothesized that changes in brain gene expression following fenofibrate and tesaglitazar treatment lead to reduced ethanol drinking. We studied unbiased genomic profiles in areas of the brain known to be important for ethanol dependence, the prefrontal cortex (PFC) and amygdala, and also profiled gene expression in liver. Genomic profiles from the non-effective bezafibrate treatment were used to filter out genes not associated with ethanol consumption. Because PPAR agonists are anti-inflammatory, they would be expected to target microglia and astrocytes. Surprisingly, PPAR agonists produced a strong neuronal signature in mouse brain, and fenofibrate and tesaglitazar (but not bezafibrate) targeted a subset of GABAergic interneurons in the amygdala. Weighted gene co-expression network analysis (WGCNA) revealed co-expression of treatment-significant genes. Functional annotation of these gene networks suggested that PPAR agonists might act via neuropeptide and dopaminergic signaling pathways in the amygdala. Our results reveal gene targets through which PPAR agonists can affect alcohol consumption behavior. PMID:25036611

  9. Antimitogenic effect of bitter taste receptor agonists on airway smooth muscle cells.

    PubMed

    Sharma, Pawan; Panebra, Alfredo; Pera, Tonio; Tiegs, Brian C; Hershfeld, Alena; Kenyon, Lawrence C; Deshpande, Deepak A

    2016-02-15

    Airway remodeling is a hallmark feature of asthma and chronic obstructive pulmonary disease. Clinical studies and animal models have demonstrated increased airway smooth muscle (ASM) mass, and ASM thickness is correlated with severity of the disease. Current medications control inflammation and reverse airway obstruction effectively but have limited effect on remodeling. Recently we identified the expression of bitter taste receptors (TAS2R) on ASM cells, and activation with known TAS2R agonists resulted in ASM relaxation and bronchodilation. These studies suggest that TAS2R can be used as new therapeutic targets in the treatment of obstructive lung diseases. To further establish their effectiveness, in this study we aimed to determine the effects of TAS2R agonists on ASM growth and promitogenic signaling. Pretreatment of healthy and asthmatic human ASM cells with TAS2R agonists resulted in a dose-dependent inhibition of ASM proliferation. The antimitogenic effect of TAS2R ligands was not dependent on activation of protein kinase A, protein kinase C, or high/intermediate-conductance calcium-activated K(+) channels. Immunoblot analyses revealed that TAS2R agonists inhibit growth factor-activated protein kinase B phosphorylation without affecting the availability of phosphatidylinositol 3,4,5-trisphosphate, suggesting TAS2R agonists block signaling downstream of phosphatidylinositol 3-kinase. Furthermore, the antimitogenic effect of TAS2R agonists involved inhibition of induced transcription factors (activator protein-1, signal transducer and activator of transcription-3, E2 factor, nuclear factor of activated T cells) and inhibition of expression of multiple cell cycle regulatory genes, suggesting a direct inhibition of cell cycle progression. Collectively, these findings establish the antimitogenic effect of TAS2R agonists and identify a novel class of receptors and signaling pathways that can be targeted to reduce or prevent airway remodeling as well as bronchoconstriction in obstructive airway disease. PMID:26684251

  10. Agonistic onset during development differentiates wild house mouse males (Mus domesticus)

    NASA Astrophysics Data System (ADS)

    Krackow, Sven

    2005-02-01

    Wild house mouse populations have been suggested to locally adapt to varying dispersal regimes by expressing divergent aggressivity phenotypes. This conjecture implies, first, genetic polymorphism for dispersive strategies which is supported by the finding of heritable variation for male dispersal tendency in feral house mice. Secondly, aggressivity is assumed to translate into dispersal rates. This speculation is reinforced by experimental evidence showing that non-agonistic males display lower dispersal propensity than same-aged males that have established agonistic dominance. However, the actual ontogenetic behavioural pattern and its variability among populations remain unknown. Hence, in this study the timing of agonistic onset is quantified within laboratory-reared fraternal pairs, and compared between descendants from two different feral populations. Males from the two populations (G and Z) differed strongly in agonistic development, as Z fraternal pairs had a 50% risk of agonistic onset before 23.5±2.7 days of age, while this took 57.3±5.4 days in males from population G. This difference coincided with significant genetic differentiation between the males of the two populations as determined by 11 polymorphic microsatellite markers. Furthermore, in population G, males from agonistic and amicable fraternal pairs exhibited significant genetic differentiation. These results corroborate the supposition of genetic variability for dispersive strategies in house mice, and identify the ontogenetic timing of agonistic phenotype development as the potential basis for genetic differentiation. This opens a unique opportunity to study the genetic determination of a complex mammalian behavioural syndrome in a life history context, using a simple laboratory paradigm.

  11. Glucagon-like peptide-1 receptor agonists suppress water intake independent of effects on food intake

    PubMed Central

    McKay, Naomi J.; Kanoski, Scott E.; Hayes, Matthew R.

    2011-01-01

    Glucagon-like peptide-1 (GLP-1) is produced by and released from the small intestine following ingestion of nutrients. GLP-1 receptor (GLP-1R) agonists applied peripherally or centrally decrease food intake and increase glucose-stimulated insulin secretion. These effects make the GLP-1 system an attractive target for the treatment of type 2 diabetes mellitus and obesity. In addition to these more frequently studied effects of GLP-1R stimulation, previous reports indicate that GLP-1R agonists suppress water intake. The present experiments were designed to provide greater temporal resolution and site specificity for the effect of GLP-1 and the long-acting GLP-1R agonists, exendin-4 and liraglutide, on unstimulated water intake when food was and was not available. All three GLP-1R ligands suppressed water intake after peripheral intraperitoneal administration, both in the presence of and the absence of food; however, the magnitude and time frame of water intake suppression varied by drug. GLP-1 had an immediate, but transient, hypodipsic effect when administered peripherally, whereas the water intake suppression by IP exendin-4 and liraglutide was much more persistent. Additionally, intracerebroventricular administration of GLP-1R agonists suppressed water intake when food was absent, but the suppression of intake showed modest differences depending on whether the drug was administered to the lateral or fourth ventricle. To the best of our knowledge, this is the first demonstration of GLP-1 receptor agonists affecting unstimulated, overnight intake in the absence of food, the first test for antidipsogenic effects of hindbrain application of GLP-1 receptor agonists, and the first test of a central effect (forebrain or hindbrain) of liraglutide on water intake. Overall, these results show that GLP-1R agonists have a hypodipsic effect that is independent of GLP-1R-mediated effects on food intake, and this occurs, in part, through central nervous system GLP-1R activation. PMID:21975647

  12. PPAR agonists regulate brain gene expression: relationship to their effects on ethanol consumption.

    PubMed

    Ferguson, Laura B; Most, Dana; Blednov, Yuri A; Harris, R Adron

    2014-11-01

    Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that act as ligand-activated transcription factors. Although prescribed for dyslipidemia and type-II diabetes, PPAR agonists also possess anti-addictive characteristics. PPAR agonists decrease ethanol consumption and reduce withdrawal severity and susceptibility to stress-induced relapse in rodents. However, the cellular and molecular mechanisms facilitating these properties have yet to be investigated. We tested three PPAR agonists in a continuous access two-bottle choice (2BC) drinking paradigm and found that tesaglitazar (PPAR?/?; 1.5mg/kg) and fenofibrate (PPAR?; 150mg/kg) decreased ethanol consumption in male C57BL/6J mice while bezafibrate (PPAR?/?/?; 75mg/kg) did not. We hypothesized that changes in brain gene expression following fenofibrate and tesaglitazar treatment lead to reduced ethanol drinking. We studied unbiased genomic profiles in areas of the brain known to be important for ethanol dependence, the prefrontal cortex (PFC) and amygdala, and also profiled gene expression in liver. Genomic profiles from the non-effective bezafibrate treatment were used to filter out genes not associated with ethanol consumption. Because PPAR agonists are anti-inflammatory, they would be expected to target microglia and astrocytes. Surprisingly, PPAR agonists produced a strong neuronal signature in mouse brain, and fenofibrate and tesaglitazar (but not bezafibrate) targeted a subset of GABAergic interneurons in the amygdala. Weighted gene co-expression network analysis (WGCNA) revealed co-expression of treatment-significant genes. Functional annotation of these gene networks suggested that PPAR agonists might act via neuropeptide and dopaminergic signaling pathways in the amygdala. Our results reveal gene targets through which PPAR agonists can affect alcohol consumption behavior. PMID:25036611

  13. Detection of glucocorticoid receptor agonists in effluents from sewage treatment plants in Japan.

    PubMed

    Suzuki, Go; Sato, Kentaro; Isobe, Tomohiko; Takigami, Hidetaka; Brouwer, Abraham; Nakayama, Kei

    2015-09-15

    Glucocorticoids (GCs) are widely used as anti-inflammatory drugs. Our previous study demonstrated that several GCs such as cortisol and dexamethasone (Dex) were frequently detected in effluents collected from Japanese sewage treatment plants (STPs) in 2012. In this study, we used the GC-Responsive Chemical-Activated LUciferase gene eXpression (GR-CALUX) assay to elucidate GC receptor (GR) agonistic activities of ten pure synthetic GCs and selected STP effluents in Japan for assessment of the risks associated with the presence of GR agonists. The tested GCs demonstrated dose-dependent agonistic effects in the GR-CALUX assay and their EC50 values were calculated for estimation of relative potencies (REPs) compared to Dex. The GR agonistic potency was in the rank of: clobetasol propionate > clobetasone butyrate > betamethasone 17-valerate > difluprednate > betamethasone 17,21-dipropionate > Dex > betamethasone > 6?-methylprednisolone > prednisolone > cortisol. The GR agonistic activity in STP effluents as measured in Dex-equivalent (Dex-EQ) activities ranged from < 3.0-78 ng L(-1) (median: 29 ng L(-1), n = 50). To evaluate the contribution of the target GCs, theoretical Dex-EQs were calculated by multiplying the concentrations of each GC by its respective REP. Our calculation of Dex-EQ contribution for individual GR agonists indicated that the well-known GCs cortisol and Dex should not be given priority for subsequent in vivo testing, monitoring and removal experiments, but rather the highly potent synthetic GCs clobetasol propionate and betamethasone 17-valerate (REP = 28 and 3.1) as well as other unidentified compounds are important GR agonists in STP effluents in Japan. PMID:25965047

  14. Gonadotropin-releasing Hormone Agonist Overuse: Urologists Response to Reimbursement and Characteristics Associated with Persistent Overuse

    PubMed Central

    Ellis, Shellie D.; Nielsen, Matthew E.; Carpenter, William R.; Jackson, George L.; Wheeler, Stephanie B.; Liu, Huan; Weinberger, Morris

    2015-01-01

    BACKGROUND Medicare reimbursement cuts have been associated with declining Gonadotropin-releasing Hormone (GnRH) agonist overuse in localized prostate cancer. Medical school affiliation and foreign training have been associated with persistent overuse. However, physician-level prescribing changes and the practice type of persistent overusers have not been examined. We sought to describe physician-level changes in GnRH agonist overuse and test the association of time in practice and solo practice type with GnRH agonist overuse. METHODS We matched American Medical Association physician data for 2,138 urologists to SEERMedicare data for 12,943 men diagnosed with early stage and lower grade adenocarcinoma of the prostate between 2000 and 2007. We conducted a population-based, retrospective study using multi-level modeling to control for patient and provider characteristics. RESULTS Three distinct patterns of GnRH agonist overuse were observed. Urologists time in practice was not associated with GnRH agonist overuse (OR 0.89; 95% CI 0.751.05).However, solo practice type (OR 1.65; 95% CI 1.342.02), medical school affiliation (OR 0.65; 95% CI 0.550.77), and patient race were. Compared to non-Hispanic whites, non-Hispanic blacks (OR 1.76; 95% CI 1.372.27), Hispanics (OR 1.41; 95% CI 1.121.79) and men of other race (OR 1.44; 95% CI 1.041.99) had greater odds of receiving unnecessary GnRH agonists. CONCLUSIONS GnRH agonist overuse remains high among some urologists who may be professionally isolated and difficult to reach. These urologists treat more vulnerable populations, which may contribute to health disparities in prostate cancer treatment quality. Nonetheless, these findings provide guidance to develop interventions to address overuse in prostate cancer. PMID:25849354

  15. Evaluation of Computational Docking to Identify Pregnane X Receptor Agonists in the ToxCast Database

    PubMed Central

    Kortagere, Sandhya; Krasowski, Matthew D.; Reschly, Erica J.; Venkatesh, Madhukumar; Mani, Sridhar; Ekins, Sean

    2010-01-01

    Background The pregnane X receptor (PXR) is a key transcriptional regulator of many genes [e.g., cytochrome P450s (CYP2C9, CYP3A4, CYP2B6), MDR1] involved in xenobiotic metabolism and excretion. Objectives As part of an evaluation of different approaches to predict compound affinity for nuclear hormone receptors, we used the molecular docking program GOLD and a hybrid scoring scheme based on similarity weighted GoldScores to predict potential PXR agonists in the ToxCast database of pesticides and other industrial chemicals. We present some of the limitations of different in vitro systems, as well as docking and ligand-based computational models. Methods Each ToxCast compound was docked into the five published crystallographic structures of human PXR (hPXR), and 15 compounds were selected based on their consensus docking scores for testing. In addition, we used a Bayesian model to classify the ToxCast compounds into PXR agonists and nonagonists. hPXR activation was determined by luciferase-based reporter assays in the HepG2 and DPX-2 human liver cell lines. Results We tested 11 compounds, of which 6 were strong agonists and 2 had weak agonist activity. Docking results of additional compounds were compared with data reported in the literature. The prediction sensitivity of PXR agonists in our sample ToxCast data set (n = 28) using docking and the GoldScore was higher than with the hybrid score at 66.7%. The prediction sensitivity for PXR agonists using GoldScore for the entire ToxCast data set (n = 308) compared with data from the NIH (National Institutes of Health) Chemical Genomics Center data was 73.8%. Conclusions Docking and the GoldScore may be useful for prioritizing large data sets prior to in vitro testing with good sensitivity across the sample and entire ToxCast data set for hPXR agonists. PMID:20558333

  16. Effect of adrenoceptor agonists on striated muscle strips of the canine oesophagus.

    PubMed Central

    Tokuhara, T.; Meulemans, A. L.; De Ridder, W. J.; Higashino, M.; Kinoshita, H.; Schuurkes, J. A.

