Sample records for agonist diethylstilbestrol des

  1. Menstrual and reproductive characteristics of women whose mothers were exposed in utero to diethylstilbestrol (DES)

    Microsoft Academic Search

    Linda Titus-Ernstoff; Rebecca Troisi; Elizabeth E Hatch; Lauren A Wise; Julie Palmer; Marianne Hyer; Raymond Kaufman; Ervin Adam; William Strohsnitter; Kenneth Noller; Arthur L Herbst; Jennifer Gibson-Chambers; Patricia Hartge; Robert N Hoover

    2006-01-01

    Background In women, prenatal exposure to diethylstilbestrol (DES) is associated with adult reproductive dysfunction. The mouse model, which replicates many DES outcomes, suggests DES causes epigenetic alterations, which are transmissable to daughters of prenatally exposed animals. We report menstrual and reproductive characteristics in a unique cohort comprising daughters of women exposed prenatally to DES. Methods Menstrual and reproductive outcomes and

  2. 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

    Microsoft Academic Search

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

    2010-01-01

    Diethylstilbestrol (DES) and bisphenol-A (BPA) are estrogen-like endocrine-disrupting chemicals that induce persistent epigenetic\\u000a changes in the developing uterus. However, DES exposure in utero is also associated with an increased risk of breast cancer\\u000a in adult women. Similarly, fetal exposure to BPA induces neoplastic changes in mammary tissue of mice. We hypothesized that\\u000a epigenetic alterations would precede the increased risk of

  3. [Prenatal diethylstilbestrol exposure and breast cancer].

    PubMed

    Frigo, S; Malina, C; Mathelin, C

    2012-12-01

    Diethylstilbestrol (DES) is a synthetic estrogen prescribed to prevent miscarriages until 1977. Its role in the development of vaginal adenocarcinoma and cervical dysplasia is known and screening codified. Recent cohort studies show that exposure to DES in utero increases breast cancer risk especially after 40 years. This article reports the observation of a breast cancer of exceptional gravity in a patient exposed to DES in utero. It details the risk of breast cancer for "DES daughters" and support possible screening modalities. PMID:23102737

  4. The endocrine disruptors dibutyl phthalate (DBP) and diethylstilbestrol (DES) influence Leydig cell regeneration following ethane dimethane sulphonate treatment of adult male rats.

    PubMed

    Heng, K; Anand-Ivell, R; Teerds, K; Ivell, R

    2012-06-01

    The manner by which endocrine-disrupting xenobiotics, such as phthalates, can induce changes in the development of the male reproductive system still remains largely unknown. Herein, we have explored the application of ethane dimethane sulphonate (EDS) to eliminate adult-type Leydig cells in the mature rat testis, leading to their regeneration from resident stem cells, as a novel system to investigate the effects of dibutyl phthalate (DBP) and diethylstilbestrol (DES) on adult-type Leydig cell differentiation. The advantage of this model is that one can study adult-type Leydig cell differentiation in vivo divorced from the concomitant endocrine development of puberty. In these preliminary studies, we show that both DBP and/or DES, given for 2 or 4 days following EDS application, indeed affect Leydig cell differentiation in the adult testis, largely by increasing early Leydig cell proliferation and possibly thereby delaying early differentiation. In particular, on day 27 post-EDS, a time-point when the differentiation trajectory appears to be most discriminating, we observe that both DBP and/or DES cause a fourfold increase in Leydig cell density, and a significant increase in the expression of the Leydig cell-specific marker transcripts INSL3, LH receptor, Cyp17a1 and Cyp 11a1. In conclusion, both DBP and DES are able to affect adult-type Leydig cells during their differentiation to cause a significant perturbation in their ultimate functional capacity. PMID:22150342

  5. Diethylstilbestrol (DES) and Cancer

    MedlinePLUS

    ... their care to request a review of their medical records. If any pills were taken during pregnancy, obstetrical ... determine the name of the drug. However, finding medical records after a long period of time can be ...

  6. Prenatal exposure to diethylstilbestrol in mice: Toxicological studies

    Microsoft Academic Search

    J. A. McLachlan

    1977-01-01

    The effect of prenatal exposure to diethylstilbestrol (DES) on the postnatal development of male and female genital tract function was studied. The placental transfer of radiolabeled (H or C) DES was studied in pregnant mice. DES?associated radioactivity in the fetal plasma approximated that in maternal plasma #fr1\\/2> hr after intravenous administration of [H]DES; H activity corresponding to DES in the

  7. Diethylstilbestrol in the Treatment of Rape Victims

    PubMed Central

    Glover, Dianne; Gerety, Meghan; Bromberg, Shirley; Fullam, Susan; Divasto, Peter; Kaufman, Arthur

    1976-01-01

    Despite growing controversy surrounding its use as a “morning after pill,” diethylstilbestrol (DES) is prescribed liberally for rape victims. Guidelines for its use in these patients is lacking. Of 150 consecutive rape victims treated at a university medical center, 63 (42 percent) received prescriptions for DES. Of the 55 (87 percent) on whom follow-up was obtained, in 40 (73 percent) there were substantial side effects—nausea or vomiting, or both. At least six (11 percent) did not complete therapy because of these side effects. The authors offer guidelines for use of DES for rape victims and a plan for patient education and follow-up. PMID:1032235

  8. Diethylstilbestrol (DES)-Stimulated Hormonal Toxicity is Mediated by ER? Alteration of Target Gene Methylation Patterns and Epigenetic Modifiers (DNMT3A, MBD2, and HDAC2) in the Mouse Seminal Vesicle

    PubMed Central

    Li, Yin; Hamilton, Katherine J.; Lai, Anne Y.; Burns, Katherine A.; Li, Leping; Wade, Paul A.

    2013-01-01

    Background: Diethylstilbestrol (DES) is a synthetic estrogen associated with adverse effects on reproductive organs. DES-induced toxicity of the mouse seminal vesicle (SV) is mediated by estrogen receptor ? (ER?), which alters expression of seminal vesicle secretory protein IV (Svs4) and lactoferrin (Ltf) genes. Objectives: We examined a role for nuclear receptor activity in association with DNA methylation and altered gene expression. Methods: We used the neonatal DES exposure mouse model to examine DNA methylation patterns via bisulfite conversion sequencing in SVs of wild-type (WT) and ER?-knockout (?ERKO) mice. Results: The DNA methylation status at four specific CpGs (–160, –237, –306, and –367) in the Svs4 gene promoter changed during mouse development from methylated to unmethylated, and DES prevented this change at 10 weeks of age in WT SV. At two specific CpGs (–449 and –459) of the Ltf gene promoter, DES altered the methylation status from methylated to unmethylated. Alterations in DNA methylation of Svs4 and Ltf were not observed in ?ERKO SVs, suggesting that changes of methylation status at these CpGs are ER? dependent. The methylation status was associated with the level of gene expression. In addition, gene expression of three epigenetic modifiers—DNMT3A, MBD2, and HDAC2—increased in the SV of DES-exposed WT mice. Conclusion: DES-induced hormonal toxicity resulted from altered gene expression of Svs4 and Ltf associated with changes in DNA methylation that were mediated by ER?. Alterations in gene expression of DNMT3A, MBD2, and HDAC2 in DES-exposed male mice may be involved in mediating the changes in methylation status in the SV. Citation: Li Y, Hamilton KJ, Lai AY, Burns KA, Li L, Wade PA, Korach KS. 2014. Diethylstilbestrol (DES)-stimulated hormonal toxicity is mediated by ER? alteration of target gene methylation patterns and epigenetic modifiers (DNMT3A, MBD2, and HDAC2) in the mouse seminal vesicle. Environ Health Perspect 122:262–268;?http://dx.doi.org/10.1289/ehp.1307351 PMID:24316720

  9. 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

  10. Age at menarche among diethylstilbestrol granddaughters

    Microsoft Academic Search

    Allen J. Wilcox; David M. Umbach; Paige P. Hornsby; Arthur L. Herbst

    1995-01-01

    We interviewed 542 women whose mothers were in a randomized trial of diethylstilbestrol. Effects of diethylstilbestrol on the third generation were explored by ascertaining age at menarche for the women's daughters. A total of 123 daughters were ?10 years old (52 exposed and 71 unexposed). Age at menarche was unaffected by mother's prenatal diethylstilbestrol exposure.

  11. 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...

  12. 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...

  13. Urogenital abnormalities in men exposed to diethylstilbestrol in utero: a cohort study

    Microsoft Academic Search

    Julie R Palmer; Arthur L Herbst; Kenneth L Noller; Deborah A Boggs; Rebecca Troisi; Linda Titus-Ernstoff; Elizabeth E Hatch; Lauren A Wise; William C Strohsnitter; Robert N Hoover

    2009-01-01

    BACKGROUND: Diethylstilbestrol (DES), a synthetic estrogen widely prescribed to pregnant women during the 1940s-70s, has been shown to cause reproductive problems in the daughters. Studies of prenatally-exposed males have yielded conflicting results. METHODS: In data from a collaborative follow-up of three U.S. cohorts of DES-exposed sons, we examined the relation of prenatal DES exposure to occurrence of male urogenital abnormalities.

  14. The DES Story: Lessons Learned

    Cancer.gov

    Dr. Robert Hoover discusses the DES followup study, which follows diethylstilbestrol (DES) exposed and unexposed mothers, daughters and sons, and granddaughters for adverse health effects resulting from this exposure.

  15. Mouse bioassay to assess oestrogenic and anti-oestrogenic compounds: hydroxytamoxifen, diethylstilbestrol and genistein.

    PubMed

    Köhlerová, E; Skarda, J

    2004-06-01

    Young intact and adult gonadectomized C3H male and female mice were utilized as bioassay models to detect endocrine disruption chemicals. Animals treated with oestradiol (E) or progesterone (Prog) or E plus Prog were used to assess steroid hormone agonist and antagonist activities of 4-OH-tamoxifen (TAM), diethylstilbestrol (DES) and genistein (GEN) by bioassay. The stimulation or inhibition of mammary growth by TAM depended on sex, the state of animal (intact or gonadectomized), hormonal treatment (Prog, E, E plus Prog) and dose of TAM. TAM stimulated mammary growth in untreated ovariectomized (OV-X) females and in Prog-treated intact males and OV-X females. In intact males, mammary growth was increased by TAM at dose 0.1-1 microg day(-1) and decreased at dose 10 microg day(-1). Mammary growth was inhibited by TAM in Prog-treated intact females and in E or E plus Prog-treated intact and gonadectomized males and females. Uterine weights were increased by TAM in both untreated and treated (E, Prog, E plus Prog) intact and OV-X females; however, seminal vesicle weights were decreased by TAM in both untreated and treated (E, Prog, E plus Prog) intact males. DES alone affected mammary growth (an inverted-U-shaped dose-response curve) both in male and female mice. DES increased uterine weights; however, seminal vesicle weights were decreased. GEN increased mammary and uterine growth in OV-X females, GEN plus Prog stimulated mammary growth in intact males. The results obtained in these studies show clearly that only a bioassay consisting of several endpoints reflective to the mechanism of oestrogen and anti-oestrogen action has the ability to evaluate activities of a molecule. PMID:15315699

  16. Demonstrating the importance of polymer-conjugate conformation in solution on its therapeutic output: Diethylstilbestrol (DES)-polyacetals as prostate cancer treatment.

    PubMed

    Giménez, Vanessa; James, Craig; Armiñán, Ana; Schweins, Ralf; Paul, Alison; Vicent, María J

    2012-04-30

    The design of improved polymeric carriers to be used in the next generation of polymer therapeutics is an ongoing challenge. Biodegradable systems present potential advantages regarding safety benefit apart from the possibility to use higher molecular weight (Mw) carriers allowing PK optimization, by exploiting the enhanced permeability and retention (EPR)-mediated tumor targeting. Within this context, we previously designed pH-responsive polyacetalic systems, tert-polymers, where a drug with the adequate diol-functionality was incorporated within the polymer mainchain. The synthetic, non-steroidal estrogen, diethylstilboestrol (DES) clinically used for the treatment of advanced prostate cancer was chosen as drug. In order to improve the properties of this tert-polymer, novel polyacetalic systems as block-co-polymers, with more defined structure have been obtained. This second generation polyacetals allowed higher drug capacity than the tert-polymer, a biphasic DES release profile at acidic pH and due to its controlled amphiphilic character readily formed micelle-like structures in solution. These features result in an enhancement of conjugate therapeutic value in selected prostate cancer cell models. Exhaustive physico-chemical characterization focusing on nanoconjugate solution behavior and using advanced techniques, such as, pulsed-gradient spin-echo NMR (PGSE-NMR) and small-angle neutron scattering (SANS), has been carried out in order to demonstrate this hypothesis. Clear evidence of significantly different conformation in solution has been obtained for both polyacetals. These results demonstrate that an adequate control on molecular or supramolecular conformation in solution with polymer therapeutics is crucial in order to achieve the desired therapeutic output. PMID:22230343

  17. Sexually disrupting effects of nonylphenol and diethylstilbestrol on male silver carp ( Carassius auratus) in aquatic microcosms

    Microsoft Academic Search

    Lihua Yang; Li Lina; Shaoping Weng; Zhiqin Feng; Tiangang Luan

    2008-01-01

    Based on detected nonylphenol (NP) levels in aquaculture water, this study investigated sexually disrupting effects in mature male silver carp (Carassius auratus) exposed to NP and a positive control diethylstilbestrol (DES). The combined evidences of steroid hormone (17?-estradiol, estrone and testosterone) levels and hispathological pictures showed that NP (?10?g\\/L) and DES could exert estrogenic effects through indirect mechanisms [i.e. increased

  18. Characterization of diethylstilbestrol-induced hypospadias in female mice.

    PubMed

    Miyagawa, Shinichi; Buchanan, David L; Sato, Tomomi; Ohta, Yasuhiko; Nishina, Yukio; Iguchi, Taisen

    2002-01-01

    The urethral duct and vagina are formed from the urogenital sinus (UGS) during the early neonatal period in mice. Neonatal estrogen exposure results in hypospadias, or the malpositioning of vaginal and urethral openings, with wide cleft clitoris. We sought to characterize diethylstilbestrol (DES) influence on UGS morphogenesis and hypospadias formation. Newborn (day 0) and 1-4-day-old female mice (ICR/Jcl) were given (s.c.) oil or 3.0 microg DES. Animals were killed 24 hr later; then hypospadias formation and epithelial apoptosis and proliferation within the developing UGS were assessed. DES did not alter normal UGS morphogenesis by day 1, in comparison with controls. However, hypospadias formation was observed in DES-treated mice by day 3. In these mice, the distal dorsal urethral duct appeared to fuse with and open into the lower vaginal solid cord region. Further, DES treatment produced a gradual significant increase in dorsal urethral epithelial apoptosis (P < 0.05) just prior to and during fusion and hypospadias formation. DES-induced urethral epithelial and sinus cord proliferation appeared significantly increased (P < 0.05) and unchanged, respectively, just prior to fusion. By day 5, DES-treated mice exhibited wide cleft clitoris. In addition, if DES was given on day 3 or 5, a gradual, distinct caudal shift in the vaginal-urethral junction was observed compared to mice treated on days 0-2. Although hypospadias was not induced when neonates were given DES on day 7, these mice continued to display early vaginal opening. Dose-response analysis indicated that 0.03 microg DES for 5 days is the lowest known critical dose for hypospadias induction. We have shown for the first time that DES-induced hypospadias onset may primarily be the result of changes in developing dorsal urethral epithelial cell apoptotic and proliferative activity, and that the location of DES-induced hypospadias formation is dependent on age at time of exposure. PMID:11748570

  19. Subchronic exposure to phytoestrogens alone and in combination with diethylstilbestrol - pituitary tumor induction in Fischer 344 rats

    Microsoft Academic Search

    Yow-Jiun Jeng; Mikhail Kochukov; Dhananjaya Nauduri; Bhupendra S Kaphalia; Cheryl S Watson

    2010-01-01

    BACKGROUND: Subchronic administration of the potent pharmaceutical estrogen diethylstilbestrol (DES) to female Fischer 344 (F344) rats induces growth of large, hemorrhagic pituitaries that progress to tumors. Phytoestrogens (dietary plant estrogens) are hypothesized to be potential tumor inhibitors in tissues prone to estrogen-induced cancers, and have been suggested as \\

  20. Gender-related behavior in women exposed prenatally to diethylstilbestrol.

    PubMed Central

    Newbold, R R

    1993-01-01

    Accumulating evidence in experimental animals over the past three decades suggests that mammalian brain development and differentiation of the central nervous system are influenced by perinatal exposure to sex hormones. Hence, changes in human behavioral patterns may be associated with prenatal exposure to estrogenic substances such as diethylstilbestrol (DES). This paper reviews relevant studies from a series of laboratories and finds that no clear-cut differences can be demonstrated to date between unexposed and DES-exposed women in gender-related behavior, although the physical and psychological impact of the problems associated with exposure to DES are well documented. If both prenatal and postnatal influences such as social, economic, and environmental factors are taken into consideration, individual variation is more apparent than differences in gender-related behavior between unexposed and DES-exposed women. In summary, gender-related behavior is determined by a complex array of interacting factors, and prenatal influences are only one of many developmental events. More studies are needed using larger populations with carefully controlled selection criteria to suggest a direct role of prenatal DES exposure on subsequent gender-related behavior. Images p208-a PMID:8404755

  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. Transplacental Action of Diethylstilbestrol on Mammary Carcinogenesis in Female Rats Given One or Two Doses of 7,12-Dimethylbenz(a)anthracene1

    Microsoft Academic Search

    Elizabeth S. Boylan; Robert E. Calhoon

    Aspects of the development, morphology, and estrogen bind ing capacity of mammary tumors in rats exposed prenatally to the synthetic estrogen, diethylstilbestrol (DES), and treated post- natally with 7,12-dimethylbenz(s)anthracene (DMBA) were ana lyzed as part of a project aimed at understanding the effects of transplacental exposure to DES on estrogen-sensitive tissues. Pregnant Sprague-Dawley rats were given injections of DES (total

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

    SciTech Connect

    Hao, Chan-Juan; Cheng, Xue-Jia; Xia, Hong-Fei, E-mail: hongfeixia@yahoo.com.cn; 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) ? as well as its target genes required for adipogenesis in vitro. ER mediated the enhancement of DES-induced PPAR? 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.

  4. Phenotypic Variations and Dynamic Topography of Transformed Cells in an Experimental Model of Diethylstilbestrol-Induced Renal Tumour in Male Syrian Hamster

    Microsoft Academic Search

    Denis Nonclercq; Vanessa Liénard; Jacqueline Zanen; Guy Laurent; Gérard Toubeau

    2002-01-01

    This work explores the phenotypic changes affecting transformed cells in an experimental model of diethylstilbestrol (DES)-induced renal tumours in male Syrian hamster. This estrogen-induced neoplasm presents an important cytological pleomorphism and its origin remains largely controversial. In order to characterize phenotypic variations during tumour progression, the occurrence of seven lineage markers was analysed by a morphometric approach in kidney sections

  5. Mechanisms of estrogen-induced effects in avian reproduction caused by transovarian application of a xenoestrogen, diethylstilbestrol

    Microsoft Academic Search

    Ryo Kamata; Fujio Shiraishi; Tokukazu Izumi; Shinji Takahashi; Akira Shimizu; Hiroaki Shiraishi

    2009-01-01

    To clarify breeding failure in avian species caused by the estrogenicity of chemicals, alterations in the reproductive systems\\u000a of Japanese quail exposed in ovo to a xenoestrogen were investigated. An injection of diethylstilbestrol (DES) into the yolk\\u000a before incubation decreased, after sexual maturation, egg-laying performance of female quails, which accompanied inducing\\u000a abnormal development of the oviducts. All females treated with

  6. Suppression of erythropoietin induction by diethylstilbestrol in rats.

    PubMed

    Horiguchi, Hyogo; Oguma, Etsuko; Sakamoto, Takako; Murata, Katsuyuki; Kayama, Fujio

    2014-01-01

    Diethylstilbestrol is an estrogenic endocrine disrupter that has diverse health effects in humans. Bisphenol A is another estrogen-like chemical with possible similar effects to diethylstilbestrol, which has been increasingly used for industry to lead to globally widespread human exposure to it. Hematopoiesis is another of their possible targets, since estrogen suppresses erythropoietin induction to induce anemia. The aim of this study was to clarify the effects of diethylstilbestrol and bisphenol A on erythropoietin induction in rats. We observed the effects of one-shot subcutaneous injection of diethylstilbestrol or bisphenol A on hypoxia-, bleeding-, and cobalt-stimulated erythropoietin induction within 24 h and the hematological outcomes after repeated subcutaneous injection of diethylstilbestrol three times a week for 1 month in rats. Diethylstilbestrol at 10-1,000 ?g/kg suppressed stimulus-elevated levels of plasma erythropoietin and its renal mRNA induction. In contrast, bisphenol A at 1,000 ?g/kg did not suppress plasma erythropoietin elevated by any stimuli. Repeated injection of diethylstilbestrol at 1,000 ?g/kg to rats for 1 month induced an anemic trend due to decelerated erythropoiesis through the insufficient production of erythropoietin, mimicking the effects of estradiol. In conclusion, diethylstilbestrol has a suppressive effect on erythropoietin induction, leading to deceleration of erythropoiesis and the development of anemia. PMID:23877121

  7. The study of diethylstilbestrol toxic effect in the mouse sertoli cell line by comparison of miRNA and mRNA expression

    Microsoft Academic Search

    Yu Ri An; Jeong Han; Seung Jun Kim; Moon-Ju Oh; Jung-Hwa Oh; Seok-Joo Yoon; Seung Yong Hwang

    2010-01-01

    It is important to acknowledge the harmful effects of environmental chemicals in human’s lives. The toxic effects of Diethylstilbestrol\\u000a (DES), one of the endocrine-disrupting chemicals (EDCs), have been documented in many studies. As expected, DES affect male\\u000a gendal hormone as well as female’s; therefore, epigenetic study should be considered. In this study, microarray technology\\u000a was used to study harmful effects

  8. 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.

  9. 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. [North Carolina State Univ., Raleigh, NC (United States). Dept. of Toxicology

    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.

  10. Response of Steers to Implantation of Diethylstilbestrol During Suckling, Wintering and Finishing Periods.

    E-print Network

    Melton, A. A.; Riggs, J. K.

    1965-01-01

    ............................................................ 6 Influence of Diethylstilbestrol on Suckling Calves ...... 6 Infl~~ence of Diethylstilbestrol on Growth During a Wintering Period ........................ 7 Itlfluence of Diethylstilbestrol on Performance During the Finishing Period.... Implanting 3-month-old suckling steer calves with I? milligrams (mg.) of diethylstilbestrol increased weaning weight under West Texas range conditions by approximately 15 pounds, an average for 4 years. The weight advantage of tlie implanted calves ranged...

  11. Mammary gland morphology and responsiveness to regulatory molecules following prenatal exposure to diethylstilbestrol.

    PubMed

    Vassilacopoulou, D; Boylan, E S

    1993-01-01

    Female ACI rats were exposed to diethylstilbestrol (DES) in utero to evaluate the effects on the peri-pubertal mammary gland with respect to 1) mammary gland morphology, 2) sensitivity to natural and synthetic estrogens, and 3) sensitivity to endogenous epidermal growth factor (EGF). Pregnant rats were injected with vehicle (sesame oil) or DES (total dose, 8.0 micrograms) on days 15 and 18 of gestation. DES-exposed and control offspring were ovariectomized at 34 days of age and sacrificed at day 53 to ascertain the morphology of the mammary glands in peri-pubertal rats. Elvax pellets containing 5 or 11 ng 17 beta-estradiol (E2) or DES were implanted subcutaneously adjacent to the third mammary gland pair. Furthermore, additional groups of rats were subjected to bilateral sialoadenectomy at the day of ovariectomy to remove the major source of endogenous EGF. A significant proportion of mammary glands of DES-exposed animals exhibited atypical mammary gland morphology, with approximately 25% displaying hypo-differentiation, and about 5% with aberrant hyper-proliferation. From the pellet implantation experiments, the DES-exposed glands were found to be refractory to stimulation by 5 and 11 ng DES; however, there was no significant difference in the degree of local stimulation elicited by either dose of E2. Sialoadenectomy at d34 had no apparent effect on mammary gland morphology in either the DES-exposed or vehicle-exposed groups. These data support the premise that the mammary gland of the peri-pubertal ACI rat is morphologically and physiologically aberrant as a function of transplacental exposure to DES, with a significant percentage hypo-differentiated and refractory to subsequent hormonal stimulation. PMID:8102210

  12. Lack of Effects for Low Dose Levels of Bisphenol A and Diethylstilbestrol on the Prostate Gland of CF1 Mice Exposed in Utero

    Microsoft Academic Search

    John Ashby; H. Tinwell; J. Haseman

    1999-01-01

    vom Saal et al. (Proc. Natl. Acad. Sci. 94, 2056–2061, 1997) have reported that low dose exposure (0.02–2 ?g\\/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

  13. Mechanisms of angiogenic suppression in uteri exposed to diethylstilbestrol neonatally in the mouse.

    PubMed

    Yamashita, Shuji; Kudo, Akihiko; Kawakami, Hayato; Okada, Yasunori

    2013-05-01

    Perinatal estrogen exposure elicits a wide range of abnormalities in the female genital tract. Since angiogenesis is essential for morphogenesis, we investigated the vascular density, integrity of vasculatures, and expression of angiogenic factors and their receptors in the uteri of mice treated with diethylstilbestrol (DES) neonatally (DES-mice); the uteri were collected from Day 4 to Day 20. DES treatment reduced the number and density of vasculatures immunostained with PECAM1 (platelet and endothelial cell adhesion molecule 1) in the stroma. Horseradish peroxidase injected into the left ventricle leaked into the endometrium and myometrium on Day 10 in the DES-mice but not in the controls. Electron microscopy confirmed the immaturity of the capillaries, which had an incomplete basal lamina and fewer pericytes. Immunohistochemical studies demonstrated that VEGFA (vascular endothelial growth factor A) expression and ANGPT1 (angiopoietin 1) expression were down-regulated in the stromal cells until Days 20 and 10, respectively. The number of vasculatures with ANGPT2 immunoreaction was reduced in the DES-mice. DES treatment suppressed the expression of VEGFR2 (VEGF receptor 2) and the co-receptor NRP1 (neuropilin 1) as well as TEI2 in the vasculatures. The results of RT-PCR and Western blotting supported the down-regulation of the expression of angiogenic factors and their receptors in DES-mice, whereas the VEGFR1 protein expression was up-regulated. These results suggested that the low concentration of angiogenic factors in the stroma was primarily responsible for the low vascular density in the stroma of the DES-mice, and that the low vascular density and immature vasculatures resulted in uterine malformations. PMID:23536370

  14. Modulation of murine liver macrophage clearance of liposomes by diethylstilbestrol. The effect of vesicle surface charge and a role for the complement receptor Mac1 (CD11b\\/CD18) of newly recruited macrophages in liposome recognition

    Microsoft Academic Search

    S. M Moghimi; H. M Patel

    2002-01-01

    We have studied the blood clearance and reticuloendothelial organ distribution of intravenously injected neutral (egg phosphatidylcholine, egg PC\\/cholesterol, mol ratio 7:2), anionic (egg PC\\/cholesterol\\/dicetylphosphate, mol ratio 7:2:1), and cationic (egg PC\\/cholesterol\\/stearylamine, mol ratio 7:2:1) liposomes of approximately the same size distribution in mice 3 days after treatment with the synthetic oestrogen diethylstilbestrol (DES). Male mice administered DES intraperitoneally at a

  15. Center for Disease Control's Diethylstilbestrol Update: a case for effective operationalization of messaging in social marketing practice.

    PubMed

    Mattson, Marifran; Basu, Ambar

    2010-07-01

    The Center for Disease Control's (CDC) Diethylstilbestrol (DES) Update, a campaign to educate people who may have been exposed to the drug DES, is framed on the premises of the social marketing model, namely formative research, audience segmentation, product, price, placement, promotion, and campaign evaluation. More than that, the campaign takes a critical step in extending the social marketing paradigm by highlighting the need to situate the messaging process at the heart of any health communication campaign. This article uses CDC's DES Update as a case study to illustrate an application of a message development tool within social marketing. This tool promotes the operationalization of messaging within health campaigns. Ultimately, the goal of this project is to extend the social marketing model and provide useful theoretical guidance to health campaign practitioners on how to accomplish stellar communication within a social marketing campaign. PMID:19116422

  16. A time-resolved fluorescence immunoassay for the ultrasensitive determination of diethylstilbestrol based on the double-codified gold nanoparticles.

    PubMed

    Wang, Longjun; Zhang, Yuanfu; Liu, Guofu; Zhang, Chunyan; Wang, Shuhao

    2014-11-01

    An ultrasensitive and selective method is presented for the determination of diethylstilbestrol (DES) using time-resolved fluorescence immunoassay (TRFIA) based on double-codified gold nanoparticles (DC-AuNPs). In this system, the DC-AuNPs, that are gold nanoparticles (AuNPs) modified with anti-DES antibody and SH-dsDNA-biotin, was regarded as signal amplifier. A competitive immunoreaction was performed on polystyrene microtitration plates, where the DES compete with the immobilized DES-ovalbumin on polystyrene microtitration plates to bind to anti-DES antibodies on DC-AuNPs, and the europium(III)-labeled streptavidin was added to link to the SH-dsDNA-biotin as a tracer. Fluorescence signal was amplified via the AuNPs and the biotin-streptavidin double amplification systems. Under the optimized condition, DES can be quantified by TRFIA. The linear range and the limit of detection of DES were 1.0×10(-6)-10ngmL(-1) and 0.4fgmL(-1), respectively. This method was applied to determine DES in beef sample, with the recoveries ranging from 88% to 105%. PMID:25091151

  17. Effects of diethylstilbestrol exposure during gestation on both maternal and offspring behavior

    PubMed Central

    Tomihara, Kazuya; Zoshiki, Takahiro; Kukita, Sayaka Y.; Nakamura, Kanako; Isogawa, Ayuko; Ishibashi, Sawako; Tanaka, Ayumi; Kuraoka, Ayaka S.; Matsumoto, Saki

    2015-01-01

    Endocrine disruption during gestation impairs the physical and behavioral development of offspring. However, it is unclear whether endocrine disruption also impairs maternal behavior and in turn further contributes to the developmental and behavioral dysfunction of offspring. We orally administered the synthetic non-steroidal estrogen diethylstilbestrol (DES) to pregnant female C57BL/6J mice from gestation day 11–17 and then investigated the maternal behavior of mothers. In addition, we examined the direct effects of in utero DES exposure and the indirect effects of aberrant maternal behavior on offspring using the cross-fostering method. In mothers, endocrine disruption during gestation decreased maternal behavior. In addition, endocrine disruption of foster mother influenced anxiety-related behavior and passive avoidance learning of pups regardless of their exposure in utero. The influence of DES exposure in utero, irrespective of exposure to the foster mother, was also shown in female offspring. These results demonstrate the risks of endocrine disruptors on both mother as well as offspring and suggest that developmental deficits may stem from both in utero toxicity and aberrant maternal care.

  18. In Utero Exposure to Diethylstilbestrol and Blood DNA Methylation in Women Ages 40–59 Years from the Sister Study

    PubMed Central

    Harlid, Sophia; Xu, Zongli; Panduri, Vijayalakshmi; D’Aloisio, 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 40–59 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

  19. In utero exposure to diethylstilbestrol and blood DNA methylation in women ages 40-59 years from the sister study.

    PubMed

    Harlid, Sophia; Xu, Zongli; Panduri, Vijayalakshmi; D'Aloisio, 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 40-59 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

  20. Enhancement of Thrombocyte Aggregation and Thromboxane B2 Synthesis by Diethylstilbestrol

    Microsoft Academic Search

    M. T. R. Subbiah; L. Gallon; R. Yunker

    1980-01-01

    Effect of diethylstilbestrol administration on thrombocyte aggregation and thromboxane B2 synthesis was investigated in atherosclerosis-susceptible pigeons. Platelet aggregatory response to arachidonic acid and synthesis of thromboxane B2 from 14C-arachidonic acid was enhanced in thrombocytes derived from diethylstilbestrol-treated pigeons. Platelet total phospholipid concentration was increased in pigeons with diethylstilbestrol treatment. Enhanced thromboxane synthesis might be responsible for increased platelet aggregation, which

  1. 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

  2. Downregulation of cytochrome P450scc as an initial adverse effect of adult exposure to diethylstilbestrol on testicular steroidogenesis.

    PubMed

    Maeda, Naoyuki; Okumura, Kanako; Tanaka, Emi; Suzuki, Tomokazu; Miyasho, Taku; Haeno, Satoko; Ueda, Hiromi; Hoshi, Nobuhiko; Yokota, Hiroshi

    2014-12-01

    Reproductive toxicities and endocrine disruptions caused by chemicals in adult males are still poorly understood. It is our objectives to understand further details of the initial adverse effects leading severe testicular toxicities of a pharmaceutical endocrine disruptor, diethylstilbestrol (DES). Downregulations of both testicular regulatory proteins, such as the steroidogenic acute regulatory protein (StAR) and the peripheral benzodiazepine receptor (PBR), which play important roles in the transport of cholesterol into the mitochondria, and cytochrome P450 mediating the cholesterol side chain cleavage reaction (P450scc), were observed in the rat orally administered DES (340??g/kg/2 days) for 2 weeks. We found that after only 1 week treatment with DES, the blood and testicular testosterone (TS) levels were drastically decreased without abnormalities of the StAR and PBR; however, the protein and mRNA levels of P450scc were diminished. Decrease in the conversion rate of cholesterol to pregnenolone was delayed in the in vitro assay using the testicular mitochondrial fraction from the rat treated with DES for 1 week. When the precursors in TS biosynthesis containing the testis were identified and determined by liquid chromatography-mass spectrometry analysis, decreased levels of all precursors except cholesterol were observed. In conclusion, suppressed cytochrome P450scc expression in adult male rat was identified as an initial target of DES in testicular steroidogenesis disorder leading reproductive toxicities. PMID:23873838

  3. Liquid-phase exfoliated graphene as highly-sensitive sensor for simultaneous determination of endocrine disruptors: diethylstilbestrol and estradiol.

    PubMed

    Hu, Lintong; Cheng, Qin; Chen, Danchao; Ma, Ming; Wu, Kangbing

    2015-02-11

    It is quite important to develop convenient and rapid analytical methods for trace levels of endocrine disruptors because they heavily affect health and reproduction of humans and animals. Herein, graphene was easily prepared via one-step exfoliation using N-methyl-2-pyrrolidone as solvent, and then used to construct an electrochemical sensor for highly-sensitive detection of diethylstilbestrol (DES) and estradiol (E2). On the surface of prepared graphene film, two independent and greatly-increased oxidation waves were observed at 0.28V and 0.49V for DES and E2. The remarkable signal enlargements indicated that the detection sensitivity was improved significantly. The influences of pH value, amount of graphene and accumulation time on the oxidation signals of DES and E2 were discussed. As a result, a highly-sensitive and rapid electrochemical method was newly developed for simultaneous detection of DES and E2. The values of detection limit were evaluated to be 10.87 nM and 4.9 nM for DES and E2. Additionally, this new method was successfully used in lake water samples and the accuracy was satisfactory. PMID:25265595

  4. Long-term responses of the mouse uterus to neonatal diethylstilbestrol treatment and to later sex hormone exposure.

    PubMed

    Ostrander, P L; Mills, K T; Bern, H A

    1985-01-01

    The effects of ovariectomy at 1 month of age and continuous 17 beta-estradiol (E2) and/or progesterone (P) replacement on the uterus of BALB/cCrgl mice neonatally treated with diethylstilbestrol [(DES) CAS: 56-53-1; alpha-alpha'-diethyl-4,4'-stilbenediol] or sesame oil were recorded after 1, 4, 7, and 10 months of treatment. DES-exposed uteri were found to be hypoplastic, less responsive to the growth-promoting effects of E2, and more likely to develop smooth muscle abnormalities after continuous hormonal treatment than similarly treated control uteri. Neonatal DES treatment led to leukocytic infiltration, disruption in the organization of the inner circular smooth muscle layer, and development of a population of epithelial cells believed to respond to later E2 treatment by proliferation and stratification (squamous metaplasia). Qualitative and quantitative responses to continuous P treatment and the development of cystic glandular hyperplasia and adenomyosis were found to be unaltered by neonatal DES administration. The relevance of these results to the problems of uterine abnormalities observed in women exposed to DES in utero is discussed. PMID:3855473

  5. Pubertal timing after neonatal diethylstilbestrol exposure in female rats: neuroendocrine vs peripheral effects and additive role of prenatal food restriction.

    PubMed

    Franssen, Delphine; Ioannou, Yiannis S; Alvarez-real, Alexandra; Gerard, Arlette; Mueller, Johanna K; Heger, Sabine; Bourguignon, Jean-Pierre; Parent, Anne-Simone

    2014-04-01

    We studied the effects of neonatal exposure to diethylstilbestrol (DES) on pubertal timing in female rats. We examined associated neuroendocrine changes and effects of prenatal food restriction. Age at vaginal opening was advanced after exposure to 10 ?g/kg/d of DES and delayed after 1 ?g/kg/d (subcutaneous injections). Using this lower dose, pulsatile GnRH secretion was slower at 25 days of age. Both doses reduced KiSS1 mRNA levels at 15 days of age. Using functional Kisspeptin promoter assay, 1 or 10 ?M DES reduced or increased KISS1 transcription, respectively. Leptin stimulatory effect on GnRH secretion in vitro (15 days of age) was reduced after prenatal food restriction and neonatal DES exposure (higher dose), both effects being cumulative. Thus, alterations in pubertal timing by DES neonatally are not unequivocally toward precocity, the level of exposure being critical. We provide evidence of neuroendocrine disruption and interaction with prenatal food availability. PMID:24316331

  6. Interaction of sheep liver cytosolic aldehyde dehydrogenase with quercetin, resveratrol and diethylstilbestrol

    Microsoft Academic Search

    Trevor M Kitson; Kathryn E Kitson; Stanley A Moore

    2001-01-01

    The effects of quercetin and resveratrol (substances found in red wine) on the activity of cytosolic aldehyde dehydrogenase in vitro are compared with those of the synthetic hormone diethylstilbestrol. It is proposed that quercetin inhibits the enzyme by binding competitively in both the aldehyde substrate binding-pocket and the NAD+-binding site, whereas resveratrol and diethylstilbestrol can only bind in the aldehyde

  7. Differential Effects of Bisphenol A and Diethylstilbestrol on Human, Rat and Mouse Fetal Leydig Cell Function

    PubMed Central

    N’Tumba-Byn, Thierry; Moison, Delphine; Lacroix, Marlène; Lecureuil, Charlotte; Lesage, Laëtitia; Prud’homme, Sophie M.; Pozzi-Gaudin, Stéphanie; Frydman, René; Benachi, Alexandra; Livera, Gabriel

    2012-01-01

    Endocrine disruptors (ED) have been incriminated in the current increase of male reproductive alterations. Bisphenol A (BPA) is a widely used weak estrogenic environmental ED and it is debated whether BPA concentrations within the average internal exposure are toxic. In the present study we investigated the effects of 10?12 to 10?5 M BPA concentrations on fetal Leydig cell function, as fetal life is a critical period of sensitivity to ED effects on male reproductive function. To this aim, fetal testes from human at 6.5–10.5 gestational weeks (GW) or from rat and mouse at a comparable critical period of development (14.5 days post-coitum (dpc) for rat and 12.5 dpc for mouse) were explanted and cultured using our validated organotypic culture system in the presence or absence of BPA for 1–3 days. BPA concentrations as low as 10?8 M reduced testosterone secretion by human testes from day 1 of culture onwards, but not by mouse and rat testes where concentrations equal to 10?5 M BPA were required. Similarly, 10?8 M BPA reduced INSL3 mRNA levels only in human cultured testes. On the contrary, 10?5 and 10?6 M diethylstilbestrol (DES), a classical estrogenic compound, affected testosterone secretion only in rat and mouse testis cultures, but not in human testis cultures. Lastly, contrarily to the DES effect, the negative effect of BPA on testosterone produced by the mouse fetal testis was maintained after invalidation of estrogen receptor ? (ER?). In conclusion, these results evidenced i) a deleterious effect of BPA on fetal Leydig cells function in human for concentrations from 10?8 M upwards, ii) species-specific differences raising concerns about extrapolation of data from rodent studies to human risk assessment, iii) a specific signaling pathway for BPA which differs from the DES one and which does not involve ER?. PMID:23284716

  8. Mechanisms of hormonal carcinogenesis in the p53+/- hemizygous knockout mouse: studies with diethylstilbestrol.

    PubMed

    Carmichael, P L; Mills, J J; Campbell, M; Basu, M; Caldwell, J

    2001-01-01

    The 2-year rodent bioassay has long had a central role in determining whether a compound is carcinogenic. It has recently been suggested that the use of 6-month studies in transgenic mice could reduce costs and animal numbers, without impairing the validity of cancer risk assessment. The p53+/- hemizygous knockout mouse model is phenotypically stable and develops tumors during the 6-month study period only in response to chemical and physical stimuli, showing a high concordance with genotoxic rodent carcinogens. We treated p53+/- mice and wild-type parent strain (C57BL/6J) animals with diethylstilbestrol (DES). 500 micromol/kg i.p. for 4 days. Following sacrifice, DNA was extracted from various tissues and adducts measured by a modified monophosphate version of the 32P-postlabelling assay. Major DES adducts were detected in the liver DNA of DES-treated wild-type mice at a level of 118.7+/-17.0 (mean +/- SD relative adduct level [RAL]/10(10) nucleotides) compared with 207.7+/-36.4 in p53+/- mice. No such adducts were detected in vehicle-treated animals. Total adduct levels, including endogenous I-compound adducts, in wild-type mice were 192.4+/-17.5 and 311.5+/-58.6 in p53+/- animals. These data support the hypothesis that deficient p53-dependent global genomic repair of DES adducts in p53+/- mice may result in the persistence of exogenous and endogenous DNA adducts that could contribute to earlier carcinogenicity in this model. We also prepared hepatic microsomes from male and female p53+/- and wild-type mice exposed to DES or vehicle. Western blot analysis demonstrated modestly higher basal levels of various cytochrome P450 (CYP) enzymes in the untreated p53+/- mice compared to the wild-type mice. Furthermore, P450 levels were higher in female DES-treated p53+/- mice compared to treated wild-type mice. For the p53+/- knockout mice to be used with contidence in drug safety studies, a further understanding of the metabolic capacity of these animals is needed. PMID:11695552

  9. Exposure to Diethylstilbestrol during Pregnancy Modulates MicroRNA Expression Profile in Mothers and Fetuses Reflecting Oncogenic and Immunological Changes.

    PubMed

    Singh, Narendra P; Abbas, Ikbal K; Menard, Martine; Singh, Udai P; Zhang, Jiajia; Nagarkatti, Prakash; Nagarkatti, Mitzi

    2015-05-01

    Prenatal exposure to diethylstilbestrol (DES) is known to cause an increased susceptibility to a wide array of clinical disorders in humans. Previous studies from our laboratory demonstrated that prenatal exposure to DES induces thymic atrophy and apoptosis in the thymus. In the current study, we investigated if such effects on the thymus result from alterations in the expression of microRNA (miR). To that end, pregnant C57BL/6 mice who were exposed to DES and miR profiles in thymocytes of both the mother and fetuses on postnatal day 3 (gestation day 17) were studied. Of the 609 mouse miRs examined, we noted 59 altered miRs that were common for both mothers and fetuses, whereas 107 altered miRs were specific to mothers only and 101 altered miRs were specific to fetuses only. Upon further analyses in the fetuses, we observed that DES-mediated changes in miR expression may regulate genes involved in important functions, such as apoptosis, autophagy, toxicity, and cancer. Of the miRs that showed decreased expression following DES treatment, miR-18b and miR-23a were found to possess complementary sequences and binding affinity for 3' untranslated regions of the Fas ligand (FasL) and Fas, respectively. Transfection studies confirmed that DES-mediated downregulation of miR-18b and miR-23a led to increased FasL and Fas expression. These data demonstrated that prenatal DES exposure can cause alterations in miRs, leading to changes in the gene expression, specifically, miR-mediated increased expression in FasL and Fas causing apoptosis and thymic atrophy. PMID:25753120

  10. Selection of Diethylstilbestrol-Specific Single-Chain Antibodies from a Non-Immunized Mouse Ribosome Display Library

    PubMed Central

    Liu, Ming; Gao, Xianjun; Fan, Xianjun; Liu, Jianqing; Gao, Zhixian

    2012-01-01

    Single chain variable fragments (scFvs) against diethylstilbestrol (DES) were selected from the splenocytes of non-immunized mice by ribosome display technology. A naive library was constructed and engineered to allow in vitro transcription and translation using an E. coli lysate system. Alternating selection in solution and immobilization in microtiter wells was used to pan mRNA-ribosome-antibody (ARM) complexes. After seven rounds of ribosome display, the expression vector pTIG-TRX containing the selected specific scFv DNAs were transformed into Escherichia coli BL21 (DE3) for expression. Twenty-six positive clones were screened and five clones had high antibody affinity and specificity to DES as evidenced by indirect competitive ELISA. Sequence analysis showed that these five DES-specific scFvs had different amino acid sequences, but the CDRs were highly similar. Surface plasmon resonance (SPR) analysis was used to determine binding kinetics of one clone (30-1). The measured KD was 3.79 µM. These results indicate that ribosome display technology can be used to efficiently isolate hapten-specific antibody (Ab) fragments from a naive library; this study provides a methodological framework for the development of novel immunoassays for multiple environmental pollutants with low molecular weight detection using recombinant antibodies. PMID:22427984

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

    SciTech Connect

    Haddad, Rami, E-mail: rami.haddad@mail.mcgill.ca [Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 chemin Cote Ste Catherine, Montréal, Québec, Canada H3T 1E2 (Canada) [Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 chemin Cote Ste Catherine, Montréal, Québec, Canada H3T 1E2 (Canada); Division of Experimental Medicine, Department of Medicine, McGill University, 850 Sherbrooke Street, Montréal, Québec, Canada H3A 1A2 (Canada); Kasneci, Amanda, E-mail: amanda.kasneci@mail.mcgill.ca [Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 chemin Cote Ste Catherine, Montréal, Québec, Canada H3T 1E2 (Canada)] [Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 chemin Cote Ste Catherine, Montréal, Québec, Canada H3T 1E2 (Canada); Mepham, Kathryn, E-mail: katherine.mepham@mail.mcgill.ca [Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 chemin Cote Ste Catherine, Montréal, Québec, Canada H3T 1E2 (Canada) [Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 chemin Cote Ste Catherine, Montréal, Québec, Canada H3T 1E2 (Canada); Division of Experimental Medicine, Department of Medicine, McGill University, 850 Sherbrooke Street, Montréal, Québec, Canada H3A 1A2 (Canada); Sebag, Igal A., E-mail: igal.sebag@mcgill.ca [Division of Cardiology, Jewish General Hospital, 3755 chemin Cote Ste Catherine, Montréal, Québec, Canada H3T 1E2 (Canada); 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 ?g/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.

  12. 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

  13. 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

  14. Non-Diethylstilbestrol-Associated Primary Clear Cell Carcinoma of the Vagina: Two Case Reports with Immunohistochemical Studies and Literature Review

    PubMed Central

    Mufti, Shagufta T.; Ali, Hiba Hassan

    2014-01-01

    Primary clear cell adenocarcinomas most commonly involve the genitourinary system, including the vagina. Previously, primary clear cell adenocarcinomas of the vagina have been discussed within the context of prenatal exposure to diethylstilbestrol. Due to its widely proven role in the development of this carcinoma, administration of diethylstilbestrol is prohibited. We present two cases of non-diethylstilbestrol-associated primary clear cell adenocarcinoma of the vagina from the archives of the Anatomical Pathology Department at King Abdulaziz University in order to improve our understanding of its biological behavior. Our findings suggest that primary clear cell adenocarcinoma of the vagina may be unrelated to diethylstilbestrol exposure and that non-diethylstilbestrol-associated primary clear cell adenocarcinoma of the vagina, when present at a younger age, may have a worse prognosis. PMID:24850989

  15. 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. [Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute at the National Institute of Environmental Health Sciences, PO Box 12233, Mail Drop F0-09, 111 Alexander Drive, Research Triangle Park, NC 27709 (United States)]. E-mail: waalkes@niehs.nih.gov; Liu Jie [Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute at the National Institute of Environmental Health Sciences, PO Box 12233, Mail Drop F0-09, 111 Alexander Drive, Research Triangle Park, NC 27709 (United States); Ward, Jerrold M. [National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892 (United States); Diwan, Bhalchandra A. [Basic Research Program, Science Applications International Corporation, National Cancer Institute at Frederick, Frederick, MD 21702-1201 (United States)

    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.

  16. Histological changes in the uterus of the hens after embryonic exposure to bisphenol A and diethylstilbestrol

    Microsoft Academic Search

    Funda Yigit; Suzan Daglioglu

    2010-01-01

    Many employed chemicals in industries have estrogenic hormone effects on organisms, and these are called as environmental\\u000a estrogens. Environmental estrogens have adverse effects on development and function of reproductive organs of the birds. Bisphenol\\u000a A (BPA) is one of the best known environmental estrogens widely found in plastic products. In this study, we injected BPA\\u000a and the synthetic estrogen diethylstilbestrol

  17. 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 [Department of Biology, Laboratory of Animal Physiology, 20014 University of Turku, Turku (Finland) and Departments of Physiology and Pediatrics, University of Turku, Turku (Finland)]. E-mail: saanmy@utu.fi; Haavisto, Tapio [Department of Biology, Laboratory of Animal Physiology, 20014 University of Turku, Turku (Finland); Vainio, Minna [Department of Biology, Laboratory of Animal Physiology, 20014 University of Turku, Turku (Finland); Toppari, Jorma [Departments of Physiology and Pediatrics, University of Turku, Turku (Finland); Paranko, Jorma [Department of Biology, Laboratory of Animal Physiology, 20014 University of Turku, Turku (Finland)

    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.

