Sample records for agonist diethylstilbestrol des

  1. Diethylstilbestrol (DES) and Cancer

    MedlinePLUS

    ... idiopathic thrombocytopenia purpura between DES-exposed and unexposed women ( 10 ). Studies examining the risk of depression among DES daughters ... statistically significant. Researchers will continue to follow these women to study the risk of infertility. Recent studies have found ...

  2. Physical and psychological problems associated with exposure to diethylstilbestrol (DES).

    PubMed

    Saunders, E J

    1988-01-01

    The synthetic hormone diethylstilbestrol (DES) was widely prescribed between 1943 and 1971 to minimize pregnancy complications. It has caused serious physical and psychological damage to the women who took it and to their offspring. DES-exposed mothers may suffer a higher incidence of breast cancer, their exposed daughters are at risk for reproductive tract cancers and infertility, and their exposed sons are more likely to have genital abnormalities and reproductive dysfunction. Psychiatric disorders among DES-exposed persons are reportedly twice as common as for nonexposed persons, with anger, anxiety, low self-worth, identity confusion, and guilt the most frequent symptoms. The author describes therapeutic interventions designed to alleviate these problems. PMID:3276594

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

    Microsoft Academic Search

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

    2005-01-01

    The oxidation of the endocrine disruptor, diethylstilbestrol (DES) in aqueous media by ultrasound is significantly enhanced by Fe(II) catalyst. The observed enhancement is likely the result of increased levels of hydroxyl radicals from the iron-promoted reduction of the hydrogen peroxide produced during ultrasonic irradiation. The degradation is effective over a range of concentrations and is consistent with pseudo first-order kinetics.

  4. In Utero Exposure to Diethylstilbestrol (DES) or Bisphenol-A (BPA) Increases EZH2 Expression in the Mammary Gland: An Epigenetic Mechanism Linking Endocrine Disruptors to Breast Cancer

    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

  5. Transplacental administration of diethylstilbestrol (DES) causes lesions in female reproductive organs of Donryu rats, including endometrial neoplasia.

    PubMed

    Kitamura, T; Nishimura, S; Sasahara, K; Yoshida, M; Ando, J; Takahashi, M; Shirai, T; Maekawa, A

    1999-07-01

    The effects of transplacental administration of diethylstilbestrol (DES) on female reproductive organs were investigated using Donryu rats. The animals were given subcutaneous injections of DES dissolved in olive oil at doses of 0.01 or 0.1 mg/kg on days 17 and 19 of gestation. In female offspring, clinical signs, body weights and estrous cycles were continuously assessed until all survivors were killed at month 18. A low mean litter size and shortening of period of pregnancy were recognized in the 0.1 mg/kg group. Disorder and/or suspension of the estrous cycle (so called persistent estrus) also appeared very early in the 0.1 mg/kg group. Macroscopically, the incidences of hypoplasia of the oviduct, cystic dilatation of the uterus and small size of the uterine cervix were higher in the 0.1 mg/kg group than those in the control group. Histologically, in the ovary, the incidence and degree of atrophy were increased in both 0.01 and 0.1 mg/kg groups. In the uterus, total incidences of endometrial hyperplasias were about the same in all groups. However, endometrial adenocarcinomas were dose-dependently increased in the treated groups, the incidence in the 0.1 mg/kg group being significant, compared to that in the control. In the vagina, mucification was more prominent in the treated animals, especially at the higher dose, but no tumors were observed. The present results indicate that prenatal exposure to DES can produce uterine adenocarcinomas in rats, as reported earlier for mice, although its carcinogenic activity is not so strong. Increase of endometrial adenocarcinoma incidence might depend on hormonal imbalance resulting from the ovarian atrophy due to transplacental treatment of DES. PMID:10454265

  6. Effects of BPA and DES on longchin goby ( Chasmichthys dolichognathus) in vitro during the oocyte maturation

    Microsoft Academic Search

    Hea Ja Baek; In Joon Hwang; Kyung Sun Kim; Young Don Lee; Hyung Bae Kim; Myong Suk Yoo

    2007-01-01

    This study was performed in order to assess whether bisphenol (BPA) and diethylstilbestrol (DES) had agonistic or antagonistic effects on oocyte maturation using marine fish. We tested the effects of these chemicals on in vitro maturation, germinal vesicle breakdown (GVBD), assay using oocytes from the longchin goby, Chasmichthys dolichognathus. During the maturation process, low concentrations of BPA and DES triggered

  7. Developmental Diethylstilbestrol Exposure Alters Genetic Pathways of Uterine Cytodifferentiation

    Microsoft Academic Search

    Wei-Wei Huang; Yan Yin; Qun Bi; Tung-Chin Chiang; Neysa Garner; Jussi Vuoristo; John A. McLachlan; Liang Ma

    2004-01-01

    The formation of a simple columnar epithelium in the uterus is essential for implantation. Perturba- tion of this developmental process by exogenous estrogen, such as diethylstilbestrol (DES), results in uterine metaplasia that contributes to infertility. The cellular and molecular mechanism underlying this transformation event is not well understood. Here we use a combination of global gene expres- sion analysis and

  8. Prenatal Diethylstilbestrol Exposure and Risk of Breast Cancer

    Microsoft Academic Search

    Julie R. Palmer; Lauren A. Wise; Elizabeth E. Hatch; Rebecca Troisi; Linda Titus-Ernstoff; William Strohsnitter; Raymond Kaufman; Arthur L. Herbst; Kenneth L. Noller; Marianne Hyer; Robert N. Hoover

    It has been hypothesized that breast cancer risk is influenced by prenatal hormone levels. Diethylstilbestrol (DES), a synthetic estrogen, was widely used by pregnant women in the 1950s and 1960s. Women who took the drug have an increased risk of breast cancer, but whether risk is also increased in the daughters who were exposed in utero is less clear. We

  9. Management of breast cancer in patients prenatally exposed to diethylstilbestrol: are we prepared?

    PubMed

    Mano, Max S; Kerr, Janet; Kennedy, James

    2005-10-01

    The use of diethylstilbestrol (DES) for high risk pregnancy has exposed millions of mothers to an increased risk of breast cancer, and also resulted in a generation of women with genital tract abnormalities, such as vaginal adenosis. It is still too early to say that exposure to DES will also result in an increased risk of breast cancer in the offspring, though there is some preliminary evidence to support this. The employment of optimal hormonal therapy (for breast cancer) in this special population may be hampered by the fact that agents with oestrogen agonistic activity (such as tamoxifen) may be contraindicated. Though some of the newer hormonal agents, such as the pure anti-oestrogen Fulvestrant and the aromatase inhibitors, could be considered interesting alternatives for postmenopausal patients, their safety in this population has never been evaluated. Finally, the prevalence prenatal exposure to DES may have been underestimated patients diagnosed with breast cancer, though this information might have major implications in their management. We report on the interesting example of a young woman with a history of vaginal adenosis, who was also diagnosed with early breast cancer. PMID:16216745

  10. 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...

  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. Prenatal diethylstilbestrol exposure and self-reported immune-related diseases

    Microsoft Academic Search

    A. J. J. M. Vingerhoets; J. Assies; K. Goodkin; G. L Van Heck; M. H. Bekkker

    1998-01-01

    Objective: To compare self-reports of immune-related diseases in diethylstilbestrol (DES) daughters and controls. Prenatal exposure to DES has been associated with several malformations in the lower genital tract, a higher prevalence of adenosis, and increased risk of clear cell adenocarcinoma, and estrogen-dependent tumors. Lately, reports have been published indicating a link between DES exposure and alterations in the immune system.

  13. 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

  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. 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

  16. Developmental effects of perinatal exposure to bisphenol-A and diethylstilbestrol on reproductive organs in female mice

    Microsoft Academic Search

    Atsuko Suzuki; Akika Sugihara; Kaoru Uchida; Tomomi Sato; Yasuhiko Ohta; Yoshinao Katsu; Hajime Watanabe; Taisen Iguchi

    2002-01-01

    Reproductive tract development is influenced by estrogen. The aim of this study was to determine the effects of an environmental estrogenic chemical bisphenol-A (BPA) on prenatal and postnatal development of female mouse reproductive organs. In the prenatal treatment group, BPA or the synthetic estrogen diethylstilbestrol (DES) were given by subcutaneous (s.c.) injections to pregnant mice during gestational days 10–18. Some

  17. 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.

  18. 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.

  19. Myelodyspoietic syndrome associated with diethylstilbestrol therapy.

    PubMed

    Anderson, A L; Lynch, E C

    1980-07-01

    We describe a patient with a myelodysplastic syndrome characterized by pancytopenia and an excess of myeloblasts in the bone marrow. He had received massive doses of diethylstilbestrol (150 mg daily) for seven years as therapy for prostatic carcinoma. Although myelodyspoiesis has been associated with other drugs, a relationship to estrogen therapy in man has not been reported previously. However, the administration of estrogens to animals has produced pancytopenia with a relative monocytosis and vacuolization of leukocytes. Examination of bone marroa, erythroid hypoplasia, and, with prolonged therapy, aplastic anemia. Further animal studies have demonstrated that estrogens exert a suppressive effect on marrow stem cells and granuloid progenitor cells. These experimental observations suggest a possible role of estrogens in the genesis of the hematologic changes we observed. PMID:7387307

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

    PubMed Central

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

    2012-01-01

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

  1. Estrogen Participation in Induction of Cervicovaginal Adenosis-Like Lesions in Immature Mice Exposed Prenatally to Diethylstilbestrol

    Microsoft Academic Search

    Taisen Iguchi; Toshiharu Takei; Minoru Takase; Noboru Takasugi

    1986-01-01

    A high incidence of vaginal adenosis-like lesions (ADL, 67%) was found in 30-day-old offspring of ICR\\/JCLmice given 4 daily subcutaneous injections of 2,000 ?g diethylstilbestrol (DES) on days 15–18 of gestation. The prenatally DES-exposed mice and the controls ovariectomized at 10 days of age were given 5 daily subcutaneous injections of 10–4, 10–3, 10–2, 10–1, or 1 ?g 17?-estradiol (E2),

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

    PubMed

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

    2015-04-28

    Laminin, a major basement membrane component, is important in structural support and cell proliferation and differentiation. Its 19 isoforms are assemblies of ?, ?, and ? chains, and the ? chains (?1-5) determine the isoform characteristics. Although our previous studies showed alterations in ? chain expressions during anterior pituitary development, their expressions in pituitary tumors yet to be determined. The present study used a rat model of diethylstilbestrol (DES)-induced prolactinoma to examine ? chain expressions during prolactinoma tumorigenesis (0-12 weeks of DES treatment) by in situ hybridization and immunohistochemistry. mRNA of ?1, ?3, and ?4 chains was detected in control and after 4 weeks of DES treatment. These expressions were undetectable after 8 weeks of DES treatment and in prolactinoma (12 weeks of DES treatment). Immunohistochemistry showed that the ?1 chain was localized in some anterior pituitary cells in control and after 4 weeks of treatment and in endothelial cells after 8 weeks of treatment. The ?3 and ?4 chains were expressed in endothelial cells, and immunoreactivity and the number of immunopositive cells decreased during DES treatment. These findings suggest that alteration of laminin ? chains is related to abnormal cell proliferation and neovascularization during development of DES-induced prolactinoma. PMID:26019376

  3. Diethylstilbestrol inhibits tumor growth and prolactin production in rat pituitary tumors.

    PubMed Central

    Lloyd, R. V.; Landefeld, T. D.; Maslar, I.; Frohman, L. A.

    1985-01-01

    Treatment of rats bearing transplantable MtT/W15 tumors with 10 mg of diethylstilbestrol (DES) for 3 weeks led to inhibition of tumor growth. The inhibition of tumor growth was reversible after removal of the DES. Histologic examination revealed decreased mitotic activity; however, DES did not produce cell necrosis. Concomitantly, the anterior pituitary glands of animals treated with DES became hyperplastic, with an increased number of prolactin (PRL)-producing cells. DES resulted in a decreased number of PRL cells in the tumor and decreased serum PRL/tumor weight, compared with that of control rats. There was also an increase in the number of growth hormone (GH) tumor cells and an increased serum GH/tumor weight. 17 beta-Estradiol had an effect similar to that of DES, while progesterone did not inhibit tumor growth or cause pituitary cell hyperplasia. Ovariectomy resulted in a decrease in the tumor growth rate, compared with that of control animals, suggesting that the MtT/W 15 tumors are relatively dependent on estrogens for optimal growth. These results indicate that DES inhibition of MtT/W 15 tumor growth is an excellent model for study of the mechanism of the inhibition of tumor growth and the modification of GH and PRL expression by the tumor cells. Images Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 PMID:3976841

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

    PubMed Central

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

    2015-01-01

    The aim of the present study was to observe the effects of different exogenous estrogen diethylstilbestrol (DES) concentrations on the human melanocyte proliferation and tyrosinase activity. Skin specimens were obtained following blepharoplasty, and the melanocytes were primary cultured and passaged to the third generation. The melanocytes were seeded in 96-well plates, each well had 5×103 cells. The medium was changed after 24 h, and contained 10?4-10?8 M DES. After the melanocytes were incubated, the proliferation and tyrosinase activity were detected by the MTT assay and L-DOPA reaction. DES (10?8-10?6 M) enhanced the proliferation of cultured melanocytes. The intensity was positively correlated with the concentration of drug. DES, >10?5 M, inhibited the melanocytes proliferation or even produced the toxicity effect. Following the addition of 10?6 M DES to the medium, the tyrosinase activity of melanocytes was significantly increased, with P<0.05. In conclusion, a certain concentration of DES promoted the proliferation of melanocytes, enhanced the activity of tyrosinase and promoted pigment synthesis of melanocytes, with the optimal concentration of 10?6 M.

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

    PubMed

    Oumeddour, Abdelkader; Viennois, Emilie; Caira, Françoise; Decourbey, Clélia; Maqdasy, Salwan; Tahraoui, Abdelkrim; Baron, Silvère; Volle, David H; Lobaccaro, Jean-Marc A

    2014-04-11

    Liver X receptors LXR? (NR1H3) and LXR? (NR1H2) are transcription factors belonging to the nuclear receptor superfamily, activated by specific oxysterols, oxidized derivatives of cholesterol. These receptors are involved in the regulation of testis physiology. Lxr-deficient mice pointed to the physiological roles of these nuclear receptors in steroid synthesis, lipid homeostasis and germ cell apoptosis and proliferation. Diethylstilbestrol (DES) is a synthetic estrogen considered as an endocrine disruptor that affects the functions of the testis. Various lines of evidences have made a clear link between estrogens, their nuclear receptors ER? (NR3A1) and ER? (NR3A2), and Lxr?/?. As LXR activity could also be regulated by the nuclear receptor small heterodimer partner (SHP, NR0A2) and DES could act through SHP, we wondered whether LXR could be targeted by estrogen-like endocrine disruptors such as DES. For that purpose, wild-type and Lxr-deficient mice were daily treated with 0.75 ?g DES from days 1 to 5 after birth. The effects of DES were investigated at 10 or 45 days of age. We demonstrated that DES induced a decrease of the body mass at 10 days only in the Lxr-deficient mice suggesting a protective effect of Lxr. We defined three categories of DES-target genes in testis: those whose accumulation is independent of Lxr; those whose accumulation is enhanced by the lack of both Lxr?/?; those whose accumulation is repressed by the absence of Lxr?/?. Lipid accumulation is also modified by neonatal DES injection. Lxr-deficient mice present different lipid profiles, demonstrating that DES could have its effects in part due to Lxr?/?. Altogether, our study shows that both nuclear receptors Lxr? and Lxr? are not only basally important for testicular physiology but could also have a preventive effect against estrogen-like endocrine disruptors. PMID:24333430

  6. 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

  7. 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

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

    PubMed

    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. PMID:25852458

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

    PubMed Central

    Saeed, Muhammad; Rogan, Eleanor

    2009-01-01

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

  10. Limb reduction defects in the first generation and deafness in the second generation of intrauterine exposed fetuses to diethylstilbestrol.

    PubMed

    Stoll, C; Alembik, Y; Dott, B

    2003-01-01

    Maternal treatment with diethylstilbestrol (DES) during pregnancy can produce vaginal adenocarcinoma and other abnormalities of the vagina in her daughters when they reach adolescence or adulthood, miscarriages and absence of full term infants. Concerning malformations in newborns whose mothers were treated with DES, clitoromegaly and malformations of the uterus were reported in females and genital lesions in males. However, the frequencies of major congenital anomalies were not greater than expected. We report three cases of limb reduction defects (LRD) in the first generation of children whose mothers were treated with DES during pregnancy, and two children (one male, one female) with deafness in the second generation after intrauterine exposure to DES. The LRD were not associated with other congenital anomalies. The malformed children with LRD were born between 1965 and 1973. The deafness was also isolated. The two mothers who have no hearing problems and who are healthy were exposed in utero to DES in 1963 and 1965, respectively. Their children were born in 1989 and 1994, respectively. In conclusion, the association of LRD and hearing loss with intrauterine exposure to DES could be coincidental. However, some hypothesis may explain these associations. Congenital hearing loss in the second generation may suggest a transgenerational effect. PMID:14659782

  11. 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

  12. 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.

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

    PubMed Central

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

    2014-01-01

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

  14. Diethylstilbestrol can effectively accelerate estradiol-17-O-glucuronidation, while potently inhibiting estradiol-3-O-glucuronidation.

    PubMed

    Zhu, Liangliang; Xiao, Ling; Xia, Yangliu; Zhou, Kun; Wang, Huili; Huang, Minyi; Ge, Guangbo; Wu, Yan; Wu, Ganlin; Yang, Ling

    2015-03-01

    This in vitro study investigates the effects of diethylstilbestrol (DES), a widely used toxic synthetic estrogen, on estradiol-3- and 17-O- (E2-3/17-O) glucuronidation, via culturing human liver microsomes (HLMs) or recombinant UDP-glucuronosyltransferases (UGTs) with DES and E2. DES can potently inhibit E2-3-O-glucuronidation in HLM, a probe reaction for UGT1A1. Kinetic assays indicate that the inhibition follows a competitive inhibition mechanism, with the Ki value of 2.1±0.3?M, which is less than the possible in vivo level. In contrast to the inhibition on E2-3-O-glucuronidation, the acceleration is observed on E2-17-O-glucuronidation in HLM, in which cholestatic E2-17-O-glucuronide is generated. In the presence of DES (0-6.25?M), Km values for E2-17-O-glucuronidation are located in the range of 7.2-7.4?M, while Vmax values range from 0.38 to 1.54nmol/min/mg. The mechanism behind the activation in HLM is further demonstrated by the fact that DES can efficiently elevate the activity of UGT1A4 in catalyzing E2-17-O-glucuronidation. The presence of DES (2?M) can elevate Vmax from 0.016 to 0.81nmol/min/mg, while lifting Km in a much lesser extent from 4.4 to 11?M. Activation of E2-17-O-glucuronidation is well described by a two binding site model, with KA, ?, and ? values of 0.077±0.18?M, 3.3±1.1 and 104±56, respectively. However, diverse effects of DES towards E2-3/17-O-glucuronidation are not observed in liver microsomes from several common experimental animals. In summary, this study issues new potential toxic mechanisms for DES: potently inhibiting the activity of UGT1A1 and powerfully accelerating the formation of cholestatic E2-17-O-glucuronide by UGT1A4. PMID:25596428

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

    PubMed

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

    2014-01-01

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

  16. Growth and Carcass Traits of Holstein Steers, Bulls, and Bulls Implanted with Diethylstilbestrol[1] and [2

    Microsoft Academic Search

    T. G. Martin; M. Stob

    1978-01-01

    Holstein male calves (36) were al- located at birth to one of three treatment groups, 1) castrated at 3 to 7 days of age (steers), 2) intact and untreated, and 3) implanted with diethylstilbestrol at birth, 3, 6, 8, and 10 mo of age. Daily gain and carcass traits of all animals and testicular measurements of bulls and implanted bulls

  17. Neonatal Diethylstilbestrol Exposure Disrupts Female Reproductive Tract Structure/Function Via Both Direct And Indirect Mechanisms In The Hamster

    PubMed Central

    Alwis, Imala D.; Maroni, Dulce M.; Hendry, Isabel R.; Roy, Shyamal K.; May, Jeffrey V.; Leavitt, Wendell W.; Hendry, William J.

    2011-01-01

    We assessed neonatal diethylstilbestrol (DES)-induced disruption at various endocrine levels in the hamster. In particular, we used organ transplantation into the hamster cheek pouch to determine whether abnormalities observed in the post-pubertal ovary are due to: a) a direct (early) mechanism; or b) an indirect (late) mechanism that involves altered development and function of the hypothalamus and/or pituitary. Of the various disruption endpoints and attributes assessed: 1) some were consistent with the direct mechanism (altered uterine and cervical dimensions/organization, ovarian polyovular follicles, vaginal hypospadius, endometrial hyperplasia/dysplasia); 2) some were consistent with the indirect mechanism (ovarian/oviductal salpingitis, cystic ovarian follicles); 3) some were consistent with a combination of the direct and indirect mechanisms (altered endocrine status); and 4) the mechanism(s) for one (lack of corpora lutea) was uncertain. This study also generated some surprising observations regarding vaginal estrous assessments as a means to monitor periodicity of ovarian function in the hamster. PMID:21963885

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

    SciTech Connect

    Brown, Nicole [Department of Microbiology and Immunology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA 23298 (United States); Nagarkatti, Mitzi [Department of Microbiology and Immunology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA 23298 (United States); Nagarkatti, Prakash S. [Department of Pharmacology and Toxicology, PO Box 980613, Virginia Commonwealth University Medical Center, Richmond, VA 23298-0613 (United States)]. E-mail: pnagark@hsc.vcu.edu

    2006-04-15

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

  19. 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.

  20. Growth repression in diethylstilbestrol/dimethylbenz[a]anthracene-induced rat mammary gland tumor using Hecate-CGbeta conjugate.

    PubMed

    Zaleska, Monika; Waclawik, Agnieszka; Bodek, Gabriel; Zezula-Szpyra, Anna; Li, Xiangdong; Janowski, Tomasz; Hansel, Wiliam H; Rahman, Nafis A; Ziecik, Adam J

    2004-04-01

    Recently, we have shown that Hecate-CGbeta conjugate, which is a fusion of the lytic peptide Hecate and a 15-amino acid fragment of the beta-chain of chorionic gonadotropin (CGbeta), selectively destroys mammary gland carcinoma cells that possess luteinizing hormone receptors (LHR) in vitro. We induced mammary gland tumors using combined prenatal exposure to synthetic diethylstilbestrol (DES) and additional postnatal exposure to dimethylbenz[a]anthracene (DMBA). Rats with tumors were equally randomized (10/group) and treated with either sham (control) or 12 mg/kg body wt of either Hecate or Hecate-CGbeta once a week for 3 weeks by tail vein injections. One week after the last injection, rats were killed. Reverse-transcription-nested polymerase chain reaction/Southern blotting revealed alternatively spliced mRNA for LHR in tumor tissues of 5 of 30 females, which was further confirmed by Western blot analysis. The percentage of tumor volume increase was lowest in the group treated with Hecate-CGbeta (45.3 +/- 27.6), compared with Hecate- and sham-treated, control group (324.8 +/- 78.1 and 309.9 +/- 51.2, respectively; P<0.001). Hecate-CGbeta induced a significant decrease in tumor burden compared with controls (9.5 +/- 2.1 mg/g body wt vs. 21.6 +/- 2.9; P<0.01). A smaller reduction in tumor burden was also observed in Hecate-treated females (17.6 +/- 1.6 mg/g body wt vs. 21.6 +/- 2.9; P<0.05). Our results prove the principle that Hecate-CGbeta conjugate is able to repress mammary gland tumor growth, even in tumor tissues that lack or have very low levels of LHR. The mechanism of Hecate-CGbeta conjugate action in repression of DES/DMBA-induced tumor growth needs to be further analyzed to clarify the molecular mechanisms of Hecate-CGbeta conjugate action in vivo. PMID:15044717

  1. Comparative analysis of human CYP3A4 and rat CYP3A1 induction and relevant gene expression by bisphenol A and diethylstilbestrol: implications for toxicity testing paradigms.