    1993-01-01

    1. Acute psychological stress, which could be related to the release of a large amount of catecholamines, may cause oesophageal motility disorders. Therefore, the aim of our study was to elucidate the influence of adrenoceptor agonists on the striated muscle portion of the oesophagus by use of isolated strips from dogs. 2. Contractions were evoked in isolated striated muscle strips by electrical field stimulation (1 pulse min-1, 1 ms/pulse, submaximal voltage). The effects induced by administration of adrenoceptor agonists alone or in the presence of antagonists were tested to determine the nature of the adrenoceptors on this muscle preparation. 3. The administration of both the natural adrenoceptor agonists, adrenaline and noradrenaline, and the synthetic beta-adrenoceptor agonists, isoprenaline (beta 1 + beta 2), dobutamine (beta 1) or ritodrine (beta 2), enhanced the amplitude of the contractions induced by electrical stimulation in a concentration-dependent manner. The maximum responses were 82.6 (adrenaline), 66.2 (noradrenaline), 86.2 (isoprenaline), 34.6 (dobutamine) and 80.8% (ritodrine). The EC20 values obtained were respectively 2 nM, 0.2 microM, 0.91 nM, 3 microM and 80 nM. The administration of the alpha 1-adrenoceptor agonist, phenylephrine, also enhanced the contractile response in a concentration-dependent manner (EC20 value = 0.3 microM) and the maximum response was 64.6%, but the administration of the alpha 2-adrenoceptor agonist, clonidine, did not influence the contractile response. These data suggest the involvement of beta 2- and possibly alpha 1-adrenoceptors in the responses of these adrenoceptor agonists.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8106105

  17. Inhibition by TRPA1 agonists of compound action potentials in the frog sciatic nerve.

    PubMed

    Matsushita, Akitomo; Ohtsubo, Sena; Fujita, Tsugumi; Kumamoto, Eiichi

    2013-04-26

    Although TRPV1 and TRPM8 agonists (vanilloid capsaicin and menthol, respectively) at high concentrations inhibit action potential conduction, it remains to be unknown whether TRPA1 agonists have a similar action. The present study examined the actions of TRPA1 agonists, cinnamaldehyde (CA) and allyl isothiocyanate (AITC), which differ in chemical structure from each other, on compound action potentials (CAPs) recorded from the frog sciatic nerve by using the air-gap method. CA and AITC concentration-dependently reduced the peak amplitude of the CAP with the IC50 values of 1.2 and 1.5mM, respectively; these activities were resistant to a non-selective TRP antagonist ruthenium red or a selective TRPA1 antagonist HC-030031. The CA and AITC actions were distinct in property; the latter but not former action was delayed in onset and partially reversible, and CA but not AITC increased thresholds to elicit CAPs. A CAP inhibition was seen by hydroxy-?-sanshool (by 60% at 0.05 mM), which activates both TRPA1 and TRPV1 channels, a non-vanilloid TRPV1 agonist piperine (by 20% at 0.07 mM) and tetrahydrolavandulol (where the six-membered ring of menthol is opened; IC50=0.38 mM). It is suggested that TRPA1 agonists as well as TRPV1 and TRPM8 agonists have an ability to inhibit nerve conduction without TRP activation, although their agonists are quite different in chemical structure from each other. PMID:23537660

  18. Find novel dual-agonist drugs for treating type 2 diabetes by means of cheminformatics

    PubMed Central

    Liu, Lei; Ma, Ying; Wang, Run-Ling; Xu, Wei-Ren; Wang, Shu-Qing; Chou, Kuo-Chen

    2013-01-01

    The high prevalence of type 2 diabetes mellitus in the world as well as the increasing reports about the adverse side effects of the existing diabetes treatment drugs have made developing new and effective drugs against the disease a very high priority. In this study, we report ten novel compounds found by targeting peroxisome proliferator-activated receptors (PPARs) using virtual screening and core hopping approaches. PPARs have drawn increasing attention for developing novel drugs to treat diabetes due to their unique functions in regulating glucose, lipid, and cholesterol metabolism. The reported compounds are featured with dual functions, and hence belong to the category of dual agonists. Compared with the single PPAR agonists, the dual PPAR agonists, formed by combining the lipid benefit of PPARα agonists (such as fibrates) and the glycemic advantages of the PPARγ agonists (such as thiazolidinediones), are much more powerful in treating diabetes because they can enhance metabolic effects while minimizing the side effects. This was observed in the studies on molecular dynamics simulations, as well as on absorption, distribution, metabolism, and excretion, that these novel dual agonists not only possessed the same function as ragaglitazar (an investigational drug developed by Novo Nordisk for treating type 2 diabetes) did in activating PPARα and PPARγ, but they also had more favorable conformation for binding to the two receptors. Moreover, the residues involved in forming the binding pockets of PPARα and PPARγ among the top ten compounds are explicitly presented, and this will be very useful for the in-depth conduction of mutagenesis experiments. It is anticipated that the ten compounds may become potential drug candidates, or at the very least, the findings reported here may stimulate new strategies or provide useful insights for designing new and more powerful dual-agonist drugs for treating type 2 diabetes. PMID:23630413

  19. Find novel dual-agonist drugs for treating type 2 diabetes by means of cheminformatics.

    PubMed

    Liu, Lei; Ma, Ying; Wang, Run-Ling; Xu, Wei-Ren; Wang, Shu-Qing; Chou, Kuo-Chen

    2013-01-01

    The high prevalence of type 2 diabetes mellitus in the world as well as the increasing reports about the adverse side effects of the existing diabetes treatment drugs have made developing new and effective drugs against the disease a very high priority. In this study, we report ten novel compounds found by targeting peroxisome proliferator-activated receptors (PPARs) using virtual screening and core hopping approaches. PPARs have drawn increasing attention for developing novel drugs to treat diabetes due to their unique functions in regulating glucose, lipid, and cholesterol metabolism. The reported compounds are featured with dual functions, and hence belong to the category of dual agonists. Compared with the single PPAR agonists, the dual PPAR agonists, formed by combining the lipid benefit of PPARα agonists (such as fibrates) and the glycemic advantages of the PPARγ agonists (such as thiazolidinediones), are much more powerful in treating diabetes because they can enhance metabolic effects while minimizing the side effects. This was observed in the studies on molecular dynamics simulations, as well as on absorption, distribution, metabolism, and excretion, that these novel dual agonists not only possessed the same function as ragaglitazar (an investigational drug developed by Novo Nordisk for treating type 2 diabetes) did in activating PPARα and PPARγ, but they also had more favorable conformation for binding to the two receptors. Moreover, the residues involved in forming the binding pockets of PPARα and PPARγ among the top ten compounds are explicitly presented, and this will be very useful for the in-depth conduction of mutagenesis experiments. It is anticipated that the ten compounds may become potential drug candidates, or at the very least, the findings reported here may stimulate new strategies or provide useful insights for designing new and more powerful dual-agonist drugs for treating type 2 diabetes. PMID:23630413

  20. Comparative Gene Expression Profiles Induced by PPAR? and PPAR?/? Agonists in Human Hepatocytes

    PubMed Central

    Rogue, Alexandra; Lambert, Carine; Joss, Rozenn; Antherieu, Sebastien; Spire, Catherine; Claude, Nancy; Guillouzo, Andr

    2011-01-01

    Background Several glitazones (PPAR? agonists) and glitazars (dual PPAR?/? agonists) have been developed to treat hyperglycemia and, simultaneously, hyperglycemia and dyslipidemia, respectively. However, most have caused idiosyncratic hepatic or extrahepatic toxicities through mechanisms that remain largely unknown. Since the liver plays a key role in lipid metabolism, we analyzed changes in gene expression profiles induced by these two types of PPAR agonists in human hepatocytes. Methodology/Principal Findings Primary human hepatocytes and the well-differentiated human hepatoma HepaRG cells were exposed to different concentrations of two PPAR? (troglitazone and rosiglitazone) and two PPAR?/? (muraglitazar and tesaglitazar) agonists for 24 h and their transcriptomes were analyzed using human pangenomic Agilent microarrays. Principal Component Analysis, hierarchical clustering and Ingenuity Pathway Analysis revealed large inter-individual variability in the response of the human hepatocyte populations to the different compounds. Many genes involved in lipid, carbohydrate, xenobiotic and cholesterol metabolism, as well as inflammation and immunity, were regulated by both PPAR? and PPAR?/? agonists in at least a number of human hepatocyte populations and/or HepaRG cells. Only a few genes were selectively deregulated by glitazars when compared to glitazones, indicating that PPAR? and PPAR?/? agonists share most of their target genes. Moreover, some target genes thought to be regulated only in mouse or to be expressed in Kupffer cells were also found to be responsive in human hepatocytes and HepaRG cells. Conclusions/Significance This first comprehensive analysis of gene regulation by PPAR? and PPAR?/? agonists favor the conclusion that glitazones and glitazars share most of their target genes and induce large differential changes in gene profiles in human hepatocytes depending on hepatocyte donor, the compound class and/or individual compound, thereby supporting the occurrence of idiosyncratic toxicity in some patients. PMID:21533120

  1. Cigarette smoke exposure inhibits contact hypersensitivity via the generation of platelet activating factor agonists

    PubMed Central

    Sahu, Ravi P.; Petrache, Irina; Van Demark, Mary J; Rashid, Badri M.; Ocana, Jesus A.; Tang, Yuxuan; Yi, Qiaofang; Turner, Matthew J.; Konger, Raymond L.; Travers, Jeffrey B.

    2013-01-01

    Previous studies have established that pro-oxidative stressors suppress host immunity due to their ability to generate oxidized lipids with PAF-receptor (PAF-R) agonist activity. Although exposure to the pro-oxidative stressor cigarette smoke (CS) is known to exert immunomodulatory effects, little is known regarding the role of platelet-activating factor (PAF) in these events. The current studies sought to determine the role of PAF-R signaling in CS-mediated immunomodulatory effects. We demonstrate that CS exposure induces the generation of a transient PAF-R agonistic activity in the blood of mice. CS exposure inhibits contact hypersensitivity in a PAF-R-dependent manner as PAF-R-deficient mice were resistant to these effects. Blocking PAF-R agonist production either by systemic antioxidants or treatment with serum PAF-acetyl hydrolase enzyme blocked both the CS-mediated generation of PAF-R-agonists and PAF-R dependent inhibition of CHS reactions, indicating a role for oxidized glycerophosphocholines with PAF-R agonistic activity in this process. In addition, cyclooxygenase-2 (COX-2) inhibition did not block PAF-R agonist production but prevented CS-induced inhibition of CHS. This suggests that COX-2 acts downstream of the PAF-R in mediating CS-induced systemic immunosuppression. Moreover, CS-exposure induced a significant increase in the expression of the regulatory T cell reporter gene in FoxP3EGFP mice but not in FoxP3EGFP mice on a PAF-R-deficient background. Finally, Treg depletion via anti-CD25 antibodies blocked CS-mediated inhibition of CHS, indicating the potential involvement of Tregs in CS-mediated systemic immunosuppression. These studies provide the first evidence that the pro-oxidative stressor CS can modulate cutaneous immunity via the generation of PAF-R agonists produced through lipid oxidation. PMID:23355733

  2. Cellular localization of kinin B1 receptor in the spinal cord of streptozotocin-diabetic rats with a fluorescent [N?-Bodipy]-des-Arg9-bradykinin

    PubMed Central

    Talbot, Sbastien; Thberge-Turmel, Patrick; Liazoghli, Dalinda; Sncal, Jacques; Gaudreau, Pierrette; Couture, Rjean

    2009-01-01

    Background The kinin B1 receptor (B1R) is upregulated by pro-inflammatory cytokines, bacterial endotoxins and hyperglycaemia-induced oxidative stress. In animal models of diabetes, it contributes to pain polyneuropathy. This study aims at defining the cellular localization of B1R in thoracic spinal cord of type 1 diabetic rats by confocal microscopy with the use of a fluorescent agonist, [N?-Bodipy]-des-Arg9-BK (BdABK) and selective antibodies. Methods Diabetes was induced by streptozotocin (STZ; 65 mg/kg, i.p.). Four days post-STZ treatment, B1R expression was confirmed by quantitative real-time PCR and autoradiography. The B1R selectivity of BdABK was determined by assessing its ability to displace B1R [125I]-HPP-desArg10-Hoe140 and B2R [125I]-HPP-Hoe 140 radioligands. The in vivo activity of BdABK was also evaluated on thermal hyperalgesia. Results B1R was increased by 18-fold (mRNA) and 2.7-fold (binding sites) in the thoracic spinal cord of STZ-treated rats when compared to control. BdABK failed to displace the B2R radioligand but displaced the B1R radioligand (IC50 = 5.3 nM). In comparison, IC50 values of B1R selective antagonist R-715 and B1R agonist des-Arg9-BK were 4.3 nM and 19 nM, respectively. Intraperitoneal BdABK and des-Arg9-BK elicited dose-dependent thermal hyperalgesia in STZ-treated rats but not in control rats. The B1R fluorescent agonist was co-localized with immunomarkers of microglia, astrocytes and sensory C fibers in the spinal cord of STZ-treated rats. Conclusion The induction and up-regulation of B1R in glial and sensory cells of the spinal cord in STZ-diabetic rats reinforce the idea that kinin B1R is an important target for drug development in pain processes. PMID:19323833

  3. Conopeptide-Derived κ-Opioid Agonists (Conorphins): Potent, Selective, and Metabolic Stable Dynorphin A Mimetics with Antinociceptive Properties.

    PubMed

    Brust, Andreas; Croker, Daniel E; Colless, Barbara; Ragnarsson, Lotten; Andersson, Åsa; Jain, Kapil; Garcia-Caraballo, Sonia; Castro, Joel; Brierley, Stuart M; Alewood, Paul F; Lewis, Richard J

    2016-03-24

    Opioid receptor screening of a conopeptide library led to a novel selective κ-opioid agonist peptide (conorphin T). Intensive medicinal chemistry, guided by potency, selectivity, and stability assays generated a pharmacophore model supporting rational design of highly potent and selective κ-opioid receptor (KOR) agonists (conorphins) with exceptional plasma stability. Conorphins are defined by a hydrophobic benzoprolyl moiety, a double arginine sequence, a spacer amino acid followed by a hydrophobic residue and a C-terminal vicinal disulfide moiety. The pharmacophore model was supported by computational docking studies, revealing receptor-ligand interactions similar to KOR agonist dynorphin A (1-8). A conorphin agonist inhibited colonic nociceptors in a mouse tissue model of chronic visceral hypersensitivity, suggesting the potential of KOR agonists for the treatment of chronic abdominal pain. This new conorphine KOR agonist class and pharmacophore model provide opportunities for future rational drug development and probes for exploring the role of the κ-opioid receptor. PMID:26859603

  4. Profil epidemiologique des brulures d'enfants admis au Centre National des Brules, Maroc

    PubMed Central

    Zahid, A.; Atannaz, J.; Alaoui, M.; Rafik, A.; Ezzoubi, M.; Diouri, M.; Chlihi, A.; Bahechar, N.; Boukind, E.H.