  18. GILA WOODPECKER AGONISTIC BEHAVIOR

    Microsoft Academic Search

    GENE L. BRENOWITZ

    ABSTRCT.--Agonistic behavior of Gila Woodpeckers, including vocalizations, visual displays, and other related behaviors, is described. Interactions with both con- and heterospecifics were analyzed by stochastic processes, and it is shown that the timing of aggression toward a species coincided with the time during which that species was searching for nest sites or cavities. The behavior shown toward Flickers and Starlings

  19. Melatonin agonists and insomnia.

    PubMed

    Ferguson, Sally A; Rajaratnam, Shantha M W; Dawson, Drew

    2010-02-01

    The ability of melatonin to shift biological rhythms is well known. As a result, melatonin has been used in the treatment of various circadian rhythm sleep disorders, such as advanced and delayed sleep phase disorders, jet lag and shiftwork disorder. The current evidence for melatonin being efficacious in the treatment of primary insomnia is less compelling. The development of agents that are selective for melatonin receptors provides opportunity to further elucidate the actions of melatonin and its receptors and to develop novel treatments for specific types of sleep disorders. The agonists reviewed here - ramelteon, tasimelteon and agomelatine - all appear to be efficacious in the treatment of circadian rhythm sleep disorders and some types of insomnia. However, further studies are required to understand the mechanisms of action, particularly for insomnia. Clinical application of the agonists requires a good understanding of their phase-dependent properties. Long-term effects of melatonin should be evaluated in large-scale, independent randomized controlled trials. PMID:20136385

  20. [Dopanergic agonists and schizophrenia].

    PubMed

    Pidgeon, J F; Wolf, M A

    1989-11-01

    The neutrotransmitter dopamine mediates its central nervous system actions via 2 types of receptors: D1 and D2, each of which exist in a low or a high affinity state. In schizophrenic patients, it appears that part of the symptomatology may be secondary to dopaminergic hyperactivity (the so called positive symptoms), whereas negative symptoms would be secondary to structural damage. Antipsychotic drugs that are used in clinics are antidopaminergic. It is interesting to note that those drugs are ineffective in part of the schizophrenic population, the chronic one. This inefficiency might be due to primary resistance or to adaptation of the central nervous system to the drugs. Some authors tried dopamine agonists to treat schizophrenic patients. Apomorphine, N-n-propylnorapomorphine, l-DOPA and bromocriptine were tried. The purpose of these substances was to desensitize dopaminergic system, or to inhibit it via presynaptic autoreceptor stimulation, depending of the study. Some authors hypothesized a drop in frontal cortical dopaminergic system to explain part of the schizophrenic symptomatology. Dopamine agonists might act at this level to enhance frontal dopaminergic activity. After those experimentations with dopamine agonist drugs, it appears that 2 of them might have efficiency and clinical use: l-DOPA and bromocriptine. PMID:2573101

  1. Cancer risk in DES daughters

    PubMed Central

    Verloop, Janneke; van Leeuwen, Flora E.; Helmerhorst, Theo J. M.; van Boven, Hester H.

    2010-01-01

    Objective We examined long-term risk of cancer in women exposed to diethylstilbestrol (DES) in utero. Methods A total of 12,091 DES-exposed women in the Netherlands were followed prospectively from December 1992 till June 2008. Cancer incidence was assessed through linkage with the Dutch pathology database (PALGA) and the Netherlands Cancer Registry and compared with the Dutch female population. Results A total of 348 medically verified cancers occurred; median age at end of follow-up was 44.0 years. No overall increased risk of cancer was found (standardized incidence ratio [SIR] = 1.01; 95% confidence interval [CI] = 0.91, 1.13). The risk of clear cell adenocarcinoma of the vagina and cervix (CCA) was statistically significantly increased (SIR = 24.23; 95% CI = 8.89, 52.74); the elevated risk persisted above 40 years of age. The risk of melanoma diagnosed before age 40 was increased (SIR = 1.59; 95% CI = 1.08, 2.26). No excess risks were found for other sites, including breast cancer. Conclusions Except for an elevated risk of CCA, persisting at older ages, and an increased risk of melanoma at young ages, we found no increased risk of cancer. Longer follow-up is warranted to examine cancer risk at ages when cancer occurs more frequently. Electronic supplementary material The online version of this article (doi:10.1007/s10552-010-9526-5) contains supplementary material, which is available to authorized users. PMID:20204493

  2. Women exposed to DES in the womb face increased cancer risk:

    Cancer.gov

    A large study of the daughters of women who had been given DES, the first synthetic form of estrogen, during pregnancy has found that exposure to the drug while in the womb (in utero) is associated with many reproductive problems and an increased risk of certain cancers and pre-cancerous conditions. Beginning in 1940, diethylstilbestrol, known as DES, was used clinically to prevent certain complications of pregnancy. In the 1950s, clinical studies showed DES was ineffective for this purpose. In the late 1960s, an unusual occurrence of a rare cancer of the vagina among young women, called clear cell adenocarcinoma (CCA), was observed and subsequently linked to their exposure to DES while in the womb.

  3. Discrimination between olfactory receptor agonists and non-agonists.

    PubMed

    Topin, Jérémie; de March, Claire A; Charlier, Landry; Ronin, Catherine; Antonczak, Serge; Golebiowski, Jérôme

    2014-08-11

    A joint approach combining free-energy calculations and calcium-imaging assays on the broadly tuned human 1G1 olfactory receptor is reported. The free energy of binding of ten odorants was computed by means of molecular-dynamics simulations. This state function allows separating the experimentally determined eight agonists from the two non-agonists. This study constitutes a proof-of-principle for the computational deorphanization of olfactory receptors. PMID:25043138

  4. Dopamine agonists and Othello's syndrome

    PubMed Central

    Graff-Radford, Jonathan; Ahlskog, J Eric.; Bower, James H.; Josephs, Keith A.

    2014-01-01

    Background Othello's syndrome (OS) is a delusion of infidelity. We describe seven cases of OS in Parkinson's disease (iPD) patients using dopamine agonists. Methods We searched the Mayo Clinic Medical Records System to identify all patients with OS. Clinical data abstracted include sex, age of onset of iPD, age of onset of OS, medications, effect of discontinuing the dopamine agonist, neuroimaging, and comorbidities. Results Seven non-demented iPD patients with dopamine agonist implementation time locked to the development and resolution of OS are reported. The average age of iPD onset was 46.6 years (Standard deviation: 5.0 years), and OS onset was 53.7 years (7.1 years). All seven patients had significant marital conflict as a result of the delusions. Conclusions OS can be associated with dopamine agonist use and can lead to serious consequences. Dopamine agonist cessation eliminates the delusion of infidelity and should be the first treatment option. PMID:20829092

  5. 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

  6. Agonistic Behavior in Freshwater Crayfish

    E-print Network

    Moore, Paul A.

    Agonistic Behavior in Freshwater Crayfish The Influence of Intrinsic and Extrinsic Factors on Aggressive Encounters and Dominance 5 Paul A. Moore During aggressive fights, crayfish Orconectes rusticus question, a crustacean system, based on the crayfish, has been adopted as a model for social behavior

  7. Cloning and Expression of the Delayed-Rectifier IsK Channel from Neonatal Rat Heart and Diethylstilbestrol-Primed Rat Uterus

    Microsoft Academic Search

    Kimberly Folander; Jeffrey S. Smith; Joanne Antanavage; Carl Bennett; Robert B. Stein; Richard Swanson

    1990-01-01

    cDNAs encoding a delayed-rectifier-type K^+ channel were cloned from both neonatal rat heart and ovariectomized, diethylstilbestrol-primed rat uterus by using the polymerase chain reaction. Both clones have nucleotide sequences identical to that encoding the rat kidney IsK channel [Takumi, T., Ohkubo, H. & Nakanishi, S. (1988) Science 242, 1042-1045] and encode a putative protein of 130 amino acids. Injection of

  8. 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

  9. Agonist-specific Gating of NMDA Receptors

    PubMed Central

    Kussius, Cassandra L.; Popescu, Andrei M.; Popescu, Gabriela K.

    2011-01-01

    The mechanism by which ligand binding at extracellular receptor domains gates a transmembrane ion-conducting pore is insufficiently understood. Examining a channel’s activation reaction in the presence of agonists with distinct efficacies may inform this issue and may help identify agonist-dependent transitions. We have recently applied this approach to NMDA receptors composed of GluN1 and GluN2A subunits. Based on our results with several subunit-specific partial agonists we concluded that agonist effects were distributed over several of the multiple transitions that make up NMDA receptor gating and that these changes were subunit independent. Here we examine an additional GluN2A partial agonist, 4-fluoro-D, L-glutamic acid, and we summarize the observed kinetic changes of all nine partial agonists investigated. These results support the premise that regardless of the subunit-type to which they bind, agonists influence multiple equilibria within the NMDA receptor reaction and may stabilize a slightly different family of conformers. PMID:19934647

  10. Agonists and partial agonists of rhodopsin: retinals with ring modifications.

    PubMed

    Vogel, Reiner; Siebert, Friedrich; Lüdeke, Steffen; Hirshfeld, Amiram; Sheves, Mordechai

    2005-09-01

    Activation of the visual pigment rhodopsin is initiated by isomerization of its retinal chromophore to the all-trans geometry, which drives the conformation of the protein to the active state. We have examined by FTIR spectroscopy the impact of a series of modifications at the ring of retinal on the activation process and on molecular interactions within the binding pocket. Deletion of ring methyl groups at C1 and C5 or replacement of the ring in diethyl or ethyl-methyl acyclic analogues resulted in partial agonists, for which the conformational equilibrium between the Meta I and Meta II photoproduct is shifted from the active Meta II side to the inactive Meta I side. While the Meta II states of these artificial pigments had a conformation similar to those of native Meta II, the Meta I states were different. Modifications on the ring of retinal had a particular impact on the interaction of Glu 122 within the ring-binding pocket and are shown to interfere with the Glu 134-mediated proton uptake during formation of Meta II. We further found, upon partial deletion of ring constituents, a decrease of the entropy change of the transition from Meta I to Meta II by up to 50%, while the concomitant reduction of the enthalpy term was less pronounced. These findings underline the particular importance of the ring and the ring methyl groups and are discussed in a model of receptor activation. PMID:16128569

  11. New benzimidazoles as thrombopoietin receptor agonists.

    PubMed

    Safonov, Igor G; Heerding, Dirk A; Keenan, Richard M; Price, Alan T; Erickson-Miller, Connie L; Hopson, Christopher B; Levin, Jenna L; Lord, Kenneth A; Tapley, Peter M

    2006-03-01

    A novel benzimidazole series of small-molecule thrombopoietin receptor agonists has been discovered. Herein, we discuss the preliminary exploration of structure-activity relationships within this chemotype. PMID:16376078

  12. Dopamine agonists and pathologic behaviors.

    PubMed

    Kelley, Brendan J; Duker, Andrew P; Chiu, Peter

    2012-01-01

    The dopamine agonists ropinirole and pramipexole exhibit highly specific affinity for the cerebral dopamine D3 receptor. Use of these medications in Parkinson's disease has been complicated by the emergence of pathologic behavioral patterns such as hypersexuality, pathologic gambling, excessive hobbying, and other circumscribed obsessive-compulsive disorders of impulse control in people having no history of such disorders. These behavioral changes typically remit following discontinuation of the medication, further demonstrating a causal relationship. Expression of the D3 receptor is particularly rich within the limbic system, where it plays an important role in modulating the physiologic and emotional experience of novelty, reward, and risk assessment. Converging neuroanatomical, physiological, and behavioral science data suggest the high D3 affinity of these medications as the basis for these behavioral changes. These observations suggest the D3 receptor as a therapeutic target for obsessive-compulsive disorder and substance abuse, and improved understanding of D3 receptor function may aid drug design of future atypical antipsychotics. PMID:22567537

  13. PPAR Agonists and Cardiovascular Disease in Diabetes

    PubMed Central

    Calkin, Anna C.; Thomas, Merlin C.

    2008-01-01

    Peroxisome proliferators activated receptors (PPARs) are ligand-activated nuclear transcription factors that play important roles in lipid and glucose homeostasis. To the extent that PPAR agonists improve diabetic dyslipidaemia and insulin resistance, these agents have been considered to reduce cardiovascular risk. However, data from murine models suggests that PPAR agonists also have independent anti-atherosclerotic actions, including the suppression of vascular inflammation, oxidative stress, and activation of the renin angiotensin system. Many of these potentially anti-atherosclerotic effects are thought to be mediated by transrepression of nuclear factor-kB, STAT, and activator protein-1 dependent pathways. In recent clinical trials, PPAR? agonists have been shown to be effective in the primary prevention of cardiovascular events, while their cardiovascular benefit in patients with established cardiovascular disease remains equivocal. However, the use of PPAR? agonists, and more recently dual PPAR?/? coagonists, has been associated with an excess in cardiovascular events, possibly reflecting unrecognised fluid retention with potent agonists of the PPAR? receptor. Newer pan agonists, which retain their anti-atherosclerotic activity without weight gain, may provide one solution to this problem. However, the complex biologic effects of the PPARs may mean that only vascular targeted agents or pure transrepressors will realise the goal of preventing atherosclerotic vascular disease. PMID:18288280

  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. Novel Human Interleukin-15 Agonists

    PubMed Central

    Zhu, Xiaoyun; Marcus, Warren D.; Xu, Wenxin; Lee, Hyung-Il; Han, Kaiping; Egan, Jack O.; Yovandich, Jason L.; Rhode, Peter R.; Wong, Hing C.

    2009-01-01

    IL-15 is an immunostimulatory cytokine trans-presented with the IL-15 receptor ? chain to the shared IL-2/IL-15R? and common ? chains displayed on the surface of T cells and NK cells. To further define the functionally important regions of this cytokine, activity and binding studies were conducted on human IL-15 muteins generated by site-directed mutagenesis. Amino acid substitutions of the asparagine residue at position 72, which is located at the end of helix C, were found to provide both partial agonist and superagonist activity, with various non-conservative substitutions providing enhanced activity. Particularly, the N72D substitution provided a 4–5 fold increased in biological activity of the IL-15 mutein compared to the native molecule based on proliferations assays with cells bearing human IL-15R? and common ? chains. The IL-15N72D mutein exhibited superagonist activity through improved binding ability to the human IL-15R? chain. However, the enhanced potency of IL-15N72D was not observed with cells expressing the mouse IL-15R?-IL-15R?-?c complex suggesting that this effect is specific to human IL-15 receptor. The enhanced biological activity of IL-15N72D was associated with more intense phosphorylation of Jak1 and Stat5 and better anti-apoptotic activity compared to the wild-type IL-15. IL-15N72D superagonist activity was also preserved when linked to a single-chain T cell receptor domain to generate a tumor-specific fusion protein. Thus, the human IL-15 superagonist muteins and fusions may create opportunities to construct more efficacious immunotherapeutic agents with clinical utility. PMID:19710453

  16. The structural basis for agonist and partial agonist action on a ?(1)-adrenergic receptor.

    PubMed

    Warne, Tony; Moukhametzianov, Rouslan; Baker, Jillian G; Nehmé, Rony; Edwards, Patricia C; Leslie, Andrew G W; Schertler, Gebhard F X; Tate, Christopher G

    2011-01-13

    ?-adrenergic receptors (?ARs) are G-protein-coupled receptors (GPCRs) that activate intracellular G proteins upon binding catecholamine agonist ligands such as adrenaline and noradrenaline. Synthetic ligands have been developed that either activate or inhibit ?ARs for the treatment of asthma, hypertension or cardiac dysfunction. These ligands are classified as either full agonists, partial agonists or antagonists, depending on whether the cellular response is similar to that of the native ligand, reduced or inhibited, respectively. However, the structural basis for these different ligand efficacies is unknown. Here we present four crystal structures of the thermostabilized turkey (Meleagris gallopavo) ?(1)-adrenergic receptor (?(1)AR-m23) bound to the full agonists carmoterol and isoprenaline and the partial agonists salbutamol and dobutamine. In each case, agonist binding induces a 1?Å contraction of the catecholamine-binding pocket relative to the antagonist bound receptor. Full agonists can form hydrogen bonds with two conserved serine residues in transmembrane helix 5 (Ser(5.42) and Ser(5.46)), but partial agonists only interact with Ser(5.42) (superscripts refer to Ballesteros-Weinstein numbering). The structures provide an understanding of the pharmacological differences between different ligand classes, illuminating how GPCRs function and providing a solid foundation for the structure-based design of novel ligands with predictable efficacies. PMID:21228877

  17. Characteristics of the synergistic actions of platelet agonists.

    PubMed

    Huang, E M; Detwiler, T C

    1981-04-01

    Platelets are activated by many different agonists that act synergistically. Since there is a characteristic pattern of responses to each agonist, and since there is a clear distinction between weak and strong agonists, understanding the nature of the synergism and its physiologic significance requires characterization of the pattern of responses to the synergistic action of the various agonists. Shape change, aggregation, and secretion of ATP by human platelets in citrated plasma were analyzed after activation by ADP, epinephrine, arachidonic acid, gamma-thrombin, or collagen, either singly or in pairs. The patterns of responses were characteristic of the agonist in higher concentration relative to its threshold concentration; if neither was clearly higher, the pattern of responses was intermediate between the responses characteristic of each agonist. No combination of weak agonists had the characteristics of a strong agonist. These results help define the extent to which platelet responses can be attributed to the synergistic actions of weak agonists. PMID:7470619

  18. TLR3 Agonists and Proinflammatory Antitumor Activities

    PubMed Central

    Sharma, Sherven; Zhu, Li; Davoodi, Michael; Harris White, Marni; Lee, Jay M.; John, Maie St.; Salgia, Ravi; Dubinett, Steven

    2013-01-01

    Although tumor growth leads to inflammatory responses, the immune system develops tolerance to cancer. One way to break host tolerance to tumors is to activate key immune effector activities. Toward this end, various adjuvants are under investigation in an effort to harness the immune system to overcome tolerance to tumor associated self-antigens. There is enthusiasm for the use of specific ligands for toll-like 3 receptors (TLR3) that play a key role in the innate immune system. TLR3 agonists serve as immune adjuvants because they potently induce innate immune responses by activating dendritic cell (DC) maturation and inflammatory cytokine secretion. These activities facilitate the bridge between the innate and adaptive immune systems promoting the expansion of cytotoxic T lymphocytes (CTL) that destroy cancer cells. TLR3 agonists either alone or in combination with tumor antigens have shown success in terms of enhancing immune responses and eliciting antitumor activity in preclinical models. However, TLR3 agonists can also impact regulatory cells that dampen immune responses. Thus, immune strategies that utilize TLR3 agonists should consider the relative induction of suppressive as well as beneficial anti tumor immune activities. Herein, we summarize the TLR3 agonists that will hopefully come to clinical fruition. PMID:23506058

  19. 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

  20. Direction des Ressources Humaines Gestion Prvisionnelle des

    E-print Network

    Sart, Remi

    et des plantes transgéniques (OGM). Contraintes / sujétions particulières du poste : Déplacements à l produits toxiques, des produits contaminants et des plantes transgéniques (OGM) CONNAISSANCES REQUISES #12

  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; (GSKNC)

    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. Reciprocity of agonistic support in ravens.

    PubMed

    Fraser, Orlaith N; Bugnyar, Thomas

    2012-01-01

    Cooperative behaviour through reciprocation or interchange of valuable services in primates has received considerable attention, especially regarding the timeframe of reciprocation and its ensuing cognitive implications. Much less, however, is known about reciprocity in other animals, particularly birds. We investigated patterns of agonistic support (defined as a third party intervening in an ongoing conflict to attack one of the conflict participants, thus supporting the other) in a group of 13 captive ravens, Corvus corax. We found support for long-term, but not short-term, reciprocation of agonistic support. Ravens were more likely to support individuals who preened them, kin and dominant group members. These results suggest that ravens do not reciprocate on a calculated tit-for-tat basis, but aid individuals from whom reciprocated support would be most useful and those with whom they share a good relationship. Additionally, dyadic levels of agonistic support and consolation (postconflict affiliation from a bystander to the victim) correlated strongly with each other, but we found no evidence to suggest that receiving agonistic support influences the victim's likelihood of receiving support (consolation) after the conflict ends. Our findings are consistent with an emotionally mediated form of reciprocity in ravens and provide additional support for convergent cognitive evolution in birds and mammals. PMID:22298910

  3. Social behavior of the emperor tamarin in captivity: Components of agonistic display and the agonistic network

    Microsoft Academic Search

    Kerry L. Knox; Donald Stone Sade

    1991-01-01

    Agonistic behavior was studied longitudinally for 16 months in an intact family groups of captive emperor tamarins (Saguinus\\u000a imperator subgrisescens) using methods from quantitative ethology and social network analysis. A motivational analysis of\\u000a the components of agonistic display revealed the relative strength of each component along a continuum from strongly dominant\\u000a to strongly subordinate. Tabulations of exchanges of strongly dominant

  4. [Study of combined effects of DES and EV on the proliferation of MCF-7 cells by two experimental designs].

    PubMed

    Liu, Qian; Lei, Bing-Li; An, Jing; Shang, Yu; Zhong, Yu-Fang; Kang, Jia; Wen, Yu

    2013-08-01

    The single toxicity of diethylstilbestrol (DES) and beta-estradiol 17-valerate (EV) and the joint toxicity of their binary mixtures in equiconcentration to the proliferation of MCF-7 cells were investigated, respectively. Additive index (AI) method was adopted to evaluate the joint toxicity effect. At the same time, 3 x 3 factorial experimental design was used to verify the joint toxiciy types derived from equiconcentration of DES and EV. The results show that the EC50 values of single EV and DES for 24, 48 and 72 h are 6.02, 0.40 and 0.33 nmol x L(-1) and 5.90, 6.98 and 2.90 nmol x L(-1), respectively. The EC50 values of the binary mixtures of DES and EV for 24, 48 and 72 h are 2.33, 0.71 and 0.39 nmol x L(-1). The binary joint effects of DES and EV for 24 h were synergistic, and the joint effects of DES and EV for 48 and 72 h were antagonistic. But synergistic and antagonistic effects are not strong; their values can be found close to the values of additive effects. Factorial experiment results show that combined effects of DES and EV to proliferation of MCF-7 cells for 24, 48 and 72 h three exposure periods are additive effect types. The consistent joint combined effect types can be drawn from both factorial experimental design and equiconcentration ratio of DES and EV to the proliferation of MCF-7 cells. However, the factorial experimental design is simpler and more convenient, and can avoid unnecessary mistakes due to the derivation of EC50 values. PMID:24191583

  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 mg·kg?1), unmasked etorphine (3 mg·kg?1) antinociception in MOP KO mice. Further, in wild-type mice, KOP-mediated antinociception by systemic U50,488H (10 mg·kg?1) was blocked by pretreatment with the DOP agonist SNC80 (5 mg·kg?1) and diazepam (1 mg·kg?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. 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. [Brigham Young Univ., Provo, UT (United States); Allen, S.D. [Utah State Univ., Logan, UT (United States)

    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.

  7. A comparison of the estrogenic potencies of estradiol, ethynylestradiol, diethylstilbestrol, nonylphenol and methoxychlor in vivo and in vitro

    Microsoft Academic Search

    Leroy C Folmar; Michael J Hemmer; Nancy D Denslow; Kevin Kroll; Jian Chen; Ann Cheek; Harold Richman; Hillary Meredith; E. Gordon Grau

    2002-01-01

    Five natural, pharmaceutical, or xenobiotic chemicals [17?-estradiol (E2), ethynylestradiol (EE2), diethystilbestrol (DES), methoxychlor (MXC), nonylphenol (NP)] were tested in two in vitro assays [yeast estrogen screen (YES), MCF-7 breast tumor cell proliferation (E-Screen)], and compared with previously reported results from two in vivo male sheepshead minnow vitellogenin (VTG) production studies. The purpose of this investigation was to determine how accurately

  8. 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

  9. MASS SPECTROMETRIC IDENTIFICATION OF BETA2-AGONISTS

    Microsoft Academic Search

    M. K. Henze; G. Opfermann

    After isolation and derivatisation the beta-2-agonists are analysed by GC\\/MS in the EI mode. The derivatisation is performed by trimethylsilylation with N-Methyl-N-trimethylsilyl- trifluoroacetamide(MSTFA)\\/ammoniumiodide(NH4I)\\/ethanethiol-TMS and in case of fenoterol, orciprenaline, reproterol and terbutaline by condensation with formaldehyde followed by trimethylsilylation. The obtained mass spectra are presented. Also corresponding deuterated derivatives have been investigated. The knowledge of the fragment ions is useful

  10. Sports doping: emerging designer and therapeutic ?2-agonists.

    PubMed

    Fragkaki, A G; Georgakopoulos, C; Sterk, S; Nielen, M W F

    2013-10-21

    Beta2-adrenergic agonists, or ?2-agonists, are considered essential bronchodilator drugs in the treatment of bronchial asthma, both as symptom-relievers and, in combination with inhaled corticosteroids, as disease-controllers. The use of ?2-agonists is prohibited in sports by the World Anti-Doping Agency (WADA) due to claimed anabolic effects, and also, is prohibited as growth promoters in cattle fattening in the European Union. This paper reviews the last seven-year (2006-2012) literature concerning the development of novel ?2-agonists molecules either by modifying the molecule of known ?2-agonists or by introducing moieties producing indole-, adamantyl- or phenyl urea derivatives. New emerging ?2-agonists molecules for future therapeutic use are also presented, intending to emphasize their potential use for doping purposes or as growth promoters in the near future. PMID:23954776

  11. 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.

  12. Small Molecule Bax Agonists for Cancer Therapy

    PubMed Central

    Xin, Meiguo; Li, Rui; Xie, Maohua; Park, Dongkyoo; Owonikoko, Taofeek K.; Sica, Gabriel L.; Corsino, Patrick E.; Zhou, Jia; Ding, Chunyong; White, Mark A.; Magis, Andrew T.; Ramalingam, Suresh S.; Curran, Walter J.; Khuri, Fadlo R.; Deng, Xingming

    2014-01-01

    Bax, a central death regulator, is required at the decisional stage of apoptosis. We recently identified serine 184 (S184) of Bax as a critical functional switch controlling its proapoptotic activity. Here, we employed the structural pocket around S184 as a docking site to screen the NCI library of small molecules using the UCSF-DOCK program suite. Three compounds, small molecule Bax agonists SMBA1, SMBA2 and SMBA3, induce conformational changes in Bax by blocking S184 phosphorylation, facilitating Bax insertion into mitochondrial membranes and forming Bax oligomers. The latter leads to cytochrome c release and apoptosis in human lung cancer cells, which occurs in a Bax- but not Bak-dependent fashion. SMBA1 potently suppresses lung tumor growth via apoptosis by selectively activating Bax in vivo without significant normal tissue toxicity. Development of Bax agonists as a new class of anti-cancer drugs offers a strategy for the treatment of lung cancer and other Bax-expressing malignancies. PMID:25230299

  13. Activity patterns, behavioural repertoires, and agonistic interactions of crayfish: A non-manipulative

    E-print Network

    Huber, Robert

    Activity patterns, behavioural repertoires, and agonistic interactions of crayfish: A non, USA) (Accepted: 16 January 2007) Summary Agonistic behaviour of crayfish has been studied extensively. Crayfish agonistic behaviour within its natural context, however, has received little attention to date

  14. Mini Rev Med Chem. Author manuscript Fluorescent agonists and antagonists for vasopressin/oxytocin G

    E-print Network

    Paris-Sud XI, Université de

    for vasopressin/oxytocin G protein-coupled receptors: usefulness in ligand screening assays and receptor studies agonists and antagonists have been developed and characterized for arginine-vasopressin and oxytocin G, Oxytocin ; agonists ; antagonists & inhibitors ; metabolism ; Receptors, Vasopressin ; agonists

  15. 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…

  16. [Glucagon-like peptide-1 receptor agonists].

    PubMed

    Mashimo, Yamato; Eto, Kazuhiro

    2015-03-01

    Recently, the number of diabetic patients with obesity has increased by changes in life-style including food and physical exercise. Appearance of incretin-related drugs has given us more options for treating type 2 diabetes, and they are evaluated in regard to realizing appropriately controlled glycemic status. One of incretin-related drugs, glucagon-like peptide-1 receptor agonist (GLP-1RA), possesses pleiotropic actions to pancreatic ?/? cells and other targets, and is highly expected from the clinical aspect. Specifically, the long-acting GLP-1RAs lower fasting glucose levels, and the short-acting GLP-1RAs lower post-prandial glucose levels. By optimally employing these drugs, better glycemic management should be enabled. PMID:25812369

  17. 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

  18. [Pathological gambling induced by dopamine agonists].

    PubMed

    Gahr, M; Connemann, B J; Schönfeldt-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

  19. Analysis of agonist-agonist interactions: the crucial influence of curve shape.

    PubMed

    Scaramellini, C; Bennett, G; Leff, P

    1997-04-01

    The two-receptor:one-transducer model (Leff, 1987) is here extended to analyze interactions between agonists displaying E[A] curves of different shapes, by incorporating slope factors into the separate and common parts of the transduction pathway. Interactions were modelled as the effect of one agonist, at fixed concentration, on the curve to the other. A variety of patterns of position and slope changes are predicted. These do not depend on the shape of the control curve, rather, they depend on the slope factors in the separate and common pathways. The following specific predictions are made: (1) when the common pathway is steep, curves undergo potentiation and flattening; (2) when the common pathway is flat, curves undergo right-shift and steepening; (3) when the common pathway is hyperbolic, curves undergo right-shift, with no slope change; (4) when the slope depends on the separate pathways, curves only undergo right-shift with no change in slope. The model provides a sound basis for classifying agonist interactions and for detecting additional, synergistic or antagonistic properties. This analysis indicates that methods based on dose-additivity or independence are less reliable for these purposes. The model provides a practical test, based on slope changes, to detect and quantify additional properties. PMID:9253753

  20. 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

  1. Effet des innovations organisationnelles et des technologies de l'information sur le rendement des entreprises

    Microsoft Academic Search

    Wulong Gera Surendra Gu

    2004-01-01

    Dans ce document, on vise a determiner si les investissements dans les technologies de l'information et des communications, combines a des changements organisationnels et aux competences des travailleurs, contribuent a ameliorer le rendement des entreprises canadiennes.

  2. Dopamine agonist withdrawal syndrome: implications for patient care.

    PubMed

    Nirenberg, Melissa J

    2013-08-01

    Dopamine agonists are effective treatments for a variety of indications, including Parkinson's disease and restless legs syndrome, but may have serious side effects, such as orthostatic hypotension, hallucinations, and impulse control disorders (including pathological gambling, compulsive eating, compulsive shopping/buying, and hypersexuality). The most effective way to alleviate these side effects is to taper or discontinue dopamine agonist therapy. A subset of patients who taper a dopamine agonist, however, develop dopamine agonist withdrawal syndrome (DAWS), which has been defined as a severe, stereotyped cluster of physical and psychological symptoms that correlate with dopamine agonist withdrawal in a dose-dependent manner, cause clinically significant distress or social/occupational dysfunction, are refractory to levodopa and other dopaminergic medications, and cannot be accounted for by other clinical factors. The symptoms of DAWS include anxiety, panic attacks, dysphoria, depression, agitation, irritability, suicidal ideation, fatigue, orthostatic hypotension, nausea, vomiting, diaphoresis, generalized pain, and drug cravings. The severity and prognosis of DAWS is highly variable. While some patients have transient symptoms and make a full recovery, others have a protracted withdrawal syndrome lasting for months to years, and therefore may be unwilling or unable to discontinue DA therapy. Impulse control disorders appear to be a major risk factor for DAWS, and are present in virtually all affected patients. Thus, patients who are unable to discontinue dopamine agonist therapy may experience chronic impulse control disorders. At the current time, there are no known effective treatments for DAWS. For this reason, providers are urged to use dopamine agonists judiciously, warn patients about the risks of DAWS prior to the initiation of dopamine agonist therapy, and follow patients closely for withdrawal symptoms during dopamine agonist taper. PMID:23686524

  3. Universit de Lausanne, Institut des sciences sociales des religions contemporaines cole Pratique des Hautes tudes, Section des sciences religieuses

    E-print Network

    Paris-Sud XI, Université de

    Université de Lausanne, Institut des sciences sociales des religions sciences des religions de l'Université de Lausanne (Suisse) pour l'obtention du Doctorat en Sciences des contemporaines �cole Pratique des Hautes �tudes, Section des sciences religieuses

  4. Toll-like receptor agonists in cancer therapy

    PubMed Central

    Adams, Sylvia

    2010-01-01

    Toll-like receptors (TLRs) are pattern-recognition receptors related to the Drosophila Toll protein. TLR activation alerts the immune system to microbial products and initiates innate and adaptive immune responses. The naturally powerful immunostimulatory property of TLR agonists can be exploited for active immunotherapy against cancer. Antitumor activity has been demonstrated in several cancers, and TLR agonists are now undergoing extensive clinical investigation. This review discusses recent advances in the field and highlights potential opportunities for the clinical development of TLR agonists as single agent immunomodulators, vaccine adjuvants and in combination with conventional cancer therapies. PMID:20563267

  5. 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.

  6. AGONISTIC BEHAVIOR IN FOOD ANIMALS: REVIEW OF RESEARCH AND TECHNIQUES 1,2

    Microsoft Academic Search

    John J. McGlone

    2010-01-01

    One type of social behavior-agonistic behavior-is commonly observed among food animals. Agonistic behaviors are those behaviors which cause, threaten to cause or seek to reduce physical damage. Agonistic behavior is comprised of threats, aggression and submission. While any one of these divisions of agonistic behavior may be observed alone, they usually are found, in sequence, from the start to the

  7. Agonist replacement therapy for cocaine dependence: a translational review

    PubMed Central

    Rush, Craig R; Stoops, William W

    2012-01-01

    Cocaine use disorders are prevalent throughout the world. Agonist replacement therapy is among the most effective strategies for managing substance use disorders including nicotine and opioid dependence. This paper reviews the translational literature, including preclinical experiments, human laboratory studies and clinical trials, to determine whether agonist-replacement therapy is a viable strategy for managing cocaine dependence. Discussion is limited to transporter blockers (i.e., methylphenidate) and releasers (i.e., amphetamine analogs) that are available for use in humans in the hope of impacting clinical research and practice more quickly. The translational review suggests that agonist-replacement therapy, especially monoamine releasers, may be effective for managing cocaine dependence. Future directions for medications development are also discussed because the viability of agonist-replacement therapy for cocaine dependence may hinge on identifying novel compounds or formulations that have less abuse and diversion potential. PMID:22300101

  8. Alteration of Lymphocyte Trafficking by Sphingosine 1Phosphate Receptor Agonists

    Microsoft Academic Search

    Suzanne Mandala; Richard Hajdu; James Bergstrom; Elizabeth Quackenbush; Jenny Xie; James Milligan; Rosemary Thornton; Gan-Ju Shei; Deborah Card; CarolAnn Keohane; Mark Rosenbach; Jeffrey Hale; Christopher L. Lynch; Kathleen Rupprecht; William Parsons; Hugh Rosen

    2002-01-01

    Blood lymphocyte numbers, essential for the development of efficient immune responses, are maintained by recirculation through secondary lymphoid organs. We show that lymphocyte trafficking is altered by the lysophospholipid sphingosine-1-phosphate (S1P) and by a phosphoryl metabolite of the immunosuppressive agent FTY720. Both species were high-affinity agonists of at least four of the five S1P receptors. These agonists produce lymphopenia in

  9. Differential agonist sensitivity of glycine receptor ?2 subunit splice variants

    PubMed Central

    Miller, Paul S; Harvey, Robert J; Smart, Trevor G

    2004-01-01

    The glycine receptor (GlyR) ?2A and ?2B splice variants differ by a dual, adjacent amino acid substitution from ?2AV58,T59 to ?2BI58,A59 in the N-terminal extracellular domain. Comparing the effects of the GlyR agonists, glycine, ?-alanine and taurine, on the GlyR ?2 isoforms, revealed a significant increase in potency for all three agonists at the ?2B variant. The sensitivities of the splice variants to the competitive antagonist, strychnine, and to the biphasic modulator Zn2+, were comparable. In contrast, the allosteric inhibitor picrotoxin was more potent on GlyR ?2A compared to GlyR ?2B receptors. Coexpression of ?2A or ?2B subunits with the GlyR ? subunit revealed that the higher agonist potencies observed with the ?2B homomer were retained for the ?2B? heteromer. The identical sensitivity to strychnine combined with a reduction in the maximum current induced by the partial agonist taurine at the GlyR ?2A homomer, suggested that the changed sensitivity to agonists is in accordance with a modulation of agonist efficacy rather than agonist affinity. An effect on agonist efficacy was also supported by using a structural model of the GlyR, localising the region of splice variation to the proposed docking region between GlyR loop 2 and the TM2-3 loop, an area associated with channel activation. The existence of a spasmodic mouse phenotype linked to a GlyR ?1A52S mutation, the equivalent position to the source of the ?2 splice variation, raises the possibility that the GlyR ?2 splice variants may be responsible for distinct roles in neuronal function. PMID:15302677

  10. Identification of M-CSF agonists and antagonists

    DOEpatents

    Pandit, Jayvardhan (Mystic, CT); Jancarik, Jarmila (Walnut Creek, CA); Kim, Sung-Hou (Moraga, CA); Koths, Kirston (El Cerrito, CA); Halenbeck, Robert (San Rafael, CA); Fear, Anna Lisa (Oakland, CA); Taylor, Eric (Oakland, CA); Yamamoto, Ralph (Martinez, CA); Bohm, Andrew (Armonk, NY)

    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.

  11. Protective effects of PPAR? agonist in acute nephrotic syndrome

    PubMed Central

    Zuo, Yiqin; Yang, Hai-Chun; Potthoff, Sebastian A.; Najafian, Behzad; Kon, Valentina; Ma, Li-Jun

    2012-01-01

    Background. Peroxisome proliferator-activated receptor gamma (PPAR?) agonists have beneficial effects on renal structure and function in models of diabetes and chronic kidney diseases. However, the increased incidence of weight gain and edema potentially limits their usefulness. We studied an acute minimal-change disease-like nephrotic syndrome model to assess effects of PPAR? agonist on acute podocyte injury and effects on fluid homeostasis. Methods. Acute podocyte injury and nephrotic syndrome were induced by puromycin aminonucleoside (PAN) injection in rats. Results. PPAR? agonist, given at the time or after, but not before PAN, reduced proteinuria, restored synaptopodin, decreased desmin and trended to improve foot process effacement. There was no significant difference in glomerular filtration, effective circulating volume, blood pressure or fractional sodium excretion. PAN-injured podocytes had decreased PPAR?, less nephrin and ?-actinin-4, more apoptosis and reduced phosphorylated Akt. In PAN-injured cultured podocytes, PPAR? agonist also reversed abnormalities only when given simultaneously or after injury. Conclusions. These results show that PPAR? agonist has protective effects on podocytes in acute nephrotic syndrome without deleterious effects on fluid homeostasis. PPAR? agonist-induced decrease in proteinuria in acute nephrotic syndrome is dependent at least partially on regulation of peroxisome proliferator-response element-sensitive gene expression such as ?-actinin-4 and nephrin and the restoration of podocyte structure. PMID:21565943

  12. Pairwise agonist scanning predicts cellular signaling responses to combinatorial stimuli.

    PubMed

    Chatterjee, Manash S; Purvis, Jeremy E; Brass, Lawrence F; Diamond, Scott L

    2010-07-01

    Prediction of cellular response to multiple stimuli is central to evaluating patient-specific clinical status and to basic understanding of cell biology. Cross-talk between signaling pathways cannot be predicted by studying them in isolation and the combinatorial complexity of multiple agonists acting together prohibits an exhaustive exploration of the complete experimental space. Here we describe pairwise agonist scanning (PAS), a strategy that trains a neural network model based on measurements of cellular responses to individual and all pairwise combinations of input signals. We apply PAS to predict calcium signaling responses of human platelets in EDTA-treated plasma to six different agonists (ADP, convulxin, U46619, SFLLRN, AYPGKF and PGE(2)) at three concentrations (0.1, 1 and 10 x EC(50)). The model predicted responses to sequentially added agonists, to ternary combinations of agonists and to 45 different combinations of four to six agonists (R = 0.88). Furthermore, we use PAS to distinguish between the phenotypic responses of platelets from ten donors. Training neural networks with pairs of stimuli across the dose-response regime represents an efficient approach for predicting complex signal integration in a patient-specific disease milieu. PMID:20562863

  13. Evidence for postsynaptic dopamine agonist effects of BHT 920 in the presence of the dopamine D-1 agonist SKF 38393

    Microsoft Academic Search

    Leonard T. Meltzer; James N. Wiley; Ann E. Williams; Thomas G. Heffner

    1988-01-01

    The ability of B-HT 920, a selective dopamine (DA) D-2 agonist, to stimulate postsynaptic DA receptors in brain was evaluated by assessing its ability to induce stereotypy and to increase locomotor activity in rats. When administered alone, B-HT 920 (0.03–3.0 mg\\/kg) did not induce stereotypy and produced only inhibition of locomotor activity, suggesting a lack of postsynaptic DA agonist actions.

  14. Identification of Determinants Required for Agonistic and Inverse Agonistic Ligand Properties at the ADP Receptor P2Y12

    PubMed Central

    Schmidt, Philipp; Ritscher, Lars; Dong, Elizabeth N.; Hermsdorf, Thomas; Cöster, Maxi; Wittkopf, Doreen; Meiler, Jens

    2013-01-01

    The ADP receptor P2Y12 belongs to the superfamily of G protein–coupled receptors (GPCRs), and its activation triggers platelet aggregation. Therefore, potent antagonists, such as clopidogrel, are of high clinical relevance in prophylaxis and treatment of thromboembolic events. P2Y12 displays an elevated basal activity in vitro, and as such, inverse agonists may be therapeutically beneficial compared with antagonists. Only a few inverse agonists of P2Y12 have been described. To expand this limited chemical space and improve understanding of structural determinants of inverse agonist-receptor interaction, this study screened a purine compound library for lead structures using wild-type (WT) human P2Y12 and 28 constitutively active mutants. Results showed that ATP and ATP derivatives are agonists at P2Y12. The potency at P2Y12 was 2-(methylthio)-ADP > 2-(methylthio)-ATP > ADP > ATP. Determinants required for agonistic ligand activity were identified. Molecular docking studies revealed a binding pocket for the ATP derivatives that is bordered by transmembrane helices 3, 5, 6, and 7 in human P2Y12, with Y105, E188, R256, Y259, and K280 playing a particularly important role in ligand interaction. N-Methyl-anthraniloyl modification at the 3?-OH of the 2?-deoxyribose leads to ligands (mant-deoxy-ATP [dATP], mant-deoxy-ADP) with inverse agonist activity. Inverse agonist activity of mant-dATP was found at the WT human P2Y12 and half of the constitutive active P2Y12 mutants. This study showed that, in addition to ADP and ATP, other ATP derivatives are not only ligands of P2Y12 but also agonists. Modification of the ribose within ATP can result in inverse activity of ATP-derived ligands. PMID:23093496

  15. 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

  16. DTERMINISME DE LA CONSTRUCTION DES CELLULES DE MALES ET DES

    E-print Network

    Paris-Sud XI, Université de

    DÉTERMINISME DE LA CONSTRUCTION DES CELLULES DE MALES ET DES CELLULES D'OUVRIÈRES CHEZ APIS-sur-Yvette Faculté des Sciences Rennes I,e problème du déterminisme de construction des cellules mâles et des cellules d'ouvrières chez APis Mellifica n'a pas été étudié jusqu'à présent par beaucoup d'auteurs. 1,e

  17. Cytisine-Based Nicotinic Partial Agonists as Novel Antidepressant Compounds

    PubMed Central

    Mineur, Yann S.; Eibl, Christoph; Young, Grace; Kochevar, Christopher; Papke, Roger L.; Gündisch, Daniela; Picciotto, Marina R.

    2009-01-01

    Nicotine and other nicotinic agents are thought to regulate mood in human subjects and have antidepressant-like properties in animal models. Recent studies have demonstrated that blockade of nicotinic acetylcholine receptors (nAChRs) including those containing the ?2 subunit (?2*), results in antidepressant-like effects. Previous studies have shown that cytisine, a partial agonist at ?4/?2* nAChRs, and a full agonist at ?3/?4* and ?7 nAChRs, has antidepressant-like properties in several rodent models of antidepressant efficacy; however, it is not clear whether more selective partial agonists will also be effective in these models. We tested cytisine and two derivatives, 5-bromo-cytisine (5-Br-Cyt) and 3-(pyridin-3?-yl)-cytisine (3-pyr-Cyt) for their ability to act as a partial agonist of different nAChR subtypes and to show antidepressant-like activity in C57/BL6 mice in the tail suspension, the forced-swim, and the novelty-suppressed feeding tests. 3-pyr-Cyt was a partial agonist with very low efficacy at ?4/?2* nAChRS but had no agonist effects at other nAChRs normally targeted by cytisine, and it was effective in mouse models of antidepressant efficacy. Animals showed dose-dependent antidepressant-like effects in all three behavioral paradigms. 5-Br-Cyt was not effective in behavioral tests when administered peripherally, probably because of its inability to penetrate the blood-brain barrier, because it efficiently reduced immobility in the tail suspension test when administered intraventricularly. These results suggest that novel nicotinic partial agonists may provide new possibilities for development of drugs to treat mood disorders. PMID:19164465

  18. Triangle des vitesses Failles transformantes

    E-print Network

    Grigné, Cécile

    Triangle des vitesses ab Failles transformantes A B A B TD - UE Terre Profonde #12;Triangle des vitesses ab A B Dorsales A B TD - UE Terre Profonde #12;Triangle des vitesses ab B A B A Subduction TD - UE Terre Profonde #12;Triangle des vitesses B A A B C C TD - UE Terre Profonde #12;Triangle des vitesses B

  19. UN DES ROLES DES CHAINES D'ABEILLES : LA TORSION DES RAYONS

    E-print Network

    Paris-Sud XI, Université de

    UN DES ROLES DES CHAINES D'ABEILLES : LA TORSION DES RAYONS POUR LES RENDRE PARALLÈLES ENTRE EUX R régissant le parallé- lisme des rayons et décrit la technique des Abeilles qui l'établissent. Ces insectes utilisent en particulier deux méthodes pour rendre parallèle un rayon placé anormalement : W Ils allongent

  20. 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.

  1. Rat Urinary Bladder Carcinogenesis by Dual-Acting PPAR? + ? Agonists

    PubMed Central

    Oleksiewicz, Martin B.; Southgate, Jennifer; Iversen, Lars; Egerod, Frederikke L.

    2008-01-01

    Despite clinical promise, dual-acting activators of PPAR? and ? (here termed PPAR?+? agonists) have experienced high attrition rates in preclinical and early clinical development, due to toxicity. In some cases, discontinuation was due to carcinogenic effect in the rat urothelium, the epithelial layer lining the urinary bladder, ureters, and kidney pelvis. Chronic pharmacological activation of PPAR? is invariably associated with cancer in rats and mice. Chronic pharmacological activation of PPAR? can in some cases also cause cancer in rats and mice. Urothelial cells coexpress PPAR? as well as PPAR?, making it plausible that the urothelial carcinogenicity of PPAR?+? agonists may be caused by receptor-mediated effects (exaggerated pharmacology). Based on previously published mode of action data for the PPAR?+? agonist ragaglitazar, and the available literature about the role of PPAR? and ? in rodent carcinogenesis, we propose a mode of action hypothesis for the carcinogenic effect of PPAR?+? agonists in the rat urothelium, which combines receptor-mediated and off-target cytotoxic effects. The proposed mode of action hypothesis is being explored in our laboratories, towards understanding the human relevance of the rat cancer findings, and developing rapid in vitro or short-term in vivo screening approaches to faciliate development of new dual-acting PPAR agonist compounds. PMID:19197366

  2. Sound production during agonistic behavior of male Drosophila melanogaster

    PubMed Central

    Jonsson, Thorin; Kravitz, Edward A

    2011-01-01

    Male Drosophila fruit flies acquire and defend territories in order to attract females for reproduction. Both, male-directed agonistic behavior and female-directed courtship consist of series of recurrent stereotypical components. Various studies demonstrated the importance of species-specific sound patterns generated by wing vibration as being critical for male courtship success. In this study we analyzed the patterns and importance of sound signals generated during agonistic interactions of male Drosophila melanogaster. In contrast to acoustic courtship signals that consist of sine and pulse patterns and are generated by one extended wing, agonistic signals lack sine-like components and are generally produced by simultaneous movements of both wings. Though intra-pulse oscillation frequencies (carrier frequency) are identical, inter-pulse intervals are twice as long and more variable in aggression signals than in courtship songs, where their precise temporal pattern serves species recognition. Acoustic signals accompany male agonistic interactions over their entire course but occur particularly often after tapping behavior which is a major way to identify the gender of the interaction partner. Since similar wing movements may either be silent or generate sound and wing movements with sound have a greater impact on the subsequent behavior of a receiver, sound producing wing movements seem to be generated intentionally to serve as a specific signal during fruit fly agonistic encounters. PMID:20953152

  3. Beta2-agonists potentiate corticosteroid-induced neutrophil survival.

    PubMed

    Perttunen, Heli; Moilanen, Eeva; Zhang, Xianzhi; Barnes, Peter J; Kankaanranta, Hannu

    2008-06-01

    Neutrophils are considered to play a role in the pathogenesis of chronic obstructive pulmonary disease (COPD) and severe asthma. Recent guidelines recommend the use of a combination of inhaled corticosteroids (ICS) and long-acting beta2-agonists (LABA) in the treatment of COPD with exacerbations and asthma not adequately controlled by ICS alone. LABA have been proposed to have a synergistic effect with corticosteroids by activating glucocorticoid receptors. The aim of this study was to investigate the effect of beta2-agonists on the inhibitory effects of corticosteroids on human neutrophil apoptosis. In addition, the effects of beta2-agonists on spontaneous neutrophil apoptosis and on GM-CSF- and LTB4-afforded survival were also evaluated. Neutrophils were isolated from human blood under sterile conditions and cultured for 16 hours. Apoptosis was assessed by relative DNA fragmentation assay. Morphological analysis was used as a control method to confirm the occurrence of apoptosis. Salbutamol, formoterol and salmeterol prolonged the lifespan of budesonide- and fluticasone propionate-treated neutrophils by inhibiting apoptosis. Formoterol and salbutamol partly reversed the inhibitory effect of GM-CSF on neutrophil apoptosis. In contrast, the effects of beta(2)-agonists on spontaneous neutrophil apoptosis and on LTB(4)-afforded survival were negligible. beta2-agonists potentiate corticosteroid-induced neutrophil survival at clinically relevant drug concentrations. Whether these effects translate into clinically relevant changes in lung neutrophil numbers remains to be demonstrated. PMID:18568840

  4. 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.