    PubMed

    Kuzbari, Oumar; Peterson, C Matthew; Franklin, Michael R; Hathaway, Laura B; Johnstone, Erica B; Hammoud, Ahmad O; Lamb, John G

    2013-06-01

    Bisphenol A (BPA) and diethylstilbestrol (DES) are endocrine-disrupting chemicals that interact with the human pregnane X receptor (PXR). CYP3A4 enzyme is essential in the hydroxylation of steroid hormones and is regulated by PXR. In the present study, human and rat hepatoma cell lines were exposed to BPA and DES. Both BPA and DES (10-50?M) caused a significant activation of the CYP3A4 promoter via the PXR in the DPX2 human hepatoma cell line. No activation of rat PXR was seen. BPA and DES treated DPX2 cells demonstrated increased expression of CYP3A4 mRNA, and increased enzyme activity. In summary, BPA, in concentrations relevant to current safety levels of human exposure, activates the human PXR and demonstrates an increase in CYP3A4 mRNA expression and enzyme activity. BPA actions in this model system occur to a greater extent than DES. This study raises concerns regarding our current toxicity testing paradigms and species utilization. PMID:23384967

  2. Mal-Development of the Penis and Loss of Fertility in Male Rats Treated Neonatally with Female Contraceptive 17?-Ethinyl Estradiol: A Dose-Response Study and a Comparative Study with a Known Estrogenic Teratogen Diethylstilbestrol

    PubMed Central

    Mathews, Ensa; Braden, Tim D.; Williams, Carol S.; Williams, John W.; Bolden-Tiller, Olga; Goyal, Hari O.

    2009-01-01

    The objectives of this study were to find a minimal dose of 17?-ethinyl estradiol (EE) that is detrimental to the developing penis and fertility and to compare estrogenic effects between EE and diethylstilbestrol (DES). Neonatal rats received EE at 10 ng (1 ?g/kg), 100 ng, 1 ?g, or 10 ?g per pup on alternate days from postnatal days 1 to 11 (dose-response study) or received EE or DES at 100 ng per pup daily from postnatal days 1 to 6 (comparative study). Effects of EE were dose dependent, with ? 100-ng dose inducing significant (p < 0.05) reductions in penile length, weight, and diameter. Additionally, the penis was malformed, characterized by underdeveloped os penis and accumulation of fat cells. Fertility was 0% in the ? 1-?g groups, in contrast to 60% in the 100-ng group and 100% in the 10-ng and control groups. Animals treated with ? 10 ng had significant reductions in the weight of bulbospongious muscle, testis, seminal vesicle, epididymal fat pad, and in epididymal sperm numbers. A comparison of EE and DES effects showed similar reductions in penile weight and length and the weight of bulbospongiosus muscle, testis, seminal vesicle, epididymis, and epididymal fat pad in both adolescent and adult rats. While 5/6 control males sired, only 1/6 in the EE group and 0/6 in the DES group sired. Hence, neonatal exposure to EE at 10 ng (environmentally relevant dose) adversely affects male reproductive organs. A dose ten times higher than this leads to permanently mal-developed penis and infertility. Furthermore, EE and DES exposures show similar level of toxicity to male reproductive organs. PMID:19729556

  3. [Melatonin receptor agonist].

    PubMed

    Uchiyama, Makoto

    2015-06-01

    Melatonin is a hormone secreted by the pineal gland and is involved in the regulation of human sleep-wake cycle and circadian rhythms. The melatonin MT1 and MT2 receptors located in the suprachiasmatic nucleus in the hypothalamus play a pivotal role in the sleep-wake regulation. Based on the fact that MT1 receptors are involved in human sleep onset process, melatonin receptor agonists have been developed to treat insomnia. In this article, we first reviewed functions of melatonin receptors with special reference to MT1 and MT2, and properties and clinical application of melatonin receptor agonists as hypnotics. PMID:26065135

  4. 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

  5. Agonist-activated ion channels

    PubMed Central

    Colquhoun, David

    2006-01-01

    This paper looks at ion channels as an example of the pharmacologist's stock in trade, the action of an agonist on a receptor to produce a response. Looked at in this way, ion channels have been helpful because they are still the only system which is simple enough for quantitative investigation of transduction mechanisms. A short history is given of attempts to elucidate what happens between the time when agonist first binds, and the time when the channel opens. PMID:16402101

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

    PubMed

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

    2015-07-01

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

  7. The Structural Basis of Estrogen Receptor\\/Coactivator Recognition and the Antagonism of This Interaction by Tamoxifen

    Microsoft Academic Search

    Andrew K. Shiau; Danielle Barstad; Paula M. Loria; Lin Cheng; Peter J. Kushner; David A. Agard; Geoffrey L. Greene

    1998-01-01

    Ligand-dependent activation of transcription by nuclear receptors (NRs) is mediated by interactions with coactivators. Receptor agonists promote coactivator binding, and antagonists block coactivator binding. Here we report the crystal structure of the human estrogen receptor ? (hER?) ligand-binding domain (LBD) bound to both the agonist diethylstilbestrol (DES) and a peptide derived from the NR box II region of the coactivator

  8. Feedlot Performance and Blood Plasma Amino Acid Patterns in Beef Steers Fed Diethylstilbestrol Under Ad Libitum, Restricted, and Compensatory Conditions

    Microsoft Academic Search

    R. R. OLTJEN; H. SWAN; T. S. RUMSEY; D. J. BOLT; T. WEINLAND

    The purpose of this study was to determine the influence of diethyl- stilbestrol ( DES ) and widely differing nutritional regimens on the feedlot performance and blood plasma amino acid patterns of beef steers. Sixteen 276-kg steers were fed a high protein finishing diet ad libitum for 28 days, then feed was restricted to 2 kg\\/steer\\/ day for 35 days

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

    PubMed Central

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

    2011-01-01

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

  10. 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

  11. Agonist activation of a nicotinic acetylcholine receptor.

    PubMed

    Auerbach, Anthony

    2015-09-01

    How does an agonist activate a receptor? In this article I consider the activation process in muscle nicotinic acetylcholine receptors (AChRs), a prototype for understanding the energetics of binding and gating in other ligand-gated ion channels. Just as movements that generate gating currents activate voltage-gated ion channels, movements at binding sites that generate an increase in affinity for the agonist activate ligand-gated ion channels. The main topics are: i) the schemes and intermediate states of AChR activation, ii) the energy changes of each of the steps, iii) the sources of the energies, iv) the three kinds of AChR agonist binding site and v) the correlations between binding and gating energies. The binding process is summarized as sketches of different conformations of an agonist site. The results suggest that agonists lower the free energy of the active conformation of the protein in stages by establishing favorable, local interactions at each binding site, independently. This article is part of the Special Issue entitled 'The Nicotinic Acetylcholine Receptor: From Molecular Biology to Cognition'. PMID:25446670

  12. 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.

  13. Reciprocity of agonistic support in ravens

    PubMed Central

    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

  14. 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

  15. Lead Exposure Alters the Development of Agonistic

    E-print Network

    Delville, Yvon

    Lead Exposure Alters the Development of Agonistic Behavior in Golden Hamsters M. Catalina Cervantes@mail.utexas.edu ABSTRACT: We tested the effects of exposure to different doses of lead acetate (either 0, 25, 100, or 400-specific effect of lead exposure on the development of aggression during puberty at doses resulting in blood

  16. Histrionicotoxin enhances agonist-induced desensitization of acetylcholine receptor.

    PubMed Central

    Burgermeister, W; Catterall, W A; Witkop, B

    1977-01-01

    Dihydroisohistrionicotoxin inhibits acetylcholine receptor-dependent 22Na+ uptake of cultured chick muscle cells with a KI of 0.2 micrometer. The inhibition is noncompetitive with respect to agonists. The toxin enhances desensitization of the receptor by agonists which is accompanied by a 10-fold increase in receptor affinity for agonists. Dihydroisohistrionicotoxin increases the affinity of the desensitized form of the receptor for agonists but not antagonists. The results suggest that dihydroisohistrionicotoxin inhibits the acetylcholine receptor by causing an increase in the affinity of the desensitized form of the receptor for agonists and thereby stabilizing the desensitized state. PMID:272000

  17. 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

  18. Comparison with the Muscarinic Agonist Carbachol

    Microsoft Academic Search

    STEPHEN P. SOLTOFF; MICHAEL K. MCMILLIAN; EDWARD J. CRAGOE; LEWIS C. CANTLEY; BARBARA R. TALAMO

    The effects of extracellular ATP on ion fluxes and the intracellular free Ca 2§ concentration ((Ca~+)i) were examined using a suspension of rat parotid acinar cells and were contrasted with the effects of the muscarinic agonist carba- chol. Although ATP and carbachol both rapidly increased (Ca2+) i about threefold above the resting level (200-250 nM), the effect of ATP was

  19. Novel endogenous peptide agonists of cannabinoid receptors

    PubMed Central

    Gomes, Ivone; Grushko, Julia S.; Golebiewska, Urszula; Hoogendoorn, Sascha; Gupta, Achla; Heimann, Andrea S.; Ferro, Emer S.; Scarlata, Suzanne; Fricker, Lloyd D.; Devi, Lakshmi A.

    2009-01-01

    Hemopressin (Hp), a 9-residue ?-hemoglobin-derived peptide, was previously reported to function as a CB1 cannabinoid receptor antagonist (1). In this study, we report that mass spectrometry (MS) data from peptidomics analyses of mouse brain extracts identified N-terminally extended forms of Hp containing either three (RVD-Hp?) or two (VD-Hp?) additional amino acids, as well as a ?-hemoglobin-derived peptide with sequence similarity to that of hemopressin (VD-Hp?). Characterization of the ?-hemoglobin-derived peptides using binding and functional assays shows that in contrast to Hp, which functions as a CB1 cannabinoid receptor antagonist, both RVD-Hp? and VD-Hp? function as agonists. Studies examining the increase in the phosphorylation of ERK1/2 levels or release of intracellular Ca2+ indicate that these peptides activate a signal transduction pathway distinct from that activated by the endocannabinoid, 2-arachidonoylglycerol, or the classic CB1 agonist, Hu-210. This finding suggests an additional mode of regulation of endogenous cannabinoid receptor activity. Taken together, these results suggest that the CB1 receptor is involved in the integration of signals from both lipid- and peptide-derived signaling molecules.—Gomes, I., Grushko, J. S., Golebiewska, U., Hoogendoorn, S., Gupta, A., Heimann, A. S., Ferro, E. S., Scarlata, S., Fricker, L. D., Devi, L. A. Novel endogenous peptide agonists of cannabinoid receptors. PMID:19380512

  20. Incidence of squamous neoplasia of the cervix and vagina in des-exposed daughters.

    PubMed

    Hatch; Herbst; Hoover; Noller; Adam; Kaufman; Palmer; Titus-Ernstoff; Hyer; Robboy

    2000-10-01

    PURPOSE: Women exposed to diethylstibestrol (DES) in utero are known to have an excess risk of clear cell adenocarcinoma of the vagina and cervix, in addition to vaginal epithelial changes, but the effect on the incidence of squamous neoplasia is uncertain. This study evaluated the long-term risk of developing high-grade squamous neoplasia of the genital tract among women exposed prenatally to diethylstilbestrol.METHODS: A cohort comprising 3899 DES-exposed and 1374 unexposed daughters was followed for thirteen years (1982-1995) for pathology-confirmed diagnoses of high-grade squamous neoplasia. A pathologist blinded to exposure status reviewed seventy-seven percent of cases. Poisson regression analysis was used to compute relative risks (RR) and 95% confidence intervals (CI) controlling for age, calendar year, screening history and other covariates.RESULTS: The RR (95% CI) among DES-exposed versus unexposed, based on 111 cases of high-grade disease, was 2.12 (1.19-3.77). Adjustment for screening history had little effect, but when the analysis was restricted to a group highly screened before 1982, the risk was reduced. Risk estimates were higher among women exposed earlier in gestation; the RR (95% CI) for exposure within 7 weeks of the last menstrual period was 2.82 (1.43-5.53).CONCLUSIONS: The findings support an association between in utero DES exposure and high-grade squamous neoplasia, although a role for more intensive screening among DES-exposed women in the production of this excess could not be completely ruled out. PMID:11018391

  1. Modulation of PPAR subtype selectivity. Part 2: Transforming PPAR ?\\/ ? dual agonist into ? selective PPAR agonist through bioisosteric modification

    Microsoft Academic Search

    Pandurang Zaware; Shailesh R. Shah; Harikishore Pingali; Pankaj Makadia; Baban Thube; Suresh Pola; Darshit Patel; Priyanka Priyadarshini; Dinesh Suthar; Maanan Shah; Jeevankumar Jamili; Kalapatapu V. V. M. Sairam; Suresh Giri; Lala Patel; Harilal Patel; Hareshkumar Sudani; Hiren Patel; Mukul Jain; Pankaj Patel; Rajesh Bahekar

    2011-01-01

    A novel series of oxime containing benzyl-1,3-dioxane-r-2-carboxylic acid derivatives (6a–k) were designed as selective PPAR? agonists, through bioisosteric modification in the lipophilic tail region of PPAR?\\/? dual agonist. Some of the test compounds (6a, 6b, 6c and 6f) showed high selectivity towards PPAR? over PPAR? in vitro. Further, highly potent and selective PPAR? agonist 6c exhibited significant antihyperglycemic and antihyperlipidemic

  2. Elimination of a cholecystokinin receptor agonist 'trigger' in an effort to develop positive allosteric modulators without intrinsic agonist activity.

    PubMed

    Desai, Aditya J; Henke, Brad R; Miller, Laurence J

    2015-05-01

    Cholecystokinin (CCK) acts at the type 1 cholecystokinin receptor (CCK1R) to elicit satiety and is a well-established drug target for obesity. To date, small molecule agonists have been developed, but have failed to demonstrate adequate efficacy in clinical trials, and concerns about side effects and potential toxicity have limited further development of full agonists. The use of positive allosteric modulators (PAMs) without intrinsic agonist activity that are active only for a brief period of time after a meal might represent a safer alternative. Here, we propose a possible novel strategy to develop such compounds by modifying the agonist 'trigger' of an existing small molecule agonist. We have studied analogues of the 1,5-benzodiazepine agonist, GI181771X, in which the N1-isopropyl agonist 'trigger' was modified. While agonist activity was greatly reduced in these compounds, they acted as negative, rather than positive modulators. The parent drug was also found to exhibit no positive modulation of CCK action. Receptor structure-activity relationship studies demonstrated that the mode of docking these derivatives was distinct from that of the parent compound, perhaps explaining their action as negative allosteric modulators. We conclude that this outcome is likely characteristic of the parental agonist, and that this strategy may be more successfully utilized with a parental ago-PAM, possessing intrinsic positive modulatory activity. PMID:25862198

  3. 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

  4. Chimpanzees Extract Social Information from Agonistic Screams

    PubMed Central

    Slocombe, Katie E.; Kaller, Tanja; Call, Josep; Zuberbühler, Klaus

    2010-01-01

    Chimpanzee (Pan troglodytes) agonistic screams are graded vocal signals that are produced in a context-specific manner. Screams given by aggressors and victims can be discriminated based on their acoustic structure but the mechanisms of listener comprehension of these calls are currently unknown. In this study, we show that chimpanzees extract social information from these vocal signals that, combined with their more general social knowledge, enables them to understand the nature of out-of-sight social interactions. In playback experiments, we broadcast congruent and incongruent sequences of agonistic calls and monitored the response of bystanders. Congruent sequences were in accordance with existing social dominance relations; incongruent ones violated them. Subjects looked significantly longer at incongruent sequences, despite them being acoustically less salient (fewer call types from fewer individuals) than congruent ones. We concluded that chimpanzees categorised an apparently simple acoustic signal into victim and aggressor screams and used pragmatics to form inferences about third-party interactions they could not see. PMID:20644722

  5. 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…

  6. Agomelatine, a melatonin agonist with antidepressant properties.

    PubMed

    Dubovsky, Steven L; Warren, Calvert

    2009-10-01

    Agomelatine (beta-methyl-6-chloromelatonin), which is structurally homologous to melatonin, is a potent agonist of melatonin MT1 and MT2 receptors as well as an antagonist of serotonin 5-HT(2C) receptors. Agomelatine appears to improve sleep without causing daytime sedation. It has not been found to be associated with sexual side effects and discontinuation symptoms. Three placebo-controlled trials, one of them a dose finding study and two of them pivotal trials, suggest that agomelatine is an antidepressant at doses of 25 - 50 mg/day. Agomelatine appears to be well tolerated, without sexual or cardiac adverse effects, weight gain or discontinuation syndromes. Animal studies suggest a possible neuroprotective action of agomelatine, although there are more data in favor of an anxiolytic effect. Substantially more research is needed to establish its role in the treatment of mood and circadian rhythm disorders. PMID:19758108

  7. 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

  8. [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

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

    PubMed Central

    2010-01-01

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

  10. 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

  11. Sociologie des prenoms... des chiens Baptiste Coulmont

    E-print Network

    Paris-Sud XI, Université de

    Sociologie des pr´enoms... des chiens Baptiste Coulmont 23 septembre 2011 Introduction L'´etude de donn´ees concernant plus de 10 millions de chiens (ann´ee de naissance, pr´enom, d´epartement de naissance, race), nous donne les infor- mations suivantes : 1. Les pr´enoms des chiens suivent des modes sp

  12. Antifertility effects of luteinizing hormone-releasing hormone (LHRH) agonists.

    PubMed

    Labrie, F; Bélanger, A; Kelly, P A; Séguin, C; Cusan, L; Lefebvre, F A; Reeves, J J; Lemay, A; Faure, N; Gourdeau, Y; Raynaud, J P

    1981-01-01

    This paper reviews the mechanisms responsible for the antifertility effects of luteinizing hormone-releasing hormone (LHRH) agonists. Large doses of the LHRH agonist LHRH-EA lead to a marked reduction of testicular and secondary sex organ weight, LH receptor levels, and plasma testosterone concentration. A marked inhibition of basal testicular and testosterone concentrations is obtained after daily administration of the LHRH agonists at doses greater than 10 ng. Treatment with low doses of the LHRH agonist can lead to an increased steroidogenic response to LH. Treatment with low doses of LHRH agonists could stimulate Leydig cell function while high doses are history. A study of the effects of longterm treatment with an LHRH agonsist on spermatogenesis revelaed that testis, prostate, and seminal vesicle weight decreased and plasma LH and FSH levels increased over 12 weeks. Comparison of the effects of increasing doses of LHRH agonist on testicular and ovarian gonadotropin receptors and steroidogenesis in male rats indicates that single or repeated administration of LHRH agonists can lead to loss of testicular LH receptors in the absence of the pituitary gland. The loss of ovarian gonadotropin receptors in female rats is also investigated. Antifertility effects of LHRH ethylamide are accompanied by a marked loss of LH/hCG and FSH receptors in ovarian tissue. The injection of 1,3, or 10 ng LHRH-EA in intact rats has no significant effect on ovarian LH receptor levels. A study of the direct action of LHRH agonists at the ovarian level demonstrates a close relationship between the binding activity of a large series of LHRH agonists and antagonists in the anterior pituitary gland and the ovary. Inhibition of testicular steroidogenesis in man by treatment with a potent LHRH agonist is also demonstrated. Intranasal administration of LHRH ethylamide has luteolytic effects in normal women. Daily administration of LHRH-EA inhibited ovulation in all but 2 of 89 treatment cycles in the normal women studied. These studies demonstrate a luteolytic action of LHRH and its agonists in women. LRHR agonists may be used as a new and near-physiological approach to contraception as inhibitors of ovulation or for the induction of menses and as an alternative to the postcoital estrogenic pill. PMID:6275404

  13. Improving the Pharmacokinetics of GPR40/FFA1 Full Agonists

    PubMed Central

    2014-01-01

    We recently reported the discovery of a potent GPR40 full agonist AM-1638 (1). Herein, we describe our efforts in improving the drug-like properties of the full agonists through the systematic introduction of polar groups in the C-, D-, and A-rings. This led to the discovery of new GPR40 full agonists with significantly improved pharmacokinetic propeties. Compound 8 and 20 also showed potent in vivo efficacy in oral glucose tolerance tests in mice in addition to the improvement in properties. PMID:24900845

  14. 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

  15. Des Moines.

    ERIC Educational Resources Information Center

    Gore, Deborah, Ed.