    2011-01-01

    Summary Ce travail rtrospectif analyse les particularits pidmiologiques de 543 cas de brlures d'enfants, reprsentant 45,7% des admissions de notre centre, en vue de dterminer les lments pouvant contribuer renforcer la prvention, qui reste le traitement de choix de cette pathologie. La moyenne d'ge est de 4,25 ans avec une prdilection pour la tranche d'ge d'un cinq ans, avec 42,5% des cas. Une atteinte masculine est retrouve dans 63,5% des cas. La brlure survient domicile dans 85,1% et accidentellement dans 95% des cas. Les brlures thermiques reprsentent 96,5% des causes domines par les liquides dans 69,3% des cas. La surface cutane brle est ? 20% dans 52,3%. La brlure intresse essentiellement les membres suprieurs (79,1%). 56,8% des enfants sont transfrs par d'autres hpitaux et le dlai de prise en charge hospitalire est suprieur 6 heures dans 65,5%. Le taux de mortalit a t de 13,2%. PMID:22639559

  5. Pharmacology of moxonidine, an I1-imidazoline receptor agonist.

    PubMed

    Ziegler, D; Haxhiu, M A; Kaan, E C; Papp, J G; Ernsberger, P

    1996-01-01

    Moxonidine is a second-generation, centrally acting antihypertensive drug with a distinctive mode of action. Moxonidine activates I1-imidazoline receptors (I1-receptors) in the rostroventrolateral medulla (RVLM), thereby reducing the activity of the sympathetic nervous system. Moxonidine leads to a pronounced and long-lasting blood pressure reduction in different animal models of hypertension, e.g., spontaneously hypertensive rats, renal hypertensive rats, and renal hypertensive dogs. Blood pressure reduction with moxonidine is usually accompanied by a reduction in heart rate which, however, in most studies is of shorter duration and lesser magnitude than the fall in blood pressure. Chronic administration of moxonidine to SHRs with established hypertension causes normalization of myocardial fibrosis, capillarization, and regressive changes in myocytes, in parallel with the reduction of blood pressure. Left ventricular hypertrophy and renal glomerulosclerosis are also significantly reduced. After withdrawal of chronic moxonidine treatment, blood pressure gradually rises to pretreatment values. Direct injection of moxonidine into the vertebral artery of cats elicits a more pronounced fall in blood pressure compared with i.v. injection of an equivalent dose. This observation and others clearly indicate that moxonidine's antihypertensive activity is centrally mediated. The RVLM is the site of action within the CNS that mediates pronounced blood pressure reduction after direct administration of moxonidine into the RVLM of anesthetized SHRs. Selective I1-receptor antagonists introduced into this area abolish the action of systemic moxonidine. Receptor binding studies have shown high and selective affinity of moxonidine for I1-receptors vs. alpha(2)-adrenergic receptors. In vivo studies using a variety of selective I1 or alpha(2)-adrenergic agonists and antagonists have confirmed the primary role of I1-receptors in blood pressure regulation by moxonidine. In addition to lowering blood pressure, moxonidine possesses further properties that appear likely to be relevant in its therapeutic application in the hypertensive syndrome. Moxonidine increases urine flow rate and sodium excretion after central and direct intrarenal administration. It is active against ventricular arrhythmias in a variety of experimental settings. It lacks the respiratory depressant effect attributed to central alpha 2 activation. It exerts beneficial effects on glucose metabolism and blood lipids in genetically hypertensive obese rats. It exhibits anti-ulcer activity. And, finally, moxonidine lowers intraocular pressure, suggesting a possible benefit in glaucoma. Therefore, moxonidine, by its novel mode of action, represents a new therapeutic principle in the treatment of hypertension. Because of its unique profile, moxonidine may prove to be effective in slowing progression of the disease by providing protective effects beyond merely blood pressure reduction. Further studies are needed to verify this potential. PMID:8872297

  6. Effects of PPARg agonist pioglitazone on rat hepatic fibrosis

    PubMed Central

    Yuan, Guang-Jin; Zhang, Ming-Liang; Gong, Zuo-Jiong

    2004-01-01

    AIM: To investigate effects of pioglitazone on rat hepatic fibrosis and to explore its mechanism. METHODS: Rat hepatic fibrosis was induced by carbon tetrachloride (CCl4). Forty Sprague-Dawley rats were divided randomly into 4 groups: control, model, and two treatment (PI, PII) groups. Except for rats in control group, all rats were given subcutaneous injection of 400 mL/L CCl4, twice a wk for 8 wk. Rats in PI and PII groups were also treated with pioglitazone of 3 mg/kg, daily via gastrogavage beginning on the 1st day and at the end of the 2nd week, administration of CCl4 respectively. Liver functions (ALT, AST), serum fibrotic markers (HA, LN, PCIII) and hepatic hydroxyproline (HP) concentration were determined respectively. Histochemical staining of formalin-fixed liver sections with HE, Masson-Trichrome, and immunohistochemical staining for ?-smooth muscle actin (?-SMA) were performed. Modified Knodell and Chevallier semi-quantitative scoring system (SSS) was used to evaluate necroinflammatory activity and fibrosis degree. RESULTS: Compared with model group, pioglitazone significantly reduced the serum levels of ALT, AST , HA, LN and PCIII (P < 0.05 or < 0 .01). The HP concentrations in PI (210.90 24.07 ?g/g), and PII (257.36 30.55 ?g/g) groups were also lower than those in model group (317.80 36.44 ?g/g) (P < 0.01). Histologic examination showed that PI and PII groups had milder hepatocellular degeneration, necrosis and infiltration of inflammatory cells, and thinner or less fibrotic septa than did model group. The scores for necroinflammation in PI (2.80 1.03), and PII (3.00 1.05) groups were significantly reduced as compared with model group (4.88 2.30) (P < 0.05 or < 0.01); the fibrosis scores in PI (3.40 1.65), and PII (4.601.35) groups were also markedly lower than those in model group (7.00 3.21) (P < 0.05 or < 0.01). Immunohistochemical staining showed that expression of ?-SMA in PI and PII groups was ameliorated dramatically compared with model group. CONCLUSION: PPAR? agonist pioglitazone greatly retards the progression of rat hepatic fibrosis induced by CCl4 through inhibition of HSC activation and amelioration of hepatocyte necroinflammation in rats. PMID:15052691

  7. Cervical Cancer

    MedlinePLUS

    ... transmitted infections , such as chlamydia Problems with the immune system Having a mother who took a drug called diethylstilbestrol (DES) during pregnancy Is there a screening test for cervical cancer? ...

  8. Design and synthesis of potent, highly selective vasopressin hypotensive agonists.

    PubMed

    Stoev, Stoytcho; Cheng, Ling Ling; Manning, Maurice; Wo, Nga Ching; Szeto, Hazel H

    2006-09-01

    We report here the solid-phase synthesis and vasodepressor potencies of a new lead vasopressin (VP) hypotensive peptide [1(beta-mercapto-beta,beta-pentamethylenepropionic acid)-2-0-ethyl-D-tyrosine, 3-arginine, 4-valine, 7-lysine, 9-ethylenediamine] lysine vasopressin, d(CH(2))(5)[D-Tyr(Et)(2), Arg(3), Val(4), Lys(7), Eda(9)]LVP (C) and 21 analogues of C with single modifications at positions 9 (1-13), 6 (14), 2 (16-20) and combined modifications at positions 6 and 10 (15) and 2 and 10 (21). Peptides 1-13 have the following replacements for the Eda residue at position 9 in C: (1) Gly-NH(2); (2) Gly-NH-CH(3); (3) Ala-NH(2); (4) Ala-NH-CH(3), (5) Val-NH(2); (6) Cha-NH(2); (7) Thr-NH(2); (8) Phe-NH(2); (9) Tyr-NH(2); (10) Orn-NH(2); (11) Lys-NH(2); (12) D-Lys-NH(2); (13) Arg-NH(2). Peptide 14 has the Cys residue at position 6 replaced by Pen. Peptide 15 is the retro-Tyr(10) analogue of peptide 14. Peptides 16-20 have the D-Tyr(Et) residue at position 2 in C replaced by the following substituents: D-Trp (16); D-2-Nal (17); D-Tyr(Bu(t))(18); D-Tyr(Pr(n)) (19); D-Tyr(Pr(i)) (20). Peptide 21 is the retro-Tyr(10) analogue of peptide 20. C and peptides 1-21 were evaluated for agonistic and antagonistic activities in in vivo vasopressor (V(1a)-receptor), antidiuretic (V(2)-receptor), and in in vitro (no Mg(2+)) oxytocic (OT-receptor) assays in the rat, and, like the original hypotensive peptide, d(CH(2))(5)[D-Tyr(Et)(2), Arg(3), Val(4)]AVP (A) (Manning et al., J. Peptide Science 1999, 5:472-490), were found to exhibit no or negligible activities in these assays. Vasodepressor potencies were determined in anesthetized male rats with baseline mean arterial blood pressure (BP) maintained at 100-120 mmHg. The effective dose (ED), in microg/100 g i.v., the dose required to produce a vasodepressor response of 5 cm(2) area under the vasodepressor response curve (AUC) during the 5-min period following the injection of the test peptide, was determined. The EDs measure the vasodepressor potencies of the hypotensive peptides C and 1-21 relative to that of A (ED = 4.66 microg/100 g) and to each other. The following ED values in microg/100 g were obtained for C and for peptides 1-21; C 0.53; (1) 2.41; (2) 1.13; (3) 1.62; (4) 0.80; (5) 1.83; (6) 1.56; (7) 2.12, (8) 2.58; (9) 1.40; (10) 0.88; (11) 0.90; (12) 0.85; (13) 0.68; (14) 0.99; (15) 1.05; (16) 0.66; (17) 0.54; (18) 0.33; (19) 0.18; (20) 0.15; (21) 0.14. All of the hypotensive peptides reported here are more potent than A. Peptides 20 and 21 exhibit a striking 30-fold enhancement in vasodepressor potencies relative to A. With a vasodepressor ED = 0.14, peptide 21 is the most potent VP vasodepressor agonist reported to date. Because it contains a retro-Tyr(10) residue, it is a promising new radioiodinatable ligand for the putative VP vasodilating receptor. Some of these new hypotensive peptides may be of value as research tools for studies on the complex cardiovascular actions of VP and may lead to the development of a new class of antihypertensive agents. PMID:16625682

  9. Reconstitution of high-affinity opioid agonist binding in brain membranes

    SciTech Connect

    Remmers, A.E.; Medzihradsky, F. )

    1991-03-15

    In synaptosomal membranes from rat brain cortex, the {mu} selective agonist ({sup 3}H)dihydromorphine in the absence of sodium, and the nonselective antagonist ({sup 3}H)naltrexone in the presence of sodium, bound to two populations of opioid receptor sites with K{sub d} values of 0.69 and 8.7 nM for dihydromorphine, and 0.34 and 5.5 nM for naltrexone. The addition of 5 {mu}M guanosine 5{prime}-({gamma}-thio)triphosphate (GTP({gamma}S)) strongly reduced high-affinity agonist but not antagonist binding. Exposure of the membranes to high pH reduced the number of GTP({gamma}-{sup 35}S) binding sites by 90% and low K{sub m}, opioid-sensitive GTPase activity by 95%. In these membranes, high-affinity agonist binding was abolished and modulation of residual binding by GTP({gamma}S) was diminished. Alkali treatment of the glioma cell membranes prior to fusion inhibited most of the low K{sub m} GTPase activity and prevented the reconstitution of agonist binding. The results show that high-affinity opioid agonist binding reflects the ligand-occupied receptor - guanine nucleotide binding protein complex.

  10. Alcohol Screening among Opioid Agonist Patients in a Primary Care Clinic and an Opioid Treatment Program.

    PubMed

    Klimas, Jan; Muench, John; Wiest, Katharina; Croff, Raina; Rieckman, Traci; McCarty, Dennis

    2015-01-01

    Problem alcohol use is associated with adverse health and economic outcomes, especially among people in opioid agonist treatment. Screening, brief intervention, and referral to treatment (SBIRT) are effective in reducing alcohol use; however, issues involved in SBIRT implementation among opioid agonist patients are unknown. To assess identification and treatment of alcohol use disorders, we reviewed clinical records of opioid agonist patients screened for an alcohol use disorder in a primary care clinic (n = 208) and in an opioid treatment program (n = 204) over a two-year period. In the primary care clinic, 193 (93%) buprenorphine patients completed an annual alcohol screening and six (3%) had elevated AUDIT scores. In the opioid treatment program, an alcohol abuse or dependence diagnosis was recorded for 54 (27%) methadone patients. Practitioner focus groups were completed in the primary care (n = 4 physicians) and the opioid treatment program (n = 11 counselors) to assess experience with and attitudes towards screening opioid agonist patients for alcohol use disorders. Focus groups suggested that organizational, structural, provider, patient, and community variables hindered or fostered alcohol screening. Alcohol screening is feasible among opioid agonist patients. Effective implementation, however, requires physician training and systematic changes in workflow. PMID:25715074

  11. Agonist-dependent modulation of arterial endothelinA receptor function

    PubMed Central

    Compeer, MG; Meens, MJPMT; Hackeng, TM; Neugebauer, WA; Hltke, C; De Mey, JGR

    2012-01-01

    BACKGROUND AND PURPOSE Endothelin-1 (ET-1) causes long-lasting vasoconstrictions. These can be prevented by ETA receptor antagonists but are only poorly reversed by these drugs. We tested the hypothesis that endothelin ETA receptors are susceptible to allosteric modulation by endogenous agonists and exogenous ligands. EXPERIMENTAL APPROACH Rat isolated mesenteric resistance arteries were pretreated with capsaicin and studied in wire myographs, in the presence of L-NAME and indomethacin to concentrate on arterial smooth muscle responses. KEY RESULTS Endothelins caused contractions with equal maximum but differing potency (ET-1 = ET-2 > ET-3). ET-1115 neither mimicked nor antagonized these effects in the absence and presence of ET1621. 4AlaET-1 (ETB agonist) and BQ788 (ETB antagonist) were without effects. BQ123 (peptide ETA antagonist) reduced the sensitivity and relaxed the contractile responses to endothelins. Both effects depended on the agonist (pKB: ET-3 = ET-1 > ET-2; % relaxation: ET-3 = ET-2 > ET-1). Also, with PD156707 (non-peptide ETA antagonist) agonist-dependence and a discrepancy between preventive and inhibitory effects were observed. The latter was even more marked with bulky analogues of BQ123 and PD156707. CONCLUSIONS AND IMPLICATIONS These findings indicate allosteric modulation of arterial smooth muscle ETA receptor function by endogenous agonists and by exogenous endothelin receptor antagonists. This may have consequences for the diagnosis and pharmacotherapy of diseases involving endothelins. PMID:22324472