  5. 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

  6. Supra-physiological efficacy at GPCRs: superstition or super agonists?

    PubMed Central

    Langmead, Christopher J; Christopoulos, Arthur

    2013-01-01

    The concept of ‘super agonism’ has been described since the discovery of peptide hormone analogues that yielded greater functional responses than the endogenous agonists, in the early 1980s. It has remained an area of debate as to whether such compounds can really display greater efficacy than an endogenous agonist. However, recent pharmacological data, combined with crystal structures of different GPCR conformations and improved analytical methods for quantifying drug action, are starting to shed light on this phenomenon and indicate that super agonists may be more than superstition. Linked Article This article is a commentary on Schrage et al., pp. 357–370 of this issue. To view this paper visit http://dx.doi.org/10.1111/bph.12003 PMID:23441648

  7. A reversed sulfonamide series of selective RORc inverse agonists.

    PubMed

    van Niel, Monique B; Fauber, Benjamin P; Cartwright, Matthew; Gaines, Simon; Killen, Jonathan C; René, Olivier; Ward, Stuart I; de Leon Boenig, Gladys; Deng, Yuzhong; Eidenschenk, Céline; Everett, Christine; Gancia, Emanuela; Ganguli, Arunima; Gobbi, Alberto; Hawkins, Julie; Johnson, Adam R; Kiefer, James R; La, Hank; Lockey, Peter; Norman, Maxine; Ouyang, Wenjun; Qin, Ann; Wakes, Nicole; Waszkowycz, Bohdan; Wong, Harvey

    2014-12-15

    The identification of a new series of RORc inverse agonists is described. Comprehensive structure-activity relationship studies of this reversed sulfonamide series identified potent RORc inverse agonists in biochemical and cellular assays which were also selective against a panel of nuclear receptors. Our work has contributed a compound that may serve as a useful in vitro tool to delineate the complex biological pathways involved in signalling through RORc. An X-ray co-crystal structure of an analogue with RORc has also provided useful insights into the binding interactions of the new series. PMID:25453817

  8. 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

  9. 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.

  10. Early exposure of 17?-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 17?-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. © 2013 Wiley Periodicals, Inc. Environ Toxicol 30: 439-451, 2015. PMID:24273110

  11. Mechanism of Selective Retinoid X Receptor Agonist-Induced Hypothyroidism in the Rat

    E-print Network

    Lawson, Mark A.

    , including hypothyroidism (12). Patients receiving bexarotene treat- ment develop symptoms of hypothyroidismMechanism of Selective Retinoid X Receptor Agonist- Induced Hypothyroidism in the Rat SHA LIU 92121 The retinoid X receptor (RXR) agonist bexarotene can cause clinically significant hypothyroidism

  12. EVOLUTION DES OUTILS DE CONTRLE ET DES CRITERES DE

    E-print Network

    Paris-Sud XI, Université de

    EVOLUTION DES OUTILS DE CONTRÔLE ET DES CRITERES DE PERFORMANCE, FACE AUX DEFIS DE CHANGEMENT communication étudie tout d'abord le nouveau contexte stratégique et organisationnel des entreprises contexte stratégique et organisationnel des entreprises en mutation interpelle les outils de contrôle de

  13. Elimination des noeuds dans le probleme newtonien des quatre corps

    Microsoft Academic Search

    Françoise Boigey; M. Curie

    1982-01-01

    Résumé Nous appliquons la méthode des transformations canoniques à variables imposées à la réduction du problème newtonien des quatre corps. L'élimination du centre de gravité étant supposée faite, le problème est ramené à celui des trois corps fictifs. Alors nous menons à bien la réduction dûe aux intégrales des aires explicitement sous forme Hamiltonienne en tenant compte de l'aspect géométrique

  14. Modelisation des interactions lors de la migration des cellules tumorales

    E-print Network

    Aubert, Marine

    Mod´elisation des interactions lors de la migration des cellules tumorales Marine AUBERT IMNC% des tumeurs du syst`eme nerveux central. Elles d´erivent des cellules gliales (astrocytes par exemple. En effet, lorsque cette tumeur est diagnostiqu´ee, les cellules tumorales ont d´ej`a envahit une

  15. Politique de gestion des documents administratifs et des archives

    E-print Network

    Politique de gestion des documents administratifs et des archives Préparation : Division de la gestion des documents administratifs et des archives Révision : Bureau du secrétaire général Entrée en vigueur : 15 février 2012 Approbation : (CA-2012-6) Cadre juridique : Loi sur les archives (L

  16. Fawn hooded rats are subsensitive to the food intake suppressant effects of 5HT agonists

    Microsoft Academic Search

    Philip Wang; Charanjit S. Aulakh; James L. Hill; Dennis L. Murphy

    1988-01-01

    The food intake suppressant effects of three serotonin agonists, m-CPP (a selective 5-HT1B agonist), 8-OHDPAT (a selective 5-HT1A agonist) and fenfluramine (a 5-HT releasing agent) were compared in three different rat strains: Wistar, Sprague-Dawley (SD) and Fawn-Hooded (FH) rats. Administration of all three serotonin agonists produced dose-dependent decreases in 1 h food intake in all three strains. FH animals were

  17. Chemotype-selective Modes of Action of ?-Opioid Receptor Agonists*

    PubMed Central

    Vardy, Eyal; Mosier, Philip D.; Frankowski, Kevin J.; Wu, Huixian; Katritch, Vsevolod; Westkaemper, Richard B.; Aubé, Jeffrey; Stevens, Raymond C.; Roth, Bryan L.

    2013-01-01

    The crystal structures of opioid receptors provide a novel platform for inquiry into opioid receptor function. The molecular determinants for activation of the ?-opioid receptor (KOR) were studied using a combination of agonist docking, functional assays, and site-directed mutagenesis. Eighteen positions in the putative agonist binding site of KOR were selected and evaluated for their effects on receptor binding and activation by ligands representing four distinct chemotypes: the peptide dynorphin A(1–17), the arylacetamide U-69593, and the non-charged ligands salvinorin A and the octahydroisoquinolinone carboxamide 1xx. Minimally biased docking of the tested ligands into the antagonist-bound KOR structure generated distinct binding modes, which were then evaluated biochemically and pharmacologically. Our analysis identified two types of mutations: those that affect receptor function primarily via ligand binding and those that primarily affect function. The shared and differential mechanisms of agonist binding and activation in KOR are further discussed. Usually, mutations affecting function more than binding were located at the periphery of the binding site and did not interact strongly with the various ligands. Analysis of the crystal structure along with the present results provide fundamental insights into the activation mechanism of the KOR and suggest that “functional” residues, along with water molecules detected in the crystal structure, may be directly involved in transduction of the agonist binding event into structural changes at the conserved rotamer switches, thus leading to receptor activation. PMID:24121503

  18. Agonistic and reproductive interactions in ^I Betta splendens

    Microsoft Academic Search

    Paul M. Bronstein

    1984-01-01

    Conducted 8 experiments to investigate the reproductive and agonistic behaviors of Siamese fighting fish and isolated some consequences and determinants of these sequences. Fights and the formation of dominance–subordinancy relations were studied, using 536 pairs of male fish. The effect and magnitude of prior residency, the importance of body length, chemical cues, and intratank visual\\/tactile clues were observed. Findings indicate

  19. Original article Design of subtype selective melatonin receptor agonists

    E-print Network

    Paris-Sud XI, Université de

    Original article Design of subtype selective melatonin receptor agonists and antagonists David of the physiological actions of melatonin have been hindered by the lack of specific, potent and subtype selective Xenopus laevis for exploring structure-activity relationships among novel melatonin analogues and report

  20. Dopamine agonists in prevention of ovarian hyperstimulation syndrome.

    PubMed

    Kasum, Miro; Vr?i?, Hrvoje; Stani?, Patrik; Ježek, Davor; Oreškovi?, Slavko; Beketi?-Oreškovi?, Lidija; Pekez, Marijeta

    2014-08-01

    Abstract The aim of this review is to analyze the efficacy of different dopamine agonists in the prevention of ovarian hyperstimulation syndrome (OHSS). Cabergoline, quinagolide and bromocriptine are the most common dopamine agonists used. There are wide clinical variations among the trials in the starting time (from the day of human chorionic gonadotrophin (hCG) to the day following oocyte retrieval); the duration of the treatment (4-21 days), the dose of cabergoline (0.5?mg or 0.25?mg orally) and in the regimens used. At present, the best known effective regimen is 0.5?mg of cabergoline for 8 days or rectal bromocriptine at a daily dose of 2.5?mg for 16 days. Dopamine agonists have shown significant evidences of their efficacy in the prevention of moderate and early-onset OHSS (9.41%), compared with a placebo (21.45%), which cannot be confirmed for the treatment of late OHSS. It would be advisable to start with the treatment on the day of hCG injection or preferably a few hours earlier. The use of dopamine agonists should be indicated in patients at high risk of OHSS, as well as in patients with a history of previous OHSS even without evident signs of the syndrome. PMID:25093428

  1. 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…

  2. CLINICAL STUDIES Inhaled Beta-2 Adrenergic Receptor Agonists and

    E-print Network

    Lin, Danyu

    with higher risk of primary cardiac arrest in patients with asthma or chronic obstructive pulmonary diseaseCLINICAL STUDIES Inhaled Beta-2 Adrenergic Receptor Agonists and Primary Cardiac Arrest Rozenn N (COPD). SUBJECTS AND METHODS: We conducted a population- based study involving 454 patients enrolled

  3. Suppression of methamphetamine-seeking behavior by nicotinic agonists

    Microsoft Academic Search

    Takato Hiranita; Yoko Nawata; Katsuya Sakimura; Kusnandar Anggadiredja; Tsuneyuki Yamamoto

    2006-01-01

    To understand the mechanism of methamphetamine (MAP) craving from the viewpoint of nicotinic acetylcholinergic transmission, we examined the responsible site of the brain for anticraving effects produced by nicotinic agonists by using a MAP self-administration paradigm in rats. Systemic nicotine and an acetylcholinesterase inhibitor, donepezil, attenuated the reinstatement of MAP-seeking behavior by means of the activation of nicotinic acetylcholinergic receptors,

  4. ?-Adrenoceptor agonists and asthma—100 years of development

    Microsoft Academic Search

    Bertil Waldeck

    2002-01-01

    Inhaled ?2-adrenoceptor agonists are by far the most effective and safe bronchodilators currently available. They have not been surpassed by any other bronchodilating principle. The way to this position has been long and started with the first successful treatment of acute, severe asthma with s.c. injections of adrenaline 100 years ago. Over the years, synthetic congeners of adrenaline have been

  5. Potential role of muscarinic agonists in Alzheimer's disease.

    PubMed

    Avery, E E; Baker, L D; Asthana, S

    1997-12-01

    Alzheimer's disease (AD) is a common neurodegenerative disorder and a leading cause of death among the elderly. Recent advances in our understanding of the neurobiology of AD have provided scientific groundwork for the development of potentially more effective and less toxic treatment strategies for the disease. Some of the neuropathological hallmarks of AD include early and extensive degeneration of cortically projecting cholinergic neurons in the basal forebrain, and a reduced number of muscarinic acetylcholine receptors. Of note, neocortical muscarinic receptors of the M1 subtype are relatively preserved in the brains of patients with AD, whereas the presynaptic receptors, which are of the M2 subtype, are reduced in number. Therefore, activation of relatively intact postsynaptic mechanisms by muscarinic M1 receptor-specific agonists could theoretically be more efficacious in the treatment of AD compared with agents (e.g. acetylcholinesterase inhibitors) that predominantly act on dysfunctional presynaptic terminals. The administration of muscarinic agonists can demonstrably enhance cognition and significantly improve some of the disturbing behaviours in patients with AD. Recent advances in our knowledge of the molecular biology of muscarinic receptors, together with a better understanding of signal transduction pathways in AD, are likely to result in the development of receptor-specific muscarinic agonists that are more efficacious and less toxic. Moreover, preliminary evidence concerning the effects of muscarinic agonists on the processing of amyloid precursor protein and the formation of neurofibrillary tangles suggests that these agents might favourably alter the pathobiology of AD. PMID:9413702

  6. Initial therapy for Parkinson's disease: levodopa vs. dopamine receptor agonists

    Microsoft Academic Search

    Tomoyoshi Kondo

    2002-01-01

    Levodopa therapy is essential for patients in the advanced stages of Parkinson's disease. However, at early stages, DA agonist therapy has similar efficacy in the treatment of parkinsonism and a lower incidence of motor complications compared to levodopa therapy several years after the initiation of the therapy. The main factors causing motor complications have been speculated to be a severe

  7. Synthetic LXR agonists increase LDL in CETP species

    Microsoft Academic Search

    Pieter H. E. Groot; Nigel J. Pearce; John W. Yates; Claire Stocker; Charles Sauermelch; Christopher P. Doe; Robert N. Willette; Alan Olzinski; Tambra Peters; Denise d'Epagnier; Kathleen O. Morasco; John A. Krawiec; Christine L. Webb; Karpagam Aravindhan; Beat Jucker; Mark Burgert; Chun Ma; Joseph P. Marino; Jon L. Collins; Colin H. Macphee; Scott K. Thompson; Michael Jaye

    2005-01-01

    Liver X receptor (LXR) nuclear receptors regu- late the expression of genes involved in whole body cholesterol trafficking, including absorption, excretion, catabolism, and cellular efflux, and possess both anti-inflammatory and an- tidiabetic actions. Accordingly, LXR is considered an ap- pealing drug target for multiple indications. Synthetic LXR agonists demonstrated inhibition of atherosclerosis progres- sion in murine genetic models; however, these

  8. Role of nicotine receptor partial agonists in tobacco cessation

    PubMed Central

    Maity, Nivedita; Chand, Prabhat; Murthy, Pratima

    2014-01-01

    One in three adults in India uses tobacco, a highly addictive substance in one or other form. In addition to prevention of tobacco use, offering evidence-based cessation services to dependent tobacco users constitutes an important approach in addressing this serious public health problem. A combination of behavioral methods and pharmacotherapy has shown the most optimal results in tobacco dependence treatment. Among currently available pharmacological agents, drugs that preferentially act on the ?4 ?2-nicotinic acetyl choline receptor like varenicline and cytisine appear to have relatively better cessation outcomes. These drugs are in general well tolerated and have minimal drug interactions. The odds of quitting tobacco use are at the very least doubled with the use of partial agonists compared with placebo and the outcomes are also superior when compared to nicotine replacement therapy and bupropion. The poor availability of partial agonists and specifically the cost of varenicline, as well as the lack of safety data for cytisine has limited their use world over, particularly in developing countries. Evidence for the benefit of partial agonists is more robust for smoking rather than smokeless forms of tobacco. Although more studies are needed to demonstrate their effectiveness in different populations of tobacco users, present literature supports the use of partial agonists in addition to behavioral methods for optimal outcome in tobacco dependence. PMID:24574554

  9. Agonistic displays in the rock bass, Ambloplites rupestris

    Microsoft Academic Search

    Martha E. Casterlin; William W. Reynolds

    1979-01-01

    Agonistic encounters between pairs of adult rick bass, Ambloplites rupestris were observed and the behaviour and changes in coloration of the dominant and subordinate individuals analysed. Dominance coloration involved the establishment of a high degree of visual contrast, whereas subordinate coloration made the animals darker and their coloration less striking, thus perhaps serving a protective function.

  10. Effects of Melanocortin 1 Receptor Agonists in Experimental Nephropathies

    PubMed Central

    Elvin, Johannes; Johansson, Martin E.; Haraldsson, Börje; Nyström, Jenny

    2014-01-01

    Nephrotic syndrome, characterized by massive proteinuria, is caused by a large group of diseases including membranous nephropathy (MN) and focal segmental glomerulosclerosis (FSGS). Although the underlying mechanisms are beginning to unravel, therapy is unspecific and far from efficient. It has been suggested that adrenocorticotropic hormone (ACTH) has beneficial effects in patients with MN and possibly in other nephrotic diseases. We have previously reported that ACTH may act directly on podocytes through the melanocortin 1 receptor (MC1R). In the present study, we evaluate the effect of highly specific MC1R agonists in two different nephrotic disease models. Experimental MN: Passive Heymann nephritis (PHN) was induced in rats that were treated for four weeks with MS05, a selective MC1R agonist, or saline. The degree of albuminuria was significantly reduced over time and the effect was sustained one week after treatment withdrawal (p<0.05). Experimental FSGS: Based on a dose-response study, two doses of adriamycin were used for induction of nephropathy in Balb/c mice. Mice were treated with either a synthetic MC1R agonist (BMS-470539), with ?-melanocyte stimulating hormone (?-MSH) or with saline. There was no beneficial effect of treatment. In summary, MC1R agonists reduce albuminuria and improve morphology in experimentally induced MN whereas they have no effect in experimental FSGS. The results illustrate the differences in these podocytopathies in terms of signaling mechanisms underlying proteinuria, and progression of disease. PMID:24498203

  11. Pathological behaviors provoked by dopamine agonist therapy of Parkinson's disease.

    PubMed

    Ahlskog, J Eric

    2011-07-25

    The dopamine agonist medications, pramipexole and ropinirole, are commonly used to treat Parkinson's disease. These two drugs have a highly specific affinity for cerebral D3 receptors, known to be localized to the mesolimbic system. Herein is described a common side effect of these drugs, encountered in our routine clinical practice: pathological behaviors. This includes excessive gambling, hypersexuality, shopping, hyperphagia or obsessive hobbying, which may develop in up to 30% of people taking higher agonist doses. In contrast, treatment with the dopamine precursor, levodopa, in the absence of D3 agonist therapy very rarely provokes such behavioral syndromes. Although these agonist-induced behaviors have been called "impulse control disorders", the problem is not simply loss of impulse control, but rather a novel obsessive-compulsion directed at one or a few behaviors, often taking on pathological proportions. This experience points to the dopamine D3 receptor as a potential therapeutic target for gambling, sex or other addictions occurring spontaneously in the general population. PMID:21557955

  12. 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.; (GSKNC); (GSKPA)

    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.

  13. MOUVEMENTS DES TROMPES ET PROGRESSION DES ŒUFS CHEZ LA BREBIS

    E-print Network

    Boyer, Edmond

    MOUVEMENTS DES TROMPES ET PROGRESSION DES ŒUFS CHEZ LA BREBIS S. WINTENBERGER, Jouy-en-Josas. SOMMAIRE Nous avons étudié la motilité des trompes utérines, et leur rôle dans la trompe étudiée soit des ovocytes colorés, soit des particules de matière plastique noire de même taille

  14. Osmose électrique des tissues et des cellules sur le vivant

    Microsoft Academic Search

    Pierre Girard

    1932-01-01

    Sommaire I.Sur des tissus vivants, en place sur l'animal, et normalement irrigués, on peut réaliser soit à travers les interstices cellulaires soit sur la cellule elle même à travers les interstices des micelles protoplasmiques des endosmoses et des exosmoses électriques.II.Sur l'oeil du lapin ou du chat c'est à travers des interstices que les cellules de la cornée laissent entre-elles que

  15. The ?2-Adrenoceptor Agonist Formoterol Stimulates Mitochondrial Biogenesis

    PubMed Central

    Wills, Lauren P.; Trager, Richard E.; Beeson, Gyda C.; Lindsey, Christopher C.; Peterson, Yuri K.; Beeson, Craig C.

    2012-01-01

    Mitochondrial dysfunction is a common mediator of disease and organ injury. Although recent studies show that inducing mitochondrial biogenesis (MB) stimulates cell repair and regeneration, only a limited number of chemicals are known to induce MB. To examine the impact of the ?-adrenoceptor (?-AR) signaling pathway on MB, primary renal proximal tubule cells (RPTC) and adult feline cardiomyocytes were exposed for 24 h to multiple ?-AR agonists: isoproterenol (nonselective ?-AR agonist), (±)-(R*,R*)-[4-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]phenoxy] acetic acid sodium hydrate (BRL 37344) (selective ?3-AR agonist), and formoterol (selective ?2-AR agonist). The Seahorse Biosciences (North Billerica, MA) extracellular flux analyzer was used to quantify carbonylcyanide p-trifluoromethoxyphenylhydrazone (FCCP)-uncoupled oxygen consumption rate (OCR), a marker of maximal electron transport chain activity. Isoproterenol and BRL 37244 did not alter mitochondrial respiration at any of the concentrations examined. Formoterol exposure resulted in increases in both FCCP-uncoupled OCR and mitochondrial DNA (mtDNA) copy number. The effect of formoterol on OCR in RPTC was inhibited by the ?-AR antagonist propranolol and the ?2-AR inverse agonist 3-(isopropylamino)-1-[(7-methyl-4-indanyl)oxy]butan-2-ol hydrochloride (ICI-118,551). Mice exposed to formoterol for 24 or 72 h exhibited increases in kidney and heart mtDNA copy number, peroxisome proliferator-activated receptor ? coactivator 1?, and multiple genes involved in the mitochondrial electron transport chain (F0 subunit 6 of transmembrane F-type ATP synthase, NADH dehydrogenase subunit 1, NADH dehydrogenase subunit 6, and NADH dehydrogenase [ubiquinone] 1? subcomplex subunit 8). Cheminformatic modeling, virtual chemical library screening, and experimental validation identified nisoxetine from the Sigma Library of Pharmacologically Active Compounds and two compounds from the ChemBridge DIVERSet that increased mitochondrial respiratory capacity. These data provide compelling evidence for the use and development of ?2-AR ligands for therapeutic MB. PMID:22490378

  16. Identification of raloxifene as a novel CB2 inverse agonist.

    PubMed

    Kumar, Pritesh; Song, Zhao-Hui

    2013-05-24

    The purpose of the current study was to apply a high throughput assay to systematically screen a library of food and drug administration (FDA)-approved drugs as potential ligands for the cannabinoid receptor 2 (CB2). A cell-based, homogenous time resolved fluorescence (HTRF) method for measuring changes in intracellular cAMP levels was validated and found to be suitable for testing ligands that may act on CB2. Among the 640 FDA-approved drugs screened, raloxifene, a drug used to treat/prevent post-menopausal osteoporosis, was identified for the first time to be a novel CB2 inverse agonist. Our results demonstrated that by acting on CB2, raloxifene enhances forskolin-stimulated cAMP accumulation in a concentration-dependant manner. Furthermore, our data showed that raloxifene competes concentration-dependently for specific [(3)H]CP-55,940 binding to CB2. In addition, raloxifene pretreatment caused a rightward shift of the concentration-response curves of the cannabinoid agonists CP-55,940, HU-210, and WIN55,212-2. Raloxifene antagonism is most likely competitive in nature, as these rightward shifts were parallel and were not associated with any changes in the efficacy of cannabinoid agonists on CB2. Our discovery that raloxfiene is an inverse agonist for CB2 suggests that it might be possible to repurpose this FDA-approved drug for novel therapeutic indications for which CB2 is a target. Furthermore, identifying raloxifene as a CB2 inverse agonist also provides important novel mechanisms of actions to explain the known therapeutic effects of raloxifene. PMID:23611779

  17. 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

  18. Chirurgie des prolactinomes

    Microsoft Academic Search

    M. Jan; H. Dufour; T. Brue; P. Jaquet

    2007-01-01

    Surgery usually represents a second line treatment in prolactinomas. In microprolactinomas, it may be indicated in cases of resistance or intolerance to dopamine agonist treatment or when the patient prefers a definitive cure over lifelong medical treatment. In highly trained hands, selective adenomectomy allows normalization of prolactin levels in 75–90% with little morbidity and no mortality. Late recurrence may however

  19. Medications for Stimulant Abuse: Agonist-Based Strategies and Preclinical Evaluation of the Mixed-Action D2 Partial Agonist Aripiprazole (Abilify®)

    Microsoft Academic Search

    Jack Bergman

    2008-01-01

    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 D2 partial agonist actions, has been studied in mice, rats, and man, but its ability to attenuate abuse- and addiction-related effects

  20. Prediction of estrogen receptor agonists and characterization of associated molecular descriptors by statistical learning methods.

    PubMed

    Li, H; Ung, C Y; Yap, C W; Xue, Y; Li, Z R; Chen, Y Z

    2006-11-01

    Specific estrogen receptor (ER) agonists have been used for hormone replacement therapy, contraception, osteoporosis prevention, and prostate cancer treatment. Some ER agonists and partial-agonists induce cancer and endocrine function disruption. Methods for predicting ER agonists are useful for facilitating drug discovery and chemical safety evaluation. Structure-activity relationships and rule-based decision forest models have been derived for predicting ER binders at impressive accuracies of 87.1-97.6% for ER binders and 80.2-96.0% for ER non-binders. However, these are not designed for identifying ER agonists and they were developed from a subset of known ER binders. This work explored several statistical learning methods (support vector machines, k-nearest neighbor, probabilistic neural network and C4.5 decision tree) for predicting ER agonists from comprehensive set of known ER agonists and other compounds. The corresponding prediction systems were developed and tested by using 243 ER agonists and 463 ER non-agonists, respectively, which are significantly larger in number and structural diversity than those in previous studies. A feature selection method was used for selecting molecular descriptors responsible for distinguishing ER agonists from non-agonists, some of which are consistent with those used in other studies and the findings from X-ray crystallography data. The prediction accuracies of these methods are comparable to those of earlier studies despite the use of significantly more diverse range of compounds. SVM gives the best accuracy of 88.9% for ER agonists and 98.1% for non-agonists. Our study suggests that statistical learning methods such as SVM are potentially useful for facilitating the prediction of ER agonists and for characterizing the molecular descriptors associated with ER agonists. PMID:16497524

  1. Archives participatives Au milieu des ralisations remarquables de mdiation numrique des bibliothques et des

    E-print Network

    Paris-Sud XI, Université de

    Archives participatives Au milieu des réalisations remarquables de médiation numérique des bibliothèques et des musées sur les médias sociaux, les services d'archives ont un positionnement relativement en revanche des projets ambitieux de crowdsourcing, d'« archives participatives » (voir encart

  2. Agonists and partial agonists of rhodopsin: retinal polyene methylation affects receptor activation.

    PubMed

    Vogel, Reiner; Lüdeke, Steffen; Siebert, Friedrich; Sakmar, Thomas P; Hirshfeld, Amiram; Sheves, Mordechai

    2006-02-14

    Using Fourier transform infrared (FTIR) difference spectroscopy, we have studied the impact of sites and extent of methylation of the retinal polyene with respect to position and thermodynamic parameters of the conformational equilibrium between the Meta I and Meta II photoproducts of rhodopsin. Deletion of methyl groups to form 9-demethyl and 13-demethyl analogues, as well as addition of a methyl group at C10 or C12, shifted the Meta I/Meta II equilibrium toward Meta I, such that the retinal analogues behaved like partial agonists. This equilibrium shift resulted from an apparent reduction of the entropy gain of the transition of up to 65%, which was only partially offset by a concomitant reduction of the enthalpy increase. The analogues produced Meta II photoproducts with relatively small alterations, while their Meta I states were significantly altered, which accounted for the aberrant transitions to Meta II. Addition of a methyl group at C14 influenced the thermodynamic parameters but had little impact on the position of the Meta I/Meta II equilibrium. Neutralization of the residue 134 in the E134Q opsin mutant increased the Meta II content of the 13-demethyl analogue, but not of the 9-demethyl analogue, indicating a severe impairment of the allosteric coupling between the conserved cytoplasmic ERY motif involved in proton uptake and the Schiff base/Glu 113 microdomain in the 9-demethyl analogue. The 9-methyl group appears therefore essential for the correct positioning of retinal to link protonation of the cytoplasmic motif with protonation of Glu 113 during receptor activation. PMID:16460011

  3. Influence des tanins hydrolysables de chtaignier sur le mtabolisme azot des ovins et des caprins

    E-print Network

    Paris-Sud XI, Université de

    Influence des tanins hydrolysables de châtaignier sur le métabolisme azoté des ovins et des caprins Les tanins ont la propriété de se complexer aux protéines. Ceci peut conduire à l'insolubilisation de effets de l'ingestion de tanins sur le métabolisme azoté des ovins et caprins. Des tanins hydrolysables

  4. Dopamine Agonists and the Suppression of Impulsive Motor Actions in Parkinson’s Disease

    PubMed Central

    Wylie, S.A.; Claassen, D.O.; Huizenga, H.M.; Schewel, K.D.; Ridderinkhof, K.R.; Bashore, T.R.; van den Wildenberg, W.P.M.

    2012-01-01

    The suppression of spontaneous motor impulses is an essential facet of cognitive control that is linked to frontal-basal ganglia circuitry. Basal ganglia dysfunction caused by Parkinson’s disease (PD) disrupts the proficiency of action suppression, but how pharmacotherapy for PD impacts impulsive motor control is poorly understood. Dopamine agonists improve motor symptoms of PD, but can also provoke impulsive-compulsive behaviors (ICB). We investigated whether dopamine agonist medication has a beneficial or detrimental effect on impulsive action control in thirty-eight PD patients, half of whom had current ICB. Participants performed the Simon conflict task, which measures susceptibility to acting on spontaneous action impulses as well as the proficiency of suppressing these impulses. Compared to an off agonist state, patients on their agonist were no more susceptible to reacting impulsively, but were less proficient at suppressing the interference from the activation of impulsive actions. Importantly, agonist effects depended on baseline performance in the off agonist state; more proficient suppressors off agonist experienced a reduction in suppression on agonist, whereas less proficient suppressors off agonist showed improved suppression on agonist. Patients with active ICB were actually less susceptible to making fast, impulsive response errors than patients without ICB, suggesting that behavioral problems in this subset of patients may be less related to impulsivity in motor control. Our findings provide further evidence that dopamine agonist medication impacts specific cognitive control processes and that the direction of its effects depends on individual differences in performance off medication. PMID:22571461

  5. Dopamine agonists and the suppression of impulsive motor actions in Parkinson disease.

    PubMed

    Wylie, Scott A; Claassen, Daniel O; Huizenga, Hilde M; Schewel, Kerilyn D; Ridderinkhof, K Richard; Bashore, Theodore R; van den Wildenberg, Wery P M

    2012-08-01

    The suppression of spontaneous motor impulses is an essential facet of cognitive control that is linked to frontal-BG circuitry. BG dysfunction caused by Parkinson disease (PD) disrupts the proficiency of action suppression, but how pharmacotherapy for PD impacts impulsive motor control is poorly understood. Dopamine agonists improve motor symptoms of PD but can also provoke impulsive-compulsive behaviors (ICB). We investigated whether dopamine agonist medication has a beneficial or detrimental effect on impulsive action control in 38 PD patients, half of whom had current ICB. Participants performed the Simon conflict task, which measures susceptibility to acting on spontaneous action impulses as well as the proficiency of suppressing these impulses. Compared with an off-agonist state, patients on their agonists were no more susceptible to reacting impulsively but were less proficient at suppressing the interference from the activation of impulsive actions. Importantly, agonist effects depended on baseline performance in the off-agonist state; more proficient suppressors off agonist experienced a reduction in suppression on agonist, whereas less-proficient suppressors off agonist showed improved suppression on agonist. Patients with active ICB were actually less susceptible to making fast, impulsive response errors than patients without ICB, suggesting that behavioral problems in this subset of patients may be less related to impulsivity in motor control. Our findings provide further evidence that dopamine agonist medication impacts specific cognitive control processes and that the direction of its effects depends on individual differences in performance off medication. PMID:22571461

  6. Do ?-adrenoceptor agonists induce homologous or heterologous desensitization in rat urinary bladder?

    PubMed

    Michel, Martin C

    2014-03-01

    ?3-Adrenoceptor agonists have recently been introduced for the symptomatic treatment of the overactive bladder syndrome. As such treatment is not curative, long-term treatment is anticipated to be required. As the susceptibility of ?3-adrenoceptors to undergo agonist-induced desensitization is cell type- and tissue-dependent, we have explored whether pre-treatment with a ?-adrenoceptor agonist will attenuate subsequent relaxation responses to freshly added agonist using rat urinary bladder as a model. We have used the prototypical ?-adrenoceptor agonist isoprenaline, the ?2-selective fenoterol and the ?3-selective CL 316,243 and mirabegron as well as the receptor-independent bladder relaxant forskolin. We show that a 6-h pre-treatment with agonist can significantly reduce subsequent relaxation against KCl-induced smooth muscle tone, but agonist-induced desensitization was also observed with longer pre-treatments or against passive tension. The agonist-induced desensitization was prominent for the ?2 component of rat bladder relaxation but much weaker or even absent for the ?3 component. Moreover, ?-adrenoceptor agonist pre-treatment reduced contractile responses to the muscarinic agonist carbachol and the receptor-independent stimulus KCl. Taken together these data do not support the hypothesis that the long-term clinical efficacy of ?3-adrenoceptor agonists in the treatment of the overactive bladder syndrome will be limited by receptor desensitization. Rather they raise the possibility that such treatment may not only cause smooth muscle relaxation but also may attenuate hyper-contractility of the bladder. PMID:24213882

  7. Mixed kappa/mu opioid receptor agonists: the 6 beta-naltrexamines.

    PubMed

    Cami-Kobeci, Gerta; Neal, Adrian P; Bradbury, Faye A; Purington, Lauren C; Aceto, Mario D; Harris, Louis S; Lewis, John W; Traynor, John R; Husbands, Stephen M

    2009-03-26

    Ligands from the naltrexamine series have consistently demonstrated agonist activity at kappa opioid receptors (KOR), with varying activity at the mu opioid receptor (MOR). Various 6 beta-cinnamoylamino derivatives were made with the aim of generating ligands with a KOR agonist/MOR partial agonist profile, as ligands with this activity may be of interest as treatment agents for cocaine abuse. The ligands all displayed the desired high affinity, nonselective binding in vitro and in the functional assays were high efficacy KOR agonists with some partial agonist activity at MOR. Two of the new ligands (12a, 12b) have been evaluated in vivo, with 12a acting as a KOR agonist and therefore somewhat similar to the previously evaluated analogues 3-6, while 12b displayed predominant MOR agonist activity. PMID:19253970

  8. 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 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-? (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 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

  9. Cytokine-induced loss of glucocorticoid function: effect of kinase inhibitors, long-acting ?2-adrenoceptor 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-? (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 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

  10. INTERACTIONS DES MATHMATIQUES

    E-print Network

    Pouyanne, Nicolas

    - tégral sont venus s'adjoindre de nombreux autres concepts et techniques mathématiques- Maïs les échanges plusieurs phases : étude de leur cohérence, existence de so- lutions, comportement des solutions, résolution

  11. Slectionner Des peuplements endmiques

    E-print Network

    milieu naturel, comme pour la bêche de mer. Peuplement naturel d'Araucaria columnaris sélectionné. plantation expérimentale d'Araucaria columnaris, une des principales espèces destinées à la forêt cultivée

  12. Grooming, rank, and agonistic support in tufted capuchin monkeys.

    PubMed

    Schino, Gabriele; Di Giuseppe, Francesca; Visalberghi, Elisabetta

    2009-02-01

    Studies investigating the relation between allogrooming and social rank in capuchin monkeys (genus Cebus) have yielded inconsistent results. In this study, we investigated the relation between grooming, agonistic support, aggression and social rank in a captive group of tufted capuchin monkeys (C. apella). Differently from most previous studies, we based our analyses on a relatively large database and studied a group with known genealogical relationships. Tufted capuchin females did not exchange grooming for rank-related benefits such as agonistic support or reduced aggression. Coherently with this picture, they did not groom up the hierarchy and did not compete for accessing high-ranking grooming partners. It is suggested that a small group size, coupled with a strong kin bias, may make the exchange of grooming for rank-related benefits impossible or unprofitable, thus eliminating the advantages of grooming up the hierarchy. We provide several possible explanations for the heterogeneity of results across capuchin studies that have addressed similar questions. PMID:19025780

  13. Imidazole - Derived Agonists for the Neurotensin 1 Receptor

    PubMed Central

    Hershberger, Paul M.; Hedrick, Michael P.; Peddibhotla, Satyamaheshwar; Mangravita-Novo, Arianna; Gosalia, Palak; Li, Yujie; Gray, Wilson; Vicchiarelli, Michael; Smith, Layton H.; Chung, Thomas D. Y.; Thomas, James B.; Caron, Marc G.; Pinkerton, Anthony B.; Barak, Lawrence S.; Roth, Gregory P.

    2014-01-01

    A scaffold-hop program seeking full agonists of the neurotensin-1 (NTR1) receptor identified the probe molecule ML301 (1) and associated analogs, including its naphthyl analog (14) which exhibited similar properties. Compound 1 showed full agonist behavior (79 – 93%) with an EC50 of 2.0 – 4.1 ?M against NTR1. Compound 1 also showed good activity in a Ca mobilization FLIPR assay (93% efficacy at 298 nM), consistent with it functioning via the Gq coupled pathway, and good selectivity relative to NTR2 and GPR35. In further profiling, 1 showed low potential for promiscuity and good overall pharmacological data. This report describes the discovery, synthesis, and SAR of 1 and associated analogs. Initial in vitro pharmacologic characterization is also presented. PMID:24332089

  14. ?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

  15. Structure of an agonist-bound ionotropic glutamate receptor

    PubMed Central

    Yelshanskaya, Maria V.; Li, Minfen; Sobolevsky, Alexander I.

    2015-01-01

    Ionotropic glutamate receptors (iGluRs) mediate most excitatory neurotransmission in the central nervous system and function by opening their ion channel in response to binding of agonist glutamate. Here we report a structure of a homotetrameric rat GluA2 receptor in complex with partial agonist (S)-5-Nitrowillardiine. Comparison of this structure with the closed state structure in complex with competitive antagonist ZK 200775 suggests conformational changes that occur during iGluR gating. Guided by the structures, we engineered disulfide crosslinks to probe domain interactions that are important for iGluR gating events. The combination of structural information, kinetic modeling, biochemical and electrophysiological experiments provide s insight into the mechanism of iGluR gating. PMID:25103407

  16. Cramiques des vivants, cramiques des morts et des sites cultuels l'ge du Bronze en France.

    E-print Network

    Paris-Sud XI, Université de

    , European Societies in the Bronze Age, Cambridge, 2000, p. 308. « [ ...] des lieux de culte, [...] desCéramiques des vivants, céramiques des morts et des sites cultuels à l'âge du Bronze en France disparues, ou de vaisselle pour leur consommation. Les céramiques des sépultures de l'âge du Bronze halshs

  17. A Human Platelet Calcium Calculator Trained by Pairwise Agonist Scanning

    PubMed Central

    Lee, Mei Yan; Diamond, Scott L.

    2015-01-01

    Since platelet intracellular calcium mobilization [Ca(t)]i controls granule release, cyclooxygenase-1 and integrin activation, and phosphatidylserine exposure, blood clotting simulations require prediction of platelet [Ca(t)]i in response to combinatorial agonists. Pairwise Agonist Scanning (PAS) deployed all single and pairwise combinations of six agonists (ADP, convulxin, thrombin, U46619, iloprost and GSNO used at 0.1, 1, and 10xEC50; 154 conditions including a null condition) to stimulate platelet P2Y1/P2Y12 GPVI, PAR1/PAR4, TP, IP receptors, and guanylate cyclase, respectively, in Factor Xa-inhibited (250 nM apixaban), diluted platelet rich plasma that had been loaded with the calcium dye Fluo-4 NW. PAS of 10 healthy donors provided [Ca(t)]i data for training 10 neural networks (NN, 2-layer/12-nodes) per donor. Trinary stimulations were then conducted at all 0.1x and 1xEC50 doses (160 conditions) as was a sampling of 45 higher ordered combinations (four to six agonists). The NN-ensemble average was a calcium calculator that accurately predicted [Ca (t)]i beyond the single and binary training set for trinary stimulations (R = 0.924). The 160 trinary synergy scores, a normalized metric of signaling crosstalk, were also well predicted (R = 0.850) as were the calcium dynamics (R = 0.871) and high-dimensional synergy scores (R = 0.695) for the 45 higher ordered conditions. The calculator even predicted sequential addition experiments (n = 54 conditions, R = 0.921). NN-ensemble is a fast calcium calculator, ideal for multiscale clotting simulations that include spatiotemporal concentrations of ADP, collagen, thrombin, thromboxane, prostacyclin, and nitric oxide. PMID:25723389

  18. The effect of fenoldopam, a dopaminergic agonist, on renal hemodynamics

    Microsoft Academic Search

    Nancy L Allison; Jeffrey W Dubb; John A Ziemniak; Fred Alexander; Robert M Stote

    1987-01-01

    Fenoldopam, a dopaminergic agonist, was administered intravenously to 18 healthy male subjects in doses ranging from 0.025 to 1.0 ?g\\/kg\\/min for 2 hours. Three subjects were studied in a three-way crossover of fenoldopam at doses of 0.025, 0.10, and 0.50 ?g\\/kg\\/min. Fenoldopam decreased diastolic blood pressure and increased pulse rate without changing systolic blood pressure. Fenoldopam produced dose-related increases in

  19. Agonistic behavior enhances adult neurogenesis in male Acheta domesticus crickets

    Microsoft Academic Search

    Kaushik Ghosal; Mohit Gupta; Kathleen A. Killian

    2009-01-01

    SUMMARY We examined the effect of agonistic behavior on cell proliferation and neurogenesis in the central nervous system (CNS) of adult male Acheta domesticus crickets. We combined 5-bromo,2deoxyuridine (BrdU)-labeling of dividing cells with immunocytochemical detection of the neuronal marker horseradish peroxidase to examine the proliferation of progenitor cells and the survival of newborn neurons. In crickets, the mushroom bodies of

  20. Synthesis and evaluation of novel peripherally restricted ?-opioid receptor agonists

    Microsoft Academic Search

    Virendra Kumar; Deqi Guo; Joel A. Cassel; Jeffrey D. Daubert; Robert N. DeHaven; Diane L. DeHaven-Hudkins; Erin K. Gauntner; Susan L. Gottshall; Susan L. Greiner; Michael Koblish; Patrick J. Little; Erik Mansson; Alan L. Maycock

    2005-01-01

    A series of 3-substituted analogs (3) of the parent ? agonist, 1, were prepared to limit access to the central nervous system. With the exception of compound 3j, all other compounds bound to the human ? opioid receptor with high affinity (Ki=0.31–9.5nM) and were selective for ? over ? and ? opioid receptors. Compounds 3c, d, and 3g–i produced potent

  1. A human platelet calcium calculator trained by pairwise agonist scanning.

    PubMed

    Lee, Mei Yan; Diamond, Scott L

    2015-02-01

    Since platelet intracellular calcium mobilization [Ca(t)]i controls granule release, cyclooxygenase-1 and integrin activation, and phosphatidylserine exposure, blood clotting simulations require prediction of platelet [Ca(t)]i in response to combinatorial agonists. Pairwise Agonist Scanning (PAS) deployed all single and pairwise combinations of six agonists (ADP, convulxin, thrombin, U46619, iloprost and GSNO used at 0.1, 1, and 10xEC50; 154 conditions including a null condition) to stimulate platelet P2Y1/P2Y12 GPVI, PAR1/PAR4, TP, IP receptors, and guanylate cyclase, respectively, in Factor Xa-inhibited (250 nM apixaban), diluted platelet rich plasma that had been loaded with the calcium dye Fluo-4 NW. PAS of 10 healthy donors provided [Ca(t)]i data for training 10 neural networks (NN, 2-layer/12-nodes) per donor. Trinary stimulations were then conducted at all 0.1x and 1xEC50 doses (160 conditions) as was a sampling of 45 higher ordered combinations (four to six agonists). The NN-ensemble average was a calcium calculator that accurately predicted [Ca (t)]i beyond the single and binary training set for trinary stimulations (R = 0.924). The 160 trinary synergy scores, a normalized metric of signaling crosstalk, were also well predicted (R = 0.850) as were the calcium dynamics (R = 0.871) and high-dimensional synergy scores (R = 0.695) for the 45 higher ordered conditions. The calculator even predicted sequential addition experiments (n = 54 conditions, R = 0.921). NN-ensemble is a fast calcium calculator, ideal for multiscale clotting simulations that include spatiotemporal concentrations of ADP, collagen, thrombin, thromboxane, prostacyclin, and nitric oxide. PMID:25723389

  2. GABAA agonists: resolution and pharmacology of (+)- and (-)-isoguvacine oxide.

    PubMed

    Frølund, B; Jeppesen, L; Krogsgaard-Larsen, P; Hansen, J J

    1995-01-01

    (3SR,4RS)-3,4-Epoxypiperidine-4-carboxylic acid (isoguvacine oxide) is a potent and specific GABAA receptor agonist. Isoguvacine oxide, originally designed as a potentially alkylating agonist, turned out to interact with the GABAA receptor in a fully reversible manner. The protected form of isoguvacine oxide, benzyl (3SR,4RS)-1-(benzyl-oxycarbonyl)-3,4-epoxypiperidin e-4-carboxylate (1) (Scheme 1), has now been resolved by chiral chromatography using cellulose triacetate as a chiral stationary phase. The enantiomers of 1 (ee > or = 98.8%) were subsequently deprotected by hydrogenolysis. Whereas both enantiomers of isoguvacine oxide were inactive as inhibitors of the binding of [3H]GABA to GABAB receptor sites (IC50 > 100 microM), (+)-isoguvacine oxide (IC50 = 0.20 +/- 0.03 microM) and (-)-isoguvacine oxide (IC50 = 0.32 +/- 0.05 microM) showed comparable potencies as inhibitors of the binding of [3H]GABA to GABAA receptor sites. Furthermore, (+)-isoguvacine oxide (EC50 = 6 microM; 33% relative efficacy) and (-)-isoguvacine oxide (EC50 = 5 microM; 38% efficacy relative to 10 microM muscimol) were approximately equipotent and equiefficacious as stimulators of the binding of [3H]diazepam to the GABAA receptor-associated benzodiazepine site. This latter effect is an in vitro estimate of GABAA agonist efficacy. These pharmacological data for isoguvacine oxide and its enantiomers do not seem to support our earlier conception of the topography of the GABAA recognition site(s), derived from extensive structure-activity studies on GABAA agonists.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7577350

  3. 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

  4. 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

  5. Behavioral profile of quinpirole in agonistic encounters between male mice.

    PubMed

    Navarro, J F; Maldonado, E

    1999-09-01

    Most neuroleptic drugs that act as dopaminergic D2 receptor antagonists are effective antiaggressive agents. Although the action of D2 antagonists on aggression has been extensively documented, little is known about the influence of D2 agonists. This study was designed to examine the effect of quinpirole (0.2, 0.4 and 0.8 mg/kg i.p.), a potent agonist at D2 receptors,on agonistic behavior elicited by isolation in male mice. Individually housed mice were exposed to anosmic standard opponents 30 min after drug administration and encounters were videotaped and evaluated using an ethologically based analysis. Quinpirole exhibited an ethopharmacological profile characterized by a selective decrease in offensive behaviors (threat and attack) at low doses (0.2 mg/kg) without affecting motility or exploratory behaviors. This action could be related to the activation of presynaptic D2 receptors. In contrast, at higher doses (0.8 mg/kg), this drug produced a behavioral pattern defined by a significant increase in defense/submission and avoidance/fleeing as well as a reduction in digging and social investigation behaviors suggesting that it could also show anxiogenic-like properties. PMID:10544391

  6. 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

  7. Inverse Agonists: Tools to Reveal Ligand-Specific Conformations of G Protein-Coupled Receptors

    NSDL National Science Digital Library

    Paul L. Prather (University of Arkansas for Medical Sciences; Department of Pharmacology and Toxicology REV)

    2004-01-13

    G protein–coupled receptors (GPCRs) traverse the plasma membrane seven times and produce intracellular effects through interaction with G proteins. Three classes of ligands bind and regulate the activity of GPCRs: agonists, antagonists, and inverse agonists. To describe the activity of these ligands at GPCRs, a two-state receptor model has been proposed in which receptors exist in an equilibrium between inactive (R) and active (R*) states. Agonists preferentially bind and stabilize the active (R*) state. This results in an enrichment of the proportion of active receptors, producing an increase in receptor activity. In contrast, inverse agonists preferentially bind and stabilize receptors in the inactive (R) state. This results in an enrichment of the proportion of inactive receptors, producing a reduction in spontaneous receptor activity. Neutral antagonists have equal preferences for both R and R* states, lack any intrinsic activity, and are able to block actions produced by either agonists or inverse agonists. Exciting observations reported in two recent manuscripts by Gbahou et al. and Azzi et al. indicate that some inverse agonists act not only in opposition to agonists by suppressing constitutive receptor activity, but may also initiate unique signal transduction cascades as well. Specifically, it is proposed that these unique ligands are able to enrich several distinct active receptor conformations, each demonstrating a preference for regulation of a discrete intracellular effector. This suggests that inverse agonists are not merely "the opposite of agonists," but instead may serve as useful tools to investigate ligand-specific conformations of GPCRs.

  8. Enhancement of D2 receptor agonist-induced inhibition by D1 receptor agonist in the ventral tegmental area.

    PubMed Central

    Momiyama, T.; Sasa, M.; Takaori, S.