    1988-01-01

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

  16. 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 Sugdena Li-Kuan Yehb Muy-Teck Teha aPhysiology Division, GKT School of Biomedical Science, King's College

  17. Overview of receptor interactions of agonists and antagonists.

    PubMed

    Kenakin, Terry

    2008-09-01

    Historically, the earliest methods used to quantitatively measure the fundamental properties of drugs (namely affinity and efficacy) employed isolated tissues, and it is in this realm that the null methods used to define "receptor pharmacology" were described. This unit describes these methods and their use to specifically classify agonists (through potency ratios and determination of relative affinities and efficacies) and antagonists (through analysis of surmountable and insurmountable antagonism) to yield estimates of potency. Different drugs can yield different behaviors in various tissues, so this unit is centered on a flow diagram to indicate the type of analysis appropriate for the behavior observed. For example, some agonists may be full agonists in some tissues and partial agonists in others, while some antagonists may demonstrate surmountable simple competitive antagonism in some tissues and insurmountable non-competitive antagonism in others. Methods exist for determination of affinity and efficacy for all of these behaviors, and these are delineated in this unit. PMID:22294222

  18. TARP auxiliary subunits switch AMPA receptor antagonists into partial agonists.

    PubMed

    Menuz, Karen; Stroud, Robert M; Nicoll, Roger A; Hays, Franklin A

    2007-11-01

    Quinoxalinedione compounds such as 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) are the most commonly used alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonists. However, we find that in the presence of transmembrane AMPA receptor regulatory proteins (TARPs), which are AMPA receptor auxiliary subunits, CNQX acts as a partial agonist. CNQX induced small depolarizing currents in neurons of the central nervous system, and reconstitution of this agonist activity required coexpression of TARPs. A crystal structure of CNQX bound to the TARP-less AMPA receptor ligand-binding domain showed that, although CNQX induces partial domain closure, this movement is not transduced into linker separation, suggesting that TARPs may increase agonist efficacy by strengthening the coupling between domain closure and channel opening. Our results demonstrate that the presence of an auxiliary subunit can determine whether a compound functions as an agonist or antagonist. PMID:17975069

  19. 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

  20. Agonistic Properties of Cannabidiol at 5HT1a Receptors

    Microsoft Academic Search

    Ethan B. Russo; Andrea Burnett; Brian Hall; Keith K. Parker

    2005-01-01

    Cannabidiol (CBD) is a major, biologically active, but psycho-inactive component of cannabis. In this cell culture-based report, CBD is shown to displace the agonist, [3H]8-OH-DPAT from the cloned human 5-HT1a receptor in a concentration-dependent manner. In contrast, the major psychoactive component of cannabis, tetrahydrocannabinol (THC) does not displace agonist from the receptor in the same micromolar concentration range. In signal

  1. Peripheral kappa-opioid agonists for visceral pain.

    PubMed

    Rivière, Pierre J-M

    2004-04-01

    Kappa (kappa)-opioid receptor agonists are particularly effective analgesics in experimental models of visceral pain. Their analgesic effects are mediated in the periphery. The molecular targets involved include peripherally located kappa-receptors and possibly, at least for some nonpeptidic kappa-agonists, additional nonopioid molecular targets such as sodium channels located on primary sensory afferents. Overall, these properties are expected to be of therapeutic interest in various visceral pain conditions, including abdominal surgery associated with postoperative pain and ileus, pancreatitis pain, dysmenorrhea, labor pain and functional disorders such as irritable bowel syndrome or dyspepsia. The first kappa-agonists to be developed were brain-penetrating organic small molecules. Their development was eventually discontinued due to central side effects such as sedation and dysphoria attributed to kappa-receptors located behind the blood-brain barrier. New drug discovery programs are now geared towards the design of peripherally-selective kappa-agonists. So far, most of the organic molecule-based peripheral kappa-agonists have achieved limited peripheral selectivity and a practically insufficient therapeutic window to justify full development. These compounds have been used in a small number of clinical pilot studies involving visceral pain. Although encouraging, the clinical data available so far with this class of compounds are too limited and fragmented to fully validate the therapeutic utility of kappa-agonists in visceral pain. Additional clinical studies with safer kappa-agonists (i.e. with higher peripheral selectivity) are still required. The most suitable tools to address this question in the future appear to be the newly discovered class of tetrapeptide-based kappa-agonists, which have shown unprecedented levels of peripheral selectivity. PMID:15051626

  2. Nociceptive and antinociceptive responses to intrathecally administered nicotinic agonists

    Microsoft Academic Search

    Imran M. Khan; Hartmut Buerkle; Palmer Taylor; Tony L. Yaksh

    1998-01-01

    Activation of spinal nicotinic receptors evokes a prominent algogenic response. Recently, epibatidine, a potent nicotinic agonist, was found to display an antinociceptive response after systemic administration. To examine the spinal component of this action, effects of three nicotinic agonists—epibatidine, cytisine and nicotine—were given intrathecally (IT) and their antinociceptive activity was subsequently assessed. All agents elicited dose-dependent algogenic activity, characterized at

  3. Use of ?2-Agonists in Neuroanesthesia: An Overview

    PubMed Central

    Farag, Ehab; Argalious, Maged; Sessler, Daniel I.; Kurz, Andrea; Ebrahim, Zeyd Y.; Schubert, Armin

    2011-01-01

    ?2-Agonists are a novel class of drugs with mechanisms of action that differ from other commonly used anesthetic drugs. They have neuroprotective, cardioprotective, and sedative effects. These unique characteristics make them potentially useful during neuroanesthesia and intensive care. We review the effects of dexmedetomidine on cerebral blood flow and cerebral metabolism, along with recent advances in using ?2-agonists in neuroanesthesia and neurointensive care. PMID:21603337

  4. Immunomodulatory Activity of mu- and kappa-Selective Opiod Agonists

    Microsoft Academic Search

    Dennis D. Taub; Toby K. Eisenstein; Ellen B. Geller; Martin W. Adler; Thomas J. Rogers

    1991-01-01

    Opioids and opioid peptides have been shown by numerous laboratories to modulate various parameters of the immune response, but little attention has been given to the type of opioid receptor that might be involved. This study focuses on the in vitro influences of morphine and DAMGE (Tyr-D-Ala-Gly-N-Me-Phe-Gly-ol), mu-selective agonists, and U50, 488H and U69, 593, kappa-selective agonists, on the generation

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

    Microsoft Academic Search

    Anu S Maharjan; Darrell Pilling; Richard H Gomer

    2010-01-01

    BACKGROUND: In healing wounds, some monocytes enter the wound and differentiate into fibroblast-like cells called fibrocytes. Since Toll-like receptors (TLRs) are present on monocytes, and pathogens that can infect a wound have and\\/or release TLR agonists, we examined whether TLR agonists affect fibrocyte differentiation. RESULTS: When human peripheral blood mononuclear cells (PBMCs) were cultured with TLR3, TLR4, TLR5, TLR7, TLR8

  6. TARP Auxiliary Subunits Switch AMPA Receptor Antagonists into Partial Agonists

    Microsoft Academic Search

    Karen Menuz; Robert M. Stroud; Roger A. Nicoll; Franklin A. Hays

    2008-01-01

    Quinoxalinedione compounds such as 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) are the most commonly used a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonists. However, we find that in the presence of transmembrane AMPA receptor regulatory proteins (TARPs), which are AMPA receptor auxiliary subunits, CNQX acts as a partial agonist. CNQX induced small depolarizing currents in neurons of the central nervous system, and reconstitution of this agonist activity

  7. TARP Auxiliary Subunits Switch AMPA Receptor Antagonists into Partial Agonists

    Microsoft Academic Search

    Karen Menuz; Robert M. Stroud; Roger A. Nicoll; Franklin A. Hays

    2007-01-01

    Quinoxalinedione compounds such as 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) are the most commonly used alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonists. However, we find that in the presence of transmembrane AMPA receptor regulatory proteins (TARPs), which are AMPA receptor auxiliary subunits, CNQX acts as a partial agonist. CNQX induced small depolarizing currents in neurons of the central nervous system, and reconstitution of this agonist activity

  8. Pharmacogenetics of beta2 adrenergic receptor agonists in asthma management.

    PubMed

    Ortega, V E

    2014-07-01

    Beta2 (?2) adrenergic receptor agonists (beta agonists) are a commonly prescribed treatment for asthma despite the small increase in risk for life-threatening adverse responses associated with long-acting beta agonist (LABA). The concern for life-threatening adverse effects associated with LABA and the inter-individual variability of therapeutic responsiveness to LABA-containing combination therapies provide the rationale for pharmacogenetic studies of beta agonists. These studies primarily evaluated genes within the ?2-adrenergic receptor and related pathways; however, recent genome-wide studies have identified novel loci for beta agonist response. Recent studies have identified a role for rare genetic variants in determining beta agonist response and, potentially, the risk for rare, adverse responses to LABA. Before genomics research can be applied to the development of genetic profiles for personalized medicine, it will be necessary to continue adapting to the analysis of an increasing volume of genetic data in larger cohorts with a combination of analytical methods and in vitro studies. PMID:24641588

  9. Modulation of PPAR subtype selectivity. Part 2: Transforming PPAR?/? dual agonist into ? selective PPAR agonist through bioisosteric modification.

    PubMed

    Zaware, Pandurang; Shah, Shailesh R; Pingali, Harikishore; Makadia, Pankaj; Thube, Baban; Pola, Suresh; Patel, Darshit; Priyadarshini, Priyanka; Suthar, Dinesh; Shah, Maanan; Jamili, Jeevankumar; Sairam, Kalapatapu V V M; Giri, Suresh; Patel, Lala; Patel, Harilal; Sudani, Hareshkumar; Patel, Hiren; Jain, Mukul; Patel, Pankaj; Bahekar, Rajesh

    2011-01-15

    A novel series of oxime containing benzyl-1,3-dioxane-r-2-carboxylic acid derivatives (6a-k) were designed as selective PPAR? agonists, through bioisosteric modification in the lipophilic tail region of PPAR?/? dual agonist. Some of the test compounds (6a, 6b, 6c and 6f) showed high selectivity towards PPAR? over PPAR? in vitro. Further, highly potent and selective PPAR? agonist 6c exhibited significant antihyperglycemic and antihyperlipidemic activity in vivo, along with its improved pharmacokinetic profile. Favorable in-silico interaction of 6c with PPAR? binding pocket correlate its in vitro selectivity profile toward PPAR? over PPAR?. Together, these results confirm discovery of novel series of oxime based selective PPAR? agonists for the safe and effective treatment of various metabolic disorders. PMID:21195611

  10. Glucagon Receptor Agonists and Antagonists Affect the Growth of the Chick Eye: A Role for Glucagonergic Regulation of Emmetropization?

    PubMed Central

    Vessey, Kirstan A.; Lencses, Kathy A.; Rushforth, David A.; Hruby, Victor J.; Stell, William K.

    2006-01-01

    Purpose In chicks, plus defocus retards eye growth, thickens the choroid, and activates glucagonergic amacrine cells, probably releasing glucagon. Glucagon receptor antagonists (expected to inhibit compensation to plus defocus) and agonists (expected to block myopia induction by form deprivation) were administered to eyes of chicks, to test the hypothesis that glucagon mediates the induction of changes in eye growth by plus defocus. Methods Seven-day-old (P7) chick eyes were injected intravitreally with peptides at concentrations of ~10?9 to 10?5 M in 20 ?L (injection volume). The glucagon-receptor antagonists [des-His1,des- Phe6,Glu9]-glucagon-NH2 (des- Phe6-antagonist) and [des-His1,Glu9]-glucagon-NH2 (Phe6-antagonist) were administered daily for 4 to 5 days to plus-defocused eyes. Agonists (porcine glucagon-[1–29] and [Lys17,18,Glu21]-glucagon-NH2) were monocularly administered daily for 5 days to form-deprived eyes. The contralateral eye remained open and received saline. After treatment, eyes were refracted, measured, and examined for histologic changes. Results The Phe6-antagonist at 10?5 M (in the syringe) inhibited changes in both refractive error and axial length compensation induced by +7-D lens wear; however, des-Phe6-antagonist (10?5 M) had weak, inconsistent effects and did not antagonize the action of exogenous glucagon. Glucagon prevented ocular elongation and myopia and induced choroidal thickening in form-deprived eyes. [Lys17,18,Glu21]-glucagon-NH2 had little effect at 1037 M, but at 10?6 to 10?5 M altered rod structure and inhibited eye growth. Conclusions Exogenous glucagon inhibited the growth of form-deprived eyes, whereas Phe6-antagonist inhibited compensation to plus defocus, as might be expected if glucagon is an endogenous mediator of emmetropization. The reason for the failure of des-Phe6-antagonist to counteract the effects of exogenous glucagon requires further investigation. PMID:16249465

  11. Antinociceptive and antiedematogenic activities of fenofibrate, an agonist of PPAR alpha, and pioglitazone, an agonist of PPAR gamma

    Microsoft Academic Search

    Antônio Carlos P. Oliveira; Caryne M. Bertollo; Leonardo Tadeu S. Rocha; Elias B. Nascimento; Karina A. Costa; Márcio M. Coelho

    2007-01-01

    Peroxisome proliferator activated receptors (PPAR) are ligand-regulated transcription factors that control the expression of many genes. The antiinflammatory activity of fibrates, PPAR? agonists, and thiazolidinediones, PPAR? agonists, has been demonstrated in many in vitro and a few in vivo studies. In the present study, we evaluated the effect of acute (100 or 300 mg\\/kg, p.o.) or prolonged (100 or 300 mg\\/kg day,

  12. A step ahead of PPAR? full agonists to PPAR? partial agonists: therapeutic perspectives in the management of diabetic insulin resistance.

    PubMed

    Chigurupati, Sridevi; Dhanaraj, Sokkalingam A; Balakumar, Pitchai

    2015-05-15

    Described since long as a member of the nuclear receptor superfamily, peroxisome proliferator-activated receptors (PPARs) regulate the gene expression of proteins involved in glucose and lipid metabolism. PPARs indeed regulate several physiologic processes, including lipid homeostasis, adipogenesis, inflammation, and wound healing. PPARs bind natural or synthetic PPAR ligands can function as cellular sensors to regulate the gene transcription. Dyslipidemia, and type 2 diabetes mellitus (T2DM) with insulin resistance are treated using agonists of PPAR? and PPAR?, respectively. The PPAR? is a key regulator of insulin sensitization and glucose metabolism, and therefore is considered as an imperative pharmacological target to combat diabetic metabolic disease and insulin resistance. Of note, currently available PPAR? full agonists like rosiglitazone display serious adverse effects such as fluid retention/oedema, weight gain, and increased incidence of cardiovascular events. On the other hand, PPAR? partial agonists are being suggested to devoid or having less incidence of these undesirable events, and are under developmental stages. Current research is on the way for the development of novel PPAR? partial agonists with enhanced therapeutic efficacy and reduced adverse effects. This review sheds lights on the current status of development of PPAR? partial agonists, for the management of T2DM, having comparatively less or no adverse effects to that of PPAR? full agonists. PMID:25748601

  13. Perception of specific trigeminal chemosensory agonists

    PubMed Central

    Frasnelli, J; Albrecht, J; Bryant, B; Lundström, JN

    2011-01-01

    The intranasal trigeminal system is a third chemical sense in addition to olfaction and gustation. As opposed to smell and taste, we still lack knowledge on the relationship between receptor binding and perception for the trigeminal system. We therefore investigated the sensitivity of the intranasal trigeminal system towards agonists of the trigeminal receptors TRPM8 and TRPA1 by assessing subjects’ ability to identify which nostril has been stimulated in a monorhinal stimulation design. We summed the number of correct identifications resulting in a lateralization score. Stimuli were menthol (activating TRPM8 receptors), eucalyptol (TRPM8), mustard oil (TRPA1) and two mixtures thereof (menthol/eucalyptol and menthol/mustard oil). In addition, we examined the relationship between intensity and lateralization scores and investigated whether intensity evaluation and lateralization scores of the mixtures show additive effects. All stimuli were correctly lateralized significantly above chance. Across subjects the lateralization scores for single compounds activating the same receptor showed a stronger correlation than stimuli activating different receptors. Although single compounds were isointense, the mixture of menthol and eucalyptol (activating only TRPM8) was perceived as weaker and was lateralized less accurately than the mixture of menthol and mustard oil (activating both TRPM8 and TRPA1) suggesting suppression effects in the former mixture. In conclusion, sensitivity of different subpopulations of trigeminal sensory neurons seems to be related, but only to a certain degree. The large coherence in sensitivity between various intranasal trigeminal stimuli suggests that measuring sensitivity to one single trigeminal chemical stimulus may be sufficient to generally assess the trigeminal system’s chemosensitivity. Further, for stimuli activating the same receptor a mixture suppression effect appears to occur similar to that observed in the other chemosensory systems. PMID:21575683

  14. 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

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

    PubMed

    Desai, Rajeev I; Bergman, Jack

    2014-03-01

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

  16. Methamphetamine-Like Discriminative-Stimulus Effects of Nicotinic Agonists

    PubMed Central

    Bergman, Jack

    2014-01-01

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

  17. LA REVUE DE L'EPI N 77 DES IMAGES, DES TROUS ET DES BOSSES DES IMAGES, DES TROUS ET DES BOSSES...

    E-print Network

    Paris-Sud XI, Université de

    images (fixes, car pour les images animées c'est encore une autre histoire, au format ".PCX", 320x200 en 256 couleurs). Qu'allons nous en faire ? Les idées ne manquent pas, car une fois numérisée l'image131 LA REVUE DE L'EPI N° 77 DES IMAGES, DES TROUS ET DES BOSSES DES IMAGES, DES TROUS ET DES BOSSES

  18. 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.

  19. Honokiol: A non-adipogenic PPAR? agonist from nature?

    PubMed Central

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

    2013-01-01

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

  20. 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

  1. Regional- and agonist-dependent facilitation of human neurogastrointestinal functions by motilin receptor agonists

    PubMed Central

    Broad, J; Mukherjee, S; Samadi, M; Martin, JE; Dukes, GE; Sanger, GJ

    2012-01-01

    BACKGROUND AND PURPOSE Delayed gastric emptying is poorly managed. Motilin agonists are potential treatments but inadequate understanding into how enteric nerve functions are stimulated compromises drug/dose selection. Resolution is hampered by extreme species dependency so methods were developed to study human gastrointestinal neuromuscular activities and the neurobiology of motilin. EXPERIMENTAL APPROACH Protocols to study neuromuscular activities were developed for different regions of human stomach and intestine (71 patients) using circular muscle preparations and electrical field stimulation (EFS) of intrinsic nerves. Other tissues were fixed for immunohistochemistry. KEY RESULTS EFS evoked contractions and/or relaxations via cholinergic and nitrergic neurons, with additional tachykinergic activity in colon; these were consistent after 154 min (longer if stored overnight). Motilin 1–300 nM and the selective motilin agonist GSK962040 0.1–30 µM acted pre-junctionally to strongly facilitate cholinergic contractions of the antrum (Emax? 1000% for motilin), with smaller increases in fundus, duodenum and ileum; high concentrations increased baseline muscle tension in fundus and small intestine. There were minimal effects in the colon. In the antrum, cholinergic facilitation by motilin faded irregularly, even with peptidase inhibitors, whereas facilitation by GSK962040 was long lasting. Motilin receptor immunoreactivity was identified in muscle and myenteric plexus predominantly in the upper gut, co-expressed with choline acetyltransferase in neurons. CONCLUSIONS AND IMPLICATIONS Motilin and GSK962040 strongly facilitated cholinergic activity in the antrum, with lower activity in fundus and small intestine only. Facilitation by motilin was short lived, consistent with participation in migrating motor complexes. Long-lasting facilitation by GSK962040 suggests different receptor interactions and potential for clinical evaluation. LINKED ARTICLE This article is commented on by Depoortere, pp. 760–762 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476-5381.2012.02046.x PMID:22537158

  2. Optimization of GPR40 Agonists for Type 2 Diabetes

    PubMed Central

    2014-01-01

    GPR40 (FFA1 and FFAR1) has gained significant interest as a target for the treatment of type 2 diabetes. TAK-875 (1), a GPR40 agonist, lowered hemoglobin A1c (HbA1c) and lowered both postprandial and fasting blood glucose levels in type 2 diabetic patients in phase II clinical trials. We optimized phenylpropanoic acid derivatives as GPR40 agonists and identified AMG 837 (2) as a clinical candidate. Here we report our efforts in searching for structurally distinct back-ups for AMG 837. These efforts led to the identification of more polar GPR40 agonists, such as AM-4668 (10), that have improved potency, excellent pharmacokinetic properties across species, and minimum central nervous system (CNS) penetration. PMID:24900872

  3. Novel Delta Opioid Receptor Agonists with Oxazatricyclodecane Structure

    PubMed Central

    2014-01-01

    We synthesized compounds 4a,c–f,h,i containing the oxazatricyclodecane structure from a novel rearrangement reaction product 2a. All the prepared compounds 4a,c–f,h,i exhibited full agonistic activities for the ? opioid receptor (DOR). Among them, the N-methyl derivative 4c was highly selective, and the most effective DOR agonist in functional assays. Subcutaneous administration of 4c produced dose-dependent and NTI (selective DOR antagonist)-reversible antinociception lacking any convulsive behaviors in the mice acetic acid writhing tests. The N-methyl derivative 4c is expected to be a promising lead compound for selective DOR agonists with a novel chemotype. PMID:24900842

  4. Discovery of biaryl carboxylamides as potent ROR? inverse agonists.

    PubMed

    Chao, Jianhua; Enyedy, Istvan; Van Vloten, Kurt; Marcotte, Douglas; Guertin, Kevin; Hutchings, Richard; Powell, Noel; Jones, Howard; Bohnert, Tonika; Peng, Chi-Chi; Silvian, Laura; Hong, Victor Sukbong; Little, Kevin; Banerjee, Daliya; Peng, Liaomin; Taveras, Arthur; Viney, Joanne L; Fontenot, Jason

    2015-08-01

    ROR?t is a pivotal regulator of a pro-inflammatory gene expression program implicated in the pathology of several major human immune-mediated diseases. Evidence from mouse models demonstrates that genetic or pharmacological inhibition of ROR? activity can block the production of pathogenic cytokines, including IL-17, and convey therapeutic benefit. We have identified and developed a biaryl-carboxylamide series of ROR? inverse agonists via a structure based design approach. Co-crystal structures of compounds 16 and 48 supported the design approach and confirmed the key interactions with ROR? protein; the hydrogen bonding with His479 was key to the significant improvement in inverse agonist effect. The results have shown this is a class of potent and selective ROR? inverse agonists, with demonstrated oral bioavailability in rodents. PMID:26048806

  5. Multiple inhibitory actions of luteinizing hormone-releasing hormone agonist on luteinizing hormone/human chorionic gonadotropin receptor-mediated ovarian responses.

    PubMed

    Reddy, P V; Azhar, S; Menon, K M

    1980-10-01

    The administration to female rats of the LHRH agonist, [des-GlyNH2(10)]LHRH ethylamide, as either a single dose or repeated injections resulted in a decrease in the binding of 125I-labeled hCG to ovarian plasma membranes. An ovarian cell suspension prepared from the agonist-injected group of rats also responded to hCG with a decreased ability to accumulate cAMP and progesterone compared with the saline-treated controls. The receptor loss was due to a decreased number of hormone-binding sites rather than to a change in the affinity of the receptor for the hormone. Preincubation of ovarian cells with the agonistic analog in vitro also caused an inhibition of progesterone synthesis in response to hCG, cholera toxin, and 8-Bromo-cAMP, suggesting a direct inhibitory effect of the analog on ovarian steroidogenesis. Prior exposure to the agonistic analog, however, had no effect on cAMP accumulation by the ovarian cells in response to either hCG or cholera enterotoxin, further suggesting that the site of inhibitory action lies at a point after cAMP accumulation. In summary, the present study demonstrates that 1) the inhibition of ovarian steroidogenesis observed in response to the injection of the LHRH agonist is primarily due to down-regulation of ovarian hCG/LH receptors with a resultant decrease in cAMP accumulation, and this effect may be caused by the pulses of LH release from the pituitary, and 2) the direct inhibitory effect on steroidogenesis observed under in vitro conditions is independent of gonadotropin receptor, and the site of this inhibitory action lies at a point after cAMP accumulation. PMID:6250799

  6. Facult des arts et des sciences Dpartement de communication

    E-print Network

    Parrott, Lael

    Faculté des arts et des sciences Département de communication Plans de cours cadre Cours des programmes de premier cycle en sciences de la communication Comité des études de premier cycle Adopté par l..................................................................................................................................3 COM 1150 Rédaction en communication 1

  7. TRPA1 agonists delay gastric emptying in rats through serotonergic pathways

    Microsoft Academic Search

    Hitoshi Doihara; Katsura Nozawa; Eri Kawabata-Shoda; Ryosuke Kojima; Toshihide Yokoyama; Hiroyuki Ito

    2009-01-01

    Our recent study found that TRPA1 is highly expressed in enterochromaffin cells and that stimulation of these cells with TRPA1\\u000a agonists enhances 5-hydroxytryptamine (5-HT) secretion in vitro. Here, to demonstrate the 5-HT-releasing effect of TRPA1 agonists\\u000a in vivo, we examined the effect of TRPA1 agonists on gastric emptying in rats. The results showed that TRPA1 agonists dose-dependently\\u000a delayed gastric emptying.