  12. Modulation Effect of Peroxisome Proliferator-Activated Receptor Agonists on Lipid Droplet Proteins in Liver

    PubMed Central

    Zhu, Yun-Xia; Zhang, Ming-Liang; Zhong, Yuan; Wang, Chen; Jia, Wei-Ping

    2016-01-01

    Peroxisome proliferator-activated receptor (PPAR) agonists are used for treating hyperglycemia and type 2 diabetes. However, the mechanism of action of these agonists is still under investigation. The lipid droplet-associated proteins FSP27/CIDEC and LSDP5, regulated directly by PPARγ and PPARα, are associated with hepatic steatosis and insulin sensitivity. Here, we evaluated the expression levels of FSP27/CIDEC and LSDP5 and the regulation of these proteins by consumption of a high-fat diet (HFD) or administration of PPAR agonists. Mice with diet-induced obesity were treated with the PPARγ or PPARα agonist, pioglitazone or fenofibrate, respectively. Liver tissues from db/db diabetic mice and human were also collected. Interestingly, FSP27/CIEDC was expressed in mouse and human livers and was upregulated in obese C57BL/6J mice. Fenofibrate treatment decreased hepatic triglyceride (TG) content and FSP27/CIDEC protein expression in mice fed an HFD diet. In mice, LSDP5 was not detected, even in the context of insulin resistance or treatment with PPAR agonists. However, LSDP5 was highly expressed in humans, with elevated expression observed in the fatty liver. We concluded that fenofibrate greatly decreased hepatic TG content and FSP27/CIDEC protein expression in mice fed an HFD, suggesting a potential regulatory role for fenofibrate in the amelioration of hepatic steatosis. PMID:26770990

  13. Effect of dual agonists on phosphoinositide pools in WRK-1 cells.

    PubMed Central

    Monaco, M E; Attinasi, M; Koréh, K

    1990-01-01

    Both vasopressin and bradykinin activate the phosphoinositide cycle in WRK-1 rat mammary tumour cells. When the two agonists are added simultaneously, partial additivity is observed with respect to disappearance of prelabelled phosphoinositides and accumulation of inositol phosphates; no additivity is observed with respect to resynthesis of phosphatidylinositol as assessed by monitoring [32P]Pi incorporation. Lack of complete additivity can be explained, at least in part, by heterologous desensitization. In order to determine whether the two agonists were accessing a common or individual hormone-sensitive phosphoinositide pools, cells were incubated with [32P]Pi in the presence of either vasopressin or bradykinin and subsequently restimulated with the alternative agonist. The lipid pool labelled in the presence of either agonist was sensitive to subsequent treatment by the other ligand, suggesting a common phosphoinositide pool. However, when cells were incubated with [32P]Pi in the absence of agonists, the time course of labelling of the hormone-sensitive pool was different for bradykinin and vasopressin, with that for bradykinin becoming labelled within a much shorter time. Thus although there is a significant overlap between the phosphoinositide pools responding to vasopressin and bradykinin, there is a small fraction of the hormone-sensitive lipid which responds only to bradykinin. PMID:2167661

  14. Alcohol Screening among Opioid Agonist Patients in a Primary Care Clinic and an Opioid Treatment Program

    PubMed Central

    Klimas, Jan; Muench, John; Wiest, Katharina; Croff, Raina; Rieckmann, Traci; McCarty, Dennis

    2016-01-01

    Problem alcohol use is associated with adverse health and economic outcomes, especially among people in opioid agonist treatment. Screening, brief intervention and referral to treatment (SBIRT) are effective in reducing alcohol use; however, issues involved in SBIRT implementation among opioid agonist patients are unknown. To assess identification and treatment of alcohol use disorders, we reviewed clinical records of opioid agonist patients screened for an alcohol use disorder in a primary care clinic (n =208) and in an opioid treatment program (n = 204) over a two year period. In the primary care clinic, 193 (93%) buprenorphine patients completed an annual alcohol screening and six (3%) had elevated AUDIT scores. Among the patients treated in the opioid treatment program, an alcohol abuse or dependence diagnosis was recorded for 54 (27%) methadone patients. Practitioner focus groups were completed in the primary care (n = 4 physicians) and the opioid treatment program (n = 11 counsellors) to assess experience with and attitudes towards screening opioid agonist patients for alcohol use disorders. Focus groups suggested organizational, structural, provider, patient and community variables hindered or fostered alcohol screening. Alcohol screening is feasible among opioid agonist patients. Effective implementation, however, requires physician training and systematic changes in workflow. PMID:25715074

  15. A combined ligand and structure based approach to design potent PPAR-alpha agonists

    NASA Astrophysics Data System (ADS)

    Dhoke, Gaurao V.; Gangwal, Rahul P.; Sangamwar, Abhay T.

    2012-11-01

    A combined ligand and structure based pharmacophore modeling approach was employed to reveal structural and chemical features necessary for PPAR-alpha agonistic activity. The best HypoGen pharmacophore model Hypo1 for PPAR-alpha agonists contains two hydrogen-bond acceptor (HBA), two general hydrophobic (H), and one negative ionizable (NI) feature. In addition, one structure based pharmacophore model was developed using LigandScout3.0, which has identified additional three hydrophobic features. Further, molecular docking studies of all agonists showed hydrogen bond interactions with important amino acids (Ser280, Tyr314 and Tyr464) and these interactions were compared with Hypo1, which shows that the Hypo1 has a good predictive ability. The screened virtual hits from Hypo1 were subjected to the Lipinski's rule of five, structure based pharmacophore screening and molecular docking analysis. Finally, three novel compounds with diverse scaffolds were selected as possible candidates for the designing of potent PPAR-alpha agonists. Combination of these two approaches results in designing an ideal pharmacophore model, which provides a powerful tool for the discovery of novel PPAR-alpha agonists.

  16. Identification of Adiponectin Receptor Agonist Utilizing a Fluorescence Polarization Based High Throughput Assay

    PubMed Central

    Sun, Yiyi; Zang, Zhihe; Zhong, Ling; Wu, Min; Su, Qing; Gao, Xiurong; Zan, Wang; Lin, Dong; Zhao, Yan; Zhang, Zhonglin

    2013-01-01

    Adiponectin, the adipose-derived hormone, plays an important role in the suppression of metabolic disorders that can result in type 2 diabetes, obesity, and atherosclerosis. It has been shown that up-regulation of adiponectin or adiponectin receptor has a number of therapeutic benefits. Given that it is hard to convert the full size adiponectin protein into a viable drug, adiponectin receptor agonists could be designed or identified using high-throughput screening. Here, we report on the development of a two-step screening process to identify adiponectin agonists. First step, we developed a high throughput screening assay based on fluorescence polarization to identify adiponectin ligands. The fluorescence polarization assay reported here could be adapted to screening against larger small molecular compound libraries. A natural product library containing 10,000 compounds was screened and 9 hits were selected for validation. These compounds have been taken for the second-step in vitro tests to confirm their agonistic activity. The most active adiponectin receptor 1 agonists are matairesinol, arctiin, (-)-arctigenin and gramine. The most active adiponectin receptor 2 agonists are parthenolide, taxifoliol, deoxyschizandrin, and syringin. These compounds may be useful drug candidates for hypoadiponectin related diseases. PMID:23691032

  17. Identification of dual PPAR?/? agonists and their effects on lipid metabolism.

    PubMed

    Gao, Quanqing; Hanh, Jacky; Vradi, Linda; Cairns, Rose; Sjstrm, Helena; Liao, Vivian W Y; Wood, Peta; Balaban, Seher; Ong, Jennifer Ai; Lin, Hsuan-Yu Jennifer; Lai, Felcia; Hoy, Andrew J; Grewal, Thomas; Groundwater, Paul W; Hibbs, David E

    2015-12-15

    The three peroxisome proliferator-activated receptor (PPAR) isoforms; PPAR?, PPAR? and PPAR?, play central roles in lipid metabolism and glucose homeostasis. Dual PPAR?/? agonists, which stimulate both PPAR? and PPAR? isoforms to similar extents, are gaining popularity as it is believed that they are able to ameliorate the unwanted side effects of selective PPAR? and PPAR? agonists; and may also be used to treat dyslipidemia and type 2 diabetes mellitus simultaneously. In this study, virtual screening of natural product libraries, using both structure-based and ligand-based drug discovery approaches, identified ten potential dual PPAR?/? agonist lead compounds (9-13 and 16-20). In vitro assays confirmed these compounds to show no statistically significant toxicity to cells, with the exception of compound 12 which inhibited cell growth to 74.5%3.5 and 54.1%3.7 at 50?M and 100?M, respectively. In support of their potential as dual PPAR?/? agonists, all ten compounds upregulated the expression of cholesterol transporters ABCA1 and ABCG1 in THP-1 macrophages, with indoline derivative 16 producing the greatest elevation (2.3-fold; 3.3-fold, respectively). Furthermore, comparable to the activity of established PPAR? and PPAR? agonists, compound 16 stimulated triacylglycerol accumulation during 3T3-L1 adipocyte differentiation as well as fatty acid ?-oxidation in HuH7 hepatocytes. PMID:26616289

  18. Behavioral effects of the novel potent cannabinoid CB1 agonist AM 4054.

    PubMed

    McLaughlin, Peter J; Thakur, Ganesh A; Vemuri, V Kiran; McClure, Evan D; Brown, Cara M; Winston, Keisha M; Wood, Jodianne T; Makriyannis, Alexandros; Salamone, John D

    2013-08-01

    Due to the ubiquity of the CB1 cannabinoid receptor throughout the nervous system, as well as the many potential therapeutic uses of CB1 agonist-based interventions, it is desirable to synthesize novel probes of the CB1 receptor. Here, the acute behavioral effects of systemic (i.p.) administration of the putative novel CB1 full agonist AM 4054 were tested in rats. In Experiment 1, a dose range (0.15625-1.25 mg/kg) of AM 4054 produced effects consistent with CB1 agonism in the cannabinoid tetrad of tasks in rats, including induction of analgesia, catalepsy, hypothermia, and locomotor suppression. These effects were reversed with the CB1-selective inverse agonist AM 251 in Experiment 2, indicating that AM 4054 produced CB1 receptor-mediated effects. Analysis of open-field activity indicated that the reduction in locomotion is more consistent with general motor slowing than anxiogenesis. AM 4054 (0.0625-0.5 mg/kg) also dose-dependently reduced fixed-ratio 5 (FR5) operant responding for food in Experiment 3, and microanalysis of the timing and rate of lever pressing indicated a pattern of suppression similar to other CB1 agonists. Minimum doses of AM 4054 (0.125-0.3125 mg/kg) required to produce significant effects in these behavioral assays were lower than those of many CB1 agonists. It is likely that AM 4054 is a potent pharmacological tool for assessment of cannabinoid receptor function. PMID:23603029

  19. Can the anti-inflammatory activities of ?2-agonists be harnessed in the clinical setting?

    PubMed

    Theron, Annette J; Steel, Helen C; Tintinger, Gregory R; Feldman, Charles; Anderson, Ronald

    2013-01-01

    Beta2-adrenoreceptor agonists (?2-agonists) are primarily bronchodilators, targeting airway smooth muscle and providing critical symptomatic relief in conditions such as bronchial asthma and chronic obstructive pulmonary disease. These agents also possess broad-spectrum, secondary, anti-inflammatory properties. These are mediated largely, though not exclusively, via interactions with adenylyl cyclase-coupled ?2-adrenoreceptors on a range of immune and inflammatory cells involved in the immunopathogenesis of acute and chronic inflammatory disorders of the airways. The clinical relevance of the anti-inflammatory actions of ?2-agonists, although often effective in the experimental setting, remains contentious. The primary objectives of the current review are: firstly, to assess the mechanisms, both molecular and cell-associated, that may limit the anti-inflammatory efficacy of ?2-agonists; secondly, to evaluate pharmacological strategies, several of which are recent and innovative, that may overcome these limitations. These are preceded by a consideration of the various types of ?2-agonists, their clinical applications, and spectrum of anti-inflammatory activities, particularly those involving adenosine 3',5'-cyclic adenosine monophosphate-activated protein kinase-mediated clearance of cytosolic calcium, and altered gene expression in immune and inflammatory cells. PMID:24285920

  20. Effects of glucagon-like peptide-1 receptor agonists on renal function

    PubMed Central

    Filippatos, Theodosios D; Elisaf, Moses S

    2013-01-01

    Glucagon-like peptide-1 (GLP-1) receptor agonists result in greater improvements in glycemic control than placebo and promote weight loss with minimal hypoglycemia in patients with type 2 diabetes mellitus. A number of case reports show an association of GLP-1 receptor agonists, mainly exenatide, with the development of acute kidney injury. The present review aims to present the available data regarding the effects of GLP-1 receptor agonists on renal function, their use in subjects with chronic renal failure and their possible association with acute kidney injury. Based on the current evidence, exenatide is eliminated by renal mechanisms and should not be given in patients with severe renal impairment or end stage renal disease. Liraglutide is not eliminated by renal or hepatic mechanisms, but it should be used with caution since there are only limited data in patients with renal or hepatic impairment. There is evidence from animal studies that GLP-1 receptor agonists exert protective role in diabetic nephropathy with mechanisms that seem to be independent of their glucose-lowering effect. Additionally, there is evidence that GLP-1 receptor agonists influence water and electrolyte balance. These effects may represent new ways to improve or even prevent diabetic nephropathy. PMID:24147203

  1. GLP-1 Receptor Agonists: Nonglycemic Clinical Effects in Weight Loss and Beyond

    PubMed Central

    Ryan, Donna; Acosta, Andres

    2015-01-01

    Obective Glucagon-like peptide-1 (GLP-1) receptor agonists are indicated for treatment of type 2 diabetes since they mimic the actions of native GLP-1 on pancreatic islet cells, stimulating insulin release, while inhibiting glucagon release, in a glucose-dependent manner. The observation of weight loss has led to exploration of their potential as antiobesity agents, with liraglutide 3.0 mg day−1 approved for weight management in the US on December 23, 2014, and in the EU on March 23, 2015. This review examines the potential nonglycemic effects of GLP-1 receptor agonists. Methods A literature search was conducted to identify preclinical and clinical evidence on nonglycemic effects of GLP-1 receptor agonists. Results GLP-1 receptors are distributed widely in a number of tissues in humans, and their effects are not limited to the well-recognized effects on glycemia. Nonglycemic effects include weight loss, which is perhaps the most widely recognized nonglycemic effect. In addition, effects on the cardiovascular, neurologic, and renal systems and on taste perception may occur independently of weight loss. Conclusions GLP-1 receptor agonists may provide other nonglycemic clinical effects besides weight loss. Understanding these effects is important for prescribers in using GLP-1 receptor agonists for diabetic patients, but also if approved for chronic weight management. PMID:25959380