    1993-01-01

    1. A microiontophoretic study was performed on chloral hydrate-anaesthetized rats to examine the role of D1 receptors in the ventral tegmental area (VTA) neurones, which are inhibited by autoreceptor and D2 receptor agonists. 2. Inhibition by microiontophoretic application of quinpirole (a D2 agonist) of antidromic spikes elicited by stimulation of the nucleus accumbens in dopaminergic neurones of the VTA, was significantly enhanced by simultaneous application of SKF 38393 (D1 agonist), although SKF 38393 alone had little effect on the neurones. 3. In addition, quinpirole-induced inhibition was antagonized by iontophoretic application of domperidone (D2 antagonist), but was not affected by SCH 23390 (D1 antagonist). 4. Furthermore, SKF 38393-induced enhancement of inhibition by quinpirole was antagonized by simultaneous application of SCH 23390. 5. These results suggest that activation of D1 receptors located on the VTA dopaminergic neurones or on non-dopaminergic nerve terminals is not essential for inducing inhibition of the dopaminergic neurones, but enhances D2 receptor-mediated inhibition directly or indirectly via inhibitory neurones. Images Figure 1 PMID:7902179

  9. NOD2 Agonist Promotes the Production of Inflammatory Cytokines in VSMC in Synergy with TLR2 and TLR4 Agonists

    PubMed Central

    Sun, Jinghua; Ding, Yanchun

    2012-01-01

    Objective. To investigate the expression of NOD2 in human VSMCs, its role in the production of inflammatory cytokines in VSMC and the possible interaction of NOD2-mediated signaling pathway with those mediated by TLR2 and TLR4. Methods. Human coronary artery smooth muscle cells were stimulated with NOD2 agonist MDP alone or in combination with either TLR2 agonist PAM3 or TLR4 agonist LPSs. The mRNA expression of NOD2 and FGF-2 were measured by RT-PCR. The concentration of IL-8 and TNF-? in the culture supernatants was determined by ELISA. VSMC proliferation ability was analyzed by MTT assay. Results. MDP up regulated the expression of NOD2 mRNA in VSMC in a time-dependent manner, up regulated the expression of FGF-2 mRNA in VSMC, induced the production of IL-8 and TNF-?, and promoted the proliferation of VSMC. Additionally, MDP synergied with LPS and PAM3 to promote the proliferation of VSMC and induce the production of IL-8 and TNF-?. Conclusion. The activation of NOD2-mediated innate immune signaling pathway can increase the proliferation ability of VSMC and induce the production of inflammatory cytokines in VSMC. It is also shown a synergistic effect with TLR2- and TLR4-mediated signaling pathways in this process. PMID:22997500

  10. Antinociceptive Interactions between Mu-Opioid Receptor Agonists and the Serotonin Uptake Inhibitor Clomipramine in Rhesus Monkeys: Role of Mu Agonist Efficacy

    PubMed Central

    Banks, Matthew L.; Rice, Kenner C.

    2010-01-01

    Mu-opioid agonists are effective analgesics but have undesirable effects such as sedation and abuse liability that limit their clinical effectiveness. Serotonergic systems also modulate nociception, and serotonin uptake inhibitors may be useful as adjuncts to enhance analgesic effects and/or attenuate undesirable effects of mu agonists. This study examined the effects of the serotonin uptake inhibitor clomipramine on behavioral effects produced in rhesus monkeys by mu agonists with varying efficacy at mu receptors (nalbuphine < morphine < methadone). Clomipramine and each mu agonist were studied alone and in fixed-proportion mixtures in assays of schedule-controlled responding, thermal nociception, and capsaicin-induced thermal allodynia. In the assay of schedule-controlled responding, all mu agonists dose-dependently decreased response rates. Clomipramine was inactive alone and did not alter the effects of mu agonists. In the assay of thermal nociception, all mu agonists produced dose-dependent antinociception. Clomipramine was inactive alone but produced a proportion-dependent enhancement of the antinociceptive effects of nalbuphine > morphine > methadone. In the assay of capsaicin-induced allodynia, nalbuphine produced dose-dependent antiallodynia. Clomipramine alone was inactive, but as in the assay of thermal nociception, it produced a proportion-dependent enhancement in the effects of nalbuphine. These findings suggest that serotonin uptake inhibitors can selectively enhance the antinociceptive effects of mu agonists in nonhuman primates. These effects of serotonin uptake inhibitors may depend on the proportion of the serotonin uptake inhibitor and the efficacy of the mu agonist. The greatest enhancement was observed with intermediate proportions of clomipramine in combination with the low-efficacy mu agonist nalbuphine. PMID:20675432

  11. Qualit des composts et des digestats Fabienne MULLER

    E-print Network

    Boyer, Edmond

    Qualité des composts et des digestats Fabienne MULLER Direction consommation durable et déchets organiques se construit, avec aujourd'hui le développement important de la méthanisation. Les composts actuellement produits, peuvent l'être avec des digestats ou non. Les quantités de compost produit ne cessent d

  12. La biogenèse des mélanosomes

    PubMed Central

    Delevoye, Cédric; Giordano, Francesca; van Niel, Guillaume; Raposo, Graça

    2012-01-01

    Les mélanocytes situés à la base de l’épiderme produisent des mélanosomes qui sont transférés aux kératinocytes pour assurer la pigmentation de l’épiderme et sa photoprotection contre les rayons ultraviolets. Les mélanosomes, organites apparentés aux lysosomes, sont le lieu de synthèse et de stockage d’un pigment, la mélanine. Leur formation dépend de protéines mélanosomales qui transitent par les voies de biosynthèse et d’endocytose et exploitent les mécanismes moléculaires du trafic intracellulaire. Les acteurs moléculaires impliqués dans le transport des protéines mélanosomales et la biogenèse des mélanosomes sont la cible de mutations dans des maladies génétiques accompagnées d’hypopigmentation comme l’albinisme et les maladies lysosomales. Les études menées sur les mélanocytes issus de souris modèles de ces maladies permettent de comprendre certaines des étapes-clés de la mélanogenèse ainsi que les dysfonctionnements associés à ces pathologies. De plus, décrypter la mélanogenèse facilite également la compréhension d’autres processus physiologiques, comme l’illustrent les similitudes inattendues avec l’amyloïdogenèse dans les maladies neurodégénératives. PMID:21382323

  13. 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.

  14. PPAR-a and -g agonists attenuate diabetic kidney disease in the apolipoprotein E knockout mouse

    Microsoft Academic Search

    Anna C. Calkin; Sara Giunti; Karin A. Jandeleit-Dahm; Terri J. Allen; Mark E. Cooper; Merlin C. Thomas

    2006-01-01

    Backgound. Peroxisome proliferator-activated receptor (PPAR)-a and PPAR-g agonists are widely used in diabetes. In addition to their effects on lipid and glucose homeostasis, these agents have been postulated to have independent renoprotective actions. In the current study, we assess the efficacy of the PPAR-a agonist, gemfibrozil, the PPAR-g agonist rosiglitazone and the non-thiazolidinedione PPAR-a\\/g coagonist, compound 3q, on kidney structure

  15. 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; (GSKNC)

    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.

  16. Effect of Cannabinoid Receptor Agonists on Streptozotocin-Induced Hyperalgesia in Diabetic Neuropathy

    Microsoft Academic Search

    Magdalena Bujalska

    2008-01-01

    The effect of CB-1 and CB-2 receptor agonists, as well as an influence of a non-selective inhibitor of nitric oxide synthase (NOS), L-NOArg, and an inhibitor acting preferentially on cyclooxygenase-1 (COX-1), indomethacin, on the action of cannabinoid receptor agonists in a streptozotocin (STZ)-induced neuropathic model was investigated. When administered alone, a non-selective cannabinoid receptor agonist, WIN 55,212-2, a potentially selective

  17. Impact of Secondary Structure of Toll-Like Receptor 9 Agonists on Interferon Alpha Induction

    Microsoft Academic Search

    Dong Yu; Mallikarjuna R. Putta; Lakshmi Bhagat; Meiru Dai; Daqing Wang; Anthony F. Trombino; Tim Sullivan; Ekambar R. Kandimalla; Sudhir Agrawal

    2008-01-01

    Oligodeoxynucleotides containing a CpG motif and double- or multistranded structure-forming sequences act as agonists of Toll-like receptor 9 (TLR9) and induce high levels of interferon alpha (IFN-) in addition to other Th1-type cytokines. In the present study, we evaluated three highly effective IFN--inducing agonists of TLR9 to determine the type of duplex structures formed and the agonist's ability to induce

  18. Magnesium Ions and Opioid Agonist Activity in Streptozotocin-Induced Hyperalgesia

    Microsoft Academic Search

    Magdalena Bujalska; Ewelina Malinowska; Helena Makulska-Nowak

    2008-01-01

    Streptozotocin-induced hyperglycemia accompanied by a chronic decrease in the nociceptive threshold is considered a useful model of experimental hyperalgesia. We examined (1) the effect of the opioid receptor agonists and (2) the effect of the magnesium ions (Mg2+) on the antinociceptive action of opioid agonists in a diabetic neuropathic pain model. When administered alone, opioid agonists like morphine (5 mg\\/kg

  19. 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<2×10?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

  20. Contextual modulation of androgen effects on agonistic interactions.

    PubMed

    Pradhan, D S; Connor, K R; Pritchett, E M; Grober, M S

    2014-01-01

    Seasonal changes in steroid hormones are known to have a major impact on social behavior, but often are quite sensitive to environmental context. In the bi-directionally sex changing fish, Lythrypnus dalli, stable haremic groups exhibit baseline levels of interaction. Status instability follows immediately after male removal, causing transiently elevated agonistic interactions and increase in brain and systemic levels of a potent fish androgen, 11-ketotestosterone (KT). Coupling KT implants with a socially inhibitory environment for protogynous sex change induces rapid transition to male morphology, but no significant change in social behavior and status, which could result from systemically administered steroids not effectively penetrating into brain or other tissues. Here, we first determined the degree to which exogenously administered steroids affect the steroid load within tissues. Second, we examined whether coupling a social environment permissive to sex change would influence KT effects on agonistic behavior. We implanted cholesterol (Chol, control) or KT in the dominant individual (alpha) undergoing sex change (on d0) and determined the effects on behavior and the degree to which administered steroids altered the steroid load within tissues. During the period of social instability, there were rapid (within 2 h), but transient effects of KT on agonistic behavior in alphas, and secondary effects on betas. On d3 and d5, all KT, but no Chol, treated females had male typical genital papillae. Despite elevated brain and systemic KT 5 days after implant, overall rates of aggressive behavior remained unaffected. These data highlight the importance of social context in mediating complex hormone-behavior relationships. PMID:24315925

  1. 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

  2. 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

  3. Evaluation of Molecular Modeling of Agonist Binding in Light of the Crystallographic Structure of an Agonist-Bound A2A Adenosine Receptor

    PubMed Central

    Deflorian, Francesca; Kumar, T. Santhosh; Phan, Khai; Gao, Zhan-Guo; Xu, Fei; Wu, Huixian; Katritch, Vsevolod; Stevens, Raymond C.; Jacobson, Kenneth A.

    2011-01-01

    Molecular modeling of agonist binding to the human A2A adenosine receptor (AR) was assessed and extended in light of crystallographic structures. Heterocyclic adenine nitrogens of co-crystallized agonist overlayed corresponding positions of the heterocyclic base of a bound triazolotriazine antagonist, and ribose moiety was coordinated in a hydrophilic region, as previously predicted based on modeling using the inactive receptor. Automatic agonist docking of 20 known potent nucleoside agonists to agonist-bound A2AAR crystallographic structures predicted new stabilizing protein interactions, to provide a structural basis for previous empirical structure activity relationships consistent with previous mutagenesis results. We predicted binding of novel C2 terminal amino acid conjugates of A2AAR agonist CGS21680 and used these models to interpret effects on binding affinity of newly-synthesized agonists. D-Amino acid conjugates were generally more potent than L- stereoisomers, and free terminal carboxylates more potent than corresponding methyl esters. Amino acid moieties were coordinated close to extracellular loops 2 and 3. Thus, molecular modeling is useful in probing ligand recognition and rational design of GPCR–targeting compounds with specific pharmacological profiles. PMID:22104008

  4. Comparative Gene Expression Profiles Induced by PPARc and PPARa/c Agonists in Human Hepatocytes

    E-print Network

    Boyer, Edmond

    ) and glitazars (dual PPARa/c agonists) have been developed to treat hyperglycemia and, simultaneously, hyperglycemia and dyslipidemia, respectively. However, most have caused idiosyncratic hepatic or extrahepatic

  5. 3D-Pharmacophore Identification for ?-Opioid Agonists Using Ligand-Based Drug-Design Techniques

    NASA Astrophysics Data System (ADS)

    Yamaotsu, Noriyuki; Hirono, Shuichi

    A selective ?-opioid receptor (KOR) agonist might act as a powerful analgesic without the side effects of ?-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 ?-opioid agonists and propose a new three-dimensional pharmacophore model that encompasses the ?-activities of all classes. This utilizes conformational sampling of agonists by high-temperature molecular dynamics and pharmacophore extraction through a series of molecular superpositions.

  6. Comparative nasal effects of bradykinin, kallidin and [Des-Arg9]-bradykinin in atopic rhinitic and normal volunteers.

    PubMed Central

    Rajakulasingam, K; Polosa, R; Holgate, S T; Howarth, P H

    1991-01-01

    1. The structure-activity relationship of kinins within the nose has been investigated in atopic rhinitic (n = 7) and non-rhinitic (n = 7) subjects. On 4 separate days, each separated by a week, subjects randomly underwent nasal challenge with incremental doses of either the B1 agonist [Des-Arg9]-bradykinin, the B2 agonists kallidin or bradykinin, or vehicle placebo in a double-blind comparative study. The nasal response was monitored objectively by measurement of nasal airways resistance (NAR) by active posterior rhinomanometry and subjectively by symptom reporting of nasal blockage, rhinorrhoea, nasal itch and nasal pain. 2. The B2 agonists kallidin and bradykinin both induced a dose-dependent increase in NAR (P less than 0.001) and were associated with symptomatic reporting of nasal blockage (P less than 0.05), rhinorrhoea (P less than 0.01) and nasal discomfort (P less than 0.05) compared to placebo. In contrast the effects of the B1 agonist [Des-Arg9]-bradykinin on NAR and symptom reporting were indistinguishable from placebo. No difference could be identified in the nasal response to kallidin and bradykinin between rhinitic and non-rhinitic subjects and there was no evidence of B1 receptor upregulation in the disease state. For the whole group the provocative dose of agonist inducing a 50% increase in NAR (PD50) was 1.77 x 10(-4) mol for bradykinin and 2.86 x 10(-4) mol for kallidin (P greater than 0.05). 3. These findings identify that the nasal effects of kinins are mediated through B2 receptors and the advent of B2 receptor antagonists will permit a further evaluation of the role of kinins in rhinitis. PMID:1890650

  7. Agonistic behaviour and dominance in stoats (Mustela erminea L.).

    PubMed

    Erlinge, S

    1977-08-01

    Behavioural mechanisms underlying distribution in a stoat (Mustela erminea) population were examined experimentally in an enclosure simulating natural habitats with living prey. Agonistic behaviours, displayed by individual stoats of different sex and age while being tested in pairs in various combinations were recorded. Dominance relationships between different categories of stoats (femalefemale, adult and juvenile male male) were examined, as was social dominance between individual stoats of the same sex. In further experiments designed to examine the influence of establishment on the social dominance, the behaviour of established introduced animals was observed. PMID:563152

  8. An efficient synthesis of a potent PPARpan agonist.

    PubMed

    Guo, Jiasheng; Erickson, Greg A; Fitzgerald, Russ N; Matsuoka, Richard T; Rafferty, Stephen W; Sharp, Matthew J; Sickles, Barry R; Wisowaty, James C

    2006-10-13

    An efficient synthesis of 2-{4-[({4-{[4-(4-methoxyphenyl)piperazin-1-yl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)thio]phenoxy}-2-methylpropanoic acid (1), a potent PPARpan agonist, is described. The seven-step synthesis, which afforded 1 in 30% overall yield, includes a highly regioselective carbon-sulfur bond formation via coupling of a bishydroxymethylthiazole (3) with 4-hydroxythiophenol, displacement of the remaining alcohol through a three-step telescoped sequence involving an efficient cleavage of an aryl mesylate, and an efficient and practical method of introducing an isobutyric acid fragment. PMID:17025332

  9. Agonist and inhibitory effects of pyridostigmine at the neuromuscular junction.

    PubMed

    Bradley, R J; Sterz, R; Peper, K

    1986-06-18

    When all of the AChE at the endplate is irreversibly inhibited by phospholine iodide the ionophoretically induced ACh endplate currents are increased more than 10-fold in amplitude. The reversible AChE inhibitor pyridostigmine only increases the current to about half this value because its effects are obscured by receptor blocking. It was found that pyridostigmine can activate the receptor ion channels when released by ionophoresis at the endplate, thus suggesting that agonist-like desensitization could contribute to the blocking effects. PMID:3719368

  10. 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.

  11. 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

  12. Melatonin and melatonin agonist for delirium in the elderly patients.

    PubMed

    Chakraborti, Dwaipayan; Tampi, Deena J; Tampi, Rajesh R

    2015-03-01

    The objective of this review is to summarize the available data on the use of melatonin and melatonin agonist for the prevention and management of delirium in the elderly patients from randomized controlled trials (RCTs). A systematic search of 5 major databases PubMed, MEDLINE, PsychINFO, Embase, and Cochrane Library was conducted. This search yielded a total of 2 RCTs for melatonin. One study compared melatonin to midazolam, clonidine, and control groups for the prevention and management of delirium in individuals who were pre- and posthip post-hip arthroplasty. The other study compared melatonin to placebo for the prevention of delirium in older adults admitted to an inpatient internal medicine service. Data from these 2 studies indicate that melatonin may have some benefit in the prevention and management of delirium in older adults. However, there is no evidence that melatonin reduces the severity of delirium or has any effect on behaviors or functions in these individuals. Melatonin was well tolerated in these 2 studies. The search for a melatonin agonist for delirium in the elderly patients yielded 1 study of ramelteon. In this study, ramelteon was found to be beneficial in preventing delirium in medically ill individuals when compared to placebo. Ramelteon was well tolerated in this study. PMID:24946785

  13. Ropinirole: a dopamine agonist for the treatment of Parkinson's disease.

    PubMed

    Kuzel, M D

    1999-02-01

    The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, dosage and administration, and formulary considerations of ropinirole are reviewed. Ropinirole is a nonergoline dopamine agonist that binds to dopamine D2-receptors; the drug is indicated for use in the symptomatic treatment of early and late Parkinson's disease (PD). Ropinirole is rapidly absorbed after oral administration and undergoes extensive hepatic metabolism to active metabolites. The elimination half-life averages about six hours. Ropinirole has a low potential to interact with other drugs likely to be administered to PD patients. In patients with early PD, initial monotherapy with ropinirole was more effective than placebo or bromocriptine in the absence of selegiline and was as effective as bromocriptine in the presence of selegiline. Ropinirole was as effective as levodopa in patients with earlier stages of PD. In one subset of patients with advanced PD not adequately controlled by levodopa, adjunctive ropinirole was more effective than placebo and bromocriptine. Ropinirole was more effective than bromocriptine in patients previously given high-dose levodopa and was as effective in patients previously given low-dose levodopa or adjunctive dopamine agonist therapy. The most frequent adverse effects are nausea, somnolence, and dizziness; the dosage should be increased gradually to minimize adverse effects. Ropinirole is less expensive than bromocriptine and pergolide and similar in cost to pramipexole. Ropinirole appears to be a useful addition to existing therapeutic approaches to PD and is approved for both early and later stages of the disease. PMID:10030505

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

    PubMed Central

    Gonzalez-Kristeller, Daniela C.; do Nascimento, João 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

  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. Cytokines induce airway smooth muscle cell hyperresponsiveness to contractile agonists.

    PubMed

    Amrani, Y; Panettieri, R A

    1998-08-01

    The important pathophysiological features of the airways in asthma include exaggerated narrowing to bronchoconstrictor agonists and attenuated relaxation to beta adrenoceptor stimulation. These physiological perturbations are associated with inflammation and remodelling of the airways, the latter including an increase in airway smooth muscle cell mass, disruption of the airway epithelium, and changes in the airway tissue extracellular matrix. Recent evidence suggests that cytokines, important molecules modulating airway inflammation, also directly decrease airway smooth muscle responsiveness to beta adrenergic agents, stimulate cytokine secretion, inhibit or promote airway smooth muscle proliferation, and "prime" airway smooth muscle to become hyperresponsive to bronchoconstrictors. Characterisation of the cellular and biochemical events that are involved in activation of airway smooth muscle is likely to be the major consideration in the design of future therapies for asthma. Because calcium is an essential regulatory element for cell growth and cell contraction, it is likely that alterations in calcium mobilisation may, in part, play a role in creating an airway smooth muscle phenotype that is hyperresponsive to contractile agonists. Further studies will be required to determine the precise mechanisms involved in cytokine modulation of calcium homeostasis in airway smooth muscle. PMID:9828861

  17. Cold Suppresses Agonist-induced Activation of TRPV1

    PubMed Central

    Chung, M.-K.; Wang, S.

    2011-01-01

    Cold therapy is frequently used to reduce pain and edema following acute injury or surgery such as tooth extraction. However, the neurobiological mechanisms of cold therapy are not completely understood. Transient receptor potential vanilloid 1 (TRPV1) is a capsaicin- and heat-gated nociceptive ion channel implicated in thermosensation and pathological pain under conditions of inflammation or injury. Although capsaicin-induced nociception, neuropeptide release, and ionic currents are suppressed by cold, it is not known if cold suppresses agonist-induced activation of recombinant TRPV1. We demonstrate that cold strongly suppressed the activation of recombinant TRPV1 by multiple agonists and capsaicin-evoked currents in trigeminal ganglia neurons under normal and phosphorylated conditions. Cold-induced suppression was partially impaired in a TRPV1 mutant that lacked heat-mediated activation and potentiation. These results suggest that cold-induced suppression of TRPV1 may share a common molecular basis with heat-induced potentiation, and that allosteric inhibition may contribute, in part, to the cold-induced suppression. We also show that combination of cold and a specific antagonist of TRPV1 can produce an additive suppression. Our results provide a mechanistic basis for cold therapy and may enhance anti-nociceptive approaches that target TRPV1 for managing pain under inflammation and tissue injury, including that from tooth extraction. PMID:21666106

  18. Conservation des Textiles

    E-print Network

    Brest, Université de

    Conservation des Textiles Les 22 et 23 mai 2013 Soit 2 jours - 14 heures OBJECTIFS DE LA FORMATION essentielles dans la gestion de collections textiles, depuis leur identification jusqu'à leur conservation conservation d'éléments et de collections textiles, et toutes personnes travaillant dans le domaine du

  19. Fachprfungsordnung des Bachelorstudiengangs Geographie

    E-print Network

    Greifswald, Ernst-Moritz-Arndt-Universität

    Fachprüfungsordnung des Bachelorstudiengangs Geographie an der Ernst Geographie: Inhaltsverzeichnis: § 1 Studium § 2 Zulassungsvoraussetzungen § 3 Module § 4 Berufsbezogenes Bachelorstudiengang Geographie. Ergänzend gilt die Gemeinsame Prüfungsordnung für Bachelor- und Masterstudiengänge

  20. Das Bandenspektrum des CO +

    Microsoft Academic Search

    D. Coster; H. H. Brons; H. Bulthuis

    1932-01-01

    Zusammenfassung Es wird die Rotationsstruktur der s ? s Banden (1 ? 4, 2 ? 4, 2 ? 5, 3 ? 5, 3 ? 6, 4 ? 7) des CO+ analysiert und eine Nullinienformel für diese Banden abgeleitet. Von denII ? s-Banden (5 ? 0, 6 ? 0, 7 ? 0, 8 ? 0) wird die Rotationsstruktur analysiert. Jede Bande

  1. Die Stoffwechselsituation des Reizleitungssystems

    Microsoft Academic Search

    Th. H. Schiebler; M. Stark; R. Caesar

    1956-01-01

    Zusammenfassung Die spezifische Muskulatur des Reizleitungssystems unterscheidet sich u. a. von der Arbeitsmuskulatur durch ein vermindertes Vorkommen von Sarkosomen, eine schwächere Bernsteinsäuredehydrogenase-und Oxydasereaktion und einen geringeren Sauerstoffverbrauch. Wir schließen daraus auf einen stoffwechselmäßigen Unterschied zwischen den beiden Muskelarten und stellen zur Diskussion, ob das Reizleitungssystem relativ unabhängig von der Sauerstoffversorgung ist. Das Reizleitungssystem weist auch unter Thyroxinbelastung einen zäh festgehaltenen,

  2. des sciences pharmaceutiques

    E-print Network

    Pellier, Damien

    .-M. Scherrmann La faculté de pharmacie de Paris est habilitée à percevoir 45 % du montant total de votre Taxe d pharmacie de paris en sera bénéficiaire ! En indiquant précisément lors de votre déclaration de versement de'Observatoire - 75006 Paris Diplôme : docteur en pharmacie - Monsieur le doyen Faculté des sciences pharmaceutiques et

  3. 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.

  4. Cellular localization of kinin B1 receptor in the spinal cord of streptozotocin-diabetic rats with a fluorescent [N?-Bodipy]-des-Arg9-bradykinin

    Microsoft Academic Search

    Sébastien Talbot; Patrick Théberge-Turmel; Dalinda Liazoghli; Jacques Sénécal; Pierrette Gaudreau; Réjean Couture

    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

  5. CHROMATOGRAPHIE EN PHASE GAZEUSE DES COMPOSS VOLATILS

    E-print Network

    Boyer, Edmond

    CHROMATOGRAPHIE EN PHASE GAZEUSE DES COMPOSÉS VOLATILS DES GLANDES A PHÉROMONES DES ABEILLES'introduction directe et en petit nombre des glances à phéromones à l'entrée d'une colonne à chromatographie; le procédé : chromatographie phase gazeuse, glande, phéromone, substance d'alarme, abeille ouvrière. INTRODUCTION La vie des

  6. TRANSFORMATION ET DEVENIR DES CELLULES ADIPEUSES

    E-print Network

    Paris-Sud XI, Université de

    TRANSFORMATION ET DEVENIR DES CELLULES ADIPEUSES AU COURS DE L'AMAIGRISSEMENT. ÉTUDE environ 400 g, les transformations ultrastructurales des cellules adipeuses et leur devenir ont été. Le reste des cellules adipeuses des dépôts, représentant environ 90 p. 100 de la totalité des

  7. fevrier 2012 Journes Francophones des Langages Applicatifs JFLA12 Separation des couleurs dans un -calcul bichrome

    E-print Network

    Paris-Sud XI, Université de

    AlligatorEggs3 cherche `a expliquer le -calcul `a des enfants. Pour cela il utilise la couleur pour relier des alligators affam´es et des oeufs afin de constituer des familles. La couleur sert `a expliciter les liaisons des variables dans les termes, des oeufs naissent de nouveaux alligators ou familles lors

  8. 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

  9. Field Observations of Intraspecific Agonistic Behavior of Two Crayfish Species, Orconectes rusticus and

    E-print Network

    Moore, Paul A.

    Field Observations of Intraspecific Agonistic Behavior of Two Crayfish Species, Orconectes rusticus, the nocturnal behavior of two crayfish species was observed by scuba diving and snorkeling in two northern as having the potential to alter agonistic behavior. Introduction Many observations of crayfish behavior

  10. 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 ?2·eGFP 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

  11. A Quantitative Analysis of Agonistic Behavior in Juvenile American Lobsters (Homarus americanus L.)

    Microsoft Academic Search

    R. Huber; E. A. Kravitz

    1995-01-01

    In these studies a quantitative analysis of agonistic (fighting) behavior in lobsters is presented as a first step in our attempt to relate patterns of behavior to underlying neurobiological mechanisms. The agonistic behavior of juvenile American lobsters (Homarus americanus L.) was studied in laboratory tanks at the New England Aquarium. Using video analyses and statistical techniques: (1) an ethogram of

  12. Dominance relations and agonistic behaviour of Tundra Swans ( Cygnus columbianus columbianus ) during fall and spring migration

    Microsoft Academic Search

    Shannon S. Badzinski

    2003-01-01

    Social interactions and agonistic activities of Tundra Swans (Cygnus columbianus columbianus ) were docu- mented at Long Point, Ontario, to determine (i) dominance relations among social groups and (ii) the frequency and in- tensity of agonistic acts by swans. Families were involved in one-third as many interactions as were nonfamily groups. Nonfamily groups initiated interactions with other nonfamily groups more

  13. Neuroprotective effect of ? 2 agonist (brimonidine) on adult rat retinal ganglion cells after increased intraocular pressure

    Microsoft Academic Search

    Farid A. K. M Ahmed; K Hegazy; P Chaudhary; S. C Sharma

    2001-01-01

    Brimonidine, a selective ?2-adrenoceptor agonist, has recently been shown to be neuroprotective as it significantly improves survival of retinal ganglion cells (RGCs) after calibrated optic nerve injury in rats. In the present study, we examined the effect of brimonidine (?2-adrenoceptor agonist) on RGC survival after increased intraocular pressure (IOP) in adult rats. RGCs were prelabeled by bilateral tectal injection of

  14. Design, synthesis, and evaluation of phenylglycinols and phenyl amines as agonists of GPR88.

    PubMed

    Dzierba, Carolyn D; Bi, Yingzhi; Dasgupta, Bireshwar; Hartz, Richard A; Ahuja, Vijay; Cianchetta, Giovanni; Kumi, Godwin; Dong, Li; Aleem, Saadat; Fink, Cynthia; Garcia, Yudith; Green, Michael; Han, Jianxin; Kwon, Soojin; Qiao, Ying; Wang, Jiancheng; Zhang, Yulian; Liu, Ying; Zipp, Greg; Liang, Zhi; Burford, Neil; Ferrante, Meredith; Bertekap, Robert; Lewis, Martin; Cacace, Angela; Grace, James; Wilson, Alan; Nouraldeen, Amr; Westphal, Ryan; Kimball, David; Carson, Kenneth; Bronson, Joanne J; Macor, John E

    2015-04-01

    Small molecule modulators of GPR88 activity (agonists, antagonists, or modulators) are of interest as potential agents for the treatment of a variety of psychiatric disorders including schizophrenia. A series of phenylglycinol and phenylamine analogs have been prepared and evaluated for their GPR88 agonist activity and pharmacokinetic (PK) properties. PMID:25690789

  15. Free energy calculations of A2A adenosine receptor mutation effects on agonist binding.

    PubMed

    Keränen, Henrik; Åqvist, Johan; Gutiérrez-de-Terán, Hugo

    2015-02-12

    A general computational scheme to evaluate the effects of single point mutations on ligand binding is reported. This scheme is applied to characterize agonist binding to the A2A adenosine receptor, and is found to accurately explain how point mutations of different nature affect the binding affinity of a potent agonist. PMID:25633558

  16. Pleuropulmonary Fibrosis After Long-term Treatment With the Dopamine Agonist Pergolide for Parkinson Disease

    Microsoft Academic Search

    Ron Tintner; Prasad Manian; Polly Gauthier; Joseph Jankovic

    2005-01-01

    opamine agonists are increasingly used in the treatment of Parkinson disease, but they may cause serious adverse effects. In December 1983, symptoms of Parkinson disease developed in a 55-year-old man with no history of pulmonary disease, smok- ing, or asbestos exposure. He began treatment with dopamine agonists bromocrip- tine mesylate (in 1984) and pergolide mesylate (in 1989). In late 2000,

  17. DETERMINANTS OF OUTCOMES OF AGONISTIC INTERACTIONS AMONG MALE CALIFORNIA SEA LIONS

    E-print Network

    Gerber, Leah R.

    Conservation Society, The University of Montana, Missoula, MT 59812-4824, USA Agonistic behavior in territorial the encounter and not by territory ownership. Key words: agonistic behavior, displays, pinnipeds, territorial initiates an interaction and who owns the territory on which an encounter takes place. We studied predictors

  18. 4?-Methyl-5-(3-hydroxyphenyl)morphan Opioid Agonist and Partial Agonist Derived from a 4?-Methyl-5-(3-hydroxyphenyl)morphan Pure Antagonist

    PubMed Central

    Carroll, F. Ivy; Gichinga, Moses G.; Williams, John D.; Vardy, Eyal; Roth, Bryan L.; Mascarella, S. Wayne; Thomas, James B.; Navarro, Hernán A.

    2013-01-01

    In previous studies we reported that addition of 7?-acylamino groups to N-phenylpropyl-4?-methyl-5-(3-hydroxyphenyl)morphan (4) led to compounds that were pure opioid receptor antagonists. In contrast to these findings we report in this study that addition of a 7?-amino (5a), 7?-alkylamino (5b–e), or 7?-dialkylamino (5f–h) group to 4 leads to opioid receptor ligands with varying degrees of agonist/antagonist activity. The 7?-amino and 7?-methylamino analogues were full agonists at the ? and ? receptors and antagonists at the ? receptor. The 7?-cyclopropylmethylamino analogue 5h was a full agonist at the ? receptor with weaker agonist activity at the ? and ? receptors. Whereas the addition of a 7?-acylamino group to the pure non-selective opioid receptor antagonist N-phenylpropyl-4?-methyl-5-(3-hydroxyphenyl)morphan (4) led to ? selective pure opioid receptor antagonist, the addition of a 7?-amino, 7?-alkylamino or 7?-dialkylamino group to 4 leads to opioid ligands that are largely ? or ? agonist with mixed agonist/antagonist properties. PMID:24144404

  19. Postsynaptic dopamine (DA) receptor stimulator properties of the putative DA autoreceptor-selective agonist BHT 920 uncovered by co-treatment with the D-1 agonist SK&F 38393

    Microsoft Academic Search

    S. Hjorth; A. Carlsson

    1987-01-01

    Postsynaptic dopaminergic behavioural effects of D-2 agonists can be promoted by concomitant D-1 receptor activation. The present experiment explored whether such effects could be elicited by the putative autoreceptor-selective D-2 agonist B-HT 920, when combined with the D-1 agonist SK&F 38393. Except for occasional jerks induced by B-HT 920, neither agonist caused significant dopaminergic stimulation when given separately, whereas combined

  20. 1984 - 1992 : alourdissement des loyers et des charges

    Microsoft Academic Search

    Laure Pitrou

    1995-01-01

    [fre] 1984-1992 : alourdissement des loyers et . Au cours des années 1984-1992 les loyers ont augmenté beaucoup plus rapidement que le niveau général des prix. Cette évolution reflète à la fois le coût plus élevé que par le passé conféré au droit d'usage du logement et l'amélioration du confort du parc locatif. Elle est à nuancer suivant le secteur

  1. The link between non-ergot-derived dopamine agonists and heart failure: how strong is it?

    PubMed

    Lockett, Katrina; DeBacker, Danielle; Cauthon, Kimberly A B

    2015-01-01

    Dopamine agonists are commonly used as initial monotherapy and adjunct treatment for Parkinson's disease. However, the Food and Drug Administration recently linked pramipexole use with an increased risk of heart failure (HF). Several case-control studies demonstrate a possible increased risk of the development of HF in patients taking non-ergot-derived dopamine agonists compared with patients not taking dopamine agonists. In patients taking non-ergot-derived dopamine agonists, the studies associated the risk of increased HF with pramipexole. These studies did not find a possible increased risk with ropinirole, but to date no randomized, controlled trials have been conducted to directly compare ropinirole with pramipexole and the risk of HF. The mechanism by which HF occurs is unknown, but the development of edema after dopamine agonist use could increase the risk of HF. If patients with a history of cardiovascular disease or edema are prescribed pramipexole, additional monitoring for HF signs and symptoms is recommended. PMID:25760663

  2. Pharmacology and clinical potential of guanylyl cyclase C agonists in the treatment of ulcerative colitis

    PubMed Central

    Pitari, Giovanni M

    2013-01-01

    Agonists of the transmembrane intestinal receptor guanylyl cyclase C (GCC) have recently attracted interest as promising human therapeutics. Peptide ligands that can specifically induce GCC signaling in the intestine include endogenous hormones guanylin and uroguanylin, diarrheagenic bacterial enterotoxins (ST), and synthetic drugs linaclotide, plecanatide, and SP-333. These agonists bind to GCC at intestinal epithelial surfaces and activate the receptor’s intracellular catalytic domain, an event initiating discrete biological responses upon conversion of guanosine-5?-triphosphate to cyclic guanosine monophosphate. A principal action of GCC agonists in the colon is the promotion of mucosal homeostasis and its dependent barrier function. Herein, GCC agonists are being developed as new medications to treat inflammatory bowel diseases, pathological conditions characterized by mucosal barrier hyperpermeability, abnormal immune reactions, and chronic local inflammation. This review will present important concepts underlying the pharmacology and therapeutic utility of GCC agonists for patients with ulcerative colitis, one of the most prevalent inflammatory bowel disease disorders. PMID:23637522

  3. Identification, optimization, and pharmacology of acylurea GHS-R1a inverse agonists.

    PubMed

    McCoull, William; Barton, Peter; Brown, Alastair J H; Bowker, Suzanne S; Cameron, Jennifer; Clarke, David S; Davies, Robert D M; Dossetter, Alexander G; Ertan, Anne; Fenwick, Mark; Green, Clive; Holmes, Jane L; Martin, Nathaniel; Masters, David; Moore, Jane E; Newcombe, Nicholas J; Newton, Claire; Pointon, Helen; Robb, Graeme R; Sheldon, Christopher; Stokes, Stephen; Morgan, David

    2014-07-24

    Ghrelin plays a major physiological role in the control of food intake, and inverse agonists of the ghrelin receptor (GHS-R1a) are widely considered to offer utility as antiobesity agents by lowering the set-point for hunger between meals. We identified an acylurea series of ghrelin modulators from high throughput screening and optimized binding affinity through structure-activity relationship studies. Furthermore, we identified specific substructural changes, which switched partial agonist activity to inverse agonist activity, and optimized physicochemical and DMPK properties to afford the non-CNS penetrant inverse agonist 22 (AZ-GHS-22) and the CNS penetrant inverse agonist 38 (AZ-GHS-38). Free feeding efficacy experiments showed that CNS exposure was necessary to obtain reduced food intake in mice, and it was demonstrated using GHS-R1a null and wild-type mice that this effect operates through a mechanism involving GHS-R1a. PMID:24967667

  4. Structure-activity relationships of phenylalkylamines as agonist ligands for 5-HT(2A) receptors.

    PubMed

    Blaazer, Antoni R; Smid, Pieter; Kruse, Chris G

    2008-09-01

    Agonist activation of central 5-HT(2A) receptors results in diverse effects, such as hallucinations and changes of consciousness. Recent findings indicate that activation of the 5-HT(2A) receptor also leads to interesting physiological responses, possibly holding therapeutic value. Selective agonists are needed to study the full therapeutic potential of this receptor. 5-HT(2A) ligands with agonist profiles are primarily derived from phenylalkylamines, indolealkylamines, and certain piperazines. Of these, phenylalkylamines, most notably substituted phenylisopropylamines, are considered the most selective agonists for 5-HT(2) receptors. This review summarizes the structure-activity relationships (SAR) of phenylalkylamines as agonist ligands for 5-HT(2A) receptors. Selectivity is a central theme, as is selectivity for the 5-HT(2A) receptor and for its specific signaling pathways. SAR data from receptor affinity studies, functional assays, behavioral drug discrimination as well as human studies are discussed. PMID:18666267

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

    PubMed Central

    Velázquez-Martínez, D N; López Cabrera, M; Sánchez, H; Ramírez, 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

  6. PPAR-Alpha Agonists as Novel Antiepileptic Drugs: Preclinical Findings

    PubMed Central

    Melis, Miriam; Lecca, Salvatore; Marrosu, Francesco; De Montis, Maria Graziella; Scheggi, Simona; Carta, Gianfranca; Murru, Elisabetta; Aroni, Sonia; Muntoni, Anna Lisa; Pistis, Marco

    2013-01-01

    Nicotinic acetylcholine receptors (nAChRs) are involved in seizure mechanisms. Hence, nocturnal frontal lobe epilepsy was the first idiopathic epilepsy linked with specific mutations in ?4 or ?2 nAChR subunit genes. These mutations confer gain of function to nAChRs by increasing sensitivity toward acetylcholine. Consistently, nicotine elicits seizures through nAChRs and mimics the excessive nAChR activation observed in animal models of the disease. Treatments aimed at reducing nicotinic inputs are sought as therapies for epilepsies where these receptors contribute to neuronal excitation and synchronization. Previous studies demonstrated that peroxisome proliferator-activated receptors-? (PPAR?), nuclear receptor transcription factors, suppress nicotine-induced behavioral and electrophysiological effects by modulating nAChRs containing ?2 subunits. On these bases, we tested whether PPAR? agonists were protective against nicotine-induced seizures. To this aim we utilized behavioral and electroencephalographic (EEG) experiments in C57BL/J6 mice and in vitro patch clamp recordings from mice and rats. Convulsive doses of nicotine evoked severe seizures and bursts of spike-waves discharges in ?100% of mice. A single dose of the synthetic PPAR? agonist WY14643 (WY, 80 mg/kg, i.p.) or chronic administration of fenofibrate, clinically available for lipid metabolism disorders, in the diet (0.2%) for 14 days significantly reduced or abolished behavioral and EEG expressions of nicotine-induced seizures. Acute WY effects were reverted by the PPAR? antagonist MK886 (3 mg/kg, i.p.). Since neocortical networks are crucial in the generation of ictal activity and synchrony, we performed patch clamp recordings of spontaneous inhibitory postsynaptic currents (sIPSCs) from frontal cortex layer II/III pyramidal neurons. We found that both acute and chronic treatment with PPAR? agonists abolished nicotine-induced sIPSC increases. PPAR? within the CNS are key regulators of neuronal activity through modulation of nAChRs. These effects might be therapeutically exploited for idiopathic or genetically determined forms of epilepsy where nAChRs play a major role. PMID:23724059

  7. Enemy attraction: bacterial agonists for leukocyte chemotaxis receptors.

    PubMed

    Bloes, Dominik Alexander; Kretschmer, Dorothee; Peschel, Andreas

    2015-02-01

    The innate immune system recognizes conserved microorganism-associated molecular patterns (MAMPs), some of which are sensed by G protein-coupled receptors (GPCRs), and this leads to chemotactic leukocyte influx. Recent studies have indicated that these processes are crucial for host defence and rely on a larger set of chemotactic MAMPs and corresponding GPCRs than was previously thought. Agonists, such as bacterial formyl peptides, enterococcal pheromone peptides, staphylococcal peptide toxins, bacterial fermentation products and the Helicobacter pylori peptide HP(2-20), stimulate specific GPCRs. The importance of leukocyte chemotaxis in host defence is highlighted by the fact that some bacterial pathogens produce chemotaxis inhibitors. How the various chemoattractants, receptors and antagonists shape antibacterial host defence represents an important topic for future research. PMID:25534805

  8. Choosing the right dopamine agonist for patients with Parkinson's disease.

    PubMed

    Lebrun-Frenay, C; Borg, M

    2002-01-01

    Dopamine receptor agonists (DA) are assuming an increasing importance in the treatment of both early and advanced symptoms of Parkinson's disease (PD). However, choosing the right DA for patients with PD unfortunately remains more a pragmatic medical art than a science. The aim of this review is to provide a realistic point of view on the strengths and weaknesses of five DAs: bromocriptine, ropinirole, pergolide, pramipexole and piribedil. This has been done by analysing their respective: (1) flexibility in PD, i.e. in monotherapy, in early and in late combination with levodopa; (2) safety profile and (3) titration schedule. These five DAs are not evenly matched regarding these three criteria. The differences observed highlight the therapeutic value of piribedil, which has a flexible indication, adapted to all stages of PD, a safer profile and the most simple initiation schedule. PMID:12201621

  9. Small molecule ghrelin receptor inverse agonists and antagonists.

    PubMed

    Cameron, Kimberly O; Bhattacharya, Samit K; Loomis, A Katrina

    2014-11-13

    Ghrelin is an endogenous peptide hormone secreted primarily by the stomach and is involved in a number of physiological processes including growth hormone secretion, food intake, as well as energy and glucose homeostasis. The physiological actions of ghrelin are mediated through the growth hormone secretagogue receptor 1a (ghrelin receptor), a peptidic G-protein-coupled receptor. This target has attracted much interest, as agents that block ghrelin's actions on its receptor are anticipated to be pharmaceutical interventions for a number of diseases. This review provides an overview of ghrelin biology with a focus on metabolic diseases and summarizes recent medicinal chemistry programs aimed at delivering small molecule ghrelin receptor antagonists and inverse agonists to the clinic. PMID:25036503

  10. [Safety and tolerability of GLP-1 receptor agonists].

    PubMed

    Soldevila, Berta; Puig-Domingo, Manel

    2014-01-01

    Glucagon-like peptide-1 receptor agonists (GLP-1ra) are a new group of drugs with a glucose-lowering action due to their incretin effect. The GLP-1 receptor is expressed in various human tissues, which could be related to the pleiotropic effects of human GLP-1, as well as to the adverse effects described in patients treated with GLP-1ra. The risk of hypoglycaemia is low, which is one of the main considerations in the safety of this family of compounds and is also important to patients with diabetes. The most frequent adverse effect is nausea, which usually occurs at the start of treatment and is transient in 20-60% of affected patients. This article also reviews the information available on antibody formation, the potential effect on the thyroid gland, and the controversial association between this group of drugs with pancreatitis and cancer. PMID:25326842

  11. [Safety and tolerability of GLP-1 receptor agonists].

    PubMed

    Soldevila, Berta; Puig-Domingo, Manel

    2014-09-01

    Glucagon-like peptide-1 receptor agonists (GLP-1ra) are a new group of drugs with a glucose-lowering action due to their incretin effect. The GLP-1 receptor is expressed in various human tissues, which could be related to the pleiotropic effects of human GLP-1, as well as to the adverse effects described in patients treated with GLP-1ra. The risk of hypoglycaemia is low, which is one of the main considerations in the safety of this family of compounds and is also important to patients with diabetes. The most frequent adverse effect is nausea, which usually occurs at the start of treatment and is transient in 20-60% of affected patients. This article also reviews the information available on antibody formation, the potential effect on the thyroid gland, and the controversial association between this group of drugs with pancreatitis and cancer. PMID:25437464

  12. Therapeutic potential of ?-arrestin- and G protein-biased agonists

    PubMed Central

    Whalen, Erin J.; Rajagopal, Sudarshan; Lefkowitz, Robert J.

    2013-01-01

    Members of the seven-transmembrane receptor (7TMR), or G protein-coupled receptor (GPCR), superfamily represent some of the most successful targets of modern drug therapy, with proven efficacy in the treatment of a broad range of human conditions and disease processes. It is now appreciated that ?-arrestins, once viewed simply as negative regulators of traditional 7TMR-stimulated G protein signaling, act as multifunctional adapter proteins that regulate 7TMR desensitization and trafficking and promote distinct intracellular signals in their own right. Moreover, several 7TMR biased agonists, which selectively activate these divergent signaling pathways, have been identified. Here we highlight the diversity of G protein- and ?-arrestin-mediated functions and the therapeutic potential of selective targeting of these in disease states. PMID:21183406

  13. 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

  14. Possible therapeutic application of GABAB receptor agonists and antagonists.

    PubMed

    Malcangio, M; Bowery, N G

    1995-08-01

    After their discovery within the mammalian periphery in 1981, gamma-aminobutyric acid-B (GABAB) receptors have been characterized also in the central nervous system (CNS). The highest concentrations of GABAB binding sites appear to be in the cerebellum, frontal cortex, and thalamic nuclei, where they are located on pre- and postsynaptic neurons. On activation, the primary effects appear to be membrane hyperpolarization, suppression of transmitter release, and changes in the levels of cyclic nucleotides. GABAB receptors have been implicated in a variety of neurological phenomena and, as a consequence, receptor agonists and antagonists may well have therapeutic potential. This article is an introduction to GABAB receptor pharmacology and reviews the future of the receptor ligands. Particular attention is given to the role of spinal cord GABAB receptors in chronic pain. PMID:8665542

  15. Immobilized thrombin receptor agonist peptide accelerates wound healing in mice.

    PubMed

    Strukova, S M; Dugina, T N; Chistov, I V; Lange, M; Markvicheva, E A; Kuptsova, S; Zubov, V P; Glusa, E

    2001-10-01

    To accelerate the healing processes in wound repair, attempts have been repeatedly made to use growth factors including thrombin and its peptide fragments. Unfortunately, the employment of thrombin is limited because of its high liability and pro-inflammatory actions at high concentrations. Some cellular effects of thrombin in wound healing are mediated by the activation of protease activated receptor-1 (PAR-1). The thrombin receptor agonist peptide (TRAP:SFLLRN) activates this receptor and mimics the effects of thrombin, but TRAP is a relatively weak agonist. We speculated that the encapsulated peptide may be more effective for PAR-1 activation than nonimmobilized peptide and developed a novel method for TRAP encapsulation in hydrogel films based on natural and synthetic polymers. The effects of an encapsulated TRAP in composite poly(N-vinyl caprolactam)-calcium alginate (PVCL) hydrogel films were investigated in a mouse model of wound healing. On day 7 the wound sizes decreased by about 60% under TRAP-chitosan-containing PVCL films, as compared with control films without TRAP. In the case of TRAP-polylysine-containing films no significant decrease in wound sizes was found. The fibroblast/macrophage ratio increased under TRAP-containing films on day 3 and on day 7. The number of proliferating fibroblasts increased to 150% under TRAP-chitosan films on day 7 as compared with control films. The number of [3H]-thymidine labeled endothelial and epithelial cells in granulation tissues was also enhanced. Thus, the immobilized TRAP to PVCL-chitosan hydrogel films were found to promote wound healing following the stimulation of fibroblast and epithelial cell proliferation and neovascularization. Furthermore, TRAP was shown to inhibit the secretion of the inflammatory mediator PAF from stimulated rat peritoneal mast cells due to augmentation of NO release from the mast cells. The encapsulated TRAP is suggested to accelerate wound healing due to the anti-inflammatory effects and earlier development of the proliferative phase of wound healing. PMID:11697718

  16. 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.