  8. Estradiol and ER? agonists enhance recognition memory, and DPN, an ER? agonist, alters brain monoamines

    PubMed Central

    Jacome, Luis F.; Gautreaux, Claris; Inagaki, Tomoko; Mohan, Govini; Alves, Stephen; Lubbers, Laura S.; Luine, Victoria

    2010-01-01

    Effects of estradiol benzoate (EB), ER?-selective agonist, propyl pyrazole triol (PPT) and ER?-selective agonists, diarylpropionitrile (DPN) and Compound 19 (C-19) on memory were investigated in OVX rats using object recognition (OR) and placement (OP) memory tasks. Treatments were acute (behavior 4 h later) or sub chronic (daily injections for 2 days with behavior 48 h later). Objects were explored in sample trials (T1), and discrimination between sample (old) and new object/location in recognition trials (T2) was examined after 2–4 h inter-trial delays. Subjects treated sub chronically with EB, DPN, and C-19, but not PPT, discriminated between old and new objects and objects in old and new locations, suggesting that, at these doses and duration of treatments, estrogenic interactions with ER? contributes to enhancements in recognition memory. Acute injections of DPN, but not PPT, immediately after T1, also enhanced discrimination for both tasks (C19 was not investigated). Effects of EB, DPN and PPT on anxiety and locomotion, measured on elevated plus maze and open field, did not appear to account for the mnemonic enhancements. Monoamines and metabolites were measured following DPN treatment in subjects that did not receive behavioral testing. DPN was associated with alterations in monoamines in several brain areas: indexed by the metabolite, 3-methoxy-4-hydroxyphenylglycol (MHPG), or the MHPG/norepinephrine (NE) ratio, NE activity was increased by 60–130% in the prefrontal cortex (PFC) and ventral hippocampus, and NE activity was decreased by 40–80% in the v. diagonal bands and CA1. Levels of the dopamine (DA) metabolite, homovanillic acid (HVA), increased 100% in the PFC and decreased by 50% in the dentate gyrus following DPN treatment. The metabolite of serotonin, 5-hydroxyindole acetic acid (5-HIAA), was increased in the PFC and CA3, by approximately 20%. No monoaminergic changes were noted in striatum or medial septum. Results suggest that ER? mediates sub chronic and acute effects of estrogens on recognition memory and that memory enhancements by DPN may occur, in part, through alterations in monoaminergic containing systems primarily in PFC and hippocampus. PMID:20828630

  9. Neuroprotective Mechanisms of Antiparkinsonian Dopamine D 2 Receptor Subfamily Agonists

    Microsoft Academic Search

    Yoshihisa Kitamura; Takashi Taniguchi; Shun Shimohama; Akinori Akaike; Yasuyuki Nomura

    2003-01-01

    Numerous studies have shown that endogenous and\\/or environmental neurotoxins and oxidative stress may participate in the pathogenesis of Parkinson's disease (PD), but the detailed mechanisms are still unclear. While dopamine (DA) replacement therapy with L-DOPA (levodopa) improves PD symptoms, it does not inhibit the degeneration of DA neurons in the substantia nigra. Recently, bromocriptine, pramipexole and several other agonists of

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

  11. Alpha-adrenoceptor agonistic activity of oxymetazoline and xylometazoline.

    PubMed

    Haenisch, Britta; Walstab, Jutta; Herberhold, Stephan; Bootz, Friedrich; Tschaikin, Marion; Ramseger, René; Bönisch, Heinz

    2010-12-01

    Oxymetazoline and xylometazoline are both used as nasal mucosa decongesting ?-adrenoceptor agonists during a common cold. However, it is largely unknown which of the six ?-adrenoceptor subtypes are actually present in human nasal mucosa, which are activated by the two alpha-adrenoceptor agonists and to what extent. Therefore, mRNA expression in human nasal mucosa of the six ?-adrenoceptor subtypes was studied. Furthermore, the affinity and potency of the imidazolines oxymetazoline and xylometazoline at these ?-adrenoceptor subtypes were examined in transfected HEK293 cells. The rank order of mRNA levels of ?-adrenoceptor subtypes in human nasal mucosa was: ?(2A) > ?(1A) ? ?(2B) > ?(1D) ? ?(2C) > ?(1B) . Oxymetazoline and xylometazoline exhibited in radioligand competition studies higher affinities than the catecholamines adrenaline and noradrenaline at most ?-adrenoceptor subtypes. Compared to xylometazoline, oxymetazoline exhibited a significantly higher affinity at ?(1A) - but a lower affinity at ?(2B) -adrenoceptors. In functional studies in which adrenoceptor-mediated Ca(2+) signals were measured, both, oxymetazoline and xylometazoline behaved at ?(2B) -adrenoceptors as full agonists but oxymetazoline was significantly more potent than xylometazoline. Furthermore, oxymetazoline was also a partial agonist at ?(1A) -adrenoceptors; however, its potency was relatively low and it was much lower than its affinity. The higher potency at ?(2B) -adrenoceptors, i.e. at receptors highly expressed at the mRNA level in human nasal mucosa, could eventually explain why in nasal decongestants oxymetazoline can be used in lower concentrations than xylometazoline. PMID:20030735

  12. The Agonistic Approach: Reframing Resistance in Qualitative Research

    ERIC Educational Resources Information Center

    Vitus, Kathrine

    2008-01-01

    The agonistic approach--aimed at embracing opposing perspectives as part of a qualitative research process and acknowledging that process as fundamentally political--sheds light on both the construction of and the resistance to research identities. This approach involves reflexively embedding interview situations into the ethnographic context as a…

  13. Role of nicotine receptor partial agonists in tobacco cessation.

    PubMed

    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

  14. 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

  15. Chemotype-selective modes of action of ?-opioid receptor agonists.

    PubMed

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

    2013-11-29

    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

  16. 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

  17. Heritable victimization and the benefits of agonistic relationships

    E-print Network

    Blumstein, Daniel T.

    Heritable victimization and the benefits of agonistic relationships Amanda J. Leaa , Daniel T, and approved October 19, 2010 (received for review July 11, 2010) Here, we present estimates of heritability have some heritable basis, yet the heritability of social relationships is largely unknown. Recent

  18. 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

  19. Sleep attacks in patients taking dopamine agonists: review

    Microsoft Academic Search

    Carl Nikolaus Homann; Karoline Wenzel; Klaudia Suppan; Gerd Ivanic; Norbert Kriechbaum; Richard Crevenna; Erwin Ott

    2002-01-01

    Objectives To assess the evidence for the existence and prevalence of sleep attacks in patients taking dopamine agonists for Parkinson's disease, the type of drugs implicated, and strategies for prevention and treatment. Design Review of publications between July 1999 and May 2001 in which sleep attacks or narcoleptic›like attacks were discussed in patients with Parkinson's disease. Results 124 patients with

  20. QSAR and mode of action studies of insecticidal ecdysone agonists

    Microsoft Academic Search

    T. Fujita; Y. Nakagawa

    2007-01-01

    A series of our SAR and QSAR studies of synthetic moulting hormone agonists, dibenzoylhydrazines (DBH), exhibiting insecticidal\\/larvicidal activity are reviewed in this article. We prepared a number of analogues where various substituents are introduced into the two benzene rings of DBH and measured their biological activity using various biological systems. Larvicidal activity was against larvae of the rice stem borer

  1. Alkaloid delta agonist BW373U86 increases hypoxic tolerance.

    PubMed

    Bofetiado, D M; Mayfield, K P; D'Alecy, L G

    1996-06-01

    Activation of delta opioid receptors increases survival time during acute, lethal hypoxia in mice. delta Agonists therefore present a promising avenue for therapeutic application to reduce the morbidity and mortality associated with clinical hypoxia in settings such as drowning, head injury apnea, and complicated childbirths. However, most delta agonists now available are peptides, and may have limited clinical utility. In the present study, we evaluate the neuroprotective ability of an alkaloid delta agonist, BW373U86. Alkaloid compounds, due to increased stability and increased systemic distribution, may be more favorable for clinical use. We found that BW373U86, like the peptide delta agonist, DPDPE ([D-Pen2, D-Pen5]-enkephalin), increases survival time of mice during lethal hypoxia. The mechanism of neuroprotection induced by delta receptor activation appears to involve decreasing body temperature. Further, using selective opioid receptor antagonists, it appears that BW373U86 exerts these neuroprotective effects by acting at delta-opioid receptors. PMID:8638797

  2. The Risk of Myocardial Infarction Associated with Inhaled b Adrenoceptor Agonists

    Microsoft Academic Search

    DAVID H. AU; ROZENN N. LEMAITRE; J. RANDALL CURTIS; NICHOLAS L. SMITH; BRUCE M. PSATY

    Beta-adrenoceptor agonists ( b -agonists), in widespread clinical use for obstructive lung disease, have been associated with an increased risk of cardiovascular mortality. The objective of this study was to assess the association between incident myocardial infarction and the use of inhaled b -agonists. We performed a case-control study within the Group Health Cooperative of Puget Sound (GHC). Be- tween

  3. A mathematical model of the nicotinic-agonist stimulated release of dopamine from striatal

    E-print Network

    Bath, University of

    A mathematical model of the nicotinic-agonist stimulated release of dopamine from striatal- ulation and nicotinic agonists has been well characterised experimentally. Based on these data we have of the involvement of voltage-sensitive Na + channels, whereas nicotinic agonists produce a series of Na + channel

  4. Pathological hypersexuality predominantly linked to adjuvant dopamine agonist therapy in Parkinson's disease and multiple system atrophy

    Microsoft Academic Search

    Kevin J. Klos; James H. Bower; Keith A. Josephs; Joseph Y. Matsumoto; J. Eric Ahlskog

    2005-01-01

    Pathological hypersexuality developed in 13 patients with PD and two patients ultimately diagnosed clinically with MSA. Hypersexuality began within 8 months after starting dopamine agonist therapy in 14 of 15 cases, including four on agonist monotherapy. It resolved in the four cases where the agonist was stopped, despite continued levodopa therapy. This was not an isolated behavioral problem in most,

  5. 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.

  6. 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

  7. Sex differences in opioid antinociception: kappa and 'mixed action' agonists.

    PubMed

    Craft, R M; Bernal, S A

    2001-08-01

    A number of investigators have shown that male animals are more sensitive than females to the antinociceptive effects of mu-opioid agonists. The present study was conducted to examine sex differences in opioid antinociception in the rat using agonists known to differ in selectivity for and efficacy at kappa- versus mu-receptors. Dose- and time-effect curves were obtained for s.c. U69593, U50488, ethylketazocine, (-)-bremazocine, (-)-pentazocine, butorphanol and nalbuphine on the 50 or 54 degrees C hotplate and warm water tail withdrawal assays; spontaneous locomotor activity was measured 32-52 min post-injection in the same rats. On the hotplate assay, only butorphanol (54 degrees C) and nalbuphine (50 degrees C) were significantly more potent in males than females. On the tail withdrawal assay, all agonists were significantly more potent or efficacious in males than females at one or both temperatures. In contrast, no agonist was consistently more potent in one sex or the other in decreasing locomotor activity. Estrous stage in female rats only slightly influenced opioid effects, accounting for an average of 2.6% of the variance in females' antinociceptive and locomotor responses to drug (50 degrees C experiment). These results suggest that (1) sex differences in antinociceptive effects of opioids are not mu-receptor-dependent, as they may occur with opioids known to have significant kappa-receptor-mediated activity; (2) the mechanisms underlying sex differences in kappa-opioid antinociception may be primarily spinal rather than supraspinal; (3) sex differences in antinociceptive effects of opioid agonists are not secondary to sex differences in their sedative effects. PMID:11418226

  8. The ?2-adrenoceptor agonist formoterol stimulates mitochondrial biogenesis.

    PubMed

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

    2012-07-01

    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

  9. 5-HT1A receptor agonists prevent in rats the yawning and penile erections induced by direct dopamine agonists.

    PubMed

    Simon, P; Guardiola, B; Bizot-Espiard, J; Schiavi, P; Costentin, J

    1992-01-01

    The new compound (+) S-20499, an amino chromane derivative (8[-4[N-(5-methoxychromane-3yl)N-propyl]aminobutyl] azaspiro[4-5] décane-7,9 dione), is a high affinity full 5-HT1A agonist. We have investigated its effects on dopaminergic transmission. (+) S-20499 displayed a 10(-8) M affinity for D2 dopamine (DA) receptors, 100 fold lower than for 5-HT1A receptors. The hypothermic effect of the drug was reversed by haloperidol in mice, suggesting that it behaves as a direct dopamine agonist. However, increasing doses of (+) S-20499 induced neither yawning nor penile erections, which constitute characteristic responses of direct DA agonists administered at low doses. In addition, (+) S-20499 prevented the apomorphine (100 micrograms/kg SC) induced yawning and penile erections. This inhibition appears to result from the stimulation of 5-HT1A receptors since it is an effect shared by both buspirone (from 5 mg/kg) and 8-OH-DPAT (from 0.10 mg/kg). In addition, when rats are treated with the 5-HT1A receptor antagonist tertatolol (2-5 mg/kg; SC), increasing doses of (+) S-20499 elicit the expected yawns and penile erections. It is concluded that the 5-HT1A agonist property opposes to that of D2 dopamine receptor stimulation with regard to yawning and penile erections. PMID:1357709

  10. ?4?2* neuronal nicotinic receptor ligands (agonist, partial agonist and positive allosteric modulators) as therapeutic prospects for pain.

    PubMed

    Nirogi, Ramakrishna; Goura, Venkatesh; Abraham, Renny; Jayarajan, Pradeep

    2013-07-15

    ?4?2* neuronal nicotinic acetylcholine receptor are ligand-gated ion channels and widely expressed throughout the central and peripheral nervous system. ?4?2* neuronal nicotinic acetylcholine receptor play crucial role in pain signaling via modulation of multiple neurotransmitters like acetylcholine, dopamine, ?-amino butyric acid (GABA) and norepinephrine. Both spinal and supraspinal pathways are involved in the mechanisms by which ?4?2* neuronal nicotinic acetylcholine receptor ligands modulate the neuropathic and inflammatory pain. Selective ?4?2* neuronal nicotinic acetylcholine receptor ligands are being developed for the treatment of neuropathic and inflammatory pain as they show considerable efficacy in a wide range of preclinical pain models. Agonists/partial agonists of ?4?2* neuronal nicotinic acetylcholine receptor show efficacy in animal models of pain and their anti-nociceptive properties are blocked by nicotinic antagonists. Positive allosteric modulators are being developed with the aim to increase the potency or therapeutic window of agonists/partial agonists. Accumulating evidences suggest that anti-nociceptive effects of nicotinic acetylcholine receptor ligands may not be mediated solely by ?4?2* neuronal nicotinic acetylcholine receptor. We have also reviewed the stage of clinical development of various ?4?2* neuronal nicotinic acetylcholine receptor ligands. PMID:23660369

  11. 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

  12. Interactions between ?-Opioid Receptor Agonists and Cannabinoid Receptor Agonists in Rhesus Monkeys: Antinociception, Drug Discrimination, and Drug Self-Administration

    PubMed Central

    Maguire, David R.; Yang, Wenjuan

    2013-01-01

    Cannabinoid receptor agonists enhance the antinociceptive effects of ?-opioid receptor agonists, which suggests that combinations of these drugs might enhance therapeutic effectiveness (e.g., analgesia). However, it is not clear whether combinations of these drugs also enhance abuse or dependence liability. This experiment examined whether combinations of cannabinoids and opioids that enhance antinociception also increase abuse-related effects by studying the effects of the cannabinoid receptor agonists 2-[(1R,2R,5R)-5-hydroxy-2-(3-hydroxypropyl)cyclohexyl]-5-(2-methyloctan-2-yl)phenol (CP 55,940) and (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate (WIN 55,212) on the antinociceptive, discriminative stimulus, and positive reinforcing effects of ?-opioid receptor agonists in rhesus monkeys. In one group of monkeys (n = 3), morphine (0.1–5.6 mg/kg s.c.), CP 55,940 (0.0032–0.032 mg/kg s.c.), and WIN 55,212 (0.1–1.0 mg/kg s.c.) dose-dependently increased tail withdrawal latency from 50°C water, and pretreatment with small, otherwise ineffective, doses of CP 55,940 and WIN 55,212 shifted the morphine dose-effect curve to the left. In monkeys (n = 3) discriminating 3.2 mg/kg morphine, CP 55,940 (0.01–0.032 mg/kg s.c.) and WIN 55,212 (0.1–1.78 mg/kg s.c.) attenuated the discriminative stimulus effects of morphine, shifting the dose-effect curve to the right. In monkeys (n = 4) self-administering heroin (0.32–32.0 µg/kg/infusion i.v.), CP 55,940 (0.001–0.032 mg/kg s.c.), and WIN 55,212 (0.1–1.0 mg/kg s.c.) shifted the heroin dose-effect curve rightward and downward. Cannabinoid receptor agonists CP 55,940 and WIN 55,212 enhanced the antinociceptive effects but not the discriminative stimulus or positive reinforcing effects of ?-opioid receptor agonists in rhesus monkeys, supporting the view that combining cannabinoid and opioid receptor agonists might result in enhanced treatment effectiveness for pain without similarly enhancing abuse and dependence liability. PMID:23536317

  13. Structure des ADN complmentaires des lactoprotines : application la recherche des gnes et leur localisation chromosomique

    E-print Network

    Paris-Sud XI, Université de

    Structure des ADN complémentaires des lactoprotéines : application à la recherche des gènes et à entrepris. 1) Construction de banques ovine et bovine d ADN complémentaires !ADNcJ. Sélection et identification des clones recombinants contenant les ADN complé- mentaires des ARNm des 6 principales

  14. Discovery and SAR of a Series of Agonists at Orphan G Protein-Coupled Receptor 139

    PubMed Central

    2011-01-01

    GPR139 is an orphan G-protein coupled receptor (GPCR) which is primarily expressed in the central nervous system (CNS). In order to explore the biological function of this receptor, selective tool compounds are required. A screening campaign identified compound 1a as a high potency GPR139 agonist with an EC50 = 39 nM in a calcium mobilization assay in CHO-K1 cells stably expressing the GPR139 receptor. In the absence of a known endogenous ligand, the maximum effect was set as 100% for 1a. Screening against 90 diverse targets revealed no cross-reactivity issues. Assessment of the pharmacokinetic properties showed limited utility as in vivo tool compound in rat with a poor whole brain exposure of 61 ng/g and a brain/plasma (b/p) ratio of 0.03. Attempts to identify a more suitable analogue identified the des-nitrogen analogue 1s with a reduced polar surface area of 76.7 Å2 and an improved b/p ratio of 2.8. The whole brain exposure remained low at 95 ng/g due to a low plasma exposure. PMID:24900311

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

    PubMed Central

    2010-01-01

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

  16. Linguistique Des mots et Des hommes

    E-print Network

    Loewith, Robbie

    'applique en cas de conclusion d'un nouveau contrat ou de renouvellement de contrat pour un abonnement Orange éclairage nouveau. Des rubriques variées vous attendent, sur l'activité des chercheurs dans et hors les murs témoigne de cette catastrophe 6 Histoire de l'art A partir d'une vingtaine de toiles dont certains éléments

  17. Two aromatic residues regulate the response of the human oxytocin receptor to the partial agonist arginine vasopressin

    Microsoft Academic Search

    Bice Chini; Bernard Mouillac; Marie-Nöelle Balestre; Susanne Trumpp-Kallmeyer; Jan Hoflack; Marcel Hibert; Maria Andriolo; Sandrine Pupier; Serge Jard; Claude Barberis

    1996-01-01

    We investigated the mechanisms that regulate the efficacy of agonists in the arginine-vasopressin (AVP)\\/oxytocin (OT) receptor system. In this paper, we present evidence that AVP, a full agonist of the vasopressin receptors, acts as a partial agonist on the oxytocin receptor. We also found that AVP becomes a full agonist when two aromatic residues of the oxytocin receptor are replaced

  18. Integrating costimulatory agonists to optimize immune-based cancer therapies

    PubMed Central

    Pardee, Angela D; Wesa, Amy K

    2009-01-01

    While immunotherapy for cancer has become increasingly popular, clinical benefits for such approaches remain limited. This is likely due to tumor-associated immune suppression, particularly in the advanced-disease setting. Thus, a major goal of novel immunotherapeutic design has become the coordinate reversal of existing immune dysfunction and promotion of specific tumoricidal T-cell function. Costimulatory members of the TNF-receptor family are important regulators of T-cell-mediated immunity. Notably, agonist ligation of these receptors restores potent antitumor immunity in the tumor-bearing host. Current Phase I/II evaluation of TNF-receptor agonists as single-modality therapies will illuminate their safety, mechanism(s) of action, and best use in prospective combinational immunotherapy approaches capable of yielding superior benefits to cancer patients. PMID:20046961

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

    PubMed

    Fulda, Simone

    2015-05-01

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

  20. 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

  1. 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

  2. Newspapers and newspaper ink contain agonists for the ah receptor.

    PubMed

    Bohonowych, Jessica E S; Zhao, Bin; Timme-Laragy, Alicia; Jung, Dawoon; Di Giulio, Richard T; Denison, Michael S

    2008-04-01

    Ligand-dependent activation of the aryl hydrocarbon receptor (AhR) pathway leads to a diverse array of biological and toxicological effects. The best-studied ligands for the AhR include polycyclic and halogenated aromatic hydrocarbons, the most potent of which is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). However, as new AhR ligands are identified and characterized, their structural and physiochemical diversity continues to expand. Our identification of AhR agonists in crude extracts from diverse materials raises questions as to the magnitude and extent of human exposure to AhR ligands through normal daily activities. We have found that solvent extracts of newspapers from countries around the world stimulate the AhR signaling pathway. AhR agonist activity was observed for dimethyl sulfoxide (DMSO), ethanol, and water extracts of printed newspaper, unprinted virgin paper, and black printing ink, where activation of luciferase reporter gene expression was transient, suggesting that the AhR active chemical(s) was metabolically labile. DMSO and ethanol extracts also stimulated AhR transformation and DNA binding, and also competed with [(3)H]TCDD for binding to the AhR. In addition, DMSO extracts of printed newspaper induced cytochrome P450 1A associated 7-ethoxyresorufin-O-deethylase activity in zebrafish embryos in vivo. Although the responsible bioactive chemical(s) remain to be identified, our results demonstrate that newspapers and printing ink contain relatively potent metabolically labile agonists of the AhR. Given the large amount of recycling and reprocessing of newspapers throughout the world, release of these easily extractable AhR agonists into the environment should be examined and their potential effects on aquatic organisms assessed. PMID:18203687

  3. 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

  4. 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

  5. Different Toll-like receptor agonists induce distinct macrophage responses

    Microsoft Academic Search

    Bryan W. Jones; Terry K. Means; Kurt A. Heldwein; Marc A. Keen; Preston J. Hill; John T. Belisle; Matthew J. Fenton

    2001-01-01

    We previously reported that gram-neg- ative bacterial lipopolysaccharide (LPS) activates cells via Toll-like receptor (TLR) 4, whereas the mycobacterial cell wall glycolipid lipoarabinoman- nan (LAM) activates cells via TLR2. We also iden- tified a secreted TLR2 agonist activity in short- term culture filtrates of Mycobacterium tuberculo- sis bacilli, termed soluble tuberculosis factor (STF). Here we show that STF contains mannosy-

  6. PHOTOLABILE A1-ADENOSINE RECEPTOR AGONISTS AS “CAGED” ELECTROPHYSIOLOGICAL PROBES+

    PubMed Central

    Maillard, Michel C.; Arlinghaus, Lauren; Glashofer, Marc; Lee, Kevin S.; Jacobson, Kenneth A.