  2. Modulation Effect of Peroxisome Proliferator-Activated Receptor Agonists on Lipid Droplet Proteins in Liver.

    PubMed

    Zhu, Yun-Xia; Zhang, Ming-Liang; Zhong, Yuan; Wang, Chen; Jia, Wei-Ping

    2016-01-01

    Peroxisome proliferator-activated receptor (PPAR) agonists are used for treating hyperglycemia and type 2 diabetes. However, the mechanism of action of these agonists is still under investigation. The lipid droplet-associated proteins FSP27/CIDEC and LSDP5, regulated directly by PPAR? and PPAR?, are associated with hepatic steatosis and insulin sensitivity. Here, we evaluated the expression levels of FSP27/CIDEC and LSDP5 and the regulation of these proteins by consumption of a high-fat diet (HFD) or administration of PPAR agonists. Mice with diet-induced obesity were treated with the PPAR? or PPAR? agonist, pioglitazone or fenofibrate, respectively. Liver tissues from db/db diabetic mice and human were also collected. Interestingly, FSP27/CIEDC was expressed in mouse and human livers and was upregulated in obese C57BL/6J mice. Fenofibrate treatment decreased hepatic triglyceride (TG) content and FSP27/CIDEC protein expression in mice fed an HFD diet. In mice, LSDP5 was not detected, even in the context of insulin resistance or treatment with PPAR agonists. However, LSDP5 was highly expressed in humans, with elevated expression observed in the fatty liver. We concluded that fenofibrate greatly decreased hepatic TG content and FSP27/CIDEC protein expression in mice fed an HFD, suggesting a potential regulatory role for fenofibrate in the amelioration of hepatic steatosis. PMID:26770990

  3. Agonist-induced desensitization of adenylyl cyclase in Y1 adrenocortical tumor cells

    SciTech Connect

    Olson, M.F.; Tsao, J.; Pon, D.J.; Schimmer, B.P. )

    1991-01-01

    Y1 adrenocortical tumor cells (Y1DS) and Y1 mutants resistant to ACTH-induced desensitization of adenylyl cyclase (Y1DR) were transfected with a gene encoding the mouse beta 2-adrenergic receptor (beta 2-AR). Transfectants expressed beta 2-ARs that were able to stimulate adenylyl cyclase activity and steroid biosynthesis. These transfectants were used to explore the basis for the DR mutation in Y1 cells. The authors demonstrate that beta-adrenergic agonists desensitize the adenylyl cyclase system in transfected Y1DS cells whereas transfected Y1DR cells are resistant to desensitization by beta-adrenergic agonists. The fate of the beta 2-ARs during desensitization was evaluated by photoaffinity labelling with (125I)iodocyanopindolol diazerine. Desensitization of Y1DS transfectants was accompanied by a modest loss in receptor density that was insufficient to account for the complete loss of responsiveness to beta-adrenergic agonists. The extent of receptor loss induced by beta-adrenergic agonists in Y1DR transfectants exceeded that in the Y1DS transfectants indicating that the mutation which protects Y1DR cells from agonist-induced desensitization is prior to receptor down-regulation in the desensitization pathway. From these results we infer that ACTH and isoproterenol desensitize adenylyl cyclase by a common pathway and that receptor loss is not a major component of the desensitization process in these cells.

  4. Evidence for air movement signals in the agonistic behaviour of a nocturnal arachnid (order Amblypygi).

    PubMed

    Santer, Roger D; Hebets, Eileen A

    2011-01-01

    Many arthropods possess filiform hair sensilla (termed trichobothria in arachnids), which are extremely sensitive detectors of medium particle displacement. Electrophysiological evidence in some taxa suggests that these sensilla can detect air particle displacements resulting from intraspecific communication signals. However, it has not yet been shown for any species that the air particle displacements detected by the filiform hairs are themselves perceived as a 'signal' (i.e. that individuals make behavioural decisions based upon the responses of these organs to the displays of conspecifics). We investigate the agonistic behaviour of the whip spider Phrynus marginemaculatus and the role of its trichobothria in receiving agonistic signals. Whip spiders have extremely elongated 'antenniform' first legs, which they vibrate close to their opponents during agonistic interactions, inducing air movements that excite their opponents' trichobothria. We find that ablation of the trichobothria causes significant increases in: (I) contest duration, and (II) the probability of contest escalation past aggressive displays to physical fighting. Therefore, in the absence of air movement-sensitive sensilla, contest assessment is impaired. This suggests that whip spiders exploit true air movement signals during agonistic interactions, and that these are received by the trichobothria. Furthermore, these results indicate that, in whip spiders, such signals help mitigate the cost of agonistic interaction. PMID:21853035

  5. Receptors and Channels Targeted by Synthetic Cannabinoid Receptor Agonists and Antagonists

    PubMed Central

    Pertwee, R.G.

    2010-01-01

    It is widely accepted that non-endogenous compounds that target CB1 and/or CB2 receptors possess therapeutic potential for the clinical management of an ever growing number of disorders. Just a few of these disorders are already treated with Δ9-tetrahydrocannabinol or nabilone, both CB1/CB2 receptor agonists, and there is now considerable interest in expanding the clinical applications of such agonists and also in exploiting CB2-selective agonists, peripherally restricted CB1/CB2 receptor agonists and CB1/CB2 antagonists and inverse agonists as medicines. Already, numerous cannabinoid receptor ligands have been developed and their interactions with CB1 and CB2 receptors well characterized. This review describes what is currently known about the ability of such compounds to bind to, activate, inhibit or block non-CB1, non-CB2 G protein-coupled receptors such as GPR55, transmitter gated channels, ion channels and nuclear receptors in an orthosteric or allosteric manner. It begins with a brief description of how each of these ligands interacts with CB1 and/or CB2 receptors. PMID:20166927

  6. A dopamine partial agonist and antagonist block amphetamine self-administration in a progressive ratio schedule.

    PubMed

    Izzo, E; Orsini, C; Koob, G F; Pulvirenti, L

    2001-04-01

    A recently characterized class of compounds, dopamine partial agonists, have been suggested as potential therapeutic candidates for pharmacological intervention in psychostimulant addiction. These drugs bind to dopamine receptors with high affinity and low intrinsic activity and are thought to behave as functional antagonists in conditions of high dopaminergic tone, and as agonists in conditions of low receptor occupancy by dopamine. The aim of the present study was to characterize the effects of terguride, a partial dopamine agonist at the D2 receptor subtype, on intravenous self-administration of amphetamine in a progressive ratio schedule and to compare it with the effects produced by the dopamine D2 antagonist eticlopride and the dopamine D2 full agonist quinpirole. Terguride at the doses of 0.2 and 0.4 mg/kg i.p. significantly decreased the maximum number of responses delivered for a single injection of amphetamine ("breaking point"), an effect similar to that produced by the antagonist eticlopride (0.01-0.1 mg/kg s.c.). In contrast, administration of quinpirole (0.1-1 mg/kg s.c.) did not significantly modify the breaking point for amphetamine responding. Also, terguride dose-dependently increased responding for amphetamine self-administration on a continuous reinforcement schedule. These data further confirm the effects of terguride on psychostimulant self-administration and indicate that under these conditions partial dopamine agonists act as functional dopamine receptor antagonists. PMID:11526967

  7. 3D-Pharmacophore Identification for κ-Opioid Agonists Using Ligand-Based Drug-Design Techniques

    NASA Astrophysics Data System (ADS)

    Yamaotsu, Noriyuki; Hirono, Shuichi

    A selective κ-opioid receptor (KOR) agonist might act as a powerful analgesic without the side effects of μ-opioid receptor-selective drugs such as morphine. The eight classes of known KOR agonists have different chemical structures, making it difficult to construct a pharmacophore model that takes them all into account. Here, we summarize previous efforts to identify the pharmacophore for κ-opioid agonists and propose a new three-dimensional pharmacophore model that encompasses the κ-activities of all classes. This utilizes conformational sampling of agonists by high-temperature molecular dynamics and pharmacophore extraction through a series of molecular superpositions.

  8. Design and synthesis of silicon-containing fatty acid amide derivatives as novel peroxisome proliferator-activated receptor (PPAR) agonists.

    PubMed

    Kajita, Daisuke; Nakamura, Masaharu; Matsumoto, Yotaro; Ishikawa, Minoru; Hashimoto, Yuichi; Fujii, Shinya

    2015-08-15

    We recently reported that diphenylsilane structure can function as a cis-stilbene mimetic. Here, we investigate whether silyl functionality can also serve as a mimetic of aliphatic cis-olefin. We designed and synthesized various silyl derivatives of oleoylethanolamide (OEA: 8), an endogenous cis-olefin-containing PPAR? agonist, and evaluated their PPAR?/?/? agonistic activity. We found that diethylsilyl derivative 20 exhibited PPAR?/? agonistic activity, and we also obtained a PPAR?-selective agonist, 32. Our results suggest that incorporation of silyl functionality is a useful option for structural development of biologically active compounds. PMID:26071639

  9. Identification of PPARgamma Partial Agonists of Natural Origin (I): Development of a Virtual Screening Procedure and In Vitro Validation

    PubMed Central

    Guasch, Laura; Sala, Esther; Castell-Auví, Anna; Cedó, Lidia; Liedl, Klaus R.; Wolber, Gerhard; Muehlbacher, Markus; Mulero, Miquel; Pinent, Montserrat; Ardévol, Anna; Valls, Cristina; Pujadas, Gerard; Garcia-Vallvé, Santiago

    2012-01-01

    Background Although there are successful examples of the discovery of new PPARγ agonists, it has recently been of great interest to identify new PPARγ partial agonists that do not present the adverse side effects caused by PPARγ full agonists. Consequently, the goal of this work was to design, apply and validate a virtual screening workflow to identify novel PPARγ partial agonists among natural products. Methodology/Principal Findings We have developed a virtual screening procedure based on structure-based pharmacophore construction, protein-ligand docking and electrostatic/shape similarity to discover novel scaffolds of PPARγ partial agonists. From an initial set of 89,165 natural products and natural product derivatives, 135 compounds were identified as potential PPARγ partial agonists with good ADME properties. Ten compounds that represent ten new chemical scaffolds for PPARγ partial agonists were selected for in vitro biological testing, but two of them were not assayed due to solubility problems. Five out of the remaining eight compounds were confirmed as PPARγ partial agonists: they bind to PPARγ, do not or only moderately stimulate the transactivation activity of PPARγ, do not induce adipogenesis of preadipocyte cells and stimulate the insulin-induced glucose uptake of adipocytes. Conclusions/Significance We have demonstrated that our virtual screening protocol was successful in identifying novel scaffolds for PPARγ partial agonists. PMID:23226391

  10. TRANSPLANTATION EN MASSE DES ORGANES ABDOMINAUX

    PubMed Central

    STARZL, T.

    2010-01-01

    Les transplantations multi-organes, comprenant les blocs foie-duodnum-pancras, foie-estomac-duodnum-pancras, et foie-intestin sont ralises avec un succs croissant Ces techniques et leurs combinaisons varies de transplantation monobloc ne sont pas de pratique courante. Les techniques de prlvement, de conservation et de soins post-opratoires sont dcrites pour la transplantation multi-organes complte ainsi que pour les variantes incompltes. Le problme particulier ce type de transplantation est celui de la transplantation intestinale, cest--dire la transplantation dun organe composante lymphorticulaire complexe ce qui peut provoquer un syndrome greffon contre hte. Par erreur de conception, et un peu par esprit de systme, les efforts par le pass taient dirigs sur la modification et la destruction des systmes lymphorticulaires grce au traitement pralable du donneur ou des organes transplants, par mdicaments, radiation ou autres moyens. Actuellement, Iide directrice est de garder intacte les systmes lymphorticulaires qui deviennent alors le site dune circulation double sens aprs transplantation. Avec la puissante immunodpression que fournit le FK 506, les cellules lymphorticulaires du donneur peuvent circuler chez le receveur sans crer de syndrome du greffon contre hte clinique et les cellules de la greffe sassimilent celles du receveur (chimrisme local) sans provoquer de rejet. Mme si Ion vite le rejet ou le syndrome greffon contre hte, il existe, ct de ces entits, des relations mtaboliques entre les organes greffs ainsi quentre les organes greffs et les viscres du receveur laisss en place, qui peuvent influencer Iavenir soit des organes greffs, soit des organes laisss en place. Parmi les changes mtaboliques les mieux connus actuellement, il y a les facteurs splanchniques hpatotrophes endognes, dont Iinsuline est la mieux tudie. Une meilleure comprhension de ces facteurs, dorigine immunologique ou non immunologique, combins avec la puissante immunodpression dont nous disposons prsent, doit tre une stimulation la transplantation des organes abdominaux et en particulier, des viscres creux qui, jusqu prsent, ont fait obstacle aux efforts des chirurgiens et cliniciens sintressant la transplantation dorganes. PMID:1742622

  11. Etude numerique et experimentale de la reponse vibro-acoustique des structures raidies a des excitations aeriennes et solidiennes

    NASA Astrophysics Data System (ADS)

    Mejdi, Abderrazak

    Les fuselages des avions sont generalement en aluminium ou en composite renforces par des raidisseurs longitudinaux (lisses) et transversaux (cadres). Les raidisseurs peuvent etre metalliques ou en composite. Durant leurs differentes phases de vol, les structures d'avions sont soumises a des excitations aeriennes (couche limite turbulente : TBL, champs diffus : DAF) sur la peau exterieure dont l'energie acoustique produite se transmet a l'interieur de la cabine. Les moteurs, montes sur la structure, produisent une excitation solidienne significative. Ce projet a pour objectifs de developper et de mettre en place des strategies de modelisations des fuselages d'avions soumises a des excitations aeriennes et solidiennes. Tous d'abord, une mise a jour des modeles existants de la TBL apparait dans le deuxieme chapitre afin de mieux les classer. Les proprietes de la reponse vibro-acoustique des structures planes finies et infinies sont analysees. Dans le troisieme chapitre, les hypotheses sur lesquelles sont bases les modeles existants concernant les structures metalliques orthogonalement raidies soumises a des excitations mecaniques, DAF et TBL sont reexamines en premier lieu. Ensuite, une modelisation fine et fiable de ces structures est developpee. Le modele est valide numeriquement a l'aide des methodes des elements finis (FEM) et de frontiere (BEM). Des tests de validations experimentales sont realises sur des panneaux d'avions fournis par des societes aeronautiques. Au quatrieme chapitre, une extension vers les structures composites renforcees par des raidisseurs aussi en composites et de formes complexes est etablie. Un modele analytique simple est egalement implemente et valide numeriquement. Au cinquieme chapitre, la modelisation des structures raidies periodiques en composites est beaucoup plus raffinee par la prise en compte des effets de couplage des deplacements planes et transversaux. L'effet de taille des structures finies periodiques est egalement pris en compte. Les modeles developpes ont permis de conduire plusieurs etudes parametriques sur les proprietes vibro-acoustiques des structures d'avions facilitant ainsi la tache des concepteurs. Dans le cadre de cette these, un article a ete publie dans le Journal of Sound and Vibration et trois autres soumis, respectivement aux Journal of Acoustical Society of America, International Journal of Solid Mechanics et au Journal of Sound and Vibration Mots cles : structures raidies, composites, vibro-acoustique, perte par transmission.