  17. Characterization of new PPARgamma agonists: analysis of telmisartan's structural components.

    PubMed

    Goebel, Matthias; Clemenz, Markus; Staels, Bart; Unger, Thomas; Kintscher, Ulrich; Gust, Ronald

    2009-03-01

    In addition to a proven efficacy in lowering blood pressure, the AT1 receptor blocker telmisartan has recently been shown to exert pleiotropic effects as a partial agonist of the nuclear peroxisome proliferator-activated receptor gamma (PPARgamma). Based on these findings and an excellent side-effect profile, telmisartan may serve as a lead structure for the development of new PPARgamma ligands. Therefore, we analyzed the structural components of telmisartan to identify those necessary for PPARgamma activation. Synthesized compounds were tested in a differentiation assay using 3T3-L1 preadipocytes and a luciferase assay with COS-7 cells transiently transfected with pGal4-hPPARgammaDEF, pGal5-TK-pGL3 and pRL-CMV. The data obtained in this structure-activity relationship (SAR) study provide the basis for the development of new PPARgamma ligands, which could lead to active compounds with a distinct, beneficial pharmacological profile compared with the existing full agonists. The basic 1-(biphenyl-4-ylmethyl)-1H-benzimidazole scaffold of telmisartan was identified as an essential moiety with either a carboxylic acid or tetrazole group at the C-2 position of the biphenyl. For maximum potency and activity, the alkyl chain in position 2 requires a minimum length of at least two C atoms (ethyl group), while the methyl group at position 4 of the benzimidazole core seems to contribute to partial activity. An additional benzimidazole at position 6 appears to be a further determinant of potency. Similar conclusions can be drawn for the methyl group in position 1. PMID:19197922

  18. 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 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

  19. 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

  20. PLANNING DES STAGES Dpartements

    E-print Network

    Stouls, Nicolas

    'offres PFE en laboratoire INSA de 49 jours (Peut avoir lieu en entreprise) Projets innovants Stage 20PLANNING DES STAGES Départements BIOSCIENCES : Filière Biochimie et Biotechnologies 3ère année 4ème année GENIE ENERGETIQUE ET ENVIRONNEMENT 3ère année 4ème année 5ème année Stage de 16 semaines Stage

  1. Bibliothek des indischen Parlaments

    Microsoft Academic Search

    Kaum eine prestigeträchtigere Bauaufgabe konnte in den letzten 15 Jahren in Indien ausgeschrieben werden als ein Neubau in\\u000a der Nähe der Parlamentsbauten kolonialer Vergangenheit. Ebenso wie der Auftraggeber, die Regierung, war sich der Gewinner\\u000a des Wettbewerbs, Raj Rewal, einer historischen Aufgabe bewusst, die eine sowohl zeitgemäße als auch den dominierenden Nachbarn\\u000a angemessene Lösung verlangte. Die Chance durfte nicht vertan werden,

  2. Variation and repeatability of male agonistic hiss characteristics and their relationship to social rank in Gromphadorhina portentosa

    Microsoft Academic Search

    Deborah C. Clark; Allen J. Moore

    1995-01-01

    Male Madagascar hissing cockroaches, Gromphadorhina portentosa, produce a variety of sounds or ‘hisses’ during social interactions. The agonistic signals produced during male-male competition were examined, specifically the intra- and inter-individual variation of agonistic hisses, to determine if these sounds could be reliable indicators of male rank or male size. The relationship between characteristics of the agonistic hiss and social rank

  3. 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 Márcia de Carvalho; Juruena, Mário 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

  4. Evidence for lack of modulation of mu-opioid agonist action by delta-opioid agonists in the mouse vas deferens and guinea-pig ileum.

    PubMed Central

    Elliott, J; Traynor, J R

    1995-01-01

    1. There is evidence from in vivo studies for an interaction of mu- and delta-opioid ligands. In the present work this concept has been investigated using the mouse vas deferens and guinea-pig ileum myenteric plexus-longitudinal preparations. 2. In field stimulated vasa deferentia of the mouse, co-administration of sub-effective concentrations of the delta-opioid agonist [D-Pen2,D-Pen5]enkephalin (DPDPE) and [Met5]- or [Leu5]enkephalin had no effect on the dose-response curves of the mu-agonists [D-Ala2,MePhe4, Gly-ol5]enkephalin (DAMGO) and morphine. Similarly, the delta-opioid agonists did not alter the potency of morphine and DAMGO when added at different times prior to the mu-opioid agonists, or when EC50 concentrations of delta-opioid ligands were co-administered. Compounds with preferred activity for the putative delta 1-(DPDPE) or delta 2-([D-Ala2,Glu4]deltorphin II (Delt II)) opioid receptors were ineffective in this respect. 3. The guinea-pig ileum contains delta-opioid receptors. No function of these receptors in mediating blockage of field-stimulated contractions was observed with ligands having affinity for the putative delta 1 or delta 2 subtypes nor were the agonists able to modulate responses to mu-opioid ligands in this tissue. 4. The results demonstrate the modulation of mu-opioid agonists by delta-opioid agonists does not occur in the isolated peripheral tissues examined. Thus the findings do not support the concept of a functional coupling of opioid receptors, though the results may be explained by differences between opioid systems in the brain and peripheral tissues examined. PMID:7780641

  5. Animateur 2D/3D-Illustrateur 3D Rendu des couleurs, des textures, des

    E-print Network

    Jeanjean, Louis

    spéciaux d'un produit ou d'un site grâce à des logiciels d'animation en 2D ou en 3D. Ce métier exige à la presse et l'édition, le DA élabore la charte graphique (choix des styles de caractères, taille des photos de rough (esquisse du projet) ou de story-board (scénario d'un film sous forme de BD). Il assure le

  6. Caractrisation des systmesCaractrisation des systmes industriels

    E-print Network

    Histace, Aymeric

    Chapitre 3 Caractérisation des systèmesCaractérisation des systèmes industriels Aymeric Histace 1 Plan 1. Performances d'un système industriel 2. Etude temporelle 3. Etude fréquentielleq Aymeric comment concrètement les prévoir ou les mesurer pratiquement pour un système industriel donné. Aymeric

  7. Facult des arts et des sciences Dpartement de science politique

    E-print Network

    Parrott, Lael

    Faculté des arts et des sciences Département de science politique POL6523 - Diplomatie et affaires département de science politique (responsable du cours) · Nadja Pollaert, directrice générale, Fondation Paul System," in P. Kerr and G. Wiseman (dir) Diplomacy in a Globalizing World: Theories and Practices. New

  8. Modlisation multivarie des comportements risque des conducteurs d'automobile

    E-print Network

    Paris-Sud XI, Université de

    ~ 1 ~ Modélisation multivariée des comportements à risque des conducteurs d'automobile Mériem la probabilité de l'utilisation du téléphone portable au volant. Mots clés : Assurance automobile of phoning while driving. Key words: Car insurance, risky behavior, survey, trivariate probit model

  9. Expos de synthse Etude immunochimique des molcules du CMH des

    E-print Network

    Boyer, Edmond

    Exposé de synthèse Etude immunochimique des molécules du CMH des bovins (BoLA) D. Levy, J. Goyeneche C. Demeulemester M. Baquero INRA, Ecole Nationale Vétérinaire, laboratoire pathologie et'histocompatibilité - réunion scientifique - structure - fonction Bovine CMH (BoLA) molecules : immunochemical study major

  10. The glycine transport inhibitor sarcosine is an NMDA receptor co-agonist that differs from glycine

    PubMed Central

    Zhang, Hai Xia; Hyrc, Krzysztof; Thio, Liu Lin

    2009-01-01

    Sarcosine is an amino acid involved in one-carbon metabolism and a promising therapy for schizophrenia because it enhances NMDA receptor (NMDAR) function by inhibiting glycine uptake. The structural similarity between sarcosine and glycine led us to hypothesize that sarcosine is also an agonist like glycine. We examined this possibility using whole-cell recordings from cultured embryonic mouse hippocampal neurons. We found that sarcosine is an NMDAR co-agonist at the glycine binding site. However, sarcosine differed from glycine because less NMDAR desensitization occurred with sarcosine than with glycine as the co-agonist. This finding led us to examine whether the physiological effects of NMDAR activation with these two co-agonists are the same. The difference in desensitization probably accounts for rises in intracellular Ca2+, as assessed by the fluorescent indicator fura-FF, being larger when NMDAR activation occurred with sarcosine than with glycine. In addition, Ca2+-activated K+ currents following NMDAR activation were larger with sarcosine than with glycine. Compared to glycine, NMDAR-mediated autaptic currents decayed faster with sarcosine suggesting that NMDAR deactivation also differs with these two co-agonists. Despite these differences, NMDAR-dependent neuronal death as assessed by propidium iodide was similar with both co-agonists. The same was true for neuronal bursting. Thus, sarcosine may enhance NMDAR function by more than one mechanism and may have different effects from other NMDAR co-agonists. PMID:19433577

  11. Combination corticosteroid/?-agonist inhaler as reliever therapy: a solution for intermittent and mild asthma?

    PubMed

    Beasley, Richard; Weatherall, Mark; Shirtcliffe, Philippa; Hancox, Robert; Reddel, Helen K

    2014-01-01

    The recommended treatment of mild asthma is regular maintenance inhaled corticosteroids (ICSs) with a short-acting ?-agonist as a separate inhaler used when needed for symptom relief. However, the benefits of regular ICS use in actual clinical practice are limited by poor adherence and low prescription rates. An alternative strategy would be the symptom-driven (as-required or "prn") use of a combination ICS/short-acting ?-agonist or ICS/long-acting ?-agonist inhaler as a reliever rather than regular maintenance use. The rationale for this approach is to titrate both the ICS and ?-agonist dose according to need and enhance ICS use in otherwise poorly adherent patients who overrely on their reliever ?-agonist inhaler. This strategy will only work if the ?-agonist component has a rapid onset of action for symptom relief. There is evidence to suggest that this regimen has advantages over regular ICS therapy and might represent an effective, safe, and novel therapy for the treatment of intermittent and mild asthma. In this commentary we review this evidence and propose that randomized controlled trials investigating different combination ICS/?-agonist inhaler products prescribed according to this regimen in intermittent and mild asthma are an important priority. PMID:24369798

  12. A cholecystokinin agonist/antagonist according to dose and time of action: effect on food intake.

    PubMed

    Gourch, A; Orosco, M; Rodriguez, M; Martinez, J; Jacquot, C; Cohen, Y

    1990-12-01

    A new CCK pseudopeptide (Boc-Tyr (SO3)-Nle-psi-(COCH2) Gly-Trp-Nle-Asp-Phe-NH2) has been described in a previous study as a potent CCK agonist in the peripheral system and as an antagonist in the central nervous system. When administered alone by a peripheral route, this pseudopeptide was found to decrease food intake in free/feeding rats, and thus behaved as a CCK agonist. However, it reversed the decreased feeding effect induced by a full potent agonist (Boc(Nle 28-Nle 31)-CCK26-33). This antagonistic action occurred 3-4 h after treatment, at a time when the agonistic properties of the pseudopeptide alone had disappeared, but when the effect of the full potent agonist remained. The dose-response curve of the antagonistic action was bell-shaped. These results suggest that this new pseudopeptide is not only agonistic in the periphery and antagonistic in the central nervous system as shown in the previous study, but is also both agonistic and antagonistic on the same paradigm according to the dose and time of action. PMID:2093151

  13. ?2-Adrenergic agonists and the treatment of skeletal muscle wasting disorders.

    PubMed

    Joassard, Olivier R; Durieux, Anne-Cécile; Freyssenet, Damien G

    2013-10-01

    ?2-Agonists are traditionally used for the treatment of bronchospasm associated with asthma and the treatment of symptomatic patients with COPD. However, ?2-agonists are also powerful anabolic agents that trigger skeletal muscle hypertrophy. Investigating the effects of ?2-agonists in skeletal muscle over the past 30 years in different animal models has led to the identification of potential therapeutic applications in several muscle wasting disorders, including neuromuscular diseases, cancer cachexia, sepsis or thermal injury. In these conditions, numerous studies indicate that ?2-agonists can attenuate and/or reverse the decrease in skeletal muscle mass and associated weakness in animal models of muscle wasting but also in human patients. The purpose of this review is to present the biological and clinical significance of ?2-agonists for the treatment of skeletal muscle wasting. After the description of the molecular mechanisms involved in the hypertrophy and anti-atrophy effect of ?2-agonists, we will review the anti-atrophy effects of ?2-agonist administration in several animal models and human pathologies associated with or leading to skeletal muscle wasting. This article is part of a Directed Issue entitled: Molecular basis of muscle wasting. PMID:23845739

  14. Cannabinoid Discrimination and Antagonism by CB1 Neutral and Inverse Agonist Antagonists

    PubMed Central

    Delatte, Marcus S.; Vemuri, V. Kiran; Thakur, Ganesh A.; Nikas, Spyridon P.; Subramanian, Kumara V.; Shukla, Vidyanand G.; Makriyannis, Alexandros; Bergman, Jack

    2013-01-01

    Cannabinoid receptor 1 (CB1) inverse agonists (e.g., rimonabant) have been reported to produce adverse effects including nausea, emesis, and anhedonia that limit their clinical applications. Recent laboratory studies suggest that the effects of CB1 neutral antagonists differ from those of such inverse agonists, raising the possibility of improved clinical utility. However, little is known regarding the antagonist properties of neutral antagonists. In the present studies, the CB1 inverse agonist SR141716A (rimonabant) and the CB1 neutral antagonist AM4113 were compared for their ability to modify CB1 receptor–mediated discriminative stimulus effects in nonhuman primates trained to discriminate the novel CB1 full agonist AM4054. Results indicate that AM4054 serves as an effective CB1 discriminative stimulus, with an onset and time course of action comparable with that of the CB1 agonist ?9-tetrahydrocannabinol, and that the inverse agonist rimonabant and the neutral antagonist AM4113 produce dose-related rightward shifts in the AM4054 dose-effect curve, indicating that both drugs surmountably antagonize the discriminative stimulus effects of AM4054. Schild analyses further show that rimonabant and AM4113 produce highly similar antagonist effects, as evident in comparable pA2 values (6.9). Taken together with previous studies, the present data suggest that the improved safety profile suggested for CB1 neutral antagonists over inverse agonists is not accompanied by a loss of antagonist action at CB1 receptors. PMID:23287700

  15. Toll-like receptor agonists in the treatment of chronic lymphocytic leukemia.

    PubMed

    Spaner, D E; Masellis, A

    2007-01-01

    Advances in our understanding of the Toll-like receptors (TLRs) have led to the identification of several agonists that are suitable for clinical development. Chronic lymphocytic leukemia (CLL) may be especially amenable to TLR agonists because it is an immunologically susceptible tumor with strong expression of several TLRs, particularly TLR-7 and TLR-9. TLR agonists may indirectly clear CLL cells by enhancing the activity of natural killer and tumor-reactive T cells, or by altering the tumor microenvironment and inhibiting angiogenesis. However, signaling pathways can be activated directly in CLL cells by TLR-7 and TLR-9 agonists, leading to the production of cytokines and costimulatory molecules in a manner that is dependent on the underlying cytogenetic abnormalities, but rendering the tumor cells more sensitive to killing by cytotoxic T cells, immunotoxins and some chemotherapeutic drugs. Imidazoquinolines are TLR-7 agonists with strong local activity against CLL, and phase I trials of systemically administered imidazoquinolines (and also cytosine-phosphate-guanosine oligonucleotides that are TLR-9 agonists) are currently ongoing at different centers. The potential importance of these TLR agonists in the treatment of CLL is suggested by their ability to sensitize tumor cells to cytotoxic agents, and their future probably lies in combination with radiotherapies, chemotherapies, monoclonal antibodies and cancer vaccines. PMID:17066089

  16. CB1 Receptor Allosteric Modulators Display Both Agonist and Signaling Pathway Specificity

    PubMed Central

    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.

    2013-01-01

    We have previously identified allosteric modulators of the cannabinoid CB1 receptor (Org 27569, PSNCBAM-1) that display a contradictory pharmacological profile: increasing the specific binding of the CB1 receptor agonist [3H]CP55940 but producing a decrease in CB1 receptor agonist efficacy. Here we investigated the effect one or both compounds in a broad range of signaling endpoints linked to CB1 receptor activation. We assessed the effect of these compounds on CB1 receptor agonist–induced [35S]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 CB1 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 [3H]WIN55212 binding. Org 27569 displays biased antagonism whereby it inhibits: agonist-induced guanosine 5?-O-(3-[35S]thio)triphosphate ([35S]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 CB1 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

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

    SciTech Connect

    Matsushita, Akitomo; Ohtsubo, Sena; Fujita, Tsugumi; Kumamoto, Eiichi, E-mail: kumamote@cc.saga-u.ac.jp

    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-?-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.

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

    PubMed

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

    2015-03-01

    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

  19. 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.

  20. [Treatment of paraphilia and sexually aggressive impulsive behavior with the LHRH-agonist leuprolide acetate].

    PubMed

    Briken, P; Berner, W; Noldus, J; Nika, E; Michl, U

    2000-05-01

    Up to now there are no published results of therapy of paraphilia (Pedophilia, Sadism) and sexual aggressive impulsiveness with LHRH-(luteinizing hormone-releasing hormone) Agonists in the Germanspeaking countries. In this report we describe 11 patients which were treated with the LHRH-Agonist Leuprolide Acetate in a period of 12 months. The patients showed no tendency of sexual aggressive behaviour and reported an evident reduction of penile erection, ejaculation, masturbation, sexual deviant impulsiveness and fantasies. One patient died from suicide. In combination with other treatments LHRH-Agonists seem to be a very promising alternative to cyproterone acetate and its possible carcinogene effects. PMID:10846713

  1. GABAB receptor agonist baclofen improves methamphetamine-induced cognitive deficit in mice.

    PubMed

    Arai, Sawako; Takuma, Kazuhiro; Mizoguchi, Hiroyuki; Ibi, Daisuke; Nagai, Taku; Kamei, Hiroyuki; Kim, Hyoung-Chun; Yamada, Kiyofumi

    2009-01-01

    In this study, we investigated the effects of GABA(A) and GABA(B) receptor agonists on the methamphetamine-induced impairment of recognition memory in mice. Repeated treatment with methamphetamine at a dose of 1 mg/kg for 7 days induced an impairment of recognition memory. Baclofen, a GABA(B) receptor agonist, ameliorated the repeated methamphetamine-induced cognitive impairment, although gaboxadol, a GABA(A) receptor agonist, had no significant effect. GABA(B) receptors may constitute a putative new target in treating cognitive deficits in patients suffering from schizophrenia, as well as methamphetamine psychosis. PMID:19028488

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

    PubMed

    Lüchinger, 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

  3. LABORATOIRE DE PHYSIQUE DES SOLIDES

    E-print Network

    Paris-Sud 11, Université de

    LABORATOIRE DE PHYSIQUE DES SOLIDES UMR 8502 Centre Universitaire, Bât. 510 91405 Orsay cedex) 212503. #12;LABORATOIRE DE PHYSIQUE DES SOLIDES UMR 8502 Centre Universitaire, Bât. 510 91405 Orsay cedex fundamental fine particle magnetism utilizing colloidal dispersions or ferrofluids as the medium for study

  4. STRUCTURE ET DFAUTS DES NANOTUBES

    E-print Network

    Paris-Sud 11, Université de

    STRUCTURE ET D�FAUTS DES NANOTUBES Pascale Launois Laboratoire de Physique des Solides (UMR CNRS://www.lps.u-psud.fr/Collectif/gr_23/themes/fullnano/en_fullnano.htm http://www.lps.u-psud.fr/Utilisateurs/launois/ PLAN 1. Nanotubes de carbone Structure Défauts Arrangement Autres nanofilaments 2. Nanotubes hétéroatomiques #12

  5. Ageismus – Sprachliche Diskriminierung des Alters

    Microsoft Academic Search

    Undine Kramer

    Daniel Sanders, einer der bedeutendsten Lexikografen des 19. Jahrhunderts, wertete für sein Wörterbuch Quellen seit der Lutherzeit aus und\\u000a vermerkt im Wörterbuchartikel zu alt eine „bald lobende, bald tadelnde“ Bedeutung des Adjektivs. Sein Zeit- und Berufsgenosse Jacob Grimm benennt in seiner Rede über das Alter die zeitgenössischen Synonyme zu alt und Alter: „aus einheimischen schriftstellern liesze sich eine lange reihe

  6. DEFORMATIONS EQUIVARIANTES DES COURBES SEMISTABLES

    E-print Network

    Di Girolami, Cristina

    - portement par d´eformation des points du bord, les rev^etements stables. Il est fortement souhaitable de description heuristique des points du bord, et leur comportement par d´eformation. Par exemple, peut-on donner 2, on examine les probl`emes globaux, plus particuli`erement les interactions entre les obstructions

  7. Fonctionnement et restauration des milieux

    E-print Network

    Sart, Remi

    préservation, la restauration et la valorisation des écosystèmes aquatiques ou à l'exercice des métiers de la fonctionnelle, biologie cellulaire et moléculaire, physiologie, écophysiologie, écologie), mais aussi de chimie

  8. des doublcls ainsi forms devraient tre plus petites que la vitesse des rayons B, de mme celles des

    E-print Network

    Paris-Sud XI, Université de

    88 des doublcls ainsi formés devraient être plus petites que la vitesse des rayons B, de même celles des rayons secondaires qu'ils libèrent en se brisant. Ceci est en désaccord avec les expériences des rayons B qui donnent naissance à ces pulsations, La théorie du professeur Thomson supprime cette

  9. Comptes Rendus des JNC 16 Toulouse 2009 Essais et simulations des mes Nomex sous des sollicitations de type

    E-print Network

    Paris-Sud XI, Université de

    Comptes Rendus des JNC 16 Toulouse 2009 Essais et simulations des âmes Nomex sous des sollicitations de type statique et fatigue Experimental tests and prediction of Nomex cores under statique en cisaillement hors plan des âmes nids d'abeilles Nomex® lors de sollicitations de fatigue. La

  10. Qualit germinative des semences de pois -I. Dveloppement de la gousse et des graines

    E-print Network

    Paris-Sud XI, Université de

    Qualité germinative des semences de pois - I. Développement de la gousse et des graines : incidences sur la germination des semences avec ou sans séchage Zohreh RACHIDIAN Yvon LE DEUNFF Institut étapes ; à chacune peuvent être asso- ciés des événements dans la croissance des graines. La germination

  11. Rapid modulation of synaptic plasticity by estrogens as well as endocrine disrupters in hippocampal neurons

    E-print Network

    Kawato, Suguru

    disrupter Estrogen receptor Synaptic plasticity Bisphenol A B R A I N R E S E A R C H R E V I E W S 5 7 ( 2, bisphenol A; CNQX, cyano-nitroquinoxaline-dione; DES, diethylstilbestrol; DPN, diarylpropionitrile; LTD found to significantly modulate LTD and spinogenesis. Bisphenol A (BPA) and diethylstilbestrol (DES

  12. Phytoestrogens are partial estrogen agonists in the adult male mouse.

    PubMed Central

    Mäkelä, S; Santti, R; Salo, L; McLachlan, J A

    1995-01-01

    The intake, as well as serum and urinary concentrations, of phytoestrogens is high in countries where incidence of prostate cancer is low, suggesting a chemopreventive role for phytoestrogens. Their significance could be explained by the ability to antagonize the action of more potent endogenous estrogens in initiation or promotion of tumor formation. We have studied estrogenicity and antiestrogenicity of dietary soy and two phytoestrogens, coumestrol and daidzein, in our neoDES mouse model for the study or prostatic neoplasia. Soy was chosen because it is rich in phytoestrogens, is widely used in Oriental diets, and has antiestrogenic and anticarcinogenic properties in the neoDES mouse when given from fertilization onward. In short-term tests with adult animals, no evidence for estrogenicity or antiestrogenicity (capability to antagonize the action of 17 beta-estradiol) of soy was found when development of epithelial metaplasia and expression of c-fos protooncogene in prostate were used as end points of estrogen action. Estrogenic activity of coumestrol and daidzein on c-fos expression was subtle. Coumestrol, either given alone or in combination with 17 beta-estradiol, had no effect on development of epithelial metaplasia. These marginal or missing effects in adult males could be interpreted by assuming that the neonatal period is more critical for estrogenic or antiestrogenic action of soy and phytoestrogens. Once initiated, estrogen-related lesions would develop spontaneously. Alternatively, the chemopreventive action of soy is not due to antiestrogenicity of soy-derived phytoestrogens. Images Figure 1. Figure 2. PMID:8593857

  13. Peste des petits ruminants.

    PubMed

    Lefèvre, P C; Diallo, A

    1990-12-01

    The peste des petits ruminants (PPR) is proving to be a disease which has an increasingly significant economic impact on a number of countries in Africa and the Middle East, and possibly also on the Indian sub-continent. The antigenic relationships which exist between the PPR and rinderpest viruses pose problems for diagnosis which complicates rinderpest control and eradication programmes. Progress has recently been made in regard to diagnosis (specific nucleic probes and monoclonal antibodies), as well as control (homologous vaccine). International legislation remains to be established and epidemiological surveys should be conducted in order to determine the exact geographical distribution of the disease. PMID:2132714

  14. Des Moines Water Works

    NSDL National Science Digital Library

    2001-01-01

    Users can access information about educational programs and materials for teachers and students, including tours, traveling exhibits and presentations by the staff of the Des Moines Water Works. "Water Trunks", which contain water-related literature, books, science experiments, videos, games, CD-ROMs, hands-on activities, picture cards, career information, and a teacher resource book, are available to order. There are also links to other water websites, a teachers' newsletter and pollution prevention tips for classroom use and for the general public.

  15. 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

  16. NEUROMARKETING ET NEUROSCIENCES AU SERVICE DES PUBLICITAIRES

    E-print Network

    Paris-Sud XI, Université de

    1 NEUROMARKETING ET NEUROSCIENCES AU SERVICE DES PUBLICITAIRES : QUESTIONNEMENTS ETHIQUES Didier neuromarketing et des neurosciences au service des publicitaires soulève immanquablement des questions éthiques débats éthiques entre les personnes adeptes du neuromarketing (les "pro-neuromarketing") et les "anti-neuromarketing

  17. Analyse thermographique du comportement des matriaux

    E-print Network

    Boyer, Edmond

    transfert et de traitement des images infrarouges, rendant plus conviviale l'utilisation des nouveaux de degré Celsius. L'intérêt de la thermographie pour le mécanicien vient du fait que la déformation d traitement des données infrarouges. En effet, cette analyse s'appuie sur une mesure des effets (les

  18. MINES ParisTech Centre des Matriaux

    E-print Network

    Paris-Sud XI, Université de

    instructions scientifiques, des conseils concrets, des encouragements et pour ´etaient tr`es patience et compr´eaires pour la r´ealisation de diff´erents ´equipements. Soumis `a une irradiation neutronique induite par le parti- culier l'apparition de d´efauts d'irradiation comme des boucles interstitielles, des amas

  19. DTERMINATION QUANTITATIVE DES DENSITS LEVES DES DISLOCATIONS DANS DES MONOCRISTAUX DE GERMANIUM

    E-print Network

    Boyer, Edmond

    GERMANIUM PAR DIFFUSION D'ATOMES MARQUÉS Par MAREK BRAFMAN, OLGA KRUSZEWSKA, WALDEMAR WRONSKI et KAROL'exemple des monocristaux de germanium et comparaison des résultats obtenus avec les mêmes déterminations measurement of the density of the autoradio- grams. The method is illustrated by example of germanium

  20. 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...

  1. The pharmacokinetics of Toll-like receptor agonists and the impact on the immune system

    PubMed Central

    Engel, Abbi L; Holt, Gregory E; Lu, Hailing

    2011-01-01

    Toll-like receptor (TLR) ligation activates both the innate and adaptive immune systems, and plays an important role in antiviral and anti-tumor immunity. Therefore, a significant amount of effort has been devoted to exploit the therapeutic potential of TLR agonists. Depending on the therapeutic purpose, either as adjuvants to vaccine, chemotherapy or standalone therapy, TLR agonists have been administered via different routes. Both preclinical and clinical studies have suggested that the route of administration has significant effects on pharmacokinetics, and that understanding these effects is critical to the success of TLR agonist drug development. This article will summarize the pharmacokinetics of TLR agonists with different administration routes, with an emphasis on clinical studies of TLR ligands in oncologic applications. PMID:21643519

  2. Pleuropulmonary fibrosis after long-term treatment with the dopamine agonist pergolide for Parkinson Disease.

    PubMed

    Tintner, Ron; Manian, Prasad; Gauthier, Polly; Jankovic, Joseph

    2005-08-01

    Dopamine agonists are increasingly used in the treatment of Parkinson disease, but they may cause serious adverse effects. In December 1983, symptoms of Parkinson disease developed in a 55-year-old man with no history of pulmonary disease, smoking, or asbestos exposure. He began treatment with dopamine agonists bromocriptine mesylate (in 1984) and pergolide mesylate (in 1989). In late 2000, pulmonary symptoms developed. Chest radiographs and computed tomographic findings showed a mass in the right upper lobe and effusion. A biopsy specimen showed pleural and parenchymal fibrosis. This syndrome resolved after cessation of pergolide therapy and a switch to pramipexole dihydrochloride. This case draws attention to the association of long-term ergot dopamine agonist therapy with pleuropulmonary fibrosis, which can develop as late as 11 years after the initiation of therapy. We also review evidence that the risk of this complication is substantially lower with the newer nonergot dopamine agonists. PMID:16087771

  3. 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

  4. Identification of novel multitargeted PPAR?/?/? pan agonists by core hopping of rosiglitazone

    PubMed Central

    Wang, Xue-Jiao; Zhang, Jun; Wang, Shu-Qing; Xu, Wei-Ren; Cheng, Xian-Chao; Wang, Run-Ling

    2014-01-01

    The thiazolidinedione class peroxisome proliferator-activated receptor gamma (PPAR?) agonists are restricted in clinical use as antidiabetic agents because of side effects such as edema, weight gain, and heart failure. The single and selective agonism of PPAR? is the main cause of these side effects. Multitargeted PPAR?/?/? pan agonist development is the hot topic in the antidiabetic drug research field. In order to identify PPAR?/?/? pan agonists, a compound database was established by core hopping of rosiglitazone, which was then docked into a PPAR?/?/? active site to screen out a number of candidate compounds with a higher docking score and better interaction with the active site. Further, absorption, distribution, metabolism, excretion, and toxicity prediction was done to give eight compounds. Molecular dynamics simulation of the representative Cpd#1 showed more favorable binding conformation for PPARs receptor than the original ligand. Cpd#1 could act as a PPAR?/?/? pan agonist for novel antidiabetic drug research. PMID:25422585

  5. Multivalent design of long-acting ?(2)-adrenoceptor agonists incorporating biarylamines.

    PubMed

    Jacobsen, John R; Aggen, James B; Church, Timothy J; Klein, Uwe; Pfeiffer, Juergen W; Pulido-Rios, Teresa M; Thomas, G Roger; Yu, Cecile; Moran, Edmund J

    2014-06-15

    A series of potent ?2-adrenoceptor agonists incorporating a biarylamine secondary binding group was identified. The previously reported milveterol (5), identified by a multivalent approach and containing a typical ?2-agonist primary binding group linked via a phenethylamine linker to a hydrophilic secondary binding group, served as an initiation point. A more hydrophobic set of secondary binding groups was explored, prepared rapidly from a common intermediate by Buchwald-Hartwig amination. TD-5471 (25), a potent and selective full agonist of the human ?2-adrenoceptor, was identified as the most promising agent. It is potent, with slow onset in an in vitro guinea pig trachea model and shows a dose-dependent and long duration of action in an in vivo guinea pig model of bronchoprotection. TD-5471 is structurally differentiated from milveterol and its long duration of action is consistent with a correlation with hydrophobicity observed in other long-acting ?2-agonist discovery programs. PMID:24813741

  6. Novel hedgehog agonists promote osteoblast differentiation in mesenchymal stem cells.

    PubMed

    Nakamura, Takashi; Naruse, Masahiro; Chiba, Yuta; Komori, Toshihisa; Sasaki, Keiichi; Iwamoto, Masahiro; Fukumoto, Satoshi

    2015-04-01

    Hedgehog (Hh) family members are involved in multiple cellular processes including proliferation, migration, differentiation, and cell fate determination. Recently, the novel Hh agonists Hh-Ag 1.3 and 1.7 were identified in a high-throughput screening of small molecule compounds that activate the expression of Gli1, a target of Hh signaling. This study demonstrates that Hh-Ag 1.3 and 1.7 strongly activate the expression of endogenous Gli1 and promote osteoblast differentiation in the mesenchymal stem cell line C3H10T1/2. Both compounds stimulated alkaline phosphatase activity in a dose-dependent manner, and induced osteoblast marker gene expression in C3H10T1/2 cells, which indicated that they had acquired an osteoblast identity. Of the markers, the expression of osterix/Sp7, a downstream target of runt-related transcription factor (Runx)2, was induced by Hh-Ag 1.7, which also rescued the osteoblast differentiation defect of RD-127, a mesenchymal cell line from Runx2-deficient mice. Hh-Ags also activated canonical Wnt signaling and synergized with low doses of BMP-2 to enhance osteoblastic potential. Thus, Hh-Ag 1.7 could be useful for bone healing in individuals with abnormalities in osteogenesis, such as osteoporosis patients and the elderly, and can contribute to the development of novel therapeutics for the treatment of bone fractures and defects. PMID:25215620

  7. The vanilloid agonist resiniferatoxin for interventional-based pain control.

    PubMed

    Iadarola, Michael J; Mannes, Andrew J

    2011-01-01

    The idea of selectively targeting nociceptive transmission at the level of the peripheral nervous system is attractive from multiple perspectives, particularly the potential lack of non-specific (non-targeted) CNS side effects. Out of the multiple TRP channels involved in nociception, TRPV1 is a strong candidate based on its biophysical conductance properties and its expression in inflammation-sensitive dorsal root ganglion neurons and their axons and central and peripheral nerve terminals. While TRPV1 antagonists have undergone extensive medicinal chemical and pharmacological investigation, for TRPV1 agonists nature has provided an optimized compound in RTX. RTX is not suitable for systemic administration, but it is highly adaptable to a variety of pain problems when used by local administration. This can include routes as diverse as subcutaneous, intraganglionic or intrathecal (CSF space around the spinal cord). The present review focuses on the molecular and preclinical animal experiments that form the underpinnings of our clinical trial of intrathecal RTX for pain in advanced cancer. As such this represents a new approach to pain control that emerges from a long line of research on capsaicin and other vanilloids, their physiological actions, and the molecular biology of the capsaicin receptor TRPV1. PMID:21671877

  8. The effect of fenoldopam, a dopaminergic agonist, on renal hemodynamics.

    PubMed

    Allison, N L; Dubb, J W; Ziemniak, J A; Alexander, F; Stote, R M

    1987-03-01

    Fenoldopam, a dopaminergic agonist, was administered intravenously to 18 healthy male subjects in doses ranging from 0.025 to 1.0 microgram/kg/min for 2 hours. Three subjects were studied in a three-way crossover of fenoldopam at doses of 0.025, 0.10, and 0.50 microgram/kg/min. Fenoldopam decreased diastolic blood pressure and increased pulse rate without changing systolic blood pressure. Fenoldopam produced dose-related increases in para-aminohippuric acid clearance up to 75% at the 0.50 microgram/kg/min dose. This increase in renal blood flow was accompanied by increases in urine volume, water, and solute excretion; glomerular filtration rate was unchanged. Doses greater than 0.25 microgram/kg/min caused flushing and nasal congestion. The dopamine receptor antagonist metoclopramide (0.1 mg/kg/hr) did not block the systemic hemodynamic effects of fenoldopam but attenuated the increase in para-aminohippuric acid clearance. Fenoldopam plasma levels achieved steady state between 30 and 120 minutes after the start of the infusion and were linear with respect to infusion rate. Our findings show that intravenous fenoldopam causes systemic arteriolar vasodilation, accompanied by renal vasodilation and increased sodium excretion. PMID:2880688

  9. 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

  10. The Vanilloid Agonist Resiniferatoxin for Interventional-Based Pain Control

    PubMed Central

    Iadarola, Michael J.; Mannes, Andrew J.

    2012-01-01

    The idea of selectively targeting nociceptive transmission at the level of the peripheral nervous system is attractive from multiple perspectives, particularly the potential lack of non-specific (non-targeted) CNS side effects. Out of the multiple TRP channels involved in nociception, TRPV1 is a strong candidate based on its biophysical conductance properties and its expression in inflammation-sensitive dorsal root ganglion neurons and their axons and central and peripheral nerve terminals. While TRPV1 antagonists have undergone extensive medicinal chemical and pharmacological investigation, for TRPV1 agonists nature has provided an optimized compound in RTX. RTX is not suitable for systemic administration, but it is highly adaptable to a variety of pain problems when used by local administration. This can include routes as diverse as subcutaneous, intraganglionic or intrathecal (CSF space around the spinal cord). The present review focuses on the molecular and preclinical animal experiments that form the underpinnings of our clinical trial of intrathecal RTX for pain in advanced cancer. As such this represents a new approach to pain control that emerges from a long line of research on capsaicin and other vanilloids, their physiological actions, and the molecular biology of the capsaicin receptor TRPV1. PMID:21671877

  11. 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.

  12. Sleep problems reported by patients entering opioid agonist treatment

    PubMed Central

    Burke, Christopher K.; Peirce, Jessica M.; Kidorf, Michael S.; Neubauer, David; Punjabi, Naresh M.; Stoller, Kenneth B.; Hursh, Steve; Brooner, Robert K.

    2008-01-01

    Treatment-seeking opioid dependent individuals frequently report sleep-related problems (Dyer & White, 1997; Puigdollers et al., 2004). The present study provides a detailed assessment of sleep duration and quality in this population, including their effect on daily functioning and relationship to psychiatric severity and drug use. New admissions to opioid-agonist maintenance treatment (n = 113) completed a series of questionnaires to assess sleep functioning, psychiatric severity, and drug use due to sleep problems over the past 30-days. The results showed that study participants reported considerable sleep-related difficulties that had little effect on their appraisals of daily functioning. Nevertheless, sleep problems were associated with psychiatric distress, and those reporting substance use specifically to increase or decrease sleepiness endorsed more sleep problems and lower levels of daily functioning. Overall, these results replicate and extend previous work showing poor sleep functioning in this population, and show that sleep problems are associated with variables that often have an adverse impact on substance abuse treatment outcome. PMID:18248944

  13. Neurotensin Agonist Attenuates Nicotine Potentiation to Cocaine Sensitization

    PubMed Central

    Fredrickson, Paul; Boules, Mona; Stennett, Bethany; Richelson, Elliott

    2014-01-01

    Tobacco usage typically precedes illicit drug use in adolescent and young adult populations. Several animal studies suggest nicotine increases the risk for subsequent cocaine abuse, and may be a negative prognostic factor for treatment of cocaine addiction; i.e., a “gateway drug”. Neurotensin (NT) is a 13-amino acid neuropeptide that modulates dopamine, acetylcholine, glutamate, and GABA neurotransmission in brain reward pathways. NT69L, a NT(8-13) analog, blocks behavioral sensitization (an animal model for psychostimulant addiction) to nicotine, and nicotine self-administration in rats. The present study tested the effect of NT69L on the potentiating effects of nicotine on cocaine-induced locomotor sensitization. Male Wistar rats were injected daily for seven days with nicotine or saline (control) followed by four daily injections of cocaine. NT69L was administered 30 min prior to the last cocaine injection. Behavior was recorded with the use of activity chambers. Subchronic administration of nicotine enhanced cocaine-induced behavioral sensitization in Wistar rats, consistent with an hypothesized gateway effect. These behavioral effects of cocaine were attenuated by pretreatment with NT69L. The effect of the neurotensin agonist on cocaine sensitization in the nicotine treated group indicated a possible therapeutic effect for cocaine addiction, even in the presence of enhanced behavioral sensitization induced by nicotine. PMID:25379267

  14. 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

  15. 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

  16. Intracellular calcium strongly potentiates agonist-activated TRPC5 channels

    PubMed Central

    Blair, Nathaniel T.; Kaczmarek, J. Stefan

    2009-01-01

    TRPC5 is a calcium (Ca2+)-permeable nonselective cation channel expressed in several brain regions, including the hippocampus, cerebellum, and amygdala. Although TRPC5 is activated by receptors coupled to phospholipase C, the precise signaling pathway and modulatory signals remain poorly defined. We find that during continuous agonist activation, heterologously expressed TRPC5 currents are potentiated in a voltage-dependent manner (?5-fold at positive potentials and ?25-fold at negative potentials). The reversal potential, doubly rectifying current–voltage relation, and permeability to large cations such as N-methyl-d-glucamine remain unchanged during this potentiation. The TRPC5 current potentiation depends on extracellular Ca2+: replacement by Ba2+ or Mg2+ abolishes it, whereas the addition of 10 mM Ca2+ accelerates it. The site of action for Ca2+ is intracellular, as simultaneous fura-2 imaging and patch clamp recordings indicate that potentiation is triggered at ?1 µM [Ca2+]. This potentiation is prevented when intracellular Ca2+ is tightly buffered, but it is promoted when recording with internal solutions containing elevated [Ca2+]. In cell-attached and excised inside-out single-channel recordings, increases in internal [Ca2+] led to an ?10–20-fold increase in channel open probability, whereas single-channel conductance was unchanged. Ca2+-dependent potentiation should result in TRPC5 channel activation preferentially during periods of repetitive firing or coincident neurotransmitter receptor activation. PMID:19398778

  17. Competitive molecular docking approach for predicting estrogen receptor subtype ? 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 ER?, 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

  18. Sécurité au-delà des mythes et des croyances

    ScienceCinema

    None

    2011-10-06

    Présentation orale en français, support visuel en français et en anglais. La pire des failles de sécurité est l'impression de sécurité. Le décalage entre la compréhension que l?on a des technologies utilisées, et leurs potentiels réels, ainsi que l'impact potentiellement négatif qu'elles peuvent avoir sur nos vies, n'est pas toujours compris, ou pris en compte par la plupart d'entre-nous. On se contente de nos perceptions pour ne pas avoir à se confronter à la réalité... Alors qu'en est-il vraiment ? En matière de sécurité qui de l'humain ou des technologies a le contrôle ?

  19. Sécurité au-delà des mythes et des croyances

    SciTech Connect

    None

    2010-06-24

    Présentation orale en français, support visuel en français et en anglais. La pire des failles de sécurité est l'impression de sécurité. Le décalage entre la compréhension que l’on a des technologies utilisées, et leurs potentiels réels, ainsi que l'impact potentiellement négatif qu'elles peuvent avoir sur nos vies, n'est pas toujours compris, ou pris en compte par la plupart d'entre-nous. On se contente de nos perceptions pour ne pas avoir à se confronter à la réalité... Alors qu'en est-il vraiment ? En matière de sécurité qui de l'humain ou des technologies a le contrôle ?

  20. Novel serotonin type 3 receptor partial agonists for the potential treatment of irritable bowel syndrome

    Microsoft Academic Search

    David D. Manning; Christopher L. Cioffi; Alexander Usyatinsky; Kevin Fitzpatrick; Liaqat Masih; Cheng Guo; Zhenjun Zhang; Sok Hui Choo; M. Inthikhab Sikkander; Kristen N. Ryan; Jennifer Naginskaya; Carla Hassler; Svetlana Dobritsa; Jonathan D. Wierschke; William G. Earley; Amy S. Butler; Catherine A. Brady; Nicholas M. Barnes; Marlene L. Cohen; Peter R. Guzzo

    2011-01-01

    Serotonin type 3 (5-HT3) receptor partial agonists are being targeted as potential new drugs for the treatment of irritable bowel syndrome (IBS). Two new chemical series bearing indazole and indole cores have exhibited nanomolar binding affinity for the h5-HT3A receptor. A range of partial agonist activities in HEK cells heterologously expressing the h5-HT3A receptor were measured for the indazole series.

  1. 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/?-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 ?-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/?-catenin stimulation may represent a novel therapeutic approach in the treatment of hepatic I/R. PMID:23143067

  2. Social responsiveness and physical space as determinants of agonistic behavior in Betta splendens

    Microsoft Academic Search

    Nancy Woodard Cain; Cynthia Jessen; Michael Flanagan

    1980-01-01

    Two experiments examined the conditions under whichBetta agonistic responding occurs by manipulating physical space and the species and social responsiveness of an opponent. In Experiment\\u000a 1, both the species (conspecific or nonconspecific) and the aggressiveness (aggressive or nonaggressive) of the opponent were\\u000a manipulated. The results indicated that agonistic behavior was greater with both conspecifics and aggressive opponents. Experiment\\u000a 2 examined

  3. Peripheral nociceptive effects of ? 2-adrenergic receptor agonists in the rat

    Microsoft Academic Search

    S. G. Khasar; P. G. Green; B. Chou; J. D. Levine

    1995-01-01

    We have previously shown that norepinephrine can produce hyperalgesia via an ?2-adrenergic receptor mechanism. The ?2-adrenergic receptor agonist clonidine has, however, also been shown to produce peripheral analgesia. In view of the multiple ?2-subtypes currently known (i.e. ?2A, ?2Band?2C), we evaluated the ?2-receptor subtypes mediating norepinephrine-induced peripheral hyperalgesia and clonidine analgesia.Norepinephrine and the ?2-adrenergic agonists clonidine and UK 14,304 (1–1000

  4. [Dopamin agonist treatment and fibrotic heart valve disease in hyperprolactinaemia patients.

    PubMed

    Steffensen, Charlotte; Mægbæk, Merete Lund; Laurberg, Peter; Andersen, Marianne; Kistorp, Caroline; Nørrelund, Helene; Dal, Jakob; Jørgensen, Jens Otto Lunde

    2014-01-01

    Treatment with dopamin agonists, particularly cabergoline, is the primary and preferred therapy for prolactinomas and symptomatic hyperprolactinaemia due to its effectiveness and tolerability. However, an association has been demonstrated between fibrotic heart valve disease and high-dose dopamin agonist use in patients with Parkinson's disease in several echocardiographic studies. Such observations have prompted a number of studies of valvular function in cabergoline-treated hyperprolactinaemia patients. These studies have failed to show an increased prevalence of clinically significant valvular regurgitation. PMID:24629610

  5. A comparison of the effects of agonist and antagonist muscle fatigue on performance of rapid movements

    Microsoft Academic Search

    Slobodan Jari?; Saša Radovanovi?; Sladjan Milanovi?; Miloš Ljubisavljevi?; Radmila Anastasijevi?

    1997-01-01

    The aim of this study was to investigate the effects of agonist and antagonist muscle fatigue on the performance of rapid,\\u000a self-terminating movements. Six subjects performed rapid, consecutive elbow flexion and extension movements between two targets\\u000a prior to and after fatiguing either the elbow flexor or elbow extensor muscles. The experiments demonstrated consistent results.\\u000a Agonist muscle fatigue was associated with

  6. Luteinizing Hormone-Releasing Hormone and Its Agonistic, Antagonistic, and Targeted Cytotoxic Analogs in Prostate Cancer

    Microsoft Academic Search

    Andrew V. Schally; Norman L. Block

    \\u000a Chronic administration of luteinizing hormone-releasing hormone I (LHRH-I) or its agonistic analogs leads to downregulation\\u000a of pituitary receptors for LHRH, and a gradual suppression of circulating levels of gonadotropins and sex steroids. The creation\\u000a of a state of sex-hormone deprivation produced by periodic administration of sustained delivery system of LHRH agonists forms\\u000a the basis of therapy for advanced prostate cancer

  7. Increased Risk of Pneumonia in Patients Receiving Gonadotropin-Releasing Hormone Agonists for Prostate Cancer

    PubMed Central

    Lin, Herng-Ching; Wang, Li-Hsuan

    2014-01-01

    Background This study aimed to investigate the relationship between the use of gonadotropin-releasing hormone (GnRH) agonists and subsequent risk of pneumonia in patients with prostate cancer (PC) using a population-based dataset. Methods We obtained the data from Taiwan's Longitudinal Health Insurance Database 2000. We included 2064 PC in this study. Of the sampled PC patients, 1207 received treatment with GnRH agonists. We individually traced each PC patient for a 1-year period to identify those who were hospitalized with pneumonia. We performed a Cox proportional hazard regression to explore the association between the use of GnRH agonists and the risk of pneumonia during the 1-year follow-up period. Results Incidence rates of pneumonia during the 1-year follow-up period were 4.35 (95% confidence interval (CI): 1.89?9.64) per 100 person-years and 2.14 (95% CI: 1.31?3.32) per 100 person-years for PC patients who did and those who did not receive treatment with GnRH agonists, respectively. The log-rank test suggested that there was a significant difference in the 1-year pneumonia-free survival rate between PC patients who did and those who did not receive treatment with GnRH agonists (p<0.002). After adjusting for age, monthly income, and the Charlson Comorbidities Index score, PC patients who received treatment with GnRH agonists were more likely to have been hospitalized for pneumonia during the 1-year follow-up period than PC patients who did not receive treatment with GnRH agonists (hazard ratio: 1.92, 95% CI: 1.10?3.36). Conclusions PC patients who received treatment with GnRH agonists had an increased risk of pneumonia. PMID:24971988

  8. Long and short-acting ?2 adrenoceptor agonists: interactions in human contracted bronchi

    Microsoft Academic Search

    M. Molimard; E. Naline; Y. Zhang; V. Le Gros; B. Begaud; C. Advenier

    The aim of this study was to systematically compare the interaction of the long-acting ?2-adrenoceptor agonists formoterol and salmeterol with short-acting ?2-adrenoceptor agonists in contracted human bronchi. Human bronchi were obtained at thoracotomy from patients with lung cancer. Formo- terol or salmeterol at concentrations inducing up to 92 and 94% of their maximal relax- ant effect, respectively, were added to

  9. The selectivity of ?-adrenoceptor agonists at human ?1-, ?2- and ?3-adrenoceptors

    PubMed Central

    Baker, Jillian G

    2010-01-01

    Background and purpose: There are two important properties of receptor–ligand interactions: affinity (the ability of the ligand to bind to the receptor) and efficacy (the ability of the receptor–ligand complex to induce a response). Ligands are classified as agonists or antagonists depending on whether or not they have efficacy. In theory, it is possible to develop selective agonists based on selective affinity, selective intrinsic efficacy or both. This study examined the affinity and intrinsic efficacy of 31 ?-adrenoceptor agonists at the three human ?-adrenoceptors to determine whether the current agonists are subtype selective because of affinity or intrinsic efficacy. Experimental approach: Stable clonal CHO-K1 cell lines, transfected with either the human ?1, ?2 or ?3-adrenoceptor, were used, and whole-cell [3H]-CGP 12177 radioligand binding and [3H]-cAMP accumulation were measured. Key results: Several agonists were found to be highly subtype selective because of selective affinity (e.g. salmeterol and formoterol, for the ?2-adrenoceptor over the ?1 or ?3), while others (e.g. isoprenaline) had little affinity–selectivity. However, the intrinsic efficacy of salmeterol, formoterol and isoprenaline was similar across all three receptor subtypes. Other ligands (e.g. denopamine for ?1; clenbuterol, AZ 40140d, salbutamol for ?2) were found to have subtype-selective intrinsic efficacy. Several ligands appeared to activate two agonist conformations of the ?1- and ?3-adrenoceptors. Conclusions and implications: There are agonists with subtype selectivity based upon both selective affinity and selective intrinsic efficacy. Therefore, there is scope to develop better selective agonists based upon both selective affinity and selective intrinsic efficacy. This article is commented on by Kenakin, pp. 1045–1047 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476-5381.2010.00764.x PMID:20590599

  10. PII S0196-9781(98)00023-0 Interaction of Agonist Peptide [3

    E-print Network

    Vogel, Zvi

    PII S0196-9781(98)00023-0 Interaction of Agonist Peptide [3 H]Tyr-D-Ala-Phe- Phe-NH2 with -Opioid. SCHILLER AND A. BORSODI. Interaction of agonist peptide [3 H]Tyr-D-Ala-Phe-Phe-NH2 with -opioid receptor in rat brain and CHO- /1 cell line. PEPTIDES 19(6) 1091­1098, 1998.--Opioid receptor binding properties

  11. Distinguishing a benzodiazepine agonist (triazolam) from a nonagonist anxiolytic (buspirone) by electroencephalography: Kinetic-dynamic studies

    Microsoft Academic Search

    David J Greenblatt; Jerold S Harmatz; Terry A Gouthro; Jenifer Locke; Richard I Shader

    1994-01-01

    Background and objectives: Benzodiazepine agonists and azaperone derivatives are used clinically as anxiolytics but have different neuroreceptor mechanisms of action. This study evaluated clinical pharmacodynamic approaches to distinguishing these two classes of compounds.Methods: Healthy volunteers received single oral doses of placebo, the benzodiazepine agonist triazolam (0.25 mg) or the azaperone anxiolytic buspirone (20 mg), in a double-blind, three-way crossover study.