    2012-01-01

    5'-Ether derivatives of the potent adenosine agonist N6-cyclopentyladenosine (CPA) were designed as “caged” ligands for the activation of A1-adenosine receptors following in situ photolysis. The synthesis involved a 2',3'-diol protection scheme using the acid labile ethoxymethynyl group. Generation of CPA was demonstrated chromatographically and in a bioassay measuring the inhibition of synaptic potentials in the rat hippocampus.

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

    Microsoft Academic Search

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

    2009-01-01

    Nicotine and other nicotinic agents are thought to regulate mood in human subjects and have antidepressant-like proper- ties in animal models. Recent studies have demonstrated that blockade of nicotinic acetylcholine receptors (nAChRs) includ- ing those containing the 2 subunit (2*), results in antidepres- sant-like effects. Previous studies have shown that cytisine, a partial agonist at 4\\/2* nAChRs, and a full

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

    Microsoft Academic Search

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

    2011-01-01

    In a search for more effective and safe anti-diabetic compounds, we developed a pharmacophore model based on partial agonists\\u000a of PPAR?. The model was used for the virtual screening of the Chinese Natural Product Database (CNPD), a library of plant-derived\\u000a natural products primarily used in folk medicine. From the resulting hits, we selected methyl oleanonate, a compound found,\\u000a among others,

  9. In search of potent 5-HT6 receptor inverse agonists.

    PubMed

    Hostetler, Greg; Dunn, Derek; McKenna, Beth Ann; Kopec, Karla; Chatterjee, Sankar

    2014-06-01

    A series of non-sulfonamide/non-sulfone derived potent 5-HT6 receptor inverse agonists has been disclosed. Representative compound 9 (Ki  = 14 nm) displayed selectivity against a set of family members as well as brain permeability 6 h post-oral administration. In addition, the separated enantiomers of compound 9 displayed difference in activity indicating the influence of chirality on potency. PMID:24406060

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

    PubMed

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

    2014-10-01

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

  11. Agonistic sounds signal male quality in the Lusitanian toadfish.

    PubMed

    Amorim, M Clara P; Conti, Carlotta; Modesto, Teresa; Gonçalves, Amparo; Fonseca, Paulo J

    2015-10-01

    Acoustic communication during agonistic behaviour is widespread in fishes. Yet, compared to other taxa, little is known on the information content of fish agonistic calls and their effect on territorial defence. Lusitanian toadfish males (Halobatrachus didactylus) are highly territorial during the breeding season and use sounds (boatwhistles, BW) to defend nests from intruders. BW present most energy in either the fundamental frequency, set by the contraction rate of the sonic muscles attached to the swimbladder, or in the harmonics, which are multiples of the fundamental frequency. Here we investigated if temporal and spectral features of BW produced during territorial defence reflect aspects of male quality that may be important in resolving disputes. We found that higher mean pulse period (i.e. lower fundamental frequency) reflected higher levels of 11-ketotestosterone (11KT), the main teleost androgen which, in turn, was significantly related with male condition (relative body mass and glycogen content). BW dominant harmonic mean and variability decreased with sonic muscle lipid content. We found no association between BW duration and male quality. Taken together, these results suggest that the spectral content of fish agonistic sounds may signal male features that are key in fight outcome. PMID:26048302

  12. Identification of agonist binding sites of vasopressin and oxytocin receptors.

    PubMed

    Mouillac, B; Chini, B; Balestre, M N; Jard, S; Barberis, C; Manning, M; Tribollet, E; Trumpp-Kallmeyer, S; Hoflack, J; Elands, J

    1995-01-01

    The present study aims at delineating residues in the vasopressin/oxytocin receptor family responsible for the high affinity binding of the hormone. Therefore, we have constructed a computer-generated 3 dimensional model of the rat V1a vasopressin receptor subtype which allowed us to propose residues likely to be involved in agonist binding. Among these residues, several are highly conserved in the receptor family. They were selected for site-directed mutagenesis on the basis of putative direct interaction with bound ligands. The present model and experimental results led us to conclude that the hormone is docked in a pocket completely buried in the transmembrane core of the receptor. Large polar residues, such as glutamine and lysine, located in transmembrane regions 2,3,4 and 6 are involved in the binding of the neurohypophysial hormone. Since all the mutated residues are highly conserved in AVP and OT receptors, we propose that the agonist binding site is similar in all members of the receptor family; only minor changes were found in antagonist potencies, suggesting that agonist and antagonist binding sites do not completely overlap. PMID:8713980

  13. Potent Adjuvanticity of a Pure TLR7-Agonistic Imidazoquinoline Dendrimer

    PubMed Central

    Shukla, Nikunj M.; Salunke, Deepak B.; Balakrishna, Rajalakshmi; Mutz, Cole A.; Malladi, Subbalakshmi S.; David, Sunil A.

    2012-01-01

    Engagement of toll-like receptors (TLRs) serve to link innate immune responses with adaptive immunity and can be exploited as powerful vaccine adjuvants for eliciting both primary and anamnestic immune responses. TLR7 agonists are highly immunostimulatory without inducing dominant proinflammatory cytokine responses. We synthesized a dendrimeric molecule bearing six units of a potent TLR7/TLR8 dual-agonistic imidazoquinoline to explore if multimerization of TLR7/8 would result in altered activity profiles. A complete loss of TLR8-stimulatory activity with selective retention of the TLR7-agonistic activity was observed in the dendrimer. This was reflected by a complete absence of TLR8-driven proinflammatory cytokine and interferon (IFN)-? induction in human PBMCs, with preservation of TLR7-driven IFN-? induction. The dendrimer was found to be superior to the imidazoquinoline monomer in inducing high titers of high-affinity antibodies to bovine ?-lactalbumin. Additionally, epitope mapping experiments showed that the dendrimer induced immunoreactivity to more contiguous peptide epitopes along the amino acid sequence of the model antigen. PMID:22952720

  14. Retinoic acid receptor agonist activity of naturally occurring diterpenes.

    PubMed

    Tanabe, Hiroki; Yasui, Tomohiro; Kotani, Hitoshi; Nagatsu, Akito; Makishima, Makoto; Amagaya, Sakae; Inoue, Makoto

    2014-06-15

    Recent accumulating evidence indicates that all-trans retinoic acid (ATRA) may be useful for preventing or treating inflammation, allergy, and autoimmune diseases, despite its severe side effects. In this study, screening of 99 crude drugs for retinoic acid receptor (RAR) ligands by luciferase reporter assay demonstrated that the methanol extract of Aralia cordata Rhizoma most effectively activates the transcriptional activity of RAR?. Pimaradienoic acid (ent-pimara-8(14),15-dien-19-oic acid) was subsequently isolated as the constituent capable of activating RAR. Pimaric acid and abietic acid, which have similar structures to pimaradienoic acid, were also found to be novel RAR agonists, although abietic acid only slightly activated peroxisome proliferator-activated receptor gamma. These three natural RAR agonists with diterpene structures, while structurally different from ATRA, were able to increase the mRNA levels of the constitutive androstane receptor in HepG2 cells, induce F9 cell differentiation followed by Cyp26a1 mRNA expression, and differentiate HL-60 cells via RAR activation in a different manner from ATRA. These results demonstrate that some diterpenes exist as naturally occurring RAR agonists and that the differences in chemical structure between ATRA and these diterpenes may induce distinct gene activation and a specific cellular response. PMID:24799257

  15. Endogenous ligands of benzodiazepine binding site have inverse agonistic properties.

    PubMed

    Sliva, Jiri; Hess, Ladislav; Votava, Martin; Malek, Jiri

    2013-12-01

    Benzodiazepines have been widely used in clinical praxis for many decades. They act as GABAA receptor agonists and possess muscle-relaxant, hypnotic-sedative, anticonvulsant, and anxiolytic properties. Flumazenil acts as a benzodiazepine receptor antagonist (subunits ?1, ?2, ?3, and ?5) or partial agonist (subunits ?4 and ?6). It competitively inhibits the activity at the benzodiazepine recognition site on the GABA/benzodiazepine receptor complex, thereby reversing the effects of benzodiazepines. In our experiments, administration of flumazenil in rabbits was surprisingly associated with anxiolytic effects similar to those of midazolam. Additionally, flumazenil significantly and dose-dependently decreased the total number of vocalizations in rats, i.e. it was anxiolytic. These observations seem to be in contrast to the effect of flumazenil in humans, where it is believed to produce mainly anxiogenic effects. It seems that in individuals, who exhibit anxiogenic behavior or in individuals with anticipation anxiety, flumazenil acts as an anxiolytic agent, while in individuals without any signs of anxiety, flumazenil can also act as anxiogenic agent. Thus, we hypothesize that flumazenil is associated with decreased intensity of anticipatory anxiety due to occupancy of benzodiazepine binding sites by an endogenous ligand with inverse agonistic properties. PMID:24183322

  16. Highly selective agonists for substance P receptor subtypes.

    PubMed Central

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

    1986-01-01

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

  17. SURVEILLANCE ET CONTROLE DES ACTIVITES DES NAVIRES EN MER

    E-print Network

    Paris-Sud XI, Université de

    1 SURVEILLANCE ET CONTROLE DES ACTIVITES DES NAVIRES EN MER ScanMaris Michel MOREL (DCNS), Aldo administrations en mer. Toutefois, ils ne recueillent des informations que pour des zones maritimes ou des permanente, un recueil massif de données permettant de mieux gérer les situations en mer et les interventions

  18. Different structures of the two peroxisome proliferator-activated receptor gamma (PPAR?) ligand-binding domains in homodimeric complex with partial agonist, but not full agonist.

    PubMed

    Ohashi, Masao; Oyama, Takuji; Miyachi, Hiroyuki

    2015-07-01

    We designed and synthesized acylsulfonamide derivative (3) as a human peroxisome proliferator-activated receptor gamma (hPPAR?) partial agonist by structural modification of hPPAR? full agonist 1. Co-crystallization of 3 with hPPAR? LBD afforded a homodimeric complex, and X-ray crystallographic analysis at 2.1Å resolution showed that one of the LBDs adopts a fully active structure identical with that in the complex of rosiglitazone, a full agonist; however, the other LBD in the complex of 3 exhibits a different (non-fully active) structure. Interestingly, the apo-homodimer contained similar LBD structures. Intrigued by these results, we surveyed reported X-ray crystal structures of partial agonists complexed with hPPAR? LBD homodimer, and identified several types of LBD structures distinct from the fully active structure. In contrast, both LBDs in the rosiglitazone complex have the fully active structure. These results suggest hPPAR? partial agonists lack the ability to induce fully active LBD. The presence of at least one non-fully active LBD in the agonist complex may be a useful criterion to distinguish hPPAR? partial agonists from full agonists. PMID:25987371

  19. The Contribution of Alpha1 and Alpha2 Adrenoceptors in Peripheral Imidazoline and Adrenoceptor Agonist-Induced Nociception

    Microsoft Academic Search

    Ahmet Dogrul; Tayfun Uzbay

    2006-01-01

    We evaluated the effects of activation of peripheral adrenoceptors (AR) and imidazoline receptors on nociception and the contribution of -1 and -2 AR receptors in agonist-induced nociception by using the tail-flick test in mice. Clonidine (-2 AR agonist), agmatine (imidazoline receptor and -2 AR agonist), noradrenaline (mixed -1 and -2 AR agonist), phenylephrine (-1 AR agonist), or 0.9% saline was

  20. Pharmacological characterization and therapeutic potential for the treatment of opioid abuse with ATPM-ET, an N-ethyl substituted aminothiazolomorphinan with ? agonist and ? agonist/antagonist activity.

    PubMed

    Sun, Jian-Feng; Wang, Yu-Hua; Chai, Jing-Rui; Li, Fu-Ying; Hang, Ai; Lu, Gang; Tao, Yi-Min; Cheng, Yun; Chi, Zhi-Qiang; Neumeyer, John L; Zhang, Ao; Liu, Jing-Gen; Wang, Yu-Jun

    2014-10-01

    We previously reported that the ? agonists with mixed ? activity could attenuate heroin self-administration with less potential to develop tolerance. The present study further investigated the effects of (-)-3-N-Ethylamino-thiazolo[5,4-b]-N-cyclopropylmethylmorphinan hydrochloride (ATPM-ET), a ? agonist and ? agonist/antagonist, on the acquisition and reinstatement of morphine-induced conditioned place preference (CPP), heroin self-administration and heroin-primed reinstatement of drug-seeking behavior. We found that ATPM-ET produced a longer duration of potent antinociceptive effects with less side effect of sedation. More importantly, ATPM-ET attenuated the acquisition of morphine-induced CPP, without affecting the reinstatement of morphine CPP. Furthermore, ATPM-ET significantly inhibited heroin self-administration and the reinstatement of heroin primed drug-seeking behavior. Taken together, ATPM-ET, a novel ? agonist and ? agonist/antagonist may have utility for the treatment of drug dependence. PMID:24998879

  1. Dual Activation and Inhibition of Adenylyl Cyclase by Cannabinoid Receptor Agonists: Evidence for Agonist-Specific Trafficking of Intracellular Responses

    Microsoft Academic Search

    D. W. BONHAUS; L. K. CHANG; J. KWAN; G. R. MARTIN

    Cannabinoid receptors couple to both Gs and Gi proteins and can consequently stimulate or inhibit the formation of cAMP. To test whether there is specificity among cannabinoid receptor agonists in activating Gs -o r G i-coupled pathways, the potency and intrinsic activity of various cannabinoid receptor ligands in stimulating or inhibiting cAMP accumulation were quantified. The rank order of potencies

  2. 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

  3. CULTURE DES VIVRIERS. COMBINAISON DES SAVOIRS LOCAUX ET MODERNES. ANTHROPOLOGIE COMME CONSTRUCTION DES PONTS CULTURELS

    E-print Network

    Boyer, Edmond

    DES PONTS CULTURELS BAÏNILAGO L. ISDA 2010, Montpellier 28-30 Juin 2010 CULTURE DES VIVRIERS. COMBINAISON DES SAVOIRS LOCAUX ET MODERNES:ANTHROPOLOGIE COMME CONSTRUCTION DES PONTS CULTURELS LOUIS'anthropologie, construction des ponts culturels ABSTRACT : This paper tries to criticize the radical opposition established

  4. Expression des constantes de distorsion centrifuge des hexafluorures en fonction des frquences harmoniques.

    E-print Network

    Paris-Sud XI, Université de

    L-55 Expression des constantes de distorsion centrifuge des hexafluorures en fonction des de distorsion centrifuge des molécules XY6 en fonc- tion des fréquences harmoniques ; l for the centrifugal distortion constants as a function of harmonic frequencies ; application is made to SF6 and UF6. 4

  5. Pros and cons of using alpha-2 agonists in small animal anesthesia practice.

    PubMed

    Greene, S A

    1999-02-01

    The alpha-2 agonists have been used in veterinary practice for over 30 years following the introduction of xylazine (ROMPUN, Bayer Corp., Shawnee Mission, KS) in 1962. The decision to use alpha-2 agonists in anesthesia practice should be based on factors including patient disposition, presenting complaint, type of procedure, and the veterinarian's familiarity with the drug. Controversy surrounds the issue of using anticholinergic agents concurrent with the alpha-2 agonists. Patient selection and procedure type can aid in determining when use of an anticholinergic with the alpha-2 agonist is advantageous. Antagonism of alpha-2 agonists can be readily accomplished. Commonly, alpha-2 agonists are used in combination with other agents to provide neuroleptanalgesia or sedation prior to general anesthesia. PMID:10193041

  6. Ghrelin and motilin receptor agonists: time to introduce bias into drug design.

    PubMed

    Sanger, G J

    2014-02-01

    Ghrelin and motilin receptor agonists increase gastric motility and are attractive drug targets. However, 14 years after the receptors were described (18-24 years since ligands became available) the inactivity of the ghrelin agonist TZP-102 in patients with gastroparesis joins the list of unsuccessful motilin agonists. Fundamental questions must be asked. Pustovit et al., have now shown that the ghrelin agonist ulimorelin evokes prolonged increases in rat colorectal propulsion yet responses to other ghrelin agonists fade. Similarly, different motilin agonists induce short- or long-lasting effects in a cell-dependent manner. Together, these and other data create the hypothesis that the receptors can be induced to preferentially signal ('biased agonism') via particular pathways to evoke different responses with therapeutic advantages/disadvantages. Biased agonism has been demonstrated for ghrelin. Are motilin agonists which cause long-lasting facilitation of human stomach cholinergic function (compared with motilin) biased agonists (e.g., camicinal, under development for patients with gastric hypo-motility)? For ghrelin, additional complications exist because the therapeutic aims/mechanisms of action are uncertain, making it difficult to select the best (biased) agonist. Will ghrelin agonists be useful treatments of nausea and/or as suggested by Pustovit et al., chronic constipation? How does ghrelin increase gastric motility? As gastroparesis symptoms poorly correlate with delayed gastric emptying (yet gastro-prokinetic drugs can provide relief: e.g., low-dose erythromycin), would low doses of ghrelin and motilin agonists relieve symptoms simply by restoring neuromuscular rhythm? These questions on design and functions need addressing if ghrelin and motilin agonists are to reach patients as drugs. PMID:24438586

  7. Influence of Different Adrenoceptor Agonists and Antagonists on Physostigmine-Induced Yawning in Rats

    Microsoft Academic Search

    Mohammad-Reza Zarrindast; Soheila Fazli-Tabai; Saeed Semnanian; Yaghoub Fathollahi

    1999-01-01

    In the present study, effects of adrenoceptor agonists and antagonists on physostigmine-induced yawning was investigated. Intraperitoneal (IP) injection of different doses of physostigmine (0.03, 0.05, 0.1, and 0.2 mg\\/kg) induced yawning in rats. The maximum response was obtained by 0.2 mg\\/kg of the drug. The ?1-adrenoceptor agonist, phenylephrine, and the ?2-adrenoceptor agonist, clonidine, decreased yawning induced by physostigmine. Prazosin and

  8. ADRP\\/ADFP and Mal1 expression are increased in macrophages treated with TLR agonists

    Microsoft Academic Search

    Kenneth R. Feingold; Mahmood R. Kazemi; Amy L. Magra; Carol M. McDonald; Lisa G. Chui; Judy K. Shigenaga; Sophie M. Patzek; Zoe W. Chan; Constantine Londos; Carl Grunfeld

    2010-01-01

    Activation of macrophages by TLR agonists enhances foam cell formation, but the underlying mechanisms are not understood. We examined the effects of TLR agonists on ADRP\\/ADFP, a protein associated with forming lipid droplets, and Mal1 a fatty acid-binding protein, in two mouse macrophage cell lines and human monocytes. Low doses of LPS, a TLR4 agonist increased both mRNA and protein

  9. 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.

  10. Localization of agonist and competitive antagonist binding sites on nicotinic acetylcholine receptors

    Microsoft Academic Search

    Hugo Rubén Arias

    2000-01-01

    Identification of all residues involved in the recognition and binding of cholinergic ligands (e.g. agonists, competitive antagonists, and noncompetitive agonists) is a primary objective to understand which structural components are related to the physiological function of the nicotinic acetylcholine receptor (AChR). The picture for the localization of the agonist\\/competitive antagonist binding sites is now clearer in the light of newer

  11. Effects of salvinorin A on locomotor sensitization to D2\\/D3 dopamine agonist quinpirole

    Microsoft Academic Search

    Pieter Beerepoot; Vincent Lam; Alice Luu; Bernice Tsoi; Daniel Siebert; Henry Szechtman

    2008-01-01

    Locomotor sensitization induced by the dopamine agonist quinpirole can be potentiated by co-treatment with the synthetic kappa opioid agonist U69593. The identification of salvinorin A, an active component of the psychotropic sage Salvia divinorum, as a structurally different agonist of kappa-opioid receptors raised the question of whether this compound would similarly potentiate sensitization to quinpirole. Rats were co-treated with 0.5mg\\/kg

  12. 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

  13. Discovery of potent ?1L-adrenoceptor agonists: Design and synthesis of bicyclic derivatives.

    PubMed

    Suzuki, Shinya; Okano, Tsubasa; Horiuchi, Rie; Hareyama, Nana; Amikura, Kazutoshi; Yamamoto, Naoyoshi; Yoshizawa, Yoshitaka; Yagi, Mai; Serizawa, Kanako; Hayashi, Ryoji

    2015-08-15

    We aimed to create a novel and potent ?1L-adrenoceptor agonist because such agonists are possible drug candidates for stress urinary incontinence. We used ligand-based drug design and evaluated the ?1L-adrenoceptor agonist activity of the designed compounds. Among them, tetrahydroquinoline derivative 50 showed the most potent activity (ratio of noradrenaline half maximal effective concentration, 0.0028) and effectively induced contraction of rat bladder neck. PMID:26087939

  14. Important pharmacophoric features of pan PPAR agonists: Common chemical feature analysis and virtual screening

    Microsoft Academic Search

    Sandeep Sundriyal; Prasad V. Bharatam

    2009-01-01

    HipHop program was used to generate a common chemical feature hypothesis for pan Peroxisome Proliferator-Activated Receptor (PPAR) agonists. The top scoring hypothesis (hypo-1) was found to differentiate the pan agonists (actives) from subtype-specific and dual PPAR agonists (inactives). The importance of individual features in hypo-1 was assessed by deleting a particular feature to generate a new hypothesis and observing its

  15. Gonadotropin-releasing hormone agonist influences absolute levels of lymphocyte subsets in vivo in male mice

    Microsoft Academic Search

    LV Rao; RP Cleveland; RJ Kimmel; KM Ataya

    1996-01-01

    Our earlier studies have demonstrated that gonadotropin-releasing hormone (GnRH) agonists suppress immune system function in female mice. No systematic studies regarding the effect of gender on immune system function following GnRH agonist treatment, however, have been reported. This study, therefore, investigated sequential changes in lymphocyte subsets in 3- and 10-week-old male mice following agonist or placebo administration. Changes in immunophenotypic

  16. Agonistic behaviour and electric signalling in a mormyrid fish, Gnathonemus petersii

    Microsoft Academic Search

    Bernd Kramer; Richard Bauer

    1976-01-01

    1.Agonistic motor behaviour and concurrent electric signalling were studied in individually held, residential Gnathonemus petersii. Aggressive behaviour was elicited by presenting a specimen of a closely related species, Mormyrus rume, for 3 min a day.2.The principal agonistic motor patterns are described (Fig. 2). Among them head butt, approach and lateral display were further analysed.3.The electrical activity displayed during agonistic behaviour

  17. 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.

  18. In vitro and in vivo efficacy of a potent opioid receptor agonist, biphalin, compared to subtype-selective opioid receptor agonists for stroke treatment.