  12. Synthesis and in vitro evaluation of [18F]FECIMBI-36: A potential agonist PET ligand for 5-HT2A/2C receptors

    PubMed Central

    Prabhakaran, Jaya; Underwood, Mark D.; Dileep Kumar, J. S.; Simpson, Norman R.; Kassir, Suham A.; Bakalian, Mihran J.; Mann, J. John; Arango, Victoria

    2016-01-01

    Radiosynthesis and in vitro evaluation of [18F]-2-(4-bromo-2,5-dimethoxyphenyl)-N-(2-(2-fluoroethoxy)benzyl)ethanamine, ([18F]FECIMBI-36) or ([18F]1), a potential agonist PET imaging agent for 5-HT2A/2C receptors is described. Syntheses of reference standard 1 and the corresponding des-fluoroethyl radiolabeling precursor (2) were achieved with 75% and 65% yields, respectively. In vitro pharmacology assay of FECIMBI-36 by [3H]-ketanserin competition binding assay obtained from NIMH-PDSP showed high affinities to 5-HT2AR (Ki = 1 nM) and 5-HT2CR (Ki = 1.7 nM). Radiolabeling of FECIMBI-36 was achieved from the boc-protected precursor 2 using [18F]-fluoroethyltosylate in presence of Cs2CO3 in DMSO followed by removal of the protective group. [18F]1 was isolated using RP-HPLC in 25 ± 5% yield, purity ≥95% and specific activity 1–2 Ci/μmol (N = 6). In vitro autoradiography studies demonstrate that [18F]1 selectively label 5-HT2A and 5-HT2C receptors in slide-mounted sections of postmortem human brain using phosphor imaging. Our results indicate the potential of [18F]1 for imaging 5-HT2A/2C receptors in the high affinity state in vivo using PET imaging. PMID:26253634

  13. The PPAR? Agonist Pioglitazone Ameliorates Aging-Related Progressive Renal Injury

    PubMed Central

    Yang, Hai-Chun; Deleuze, Sebastien; Zuo, Yiqin; Potthoff, Sebastian A.; Ma, Li-Jun

    2009-01-01

    Peroxisome proliferator-activated receptor-? (PPAR-?) agonists not only improve metabolic abnormalities of diabetes and consequent diabetic nephropathy, but they also protect against nondiabetic chronic kidney disease in experimental models. Here, we found that the PPAR-? agonist pioglitazone protected against renal injury in aging; it reduced proteinuria, improved GFR, decreased sclerosis, and alleviated cell senescence. Increased local expression of PPAR-? paralleled these changes. Underlying mechanisms included increased expression of klotho, decreased systemic and renal oxidative stress, and decreased mitochondrial injury. Pioglitazone also regulated p66Shc phosphorylation, which integrates many signaling pathways that affect mitochondrial function and longevity, by reducing protein kinase C-?. These results suggest that PPAR-? agonists may benefit aging-related renal injury by improving mitochondrial function. PMID:19797472

  14. Discovery of novel indazole derivatives as dual angiotensin II antagonists and partial PPARγ agonists.

    PubMed

    Lamotte, Yann; Faucher, Nicolas; Sançon, Julien; Pineau, Olivier; Sautet, Stéphane; Fouchet, Marie-Hélène; Beneton, Véronique; Tousaint, Jean-Jacques; Saintillan, Yannick; Ancellin, Nicolas; Nicodeme, Edwige; Grillot, Didier; Martres, Paul

    2014-02-15

    Identification of indazole derivatives acting as dual angiotensin II type 1 (AT1) receptor antagonists and partial peroxisome proliferator-activated receptor-γ (PPARγ) agonists is described. Starting from Telmisartan, we previously described that indole derivatives were very potent partial PPARγ agonists with loss of AT1 receptor antagonist activity. Design, synthesis and evaluation of new central scaffolds led us to the discovery of pyrrazolopyridine then indazole derivatives provided novel series possessing the desired dual activity. Among the new compounds, 38 was identified as a potent AT1 receptor antagonist (IC50=0.006 μM) and partial PPARγ agonist (EC50=0.25 μM, 40% max) with good oral bioavailability in rat. The dual pharmacology of compound 38 was demonstrated in two preclinical models of hypertension (SHR) and insulin resistance (Zucker fa/fa rat). PMID:24462665

  15. 2-Aminoalkyl nicotinamide derivatives as pure inverse agonists of the ghrelin receptor.

    PubMed

    Takahashi, Bitoku; Funami, Hideaki; Iwaki, Takehiko; Maruoka, Hiroshi; Nagahira, Asako; Koyama, Makoto; Kamiide, Yoshiyuki; Matsuo, Tsuyoshi; Muto, Tsuyoshi; Annoura, Hirokazu

    2015-07-01

    New inverse agonists of the ghrelin receptor (ghrelinR) were obtained through high-throughput screening and subsequent structural modification of 2-aminoalkyl nicotinamide derivatives. The key structural feature to improve in vitro activity was the introduction of a diazabicyclo ring at the 5-position of the pyridine ring. The final product showed potent inverse agonist activity and, despite its low brain permeability, reduced food intake in both normal and obese mice. These results implied that peripheral ghrelinR activity is important for appetite control and that a peripheral ghrelinR inverse agonist could be an anti-obesity drug with reduced risk of central nervous system (CNS)-related side effects. PMID:25981690

  16. Anticancer Role of PPAR? Agonists in Hematological Malignancies Found in the Vasculature, Marrow, and Eyes

    PubMed Central

    Simpson-Haidaris, P. J.; Pollock, S. J.; Ramon, S.; Guo, N.; Woeller, C. F.; Feldon, S. E.; Phipps, R. P.

    2010-01-01

    The use of targeted cancer therapies in combination with conventional chemotherapeutic agents and/or radiation treatment has increased overall survival of cancer patients. However, longer survival is accompanied by increased incidence of comorbidities due, in part, to drug side effects and toxicities. It is well accepted that inflammation and tumorigenesis are linked. Because peroxisome proliferator-activated receptor (PPAR)-? agonists are potent mediators of anti-inflammatory responses, it was a logical extension to examine the role of PPAR? agonists in the treatment and prevention of cancer. This paper has two objectives: first to highlight the potential uses for PPAR? agonists in anticancer therapy with special emphasis on their role when used as adjuvant or combined therapy in the treatment of hematological malignancies found in the vasculature, marrow, and eyes, and second, to review the potential role PPAR? and/or its ligands may have in modulating cancer-associated angiogenesis and tumor-stromal microenvironment crosstalk in bone marrow. PMID:20204067

  17. Design and Synthesis of Non-Peptide, Selective Orexin Receptor 2 Agonists.

    PubMed

    Nagahara, Takashi; Saitoh, Tsuyoshi; Kutsumura, Noriki; Irukayama-Tomobe, Yoko; Ogawa, Yasuhiro; Kuroda, Daisuke; Gouda, Hiroaki; Kumagai, Hidetoshi; Fujii, Hideaki; Yanagisawa, Masashi; Nagase, Hiroshi

    2015-10-22

    Orexins are a family of neuropeptides that regulate sleep/wakefulness, acting on two G-protein-coupled receptors, orexin receptors 1 (OX1R) and 2 (OX2R). Genetic and pharmacologic evidence suggests that orexin receptor agonists, especially OX2R agonist, will be useful for mechanistic therapy of the sleep disorder narcolepsy/cataplexy. We herein report the discovery of a potent (EC50 on OX2R is 0.023 μM) and OX2R-selective (OX1R/OX2R EC50 ratio is 70) agonist, 4'-methoxy-N,N-dimethyl-3'-[N-(3-{[2-(3-methylbenzamido)ethyl]amino}phenyl)sulfamoyl]-(1,1'-biphenyl)-3-carboxamide 26. PMID:26267383

  18. Clinical use of deslorelin (GnRH agonist) in companion animals: a review.

    PubMed

    Lucas, X

    2014-10-01

    Over the years, many contraceptive medications have been developed for companion animals, but many secondary adverse effects have limited their use. A major advancement was achieved with the use of gonadotropin-releasing hormone (GnRH) analogues, mainly GnRH agonists, which mimic the effects of native GnRH. The development of effective low-dose, slow-release implants with potent agonists such as deslorelin (Suprelorin, Virbac) have allowed their use to become widespread in recent years, with many potential benefits in companion animals. While the major application of deslorelin was initially male contraception, due to its two differing actions, either the stimulation of oestrus or the sterilization of fertility, its use has been increasing in the bitch as well. The aim of this study is to review the applications of deslorelin GnRH agonist implants in companion animal, such as dogs, cats and some exotic pets. PMID:25277434

  19. Optimisation of in silico derived 2-aminobenzimidazole hits as unprecedented selective kappa opioid receptor agonists.

    PubMed

    Sasmal, Pradip K; Krishna, C Vamsee; Adabala, S Sudheerkumar; Roshaiah, M; Rawoof, Khaji Abdul; Thadi, Emima; Sukumar, K Pavan; Cheera, Srisailam; Abbineni, Chandrasekhar; Rao, K V L Narasimha; Prasanthi, A; Nijhawan, Kamal; Jaleel, Mahaboobi; Iyer, Lakshmi Ramachandran; Chaitanya, T Krishna; Tiwari, Nirbhay Kumar; Krishna, N Lavanya; Potluri, Vijay; Khanna, Ish; Frimurer, Thomas M; Lckmann, Michael; Rist, ystein; Elster, Lisbeth; Hgberg, Thomas

    2015-02-15

    Kappa opioid receptor (KOR) is an important mediator of pain signaling and it is targeted for the treatment of various pains. Pharmacophore based mining of databases led to the identification of 2-aminobenzimidazole derivative as KOR agonists with selectivity over the other opioid receptors DOR and MOR. A short SAR exploration with the objective of identifying more polar and hence less brain penetrant agonists is described herewith. Modeling studies of the recently published structures of KOR, DOR and MOR are used to explain the receptor selectivity. The synthesis, biological evaluation and SAR of novel benzimidazole derivatives as KOR agonists are described. The in vivo proof of principle for anti-nociceptive effect with a lead compound from this series is exemplified. PMID:25599839

  20. Selexipag: An Oral and Selective IP Prostacyclin Receptor Agonist for the Treatment of Pulmonary Arterial Hypertension.

    PubMed

    Asaki, Tetsuo; Kuwano, Keiichi; Morrison, Keith; Gatfield, John; Hamamoto, Taisuke; Clozel, Martine

    2015-09-24

    Prostacyclin controls cardiovascular function via activation of the prostacyclin receptor. Decreased prostacyclin production occurs in several cardiovascular diseases. However, the clinical use of prostacyclin and its analogues is complicated by their chemical and metabolic instability. A medicinal chemistry program searched for novel nonprostanoid prostacyclin receptor agonists not subject to these limitations. A compound with a diphenylpyrazine structural core was synthesized. Metabolic stability and agonist potency were optimized through modification of the linear side chain. Compound 12b (MRE-269, ACT-333679) was identified as a potent and highly selective prostacyclin receptor agonist. Replacement of the terminal carboxyl group with an N-acylsulfonamide group yielded parent compound 26a (selexipag, NS-304, ACT-293987), which is orally active and provides sustained plasma exposure of 12b. Compound 26a was developed for the treatment of pulmonary arterial hypertension and shown to reduce the risk of the composite morbidity/mortality end point in a phase 3 event-driven clinical trial. PMID:26291199

  1. Metabotropic glutamate receptor agonists potentiate a slow afterdepolarization in CNS neurons

    NASA Technical Reports Server (NTRS)

    Zheng, F.; Gallagher, J. P.

    1992-01-01

    We have previously reported that, in the rat dorsolateral septal nucleus (DLSN), metabotropic glutamate receptor (met-GluR) agonists evoked a slow depolarization accompanied by an increase in membrane conductance and burst firing. We have speculated that the burst firing elicited by met-GluR agonists may be due to activation or enhancement of a non-specific cation current, which exists in some DLSN neurons. Now we report that a slow afterdepolarization (sADP) mediated by a non-specific cation current was potentiated by both 1S,3R-ACPD and quisqualate. In addition, met-GluR agonists unmask a sADP in DLSN neurons which did not show a sADP under control conditions. Our data suggest that a non-specific cation current can be potentiated by activation of the met-GluR.

  2. Electronic and structural features of γ-aminobutyric acid (GABA) and four of its direct agonists

    NASA Astrophysics Data System (ADS)

    Lipkowitz, Kenny B.; Gilardi, Richard D.; Aprison, M. H.

    1989-04-01

    To understand better how the inhibitory neurotransmitter γ-aminobutyric acid (GABA) functions at its postsynaptic receptor site, electronic and structural features of the natural inhibitor were compared with four direct GABA agonists: muscimol, trans-3-amino-1-cyclopentane carboxylic acid ( trans-3 ACPC), isoguvacine and 4,5,6,7-tetrahydroisoxazolo [5,4-c]-pyridin-3-ol (THIP). The structures of isoguvacine and THIP were determined by X-ray crystallography. The structures of GABA and muscimol were retrieved from the literature and that of trans-3 ACPC was computed with AM1. A relationship was found between published IC50 values obtained from ( 3H)-GABA binding data and the per cent polar surface area scaled by molecular ionization potential. The structural features of GABA and its agonists were compared and a hypothesis for GABA agonist activity based upon position of the ammonium ion with respect to the carboxylate is presented.

  3. Cannabinoid CB(2)-selective inverse agonist protects against antigen-induced bone loss.

    PubMed

    Lunn, Charles A; Fine, Jay; Rojas-Triana, Alberto; Jackson, James V; Lavey, Brian; Kozlowski, Joseph A; Hipkin, R William; Lundell, Daniel J; Bober, Loretta

    2007-01-01

    Work to improve the therapeutic properties of cannabinoid CB(2) receptor-selective inverse agonists has led to the development of Sch.036, an aryl substituted triaryl bis-sulfone with improved oral pharmacokinetic parameters. In this report, we show that this compound blocks in vivo trafficking of various leukocyte populations, a property consistent with other members of this chemical series. This CB(2)-selective compound also shows efficacy in leukocyte recruitment models when added in concert with suboptimal doses of selected anti-inflammatory agents, consistent with its unique function and indicative of its potential therapeutic utility. Finally, studies with Sch.036 show that this cannabinoid CB(2)-specific inverse agonist can ameliorate bone damage in a rat model of relapsing-remitting arthritis. This result suggests that a cannabinoid CB(2)-selective inverse agonist may help ameliorate a particularly harmful property of this inflammatory joint disease. PMID:18075852

  4. Cyclic AMP agonist inhibition increases at low levels of histamine release from human basophils

    SciTech Connect

    Tung, R.S.; Lichtenstein, L.M.