  12. Additive effect of PPAR-? agonist and ARB in treatment of experimental IgA nephropathy

    Microsoft Academic Search

    Kar Neng Lai; Loretta Y. Y. Chan; Hong Guo; Sydney C. W. Tang; Joseph C. K. Leung

    2011-01-01

    Our recent in vitro study demonstrated peroxisome proliferator-activated receptor-? (PPAR??) agonist potentiated the anti-inflammatory\\u000a effect of angiotensin receptor blocker (ARB) in tubular epithelial cell under milieu mimicking IgA nephropathy (IgAN). Here\\u000a we studied the therapeutic effect of combining a PPAR-? agonist, rosiglitazone (Ros), with an ARB, losartan (Los), in experimental\\u000a IgAN induced in Lewis rats by oral and intravenous immunization

  13. Peroxisome proliferator-activated receptor-? agonist troglitazone protects against nondiabetic glomerulosclerosis in rats

    Microsoft Academic Search

    Li-Jun Ma; Carmelita Marcantoni; Macrae F. Linton; Sergio Fazio; Agnes B. Fogo

    2001-01-01

    Peroxisome proliferator-activated receptor-? agonist troglitazone protects against nondiabetic glomerulosclerosis in rats.BackgroundPeroxisome proliferator-activated receptor-? (PPAR?) is a member of the nuclear receptor superfamily of ligand-dependent transcriptional factors with beneficial effects in diabetes mediated by improved insulin sensitivity and lipid metabolism, but potential adverse effects in atherosclerosis by promoting in vitro foam cell formation. We explored whether a PPAR? agonist, troglitazone (TGL),

  14. LH-RH agonists offer very good protection against the adverse gynaecological effects induced by tamoxifen

    Microsoft Academic Search

    M Berlière; C Galant; G Marques; Ph Piette; L Duck; L Fellah; J Donnez; J. P Machiels

    2004-01-01

    This study was initiated to evaluate the efficacy of luteinizing hormone-releasing hormone (LH-RH) agonists in protecting premenopausal patients against the adverse gynaecological effects induced by tamoxifen. Between January 1998 and January 2000, 85 premenopausal breast cancer patients were included in this prospective study. All were to receive LH-RH agonists and tamoxifen for a minimum of two years. All patients underwent

  15. 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

  16. Bio-analytical and chemical characterisation of offshore produced water effluents for estrogen receptor (ER) agonists.

    PubMed

    Thomas, Kevin V; Balaam, Jan; Hurst, Mark R; Thain, John E

    2004-07-01

    The in vitro estrogen receptor (ER) agonist potency and C1 to C9 alkyl substituted phenol content of offshore produced water effluents collected from the UK sector of the North Sea were determined using a combination of bio-analytical and chemical analysis techniques. An in vitro reporter gene assay was used to determine ER agonist potency, whilst gas chromatography coupled to mass spectrometry (GC-MS) was used to quantify the concentration of alkylphenols. The in vitro ER agonist potency was highly variable and ranged from less than the limit of detection (theoretically 0.03 ng 17beta-estradiol (E2) l(-1)) to 91 ng E2 l(-1). C1 to C5 alkylphenol concentrations were also highly variable ranging from 5 to 1600 microg l(-1) with a median concentration of 206 microg l(-1). These data reflect the highly variable composition of produced water discharges from different fields. The observed poor correlation of the alkylphenol isomer content and ER agonist activity suggests that other compounds present in the produced water discharges may be responsible for the ER agonist activity observed. It is recommended that further work be performed to characterise the full range of ER agonists present in offshore produced water discharges. PMID:15237289

  17. Identification of in vitro estrogen and androgen receptor agonists in North Sea offshore produced water discharges.

    PubMed

    Thomas, Kevin V; Balaam, Jan; Hurst, Mark R; Thain, John E

    2004-05-01

    The estrogen receptor (ER) agonist potency of offshore produced water discharges was examined via bioassay-directed chemical analysis. The in vitro estrogen receptor (ER) and androgen receptor (AR) agonist potency of five produced water samples collected from oil-production platforms in the British and Norwegian sectors of the North Sea was determined by using the yeast estrogen and androgen screens. Produced water samples were extracted in situ on the production platforms by using large-volume solid-phase extraction. All five extracts tested positive for the presence of ER agonists, whereas no AR agonist activity could be detected. By using the yeast estrogen screen assay in association with bioassay-directed fractionation, attempts were made to identify the ER agonist compounds present in the produced water extracts. The fractionation procedure used cyano-amino-bonded silica normal-phase high-performance liquid chromatography to isolate estrogenic compounds from produced water extract followed by full-scan gas chromatography-electron-impact mass spectrometry (GC-(EI)MS) to identify them. Isomeric mixtures of C1 to C5 and C9 alkylphenols contributed to the majority of the ER agonist potency measured in the samples. PMID:15180366

  18. Low sensitivity of the positron emission tomography ligand [11C]diprenorphine to agonist opiates.

    PubMed

    Hume, Susan P; Lingford-Hughes, Anne R; Nataf, Valerie; Hirani, Ella; Ahmad, Rabia; Davies, Andrew N; Nutt, David J

    2007-08-01

    Previously, we reported minimal opioid receptor occupancy following a clinical dose of the micro-opioid agonist, methadone, measured in vivo using positron emission tomography (PET) with [(11)C]diprenorphine and subsequently used rats to obtain experimental data in support of a high receptor reserve hypothesis (Melichar et al., 2005). Here, we report on further preclinical studies investigating opioid receptor occupancy with oxycodone (micro- and kappa-receptor agonist), morphine (micro-receptor agonist), and buprenorphine (partial agonist at the micro-receptor and antagonist at the delta- and kappa-receptors), each given at antinociceptive doses. In vivo binding of [(11)C]diprenorphine was not significantly reduced after treatment with the full agonists but was reduced by approximately 90% by buprenorphine. In addition, given that [(11)C]diprenorphine is a non-subtype-specific PET tracer, there was no regional variation that might feasibly be interpreted as due to differences in opioid subtype distribution. The data support minimal competition between the high-efficacy agonists and the non-subtype-selective antagonist radioligand and highlight the limitations of [(11)C]diprenorphine PET to monitor in vivo occupancy. Alternative means may be needed to address clinical issues regarding opioid receptor occupancy that are required to optimize treatment strategies. PMID:17488881

  19. 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

  20. Mechanism of AMPA receptor activation by partial agonists: disulfide trapping of closed lobe conformations.

    PubMed

    Ahmed, Ahmed H; Wang, Shu; Chuang, Huai-Hu; Oswald, Robert E

    2011-10-01

    The mechanism by which agonist binding to an ionotropic glutamate receptor leads to channel opening is a central issue in molecular neurobiology. Partial agonists are useful tools for studying the activation mechanism because they produce full channel activation with lower probability than full agonists. Structural transitions that determine the efficacy of partial agonists can provide information on the trigger that begins the channel-opening process. The ligand-binding domain of AMPA receptors is a bilobed structure, and the closure of the lobes is associated with channel activation. One possibility is that partial agonists sterically block full lobe closure but that partial degrees of closure trigger the channel with a lower probability. Alternatively, full lobe closure may be required for activation, and the stability of the fully closed state could determine efficacy with the fully closed state having a lower stability when bound to partial relative to full agonists. Disulfide-trapping experiments demonstrated that even extremely low efficacy ligands such as 6-cyano-7-nitroquinoxaline-2,3-dione can produce a full lobe closure, presumably with low probability. The results are consistent the hypothesis that the efficacy is determined at least in part by the stability of the state in which the lobes are fully closed. PMID:21846932

  1. Design, development and evaluation of novel dual PPAR?/PPAR? agonists.

    PubMed

    Gathiaka, Symon; Nanayakkara, Gayani; Boncher, Tracey; Acevedo, Orlando; Wyble, Johnathon; Patel, Sagar; Patel, Akash; Shane, Mary Elizabeth; Bonkowski, Blake; Wieczorek, Jason; Rong, Yinghui; Huggins, Kevin; Smith, Forest; Amin, Rajesh H

    2013-02-01

    Type 2 diabetes is at epidemic proportions and thus development of novel pharmaceutical therapies for improving insulin sensitivity has become of paramount importance. The objectives of the current study were to develop novel dual PPAR?/? agonists without the deleterious side effects associated with full PPAR? agonists. Docking simulations of 23 novel compounds within the ligand binding domain of PPAR?/? were performed using AutoDock Vina which consistently reproduced experimental binding poses from known PPAR agonists. Comparisons were made and described with other docking programs AutoDock and Surflex-Dock (from SYBYL-X). Biological evaluation of compounds was accomplished by transcriptional promoter activity assays, quantitative PCR gene analysis for known PPAR?/? targets as well as in vitro assays for lipid accumulation and mitochondrial biogenesis verses known PPAR agonists. We found one (compound 9) out of the 23 compounds evaluated, to be the most potent and selective dual PPAR?/? agonist which did not display the deleterious side effects associated with full PPAR? agonists. PMID:23273519

  2. Flow-injection chemiluminescence method to detect a ?2 adrenergic agonist.

    PubMed

    Zhang, Guangbin; Tang, Yuhai; Shang, Jian; Wang, Zhongcheng; Yu, Hua; Du, Wei; Fu, Qiang

    2015-02-01

    A new method for the detection of ?2 adrenergic agonists was developed based on the chemiluminescence (CL) reaction of ?2 adrenergic agonist with potassium ferricyanide-luminol CL. The effect of ?2 adrenergic agonists including isoprenaline hydrochloride, salbutamol sulfate, terbutaline sulfate and ractopamine on the CL intensity of potassium ferricyanide-luminol was discovered. Detection of the ?2 adrenergic agonist was carried out in a flow system. Using uniform design experimentation, the influence factors of CL were optimized. The optimal experimental conditions were 1?mmol/L of potassium ferricyanide, 10?µmol/L of luminol, 1.2?mmol/L of sodium hydroxide, a flow speed of 2.6?mL/min and a distance of 1.2?cm from 'Y2 ' to the flow cell. The linear ranges and limit of detection were 10-100 and 5?ng/mL for isoprenaline hydrochloride, 20-100 and 5?ng/mL for salbutamol sulfate, 8-200 and 1?ng/mL for terbutaline sulfate, 20-100 and 4?ng/mL for ractopamine, respectively. The proposed method allowed 200 injections/h with excellent repeatability and precision. It was successfully applied to the determination of three ?2 adrenergic agonists in commercial pharmaceutical formulations with recoveries in the range of 96.8-98.5%. The possible CL reaction mechanism of potassium ferricyanide-luminol-?2 adrenergic agonist was discussed from the UV/vis spectra. PMID:24830367

  3. Molecular Docking Screening Using Agonist-Bound GPCR Structures: Probing the A2A Adenosine Receptor.

    PubMed

    Rodríguez, David; Gao, Zhang-Guo; Moss, Steven M; Jacobson, Kenneth A; Carlsson, Jens

    2015-03-23

    Crystal structures of G protein-coupled receptors (GPCRs) have recently revealed the molecular basis of ligand binding and activation, which has provided exciting opportunities for structure-based drug design. The A2A adenosine receptor (A2AAR) is a promising therapeutic target for cardiovascular diseases, but progress in this area is limited by the lack of novel agonist scaffolds. We carried out docking screens of 6.7 million commercially available molecules against active-like conformations of the A2AAR to investigate whether these structures could guide the discovery of agonists. Nine out of the 20 predicted agonists were confirmed to be A2AAR ligands, but none of these activated the ARs. The difficulties in discovering AR agonists using structure-based methods originated from limited atomic-level understanding of the activation mechanism and a chemical bias toward antagonists in the screened library. In particular, the composition of the screened library was found to strongly reduce the likelihood of identifying AR agonists, which reflected the high ligand complexity required for receptor activation. Extension of this analysis to other pharmaceutically relevant GPCRs suggested that library screening may not be suitable for targets requiring a complex receptor-ligand interaction network. Our results provide specific directions for the future development of novel A2AAR agonists and general strategies for structure-based drug discovery. PMID:25625646

  4. [The therapeutic plasma concentrations of antiparkinson dopamine agonists and their in vitro pharmacology at dopamine receptors].

    PubMed

    Tadori, Yoshihiro; Kobayashi, Hiroyuki

    2014-11-01

    This review discusses the relationship between therapeutic plasma concentrations of antiparkinson dopamine agonists (rotigotine, pergolide, cabergoline, apomorphine, bromocriptine, ropinirole, pramipexole, and talipexole) and their in vitro pharmacology at dopamine D1, D2 and D3 receptors. A significant correlation was found between therapeutic plasma concentrations of these dopamine agonists and their agonist potencies (EC50) at D2 receptors, although no such correlation existed at D1 or D3 receptors, suggesting that D2 receptors could be the primary and common target for the antiparkinson action of all dopamine agonists. However, D1 receptor stimulation is also important for maintaining swallowing reflex, bladder function and cognition. In particular, continuous D1 and D2 receptor stimulation may be reduced to low levels among Parkinson's disease patients. Our findings revealed therapeutic plasma concentrations of rotigotine were similar to its agonist potencies at both D1 and D2 receptors. Thus, rotigotine may be beneficial for the treatment of Parkinson's disease patients in that this dopamine agonist has the potential of continuous stimulation of both D1 and D2 receptors in the clinical setting. PMID:25536763

  5. Dopamine receptor agonists for the treatment of early or advanced Parkinson's disease.

    PubMed

    Perez-Lloret, Santiago; Rascol, Olivier

    2010-11-01

    Dopamine receptor agonists are indicated for the symptomatic treatment of early, moderate or advanced Parkinson's disease as well as for the reduction of levodopa-related motor complications. Ergolinic dopamine agonists, such as bromocriptine or pergolide, were initially developed and marketed, and then non-ergolinic dopamine agonists, such as pramipexole and ropinirole, were introduced, reducing the risk of drug-induced fibrotic reactions. Once-daily, controlled-release oral and transdermal formulations have been developed aiming at providing more stable 24-hour plasma drug concentrations and more convenient administration. A disease-modifying effect of dopamine agonists has not been demonstrated clinically. As with any other drug, dopamine agonists can also cause adverse drug reactions, which can be related or unrelated to dopaminergic hyperactivation. Dopaminergic reactions include nausea, hallucinations, confusion and orthostatic hypotension, among others, which were readily identified in pre-marketing clinical trials. During post-marketing surveillance, important adverse reactions were identified, such as daytime somnolence, impulse-control disorders and heart valve fibrosis. Other issues, including the efficacy of dopamine agonists for the treatment of non-motor symptoms, remain under evaluation. PMID:20932066

  6. Long-acting beta2-agonist in addition to tiotropium versus either tiotropium or long-acting beta2-agonist alone for chronic obstructive pulmonary disease

    PubMed Central

    Karner, Charlotta; Cates, Christopher J

    2014-01-01

    Background Long-acting bronchodilators comprising long-acting beta2-agonists and the anticholinergic agent tiotropium are commonly used for managing persistent symptoms of chronic obstructive pulmonary disease. Combining these treatments, which have different mechanisms of action, may be more effective than the individual components. However, the benefits and risks of combining tiotropium and long-acting beta2-agonists for the treatment of chronic obstructive pulmonary (COPD) disease are unclear. Objectives To assess the relative effects of treatment with tiotropium in addition to long-acting beta2-agonist compared to tiotropium or long-acting beta2-agonist alone in patients with chronic obstructive pulmonary disease. Search methods We searched the Cochrane Airways Group Specialised Register of trials and clinicaltrials.gov up to January 2012. Selection criteria We included parallel group, randomised controlled trials of three months or longer comparing treatment with tiotropium in addition to long-acting beta2-agonist against tiotropium or long-acting beta2-agonist alone for patients with chronic obstructive pulmonary disease. Data collection and analysis Two review authors independently assessed trials for inclusion and then extracted data on trial quality and the outcome results. We contacted study authors for additional information. We collected information on adverse effects from the trials. Main results Five trials were included in this review, mostly recruiting participants with moderate or severe chronic obstructive pulmonary disease. All of them compared tiotropium in addition to long-acting beta2-agonist to tiotropium alone, but only one trial additionally compared a combination of the two types of bronchodilator with long-acting beta2-agonist (formoterol) alone. Two studies used the long-acting beta2-agonist indacaterol, two used formoterol and one used salmeterol. Compared to tiotropium alone (3263 patients), treatment with tiotropium plus long-acting beta2-agonist resulted in a slightly larger improvement in the mean health-related quality of life (St George’s Respiratory Questionnaire (SGRQ) MD ?1.61; 95% CI ?2.93 to ?0.29). In the control arm, tiotropium alone, the SGRQ improved by falling 4.5 units from baseline and with both treatments the improvement was a fall of 6.1 units from baseline (on average). High withdrawal rates in the trials increased the uncertainty in this result, and the GRADE assessment for this outcome was therefore moderate. There were no significant differences in the other primary outcomes (hospital admission or mortality). The secondary outcome of pre-bronchodilator FEV1 showed a small mean increase with the addition of long-acting beta2-agonist (MD 0.07 L; 95% CI 0.05 to 0.09) over the control arm, which showed a change from baseline ranging from 0.03 L to 0.13 L on tiotropium alone. None of the other secondary outcomes (exacerbations, symptom scores, serious adverse events, and withdrawals) showed any statistically significant differences between the groups. There were wide confidence intervals around these outcomes and moderate heterogeneity for both exacerbations and withdrawals. The results from the one trial comparing the combination of tiotropium and long-acting beta2-agonist to long-acting beta2-agonist alone (417 participants) were insufficient to draw firm conclusions for this comparison. Authors’ conclusions The results from this review indicate a small mean improvement in health-related quality of life for patients on a combination of tiotropium and long-acting beta2-agonist compared to tiotropium alone, but it is not clear how clinically important this mean difference may be. Hospital admission and mortality have not been shown to be altered by adding long-acting beta2-agonists to tiotropium as there were not enough data to determine the relative efficacy and safety of tiotropium plus long-acting beta2-agonist compared to long-acting beta2-agonist alone. There were insufficient data to make comparisons between the different long-acting

  7. Facult des arts et des sciences Dpartement de science politique

    E-print Network

    Leclercq, Remi

    doivent être effacés des langues modernes. Jean-Jacques Rousseau, Émile, ou De l'éducation Premier article-huitième siècle : Machiavel, James Harrington, Montesquieu, Jean-Jacques Rousseau et Immanuel Kant. Puis, nous

  8. Differential effects of opioid agonists on G protein expression in CHO cells expressing cloned human opioid receptors.

    PubMed

    Xu, Heng; Wang, Xiaoying; Partilla, John S; Bishop-Mathis, Kristen; Benaderet, Tova S; Dersch, Christina M; Simpson, Denise S; Prisinzano, Thomas E; Rothman, Richard B

    2008-09-01

    Recent evidence indicates that agonist ligands of G protein coupled receptors (GPCR) can activate different signaling systems. Such "agonist-directed" signaling also occurs with opioid receptors. Previous work from our laboratory showed that chronic morphine, but not DAMGO, up-regulates the expression of Galpha12 and that both morphine and DAMGO decreased Galphai3 expression in CHO cells expressing the cloned human mu opioid receptor. In this study, we tested the hypothesis that chronic opioid regulation of G protein expression is agonist-directed. Following a 20h treatment of CHO cells expressing the cloned human mu (hMOR-CHO), delta (hDOR-CHO) or kappa (hKOR-CHO) opioid receptors with various opioid agonists, we determined the expression level of Galpha12 and Galphai3 by Western blots. Among five mu agonists (morphine, etorphine, DADLE, DAMGO, herkinorin) tested with hMOR-CHO cells, only chronic morphine and etorphine up-regulated Galpha12 expression. All five mu agonists decreased Galphai3 expression. Among six delta agonists (SNC80, DPDPE, deltorphin-1, morphine, DADLE, etorphine) tested with hDOR-CHO cells, all six agonists down-regulated Galphai3 expression or moderately up-regulated Galpha12 expression. Among five kappa agonists, ((-)-ethylketocyclazocine, salvinorin A, U69,593, etorphine, (-)-U50,488) tested with hKOR-CHO cells, only chronic (-)-U50,488 and (-)-EKC up-regulated Galpha12 expression. All kappa agonists decreased Galphai3 expression. These data demonstrate that chronic opioid agonist regulation of G protein expression depends not only on the agonist tested, but also on the type of opioid receptor expressed in a common cellular host, providing additional evidence for agonist-directed signaling. PMID:18639745

  9. Angiotensin Receptor Agonistic Autoantibodies and Hypertension: Preeclampsia and Beyond

    PubMed Central

    Xia, Yang; Kellems, Rodney E.

    2014-01-01

    Hypertensive disorders are life-threatening diseases with high morbidity and mortality, affecting billions of individuals worldwide. A multitude of underlying conditions can contribute to hypertension, thus the need for a plethora of treatment options to identify the approach that best meets the needs of individual patients. As reviewed here a growing body of evidence indicates that i) autoantibodies that bind to and activate the major angiotensin receptor, AT1R exist in the circulation of patients with hypertensive disorders, ii) these autoantibodies contribute to disease pathophysiology, iii) antibody titers correlate to the severity of the disease, and iv) efforts to block or remove these pathogenic autoantibodies have therapeutic potential. These autoantibodies, termed AT1 agonistic autoantibodies (AT1-AA) have been extensively characterized in preeclampsia (PE), a life-threatening hypertensive condition of pregnancy. As reviewed here these autoantibodies cause symptoms of PE when injected into pregnant mice. Somewhat surprisingly, these antibodies also appear in three animal models of preeclampsia. However, the occurrence of AT1-AA is not restricted to pregnancy. These autoantibodies are prevalent among kidney transplant recipients who develop severe transplant rejection and malignant hypertension during the first week following transplantation. AT1-AA are also highly abundant among a group of patients with essential hypertension that are refractory to standard therapy. More recently these autoantibodies have been seen in patients with the autoimmune disease, systemic sclerosis. These three examples extend the clinical impact of AT1-AA beyond pregnancy. Research reviewed here raises the intriguing possibility that preeclampsia and other hypertensive conditions are autoimmune diseases characterized by the presence of pathogenic autoantibodies that activate the major angiotensin receptor, AT1R. These pathogenic autoantibodies could serve as pre-symptomatic biomarkers and therapeutic targets, thereby providing improved medical management for these conditions. PMID:23788505

  10. RXR partial agonist produced by side chain repositioning of alkoxy RXR full agonist retains antitype 2 diabetes activity without the adverse effects.

    PubMed

    Kawata, Kohei; Morishita, Ken-ichi; Nakayama, Mariko; Yamada, Shoya; Kobayashi, Toshiki; Furusawa, Yuki; Arimoto-Kobayashi, Sakae; Oohashi, Toshitaka; Makishima, Makoto; Naitou, Hirotaka; Ishitsubo, Erika; Tokiwa, Hiroaki; Tai, Akihiro; Kakuta, Hiroki

    2015-01-22

    We previously reported RXR partial agonist CBt-PMN (1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-1H-benzotriazole-5-carboxylic acid: 5, EC50 = 143 nM, Emax = 75%), which showed a potent glucose-lowering effect without causing serious adverse effects. However, it remains important to elucidate the structural requirements for RXR efficacy and the glucose-lowering effect because RXR-permissive heterodimers such as PPAR/RXR or LXR/RXR are reported to be activated differently depending upon the chemical structure of RXR agonists. In this work, we show that an RXR partial agonist, NEt-4IB (6-[ethyl-(4-isobutoxy-3-isopropylphenyl)amino]pyridine-3-carboxylic acid: 8b, EC50 = 169 nM, Emax = 55%), can be obtained simply by repositioning the side chains (interchanging the isobutoxy and isopropoxy groups) at the hydrophobic moiety of the RXR full agonist NEt-3IB (6-[ethyl-(3-isobutoxy-4-isopropylphenyl)amino]pyridine-3-carboxylic acid: 7b, EC50 = 19 nM). NEt-4IB (8b) showed antitype 2 diabetes activity without the above side effects upon repeated oral administration to mice at 10 mg/kg/day, similarly to 5. PMID:25486327

  11. Musee des Horreurs

    NSDL National Science Digital Library

    What is this Musee des Horreurs? Visitors will find out soon enough: it is a remarkable collection of 52 hand-colored lithograph caricatures of individuals involved in the Dreyfus Affair in France. These lithographs were originally produced from 1899 to 1900 by an artist who used the pseudonym V. Lenepveu and they document the anti-Semitic upsurge brought about by this well-known event. Those represented in the caricatures include prominent members of the Jewish community, Dreyfus supporters, and Republican statesmen placed on grotesque animal bodies. Visitors with an interest in the subject may wish to use the images in a class on graphic design, illustration, European history, or cultural affairs.

  12. Modulation of CB1 cannabinoid receptor functions after a long-term exposure to agonist or inverse agonist in the Chinese hamster ovary cell expression system.

    PubMed

    Rinaldi-Carmona, M; Le Duigou, A; Oustric, D; Barth, F; Bouaboula, M; Carayon, P; Casellas, P; Le Fur, G

    1998-12-01

    We have investigated the adaptive changes of the human central cannabinoid receptor (CB1) stably expressed in Chinese hamster ovary cells (CHO-CB1), after agonist (CP 55,940) or selective CB1 inverse agonist (SR 141716) treatment. CB1 receptor density and affinity constant as measured by binding assays with both tritiated ligands remained essentially unchanged after varying period exposure of CHO-CB1 cells (from 30 min to 72 hr) to saturating concentrations of CP 55,940 or SR 141716. However, using a C-myc-tagged version of the CB1 receptor, FACS analysis and confocal microscopy studies on CB1 expression indicated that the agonist promoted a disappearance of cell surface receptor although inverse agonist increased its cell surface density. Taken together these results suggest that 1) agonist induces internalization of the receptor into a cellular compartment that would be still accessible to both the hydrophobic ligands CP 55,940 or SR 141716; 2) inverse-agonist promotes externalization of the receptor from an intracellular preexisting pool to the cell surface. In parallel, we also investigated the associated effects of CP 55,940 and SR 141716 on CB1 receptor-coupled second messengers. We showed that preexposure of cells to CP 55,940 induced a rapid desensitization of the CB1 to the agonist response. The ability of CP 55,940 to inhibit the forskolin-stimulated adenylyl cyclase and to activate the mitogen-activated protein kinase activity was dramatically reduced. By striking contrast, SR 141716 pretreatment of CHO-CB1 cells not only had no significant effect on the potency of CP 55,940 to inhibit the forskolin-stimulated adenylyl cyclase but also induced a significant enhancement of the CP 55,940 ability to stimulate the mitogen-activated protein kinase activity. These results suggest that the modulation of the number of cell surface receptor could lead to functional desensitization or sensitization of the CB1 receptors. PMID:9864290

  13. Fiche technique Dtail des panneaux

    E-print Network

    Panneau 23 - Écabossage du cacao au Cameroun Panneau 24 - Culture du palmier à huile au Bénin Panneau 25 capital humain, les outils et la production font partie intégrante du patrimoine familial. L'essentiel des

  14. Die fermentative Spaltung des Acetylcholins

    Microsoft Academic Search

    R. Ammon

    1934-01-01

    Zusammenfassung Es wird eine neue Methode zum Nachweis des Fermentes, das Acetylcholin in Cholin und Essigsäure hydrolysiert, die Cholinesterase, beschrieben. Das Verfahren ist nach derWarburgschen Methode aufgebaut.

  15. Self-administration of cocaine induces dopamine-independent self-administration of sigma agonists.

    PubMed

    Hiranita, Takato; Mereu, Maddalena; Soto, Paul L; Tanda, Gianluigi; Katz, Jonathan L

    2013-03-01

    Sigma(1) receptors (?(1)Rs) are intracellularly mobile chaperone proteins implicated in several disease processes, as well as psychiatric disorders and substance abuse. Here we report that although selective ?(1)R agonists (PRE-084, (+)-pentazocine) lacked reinforcing effects in drug-naive rats, over the course of 28 experimental sessions, which was more than sufficient for acquisition of cocaine self-administration, responding was not maintained by either ?(1)R agonist. In contrast, after subjects self-administered cocaine ?(1)R agonists were readily self-administered. The induced reinforcing effects were long lasting; a response for which subjects had no history of reinforcement was newly conditioned with both ?(1)R agonists, extinguished when injections were discontinued, and reconditioned when ?(1)R agonists again followed responses. Experience with food reinforcement was ineffective as an inducer of ?(1)R agonist reinforcement. Although a variety of dopamine receptor antagonists blocked cocaine self-administration, consistent with its dopaminergic mechanism, PRE-084 self-administration was entirely insensitive to these drugs. Conversely, the ?R antagonist, BD1063, blocked PRE-084 self-administration but was inactive against cocaine. In microdialysis studies i.v. PRE-084 did not significantly stimulate dopamine at doses that were self-administered in rats either with or without a cocaine self-administration experience. The results indicate that cocaine experience induces reinforcing effects of previously inactive ?(1)R agonists, and that the mechanism underlying these reinforcing effects is dopamine independent. It is further suggested that induced ?(1)R mechanisms may have an essential role in treatment-resistant stimulant abuse, suggesting new approaches for the development of effective medications for stimulant abuse. PMID:23187725

  16. 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

  17. Metabotropic glutamate receptor agonists modify the pyloric output of the crustacean stomatogastric ganglion.

    PubMed

    Pérez-Acevedo, Nivia L; Krenz, Wulf D

    2005-11-16

    We have studied the effects of groups I, II, and III metabotropic glutamate receptor (mGluR) agonists and antagonists on pyloric activity in the stomatogastric ganglion (STG) of the Caribbean spiny lobster Panulirus argus. We have found that agonists for all three groups of mGluRs modify the pyloric output. The group I agonist, l-quisqualic acid (l-QA), activated the pyloric central pattern generator (CPG). When the pyloric rhythm was partially suppressed by sucrose-block of input fibers in the stomatogastric nerve (stn), l-QA accelerated the rhythmic activity. In addition, the number of spike discharges was increased in pyloric motoneurons: pyloric (PY), and lateral pyloric (LP). In completely blocked preparations, a slow pyloric rhythm was initiated by l-QA. Groups II and III agonists exerted an inhibitory effect on pyloric activity. The group II agonist, (2S,1'S,2'S)-2-(Carboxycyclopropyl)glycine (L-CCG-I), decreased both the frequency of the pyloric rhythm and the number of spike discharges in the motoneurons: ventricular dilator (VD), PY, and LP. The effects of L-CCG-I were dose-dependent. The group III agonist, l-(+)-2-Amino-4-phosphonobutyric acid (l-AP4), slightly decreased the frequency of the pyloric rhythm and suppressed spike discharges in the VD neuron. All effects of mGluR agonists were reversible. The effect of l-QA was blocked by the broad spectrum mGluR antagonist (S)-Methyl-4-carboxyphenylglycine (MCPG). The inhibitory effect of L-CCG-I was prevented by MCPG and by the group II/III mGluR antagonist (RS)-alpha-Methyl-4-phosphonophenylglycine (MPPG), and was partially blocked by the group II mGluR antagonist (RS)-1-amino-5-phosphonoindan-1-carboxylic acid (APICA). The inhibitory effect of l-AP4 was blocked by MPPG and partially blocked by APICA. PMID:16256086

  18. Chronic treatment with agonists of beta(2)-adrenergic receptors in neuropathic pain.

    PubMed

    Yalcin, Ipek; Tessier, Luc-Henri; Petit-Demoulière, Nathalie; Waltisperger, Elisabeth; Hein, Lutz; Freund-Mercier, Marie-José; Barrot, Michel

    2010-01-01

    Expression of beta(2)-adrenoceptors (beta(2)-ARs) within the nociceptive system suggested their potential implication in nociception and pain. Recently, we demonstrated that these receptors are essential for neuropathic pain treatment by antidepressant drugs. The aim of the present study was to investigate whether the stimulation of beta(2)-ARs could in fact be adequate to alleviate neuropathic allodynia. Neuropathy was induced in mice by sciatic nerve cuffing. We demonstrate that chronic but not acute stimulation of beta(2)-ARs with agonists such as clenbuterol, formoterol, metaproterenol and procaterol suppressed neuropathic allodynia. By using a pharmacological approach with the beta(2)-AR antagonist ICI 118,551 or a transgenic approach with mice deficient for beta(2)-ARs, we confirmed that the antiallodynic effect of these agonists was specifically related to their action on beta(2)-ARs. We also showed that chronic treatment with the beta(1)-AR agonist xamoterol or with the beta(3)-AR agonist BRL 37344 had no effect on neuropathic allodynia. Chronic stimulation of beta(2)-ARs, but not beta(1)- or beta(3)-ARs, by specific agonists is thus able to alleviate neuropathic allodynia. This action of beta(2)-AR agonists might implicate the endogenous opioid system; indeed chronic clenbuterol effect can be acutely blocked by the delta-opioid receptor antagonist naltrindole. Present results show that beta(2)-ARs are not only essential for the antiallodynic action of antidepressant drugs on sustained neuropathic pain, but also that the stimulation of these receptors is sufficient to relieve neuropathic allodynia in a murine model. Our data suggest that beta(2)-AR agonists may potentially offer an alternative therapy to antidepressant drugs for the chronic treatment of neuropathic pain. PMID:19840789

  19. Selective ?4?2 nicotinic acetylcholine receptor agonists target epigenetic mechanisms in cortical GABAergic neurons.

    PubMed

    Maloku, Ekrem; Kadriu, Bashkim; Zhubi, Adrian; Dong, Erbo; Pibiri, Fabio; Satta, Rosalba; Guidotti, Alessandro

    2011-06-01

    Nicotine improves cognitive performance and attention in both experimental animals and in human subjects, including patients affected by neuropsychiatric disorders. However, the specific molecular mechanisms underlying nicotine-induced behavioral changes remain unclear. We have recently shown in mice that repeated injections of nicotine, which achieve plasma concentrations comparable to those reported in high cigarette smokers, result in an epigenetically induced increase of glutamic acid decarboxylase 67 (GAD(67)) expression. Here we explored the impact of synthetic ?(4)?(2) and ?(7) nAChR agonists on GABAergic epigenetic parameters. Varenicline (VAR), a high-affinity partial agonist at ?(4)?(2) and a lower affinity full agonist at ?(7) neuronal nAChR, injected in doses of 1-5?mg/kg/s.c. twice daily for 5 days, elicited a 30-40% decrease of cortical DNA methyltransferase (DNMT)1 mRNA and an increased expression of GAD(67) mRNA and protein. This upregulation of GAD(67) was abolished by the nAChR antagonist mecamylamine. Furthermore, the level of MeCP(2) binding to GAD(67) promoters was significantly reduced following VAR administration. This effect was abolished when VAR was administered with mecamylamine. Similar effects on cortical DNMT1 and GAD(67) expression were obtained after administration of A-85380, an agonist that binds to ?(4)?(2) but has negligible affinity for ?(3)?(4) or ?(7) subtypes containing nAChR. In contrast, PNU-282987, an agonist of the homomeric ?(7) nAChR, failed to decrease cortical DNMT1 mRNA or to induce GAD(67) expression. The present study suggests that the ?(4)?(2) nAChR agonists may be better suited to control the epigenetic alterations of GABAergic neurons in schizophrenia than the ?(7) nAChR agonists. PMID:21368748

  20. Cigarette smoke exposure inhibits contact hypersensitivity via the generation of platelet-activating factor agonists.

    PubMed

    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

    2013-03-01

    Previous studies have established that pro-oxidative stressors suppress host immunity because of their ability to generate oxidized lipids with platelet-activating factor 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 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 contact hypersensitivity (CHS) reactions, indicating a role for oxidized glycerophosphocholines with PAF-R agonistic activity in this process. In addition, cyclooxygenase-2 inhibition did not block PAF-R agonist production but prevented CS-induced inhibition of CHS. This suggests that cyclooxygenase-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 Foxp3(EGFP) mice but not in Foxp3(EGFP) mice on a PAF-R-deficient background. Finally, regulatory T cell depletion via anti-CD25 Abs blocked CS-mediated inhibition of CHS, indicating the potential involvement of regulatory T cells in CS-mediated systemic immunosuppression. These studies provide the first evidence, to our knowledge, that the pro-oxidative stressor CS can modulate cutaneous immunity via the generation of PAF-R agonists produced through lipid oxidation. PMID:23355733

  1. Structural Determinants of Agonist Efficacy at the Glutamate Binding Site of N-Methyl-d-Aspartate Receptors

    PubMed Central

    Hansen, Kasper B.; Tajima, Nami; Risgaard, Rune; Perszyk, Riley E.; Jørgensen, Lars; Vance, Katie M.; Ogden, Kevin K.; Clausen, Rasmus P.

    2013-01-01

    N-methyl-d-aspartate (NMDA) receptors are ligand-gated ion channels assembled from GluN1 and GluN2 subunits. We used a series of N-hydroxypyrazole-5-glycine (NHP5G) partial agonists at the GluN2 glutamate binding site as tools to study activation of GluN1/GluN2A and GluN1/GluN2D NMDA receptor subtypes. Using two-electrode voltage-clamp electrophysiology, fast-application patch-clamp, and single-channel recordings, we show that propyl- and ethyl-substituted NHP5G agonists have a broad range of agonist efficacies relative to the full agonist glutamate (<1–72%). Crystal structures of the agonist binding domains (ABDs) of GluN2A and GluN2D do not reveal any differences in the overall domain conformation induced by binding of the full agonist glutamate or the partial agonist propyl-NHP5G, which is strikingly different from ABD structures of 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propanoate (AMPA) and kainate receptors bound to full and partial agonists. Subsequent evaluation of relative NHP5G agonist efficacy at GluN2A-GluN2D chimeric subunits implicates the amino-terminal domain (ATD) as a strong determinant of agonist efficacy, suggesting that interdomain interactions between the ABD and the ATD may be a central element in controlling the manner by which agonist binding leads to channel opening. We propose that variation in the overall receptor conformation, which is strongly influenced by the nature of interdomain interactions in resting and active states, mediates differences in agonist efficacy and partial agonism at the GluN2 subunits. PMID:23625947

  2. Hormonal induction of spawning in 4 species of frogs by coinjection with a gonadotropin-releasing hormone agonist and a dopamine antagonist

    PubMed Central

    2010-01-01

    Background It is well known that many anurans do not reproduce easily in captivity. Some methods are based on administration of mammalian hormones such as human chorionic gonadotropin, which are not effective in many frogs. There is a need for simple, cost-effective alternative techniques to induce spawning. Methods Our new method is based on the injection of a combination of a gonadotropin-releasing hormone (GnRH) agonist and a dopamine antagonist. We have named this formulation AMPHIPLEX, which is derived from the combination of the words amphibian and amplexus. This name refers to the specific reproductive behavior of frogs when the male mounts and clasps the female to induce ovulation and to fertilize the eggs as they are laid. Results We describe the use of the method and demonstrate its applicability for captive breeding in 3 different anuran families. We tested several combinations of GnRH agonists with dopamine antagonists using Lithobates pipiens. The combination of des-Gly10, D-Ala6, Pro-LHRH (0.4 microrams/g body weight) and metoclopramide (10 micrograms/g BWt. MET) was most effective. It was used in-season, after short-term captivity and in frogs artificially hibernated under laboratory conditions. The AMPHIPLEX method was also effective in 3 Argentinian frogs, Ceratophrys ornata, Ceratophrys cranwelli and Odontophrynus americanus. Conclusion Our approach offers some advantages over other hormonally-based techniques. Both sexes are injected only once and at the same time, reducing handling stress. AMPHIPLEX is a new reproductive management tool for captive breeding in Anura. PMID:20398399

  3. Somatic and prejunctional nicotinic receptors in cultured rat sympathetic neurones show different agonist profiles

    PubMed Central

    Kristufek, D; Stocker, E; Boehm, S; Huck, S

    1999-01-01

    The release of [3H]-noradrenaline ([3H]-NA) in response to nicotinic acetylcholine receptor (nAChR) agonists was compared with agonist-induced currents in cultured rat superior cervical ganglion (SCG) neurones. [3H]-NA release in response to high concentrations of nicotinic agonists was reduced, but not fully inhibited, by the presence of either tetrodotoxin (TTX) or Cd2+ to block voltage-gated Na+ or Ca2+ channels, respectively. We used the component of transmitter release that remained in the presence of these substances (named TTX- or Cd2+-insensitive release) to pharmacologically characterize nAChRs in proximity to the sites of vesicular exocytosis (prejunctional receptors). Prejunctional nAChRs were activated by nicotinic agonists with a rank order of potency of dimethylphenylpiperazinium iodide (DMPP) > nicotine > cytisine > ACh, and with EC50 values ranging from 22 ?M (DMPP) to 110 ?M (ACh). [3H]-NA release in response to low concentrations of nAChR agonists was fully inhibited by the presence of either TTX or Cd2+ (named TTX- or Cd2+-sensitive release). TTX-sensitive release was triggered by nicotinic agonists with a rank order of potency of DMPP > cytisine ? nicotine ? ACh, which due to its similarity to TTX-insensitive release indicates that it might also be triggered by prejunctional-type nAChRs. The EC50 values for TTX (Cd2+)-sensitive release were less than 10 ?M for all four agonists. By contrast to transmitter release, somatic nAChRs as seen by patch clamp recordings were most potently activated by cytisine, with a rank order of potency of cytisine > nicotine ? DMPP > ACh. EC50 values for the induction of currents exceeded 20 ?M for all four agonists. The nicotinic antagonist mecamylamine potently inhibited all transmitter release in response to nicotine. ?-Bungarotoxin (?-BuTX) was, on the other hand, without significant effect on nicotine-induced TTX-insensitive release. The competitive antagonist dihydro-?-erythroidine (DH?E) caused rightward shifts of the dose-response curves for both TTX-sensitive and TTX-insensitive transmitter release as well as for currents in response to nicotine, with pA2 values ranging from 4.03 to 4.58. Due to clear differences in the pharmacology of agonists we propose that nAChRs of distinct subunit composition are differentially targeted to somatic or axonal domains. PMID:10200422

  4. Evaluation of a Novel Calcium Channel Agonist for Therapeutic Potential in Lambert–Eaton Myasthenic Syndrome

    PubMed Central

    Tarr, Tyler B.; Malick, Waqas; Liang, Mary; Valdomir, Guillermo; Frasso, Michael; Lacomis, David; Reddel, Stephen W.; Garcia-Ocano, Adolfo

    2013-01-01

    We developed a novel calcium (Ca2+) channel agonist that is selective for N- and P/Q-type Ca2+ channels, which are the Ca2+ channels that regulate transmitter release at most synapses. We have shown that this new molecule (GV-58) slows the deactivation of channels, resulting in a large increase in presynaptic Ca2+ entry during activity. GV-58 was developed as a modification of (R)-roscovitine, which was previously shown to be a Ca2+ channel agonist, in addition to its known cyclin-dependent kinase activity. In comparison with the parent molecule, (R)-roscovitine, GV-58 has a ?20-fold less potent cyclin-dependent kinase antagonist effect, a ?3- to 4-fold more potent Ca2+ channel agonist effect, and ?4-fold higher efficacy as a Ca2+ channel agonist. We have further evaluated GV-58 in a passive transfer mouse model of Lambert–Eaton myasthenic syndrome and have shown that weakened Lambert–Eaton myasthenic syndrome-model neuromuscular synapses are significantly strengthened following exposure to GV-58. This new Ca2+ channel agonist has potential as a lead compound in the development of new therapeutic approaches to a variety of disorders that result in neuromuscular weakness. PMID:23785168

  5. Reconstitution of high-affinity opioid agonist binding in brain membranes

    SciTech Connect

    Remmers, A.E.; Medzihradsky, F. (Univ. of Michigan Medical School, Ann Arbor (United States))

    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.

  6. 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

  7. 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 ?9-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

  8. Chronic alcohol-induced hepatic insulin resistance and ER stress ameliorated by PPAR-? agonist treatment

    PubMed Central

    Ramirez, Teresa; Tong, Ming; Cy Chen, William; Nguyen, Quynh-Giao; Wands, Jack R.; de la Monte, Suzanne M.

    2014-01-01

    Background Chronic alcoholic liver disease is associated with hepatic insulin resistance, dysregulated lipid metabolism with increased toxic lipid (ceramide) accumulation, lipid peroxidation, and oxidative and endoplasmic reticulum (ER) stress. Peroxisome-proliferator activated receptor (PPAR) agonists are insulin sensitizers that can restore hepatic insulin responsiveness in both alcohol and non-alcohol-related steatohepatitis. Herein, we demonstrate that treatment with a PPAR-? agonist enhances insulin signaling and reduces the severities of ER stress and ceramide accumulation in an experimental model of ethanol-induced steatohepatitis. Methods Adult male Long Evans rats were pair fed with isocaloric liquid diets containing 0% or 37% ethanol (caloric) for 8 weeks. After 3 weeks on the diets, rats were treated with vehicle or PPAR-? agonist twice weekly by i.p. injection. Results Ethanol-fed rats developed steatohepatitis with inhibition of signaling through the insulin and insulin-like growth factor-1 receptors, and Akt activated pathways. Despite continued ethanol exposure, PPAR-? agonist co-treatments increased Akt activation, reduced multiple molecular indices of ER stress and steatohepatitis. Conclusions These results suggest that PPAR-? agonist rescue of chronic alcoholic liver disease is mediated by enhancement of insulin signaling through Akt/metabolic pathways that reduce lipotoxicity and ER stress. PMID:22988930

  9. PPAR? agonist attenuates alcohol-induced hepatic insulin resistance and improves liver injury and repair

    PubMed Central

    Pang, Maoyin; de la Monte, Suzanne M.; Longato, Lisa; Tong, Ming; He, Jiman; Chaudhry, Rajeeve; Duan, Kevin; Ouh, Jiyun; Wands, Jack R.

    2009-01-01

    Background/Aims Chronic ethanol exposure impairs liver regeneration due to inhibition of insulin signaling and oxidative injury. PPAR agonists function as insulin sensitizers and anti-inflammatory agents. We investigated whether treatment with a PPAR? agonist could restore hepatic insulin sensitivity, survival signaling, and regenerative responses vis-a-vis chronic ethanol feeding. Methods Adult rats were fed isocaloric liquid diets containing 0% or 37% ethanol, and administered a PPAR? agonist by i.p. injection. We used liver tissue to examine histopathology, gene expression, oxidative stress, insulin signaling, and regenerative responses to 2/3 hepatectomy. Results Chronic ethanol feeding caused insulin resistance, increased oxidative stress, lipid peroxidation, DNA damage, and hepatocellular injury in liver. These effects were associated with reduced insulin receptor binding and affinity, impaired survival signaling through PI3K/Akt/GSK3?, and reduced expression of insulin responsive genes mediating energy metabolism and tissue remodeling. PPAR? agonist treatment reduced ethanol-mediated hepatic injury, oxidative stress, lipid peroxidation, and insulin resistance, increased signaling through PI3K/Akt/GSK3?, and enhanced the regenerative response to partial hepatectomy. Conclusions PPAR? agonist administration may attenuate the severity of chronic ethanol-induced liver injury and ethanol’s adverse effects on the hepatic repair by restoring insulin responsiveness, even in the context of continued high-level ethanol consumption. PMID:19398227

  10. Enhanced ornithine decarboxylase activity of chick muscle cells in culture by beta-adrenergic agonists.

    PubMed

    Juráni, M; Vaneková, M; Vyboh, P; Lamosová, D

    1996-01-01

    The ability of beta-adrenergic agonists to stimulate ornithine decarboxylase activity (ODC) in chick muscle cell culture prepared from 11-day old embryos was evaluated. After 72 h of preincubation (myotube formation) the medium was supplemented for 4 h with noradrenaline, ritodrine, isoproterenol or clenbuterol, at concentrations of 10(-12), 10(-9) and 10(-6) mol/l. No significant response of ODC activity to noradrenaline was observed. The highest concentration (10(-6) mol/l) of the beta-adrenergic agonists ritodrine and isoproterenol elevated the activity of ODC. Clenbuterol was the most active beta-adrenergic agonist. The lowest concentration (10(-12) mol/l) had an apparent effect on ODC activity in muscle cell culture, and the substitution of media at levels of 10(-9) and 10(-6) mol/l had a similar effect in comparison to controls. The potency of beta-adrenergic agonists in increasing ODC activity was on the following order: noradrenaline, ritodrine, isoproterenol, clenbuterol. Results indicate that beta-adrenergic agonists may directly stimulate ODC activity followed by physiological processes in the muscle cells in the early stage of chick embryonic development. PMID:8721251

  11. 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

  12. Evidence for Air Movement Signals in the Agonistic Behaviour of a Nocturnal Arachnid (Order Amblypygi)

    PubMed Central

    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

  13. Agonist-induced desensitization of adenylyl cyclase in Y1 adrenocortical tumor cells

    SciTech Connect

    Olson, M.F.; Tsao, J.; Pon, D.J.; Schimmer, B.P. (Banting and Best Department of Medical Research, University of Toronto, Ontario (Canada))

    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.