    PubMed

    Yang, Li; Islam, Mohammad R; Karamyan, Vardan T; Abbruscato, Thomas J

    2015-06-01

    To meet the challenge of identification of new treatments for stroke, this study was designed to evaluate a potent, nonselective opioid receptor (OR) agonist, biphalin, in comparison to subtype selective OR agonists, as a potential neuroprotective drug candidate using in vitro and in vivo models of ischemic stroke. Our in vitro approach included mouse primary neuronal cells that were challenged with glutamate and hypoxic/aglycemic (H/A) conditions. We observed that 10nM biphalin, exerted a statistically significant neuroprotective effect after glutamate challenge, compared to all selective opioid agonists, according to lactate dehydrogenase (LDH) and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. Moreover, 10nM biphalin provided superior neuroprotection after H/A-reoxygenation compared to selective opioid agonists in all cases. Our in vitro investigations were supported by in vivo studies which indicate that the nonselective opioid agonist, biphalin, achieves enhanced neuroprotective potency compared to any of the selective opioid agonists, evidenced by reduced edema and infarct ratios. Reduction of edema and infarction was accompanied by neurological improvement of the animals in two independent behavioral tests. Collectively these data strongly suggest that concurrent agonist stimulation of mu, kappa and delta ORs with biphalin is neuroprotective and superior to neuroprotection by activation of any single OR subtype. PMID:25801116

  19. 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.

  20. Amputation des quatre membres

    PubMed Central

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

    2014-01-01

    Les auteurs présentent les cas d'amputation des quatre membres réalisée chez trois patients différents. Ce sont des amputations réalisées pour chaque patient au cours d'une seule hospitalisation et en un seul temps opératoire. Deux patients pour gangrène sèche infectée et un pour amputation traumatique des quatre membres. L'amputation d'urgence a été pratiquée en premier temps suivie de remodelage des moignons d'amputation en second temps. L’évolution de tous les patients a été bonne. PMID:25469177

  1. Klinische Wertbestimmung des Convallatoxins

    Microsoft Academic Search

    Bruno Weicker

    1932-01-01

    Zusammenfassung Untersuchungen über die pharmakologische und klinische Auswertung des Convallatoxins, eines von Karrer aus der Convallaria majalis dargestellten kristallisierten Glykosids der Firma Hoffmann-La Roche erergeben:

  2. The ?-blocker Nebivolol Is a GRK/?-arrestin Biased Agonist

    PubMed Central

    Blessing, Christopher P.; Nguyen, Jenny; Liu, Tammy; Pulakat, Lakshmi; Bastepe, Murat; Jackson, Edwin K.; Andresen, Bradley T.

    2013-01-01

    Nebivolol, a third generation ?-adrenoceptor (?-AR) antagonist (?-blocker), causes vasodilation by inducing nitric oxide (NO) production. The mechanism via which nebivolol induces NO production remains unknown, resulting in the genesis of much of the controversy regarding the pharmacological action of nebivolol. Carvedilol is another ?-blocker that induces NO production. A prominent pharmacological mechanism of carvedilol is biased agonism that is independent of G?s and involves G protein-coupled receptor kinase (GRK)/?-arrestin signaling with downstream activation of the epidermal growth factor receptor (EGFR) and extracellular signal-regulated kinase (ERK). Due to the pharmacological similarities between nebivolol and carvedilol, we hypothesized that nebivolol is also a GRK/?-arrestin biased agonist. We tested this hypothesis utilizing mouse embryonic fibroblasts (MEFs) that solely express ?2-ARs, and HL-1 cardiac myocytes that express ?1- and ?2-ARs and no detectable ?3-ARs. We confirmed previous reports that nebivolol does not significantly alter cAMP levels and thus is not a classical agonist. Moreover, in both cell types, nebivolol induced rapid internalization of ?-ARs indicating that nebivolol is also not a classical ?-blocker. Furthermore, nebivolol treatment resulted in a time-dependent phosphorylation of ERK that was indistinguishable from carvedilol and similar in duration, but not amplitude, to isoproterenol. Nebivolol-mediated phosphorylation of ERK was sensitive to propranolol (non-selective ?-AR-blocker), AG1478 (EGFR inhibitor), indicating that the signaling emanates from ?-ARs and involves the EGFR. Furthermore, in MEFs, nebivolol-mediated phosphorylation of ERK was sensitive to pharmacological inhibition of GRK2 as well as siRNA knockdown of ?-arrestin 1/2. Additionally, nebivolol induced redistribution of ?-arrestin 2 from a diffuse staining pattern into more intense punctate spots. We conclude that nebivolol is a ?2-AR, and likely ?1-AR, GRK/?-arrestin biased agonist, which suggests that some of the unique clinically beneficial effects of nebivolol may be due to biased agonism at ?1- and/or ?2-ARs. PMID:23977191

  3. Comparative endpoint sensitivity of in vitro estrogen agonist assays.

    PubMed

    Dreier, David A; Connors, Kristin A; Brooks, Bryan W

    2015-07-01

    Environmental and human health implications of endocrine disrupting chemicals (EDCs), particularly xenoestrogens, have received extensive study. In vitro assays are increasingly employed as diagnostic tools to comparatively evaluate chemicals, whole effluent toxicity and surface water quality, and to identify causative EDCs during toxicity identification evaluations. Recently, the U.S. Environmental Protection Agency (USEPA) initiated ToxCast under the Tox21 program to generate novel bioactivity data through high throughput screening. This information is useful for prioritizing chemicals requiring additional hazard information, including endocrine active chemicals. Though multiple in vitro and in vivo techniques have been developed to assess estrogen agonist activity, the relative endpoint sensitivity of these approaches and agreement of their conclusions remain unclear during environmental diagnostic applications. Probabilistic hazard assessment (PHA) approaches, including chemical toxicity distributions (CTD), are useful for understanding the relative sensitivity of endpoints associated with in vitro and in vivo toxicity assays by predicting the likelihood of chemicals eliciting undesirable outcomes at or above environmentally relevant concentrations. In the present study, PHAs were employed to examine the comparative endpoint sensitivity of 16 in vitro assays for estrogen agonist activity using a diverse group of compounds from the USEPA ToxCast dataset. Reporter gene assays were generally observed to possess greater endpoint sensitivity than other assay types, and the Tox21 ERa LUC BG1 Agonist assay was identified as the most sensitive in vitro endpoint for detecting an estrogenic response. When the sensitivity of this most sensitive ToxCast in vitro endpoint was compared to the human MCF-7 cell proliferation assay, a common in vitro model for biomedical and environmental monitoring applications, the ERa LUC BG1 assay was several orders of magnitude less sensitive than MCF-7. These observations highlight the importance of employing multiple assays with various molecular initiation and signaling events to inform selection, application, and interpretation of in vitro endpoint responses during future environmental diagnostic applications. PMID:25896097

  4. Endomorphin-2: A Biased Agonist at the ?-Opioid Receptor

    PubMed Central

    Rivero, Guadalupe; Llorente, Javier; McPherson, Jamie; Cooke, Alex; Mundell, Stuart J.; McArdle, Craig A.; Rosethorne, Elizabeth M.; Charlton, Steven J.; Krasel, Cornelius; Bailey, Christopher P.; Henderson, Graeme

    2012-01-01

    Previously we correlated the efficacy for G protein activation with that for arrestin recruitment for a number of agonists at the ?-opioid receptor (MOPr) stably expressed in HEK293 cells. We suggested that the endomorphins (endomorphin-1 and -2) might be biased toward arrestin recruitment. In the present study, we investigated this phenomenon in more detail for endomorphin-2, using endogenous MOPr in rat brain as well as MOPr stably expressed in HEK293 cells. For MOPr in neurons in brainstem locus ceruleus slices, the peptide agonists [d-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (DAMGO) and endomorphin-2 activated inwardly rectifying K+ current in a concentration-dependent manner. Analysis of these responses with the operational model of pharmacological agonism confirmed that endomorphin-2 had a much lower operational efficacy for G protein-mediated responses than did DAMGO at native MOPr in mature neurons. However, endomorphin-2 induced faster desensitization of the K+ current than did DAMGO. In addition, in HEK293 cells stably expressing MOPr, the ability of endomorphin-2 to induce phosphorylation of Ser375 in the COOH terminus of the receptor, to induce association of arrestin with the receptor, and to induce cell surface loss of receptors was much more efficient than would be predicted from its efficacy for G protein-mediated signaling. Together, these results indicate that endomorphin-2 is an arrestin-biased agonist at MOPr and the reason for this is likely to be the ability of endomorphin-2 to induce greater phosphorylation of MOPr than would be expected from its ability to activate MOPr and to induce activation of G proteins. PMID:22553358

  5. 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

  6. Loperamide--an opiate receptor agonist with gastrointestinal motility effects.

    PubMed

    Mellstrand, T

    1987-01-01

    Loperamide is an opiate agonist, also exerting activity by inhibiting the action of calmodulin. The mode of action in the clinic is probably mainly due to its action on opiate receptors, since the effects of loperamide can be reversed by naloxone. The exclusive action in the gut is explained by the specific distribution of loperamide with extensive distribution to the gut and minimal influence on opiate receptors in CNS. Loperamide is well absorbed after oral administration and extensively metabolized. The pharmacokinetic properties are linear over a wide dose range. PMID:2820051

  7. A 1 Adenosine Receptor Antagonists, Agonists, and Allosteric Enhancers

    Microsoft Academic Search

    William F. Kiesman; Elfatih Elzein; Jeff Zablocki

    \\u000a Intense efforts of many pharmaceutical companies and academicians in the A1 adenosine receptor (AR) field have led to the discovery of clinical candidates that are antagonists, agonists, and allosteric\\u000a enhancers. The A1AR antagonists currently in clinical development are KW3902, BG9928, and SLV320. All three have high affinity for the human\\u000a (h) A1AR subtype (hA1\\u000a K\\u000a i 200-fold selectivity over the

  8. Peripheral biomarkers of cognitive response to dopamine receptor agonist treatment

    Microsoft Academic Search

    Karen D. Ersche; Jonathan P. Roiser; Mark Lucas; Enrico Domenici; Trevor W. Robbins; Edward T. Bullmore

    2011-01-01

    Rationale  Using biological markers to objectively measure addiction severity or to identify individuals who might benefit most from\\u000a pro-cognitive treatment could potentially revolutionize neuropsychopharmacology. We investigated the use of dopamine receptor\\u000a mRNA levels in circulating blood cells as predictors of cognitive response following dopamine agonist treatment, and as biomarkers\\u000a of the severity of stimulant drug dependence.\\u000a \\u000a \\u000a \\u000a \\u000a Methodology  We employed a double-blind, placebo-controlled

  9. 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.

  10. Antidiabetic Actions of an Estrogen Receptor ? Selective Agonist

    PubMed Central

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

    2013-01-01

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

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

    PubMed

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

    2015-08-01

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

  12. Cannabinoid receptor agonists protect cultured rat hippocampal neurons from excitotoxicity.

    PubMed

    Shen, M; Thayer, S A

    1998-09-01

    Cannabinoid receptor agonists act presynaptically to inhibit the release of glutamate. Because other drugs with this action are known to reduce excitotoxicity, we tested several cannabimimetics in a model of synaptically mediated neuronal death. Reduction of the extracellular Mg2+ concentration to 0.1 mM evoked a repetitive pattern of intracellular Ca2+ concentration ([Ca2+]i) spiking that, when maintained for 24 hr, resulted in significant neuronal death. The [Ca2+]i spiking and cell death in this model result from excessive activation of N-methyl-D-aspartate receptors, as indicated by the inhibition of both [Ca2+]i spiking and neuronal death by the N-methyl-D-aspartate receptor antagonist CGS19755 (10 microM). The cannabimimetic drug Win55212-2 (100 nM) completely blocked [Ca2+]i spiking and prevented neuronal death induced by low extracellular Mg2+ concentrations. These effects on [Ca2+]i spiking and viability were stereoselective and were prevented by the CB1 receptor antagonist SR141716 (100 nM). The partial agonist CP55940 (100 nM) also afforded significant protection from excitotoxicity. Cannabimimetic drugs did not protect cells from the direct application of glutamate (30 microM). These data suggest that cannabimimetic drugs may slow the progression of neurodegenerative diseases. PMID:9730904

  13. 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

  14. Des Moines and Raccoon Rivers, Des Moines, Iowa

    E-print Network

    US Army Corps of Engineers

    Des Moines and Raccoon Rivers, Des Moines, Iowa 18 October 2006 Abstract: The recommended plan opportunities along the Des Moines and Raccoon Rivers in the areas of Birdland Park, Central Place and downtown Additional Information: Mississippi Valley Division Rock Island District Des Moines and Raccoon River Damage

  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. Des pionniers autoconstructeurs aux cooprateurs : histoire des Castors en Aquitaine

    E-print Network

    Boyer, Edmond

    Des pionniers autoconstructeurs aux coopérateurs : histoire des Castors en Aquitaine Julie ­ Histoire des Castors en Aquitaine - 2010 2 Préambule Ce travail est un manuscrit en cours de travail. Il Castors en Aquitaine, des pionniers autoconstructeurs aux coopérateurs (1948-1970) initialement traité

  17. MITTEILUNGSBLATT DES REKTORS

    E-print Network

    Gertz, Michael

    Landeshochschulgebühren- gesetzes (LHGebG) vom 1. Januar 2005 (GBl. S. 1, 56 ff.), zuletzt geändert durch Artikel 6 des Dritten Hochschulrechtsänderungsgesetz vom 1. April 2014 (GBl. S. 99, 167) in Verbindung mit § 19 Abs. 1 Nr. 10 Landeshochschulgesetz vom 1. Januar 2005 (GBl. S. 1), zuletzt geändert durch Artikel 1 des

  18. Echte Lipome des Meniscus

    Microsoft Academic Search

    G. Stedtfeld

    1955-01-01

    Es werden 2 Fälle beschrieben, bei denen ein echtes Lipom des Meniscus gefunden wurde. Nach kurzer Wiedergabe der Krankengeschichten und Operationsberichte werden Lokalisation, Form und histologischer Aufbau der Geschwülste in 5 Abbildungen gezeigt. In der abschließenden Epikrise wird auf die diagnostischen Schwierigkeiten hingewiesen und die Entfernung des ganzen Meniscus angeraten.

  19. Name des Akademischen Lehrkrankenhauses

    E-print Network

    Gollisch, Tim

    -5 99947 Bad Langensalza Name der / des PJ Beauftragten Kontaktaufnahme Frau Prof. Dr. Borg-von Zepelin Unterkunft In Absprache mit der Klinik Ansprechpartner: Frau Eva Ackermann Tel.: 03601- 41 1132 e Kontaktaufnahme Frau Dr. Christiane Först Sekretariat: Frau Rochner Tel.: 0441 / 9615-240 Treffpunkt am 1.Tag des

  20. 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

  1. The peroxisome proliferator-activated receptor (PPAR) alpha agonist fenofibrate maintains bone mass, while the PPAR gamma agonist pioglitazone exaggerates bone loss, in ovariectomized rats

    Microsoft Academic Search

    Astrid K Stunes; Irene Westbroek; Björn I Gustafsson; Reidar Fossmark; Jan H Waarsing; Erik F Eriksen; Christiane Petzold; Janne E Reseland; Unni Syversen

    2011-01-01

    Background  Activation of peroxisome proliferator-activated receptor (PPAR)gamma is associated with bone loss and increased fracture risk,\\u000a while PPARalpha activation seems to have positive skeletal effects. To further explore these effects we have examined the\\u000a effect of the PPARalpha agonists fenofibrate and Wyeth 14643, and the PPARgamma agonist pioglitazone, on bone mineral density\\u000a (BMD), bone architecture and biomechanical strength in ovariectomized rats.

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

    PubMed

    Randáková, Alena; Dolejší, Eva; Rudajev, Vladimír; Zim?ík, Pavel; Doležal, Vladimír; El-Fakahany, Esam E; Jakubík, Jan

    2015-07-01

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

  3. Predicting Novel Binding Modes of Agonists to ? Adrenergic Receptors Using All-Atom Molecular Dynamics Simulations

    Microsoft Academic Search

    Stefano Vanni; Marilisa Neri; Ivano Tavernelli; Ursula Rothlisberger

    2011-01-01

    Understanding the binding mode of agonists to adrenergic receptors is crucial to enabling improved rational design of new therapeutic agents. However, so far the high conformational flexibility of G protein-coupled receptors has been an obstacle to obtaining structural information on agonist binding at atomic resolution. In this study, we report microsecond classical molecular dynamics simulations of ?1 and ?2 adrenergic

  4. Effect of PK11195, a peripheral benzodiazepine receptor agonist, on insulinoma cell death and insulin secretion

    Microsoft Academic Search

    S. Y. Park; N. Cho; I. Chang; J.-H. Chung; Y.-K. Min; M.-K. Lee; K.-W. Kim; S. J. Kim; M.-S. Lee

    2005-01-01

    Functional role of peripheral benzodiazepine receptor on mitochondrial membrane in apoptosis and insulin secretion from insulinoma cells was studied. A prototypic peripheral benzodiazepine receptor agonist PK11195 induced insulinoma cell apoptosis, while a central benzodiazepine receptor agonist did not. Death of insulinoma cells by PK11195 was inhibited by cyclosporin A,{ a blocker of mitochondrial permeability transition pore}. Caspase inhibitors further inhibited

  5. Discovery of a novel trans-1,4-dioxycyclohexane GPR119 agonist series.

    PubMed

    Han, Sangdon; Narayanan, Sanju; Kim, Sun Hee; Calderon, Imelda; Zhu, Xiuwen; Kawasaki, Andrew; Yue, Dawei; Lehmann, Juerg; Wong, Amy; Buzard, Daniel J; Semple, Graeme; Carroll, Chris; Chu, Zhi-Liang; Al-Sharmma, Hussein; Shu, Hsin-Hui; Tung, Shiu-Feng; Unett, David J; Behan, Dominic P; Yoon, Woo Hyun; Morgan, Michael; Usmani, Khawja A; Chen, Chuan; Sadeque, Abu; Leonard, James N; Jones, Robert M

    2015-08-01

    The design and optimization of a novel trans-1,4-dioxycyclohexane GPR119 agonist series is described. A lead compound 21 was found to be a potent and efficacious GPR119 agonist across species, and possessed overall favorable pharmaceutical properties. Compound 21 demonstrated robust acute and chronic regulatory effects on glycemic parameters in the diabetic or non-diabetic rodent models. PMID:26048791

  6. Agonistic Behavior of the Mediterranean Gecko Hemidactylus turcicus Venetia S. Briggs1,2

    E-print Network

    Mazzotti, Frank

    Agonistic Behavior of the Mediterranean Gecko Hemidactylus turcicus Venetia S. Briggs1,2 1, USA (Accepted August 6, 2012) Venetia S. Briggs (2012) Agonistic behavior of the Mediterranean gecko of species and spatial distribution of individuals within a population. The Mediterranean gecko Hemidactylus

  7. Alpha and beta adrenergic agonists stimulate water absorption in the rat proximal tubule

    Microsoft Academic Search

    Edward J. Weinman; Steven C. Sansom; Thomas F. Knight; Harry O. Senekjian

    1982-01-01

    Summary Simultaneous capillary and luminal microperfusion studies were performed in the rat proximal tubule to determine the effects of the beta agonist isoproterenol and the alpha agonist phenylephrine on water absorption. Capillary and luminal perfusion solutions were composed such that organic solutes were not present, no bicarbonate was present in the lumen, and no chloride gradient was imposed. Under such

  8. Conformationally constrained farnesoid X receptor (FXR) agonists: Naphthoic acid-based analogs of GW 4064.

    PubMed

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

    2008-08-01

    Starting from the known FXR agonist GW 4064 1a, a series of stilbene replacements were prepared. The 6-substituted 1-naphthoic acid 1b was an equipotent FXR agonist with improved developability parameters relative to 1a. Analog 1b also reduced the severity of cholestasis in the ANIT acute cholestatic rat model. PMID:18621523

  9. Chemistry & Biology Amitriptyline is a TrkA and TrkB Receptor Agonist

    E-print Network

    Hall, Randy A

    Chemistry & Biology Article Amitriptyline is a TrkA and TrkB Receptor Agonist that Promotes Trk as a TrkA and TrkB agonist and possesses marked neurotrophic activity. INTRODUCTION Neurotrophins, which. Neurotrophins exert their phys- iological actions through two classes of receptors: Trk tyrosine kinase

  10. Selective Effects of the -Opioid Receptor Agonist DPDPE on Consummatory Successive Negative Contrast

    E-print Network

    Cooper, Brenton G.

    Selective Effects of the -Opioid Receptor Agonist DPDPE on Consummatory Successive Negative explored the role of the opioid system in a situation involving a surprising reduction in reward magnitude) reported that morphine (4 and 8 mg/kg; a nonselective opioid agonist), administered 20 min before the first

  11. Agonists at mu-opioid receptors spin the wheels to keep the action going.

    PubMed

    Cox, Brian M

    2005-01-01

    A study in this issue of Molecular Pharmacology on agonist-induced internalization of mu-opioid receptors during long-term opiate drug exposure is discussed. The study demonstrates the critical role of re-cycling of reactivated mu receptors back to the plasma membrane for the maintenance of agonist signaling during long-term opiate exposure. PMID:15496509

  12. Do autoreceptors mediate dopamine agonist — induced yawning and suppression of exploration? A critical review

    Microsoft Academic Search

    Lars Ståhle

    1992-01-01

    The hypothesis that stimulation of dopamine autoreceptors is the mechanism by which dopamine agonists induce yawning and suppression of exploration is critically examined. It is shown that the relation between reduced extracellular dopamine levels, assessed by microdialysis, and behavioural effects of dopamine agonists, a dopamine synthesis inhibitor and a granule storage blocker is highly inconsistent. The time-course and duration of

  13. Nicotinic Partial Agonists Varenicline and Sazetidine-A Have Differential Effects on Affective Behavior

    E-print Network

    Shorter, James

    Nicotinic Partial Agonists Varenicline and Sazetidine-A Have Differential Effects on Affective and preclinical studies suggest that nicotinic acetylcho- line receptors are involved in affective disorders; therefore, the potential therapeutic value of nicotinic partial agonists as treat- ments of these disorders

  14. Peroxisome proliferator-activated receptor-? and retinoid X receptor agonists inhibit inflammatory responses of astrocytes

    Microsoft Academic Search

    Jihong Xu; Janet A. Chavis; Michael K. Racke; Paul D. Drew

    2006-01-01

    The peroxisome proliferator-activated receptor-? (PPAR-?) plays a key role in lipid metabolism and inflammation. Recently, we demonstrated that administration of the PPAR-? agonists gemfibrozil and fenofibrate, inhibit the clinical signs of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). In the present study, we investigated the effects of PPAR-? agonists on primary mouse astrocytes, a cell type

  15. ?-Opioid Receptors: Correlation of Agonist Efficacy for Signalling with Ability to Activate InternalizationS?