    1981-09-01

    The relationship between the intensity of the signal for antigen-induced immunoglobulin E-mediated histamine release from human basophils and the concentration of agonist needed to inhibit release has been determined. The agonists, prostaglandin E1, dimaprit, fenoterol, isobutylmethylxanthine and dibutyryl cyclic AMP, all act by increasing the cyclic AMP level. Each agonist was 10- to 1000-fold more potent (relative ID50) at low levels of histamine release (5-10% of total histamine) than at high levels (50-80%). Thus, the inhibitory potential of a drug is a function of the concentration of antigen used to initiate the response. Our results are now more in accord with the inhibitory profile of these drugs in human lung tissue. It is suggested that in vivo release is likely to be low and that this is the level at which to evaluate drugs in vitro.

  5. Structure of an agonist-bound human A2A adenosine receptor

    PubMed Central

    Xu, Fei; Wu, Huixian; Katritch, Vsevolod; Han, Gye Won; Jacobson, Kenneth A.; Gao, Zhan-Guo; Cherezov, Vadim; Stevens, Raymond C.

    2011-01-01

    Activation of G protein-coupled receptors upon agonist binding is a critical step in the signaling cascade for this family of cell surface proteins. Here we report the crystal structure of the A2A adenosine receptor (A2AAR) bound to an agonist UK-432097 at 2.7 angstrom resolution. Relative to inactive, antagonist-bound A2AAR, the agonist-bound structure displays an outward tilt and rotation of the cytoplasmic half of helix VI, a movement of helix V and an axial shift of helix III, resembling the changes associated with the active-state opsin structure. Additionally, a seesaw movement of helix VII and a shift of extracellular loop 3 are likely specific to A2AAR and its ligand. The results define the molecule UK-432097 as a “conformationally selective agonist” capable of receptor stabilization in a specific active state configuration. PMID:21393508

  6. The four As associated with pathological Parkinson disease gamblers: anxiety, anger, age, and agonists

    PubMed Central

    Shapiro, Michael A; Chang, Yu Ling; Munson, Sarah K; Jacobson, Charles E; Rodriguez, Ramon L; Skidmore, Frank M; Okun, Michael S; Fernandez, Hubert H

    2007-01-01

    Several studies have related pathological gambling in PD to dopamine agonist therapy. A mail-in survey was sent to PD patients seen at the University of Florida Movement Disorders Center to determine gambling frequency and behavior, and any lifestyle or environmental factors associated with compulsive gambling in PD. 462 surveys were sent and 127 completed surveys were returned, of which ten were from patients who met criteria for compulsive gambling. All ten were taking dopamine agonists coincident with the compulsive gambling. Compulsive gamblers were younger, and psychological distress measures revealed that compulsive gamblers exhibited higher levels of anxiety, anger, and confusion. Thus in this cohort, we have uncovered the several characteristics of the most likely PD compulsive gambler, namely: (young) age, “angry”, “anxious”, and using a (dopamine) agonist. PMID:19300546

  7. Induction of locomotion in spinal tadpoles by excitatory amino acids and their agonists.

    PubMed

    Harrison, P H

    1990-04-01

    Bath application of the excitatory amino acids L-aspartate and/or L-glutamate or their agonists N-methyl-D,L-aspartate and/or kainate elicited swimming movements in spinal tadpoles. Swimming cycles induced by the amino acids were in the frequency range of natural movements, and could be evoked after sectioning all dorsal roots in the exposed spinal segments. Locomotion was only elicited by L-aspartate or L-glutamate at low concentrations when the bath medium was rapidly circulated over the exposed surface of the spinal cord, and was of much shorter duration than the agonist-induced movements. These results indicate some differences between the actions of L-aspartate and L-glutamate and their agonists on the tadpole spinal cord. PMID:1971849

  8. Beta-adrenergic agonists increase lung liquid clearance in anesthetized sheep.

    PubMed Central

    Berthiaume, Y; Staub, N C; Matthay, M A

    1987-01-01

    We did experiments to determine whether beta-adrenergic agonists increase lung liquid clearance in anesthetized ventilated adult sheep and, if so, whether the increase is mediated by beta receptors and what mechanism is involved. We instilled 100 ml of autologous serum either alone or with a beta-adrenergic agonist (terbutaline, 10(-5) M, or epinephrine, 5.5 X 10(-6) M) into one lower lobe. After 4 h both terbutaline and epinephrine increased lung liquid clearance. The increase in lung liquid clearance was inhibited when propranolol (a beta blocker) or amiloride (a sodium channel blocker) was added to the terbutaline. Increased clearance was not explained by changes in pulmonary hemodynamics, pulmonary blood flow, or lung lymph flow. We conclude that beta-adrenergic agonists increase lung liquid clearance in anesthetized intact adult sheep. This increase is mediated through beta receptors and probably depends on increased active transport of sodium across the alveolar barrier. Images PMID:2879851

  9. An agonist antibody that blocks autoimmunity by inducing anti-inflammatory macrophages.

    PubMed

    Han, Kyung Ho; Gonzalez-Quintial, Rosana; Peng, Yingjie; Baccala, Roberto; Theofilopoulos, Argyrios N; Lerner, Richard A

    2016-02-01

    We have devised a method of using intracellular combinatorial libraries to select antibodies that control cell fates. Many agonist antibodies have been selected with this method, and the process appears to be limited only by the availability of a phenotypic selection system. We demonstrate the utility of this approach to discover agonist antibodies that engage an unanticipated target and regulate macrophage polarization by selective induction of anti-inflammatory M2 macrophages. This antibody was used therapeutically to block autoimmunity in a classic mouse model of spontaneous systemic lupus erythematosus.-Han, K. H., Gonzalez-Quintial, R., Peng, Y., Baccala R., Theofilopoulos, A. N., Lerner, R. A. An agonist antibody that blocks autoimmunity by inducing anti-inflammatory macrophages. PMID:26481307

  10. Evaluation of difluoromethyl ketones as agonists of the ?-aminobutyric acid type B (GABAB) receptor.

    PubMed

    Han, Changho; Salyer, Amy E; Kim, Eun Hoo; Jiang, Xinyi; Jarrard, Rachel E; Powers, Matthew S; Kirchhoff, Aaron M; Salvador, Tolani K; Chester, Julia A; Hockerman, Gregory H; Colby, David A

    2013-03-28

    The design, synthesis, biological evaluation, and in vivo studies of difluoromethyl ketones as GABAB agonists that are not structurally analogous to known GABAB agonists, such as baclofen or 3-aminopropyl phosphinic acid, are presented. The difluoromethyl ketones were assembled in three synthetic steps using a trifluoroacetate-release aldol reaction. Following evaluation at clinically relevant GABA receptors, we have identified a difluoromethyl ketone that is a potent GABAB agonist, obtained its X-ray structure, and presented preliminary in vivo data in alcohol-preferring mice. The behavioral studies in mice demonstrated that this compound tended to reduce the acoustic startle response, which is consistent with an anxiolytic profile. Structure-activity investigations determined that replacing the fluorines of the difluoromethyl ketone with hydrogens resulted in an inactive analogue. Resolution of the individual enantiomers of the difluoromethyl ketone provided a compound with full biological activity at concentrations less than an order of magnitude greater than the pharmaceutical, baclofen. PMID:23428109

  11. Search for new type of PPAR? agonist-like anti-diabetic compounds from medicinal plants.

    PubMed

    Matsuda, Hisashi; Nakamura, Seikou; Yoshikawa, Masayuki

    2014-01-01

    Potent ligands of peroxisome proliferator-activated receptor ? (PPAR?) such as thiazolidinediones (pioglitazone, troglitazone, etc.) improve insulin sensitivity by increasing the levels of adiponectin, an important adipocytokine associated with insulin sensitivity in adipose tissue. Several constituents from medicinal plants were recently reported to show PPAR? agonist-like activity in 3T3-L1 cells, but did not show agonistic activity at the receptor site different from thiazolidinediones. Our recent studies on PPAR? agonist-like constituents, such as hydrangenol and hydrangeic acid from the processed leaves of Hydrangea macrophylla var. thunbergii, piperlonguminine and retrofractamide A from the fruit of Piper chaba, and tetramethylkaempferol and pentamethylquercetin from the rhizomes of Kaempferia parviflora, are reviewed. PMID:24882400

  12. PPAR{alpha} agonists up-regulate organic cation transporters in rat liver cells

    SciTech Connect

    Luci, Sebastian; Geissler, Stefanie; Koenig, Bettina; Koch, Alexander; Stangl, Gabriele I.; Hirche, Frank; Eder, Klaus . E-mail: klaus.eder@landw.uni-halle.de

    2006-11-24

    It has been shown that clofibrate treatment increases the carnitine concentration in the liver of rats. However, the molecular mechanism is still unknown. In this study, we observed for the first time that treatment of rats with the peroxisome proliferator activated receptor (PPAR)-{alpha} agonist clofibrate increases hepatic mRNA concentrations of organic cation transporters (OCTNs)-1 and -2 which act as transporters of carnitine into the cell. In rat hepatoma (Fao) cells, treatment with WY-14,643 also increased the mRNA concentration of OCTN-2. mRNA concentrations of enzymes involved in carnitine biosynthesis were not altered by treatment with the PPAR{alpha} agonists in livers of rats and in Fao cells. We conclude that PPAR{alpha} agonists increase carnitine concentrations in livers of rats and cells by an increased uptake of carnitine into the cell but not by an increased carnitine biosynthesis.

  13. Quantification des besoins en intrants antipaludiques: contribution l'actualisation des hypothses pour la quantification des intrants de prise en charge des cas de paludisme grave en Rpublique Dmocratique du Congo

    PubMed Central

    Likwela, Joris Losimba; Otokoye, John Otshudiema

    2015-01-01

    Les formes graves de paludisme Plasmodium falciparum sont une cause majeure de dcs des enfants de moins de 5 ans en Afrique Sub-saharienne. Un traitement rapide dpend de la disponibilit de mdicaments appropris au niveau des points de prestation de service. La frquence des ruptures de stock des commodits antipaludiques, en particuliers celles utilises pour le paludisme grave, avait ncessit une mise jour des hypothses de quantification. Les donnes issues de la collecte de routine du PNLP de 2007 2012 ont t compares celles rapports par d'autres pays africains et utilises pour orienter les discussions au cours d'un atelier organis par le PNLP et ses partenaires techniques et financiers afin de dgager un consensus national. La proportion des cas de paludisme rapports comme grave en RDC est rest autour d'une mdiane de 7% avec un domaine de variation de 6 9%. Hormis la proportion rapporte au Kenya (2%), les pays africains ont rapport une proportion de cas grave variant entre 5 et 7%. Il apparat que la proportion de 1% prcdemment utilise pour la quantification en RDC a t sous-estime dans le contexte de la gestion des cas graves sur terrain. Un consensus s'est dgag autour de la proportion de 5% tant entendu que des efforts de renforcement des capacits seraient dploys afin d'amliorer le diagnostic au niveau des points de prestation des services. PMID:26213595

  14. Recovery of brain biomarkers following peroxisome proliferator-activated receptor agonist neuroprotective treatment before ischemic stroke

    PubMed Central

    2014-01-01

    Background Lipid lowering agent such as agonists of peroxisome proliferator-activated receptors (PPAR) are suggested as neuroprotective agents and may protect from the sequelae of brain ischemic stroke. Although the demonstration is not clearly established in human, the underlying molecular mechanism may be of interest for future therapeutic purposes. To this end, we have used our well established rodent model of ischemia-reperfusion pre-treated or not with fenofibrate or atorvastatin and performed a differential proteomics analyses of the brain and analysed the protein markers which levels returned to “normal” following pre-treatments with PPARα agonists. Results In order to identify potential therapeutic targets positively modulated by pre-treatment with the PPARα agonists, two-dimensional gel electrophoresis proteome profiles between control, ischemia-reperfusion and pre-treated or not, were compared. The polypeptide which expression was altered following ischemia – reperfusion but whose levels remain unchanged after pre-treatment were characterized by mass spectrometry and further investigated by Western-blotting and immunohistochemistry. A series of 28 polypeptides were characterized among which the protein disulfide isomerase reduction – a protein instrumental to the unfolded protein response system - was shown to be reduced following PPARα agonists treatment while it was strongly increased in ischemia-reperfusion. Conclusions Pre-treatment with PPARα agonist or atorvastatin show potential neuroprotective effects by inhibiting the PDI overexpression in conjunction with the preservation of other neuronal markers, several of which are associated with the regulation of protein homeostasis, signal transduction and maintenance of synaptic plasticity. This proteomic study therefore suggests that neuroprotective effect of PPARα agonists supposes the preservation of the expression of several proteins essential for the maintenance of protein homeostasis not necessarily directly linked to PPARα known-regulated targets. PMID:24944524

  15. Two-component desensitization of nicotinic receptors induced by acetylcholine agonists in Lymnaea stagnalis neurones.

    PubMed Central

    Andreev, A A; Veprintsev, B N; Vulfius, C A

    1984-01-01

    The kinetics of desensitization induced by different agonists of acetylcholine (ACh) as well as the kinetics of recovery from densensitization, have been studied using the voltage-clamp technique in isolated, identified Lymnaea stagnalis neurones. Desensitization follows the sum of two exponentials: one fast and one slow. The time constant of the fast desensitization component (tau Ids) under ACh application is in the range of seconds at room temperature (18-23 degrees C). It increases upon cooling (Q10 = 2.8 +/- 0.9), decreases with increasing ACh concentration and is independent of membrane voltage. The time constant of the slow component of densensitization (tau Ids) is in the range of tens of seconds. It decreases with increasing drug concentration and is weakly dependent upon temperature (Q10 = 1.3 +/- 0.4). The relative amplitude of the fast component, estimated by back extrapolation to the position of the peak current, increases with agonist concentration and decreases upon cooling. Recovery from desensitization follows the sum of two exponentials with time constants (tau Ir and tau IIr) of the order of seconds and minutes, respectively. Cooling prolongs the slow component (Q10 of tau IIr is approx. 3) and reduces its contribution during recovery. A comparison of the desensitization induced by various agonists indicates that for the small monoquaternary agonists the onset and recovery of desensitization resemble the onset and recovery observed with ACh. For more bulky agonists, like ethoxysebacylcholine, sebacylcholine and suberylcholine, the decay of the response during prolonged application of the agonist may involve an additional blocking process. PMID:6481626

  16. Ligand-based receptor tyrosine kinase partial agonists: New paradigm for cancer drug discovery?

    PubMed Central

    Riese, David J.