  14. Can the anti-inflammatory activities of ?2-agonists be harnessed in the clinical setting?

    PubMed Central

    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

  15. Duration of L-dopa and dopamine agonist monotherapy in Parkinson's disease.

    PubMed

    Nissen, T; Newman, E J; Grosset, K A; Daghem, M; Pal, G; Stewart, M; Odin, P; Macphee, G J; Grosset, D G

    2012-11-01

    The expected duration of initial antiparkinson monotherapy before the need for supplementation is not clearly defined for routine practice. The aim of this study was to define the length of L-dopa (L-3, 4-dihydrophenylalanine) and dopamine agonist monotherapy. The duration of monotherapy and discontinuation rates were investigated in a natural observational setting by plotting Kaplan-Meier survival curves. Out of 345 patients, 180 (52.2%) received L-dopa and 165 (47.8%) received a dopamine agonist as initial monotherapy. Half of the patients starting L-dopa received supplementary therapy with- in 3.6 years (95% confidence interval, 3.2-4.6), significantly longer than for dopamine agonist monotherapy (half required a second agent at 2.3 years [2.0-2.9]; P = 0.00017). Discontinuation of L-dopa therapy was 1%. Dopamine agonists were stopped (due to side-effects like impulse control disorders [6%], somnolence [4%] and light-headedness [3%]) in 20% over four years. The duration and tolerability of L-dopa and dopamine agonists as initial Parkinson's disease monotherapy are defined in this study; this may form part of the information exchange with patients. PMID:23002158

  16. 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.

  17. Technique de prparation des minraux argileux en vue de l'analyse par diffraction des Rayons X

    E-print Network

    Boyer, Edmond

    des Rayons X et introduction à l'interprétation des diagrammes Médard Thiry Noëlia Carrillo Christine argileux en vue de l'analyse par diffraction des Rayons X et introduction à l'interprétation des diagrammes diffraction des Rayons X et introduction à l'interprétation des diagrammes. Rapport Technique N° RT131010MTHI

  18. Composition en acides amins des aliments et des rsidus de fermentation in vitro

    E-print Network

    Paris-Sud XI, Université de

    Composition en acides aminés des aliments et des résidus de fermentation in vitro M. ANTONGIOVANNI in vitro fermentation with rumen inoculum, and of the faeces relative to an in vivo digestibility trial run fermentation in vitro comme l'ont fait Dennison et Philips (1983) et des fèces. Pour des raisons de place, nous

  19. TUDE DE LA VARIATION DU NOMBRE ET DES DIMENSIONS DES FIBRES MUSCULAIRES

    E-print Network

    Paris-Sud XI, Université de

    caractéristiques histolo- giques des muscles soleus, accessovius latissimi dovsi, extensor carpi vadialis longus et sont mesurés sur les4muscles. Les 2 derniers sont mesurés seulement sur les muscles soleus et accesso Communs. Le muscle soleus des produits des croisements présente des caractères intermédiaires ou proches

  20. TUDE DES RAYONS DE RECUL RADIOACTIFS PAR LA MTHODE DES DTENTES DE WILSON Par F. JOLIOT.

    E-print Network

    Paris-Sud XI, Université de

    ÉTUDE DES RAYONS DE RECUL RADIOACTIFS PAR LA MÉTHODE DES DÉTENTES DE WILSON Par F. JOLIOT. Institut'atomes radioactifs et les trajectoires des rayons de recul. Le parcours des rayons de recul de An et AeA a été mesuré diminue tandis que son pouvoir ionisant augmente. Le rayon de recul lors d'un choc subit une déviation

  1. La nature des rayons 03B3 et des rayons X Par W. H. BRAGG

    E-print Network

    Paris-Sud XI, Université de

    213 La nature des rayons 03B3 et des rayons X Par W. H. BRAGG Université d'Adélaïde. 2014 faites par le Dr Mad- sen et moi, sur lus propriétés des rayons secondaires dus aux rayons y. Un travail travers de la matière, il apparaît des rayons B qui se meuvent d'abord dans la même direction que les

  2. LA SPECTROGRAPHIE DES PHNOMNES D'ABSORPTION DES RAYONS X1; Par M. DE BROGLIE.

    E-print Network

    Paris-Sud XI, Université de

    11 LA SPECTROGRAPHIE DES PHÉNOMÈNES D'ABSORPTION DES RAYONS X1; Par M. DE BROGLIE. 1. A partir du moment où l'étude des rayons secondaires des rayons X a permis aux physiciens anglais, Barkla, Kaye rayons de qualité définie, il a été possible de parvenir aux résultats d'ensemble suivants : . v , FIG. 1

  3. APPLICATION DE LA TOPOGRAPHIE PAR DIFFRACTION DES RAYONS X A L'TUDE DES MTAUX

    E-print Network

    Boyer, Edmond

    311. APPLICATION DE LA TOPOGRAPHIE PAR DIFFRACTION DES RAYONS X A L'ÉTUDE DES MÉTAUX Par G On rappelle le principe des différentes méthodes de topographie par diffraction des rayons X : méthode de Berg améliorations à apporter dans le cadre de l'appareillage : tubes à rayons X plus puissants, intensificateurs d

  4. Les limites de la couverture des risques en aquaculture : le cas des

    E-print Network

    Paris-Sud XI, Université de

    EA 4272 Les limites de la couverture des risques en aquaculture : le cas des conchyliculteurs en limites de la couverture des risques en aquaculture : le cas des conchyliculteurs en France Véronique Le in defining risks in aquaculture and we propose a classification that takes the specificities into account. We

  5. La transmission des textes mathmatiques : l'exemple des lments d'Euclide Bernard VITRAC

    E-print Network

    Boyer, Edmond

    1 La transmission des textes mathématiques : l'exemple des Éléments d'Euclide Bernard VITRAC Les'erreurs d'inattention par lassitude, facilité de corrections parfois abusives3. I. Les Éléments d'Euclide Le cas des Éléments d'Euclide, en treize Livres est, à bien des égards, exemplaire : · le traité a connu

  6. CAMPAGNE DE RECRUTEMENT DES ENSEIGNANTS-CHERCHEURS -SESSION SYNCHRONISEE 2014 -LISTE des MEMBRES des CDS POSTES DE MAITRES DE CONFERENCE

    E-print Network

    Arleo, Angelo

    Mathématiques, bâtiment Fermat département de Mathématiques et applications Ecole Normale Supérieure InriaCAMPAGNE DE RECRUTEMENT DES ENSEIGNANTS-CHERCHEURS - SESSION SYNCHRONISEE 2014 - LISTE des MEMBRES des CDS POSTES DE MAITRES DE CONFERENCE Numéro Poste Nature Concours Section(s) CNU Profil Labo d

  7. FACULT DES SCIENCES HUMAINES ET SOCIALES -SORBONNE

    E-print Network

    Pellier, Damien

    FACULTÉ DES SCIENCES HUMAINES ET SOCIALES - SORBONNE LICENCE EN SCIENCES HUMAINES ET SOCIALES ANNÉE UNIVERSITAIRE 2013-2014 MENTION SCIENCES DE L'ÉDUCATION L3 Faculté des Sciences humaines et sociales

  8. FACULT DES SCIENCES HUMAINES ET SOCIALES -SORBONNE

    E-print Network

    Pellier, Damien

    FACULTÉ DES SCIENCES HUMAINES ET SOCIALES - SORBONNE LICENCE EN SCIENCES HUMAINES ET SOCIALES ANNÉE UNIVERSITAIRE 2013-2014 MENTION SCIENCES DU Vaillant 92100 Boulogne-Billancourt L3, M1 et M2 Faculté des Sciences

  9. DES JUIFS LACS EN FRANCE Liliane Kuczynski

    E-print Network

    Boyer, Edmond

    familiaux. Des universitaires en vue, des écrivains ont retracé le leur : Albert Memmi le premier, Edgar Morin plus tard. Celui-ci, dans un article qui fit grand bruit (1989), définit ces « juifs laïcisés

  10. 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....

  11. Pharmacological and Therapeutic Effects of A3 Adenosine Receptor (A3AR) Agonists

    PubMed Central

    Fishman, Pnina; Bar-Yehuda, Sara; Liang, Bruce T.; Jacobson, Kenneth A.

    2011-01-01

    The Gi-coupled A3 adenosine receptor (A3AR) mediates anti-inflammatory, anticancer and anti-ischemic protective effects. The receptor is overexpressed in inflammatory and cancer cells, while low expression is found in normal cells, rendering the A3AR as a potential therapeutic target. Highly selective A3AR agonists have been synthesized and molecular recognition in the binding site has been characterized. The present review summarizes preclinical and clinical human studies demonstrating that A3AR agonists induce specific anti-inflammatory and anticancer effects via a molecular mechanism that entails modulation of the Wnt and the NF-?B signal transduction pathways. Currently, A3AR agonists are being developed for the treatment of inflammatory diseases including rheumatoid arthritis and psoriasis; ophthalmic diseases such as dry eye syndrome and glaucoma; liver diseases such as hepatocellular carcinoma and hepatitis. PMID:22033198

  12. Synthesis and biological evaluation of isoxazoline derivatives as potent M1 muscarinic acetylcholine receptor agonists.

    PubMed

    Huang, Minghua; Suk, Dae-Hwan; Cho, Nam-Chul; Bhattarai, Deepak; Kang, Soon Bang; Kim, Youseung; Pae, Ae Nim; Rhim, Hyewhon; Keum, Gyochang

    2015-04-01

    A series of azacyclic compounds substituted with isoxazole and 5-substituted isoxazolines were synthesized as acyclic modifications of the oxime class M1 mACh receptor agonist. Among them, 3-(tetrahydropyrin-3-yl)-5-(2-pyrrolodin-1-yl)isoxazoline compound 4f displayed potent and selective M1 mACh receptor agonist activity in the functional calcium mobilization assay (EC50=31nM). Introduction of 2-pyrrolidinone and 3-tetrahydropyridine groups are pivotal to the high potency. Moreover, 4f was found to facilitate non-amyloidogenic amyloid precursor protein (APP) processing by significantly increasing ERK1/2 phosphorylation and sAPP? secretion, known disease-modifying effects related to M1 mAChR agonists in Alzheimer's disease (AD). PMID:25765911

  13. Discovery and Optimization of Potent GPR40 Full Agonists Containing Tricyclic Spirocycles

    PubMed Central

    2013-01-01

    GPR40 (FFAR1 or FFA1) is a target of high interest being pursued to treat type II diabetes due to its unique mechanism leading to little risk of hypoglycemia. We recently reported the discovery of AM-1638 (2), a potent full agonist of GPR40. In this report, we present the discovery of GPR40 full agonists containing conformationally constrained tricyclic spirocycles and their structure–activity relationships leading to more potent agonists such as AM-5262 (26) with improved rat PK profile and general selectivity profile. AM-5262 enhanced glucose stimulated insulin secretion (mouse and human islets) and improved glucose homeostasis in vivo (OGTT in HF/STZ mice) when compared to AM-1638. PMID:24900707

  14. Discovery of DS-1558: A Potent and Orally Bioavailable GPR40 Agonist.

    PubMed

    Takano, Rieko; Yoshida, Masao; Inoue, Masahiro; Honda, Takeshi; Nakashima, Ryutaro; Matsumoto, Koji; Yano, Tatsuya; Ogata, Tsuneaki; Watanabe, Nobuaki; Hirouchi, Masakazu; Yoneyama, Tomoko; Ito, Shuichiro; Toda, Narihiro

    2015-03-12

    GPR40 is a G protein-coupled receptor that is predominantly expressed in pancreatic ?-cells. GPR40 agonists stimulate insulin secretion in the presence of high glucose concentration. On the basis of this mechanism, GPR40 agonists are possible novel insulin secretagogues with reduced or no risk of hypoglycemia. The improvement of in vitro activity and metabolic stability of compound 1 led to the discovery of 13, (3S)-3-ethoxy-3-(4-{[(1R)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]oxy}phenyl)propanoic acid, as a potent and orally available GPR40 agonist. Compound 13 (DS-1558) was found to have potent glucose lowering effects during an oral glucose tolerance test in ZDF rats. PMID:25815144

  15. 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

  16. 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; Lückmann, Michael; Rist, Øystein; Elster, Lisbeth; Högberg, 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

  17. 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.

  18. Electronic and structural features of ?-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 ?-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.

  19. Archives de sciences sociales des religions

    E-print Network

    Paris-Sud XI, Université de

    Archives de sciences sociales des religions Numéro 131-132 (juillet - décembre 2005) Varia », Archives de sciences sociales des religions [En ligne], 131-132 | juillet - décembre 2005, mis en ligne le religions #12;Genèse des émotions au sein des Assemblées de Dieu polynésiennes 2 Archives de sciences

  20. LA VITESSE DE REMONTE DES SPERMATOZODES

    E-print Network

    Boyer, Edmond

    vivants se trouvent dans la partie terminale de la trompe au moment où l'oeuf est pondu. Pour que cette dans la partie terminale des trompes. On relève des contradictions analogues dans les résultats obtenus spermatozoïdes dans la partie supérieure des trompes de Fallope, 2 h 25 m. après le coït. C'est pourquoi nous

  1. Rentre des tudiants UNIVERSIT BLAISE PASCAL

    E-print Network

    Sart, Remi

    Rentrée des étudiants étrangers UNIVERSIT� BLAISE PASCAL www.univ-bpclermont.fr COMMUNIQU� DE PRESSE Accueil des étudiants étrangers de l'Université Blaise Pascal Les échanges internationaux, chaque année, l'université Blaise Pascal envoie des étudiants à l'étranger et accueille des étudiants d

  2. Marché unique et développement des échanges

    Microsoft Academic Search

    Michael Freudenberg; Lionel Fontagné

    1999-01-01

    [fre] Marché unique et développement des échanges Contrairement à la théorie classique du commerce international, la première vague d'intégration européenne ne s'est pas traduite par un développement du commerce inter-branche reflétant une spécialisation accrue des pays . membres dans des produits pour lesquels ils détenaient un avantage comparatif. En revanche, le développement du commerce intra-branche reflète davantage une spécialisation des

  3. ECOLE PRATIQUE DES HAUTES ETUDES Ecole doctorale sciences des religions et systmes de pense

    E-print Network

    Paris-Sud XI, Université de

    ECOLE PRATIQUE DES HAUTES ETUDES Ecole doctorale « sciences des religions et systèmes de pensée » Doctorat de sciences des religions et systèmes de pensée, sociologie Nadia GARNOUSSI DE NOUVELLES HAUTES ETUDES Ecole doctorale « sciences des religions et systèmes de pensée » Doctorat de sciences des

  4. Additive melanoma suppression with intralesional phospholipid conjugated TLR7 agonists and systemic IL-2

    PubMed Central

    Hayashi, Tomoko; Chan, Michael; Norton, John T.; Wu, Christina C.N.; Yao, Shiyin; Cottam, Howard B.; Tawatao, Rommel I.; Corr, Maripat; Carson, Dennis A; Daniels, Gregory A.

    2010-01-01

    Objective There remains a compelling need for the development of treatments for unresectable melanoma. Agents that stimulate the innate immune response could provide advantages for cell based therapies. However there are conflicting reports concerning whether Toll-like receptor (TLR) signaling controls tumor growth. The objective of this study was to evaluate the effect of the intralesional administration of a TLR7 agonist in melanoma therapy. Methods B16cOVA melanoma was implanted to TLR7?/? mice to evaluate the roles of stromal TLR7 on melanoma growth. To capitalize on the potential deleterious effects of TLR7 stimulation on tumor growth, we injected melanoma tumor nodules with a newly developed and potent TLR7 agonist. Results B16 melanoma nodules expanded more rapidly in mice deficient in TLR7- and MyD88- compared to TLR9-deficient and wild type mice. Repeated injections with low doses of unconjugated TLR7 agonist were more effective at attenuating nodule size than a single high dose injection. To improve efficacy we conjugated the agonist to phospholipid or polyethylene glycol-phospholipid, which retained TLR7 specificity. The phospholipid conjugate was indeed more effective in reducing lesion size. Furthermore intralesional administration of the phospholipid TLR7 agonist conjugate enhanced the anti-melanoma effects of systemic IL-2 treatment and prolonged the survival of mice compared to IL-2 alone. Conclusion TLR7/MyD88 signaling in the stroma is involved in melanoma growth. Intralesional administration of a TLR7 agonist reduces the growth of melanoma nodules and enhances the anti-melanoma effects of IL-2. PMID:21030882

  5. Reversal of pertussis toxin-induced thermal allodynia by muscarinic cholinergic agonists in mice.

    PubMed

    Womer, D E; Shannon, H E

    2000-09-01

    The intrathecal administration of pertussis toxin (PTX) not only blocks the antinociceptive effects of the muscarinic cholinergic receptor agonist oxotremorine administered systemically, but also produces a long-lasting thermal allodynia in mice. The purpose of the present studies was to determine both the antinociceptive effects in normal mice and the antiallodynic effects in PTX-treated mice of systemically administered muscarinic cholinergic receptor agonists and cholinesterase inhibitors. In normal mice, antinociceptive effects were tested using a 55 degrees C water-bath tail-flick test. In mice treated 7 days previously with PTX (0.3 microg i.t.), antiallodynic effects were tested using a 45 degrees C water-bath tail-flick test. The nonselective high-efficacy muscarinic agonists oxotremorine, H-TZTP (3-(1,2, 5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine oxalate), and methylthio[2.2.1], (exo (+)3-(3-methylthio-1,2, 5-thiadiazol-4-yl)-1-azabicyclo[2.2.1]heptane oxalate), as well as vedaclidine, a mixed M(2)/M(4) muscarinic receptor partial agonist and M(1)/M(3)/M(5) muscarinic receptor antagonist, the nonselective partial agonists RS86 and pilocarpine, and the cholinesterase inhibitors physostigmine and tacrine all produced dose-related antinociception. Oxotremorine, H-TZTP and methylthio[2.2.1] produced dose-related reversals of PTX-induced thermal allodynia whereas vedaclidine produced a partial reversal and RS86 and pilocarpine, as well as physostigmine and tacrine, failed to reverse the allodynia. The present results provide further evidence that decrements in PTX-sensitive G(i/o)-protein functioning may be involved in initiating and/or maintaining some persistent or neuropathic pain states. Moreover, the present results suggest that muscarinic receptor agonists such as vedaclidine may be useful in the treatment of persistent pain states that are due at least in part to dysfunction of inhibitory second messenger systems. PMID:10974334

  6. 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 PPAR? agonists. Results In order to identify potential therapeutic targets positively modulated by pre-treatment with the PPAR? 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 PPAR? agonists treatment while it was strongly increased in ischemia-reperfusion. Conclusions Pre-treatment with PPAR? 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 PPAR? agonists supposes the preservation of the expression of several proteins essential for the maintenance of protein homeostasis not necessarily directly linked to PPAR? known-regulated targets. PMID:24944524

  7. Allosteric modulation of the glycine receptor activated by agonists differing in efficacy.

    PubMed

    Farley, Nicole-Marie M; Mihic, S John

    2015-05-01

    The glycine receptor (GlyR) is the predominant inhibitory neurotransmitter receptor in the brainstem and spinal cord but is also found in higher brain regions. GlyR function is affected by a variety of allosteric modulators including drugs of abuse, such as ethanol and inhalants and the ubiquitous divalent cation zinc. Two-electrode voltage-clamp experiments were conducted on Xenopus laevis oocytes expressing wild-type ?1 homomeric glycine receptors to compare the degree of enhancement produced by zinc on GlyR activated by two agonists (glycine vs. taurine) that vary markedly in their efficacies. Zinc potentiation of both glycine- and taurine-evoked currents was the same at the concentrations of agonists that produced the same currents, corresponding to 6% of the maximal effect of glycine compared to 23% of the maximal effect of taurine. Similar results were seen with 50 and 200mM ethanol. A direct comparison of agonist concentration-response curves showed that zinc enhancement was greater, overall, for taurine-activated than glycine-activated receptors. In addition, zinc only enhanced taurine- but not glycine-activated GlyR when agonists were applied at saturating concentrations. These data suggest that zinc affects taurine affinity, as well as the probability of channel opening at sub-maximal taurine concentrations, and that the magnitude of allosteric modulation at the GlyR depends on the efficacy of the agonist tested. This has implications for mutagenesis studies in which changes in the degree of allosteric modulation observed may result from mutation-induced changes in agonist efficacy. PMID:25721789

  8. Sigma receptor agonists: Receptor binding and effects on mesolimbic dopamine neurotransmission assessed by microdialysis

    PubMed Central

    Garcés-Ramírez, Linda; Green, Jennifer L.; Hiranita, Takato; Kopajtic, Theresa A.; Mereu, Maddalena; Thomas, Alexandra; Mesangeau, Christophe; Narayanan, Sanju; McCurdy, Christopher R.; Katz, Jonathan L.; Tanda, Gianluigi

    2010-01-01

    Background Two subtypes of sigma (?) receptors, ?1 and ?2, can be pharmacologically distinguished, and each may be involved in substance-abuse disorders. ?-receptor antagonists block cocaine place conditioning and ?-receptor agonists are self-administered in rats that previously self-administered cocaine. Self-administration has been related to increased dopamine (DA) neurotransmission for different drug classes. Actions of ?-receptor agonists on mesolimbic DA have not been fully characterized. Methods Receptor-binding studies assessed affinities of different ?-receptor ligands for ?-receptor subtypes, and for the DA transporter; effects on DA transmission in the rat nucleus accumbens shell were assessed using in-vivo microdialysis. Results Cocaine (0.1–1.0 mg/kg i.v.), the non-selective ?1/2-receptor agonist DTG (1.0–5.6 mg/kg i.v.), and the selective ?1-receptor agonist PRE-084 (0.32–10 mg/kg i.v.) dose-dependently increased DA, with maxima of about 275, 150, and 160%, respectively. DTG-induced stimulation of DA was antagonized by the nonselective ?1/2-receptor antagonist, BD 1008 (10 mg/kg i.p.), and by the preferential ?2-receptor antagonist SN79 (1–3 mg/kg i.p.), but not by the preferential ?1-receptor antagonist, BD 1063 (10–30 mg/kg i.p.). Neither PRE-084 nor cocaine was antagonized by either BD1063 or BD1008. Conclusions Stimulation of DA by ?-receptor agonists in a brain area involved in the reinforcing effects of cocaine was demonstrated. The effects appear to be mediated by ?2-receptors rather than ?1-receptors. However ?-receptors are not likely involved in mediating the acute cocaine- and PRE-084-induced stimulation of DA transmission. Different mechanisms might underlie the dopaminergic and reinforcing effects of ?-receptor agonists suggesting a dopamine-independent reinforcing pathway that may contribute to substance-abuse disorders. PMID:20950794

  9. GnRH agonists induce endometrial epithelial cell apoptosis via GRP78 down-regulation.

    PubMed

    Weng, Huinan; Liu, Fenghua; Hu, Shuiwang; Li, Li; Wang, Yifeng

    2014-11-01

    BackgroundEndometriosis is a benign chronic gynecological disease that affects women of reproductive age, characterized by the presence of functional endometrial tissues outside the uterine cavity. GnRH agonists exhibit anti-proliferative and apoptosis-enhancing activities and have long been used for the treatment of endometriosis. There is a critical need to identify the signaling modules involving GnRH agonist therapy for the treatment of endometriosis. In this study, we compared the proteomic profiles of endometriosis in patients before and after GnRH agonist therapy to identify proteins that might provide further information concerning the mechanisms underlying the functions of GnRH agonists.MethodsA total of 55 protein spots with different abundances were observed using Difference Gel Electrophoresis (DIGE), and 26 of these proteins were assigned clear identities through Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Tandem Mass Spectroscopy (MALDI-TOF/TOF MS).ResultsWe validated four of these proteins through Western blotting and immunohistochemistry using human endometrial tissue. We also characterized the effect of Leuprolide acetate (LA) on the apoptosis of eutopic endometrial epithelial cells. LA treatment significantly promoted the apoptosis of eutopic endometrial epithelial cells and inhibited the expression of the anti-apoptotic factor GRP78. GRP78 knockdown enhanced LA-induced cell apoptosis, whereas, the overexpression of GRP78 in eutopic endometrial epithelial cells suppresses LA-induced apoptosis.ConclusionThese results suggest that GnRH agonists induce endometrial epithelial cell apoptosis via GRP78 down-regulation. This study might provide an important molecular framework for further evaluation of GnRH agonist therapy. PMID:25367189

  10. A membrane-based microfluidic device for controlling the flux of platelet agonists into flowing blood†

    PubMed Central

    Neeves, Keith B.; Diamond, Scott L.

    2008-01-01

    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 × 10?18 mol ?m?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 × 10?18 mol ?m?2 s?1), we observed little to no aggregation. At the higher fluxes, we observed monolayer (2.4 × 10?18 mol ?m?2 s?1) and multilayer (4.4 × 10?18 mol ?m?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

  11. 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

  12. Peroxidative metabolism of beta2-agonists salbutamol and fenoterol and their analogues.

    PubMed

    Reszka, Krzysztof J; McGraw, Dennis W; Britigan, Bradley E

    2009-06-01

    Phenolic beta(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 beta(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 beta(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 structural analogue, metaproteronol, were detected by direct EPR. Analysis of these spectra suggests that oxidation of fenoterol and metaproterenol, but not terbutaline, causes their transformation through intramolecular cyclization by addition of their amino nitrogen to the aromatic ring. Together, these results indicate that phenolic beta(2)-agonists function as substrates for airway peroxidases and that the resulting products differ in their structural and functional properties from their parent compounds. They also suggest that these transformations can be modulated by pharmacological approaches using appropriate peroxidase inhibitors or alternative substrates. These processes may affect therapeutic efficacy and also play a role in adverse reactions of the beta(2)-agonists. PMID:19462961

  13. PPAR? Agonists Promote Oligodendrocyte Differentiation of Neural Stem Cells by Modulating Stemness and Differentiation Genes

    PubMed Central

    Kanakasabai, Saravanan; Pestereva, Ecaterina; Chearwae, Wanida; Gupta, Sushil K.; Ansari, Saif; Bright, John J.

    2012-01-01

    Neural stem cells (NSCs) are a small population of resident cells that can grow, migrate and differentiate into neuro-glial cells in the central nervous system (CNS). Peroxisome proliferator-activated receptor gamma (PPAR?) is a nuclear receptor transcription factor that regulates cell growth and differentiation. In this study we analyzed the influence of PPAR? agonists on neural stem cell growth and differentiation in culture. We found that in vitro culture of mouse NSCs in neurobasal medium with B27 in the presence of epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) induced their growth and expansion as neurospheres. Addition of all-trans retinoic acid (ATRA) and PPAR? agonist ciglitazone or 15-Deoxy-?12,14-Prostaglandin J2 (15d-PGJ2) resulted in a dose-dependent inhibition of cell viability and proliferation of NSCs in culture. Interestingly, NSCs cultured with PPAR? agonists, but not ATRA, showed significant increase in oligodendrocyte precursor-specific O4 and NG2 reactivity with a reduction in NSC marker nestin, in 3–7 days. In vitro treatment with PPAR? agonists and ATRA also induced modest increase in the expression of neuronal ?-III tubulin and astrocyte-specific GFAP in NSCs in 3–7 days. Further analyses showed that PPAR? agonists and ATRA induced significant alterations in the expression of many stemness and differentiation genes associated with neuro-glial differentiation in NSCs. These findings highlight the influence of PPAR? agonists in promoting neuro-glial differentiation of NSCs and its significance in the treatment of neurodegenerative diseases. PMID:23185633

  14. ''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.

  15. Master Management spcialit Management des relations humaines

    E-print Network

    Jeanjean, Louis

    ressources humaines ; Acquérir des connaissances pointues en matière de gestion et de pilotage du changement organisationnel ; Acquérir des connaissances approfondies dans la gestion des relations sociales ; Acquérir les collectifs de travail ; Initier, accompagner et gérer le changement dans l'organisation ; Maîtriser les

  16. Archives de sciences sociales des religions

    E-print Network

    Paris-Sud XI, Université de

    Archives de sciences sociales des religions Numéro 144 (octobre-décembre 2008) Varia de l'�tat chinois, 1900-2008 », Archives de sciences sociales des religions [En ligne], 144 sciences sociales des religions #12; #12; #12;#12; #12; #12; #12; #12; #12

  17. Archives de sciences sociales des religions

    E-print Network

    Paris-Sud XI, Université de

    Archives de sciences sociales des religions Numéro 140 (octobre - décembre 2007) Varia) © Archives de sciences sociales des religions #12;Yves Déloye, Les voix de Dieu. Pour une autre histoire du suffrage électoral : le clergé (...) 2 Archives de sciences sociales des religions, 140 | octobre

  18. Archives de sciences sociales des religions

    E-print Network

    Paris-Sud XI, Université de

    Archives de sciences sociales des religions 157 (janvier-mars 2012) Christianismes en Océanie). ................................................................................................................................................................................................................................................................................................ Référence électronique Yannick Fer, « Introduction », Archives de sciences sociales des religions [En ligne pour l'édition électronique ouverte) © Archives de sciences sociales des religions #12;Yannick Fer

  19. Archives de sciences sociales des religions

    E-print Network

    Boyer, Edmond

    Archives de sciences sociales des religions 131-132 (juillet - décembre 2005) Varia guerre indo-pakistanaise de 1999 », Archives de sciences sociales des religions [En ligne], 131 de l'édition papier. © Archives de sciences sociales des religions #12;Rites publics et deuil

  20. Archives de sciences sociales des religions

    E-print Network

    Paris-Sud XI, Université de

    Archives de sciences sociales des religions 157 (janvier-mars 2012) Christianismes en Océanie évangéliques », Archives de sciences sociales des religions [En ligne], 157 | janvier-mars 2012, mis en ligne pour l'édition électronique ouverte) © Archives de sciences sociales des religions #12;Yannick Fer Le

  1. Efficient DNA sticker algorithms for DES

    Microsoft Academic Search

    Zhihua Chen; Xiutang Geng; Jin Xu

    2008-01-01

    The data encryption standard (DES) is an algorithm with approximate 72 quadrillion possible keys. The security of the DES is based on the difficulty of picking out the right key after the 16-round nonlinear function operations. In this paper, we propose a concrete recursive sticker molecular algorithm to the DES. The molecular sticker algorithm includes three parts: initializing the key

  2. Facult des tudes suprieures et postdoctorales

    E-print Network

    Charette, André

    visiteurs de recherche. La FESP exerce donc un rôle de leader et de facilitateur tant dans la gestion desUr tant dans la gestion des dossiers coUrants qUe dans l'identiFication des grands enjeUx d'aUjoUrd'hUi et

  3. Lipodystrophies : perceptions et souffrance des personnes atteintes,

    E-print Network

    Paris-Sud XI, Université de

    Lipodystrophies : perceptions et souffrance des personnes atteintes, réponses collectives 117 Alice Desclaux, Sokhna Boye 1. INTRODUCTION Les lipodystrophies sont définies par la médecine comme des ailleurs il existe actuellement un débat sur la prévalence des lipodystrophies dans les pays du Sud. Elles

  4. CARACTRES CYTOLOGIQUES DES CELLULES GONADOTROPES, THYROTROPES, CORTICOTROPES,

    E-print Network

    Boyer, Edmond

    CARACTÈRES CYTOLOGIQUES DES CELLULES GONADOTROPES, THYRÉOTROPES, CORTICOTROPES, SOMATOTROPES ET DES CELLULES A PROLACTINE PRÉSENTES DANS LE LOBE ANTÉRIEUR DE L'HYPOPHYSE DES BOVINS M.-P. DUBOIS M. HERLANT). - Orange G, séparant entre elles les trois catégories de cellules élaborant les hormones protidiques (STH

  5. Bioclimatologie Utilisation des cellules au silicium amorphe

    E-print Network

    Paris-Sud XI, Université de

    Bioclimatologie Utilisation des cellules au silicium amorphe pour la mesure du rayonnement simulation et la confrontation expérimentale ccellules au silicium amorphe par rapport à celles des capteurs existants montrent l'intérêt des cellules au silicium amorphe pour la mesure du

  6. Treatment with LXR agonists after focal cerebral ischemia prevents brain damage

    PubMed Central

    Sironi, Luigi; Mitro, Nico; Cimino, Mauro; Gelosa, Paolo; Guerrini, Uliano; Tremoli, Elena; Saez, Enrique

    2011-01-01

    Stroke is characterized by massive inflammation in areas surrounding the injury that magnifies damage to the brain. The Liver X Receptors (LXRs) are nuclear receptors that regulate cholesterol, lipid, and glucose metabolism. Synthetic LXR agonists have potent anti-inflammatory properties in a variety of settings, including neuroinflammation. However, the ability of LXR agonists to suppress stroke-associated inflammation has not been evaluated. Here, we have used time-lapse magnetic resonance imaging (MRI) to show that a single dose of an LXR ligand administered post-injury dramatically reduces brain damage in a model of acute brain ischemia. Neuroprotection was associated with suppression of neuroinflammation. PMID:18789330

  7. Discovery and optimization of novel purines as potent and selective CB2 agonists.

    PubMed

    Hollinshead, Sean P; Astles, Peter C; Chambers, Mark G; Johnson, Michael P; Palmer, John; Tidwell, Michael W

    2012-08-01

    A focused screening strategy identified thienopyrimidine 1 as a hCB2 cannabinoid receptor agonist with moderate selectivity over the hCB1 receptor. This initial hit suffered from poor in vitro metabolic stability and high in vivo clearance. Structure-activity relationships describe the optimization and modification to a less lipophilic purine core. Examples from this novel series were found to be highly potent and fully efficacious agonists of the human CB2 receptor with excellent selectivity against CB1. Compound 10 possesses good biopharmaceutical properties, is highly water soluble and demonstrates robust oral activity in rodent models of joint pain. PMID:22765893

  8. Engineering of Crystalline Combination Inhalation Particles of a Long-Acting ? 2 -agonist and a Corticosteroid

    Microsoft Academic Search

    Chonladda Pitchayajittipong; Jagdeep Shur; Robert Price

    2009-01-01

    Purpose  Engineering of inhalation particles incorporating, in each individual particle, a combination of a long-acting ?-agonist and\\u000a a glucocorticosteroid in a pre-determined and constant ratio for delivery via a dry powder inhaler (DPI).\\u000a \\u000a \\u000a \\u000a Methods  Individual crystalline particles containing both the glucocorticosteroid fluticasone propionate (FP) and long-acting ?-agonist\\u000a salmeterol (SX) were prepared, in a ratio of 10:1, using the solution atomization and crystallization

  9. The role of inhaled long-acting beta-2 agonists in the management of asthma.

    PubMed Central

    Kelly, H. William; Harkins, Michelle S.; Boushey, Homer

    2006-01-01

    The role of inhaled beta-2 agonists in the management of asthma has changed significantly over the last several years. This review outlines the most recent understanding of the pathophysiology of asthma and the studies that define the roles that both short- and long-acting beta-2 agonists play in therapy for this disease. A concentration on the clinical pharmacology and genetic implications for clinical use of this class of drugs in accordance with the national and international guidelines are described. PMID:16532973

  10. An In Situ Autologous Tumor Vaccination with Combined Radiation Therapy and TLR9 Agonist Therapy

    PubMed Central

    Zhang, Huagang; Liu, Laibin; Yu, Dong; Kandimalla, Ekambar R.; Sun, Hui Bin; Agrawal, Sudhir; Guha, Chandan

    2012-01-01

    Purpose Recent studies have shown that a new generation of synthetic agonist of Toll-like receptor (TLR) 9 consisting a 3?-3?-attached structure and a dCp7-deaza-dG dinucultodie shows more potent immunostimulatory effects in both mouse and human than conventional CpG oligonucleotides. Radiation therapy (RT) provides a source of tumor antigens that are released from dying, irradiated, tumor cells without causing systemic immunosuppression. We, therefore, examined effect of combining RT with a designer synthetic agonist of TLR9 on anti-tumoral immunity, primary tumor growth retardation and metastases in a murine model of lung cancer. Methods Grouped C57BL/6 and congenic B cell deficient mice (B?/?) bearing footpad 3LL tumors were treated with PBS, TLR9 agonist, control oligonucelotide, RT or the combination of RT and TLR9 agonist. Immune phenotype of splenocytes and serum IFN-? and IL-10 levels were analyzed by FACS and ELISA, 24 h after treatment. Tumor growth, lung metastases and survival rate were monitored and tumor specific antibodies in serum and deposition in tumor tissue were measured by ELISA and immunofluorescence. Results TLR9 agonist expanded and activated B cells and plasmacytoid dendritic cells in wild-type mice and natural killer DCs (NKDCs) in B cell-deficient (B?/?) mice bearing ectopic Lewis lung adenocarcinoma (3LL). Combined RT with TLR9 agonist treatment inhibited 3LL tumor growth in both wild type and B?/? mice. A strong tumor-specific humoral immune response (titer: 1/3200) with deposition of mouse IgG auto-antibodies in tumor tissue were found in wildtype mice, whereas the number of tumor infiltrating NKDCs increased in B?/? mice following RT+ TLR9 agonist therapy. Furthermore, mice receiving combination therapy had fewer lung metastases and a higher survival than single treatment cohorts. Conclusions Combination therapy with TLR9 agonist and RT induces systemic anti-tumoral humoral response, augments tumoral infiltration of NKDCs, reduces pulmonary metastases and improves survival in a murine model of 3LL cancer. PMID:22666458

  11. EGF Receptor Transactivation Mediated by the Proteolytic Production of EGF-like Agonists

    NSDL National Science Digital Library

    Graham Carpenter (Vanderbilt University School of Medicine; Department of Biochemistry REV)

    2000-01-18

    The epidermal growth factor (EGF) receptor is activated not only by EGF-like ligands, but also by stimuli that do not directly act on the receptor, including agonists of G protein–coupled receptors and certain environmental stresses such as ionizing radiation. Carpenter discusses two reports that indicate EGF receptor activation by such heterologous stimuli may occur through the action of proteases that release cell surface EGF-like growth factor precursors. This mechanism of EGF receptor transactivation appears to involve the generation of soluble agonists.

  12. Beta 2-adrenergic agonist as adjunct therapy to levodopa in Parkinson's disease.

    PubMed

    Alexander, G M; Schwartzman, R J; Nukes, T A; Grothusen, J R; Hooker, M D

    1994-08-01

    We studied the effect of the beta 2-adrenergic agonist albuterol on Parkinson's disease (PD) patients receiving chronic levodopa treatment. The albuterol-treated patients demonstrated reduced parkinsonian symptoms and an increased ability to tap their index finger between two points 20 cm apart, and were able to perform a "walk test" in 70% of their control time. Three patients currently on chronic albuterol therapy still show amelioration of their parkinsonian symptoms, and two have reduced their daily levodopa dose. This study suggests that beta 2-adrenergic agonists as adjunct therapy to levodopa may be beneficial in PD. PMID:8058159

  13. Identification of spirocyclic piperidine-azetidine inverse agonists of the ghrelin receptor.

    PubMed

    Kung, Daniel W; Coffey, Steven B; Jones, Ryan M; Cabral, Shawn; Jiao, Wenhua; Fichtner, Michael; Carpino, Philip A; Rose, Colin R; Hank, Richard F; Lopaze, Michael G; Swartz, Roger; Chen, Hou Tommy; Hendsch, Zachary; Posner, Bruce; Wielis, Christopher F; Manning, Brian; Dubins, Jeffrey; Stock, Ingrid A; Varma, Sam; Campbell, Mary; DeBartola, Demetria; Kosa-Maines, Rachel; Steyn, Stefanus J; McClure, Kim F

    2012-07-01

    The discovery of spirocyclic piperidine-azetidine inverse agonists of the ghrelin receptor is described. The characterization and redressing of the issues associated with these compounds is detailed. An efficient three-step synthesis and a binding assay were relied upon as the primary means of rapidly improving potency and ADMET properties for this class of inverse agonist compounds. Compound 10 n bearing distributed polarity in the form of an imidazo-thiazole acetamide and a phenyl triazole is a unit lower in logP and has significantly improved binding affinity compared to the hit molecule 10a, providing support for further optimization of this series of compounds. PMID:22677316

  14. ? opioid receptor agonist-selective regulation of interleukin-4 in T lymphocytes.

    PubMed

    Börner, Christine; Lanciotti, Sara; Koch, Thomas; Höllt, Volker; Kraus, Jürgen

    2013-10-15

    Opioids are irreplaceable for the treatment of severe pain. However, opioid-induced immunomodulation affects therapies. Here we report that treatment of human T lymphocytes with the opioids fentanyl, methadone, loperamide and beta-endorphin resulted in a strong induction of the cytokine interleukin-4. In contrast, morphine and buprenorphine induced markedly and significantly lower levels of interleukin-4 mRNA and protein. These findings suggest agonist-biased ? opioid receptor signaling in T cells. In the future, better knowledge about agonist-specific immunomodulatory effects of opioids offers the possibility to select drugs for a therapy with more favorable and/or less detrimental side effects in immune cells. PMID:23965172

  15. Androgen Deprivation Therapy and the Re-emergence of Parenteral Estrogen in Prostate Cancer

    PubMed Central

    Phillips, Iain; Shah, Syed I A; Duong, Trinh; Abel, Paul; Langley, Ruth E

    2014-01-01

    Androgen deprivation therapy (ADT) resulting in testosterone suppression is central to the management of prostate cancer (PC). As PC incidence increases, ADT is more frequently prescribed, and for longer periods of time as survival improves. Initial approaches to ADT included orchiectomy or oral estrogen (diethylstilbestrol [DES]). DES reduces PC-specific mortality, but causes substantial cardiovascular (CV) toxicity. Currently, luteinizing hormone-releasing hormone agonists (LHRHa) are mainly used; they produce low levels of both testosterone and estrogen (as estrogen in men results from the aromatization of testosterone), and many toxicities including osteoporosis, fractures, hot flashes, erectile dysfunction, muscle weakness, increased risk for diabetes, changes in body composition, and CV toxicity. An alternative approach is parenteral estrogen, it suppresses testosterone, appears to mitigate the CV complications of oral estrogen by avoiding first-pass hepatic metabolism, and avoids complications caused by estrogen deprivation. Recent research on the toxicity of ADT and the rationale for revisiting parenteral estrogen is discussed. PMID:24932461

  16. Molecular Determinants of Agonist Selectivity in Glutamate-Gated Chloride Channels Which Likely Explain the Agonist Selectivity of the Vertebrate Glycine and GABAA-? Receptors

    PubMed Central

    Blarre, Thomas; Bertrand, Hugues-Olivier; Acher, Francine C.; Kehoe, JacSue

    2014-01-01

    Orthologous Cys-loop glutamate-gated chloride channels (GluClR’s) have been cloned and described electrophysiologically and pharmacologically in arthropods and nematodes (both members of the invertebrate ecdysozoan superphylum). Recently, GluClR’s from Aplysia californica (a mollusc from the lophotrochozoan superphylum) have been cloned and similarly studied. In spite of sharing a common function, the ecdysozoan and lophotrochozoan receptors have been shown by phylogenetic analyses to have evolved independently. The recent crystallization of the GluClR from C. elegans revealed the binding pocket of the nematode receptor. An alignment of the protein sequences of the nematode and molluscan GluClRs showed that the Aplysia receptor does not contain all of the residues defining the binding mode of the ecdysozoan receptor. That the two receptors have slightly different binding modes is not surprising since earlier electrophysiological and pharmacological experiments had suggested that they were differentially responsive to certain agonists. Knowledge of the structure of the C. elegans GluClR has permitted us to generate a homology model of the binding pocket of the Aplysia receptor. We have analyzed the differences between the two binding modes and evaluated the relative significance of their non-common residues. We have compared the GluClRs electrophysiologically and pharmacologically and we have used site-directed mutagenesis on both receptor types to test predictions made from the model. Finally, we propose an explanation derived from the model for why the nematode receptors are gated only by glutamate, whereas the molluscan receptors can also be activated by ?-alanine, GABA and taurine. Like the Aplysia receptor, the vertebrate glycine and GABAA-? receptors also respond to these other agonists. An alignment of the sequences of the molluscan and vertebrate receptors shows that the reasons we have given for the ability of the other agonists to activate the Aplysia receptor also explain the agonist profile seen in the glycine and GABAA-? receptors. PMID:25259865

  17. Exercise as an Adjunct Treatment for Opiate Agonist Treatment: Review of the Current Research and Implementation Strategies

    Microsoft Academic Search

    Jeremiah Weinstock; Heather K. Wadeson; Jaci L. VanHeest

    2012-01-01

    Opiate dependence is a significant public health concern linked to poor quality of life, co-morbid psychiatric disorders, and high costs to society. Current opiate agonist treatments are an effective but limited intervention. Adjunctive interventions could improve and augment opiate agonist treatment outcomes, including drug abstinence, quality of life, and physical health. This article reviews exercise as an adjunctive intervention for

  18. The Use of Anchored Agonists of Phagocytic Receptors for Cancer Immunotherapy: B16-F10 Murine Melanoma Model

    PubMed Central

    Janotová, Tereza; Jalovecká, Marie; Auerová, Marie; Švecová, Ivana; Bruzlová, Pavlína; Maierová, Veronika; Kumžáková, Zuzana; ?unátová, Št?pánka; Vl?ková, Zuzana; Caisová, Veronika; Rozsypalová, Petra; Luká?ová, Katarína; Vácová, Nikol; Wachtlová, Markéta; Salát, Ji?í; Lieskovská, Jaroslava; Kopecký, Jan; Ženka, Jan

    2014-01-01

    The application of the phagocytic receptor agonists in cancer immunotherapy was studied. Agonists (laminarin, molecules with terminal mannose, N-Formyl-methioninyl-leucyl-phenylalanine) were firmly anchored to the tumor cell surface. When particular agonists of phagocytic receptors were used together with LPS (Toll-like receptor agonist), high synergy causing tumour shrinkage and a temporary or permanent disappearance was observed. Methods of anchoring phagocytic receptor agonists (charge interactions, anchoring based on hydrophobic chains, covalent bonds) and various regimes of phagocytic agonist/LPS mixture applications were tested to achieve maximum therapeutic effect. Combinations of mannan/LPS and f-MLF/LPS (hydrophobic anchors) in appropriate (pulse) regimes resulted in an 80% and 60% recovery for mice, respectively. We propose that substantial synergy between agonists of phagocytic and Toll-like receptors (TLR) is based on two events. The TLR ligand induces early and massive inflammatory infiltration of tumors. The effect of this cell infiltrate is directed towards tumor cells, bearing agonists of phagocytic receptors on their surface. The result of these processes was effective killing of tumor cells. This novel approach represents exploitation of innate immunity mechanisms for treating cancer. PMID:24454822

  19. Effect of beta-ADrenergic Agonist on Cyclic AMP Synthesis in Chicken Skeletal Muscle Cells in Culture

    NASA Technical Reports Server (NTRS)

    Young, R. B.; Bridge, K. Y.; Rose, M. Franklin (Technical Monitor)

    2000-01-01

    Several beta-adrenergic receptor (bAR) agonists are known to cause hypertrophy of skeletal muscle tissue. Because it seems logical that these agonists exert their action on muscle through stimulation of cAMP synthesis, five bAR agonists encompassing a range in activity from strong to weak were evaluated for their ability to stimulate cAMP accumulation in embryonic chicken skeletal muscle cells in culture. Two strong agonists (epinephrine and isoproterenol), one moderate agonist (albuterol), and two weak agonists known to cause hypertrophy in animals (clenbuterol and cimaterol) were studied. Dose response curves were determined over six orders of magnitude in concentration for each agonist, and values were determined for their maximum stimulation of cAMP synthesis rate (Bmax) and the agonist concentration at which 50% stimulation of cAMP synthesis (EC50) occurred. Bmax values decreased in the following order: isoproterenol, epinephrine, albuterol, cimaterol, clenbuterol. Cimaterol and clenbuterol at their Bmax levels were approximately 15-fold weaker than isoproterenol in stimulating the rate of cAMP synthesis. In addition, the EC50 values for isoproterenol, cimaterol, clenbuterol, epinephrine, and albuterol were 360 nM, 630 nM, 900 nM, 2,470 nM, and 3,650 nM, respectively. Finally, dose response curves show that the concentrations of cimaterol and clenbuterol in culture media at concentrations known to cause significant muscle hypertrophy in animals had no detectable effect on stimulation of CAMP accumulation in chicken skeletal muscle cells.

  20. The interaction of cannabinoid receptor agonists, CP55940 and WIN55212-2 with membranes using solid state 2

    E-print Network

    Yang, De-Ping

    The interaction of cannabinoid receptor agonists, CP55940 and WIN55212-2 with membranes using solid Available online 1 December 2010 Keywords: Cannabinoid receptor agonist Win55212-2 CP55940 THC Lipid of the bilayer. Our studies show that the cannabinoid ligands induce lateral phase separation in the lipid

  1. Self-Administration of Agonists Selective for Dopamine D2, D3, and D4 Receptors by Rhesus Monkeys

    PubMed Central

    Koffarnus, Mikhail N.; Collins, Gregory T.; Rice, Kenner C.; Chen, Jianyong; Woods, James H.; Winger, Gail

    2013-01-01

    Dopamine receptor mechanisms are thought to play a role in the reinforcing effects of cocaine and other abused drugs. The lack of receptor-selective agonists has made it difficult to determine the role of the individual dopamine receptors in mediating these reinforcing effects. In this study, rhesus monkeys with a history of intravenous cocaine self-administration were tested for the reinforcing effects of several D3-preferring agonists, a D2-preferring agonist, and a D4 agonist. The D2-preferring agonist did not maintain responding in any monkeys, and the D4 agonist was self-administered at low rates, just above those maintained by saline in one monkey. The D3-preferring agonists were self-administered by approximately half of the animals, although at lower rates than cocaine. These results indicate the apparent limited reinforcing effectiveness of D2-like agonists requires activity at D3 receptors. Previous data from this laboratory and others also suggest that these drugs may not serve as reinforcers directly; the behavior may be maintained by response-contingent delivery of stimuli previously paired with cocaine. The ability of drug-related stimuli to maintain responding apparently differs among monkeys and other organisms, and may be related to individual differences in drug-taking behavior in humans. PMID:22785383

  2. De novo peptide design with C3a receptor agonist and antagonist activities: theoretical predictions and experimental validation.