    PubMed Central

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

    2010-01-01

    We have compared the ability of a number of ?-opioid receptor (MOPr) ligands to activate G proteins with their abilities to induce MOPr phosphorylation, to promote association of arrestin-3 and to cause MOPr internalization. For a model of G protein-coupled receptor (GPCR) activation where all agonists stabilize a single active conformation of the receptor, a close correlation between signaling outputs might be expected. Our results show that overall there is a very good correlation between efficacy for G protein activation and arrestin-3 recruitment, whereas a few agonists, in particular endomorphins 1 and 2, display apparent bias toward arrestin recruitment. The agonist-induced phosphorylation of MOPr at Ser375, considered a key step in MOPr regulation, and agonist-induced internalization of MOPr were each found to correlate well with arrestin-3 recruitment. These data indicate that for the majority of MOPr agonists the ability to induce receptor phosphorylation, arrestin-3 recruitment, and internalization can be predicted from their ability as agonists to activate G proteins. For the prototypic MOPr agonist morphine, its relatively weak ability to induce MOPr internalization can be explained by its low agonist efficacy. PMID:20647394

  16. Gene Expression Profiling of the PPAR-alpha Agonist Ciprofibrate in the Cynomolgus Monkey Liver

    Microsoft Academic Search

    Neal F. Cariello; Elizabeth H. Romach; Heidi M. Colton; Hong Ni; Lawrence Yoon; J. Greg Falls; Warren Casey; Donald Creech; Steven P. Anderson; Gina R. Benavides; Debie J. Hoivik; Roger Brown; Richard T. Miller

    2005-01-01

    Fibrates, such as ciprofibrate, fenofibrate, and clofibrate, are peroxisome proliferator-activated receptor-a (PPARa) agonists that have been in clinical use for many decades for treatment of dyslipidemia. When mice and rats are given PPARa agonists, these drugs cause hepatic peroxisome proliferation, hypertrophy, hyperplasia, and eventually hepatocarcinogenesis. Importantly, primates are relatively refractory to these effects; however, the mechanisms for the species differences

  17. Eléments de comparaison internationale des patrimoines des ménages

    Microsoft Academic Search

    Dominique Strauss-Kahn

    1979-01-01

    [fre] A partir des bribes d'information existant sur les patrimoines de divers pays européens et des USA, une comparaison de la structure des patrimoines des inégalités de répartition et de leur évolution est tentée. Actifs financiers et actifs réels figurent de façon variable dans les patrimoines des différents pays. La Grande-Bretagne, avec une forte part d'actifs financiers, notamment de valeurs

  18. In vitro and in vivo effects of the PPAR-alpha agonists fenofibrate and retinoic acid in endometrial cancer

    E-print Network

    Saidi, Samir A; Holland, Cathrine M; Charnock-Jones, D Stephen; Smith, Stephen K

    2006-03-28

    Abstract Fenofibrate, an agonist of PPAR-alpha, in doses above 25 ?M, inhibits proliferation and induces apoptosis in Ishikawa endometrial cancer cells. We show that these effects are potentiated by retinoic acid, an agonist of the retinoid...

  19. Naltrindole derivatives with fluorinated ethyl substituents on the 17-nitrogen as ? opioid receptor inverse agonists.

    PubMed

    Nemoto, Toru; Iihara, Yusuke; Hirayama, Shigeto; Iwai, Takashi; Higashi, Eika; Fujii, Hideaki; Nagase, Hiroshi

    2015-08-01

    We synthesized derivatives of the ? opioid receptor (DOR) antagonists naltrindole (NTI) and compound 1 that were modified with small alkyl or fluorinated ethyl substituents on the 17-nitrogen. Although the derivatives showed decreased binding affinities for the opioid receptors, their selectivities for the DOR were higher than the parent compounds NTI and compound 1. Surprisingly, 17-fluoroethyl NTI derivatives exerted DOR inverse agonistic activities. The DOR inverse agonism of compounds 4c-e was less efficacious but significant, as compared with a standard DOR inverse agonist ICI-174864. On the other hand, compound 1 and its derivatives with small alkyl or monofluoroethyl substituents were partial agonists, but the derivatives having di- or trifluoroethyl group showed neither agonistic nor inverse agonistic activities. PMID:26048798

  20. Benzodiazepine Site Agonists Differentially Alter Acetylcholine Release in Rat Amygdala

    PubMed Central

    Hambrecht-Wiedbusch, Viviane S.; Mitchell, Melinda F.; Firn, Kelsie A.; Baghdoyan, Helen A.; Lydic, Ralph

    2014-01-01

    Background Agonist binding at the benzodiazepine site of ?-aminobutric acid type A receptors diminishes anxiety and insomnia by actions in the amygdala. The neurochemical effects of benzodiazepine-site agonists remain incompletely understood. Cholinergic neurotransmission modulates amygdala function, and in this study we tested the hypothesis that benzodiazepine-site agonists alter acetylcholine (ACh) release in the amygdala. Methods Microdialysis and high performance liquid chromatography quantified ACh release in the amygdala of Sprague-Dawley rats (n=33). ACh was measured before and after IV administration (3 mg/kg) of midazolam or eszopiclone, with and without anesthesia. ACh in isoflurane-anesthetized rats during dialysis with Ringer’s solution(control) was compared to ACh release during dialysis with Ringer’s solution containing (100 ?M) midazolam, diazepam, eszopiclone, or zolpidem. Results In unanesthetized rats, ACh in the amygdala was decreased by IV midazolam (?51.1%; P=0.0029; 95% CI= ?73.0% to ?29.2%) and eszopiclone (?39.6%; P=0.0222; 95% CI= ?69.8% to ?9.3%). In anesthetized rats, ACh in the amygdala was decreased by IV administration of midazolam (?46.2%; P=0.0041; 95% CI= ?67.9% to ?24.5%) and eszopiclone (?34.0%; P=0.0009; 95% CI= ?44.7% to ?23.3%), and increased by amygdala delivery of diazepam (43.2%; P=0.0434; 95% CI= 2.1% to 84.3%), and eszopiclone (222.2%; P=0.0159; 95% CI= 68.5% to 375.8%). Conclusions ACh release in the amygdala was decreased by IV delivery of midazolam and eszopiclone. Dialysis delivery directly into the amygdala caused either increased (eszopiclone and diazepam) or likely no significant change (midazolam and zolpidem) in ACh release. These contrasting effects of delivery route on ACh release support the interpretation that systemically administered midazolam and eszopiclone decrease ACh release in the amygdala by acting on neuronal systems outside of the amygdala. PMID:24842176

  1. INFLAMMATION DES NUAGES DE POUSSIERES PAR DES ETINCELLES ET DES SURFACES CHAUFFEES

    E-print Network

    Paris-Sud XI, Université de

    2001-74 INFLAMMATION DES NUAGES DE POUSSIERES PAR DES ETINCELLES ET DES SURFACES CHAUFFEES C. PROUST - M. BOUDALAA INERIS-BP 2- F60550 Veraeuil-en-Halatte Résumé. Les trois types de sources d'inflammation utilisé. Pour des délais d'inflammation relativement longs (1 à 2 mn), le paramètre caractéristique de l'inflammation

  2. Agonist-promoted trafficking of human bradykinin receptors: arrestin- and dynamin-independent sequestration of the B2 receptor and bradykinin in HEK293 cells.

    PubMed Central

    Lamb, M E; De Weerd, W F; Leeb-Lundberg, L M

    2001-01-01

    In this study, we analysed the agonist-promoted trafficking of human B(2) (B(2)R) and B(1) (B(1)R) bradykinin (BK) receptors using wild-type and green fluorescent protein (GFP)-tagged receptors in HEK293 cells. B(2)R was sequestered to a major extent upon exposure to BK, as determined by the loss of cell-surface B(2)R using radioligand binding and by imaging of B(2)R-GFP using laser-scanning confocal fluorescence microscopy. Concurrent BK sequestration was revealed by the appearance of acid-resistant specific BK receptor binding. The same techniques showed that B(1)R was sequestered to a considerably lesser extent upon binding of des-Arg(10)-kallidin. B(2)R sequestration was rapid (half-life approximately 5 min) and reached a steady-state level that was significantly lower than that of BK sequestration. B(2)R sequestration was minimally inhibited by K44A dynamin (22.4+/-3.7%), and was insensitive to arrestin-(319-418), which are dominant-negative mutants of dynamin I and beta-arrestin respectively. Furthermore, the B(2)R-mediated sequestration of BK was completely insensitive to both mutants, as was the association of BK with a caveolae-enriched fraction of the cells. On the other hand, agonist-promoted sequestration of the beta(2)-adrenergic receptor was dramatically inhibited by K44A dynamin (81.2+/-16.3%) and by arrestin-(319-418) (36.9+/-4.4%). Our results show that B(2)R is sequestered to a significantly greater extent than is B(1)R upon agonist treatment in HEK293 cells. Furthermore, B(2)R appears to be recycled in the process of sequestering BK, and this process occurs in a dynamin- and beta-arrestin-independent manner and, at least in part, involves caveolae. PMID:11311137

  3. In pursuit of ?4?2 nicotinic receptor partial agonists for smoking cessation: Carbon analogs of (?)-cytisine

    Microsoft Academic Search

    Jotham W. Coe; Michael G. Vetelino; Crystal G. Bashore; Michael C. Wirtz; Paige R. Brooks; Eric P. Arnold; Lorraine A. Lebel; Carol B. Fox; Steven B. Sands; Thomas I. Davis; David W. Schulz; Hans Rollema; F. David Tingley; Brian T. O’Neill

    2005-01-01

    The preparation and biological activity of analogs of (?)-cytisine, an ?4?2 nicotinic receptor partial agonist, are discussed. All-carbon-containing phenyl ring replacements of the pyridone ring system, generated via Heck cyclization protocols, exhibited weaker affinity and lower efficacy partial agonist profiles relative to (?)-cytisine. In vivo, selected compounds exhibit lower efficacy partial agonist profiles than that of (?)-cytisine.

  4. Site of Opioid Action in the Human Brain: Mu and Kappa Agonists' Subjective and Cerebral Blood Flow Effects

    Microsoft Academic Search

    Thomas E. Schlaepfer; Eric C. Strain; Benjamin D. Greenberg; Kenzie L. Preston; Eric Lancaster; George E. Bigelow; Patrick E. Barta; Godfrey D. Pearlson

    1998-01-01

    Objective: Humans experience the subjective effects of mu and kappa opioid agonists dif- ferently: mu agonists produce mainly euphoria, while kappa agonists are more likely to pro- duce dysphoria. This study tested the hypothesis that these subjective effects would be associ- ated with anatomically distinct changes in regional cerebral blood flow (CBF) relative to baseline as assessed with single photon

  5. A review of shark agonistic displays: comparison of display features and implications for shark–human interactions

    Microsoft Academic Search

    R. Aidan Martin

    2007-01-01

    Agonistic displays in 23 species of sharks of six families are described and illustrated. These displays are reviewed in terms of ethological concepts and shark hydrodynamic models. Shark agonistic displays feature many common elements rendering them readily distinguishable from normal swimming and pseudodisplays caused by sharksucker irritation. Shark agonistic displays are most readily elicited by rapid, direct diver approach when

  6. 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

  7. 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

  8. Mutations affecting agonist sensitivity of the nicotinic acetylcholine receptor.

    PubMed Central

    Tomaselli, G F; McLaughlin, J T; Jurman, M E; Hawrot, E; Yellen, G

    1991-01-01

    The nicotinic acetylcholine receptor (AChR) is a pentameric transmembrane protein (alpha 2 beta gamma delta) that binds the neurotransmitter acetylcholine (ACh) and transduces this binding into the opening of a cation selective channel. The agonist, competitive antagonist, and snake toxin binding functions of the AChR are associated with the alpha subunit (Kao et al., 1984; Tzartos and Changeux, 1984; Wilson et al., 1985; Kao and Karlin, 1986; Pederson et al., 1986). We used site-directed mutagenesis and expression of AChR in Xenopus oocytes to identify amino acid residues critical for ligand binding and channel activation. Several mutations in the alpha subunit sequence were constructed based on information from sequence homology and from previous biochemical (Barkas et al., 1987; Dennis et al., 1988; Middleton and Cohen, 1990) and spectroscopic (Pearce and Hawrot, 1990; Pearce et al., 1990) studies. We have identified one mutation, Tyr190 to Phe (Y190F), that had a dramatic effect on ligand binding and channel activation. These mutant channels required more than 50-fold higher concentrations of ACh for channel activation than did wild type channels. This functional change is largely accounted for by a comparable shift in the agonist binding affinity, as assessed by the ability of ACh to compete with alpha-bungarotoxin binding. Other mutations at nearby conserved positions of the alpha subunit (H186F, P194S, Y198F) produce less dramatic changes in channel properties. Our results demonstrate that ligand binding and channel gating are separable properties of the receptor protein, and that Tyr190 appears to play a specific role in the receptor site for acetylcholine. PMID:1718469

  9. Could dopamine agonists aid in drug development for anorexia nervosa?

    PubMed

    Frank, Guido K W

    2014-01-01

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

  10. 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

  11. Agonist and antagonist effects of cytisine in vivo.

    PubMed

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

    2015-08-01

    Varenicline, the most successful smoking cessation aid, is a selective partial agonists at ?4?2* nicotinic receptors. Its efficacy is likely to be shared by other drugs with similar receptor action, including cytisine. The present study aimed to characterize behavioral effects of cytisine compared with nicotine using locomotor activity tests, intracranial self-stimulation of ventral tegmental area (discrete-trial threshold current intensity titration procedure), drug discrimination (0.6 mg/kg nicotine from vehicle), physical dependence (osmotic minipumps delivering 6 mg/kg/day of nicotine) and intravenous nicotine self-administration (0.01 mg/kg per infusion) in adult Wistar rats. Cytisine (1-3 mg/kg) partially substituted for nicotine and at the highest dose tended to antagonize nicotine's discriminative stimulus effects. Nicotine (0.05-0.4 mg/kg), but not cytisine (0.3-3 mg/kg), lowered ICSS thresholds and cytisine dose-dependently reversed effects of nicotine. Nicotine (0.15-0.6 mg/kg), but not cytisine (0.3-3 mg/kg), stimulated locomotor activity and cytisine (3 mg/kg) fully reversed these effects of nicotine. Acute pretreatment with nicotine (0.15-0.6 mg/kg), but not cytisine (0.3-3 mg/kg), reinstated extinguished nicotine self-administration. Continuous infusion of nicotine induced physical dependence, as indicated by reduced rates of food-reinforced responding induced by a challenge dose of mecamylamine. At the highest tested dose (3 mg/kg), cytisine tended to reduce response rates irrespective of whether the rats were continuously exposed to nicotine or saline. Cytisine behaves like a weak partial agonist, mimicking effects of nicotine to a limited degree. Although cytisine reversed several effects of nicotine, it seemed to have a reduced potential to produce withdrawal signs in nicotine-dependent subjects. PMID:25839895

  12. Theory of partial agonist activity of steroid hormones

    PubMed Central

    Chow, Carson C.; Ong, Karen M.; Kagan, Benjamin; Simons, S. Stoney

    2015-01-01

    The different amounts of residual partial agonist activity (PAA) of antisteroids under assorted conditions have long been useful in clinical applications but remain largely unexplained. Not only does a given antagonist often afford unequal induction for multiple genes in the same cell but also the activity of the same antisteroid with the same gene changes with variations in concentration of numerous cofactors. Using glucocorticoid receptors as a model system, we have recently succeeded in constructing from first principles a theory that accurately describes how cofactors can modulate the ability of agonist steroids to regulate both gene induction and gene repression. We now extend this framework to the actions of antisteroids in gene induction. The theory shows why changes in PAA cannot be explained simply by differences in ligand affinity for receptor and requires action at a second step or site in the overall sequence of reactions. The theory also provides a method for locating the position of this second site, relative to a concentration limited step (CLS), which is a previously identified step in glucocorticoid-regulated transactivation that always occurs at the same position in the overall sequence of events of gene induction. Finally, the theory predicts that classes of antagonist ligands may be grouped on the basis of their maximal PAA with excess added cofactor and that the members of each class differ by how they act at the same step in the overall gene induction process. Thus, this theory now makes it possible to predict how different cofactors modulate antisteroid PAA, which should be invaluable in developing more selective antagonists. PMID:25984562

  13. Facult des arts et des sciences Sciences sociales et psychologie | Cartographie de la recherche 2012 TABLE DES MATIRES

    E-print Network

    Leclercq, Remi

    #12;Faculté des arts et des sciences ­ Sciences sociales et psychologie | Cartographie de la ..................................................................................................................................................................... 2 La Faculté des arts et des sciences (FAS), c'est....................................................................................... 3 Sciences sociales et psychologie

  14. 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

  15. Le magazine Prsentation des

    E-print Network

    Le magazine Présentation des guides Abonnez-vous La lettre professionnelle Recevez la newsletter FINANCEMENT EUROPE ET MONDE FORMATION Innovation Online - L´actualité de l'économie de la croissance http://www.innovationonline.fr/articles-magazine

  16. Zur Pharmakologie des Cytisins

    Microsoft Academic Search

    J. Zachowski

    1938-01-01

    Zusammenfassung 1.Das goldregenalkaloid Cytisin bewirkt wie Nikotin Erregung der vegetativen Schaltganglien mit nachfolgender Lähmung. Die erregende Wirkung des Cytisins betrifft fast nur die sympathischen Schaltganglien.2.Vom Nikotin unterscheidet es sich wesentlich durch die bedeutend stärkere Erregung der sympathischen Schaltganglien und durch die stark abgeschwächte lähmende Wirkung.3.Die im Vergleich zu Nikotin vielfach stärkere adrenalinartige pressorische Wirkung des Cytisins beruht in erster Linie

  17. Agonist-specific patterns of ?2-adrenoceptor responses in human airway cells during prolonged exposure

    PubMed Central

    Düringer, Caroline; Grundström, Gunilla; Gürcan, Eylem; Dainty, Ian A; Lawson, Mandy; Korn, Solange H; Jerre, Anders; Håkansson, Hanna Falk; Wieslander, Elisabet; Fredriksson, Karin; Sköld, Carl Magnus; Löfdahl, Magnus; Löfdahl, Claes-Göran; Nicholls, David J; Silberstein, David S

    2009-01-01

    Background and purpose: ?2-Adrenoceptor agonists (?2-agonists) are important bronchodilators used in the treatment of asthma and chronic obstructive pulmonary disease. At the molecular level, ?2-adrenergic agonist stimulation induces desensitization of the ?2-adrenoceptor. In this study, we have examined the relationships between initial effect and subsequent reduction of responsiveness to restimulation for a panel of ?2-agonists in cellular and in vitro tissue models. Experimental approach: ?2-Adrenoceptor-induced responses and subsequent loss of receptor responsiveness were studied in primary human airway smooth muscle cells and bronchial epithelial cells by measuring cAMP production. Receptor responsiveness was compared at equi-effective concentrations, either after continuous incubation for 24 h or after a 1 h pulse exposure followed by a 23 h washout. Key findings were confirmed in guinea pig tracheal preparations in vitro. Key results: There were differences in the reduction of receptor responsiveness in human airway cells and in vitro guinea pig trachea by a panel of ?2-agonists. When restimulation occurred immediately after continuous incubation, loss of responsiveness correlated with initial effect for all agonists. After the 1 h pulse exposure, differences between agonists emerged, for example isoprenaline and formoterol induced the least reduction of responsiveness. High lipophilicity was, to some extent, predictive of loss of responsiveness, but other factors appeared to be involved in determining the relationships between effect and subsequent loss of responsiveness for individual agonists. Conclusions and implications: There were clear differences in the ability of different ?2 agonists to induce loss of receptor responsiveness at equi-effective concentrations. PMID:19558544

  18. Two aromatic residues regulate the response of the human oxytocin receptor to the partial agonist arginine vasopressin.

    PubMed

    Chini, B; Mouillac, B; Balestre, M N; Trumpp-Kallmeyer, S; Hoflack, J; Hibert, M; Andriolo, M; Pupier, S; Jard, S; Barberis, C

    1996-11-18

    We investigated the mechanisms that regulate the efficacy of agonists in the arginine-vasopressin (AVP)/oxytocin (OT) receptor system. In this paper, we present evidence that AVP, a full agonist of the vasopressin receptors, acts as a partial agonist on the oxytocin receptor. We also found that AVP becomes a full agonist when two aromatic residues of the oxytocin receptor are replaced by the residues present at equivalent positions in the vasopressin receptor subtypes. Our results indicate that these two residues modulate the response of the oxytocin receptor to the partial agonist AVP. PMID:8955347

  19. A comparison of current-voltage relations for full and partial agonists.

    PubMed Central

    Adams, P R; Sakmann, B

    1978-01-01

    1. Local conductance changes produced by various bath-applied agonists at frog end-plate membrane were measured using focal recording of extracellular potential in voltage-clamped muscle fibres. The potential difference between a focal micropipette placed on the nerve terminal and another micro-pipette placed on or near inactive membrane was taken as proportional to the agonist-induced current through a small patch of an end-plate membrane. 2. The current-voltage (I--V) relation of active membrane was obtained directly by increasing the membrane potential in a ramp fashion. The change in membrane potential was slow enough for post-synaptic gating processes to reach equilibrium during the ramp. 3. During application of sufficiently low concentrations of full agonists (carbachol, (ACh) and partial agonists (choline and decamethonium) the I--V relation of end-plate membrane showed strong curvature in the range of -60 to -130 mV. The slope of I--V relations increased exponentially with membrane hyperpolarization, an e-fold change in conductance occurring for about 50 mV potential shift. 4. The curvature of the I--V relation of end-plate-membrane activated by the partial agonists choline and decamethonium became less as the agonist concentration was increased, and with high concentrations (choline 15 mM; decamethonium 250 micrometer) the I--V relation became almost straight. 5. When end-plate currents produced by high concentrations of partial agonists were matched by application of equi-active concentrations of carbachol, the carbachol-activated membrane still showed as much curvature in its I--V relation as when low concentrations of carbachol were used. 6. Choline and decamethonium concentrations for which the I--V relation was straight produced much greater depression of miniature end-plate currents than did carbachol concentrations which produced the same membrane current at the holding potential. 7. I--V relations for full agonists at high concentrations were obtained after alpha-bungarotoxin pre-treatment. During application of carbachol (400--500 micrometer) and ACh (30--40 micrometer; after complete inhibition of acetylcholinesterase activity) the I--V relation of end-plate membrane is much less curved than during application of low concentrations. 8. It is concluded that either the voltage sensitivity of agonist-induced end-plate conductance reflects voltage sensitivity of agonist binding, or the partial agonists used can exert a voltage-dependent 'local anaesthetic' action in addition to their agonist activity. PMID:309943

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

    PubMed Central

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

    2015-01-01

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

  1. Liver X receptor (LXR) partial agonists: biaryl pyrazoles and imidazoles displaying a preference for LXR?.

    PubMed

    Kick, Ellen; Martin, Richard; Xie, Yinong; Flatt, Brenton; Schweiger, Edwin; Wang, Tie-Lin; Busch, Brett; Nyman, Michael; Gu, Xiao-Hui; Yan, Grace; Wagner, Brandee; Nanao, Max; Nguyen, Lam; Stout, Thomas; Plonowski, Artur; Schulman, Ira; Ostrowski, Jacek; Kirchgessner, Todd; Wexler, Ruth; Mohan, Raju

    2015-01-15

    A series of biaryl pyrazole and imidazole Liver X Receptor (LXR) partial agonists has been synthesized displaying LXR? selectivity. The LXR? selective partial agonist 18 was identified with potent induction of ATP binding transporters ABCA1 and ABCG1 in human whole blood (EC50=1.2?M, 55% efficacy). In mice 18 displayed peripheral induction of ABCA1 at 3 and 10mpk doses with no significant elevation of plasma or hepatic triglycerides at these doses, showing an improved profile compared to a full pan-agonist. PMID:25435151