    2010-01-01

    Introduction Receptor tyrosine kinases (RTKs) are validated targets for oncology drug discovery and several RTK antagonists have been approved for the treatment of human malignancies. Nonetheless, the discovery and development of RTK antagonists has lagged behind the discovery and development of agents that target G-protein coupled receptors. In part, this is because it has been difficult to discover analogs of naturally-occurring RTK agonists that function as antagonists. Areas covered Here we describe ligands of ErbB receptors that function as partial agonists for these receptors, thereby enabling these ligands to antagonize the activity of full agonists for these receptors. We provide insights into the mechanisms by which these ligands function as antagonists. We discuss how information concerning these mechanisms can be translated into screens for novel small molecule- and antibody-based antagonists of ErbB receptors and how such antagonists hold great potential as targeted cancer chemotherapeutics. Expert opinion While there have been a number of important key findings into this field, the identification of the structural basis of ligand functional specificity is still of the greatest importance. While it is true that, with some notable exceptions, peptide hormones and growth factors have not proven to be good platforms for oncology drug discovery; addressing the fundamental issues of antagonistic partial agonists for receptor tyrosine kinases has the potential to steer oncology drug discovery in new directions. Mechanism based approaches are now emerging to enable the discovery of RTK partial agonists that may antagonize both agonist-dependent and independent RTK signaling and may hold tremendous promise as targeted cancer chemotherapeutics. PMID:21532939

  17. The atypical antidepressant mianserin exhibits agonist activity at κ-opioid receptors

    PubMed Central

    Olianas, Maria C; Dedoni, Simona; Onali, Pierluigi

    2012-01-01

    BACKGROUND AND PURPOSE Antidepressants are known to interact with the opioid system through mechanisms not completely understood. We previously reported that tricyclic antidepressants act as agonists at distinct opioid receptors. Here, we investigated the effect of the atypical antidepressant mianserin at cloned and native opioid receptors. EXPERIMENTAL APPROACH Effects of mianserin were examined in CHO cells transfected with human opioid receptors, C6 glioma cells and rat brain membranes by the use of radioligand binding and functional assays including the stimulation of [35S]GTPγS binding and MAPK phosphorylation. KEY RESULTS Mianserin displayed 12- and 18-fold higher affinity for κ- than µ- and δ-opioid receptors respectively. In [35S]GTPγS assays, mianserin selectively activated κ-opioid receptors. The agonist activity was antagonized by the selective κ-opioid blocker nor-binaltorphimine (nor-BNI). The mianserin analogue mirtazapine also displayed κ-opioid agonist activity. Mianserin and mirtazapine increased ERK1/2 phosphorylation in CHO cells expressing κ-opioid receptors and C6 cells, and these effects were antagonized by nor-BNI. In rat striatum and nucleus accumbens, mianserin stimulated [35S]GTPγS binding in a nor-BNI-sensitive manner with maximal effects lower than those of the full κ-opioid agonists (–)-U50,488 and dynorphin A. When combined, mianserin antagonized the effects of the full κ-opioid receptor agonists in [35S]GTPγS assays and reduced the stimulation of p38 MAPK and ERK1/2 phosphorylation by dynorphin A. CONCLUSIONS AND IMPLICATIONS In different cell systems, mianserin directly activates κ-opioid receptors, displaying partial agonist activity at brain receptors. Thus, this property appears to be a common feature of different classes of antidepressants. PMID:22708686

  18. A membrane-based microfluidic device for controlling the flux of platelet agonists into flowing blood.

    PubMed

    Neeves, Keith B; Diamond, Scott L

    2008-05-01

    The flux of platelet agonists into flowing blood is a critical event in thrombosis and hemostasis. However, few in vitro methods exist for examining and controlling the role of platelet agonists on clot formation and stability under hemodynamic conditions. In this paper, we describe a membrane-based method for introducing a solute into flowing blood at a defined flux. The device consisted of a track-etched polycarbonate membrane reversibly sealed between two microfluidic channels; one channel contained blood flowing at a physiologically relevant shear rate, and the other channel contained the agonist(s). An analytical model described the solute flux as a function of the membrane permeability and transmembrane pressure. The model was validated using luciferase as a model solute for transmembrane pressures of 50-400 Pa. As a proof-of-concept, the weak platelet agonist ADP was introduced into whole blood flowing at 250 s(-1) at three fluxes (1.5, 2.4, and 4.4 x 10(-18) mol microm(-2) s(-1)). Platelet aggregation was monitored by fluorescence microscopy during the experiment and the morphology of aggregates was determined by post hoc confocal and electron microscopy. At the lowest flux (1.5 x 10(-18) mol microm(-2) s(-1)), we observed little to no aggregation. At the higher fluxes, we observed monolayer (2.4 x 10(-18) mol microm(-2) s(-1)) and multilayer (4.4 x 10(-18) mol microm(-2) s(-1)) aggregates of platelets and found that the platelet density within an aggregate increased with increasing ADP flux. We expect this device to be a useful tool in unraveling the role of platelet agonists on clot formation and stability. PMID:18432339

  19. STING agonists induce an innate antiviral immune response against hepatitis B virus.

    PubMed

    Guo, Fang; Han, Yanxing; Zhao, Xuesen; Wang, Jianghua; Liu, Fei; Xu, Chunxiao; Wei, Lai; Jiang, Jian-Dong; Block, Timothy M; Guo, Ju-Tao; Chang, Jinhong

    2015-02-01

    Chronicity of hepatitis B virus (HBV) infection is due to the failure of a host to mount a sufficient immune response to clear the virus. The aim of this study was to identify small-molecular agonists of the pattern recognition receptor (PRR)-mediated innate immune response to control HBV infection. To achieve this goal, a coupled mouse macrophage and hepatocyte culture system mimicking the intrahepatic environment was established and used to screen small-molecular compounds that activate macrophages to produce cytokines, which in turn suppress HBV replication in a hepatocyte-derived stable cell line supporting HBV replication in a tetracycline-inducible manner. An agonist of the mouse stimulator of interferon (IFN) genes (STING), 5,6-dimethylxanthenone-4-acetic acid (DMXAA), was found to induce a robust cytokine response in macrophages that efficiently suppressed HBV replication in mouse hepatocytes by reducing the amount of cytoplasmic viral nucleocapsids. Profiling of cytokines induced by DMXAA and agonists of representative Toll-like receptors (TLRs) in mouse macrophages revealed that, unlike TLR agonists that induced a predominant inflammatory cytokine/chemokine response, the STING agonist induced a cytokine response dominated by type I IFNs. Moreover, as demonstrated in an HBV hydrodynamic mouse model, intraperitoneal administration of DMXAA significantly induced the expression of IFN-stimulated genes and reduced HBV DNA replication intermediates in the livers of mice. This study thus proves the concept that activation of the STING pathway induces an antiviral cytokine response against HBV and that the development of small-molecular human STING agonists as immunotherapeutic agents for treatment of chronic hepatitis B is warranted. PMID:25512416

  20. Defining the Communication between Agonist and Coactivator Binding in the Retinoid X Receptor ? Ligand Binding Domain*

    PubMed Central

    Boerma, LeeAnn J.; Xia, Gang; Qui, Cheng; Cox, Bryan D.; Chalmers, Michael J.; Smith, Craig D.; Lobo-Ruppert, Susan; Griffin, Patrick R.; Muccio, Donald D.; Renfrow, Matthew B.

    2014-01-01

    Retinoid X receptors (RXRs) are obligate partners for several other nuclear receptors, and they play a key role in several signaling processes. Despite being a promiscuous heterodimer partner, this nuclear receptor is a target of therapeutic intervention through activation using selective RXR agonists (rexinoids). Agonist binding to RXR initiates a large conformational change in the receptor that allows for coactivator recruitment to its surface and enhanced transcription. Here we reveal the structural and dynamical changes produced when a coactivator peptide binds to the human RXR? ligand binding domain containing two clinically relevant rexinoids, Targretin and 9-cis-UAB30. Our results show that the structural changes are very similar for each rexinoid and similar to those for the pan-agonist 9-cis-retinoic acid. The four structural changes involve key residues on helix 3, helix 4, and helix 11 that move from a solvent-exposed environment to one that interacts extensively with helix 12. Hydrogen-deuterium exchange mass spectrometry reveals that the dynamics of helices 3, 11, and 12 are significantly decreased when the two rexinoids are bound to the receptor. When the pan-agonist 9-cis-retinoic acid is bound to the receptor, only the dynamics of helices 3 and 11 are reduced. The four structural changes are conserved in all x-ray structures of the RXR ligand-binding domain in the presence of agonist and coactivator peptide. They serve as hallmarks for how RXR changes conformation and dynamics in the presence of agonist and coactivator to initiate signaling. PMID:24187139

  1. Development of CINPA1 analogs as novel and potent inverse agonists of constitutive androstane receptor.

    PubMed

    Lin, Wenwei; Yang, Lei; Chai, Sergio C; Lu, Yan; Chen, Taosheng

    2016-01-27

    Constitutive androstane receptor (CAR, NR1I3) and pregnane X receptor (PXR, NR1I2) are master regulators of endobiotic and xenobiotic metabolism and disposition. Because CAR is constitutively active in certain cellular contexts, inhibiting CAR might reduce drug-induced hepatotoxicity and resensitize drug-resistant cancer cells to chemotherapeutic drugs. We recently reported a novel CAR inhibitor/inverse agonist CINPA1 (11). Here, we have obtained or designed 54 analogs of CINPA1 and used a time-resolved fluorescence resonance energy transfer (TR-FRET) assay to evaluate their CAR inhibition potency. Many of the 54 analogs showed CAR inverse agonistic activities higher than those of CINPA1, which has an IC50 value of 687nM. Among them, 72 has an IC50 value of 11.7nM, which is about 59-fold more potent than CINPA1 and over 10-fold more potent than clotrimazole (an IC50 value of 126.9nM), the most potent CAR inverse agonist in a biochemical assay previously reported by others. Docking studies provide a molecular explanation of the structure-activity relationship (SAR) observed experimentally. To our knowledge, this effort is the first chemistry endeavor in designing and identifying potent CAR inverse agonists based on a novel chemical scaffold, leading to 72 as the most potent CAR inverse agonist so far. The 54 chemicals presented are novel and unique tools for characterizing CAR's function, and the SAR information gained from these 54 analogs could guide future efforts to develop improved CAR inverse agonists. PMID:26717202

  2. Attenuation of HIV-1 replication in macrophages by cannabinoid receptor 2 agonists

    PubMed Central

    Ramirez, Servio H.; Reichenbach, Nancy L.; Fan, Shongshan; Rom, Slava; Merkel, Steven F.; Wang, Xu; Ho, Wen-zhe; Persidsky, Yuri

    2013-01-01

    Infiltrating monocytes and macrophages play a crucial role in the progression of HIV-1 infection in the CNS. Previous studies showed that activation of the CB2 can attenuate inflammatory responses and affect HIV-1 infectivity in T cells and microglia. Here, we report that CB2 agonists can also act as immunomodulators on HIV-1-infected macrophages. First, our findings indicated the presence of elevated levels of CB2 expression on monocytes/macrophages in perivascular cuffs of postmortem HIV-1 encephalitic cases. In vitro analysis by FACS of primary human monocytes revealed a step-wise increase in CB2 surface expression in monocytes, MDMs, and HIV-1-infected MDMs. We next tested the notion that up-regulation of CB2 may allow for the use of synthetic CB2 agonist to limit HIV-1 infection. Two commercially available CB2 agonists, JWH133 and GP1a, and a resorcinol-based CB2 agonist, O-1966, were evaluated. Results from measurements of HIV-1 RT activity in the culture media of 7 day-infected cells showed a significant decrease in RT activity when the CB2 agonist was present. Furthermore, CB2 activation also partially inhibited the expression of HIV-1 pol. CB2 agonists did not modulate surface expression of CXCR4 or CCR5 detected by FACS. We speculate that these findings indicate that prevention of viral entry is not a central mechanism for CB2-mediated suppression in viral replication. However, CB2 may affect the HIV-1 replication machinery. Results from a single-round infection with the pseudotyped virus revealed a marked decrease in HIV-1 LTR activation by the CB2 ligands. Together, these results indicate that CB2 may offer a means to limit HIV-1 infection in macrophages. PMID:23463725

  3. ''Spare'' alpha 1-adrenergic receptors and the potency of agonists in rat vas deferens

    SciTech Connect

    Minneman, K.P.; Abel, P.W.

    1984-01-01

    The existence of ''spare'' alpha 1-adrenergic receptors in rat vas deferens was examined directly using radioligand binding assays and contractility measurements. Alpha 1-adrenergic receptors in homogenates of rat vas deferens were labeled with (/sup 125/I)BE 2254 (/sup 125/IBE). Norepinephrine and other full alpha 1-adrenergic receptor agonists were much less potent in inhibiting /sup 125/IBE binding than in contracting the vas deferens in vitro. Treatment with 300 nM phenoxybenzamine for 10 min to irreversibly inactivate alpha 1-adrenergic receptors caused a large decrease in the potency of full agonists in causing contraction of this tissue and a 23-48% decrease in the maximal contraction observed. Using those data, equilibrium constants for activation (Kact values) of the receptors by agonists were calculated. These Kact values agreed well with the equilibrium binding constants (KD values) determined from displacement of /sup 125/IBE binding. The reduction in alpha 1-adrenergic receptor density following phenoxybenzamine treatment was determined by Scatchard analysis of specific /sup 125/IBE binding sites and compared with the expected reduction (q values) calculated from the agonist dose-response curves before and after phenoxybenzamine treatment. This suggests that phenoxybenzamine functionally inactivates alpha 1-adrenergic receptors at or near the receptor binding site. These experiments suggest that the potencies of agonists in activating alpha 1-adrenergic receptors in rat vas deferens agree well with their potencies in binding to the receptors. The greater potency of agonists in causing contraction may be due to spare receptors in this tissue. The data also demonstrate that phenoxybenzamine irreversibly inactivates alpha 1-adrenergic receptors in rat vas deferens, but that the decrease in receptor density is much smaller than that predicted from receptor theory.

  4. Peroxidative Metabolism of ?2-Agonists Salbutamol and Fenoterol and Their Analogs

    PubMed Central

    Reszka, Krzysztof J.; McGraw, Dennis W.; Britigan, Bradley E.

    2009-01-01

    Phenolic ?2-adrenoreceptor agonists salbutamol, fenoterol and terbutaline relax smooth muscle cells that relieve acute airway bronchospasm associated with asthma. Why their use sometimes fails to relieve bronchospasm, and why the drugs appear to be less effective in patients with severe asthma exacerbations, remains unclear. We show that in the presence of hydrogen peroxide, both myeloperoxidase, secreted by activated neutrophils present in inflamed airways, and lactoperoxidase, which is naturally present in the respiratory system, catalyze oxidation of these ?2-agonists. Azide, cyanide, thiocyanate, ascorbate, glutathione, and methimazole inhibited this process, while methionine was without effect. Inhibition by ascorbate and glutathione was associated with their oxidation to corresponding radical species by the agonists-derived phenoxyl radicals. Using electron paramagnetic resonance (EPR), we detected free radical metabolites from ?2-agonists by spin trapping with 2-methyl-2-nitrosopropane (MNP). Formation of these radicals was inhibited by pharmacologically-relevant concentrations of methimazole and dapsone. In alkaline buffers radicals from fenoterol and its structu