    PubMed

    Bellows-Peterson, Meghan L; Fung, Ho Ki; Floudas, Christodoulos A; Kieslich, Chris A; Zhang, Li; Morikis, Dimitrios; Wareham, Kathryn J; Monk, Peter N; Hawksworth, Owen A; Woodruff, Trent M

    2012-05-10

    Targeting the complement component 3a receptor (C3aR) with selective agonists or antagonists is believed to be a viable therapeutic option for several diseases such as stroke, heart attack, reperfusion injuries, and rheumatoid arthritis. We designed a number of agonists, partial agonists, and antagonists of C3aR using our two-stage de novo protein design framework. Of the peptides tested using a degranulation assay in C3aR-transfected rat basophilic leukemia cells, two were prominent agonists (EC(50) values of 25.3 and 66.2 nM) and two others were partial agonists (IC(50) values of 15.4 and 26.1 nM). Further testing of these lead compounds in a calcium flux assay in U937 cells yielded similar results although with reduced potencies compared to transfected cells. The partial agonists also displayed full antagonist activity when tested in a C3aR inhibition assay. In addition, the electrostatic potential profile was shown to potentially discriminate between full agonists and partial agonists. PMID:22500977

  3. The G protein-biased ?-opioid receptor agonist RB-64 is analgesic with a unique spectrum of activities in vivo.

    PubMed

    White, Kate L; Robinson, J Elliott; Zhu, Hu; DiBerto, Jeffrey F; Polepally, Prabhakar R; Zjawiony, Jordan K; Nichols, David E; Malanga, C J; Roth, Bryan L

    2015-01-01

    The hypothesis that functionally selective G protein-coupled receptor (GPCR) agonists may have enhanced therapeutic benefits has revitalized interest for many GPCR targets. In particular, although ?-opioid receptor (KOR) agonists are analgesic with a low risk of dependence and abuse, their use is limited by a propensity to induce sedation, motor incoordination, hallucinations, and dysphoria-like states. Several laboratories have produced a body of work suggesting that G protein-biased KOR agonists might be analgesic with fewer side effects. Although that has been an intriguing hypothesis, suitable KOR-selective and G protein-biased agonists have not been available to test this idea. Here we provide data using a G protein-biased agonist, RB-64 (22-thiocyanatosalvinorin A), which suggests that KOR-mediated G protein signaling induces analgesia and aversion, whereas ?-arrestin-2 signaling may be associated with motor incoordination. Additionally, unlike unbiased KOR agonists, the G protein-biased ligand RB-64 does not induce sedation and does not have anhedonia-like actions, suggesting that a mechanism other than G protein signaling mediates these effects. Our findings provide the first evidence for a highly selective and G protein-biased tool compound for which many, but not all, of the negative side effects of KOR agonists can be minimized by creating G protein-biased KOR agonists. PMID:25320048

  4. Are fish oil omega-3 long-chain fatty acids and their derivatives peroxisome proliferator-activated receptor agonists?

    Microsoft Academic Search

    Osman ABSM Gani

    2008-01-01

    BACKGROUND: Peroxisome proliferator-activated receptors (PPAR?, PPAR?, and PPAR?) are physiological sensors for glucose and lipid homeostasis. They are also the targets of synthetic drugs; such as fibrates as PPAR? agonists which lower lipid level, and glitazones as PPAR? agonists which lower glucose level. As diabetes and metabolic diseases are often associated with high blood glucose and lipid levels, drugs that

  5. Comptes Rendus des JNC 17 -Poitiers 2011 valuation des performances des modles d'homognisation pour des fibres alatoirement

    E-print Network

    Paris-Sud XI, Université de

    méthodes d'homogénéisation analytiques de Mori-Tanaka et auto-cohérente ont été utilisées pour évaluer les forme des fibres aléatoires. Les estimations du modèle de Mori-Tanaka sont légèrement plus rigides que que les résultats des méthodes éléments finis et Mori-Tanaka. Abstract Analytical homogenization

  6. Paternité des articles et intérêts concurrents : une analyse des recommandations aux auteurs des journaux traitant de pratique pharmaceutique

    PubMed Central

    Courbon, Ève; Tanguay, Cynthia; Lebel, Denis; Bussières, Jean-François

    2014-01-01

    RÉSUMÉ Contexte : La présence d’auteurs honorifiques et fantômes ainsi que les intérêts concurrents représentent des difficultés bien documentées, liées à la publication d’articles scientifiques. Il existe des lignes directrices encadrant la rédaction et la publication de manuscrits scientifiques, notamment celles de l’International Committee of Medical Journal Editors (ICMJE). Objectifs : L’objectif principal de cette étude descriptive et transversale visait à recenser les instructions portant sur la paternité des articles et les intérêts concurrents provenant des recommandations aux auteurs des journaux traitant de pratique pharmaceutique. L’objectif secondaire visait à déterminer des mesures correctrices pour une paternité des articles plus transparente. Méthode : La recherche a débuté par l’identification des journaux traitant de pratique pharmaceutique. La consultation des instructions aux auteurs des journaux a permis ensuite de recenser les recommandations destinées à éviter les problèmes de paternité des articles et d’intérêts concurrents. Finalement, les membres de l’équipe de recherche se sont consultés afin de définir des mesures correctrices possibles à l’intention des chercheurs. Résultats : Des 232 journaux traitant de pharmacie, 33 ont été définis comme traitant de pratique pharmaceutique. Un total de 24 (73 %) journaux mentionnaient suivre la politique de l’ICMJE, 14 (42 %) demandaient aux auteurs de remplir un formulaire de déclaration d’intérêts concurrents au moment de la soumission de l’article, 17 (52 %) présentaient une définition de la qualité d’auteur et 5 (15 %) demandaient de détailler les contributions de chaque auteur. Une grille de 40 critères a été élaborée pour définir l’attribution du statut d’auteur. Conclusion : Moins de la moitié des journaux demandait aux auteurs de transmettre un formulaire de déclaration des intérêts concurrents au moment de la soumission d’un article et seulement la moitié des journaux avait donné une définition de la qualité d’auteur. La publication scientifique de travaux sur les pratiques pharmaceutiques n’est pas à l’abri des manques de transparence liés à la publication. L’utilisation d’une grille décrivant la contribution de chaque auteur et la publication en ligne des travaux peuvent contribuer à limiter ces risques. PMID:24970938

  7. Annotation smantique pour des domaines spcialiss et des ontologies riches

    E-print Network

    sur deux textes décrivant des réglementations métier. Notre approche obtient de bons résultats. En-measure in the label and position predictions with different settings. This suggests that human annotators can

  8. Habilitation `a Diriger des Recherches "Simulation numerique des ecoulements

    E-print Network

    Franchi, Jacques

    : chromatographie ; · physique des plasmas : tokamak, vent solaire, relativit´e g´en´erale ; · autres : trafic principe de conservation de certaines quantit´es comme la masse, l'´energie, l'impul- sion ; · un principe

  9. SURVEILLANCE ET CONTROLE DES ACTIVITES DES NAVIRES EN MER

    E-print Network

    Boyer, Edmond

    : Pour garantir aujourd'hui des conditions sécuritaires de passage dans les eaux territoriales et, clandestine immigrants, piracy, toxic waste pollution, accidents, etc.). Key words: Maritime border security fréquentent par an la Méditerranée et 50 millions de passagers sont transportés. La carte suivante (figure 1

  10. Techniken & Sprachen des Semantic Web Techniken & Sprachen des Semantic Web

    E-print Network

    Pfeifer, Holger

    World Wide Web (7) Tim Berners-Lee Proposal 1989: Hypertextsystem als Infrastrukturprinzp f Berners-Lee) 1989: An intriguing possibility, given a large hypertext database with typed links, Inst. f¨ur KI, Uni Ulm 3 - 10 Techniken & Sprachen des Semantic Web Aber ... CERN Proposal, (Tim

  11. Facult des arts et des sciences Dpartement de science politique

    E-print Network

    Parrott, Lael

    . 369-384. Weapons of Mass Destruction Commission (Hans Blix Commission), rapport final, «Weapons opérations de maintien de la paix, le contrôle de la prolifération des armes de destruction massive et les et A. Roth, « Nuclear Weapons in Neo-Realist Theory », International Studies Review, automne 2007, p

  12. Toll like receptor agonists augment HPV 11 E7-specific T cell responses by modulating monocyte-derived dendritic cells.

    PubMed

    Chen, Xian-Zhen; Mao, Xiao-Hong; Zhu, Ke-Jian; Jin, Na; Ye, Jun; Cen, Jian-Ping; Zhou, Qiang; Cheng, Hao

    2010-01-01

    Impaired local cellular immunity is one of the mechanisms responsible for condyloma acuminatum (CA) recurrence. The activation of dendritic cells (DCs) is important in vaccine development. We investigated the effect of different toll like receptor (TLR) agonists including LPS (TLR4 agonist), polyinosinic acid-polycytidylic acid (PIC, TLR3 agonist), CpG oligonucleotide (TLR9 agonist), and imiquimod (TLR7 agonist) on human monocyte-derived dendritic cells (mdDCs) loading of human papillomavirus (HPV) type 11 E7 epitope. As a result, we found that mdDCs loading HLA-A*0201-restricted HPV 11 E7 CTL epitope peptide could respond to the TLR agonists, especially LPS and PIC. This was characterized by an enhanced expression of CD40, CD80, CD86, CD83 and HLA-DR, and a high level of IL-12 production. TLR agonists, especially PIC, enhanced the ability of E7-loaded mdDCs to induce IFN-gamma-secretion CD4(+) naïve T cells. Moreover, E7-loaded mdDCs exposed to TLR agonists augmented autologous T cell responses including effector cytokines production and specific cytotoxic T lymphocyte (CTL) responses. In addition, the inhibitory effect of IL-10 on mdDCs maturation could be partially restored by LPS, PIC or imiquimod. Taken together, these results demonstrate that TLR agonists promoted the maturation of E7-loaded mdDCs and their ability to induce T help type 1 polarization and augment E7-specific T cell responses. These data also indicated that TLR3/4 agonists might be effective adjuvants of mdDC-based vaccines against CA. PMID:19578865

  13. Agonist-specific voltage sensitivity at the dopamine D2S receptor--molecular determinants and relevance to therapeutic ligands.

    PubMed

    Sahlholm, Kristoffer; Barchad-Avitzur, Ofra; Marcellino, Daniel; Gómez-Soler, Maricel; Fuxe, Kjell; Ciruela, Francisco; Arhem, Peter

    2011-01-01

    Voltage sensitivity has been demonstrated for some GPCRs. At the dopamine D(2S) receptor, this voltage sensitivity is agonist-specific; some agonists, including dopamine, exhibit decreased potency at depolarized potentials, whereas others are not significantly affected. In the present study, we examined some of the receptor-agonist interactions contributing to these differences, and investigated how dopamine D(2S) receptor voltage sensitivity affects clinically used dopamine agonists. GIRK channel activation in voltage-clamped Xenopus oocytes was used as readout of receptor activation. Structurally distinct agonists and complementary site-directed mutagenesis of the receptor's binding site were used to investigate the role of agonist-receptor interactions. We also confirmed that the depolarization-induced decrease of dopamine potency in GIRK activation is correlated by decreased binding of radiolabeled dopamine, and by decreased potency in G protein activation. In the mutagenesis experiments, a conserved serine residue as well as the conserved aspartate in the receptor's binding site were found to be important for voltage sensitive potency of dopamine. Furthermore, the voltage sensitivity of the receptor had distinct effects on different therapeutic D(2) agonists. Depolarization decreased the potency of several compounds, whereas for others, efficacy was reduced. For some agonists, both potency and efficacy were diminished, whereas for others still, neither parameter was significantly altered. The present work identifies some of the ligand-receptor interactions which determine agonist-specific effects of voltage at the dopamine D(2S) receptor. The observed differences between therapeutic agonists might be clinically relevant, and make them potential tools for investigating the roles of dopamine D(2) receptor voltage sensitivity in native tissue. PMID:21752340

  14. Tests de réception des tours de réfrigération

    E-print Network

    Pirollet, B

    1999-01-01

    Dans le cadre du projet LHC, les premiers équipements de refroidissement installés, seront des tours de réfrigération de grande puissance. Contrairement à d'autres matériels construits en grande série, ces équipements, tours et stations de pompage associées sont à créer sur mesure. Différentes normalisations permettent de concevoir, de construire et de tester ces réalisations. L'ensemble des tests de réception ne peut avoir lieu avant l'achèvement complet de l'installation, de plus, ces essais sont rarement réalisés à charge nominale. Des défaillances potentielles, liées aux études ou à la réalisation, peuvent apparaître après la période de garantie. Le but de ce document est de présenter les différentes méthodes imposées par le CERN au niveau des cahiers des charges. Cela permettra la vérification des valeurs garanties par les constructeurs et de suivre l'évolution des critères de performances à long terme.

  15. Nebulized PPAR? Agonists: A Novel Approach to Augment Neonatal Lung Maturation and Injury Repair

    PubMed Central

    Morales, Edith; Sakurai, Reiko; Husain, Sumair; Paek, Dave; Gong, Ming; Ibe, Basil; Li, Yishi; Husain, Maleha; Torday, John S.; Rehan, Virender K.

    2014-01-01

    BACKGROUND By stimulating lipofibroblast maturation, parenterally administered PPAR? agonists promote lung homeostasis and injury repair in the neonatal lung. In this study, we determined whether PPAR? agonists could be delivered effectively via nebulization to neonates, and whether this approach would also protect against hyperoxia-induced lung injury. METHODS One-day old Sprague-Dawley rat pups were administered PPAR? agonists rosiglitazone (RGZ, 3 mg/kg), pioglitazone (PGZ, 3 mg/kg), or the diluent, via nebulization every 24h; animals were exposed to 21% or 95% O2 for up to 72h. Twenty-four and 72h following initial nebulization, the pups were sacrificed for lung tissue and blood collection to determine markers of lung maturation, injury repair, and RGZ and PGZ plasma levels. RESULTS Nebulized RGZ and PGZ enhanced lung maturation in both males and females, as evidenced by the increased expression of markers of alveolar epithelial and mesenchymal maturation. This approach also protected against hyperoxia-induced lung injury, since hyperoxia-induced changes in bronchoalveolar lavage cell and protein contents and lung injury markers were all blocked by nebulized PGZ. CONCLUSIONS Nebulized PPAR? agonist administration promotes lung maturation and prevents neonatal hyperoxia-induced lung injury in both males and females. PMID:24488089

  16. Effect of ?-Adrenergic Agonist and Antagonist Infusion on the Umbilical and Uterine Circulations of Pregnant Sheep

    Microsoft Academic Search

    Gary K. Oakes; Richard A. Ehrenkranz; Adrian M. Walker; Margaret K. McLaughlin; Susan C. Brennan; Ronald A. Chez

    1980-01-01

    The effects of the ?-adrenergic agonists, norepinephrine and methoxamine, and the ?-antagonist, phenoxybenzamine, on umbilical and uterine blood flows, fetal and maternal heart rates, arterial and venous pressures were examined in near-term chronic sheep preparations. Norepinephrine injection or methoxamine infusion to either fetus or ewe resulted in a respective unilateral fetal or maternal pressor response associated with bradycardia. Uterine blood

  17. Conformationally constrained farnesoid X receptor (FXR) agonists: Heteroaryl replacements of the naphthalene

    SciTech Connect

    Bass, Jonathan Y.; Caravella, Justin A.; Chen, Lihong; Creech, Katrina L.; Deaton, David N.; Madauss, Kevin P.; Marr, Harry B.; McFadyen, Robert B.; Miller, Aaron B.; Mills, Wendy Y.; Navas, III, Frank; Parks, Derek J.; Smalley, Jr., Terrence L.; Spearing, Paul K.; Todd, Dan; Williams, Shawn P.; Wisely, G. Bruce (GSKNC)

    2014-08-13

    To improve on the drug properties of GSK8062 1b, a series of heteroaryl bicyclic naphthalene replacements were prepared. The quinoline 1c was an equipotent FXR agonist with improved drug developability parameters relative to 1b. In addition, analog 1c lowered body weight gain and serum glucose in a DIO mouse model of diabetes.

  18. Estrogenic Agonist Activity of ICI 182,780 (Faslodex) in Hippocampal Neurons: Implications for Basic Science

    E-print Network

    Brinton, Roberta Diaz

    primary hippocampal neurons. We first investigated the neuroprotective efficacy of ICI 182,780 against-regulated kinase 1/2 and Akt (protein kinase B) and significantly increased expres- sion of spinophilin and Bcl-2Estrogenic Agonist Activity of ICI 182,780 (Faslodex) in Hippocampal Neurons: Implications

  19. Continuous Inhalation of Ipratropium Bromide for Acute Asthma Refractory to ?2-agonist Treatment

    PubMed Central

    Mastropietro, Christopher

    2015-01-01

    To present the case of a patient with persistent bronchospasm, refractory to treatment with ?2-agonists, that resolved promptly with continuous inhalation of large dose (1000 mcg/hr) ipratropium bromide, and to discuss the possibility of tolerance to ?2-agonists as the cause for his failure to respond to adrenergic medications. The patient had received multiple doses of albuterol, as well as subcutaneous terbutaline (0.3 mg), intravenous magnesium sulfate (1 g) and intravenous dexamethasone (10 mg) prior to his admission to the intensive care unit. He remained symptomatic despite systemic intravenous steroids, continuous intravenous terbutaline (up to 0.6 mcg/kg/min), and continuous nebulized albuterol (up to 20 mg/hr for 57 hr) followed by 49 hours of continuous levalbuterol (7 mg/hr). Due to the lack of response, all ?2-agonists were discontinued at 106 hours post-admission, and he was started on large dose ipratropium bromide (1000 mcg/hr) by continuous nebulization. Clinical improvement was evident within 1 hour and complete resolution of his symptoms within 4 hours. Continuous inhalation of large dose ipratropium bromide may be an effective regimen for the treatment of patients hospitalized with acute asthma who are deemed to be nonresponsive and/or tolerant to ?2-agonist therapy.

  20. Glucocorticoids and the Development of Agonistic Behaviour during Puberty in Male Golden Hamsters

    E-print Network

    Delville, Yvon

    investigated the effects of stress hormones on the matur- ation of agonistic behaviour. Male hamsters were increase in postdefeat cortisol levels (8). Could changes in stress hormone levels influence, The University of Texas at Austin, Austin, TX, USA. Key words: play fighting, stress, glucocorticoid receptor

  1. Sphingosine 1-phosphate and dioleoylphosphatidic acid are low affinity agonists for the orphan receptor GPR63

    E-print Network

    Hall, Randy A

    receptor GPR63 Anke Niedernberga , Sorin Tunarub , Andree Blaukatb , Ali Ardatic , Evi KostenisaPA) are agonists for the orphan receptor GPR63. All three phospholipids mobilise intracellular calcium in CHO cells transiently transfected with GPR63. Calcium signals required cotransfection of a chimeric Gaq/i protein

  2. Transgressive aggression in Sceloporus hybrids confers fitness through advantages in male agonistic encounters.

    PubMed

    Robbins, Travis R; Pruitt, Jonathan N; Straub, Lorelei E; McCoy, Earl D; Mushinsky, Henry R

    2010-01-01

    1. We investigated agonistic behaviour and associated characteristics of Sceloporus woodi (Florida scrub lizard), Sceloporus undulatus (Eastern fence lizard) and their hybrids using staged territorial encounters. 2. These Sceloporus hybrids exhibit transgressive aggression and transgressive head-girth relative to the parental species and the transgressive aggression was specifically associated with an advantage in agonistic encounters. Our results suggest a hybrid advantage in natural habitats when defending and invading territories against either parental species. 3. We further analysed general advantages in agonistic encounters across the entire three-group system to elucidate characteristics that may be advantageous under specific circumstances. Individuals with larger body size (SVL) and greater aggression had an overall advantage in agonistic encounters; however, smaller individuals could win when slightly more aggressive and fatter, and less aggressive individuals could win when slightly larger, especially with greater head-girth. 4. The extreme hybrid phenotypes likely occurred through transgressive segregation, which has been implicated as a process through which homoploid, hybrid speciation can occur. Some form of ecological divergence is necessary, however, to impede parental gene flow. Our data suggest that ecological divergence could manifest in territorial species through transgressive aggression. PMID:19682141

  3. The influence of reproductive state on the agonistic interactions between male and female crayfish

    E-print Network

    Moore, Paul A.

    The influence of reproductive state on the agonistic interactions between male and female crayfish a population. Extensive research on male­male interactions in crayfish has illustrated the mechanisms in modulating aggression between the sexes in crayfish. The purpose of this study was to investigate aggression

  4. The Effects of the Herbicide Metolachlor on Agonistic Behavior in the Crayfish, Orconectes rusticus

    E-print Network

    Moore, Paul A.

    The Effects of the Herbicide Metolachlor on Agonistic Behavior in the Crayfish, Orconectes rusticus and the ability to locate food, in aquatic organisms. In crayfish, aggressive interactions are also mediated the impact of exposure to sublethal levels of the herbicide metolachlor on the ability of crayfish to respond

  5. Endogenous Cannabinoid Receptor Agonists Inhibit Neurogenic Inflammations in Guinea Pig Airways

    Microsoft Academic Search

    Shigemi Yoshihara; Hiroshi Morimoto; Makoto Ohori; Yumi Yamada; Toshio Abe; Osamu Arisaka

    2005-01-01

    Background: Although neurogenic inflammation via the activation of C fibers in the airway must have an important role in the pathogenesis of asthma, their regulatory mechanism remains uncertain. Objective: The pharmacological profiles of endogenous cannabinoid receptor agonists on the activation of C fibers in airway tissues were investigated and the mechanisms how cannabinoids regulate airway inflammatory reactions were clarified. Methods:

  6. THE MORPHOLOGICAL BASIS FOR OLFACTORY PERCEPTION OF STEROIDS DUING AGONISTIC BEHAVIOR IN LOBSTER: PRELIMINARY EXPERIMENTS

    EPA Science Inventory

    The morphological basis for olfactory perception of steroids during agonistic behavior in lobsters: preliminary experiments. Borsay Horowitz, DJ1, Kass-Simon, G2, Coglianese, D2, Martin, L2, Boseman, M2, Cromarty, S3, Randall, K3, Fini, A.3 1US EPA, NHEERL, ORD, Atlantic Ecology...

  7. Bronchodilatory Effect of the PPAR-? Agonist Rosiglitazone in Smokers With Asthma

    Microsoft Academic Search

    M Spears; I Donnelly; L Jolly; M Brannigan; K Ito; C McSharry; J Lafferty; R Chaudhuri; G Braganza; P Bareille; L Sweeney; IM Adcock; PJ Barnes; S Wood; NC Thomson

    2009-01-01

    Smokers with asthma show a reduced response to inhaled corticosteroids. We hypothesized that a peroxisome proliferator–activated receptor-? (PPAR-?) agonist would be superior for the clinical treatment of these asthma patients. Forty-six smokers with asthma were randomized to inhaled beclometasone dipropionate (200 µg per day) or rosiglitazone (8 mg per day) for 4 weeks. Rosiglitazone produced improvements in lung function (forced

  8. Regulation of Glial Cell Functions by PPAR-? Natural and Synthetic Agonists

    PubMed Central

    Bernardo, Antonietta; Minghetti, Luisa

    2008-01-01

    In the recent years, the peroxisome proliferator-activated receptor-? (PPAR-?), a well known target for type II diabetes treatment, has received an increasing attention for its therapeutic potential in inflammatory and degenerative brain disorders. PPAR-? agonists, which include naturally occurring compounds (such as long chain fatty acids and the cyclopentenone prostaglandin 15-deoxy ?12,14 prostaglandin J2), and synthetic agonists (among which the thiazolidinediones and few nonsteroidal anti-inflammatory drugs) have shown anti-inflammatory and protective effects in several experimental models of Alzheimer's and Parkinson's diseases, amyotrophic lateral sclerosis, multiple sclerosis and stroke, as well as in few clinical studies. The pleiotropic effects of PPAR-? agonists are likely to be mediated by several mechanisms involving anti-inflammatory activities on peripheral immune cells (macrophages and lymphocytes), as well as direct effects on neural cells including cerebral vascular endothelial cells, neurons, and glia. In the present article, we will review the recent findings supporting a major role for PPAR-? agonists in controlling neuroinflammation and neurodegeneration through their activities on glial cells, with a particular emphasis on microglial cells as major macrophage population of the brain parenchyma and main actors in brain inflammation. PMID:18464925

  9. Identification of a novel partial agonist of liver X receptor ? (LXR?) via screening.

    PubMed

    Li, Ni; Wang, Xiao; Zhang, Jing; Liu, Chang; Li, Yongzhen; Feng, Tingting; Xu, Yanni; Si, Shuyi

    2014-12-01

    Liver X receptor ? (LXR?) plays an important role in the cholesterol metabolism process, and LXR? activation can reduce atherosclerosis. In the present study, using an LXR?-GAL4 luciferase reporter screening, we discovered IMB-170, a structural analog of quinazolinone, which showed potent LXR? agonistic activity. IMB-170 significantly activated LXR?, with an EC50 value of 0.27?M. Interestingly, IMB-170 not only increased the expression of ATP-binding cassette transporter A1 (ABCA1) and G1 (ABCG1), which are related to the reverse cholesterol transport (RCT) process, but also influenced the expression levels of other genes involved in the cholesterol metabolism pathway in many cell lines. Moreover, IMB-170 significantly reduced cellular lipid accumulation and increased cholesterol efflux from RAW264.7 and THP-1 macrophages. Interestingly, compared with TO901317, IMB-170 only slightly increased protein expression levels of lipogenesis-related genes in HepG2 cells, indicating that IMB-170 may have a lower lipogenesis side effect in vivo. These results suggest that IMB-170 showed the selective agonistic activity for LXR?. Moreover, compared with full LXR-agonists, IMB-170 possesses a differential ability to recruit coregulators. This suggests that IMB-170 has distinct interactions with the active sites in the LXR? ligand-binding domain. In summary, IMB-170 is a novel partial LXR? agonist without the classical lipogenesis side effects, which could be used as a potential anti-atherosclerotic leading compound in the future. PMID:25450668

  10. RELATIVE TOXICITIES AND NEUROMUSCULAR NICOTINIC RECEPTOR AGONISTIC POTENCIES OF ANABASINE ENANTIOMERS AND ANABASEINE

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Anabasine occurring in wild tree tobacco (Nicotinana glauca) and anabaseine occurring in certain animal venoms are nicotinic receptor agonist toxins. Anabasine lacks the imine double bond of anabaseine; the two possible enantiomers of anabasine occur in N. glauca. A comparision of the relative pote...

  11. MECHANISMS UNDERLYING ALC13 INHIBITION OF AGONIST-STIMULATED INOSITOL PHOSPHATE ACCUMULATION

    EPA Science Inventory

    Possible mechanisms of AlC13-induced inhibition of agonist-stimulated inositol phosphate (IP) accumulation were investigated using rat brain cortex slices, synaptosomes or homogenates. nder conditions in which AlC13 inhibits carbachol (CARB) stimulated IP accumulation (Gp-mediate...

  12. Normal filopodia extension inVASP-deficient platelets upon activation by adhesive matrices or soluble agonists

    E-print Network

    Paris-Sud XI, Université de

    Normal filopodia extension inVASP-deficient platelets upon activation by adhesive matrices platelet activation with a soluble agonist or following contact with an ad- hesive substratum (1). Platelet that ADP-activated platelets undergo transformation from a smooth discoid shape, to discs extending a few

  13. Current concepts on the use of glucocorticosteroids and beta 2-adrenoreceptor agonists to treat childhood asthma

    PubMed Central

    Nino, Gustavo; Grunstein, Michael M.

    2010-01-01

    Purpose of Review This article reviews current concepts regarding the clinical and scientific rationale for the combined use of glucocorticosteroids (GC) and beta2-adrenoreceptor (?2AR) agonists in the treatment of childhood asthma. Recent findings Several studies have demonstrated that inhaled corticosteroids (ICS) and ?2AR-agonists are the most effective medications for the management of asthma in children. Given substantial evidence of an increased clinical benefit when these agents are used together, new studies are being pursued to establish the efficacy and safety of this combinational therapy in infants and children. Ongoing research is also investigating the mechanisms of ?2AR and GC signaling and their molecular interactions. This new knowledge will likely lead to novel therapeutic approaches to asthma control. Summary There is increasing evidence demonstrating that the combination of long-acting ?2AR-agonists and ICS may be more effective than high dose ICS therapy alone in the management of children with uncontrolled asthma. In addition, the use of a single inhaler containing ICS and a quick-acting ?2AR-agonist might be a convenient alternative to prevent and treat asthma exacerbations. Future investigations should be designed to more specifically evaluate the efficacy and safety of these therapies in the different asthmatic phenotypes of infants and children. PMID:20164771

  14. Do cuttlefish (Cephalopoda) signal their intentions to conspecifics during agonistic encounters?

    Microsoft Academic Search

    SHELLEY A. ADAMO; R. T. HANLON

    1996-01-01

    Abstract. Male cuttlefish adopt a specific body pattern during agonistic behaviour called the Intense Zebra Display. Some components of the Display were variable, especially the chromatic component termed ‘dark face’, which could vary in the degree of darkness. Facial darkness was measured using a video analysis system. Males that eventually withdrew from conspecifics without fighting maintained a lighter face during

  15. Mass-spectrometric analysis of agonist-induced retinoic acid receptor gamma conformational change.

    PubMed Central

    Peterson, Valerie J; Barofsky, Elisabeth; Deinzer, Max L; Dawson, Marcia I; Feng, Kai-Chia; Zhang, Xiao-kun; Madduru, Machender R; Leid, Mark

    2002-01-01

    Apo and holo forms of retinoic acid receptors, and other nuclear receptors, display differential sensitivity to proteolytic digestion that likely reflects the distinct conformational states of the free and liganded forms of the receptor. We have developed a method for rapid peptide mapping of holo-retinoic acid receptor gamma that utilizes matrix-assisted laser-desorption-ionization time-of-flight MS to identify peptide fragments that are derived from the partially proteolysed holo-receptor. The peptide maps of retinoic acid receptor gamma bound by four different agonists were identical, suggesting that all four ligands induced a similar conformational change within the ligand-binding domain of the receptor. In all cases, this agonist-induced conformational change promoted the direct association of retinoic acid receptor gamma with the transcriptional co-activator p300 and inhibited interaction of the receptor with the nuclear receptor co-repressor. SR11253, a compound previously reported to exert mixed retinoic acid receptor gamma agonist/antagonist activities in cultured cells, was found to bind directly to, but only weakly altered the protease-sensitivity of, the receptor and failed to promote interaction of the receptor with p300 or induce dissociation of receptor-nuclear receptor co-repressor complexes. This technique should be generally applicable to other members of the nuclear receptor superfamily that undergo an induced structural alteration upon agonist or antagonist binding, DNA binding and/or protein-protein interaction. PMID:11829754

  16. ANABOLIC EFFECTS OF FEEDING BETA-2 ADRENERGIC AGONISTS ON RAINBOW TROUT MUSCLE PROTEASES AND MYOFIBRILLAR PROTEINS

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Beta-2 adrenergic agonists (BAAs) act as repartitioning agents in an intermediary metabolic pathway that redistributes nutrients to decrease adipose tissue and increase muscle accretion. This mechanism involves altering the protein degradation and synthetic rates. The aim of this study was to test...

  17. Long-Term Consequences of Agonistic Interactions Between Socially Naive Juvenile American Lobsters

    E-print Network

    Cromarty, Stuart I.

    Long-Term Consequences of Agonistic Interactions Between Socially Nai¨ve Juvenile American Lobsters¨ve juvenile American lobsters (Homarus americanus) by examining the time frame over which be- havior changes- cially nai¨ve juvenile lobsters is influenced by fight experi- ence for at least 4 days. Though

  18. NICOTINE EFFECTS ON THE ACTIVITY OF MICE EXPOSED PRENATALLY TO THE NICOTINIC AGONIST ANATOXIN-A.

    EPA Science Inventory

    Considerable research has shown long-lasting effects of early exposure in experimental animals to nicotine. Anatoxin-a is produced by cyanobacteria and has been shown to be a potent nicotinic agonist. This experiment evaluated the motor activity of adult mice, and their respons...

  19. Peroxisome Proliferator-Activated Receptor Gamma Agonists in Kidney Disease – Future Promise, Present Fears

    Microsoft Academic Search

    Zhiguo Mao; Albert C. M. Ong

    2009-01-01

    The peroxisome proliferator-activated receptor superfamily (PPARs) comprises a class of nuclear receptors with significant effects in regulating multiple cellular pathways. Much research and clinical interest has surrounded the PPAR-? isoform because of its key role in the transcriptional regulation of metabolic pathways and the efficacy of thiazolidinediones, the most clinically used PPAR-? agonist, in the management of type 2 diabetes

  20. Dopamine Agonists and the Suppression of Impulsive Motor Actions in Parkinson Disease

    Microsoft Academic Search

    Scott A. Wylie; Daniel O. Claassen; Hilde M. Huizenga; Kerilyn D. Schewel; K. Richard Ridderinkhof; Theodore R. Bashore; Wery P. M. van den Wildenberg

    2012-01-01

    The suppression of spontaneous motor impulses is an essential facet of cognitive control that is linked to frontal-BG circuitry. BG dysfunction caused by Parkinson disease (PD) disrupts the proficiency of action suppression, but how pharmacotherapy for PD impacts impulsive motor control is poorly understood. Dopamine agonists improve motor symptoms of PD but can also provoke impulsive–compulsive behaviors (ICB). We investigated

  1. Dopamine Agonists and the Suppression of Impulsive Motor Actions in Parkinson Disease

    Microsoft Academic Search

    Scott A. Wylie; Daniel O. Claassen; Hilde M. Huizenga; Kerilyn D. Schewel; K. Richard Ridderinkhof; Theodore R. Bashore; Wery P. M. van den Wildenberg

    The suppression of spontaneous motor impulses is an essential facet of cognitive control that is linked to frontal-BG circuitry. BG dysfunction caused by Parkinson disease (PD) disrupts the proficiency of action suppression, but how pharmacotherapy for PD impacts impulsive motor control is poorly understood. Dopamine agonists improve motor symptoms of PD but can also provoke impulsive–compulsive behaviors (ICB). We investigated

  2. Dopamine Agonists and the Suppression of Impulsive Motor Actions in Parkinson's Disease

    Microsoft Academic Search

    Scott A. Wylie; Daniel O. Claassen; Hilde M. Huizenga; Kerilyn D. Schewel; K. Richard Ridderinkhof; Theodore R. Bashore; Wery P. M. van den Wildenberg

    The suppression of spontaneous motor impulses is an essential facet of cognitive control that is linked to frontal-BG circuitry. BG dysfunction caused by Parkinson's disease (PD) disrupts the proficiency of action suppression, but how pharmacotherapy for PD impacts impulsive motor control is poorly understood. Dopamine agonists improve motor symptoms of PD but can also provoke impulsive–compulsive behaviors (ICB). We investigated

  3. PPAR-? receptor agonists—a review of their role in diabetic management in Trinidad and Tobago

    Microsoft Academic Search

    Steve Ian Smith

    2004-01-01

    The PPAR-? receptor agonists, as a relatively new and perhaps still not very widely used class of antidiabetic agent in the Caribbean and particularly the Trinidadian context, possess pharmacologic properties that certainly have been shown to have impact on many of the inflammatory, metabolic, biochemical and structural macrovascular aberrations that occur in the type 2 diabetic. Activation of PPAR(gamma) nuclear

  4. Subpallial and hypothalamic areas activated following sexual and agonistic encounters in male chickens

    Microsoft Academic Search

    Jingjing Xie; Wayne J. Kuenzel; Nicholas B. Anthony; Alexander Jurkevich

    2010-01-01

    Male sexual and agonistic behaviors are controlled by the common social behavior network, involving subpallial and hypothalamic brain areas. In order to understand how this common network generates different behavioral outcomes, induction of FOS protein was used to examine the patterns of neuronal activation in adult male chickens following interaction with a female or a male. Males were subjected to

  5. TIMP3 is the primary TIMP to regulate agonist-induced vascular remodelling and hypertension

    E-print Network

    MacMillan, Andrew

    3 is the primary TIMP to regulate agonist- induced vascular remodelling and hypertension Ratnadeep March 2013; online publish-ahead-of-print 21 March 2013 Time for primary review: 31 days Aims Hypertension is accompanied by structural remodelling of vascular extracellular matrix (ECM). Tissue inhibitor

  6. LETTER TO THE EDITOR Cannabinoid agonist WIN-55,212-2 partially restores

    E-print Network

    Wenk, Gary

    LETTER TO THE EDITOR Cannabinoid agonist WIN-55,212-2 partially restores neurogenesis in the aged,212-2 administra- tion for 3 weeks can partially restore neurogenesis in the hippocampus of aged rats. Cannabinoid-inflammatory cytokines and modulation of microglial activation.1­4 The endo- cannabinoid system is composed of two G

  7. New Insights into the PPAR? Agonists for the Treatment of Diabetic Nephropathy

    PubMed Central

    Jia, Zhanjun; Sun, Ying; Yang, Guangrui; Zhang, Aihua; Huang, Songming; Heiney, Kristina Marie; Zhang, Yue

    2014-01-01

    Diabetic nephropathy (DN) is a severe complication of diabetes and serves as the leading cause of chronic renal failure. In the past decades, angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin II receptor blockers (ARBs) based first-line therapy can slow but cannot stop the progression of DN, which urgently requests the innovation of therapeutic strategies. Thiazolidinediones (TZDs), the synthetic exogenous ligands of nuclear receptor peroxisome proliferator-activated receptor-? (PPAR?), had been thought to be a promising candidate for strengthening the therapy of DN. However, the severe adverse effects including fluid retention, cardiovascular complications, and bone loss greatly limited their use in clinic. Recently, numerous novel PPAR? agonists involving the endogenous PPAR? ligands and selective PPAR? modulators (SPPARMs) are emerging as the promising candidates of the next generation of antidiabetic drugs instead of TZDs. Due to the higher selectivity of these novel PPAR? agonists on the regulation of the antidiabetes-associated genes than that of the side effect-associated genes, they present fewer adverse effects than TZDs. The present review was undertaken to address the advancements and the therapeutic potential of these newly developed PPAR? agonists in dealing with diabetic kidney disease. At the same time, the new insights into the therapeutic strategies of DN based on the PPAR? agonists were fully addressed. PMID:24624137

  8. Phosphorylation\\/Dephosphorylation of Androgen Receptor as a Determinant of Androgen Agonistic or Antagonistic Activity

    Microsoft Academic Search

    Long G. Wang; Xiao M. Liu; Willi Kreis; Daniel R. Budman

    1999-01-01

    Protein phosphorylation\\/dephosphorylation is an important posttranslational modification that plays a critical role in signal transduction. The androgen receptor (AR) is under such control. We demonstrate that androgen receptor phosphorylation determines whether or not AR ligands perform as agonists or antagonists in LNCaP cells. Androgen receptor ligands (such as dihydrotestosterone and ?-estradiol) stimulate receptor expression and phosphorylation and, as a result,

  9. Conversion of the interleukin 1 receptor antagonist into an agonist by site-specific mutagenesis.

    PubMed Central

    Ju, G; Labriola-Tompkins, E; Campen, C A; Benjamin, W R; Karas, J; Plocinski, J; Biondi, D; Kaffka, K L; Kilian, P L; Eisenberg, S P

    1991-01-01

    Interleukin 1 (IL-1) receptor antagonist (IL-1ra) is a naturally occurring protein that binds to the IL-1 receptor present on T cells, fibroblasts, and other cell types and acts to block IL-1-induced responses. IL-1ra is a pure antagonist and has no agonist activity in in vitro or in vivo systems. By site-specific mutagenesis, an analog of IL-1ra was created that contained a substitution of a single amino acid, Lys-145----Asp. This analog, IL-1ra K145D, exhibited partial agonist activity in the D10.G4.1 cell proliferation assay. The newly acquired agonist activity could not be neutralized by antisera to IL-1 alpha or IL-1 beta, but it could be blocked by a monoclonal antibody to the T-cell IL-1 receptor. The analog also showed agonist activity as assayed by increased prostaglandin E2 synthesis from CHO cells expressing recombinant mouse IL-1 receptor. These results with IL-1ra K145D demonstrate the importance of the region surrounding the corresponding Asp-145 residue in IL-1 beta for triggering the biological response to IL-1. Images PMID:1826365

  10. The Glycine Transport Inhibitor Sarcosine Is an Inhibitory Glycine Receptor Agonist

    PubMed Central

    Zhang, Hai Xia; Lyons-Warren, Ariel; Thio, Liu Lin

    2009-01-01

    Summary Sarcosine is an endogenous amino acid that is a competitive inhibitor of the type I glycine transporter (GlyT1), an N-methyl-D-aspartate receptor (NMDAR) co-agonist, and an important intermediate in one-carbon metabolism. Its therapeutic potential for schizophrenia further underscores its clinical importance. The structural similarity between sarcosine and glycine and sarcosine's ability to serve as an NMDAR co-agonist led us to examine whether sarcosine is also an agonist at the inhibitory glycine receptor (GlyR). We examined this possibility using whole-cell recordings from cultured embryonic mouse hippocampal neurons and found that sarcosine evoked a dose-dependent, strychnine sensitive, Cl- current that cross-inhibited glycine currents. Sarcosine evoked this current with Li+ in the extracellular solution to block GlyT1, in neurons treated with the essentially irreversible GlyT1 inhibitor N[3-(4?-fluorophenyl)-3-(4?-phenylphenoxy)propyl]sarcosine (NFPS), and in neurons plated in the absence of glia. These results indicate that the sarcosine currents did not result from GlyT1 inhibition or heteroexchange. We conclude that sarcosine is a GlyR agonist. PMID:19619564

  11. RELATIONSHIPS BETWEEN RESIDUES OF AHR AGONISTS IN FISH AND CONCENTRATIONS IN WATER AND SEDIMENTS

    EPA Science Inventory

    Relationships between Residues of AhR Agonists in Fish and Concentrations in Water and Sediment. Cook, PM*, Burkhard, LP, Mount, DR, US-EPA, NHEERL, MED, Duluth, MN. The bioaccumulation visualization approach of Burkhard et al. (2002) can be effectively used to describe the bioa...

  12. Toll-like receptor-7 agonist decoration enhances the adjuvanticity of chitosan-DNA nanoparticles.

    PubMed

    Heuking, Simon; Borchard, Gerrit

    2012-03-01

    In order to provide an adjuvant-equipped carrier system for plasmid deoxyribonucleic acid (pDNA) vaccines, we grafted for the first time a Toll-like receptor (TLR)-7 agonistic moiety [9-benzyl-8-hydroxyadenine (HA)] through a poly(ethylene glycol) (PEG) spacer onto a water-soluble chitosan derivative [final copolymer: 6-0-carboxymethyl-N,N,N-trimethylchitosan (CTC)-graft-PEG-HA (CTCPHA)]. Successful grafting was confirmed by spectroscopic (H NMR, mass, ultraviolet-visible, and Fourier transform infrared spectroscopy) and chromatographic (size-exclusion chromatography-multi-angle laser light scattering) methods. In this article, TLR-7 agonist-decorated CTCPHA nanoparticles (NPs) were formulated by complex coacervation with pDNA expressing the green fluorescence protein. Resulting NPs had a size of around 200 nm with a positive surface charge and high DNA encapsulation efficiency. In contrast to the use of DNA alone, NP protected DNA against enzymatic degradation and enabled transfection of alveolar A549 cells. Interestingly, TLR-7 agonist decoration increased significantly the interleukin-8-related immune stimulatory capacity of polymeric chitosan and chitosan-based NP in human THP-1 macrophages when compared with controls. In summary, we demonstrate here the proof-of-principle that covalent TLR-7 agonist functionalization of chitosan-DNA NPs enhances the carrier's adjuvanticity, representing a valuable concept for future polymer-based DNA vaccination. PMID:22190381

  13. Morphine attenuates ultrasonic vocalization during agonistic encounters in adult male rats

    Microsoft Academic Search

    J. A. Vivian; K. A. Miczek

    1993-01-01

    Ultrasonic vocalizations (USV) in rats may communicate “affective” states during pain, sex and aggression. This proposal was evaluated in an experiment with adult male Long-Evans rats during agonistic encounters; specifically, morphine and naltrexone effects were studied on different types of USV by intruder rats exposed to resident attacks and to “threat of attacks” (i.e., intruder residing within the home cage

  14. MUC-1 Tumor Antigen Agonist Epitopes for Enhancing T-cell Responses to Human Tumors

    Cancer.gov

    Along with the method of use, the technology encompasses the use of these agonist epitopes in peptide- and protein-based vaccines, with dendritic cells or other antigen presenting cells, or encoding sequences in DNA, viral, bacterial, yeast, or other types of vectors, or to stimulate T-cells in vitro for adoptive immunotherapy protocols.

  15. Differential Effects of Cannabinoid Receptor Agonist on Social Discrimination and Contextual Fear in Amygdala and Hippocampus

    ERIC Educational Resources Information Center

    Segev, Amir; Akirav, Irit

    2011-01-01

    We examined whether the cannabinoid receptor agonist WIN55,212-2 (WIN; 5 [mu]g/side) microinjected into the hippocampus or the amygdala would differentially affect memory processes in a neutral vs. an aversive task. In the aversive contextual fear task, WIN into the basolateral amygdala impaired fear acquisition/consolidation, but not retrieval.…

  16. Light intensity can trigger different agonistic responses in juveniles of three cichlid species

    Microsoft Academic Search

    Thaís B. Carvalho; James C. Ha; Eliane Gonçalves-de-Freitas

    2012-01-01

    Light intensity affects aggressive behavior in fish because this variable influences physiological processes. Such effects could, however, vary according to the species and the ontogenetic stage of life because different life history can modulate behavior. Thus, we compared the effect of light intensity on the agonistic behavior of juvenile cichlids acará tinga Geophagus proximus, Nile tilapia Oreochromis niloticus, and the

  17. Rational design of a humanized glucagon-like Peptide-1 receptor agonist antibody.

    PubMed

    Zhang, Yong; Zou, Huafei; Wang, Ying; Caballero, Dawna; Gonzalez, Jose; Chao, Elizabeth; Welzel, Gus; Shen, Weijun; Wang, Danling; Schultz, Peter G; Wang, Feng

    2015-02-01

    Bovine antibody BLV1H12 possesses a unique "stalk-knob" architecture in its ultralong heavy chain CDR3, allowing substitutions of the "knob" domain with protein agonists to generate functional antibody chimeras. We have generated a humanized glucagon-like peptide-1 (GLP-1) receptor agonist antibody by first introducing a coiled-coil "stalk" into CDR3H of the antibody herceptin. Exendin-4 (Ex-4), a GLP-1 receptor agonist, was then fused to the engineered stalk with flexible linkers, and a Factor Xa cleavage site was inserted immediately in front of Ex-4 to allow release of the N-terminus of the fused peptide. The resulting clipped herceptin-Ex-4 fusion protein is more potent in?vitro in activating GLP-1 receptors than the Ex-4 peptide. The clipped herceptin-Ex-4 has an extended plasma half-life of approximately four days and sustained control of blood glucose levels for more than a week in mice. This work provides a novel approach to the development of human or humanized agonist antibodies as therapeutics. PMID:25556336

  18. Development of Functionally Selective, Small Molecule Agonists at Kappa Opioid Receptors*

    PubMed Central

    Zhou, Lei; Lovell, Kimberly M.; Frankowski, Kevin J.; Slauson, Stephen R.; Phillips, Angela M.; Streicher, John M.; Stahl, Edward; Schmid, Cullen L.; Hodder, Peter; Madoux, Franck; Cameron, Michael D.; Prisinzano, Thomas E.; Aubé, Jeffrey; Bohn, Laura M.

    2013-01-01

    The kappa opioid receptor (KOR) is widely expressed in the CNS and can serve as a means to modulate pain perception, stress responses, and affective reward states. Therefore, the KOR has become a prominent drug discovery target toward treating pain, depression, and drug addiction. Agonists at KOR can promote G protein coupling and ?arrestin2 recruitment as well as multiple downstream signaling pathways, including ERK1/2 MAPK activation. It has been suggested that the physiological effects of KOR activation result from different signaling cascades, with analgesia being G protein-mediated and dysphoria being mediated through ?arrestin2 recruitment. Dysphoria associated with KOR activation limits the therapeutic potential in the use of KOR agonists as analgesics; therefore, it may be beneficial to develop KOR agonists that are biased toward G protein coupling and away from ?arrestin2 recruitment. Here, we describe two classes of biased KOR agonists that potently activate G protein coupling but weakly recruit ?arrestin2. These potent and functionally selective small molecule compounds may prove to be useful tools for refining the therapeutic potential of KOR-directed signaling in vivo. PMID:24187130

  19. In Vivo Delta Opioid Receptor Internalization Controls Behavioral Effects of Agonists

    E-print Network

    Paris-Sud XI, Université de

    In Vivo Delta Opioid Receptor Internalization Controls Behavioral Effects of Agonists Amynah A. A: In this study, we used knock-in mice expressing functional fluorescent delta opioid receptors (DOR- e G, Tryoen-Toth P, Filliol D, et al. (2009) In Vivo Delta Opioid Receptor Internalization Controls

  20. The effects of dopaminergic agonists on genital reflexes in paradoxical sleep-deprived male rats.

    PubMed

    Andersen, Monica L; Tufik, Sergio

    2005-02-15

    Dopamine (DA) agonists provide evidence that different receptor subtypes in the central nervous system (CNS) have influence in sexual behavior. Sleep deprivation induces supersensibility of DA receptors and previous work has shown that the DA agonist apomorphine enhances spontaneous genital reflexes (penile erection-PE and ejaculation-EJ) in rats deprived of paradoxical sleep. The present study sought to extend the latter finding by assessing the effects of other DA agonists in paradoxical sleep-deprived (PSD) male rats. The DA drugs (bromocriptine and piribedil) were acutely administered to rats that had been deprived of sleep for 4 days and to normal controls. Sleep deprivation alone induced PE and this effect was potentiated by piribedil, with maximal effects occurring with the 8 mg/kg dose, whereas only one dose of bromocriptine (8 mg/kg) induced more PE in PSD rats than in non-deprived treated controls. EJs were increased in piribedil PSD groups but this response was absent after bromocriptine treatment in the dose range tested. Our data show the genital reflexes that occurred in PSD rats are potentialized by piribedil and not by bromocriptine. These DA agonists showed distinct effects in sexual response suggesting that these effects are probably due to PSD-induced DA receptor supersensitivity even though different mechanisms are involved. PMID:15708772