  2. Structure-activity relationships of the prototypical TRPM8 agonist icilin.

    PubMed

    De Petrocellis, Luciano; Ortar, Giorgio; Schiano Moriello, Aniello; Serum, Eric M; Rusterholz, David B

    2015-06-01

    A series of structural analogues of the TRPM8 agonist icilin was prepared. The compounds were examined for their ability to exert agonist or antagonist effects in HEK-293 cells expressing the TRPM8 receptor. Most structural modifications of the icilin structure largely met with diminished TRPM8 agonist activity. Cinnamamide 'open-chain' analogs of icilin, however, demonstrated significant antagonistic actions at the TRPM8 receptor. Optimal potency (IC50=73nM) was observed in the 3-iodo derivative 18l. PMID:25935641

  3. Three-Dimensional common-Feature hypotheses for octopamine agonist 2-(arylimino)imidazolidines

    Microsoft Academic Search

    Akinori Hirashima; Masako Morimoto; Eiichi Kuwano; Eiji Taniguchi; Morifusa Eto

    2002-01-01

    Three-dimensional pharmacophore hypotheses were built from a set of 10 octopamine (OA) agonist 2-(Arylimino)imidazolidines (AIIs), 2-(Arylimino)thiazolidines (AITs) and 2-(Arylimino)oxazolidines (AIOs). Among the 10 common-featured models generated by program Catalyst\\/HipHop, a hypothesis including a ring aromatic (RA), a positive ionizable (PI) and three hydrophobic aliphatic (HpAl) features was considered to be important in evaluating the OA-agonist activity. Active OA agonist 2,6-Et2

  4. Antitussive effects of the peripherally restricted GABAB receptor agonist lesogaberan in guinea pigs: comparison to baclofen and other GABAB receptor-selective agonists

    PubMed Central

    2012-01-01

    Background Gastroesophageal reflux disease (GERD) is a common cause of chronic cough. Both acid and nonacid reflux is thought to play a role in the initiation of coughing and cough hypersensitivity. The GABAB receptor agonist lesogaberan was developed as a peripherally restricted anti-reflux therapy that reduces the frequency of transient lower esophageal sphincter relaxations (TLESR; the major cause of reflux) in animals and in patients with GERD. GABAB receptor agonists have also been shown to possess antitussive effects in patients and in animals independent of their effects on TLESR, suggesting that lesogaberan may be a promising treatment for chronic cough. Methods We have assessed the direct antitussive effects of lesogaberan (AZD3355). The effects of other GABAB receptor agonists were also determined. Coughing was evoked in awake guinea pigs using aerosol challenges with citric acid. Results Lesogaberan dose-dependently inhibited citric acid evoked coughing in guinea pigs. Comparable effects of the GABAB receptor agonists baclofen and 3-aminopropylphosphinic acid (3-APPiA) on cough were also observed. Baclofen produced obvious signs of sedation and respiratory depression. By contrast, both lesogaberan and 3-APPiA (both inactivated centrally by GABA transporters) were devoid of sedative effects and did not alter respiratory rate. Conclusions Together, the data suggest that lesogaberan and related GABAB receptor agonists may hold promise as safe and effective antitussive agents largely devoid of CNS side effects. PMID:23025757

  5. Metabolism of [DES-GLY 10, D-TRP 6]LHRH ethylamide in rabbit nasal tissue

    Microsoft Academic Search

    Uday B. Kompella; Bhas A. Dani

    1996-01-01

    The objective of this study was to determine whether [Des-Gly10, D-Trp6]LHRH ethylamide, a nonapeptide LHRH agonist known as deslorelin, is degraded by the rabbit nasal tissue. Deslorelin was incubated with nasal tissue either alone or in the presence of 0.1 mM ouabain, 0.1% 2,4-dinitrophenol, 0.1 mM phosphoramidon, 0.1 mM N-tosyl-L-phenylalanine chloromethylketone (TPCK) or 2% EDTA at 37 °C. Furthermore, deslorelin

  6. PROPRITS MCANIQUES DES VERRES J. ZARZYCKI

    E-print Network

    Paris-Sud XI, Université de

    789 PROPRIÉTÉS MÉCANIQUES DES VERRES J. ZARZYCKI Université de Montpellier 2, Laboratoire des Verres du C. N. R. S., France Résumé. 2014 La résistance mécanique des verres usuels s'écarte très des propriétés mécaniques des verres. Après un brefrappel de la théorie des microfissures (Inglis

  7. Optimisation du dimensionnement des alimentations des machines rluctance variable

    E-print Network

    Paris-Sud XI, Université de

    qui minimisent le dimensionnement du convertisseur tant en courant qu'en tension. Après un rappel des dimensionnement des convertisseurs prenant en compte les valeurs efficaces ou maximales des courant et tension adjoindre un convertisseur d'alimentation à fréquences élevées (jusqu'à quelques kHz). En général, il est à

  8. 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

  9. Facult des arts et des sciences Dpartement de psychologie

    E-print Network

    Parrott, Lael

    ) L'étudiant choisit les cours du profil Enfants/adolescents (Axe 1), ou du profil Adultes (Axe 2). Cours Axe 1 : Évaluation enfants - adolescents Crédits Inscription Annulation Trimestre Année PSY7236;Faculté des arts et des sciences Département de psychologie Secrétariat des études supérieures Cours Axe 2

  10. SURVEILLANCE ET CONTROLE DES ACTIVITES DES NAVIRES EN MER

    E-print Network

    Boyer, Edmond

    1 SURVEILLANCE ET CONTROLE DES ACTIVITES DES NAVIRES EN MER ScanMaris Michel MOREL (DCNS), Aldo) «Quiconque est maître sur la mer a un grand pouvoir sur la terre» Cardinal de Richelieu Il est donc Surveillance et de Sauvetage), sémaphores, moyens nautiques et aériens des administrations en mer. Toutefois

  11. Access to 7?-analogs of codeine with mixed ?/? agonist activity via 6,7-?-epoxide opening.

    PubMed

    Magnus, Philip; Ghavimi, Bahman; Coe, Jotham W

    2013-09-01

    (-)-Codeine 1 was converted into previously unknown 7?-methyl-7,8-dihydrocodeine/morphine derivatives such as 13 via classical diaxial opening of ?-epoxide 3. Several analogs exhibited dual ?/?-agonist activity. PMID:23880538

  12. Interaction among alfaxalone, pregnenolone sulfate, and two GABAA agonists on hippocampal slices.

    PubMed

    SanMartin, S; Andrés-Trelles, F; Menendez, L; Meana, A; Hidalgo, A; Baamonde, A

    1996-06-01

    GABAA agonists do not respond to the same degree to allosteric modulators of the GABAA receptor complex such as benzodiazepines. We report there the effects of two steroids (alfaxalone and pregnenolone sulfate) on the inhibition induced by two GABAA agonists, 3-amino propane sulphonic acid (3-APS) and muscimol, on the extracellular evoked potentials obtained in CA1 of mice hippocampi. Alfaxalone (1 microM) potentiates the effects of both agonists, although incubation times longer than 15 minutes are required to potentiate the inhibitory effect of muscimol. Lower doses of pregnenolone sulfate at shorter incubation periods are able to inhibit the effects produced by single doses of 3-APS as compared to muscimol (15 microM during 5 min vs 30 microM during 5 min). Our results confirm the possibility that there might be differences in the interaction between GABAA agonists and modulatory steroids. PMID:8818409

  13. Food intake and rumen motility in dwarf goats. Effects of some serotonin receptor agonists and antagonists

    Microsoft Academic Search

    F. Kaya; C. T. M. van Duin; G. H. Veenendaal; A. S. J. P. A. M. van Miert

    1992-01-01

    The serotonergic regulation of feeding behaviour has not so far been studied in ruminants. Therefore, the effects of some serotonin (5-HT) receptor agonists and antagonists on food intake and forestomach motility were studied in dwarf goats.

  14. Structure-based Ligand Design of Novel Human Toll-like Receptor 8 Agonists

    PubMed Central

    Kokatla, Hari Prasad; Sil, Diptesh; Tanji, Hiromi; Ohto, Umeharu; Malladi, Subbalakshmi S.; Fox, Lauren M.; Shimizu, Toshiyoki; David, Sunil A.

    2014-01-01

    Toll-like receptor (TLR)-8 agonists activate adaptive immune responses by inducing robust production of T helper 1-polarizing cytokines, suggesting that TLR8-active compounds may be promising candidate adjuvants. We recently reported pure TLR8 agonistic activity in a C2-butyl furo[2,3-c]quinoline. We have obtained the structure of human TLR8 ectodomain co-crystallized with the furoquinoline compound, which indicates ligand-induced reorganization of the binding pocket of TLR8. The loss of a key H-bond between the oxygen atom of the furanyl ring of the agonist and Thr574 in TLR8 suggested that the furan ring was dispensable. We employed a disconnection strategy and examined 3- and 4-substituted aminoquinolines. Focused structure-based ligand design studies led to the identification of 3-pentyl-quinoline-2-amine as a novel, structurally simple, and highly potent human TLR8-specific agonist. PMID:24474703

  15. Lepidozenolide from the liverwort Lepidozia fauriana acts as a farnesoid X receptor agonist.

    PubMed

    Lin, Hsiang-Ru

    2015-01-01

    Lepidozenolide is a sesquiterpenoid isolated from the liverwort Lepidozia fauriana and its possible bioactivity is unclear. The farnesoid X receptor (FXR) is a member of nuclear receptor superfamily that has been widely targeted for developing treatments for chronic liver disease and hyperglycemia. In this study, whether lepidozenolide may act as a FXR agonist was determined. Indeed, in mammalian one-hybrid and transient transfection reporter assays, lepidozenolide transactivated FXR to modulate promoter action including GAL4, CYP7A1, and PLTP promoters in a dose-dependent manner, while it exhibited slightly less agonistic activity than chenodeoxycholic acid, an endogenous FXR agonist. Through the molecular modeling docking studies lepidozenolide was shown to bind to FXR ligand binding pocket fairly well. All these results indicate that lepidozenolide acts as a FXR agonist. PMID:25315435

  16. nAChR agonist-induced cognition enhancement: Integration of cognitive and neuronal mechanisms

    E-print Network

    Review nAChR agonist-induced cognition enhancement: Integration of cognitive and neuronal for cognition enhancers . . . . . . . . . . . . . . . . . . . . . 661 5. Circuitry model for signal detection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 664 1. Introduction Drug-induced improvement of the cognitive capacities of patients suffering from

  17. 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...

  18. Potent achiral agonists of the ghrelin (growth hormone secretagogue) receptor. Part I: Lead identification

    Microsoft Academic Search

    Tom D. Heightman; Jackie S. Scott; Mark Longley; Vincent Bordas; David K. Dean; Richard Elliott; Gail Hutley; Jason Witherington; Lee Abberley; Barry Passingham; Manuela Berlanga; Maite de los Frailes; Alan Wise; Ben Powney; Alison Muir; Fiona McKay; Sharon Butler; Kim Winborn; Christopher Gardner; Jill Darton; Colin Campbell; Gareth Sanger

    2007-01-01

    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.

  19. Synthesis and Biological Evaluation of a Selective N- and P/Q-Type Calcium Channel Agonist

    PubMed Central

    2012-01-01

    The acute effect of the potent cyclin-dependent kinase (cdk) inhibitor (R)-roscovitine on Ca2+ channels inspired the development of structural analogues as a potential treatment for motor nerve terminal dysfunction. On the basis of a versatile chlorinated purine scaffold, we have synthesized ca. 20 derivatives and characterized their N-type Ca2+ channel agonist action. Agents that showed strong agonist effects were also characterized in a kinase panel for their off-target effects. Among several novel compounds with diminished cdk activity, we identified a new lead structure with a 4-fold improved N-type Ca2+ channel agonist effect and a 22-fold decreased cdk2 activity as compared to (R)-roscovitine. This compound was selective for agonist activity on N- and P/Q-type over L-type calcium channels. PMID:24936234

  20. Perioperative use of selective alpha-2 agonists and antagonists in small animals

    PubMed Central

    2004-01-01

    Abstract Alpha-2 agonists are the only single class of anesthetic drugs that induce reliable, dose-dependent sedation, analgesia, and muscle relaxation in dogs and cats. Used at low doses, as adjuncts to injectable and inhalational anesthetics, selective alpha-2 agonists dramatically reduce the amount of anesthetic drug required to induce and maintain anesthesia. This reduction in anesthetic requirements is achieved without significant depression of pulmonary function and with limited effects on cardiovascular function. Selective alpha-2 agonists can also be used postoperatively to potentiate the analgesic effects of opioids and other drugs. Given the nearly ideal pharmacodynamic profile and reversibility of alpha-2 agonists, these drugs will play a central role in balanced approaches to anesthesia and the management of perioperative pain in healthy dogs and cats. PMID:15283516

  1. 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

  2. Septembre 2012 Paludisme : des moustiques

    E-print Network

    pulvérisations intra domiciliaires d'autres insecticides, les carbamates. Ces derniers agissent différemment au aux pyré- thrinoïdes et pulvérisé des carbamates à l'intérieur des habitations, les scientifiques ont

  3. 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

  4. Effects of 5HT1A receptor agonists, partial agonists and a silent antagonist on the performance of the conditioned emotional response test in the rat

    Microsoft Academic Search

    K. J. Stanhope; C. T. Dourish

    1996-01-01

    In the present study, the effects of 5-HT1A receptor ligands with varying degrees of intrinsic activity at the 5-HT1A receptor were examined in the conditioned emotional response (CER) test and their effects compared to those of the benzodiazepine\\u000a receptor agonists, diazepam and chlordiazepoxide. Diazepam (3.0?mg\\/kg) and chlordiazepoxide (3.0?mg\\/kg), and the 5-HT1A receptor partial agonists, ipsapirone (10.0?mg\\/kg) and gepirone (3.0?mg\\/kg), alleviated

  5. Does gabapentin act as an agonist at native GABA B receptors?

    Microsoft Academic Search

    Jen-Kun Cheng; Sun-Zhi Lee; Jia-Rung Yang; Chien-Hua Wang; Yan-Yu Liao; Chien-Chuan Chen; Lih-Chu Chiou

    2004-01-01

    Gabapentin, a novel anticonvulsant and analgesic, is a ?-aminobutyric acid (GABA) analogue but was shown initially to have little affinity at GABAA or GABAB receptors. It was recently reported to be a selective agonist at GABAB receptors containing GABAB1a-GABAB2 heterodimers, although several subsequent studies disproved that conclusion. In the present study, we examined whether gabapentin is an agonist at native

  6. PPAR? agonists prevent TGF?1\\/Smad3-signaling in human hepatic stellate cells

    Microsoft Academic Search

    Caiyan Zhao; Wei Chen; Liu Yang; Lihong Chen; Stephen A. Stimpson; Anna Mae. Diehl

    2006-01-01

    PPAR? agonists inhibit liver fibrosis, but the mechanisms involved are uncertain. We hypothesized that PPAR? agonists inhibit transforming growth factor (TGF)?1-activation of TGF? receptor (TGF?R)-1 signaling in quiescent stellate cells, thereby abrogating Smad3-dependent induction of extracellular matrix (ECM) genes, such as PAI-1 and collagen-1?I. To test this, human HSC were cultured to induce a quiescent phenotype, characterized by lipid accumulation

  7. [Effect of gamma-aminobutyric acid, its agonists and antagonists on uterine smooth muscle].

    PubMed

    Sizov, P I; Iasnetsov, V S

    1985-11-01

    Experiments on isolated strips of the rabbit uterus showed the ability of GABA, GABAA-receptor agonist (diazepam) and GABAB-receptor antagonist (phenibut) to inhibit uterine contractility. GABAA-receptor antagonist (bicuculline) had a stimulating effect on contractility. It is assumed that GABA-ergic system plays an important role in the regulation of functional inhibition of contractile activity in the rabbit uterus, with GABA agonists regarded as potential gravidoprotectors in uterine hyperactivity or threatening miscarriage. PMID:2998506

  8. Evaluation of muscarinic agonist-induced analgesia in muscarinic acetylcholine receptor knockout mice.

    PubMed

    Duttaroy, Alokesh; Gomeza, Jesus; Gan, Jai-Wei; Siddiqui, Nasir; Basile, Anthony S; Harman, W Dean; Smith, Philip L; Felder, Christian C; Levey, Allan I; Wess, Jürgen

    2002-11-01

    Centrally active muscarinic agonists display pronounced analgesic effects. Identification of the specific muscarinic acetylcholine receptor (mAChR) subtype(s) mediating this activity is of considerable therapeutic interest. To examine the roles of the M(2) and M(4) receptor subtypes, the two G(i)/G(o)-coupled mAChRs, in mediating agonist-dependent antinociception, we generated a mutant mouse line deficient in both M(2) and M(4) mAChRs [M(2)/M(4) double-knockout (KO) mice]. In wild-type mice, systemic, intrathecal, or intracerebroventricular administration of centrally active muscarinic agonists resulted in robust analgesic effects, indicating that muscarinic analgesia can be mediated by both spinal and supraspinal mechanisms. Strikingly, muscarinic agonist-induced antinociception was totally abolished in M(2)/M(4) double-KO mice, independent of the route of application. The nonselective muscarinic agonist oxotremorine showed reduced analgesic potency in M(2) receptor single-KO mice, but retained full analgesic activity in M(4) receptor single-KO mice. In contrast, two novel muscarinic agonists chemically derived from epibatidine, CMI-936 and CMI-1145, displayed reduced analgesic activity in both M(2) and M(4) receptor single-KO mice, independent of the route of application. Radioligand binding studies indicated that the two CMI compounds, in contrast to oxotremorine, showed >6-fold higher affinity for M(4) than for M(2) receptors, providing a molecular basis for the observed differences in agonist activity profiles. These data provide unambiguous evidence that muscarinic analgesia is exclusively mediated by a combination of M(2) and M(4) mAChRs at both spinal and supraspinal sites. These findings should be of considerable relevance for the development of receptor subtype-selective muscarinic agonists as novel analgesic drugs. PMID:12391271

  9. Role of signal transduction in anesthetic action. Alpha 2 adrenergic agonists.

    PubMed

    Maze, M; Regan, J W

    1991-01-01

    The molecular mechanism for general anesthetic action is not known. The alpha 2 adrenergic agonists represent a novel class of "anesthetic-like" agent because of their selectivity for receptor binding sites and because the transmembrane signaling systems mediating their biologic responses in non-CNS systems are known. We have begun to characterize the signal transduction pathway involved in the anesthetic-like action of the alpha 2 adrenergic agonists. The alpha 2 adrenergic agonists potently decrease both central noradrenergic neurotransmission and halothane anesthetic requirements (MAC). Since MAC is only reduced by 30-40% when noradrenergic neurotransmission is totally abolished and since the reduction in MAC with the highly selective alpha 2 adrenergic agonists exceeds 90%, factors in addition to noradrenergic neurotransmission must be contributing to the anesthetic action of the alpha 2 agonists. Studies with the superselective alpha 2 agonist dexmedetomidine confirmed this, as the alpha 2 agonist could still reduce the MAC for halothane in rats depleted of their central norepinephrine stores. The profound reduction in anesthetic requirements with dexmedetomidine raised the possibility that alpha 2 adrenergic agonists may be considered an anesthetic hypnotic agent by itself. This sole anesthetic hypnotic response was established together with the confirmation that a central alpha 2 adrenoceptor mediated this action. Subsequently, data using molecular biologic techniques suggested that the alpha 2 C4 isoreceptor was the probable receptor that mediated the anesthetic response. We further explored the postreceptor effector mechanism for the signal transduction pathway for alpha 2 anesthetic action and identified the participation of two other molecular components, namely, a pertussis-toxin-sensitive G protein and a 4-aminopyridine-sensitive ion channel. Whether the signal transduction pathway for alpha 2 anesthetic action mediates the further response to other non-alpha 2 anesthetic agents needs to be defined. PMID:1711813

  10. 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.

  11. Bedtime cabergoline in Parkinson’sdisease patients with excessive daytime sleepiness induced bydopamine agonists

    Microsoft Academic Search

    P. Del Dotto; G. Gambaccini; D. Caneparo; C. Berti; S. Bernardini; U. Bonuccelli

    2003-01-01

    Excessive daytime somnolence is a common adverse effect of dopamine-agonist treatment of Parkinson’s disease (PD). Many factors, such as age and sleep disturbances, could be involved in the pathogenesis of this phenomenon. However, pharmacokinetic factors have never been considered. In this open, prospective, pilot study, nine consecutive non-demented PD patients in early disease stages on monotherapy treatment with dopamine agonists

  12. Halogenated cytisine derivatives as agonists at human neuronal nicotinic acetylcholine receptor subtypes

    Microsoft Academic Search

    Y. E. Slater; L. M. Houlihan; P. D. Maskell; R. Exley; I. Bermúdez; R. J. Lukas; A. C. Valdivia; B. K. Cassels

    2003-01-01

    Cytisine (cy) is a potent and competitive partial agonist at ?4 subunit-containing nicotinic acetylcholine (nACh) receptors while at homomeric ?7-nACh receptors it behaves as a full agonist with a relatively lower potency. In the present study, we assessed the effects of bromination or iodination of the pyridone ring of cy and N-methylcytisine (N-Me-cy) on the effects of these compounds on

  13. Gonadotropin-releasing hormone agonist use in men without a cancer registry diagnosis of prostate cancer

    Microsoft Academic Search

    Yong-fang Kuo; James S Goodwin; Vahakn B Shahinian

    2008-01-01

    BACKGROUND: Use of gonadotropin-releasing hormone (GnRH) agonists has become popular for virtually all stages of prostate cancer. We hypothesized that some men receive these agents after only a limited work-up for their cancer. Such cases may be missed by tumor registries, leading to underestimates of the total extent of GnRH agonist use. METHODS: We used linked Surveillance, Epidemiology and End-Results

  14. Opioid agonists inhibit excitatory neurotransmission in ganglia and at the neuromuscular junction in guinea pig gallbladder

    Microsoft Academic Search

    Fay A. Guarraci; Maria J. Pozo; Sara M. Palomares; Tracy A. Firth; Gary M. Mawe

    2002-01-01

    Background & Aims:Opiates administered therapeutically could have an inhibitory effect on the neuromuscular axis of the gallbladder, and thus contribute to biliary stasis and acalculous cholecystitis.Methods:Intracellular recordings were made from gallbladder neurons and smooth muscle, and tension measurements were made from muscle strips. Opioid receptor-specific agonists tested: delta, DPDPE; kappa, U-50488H; and mu, DAIVIGO.Results:Opiod agonists had no effect on gallbladder

  15. 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

  16. The 5-hydroxytryptamine 4 receptor agonist mosapride does not antagonize morphine-induced respiratory depression

    Microsoft Academic Search

    Jörn Lötsch; Carsten Skarke; Andreas Schneider; Thomas Hummel; Gerd Geisslinger

    2005-01-01

    Background: On the basis of experiments in rats, serotonin 4 receptor (5-hydroxytryptamine 4 [5-HT4]) agonists have been proposed as a novel therapeutic strategy for the selective treatment of respiratory depression caused by opioids while leaving analgesic effects unaffected. The effects in rats have been seen with the 5-hydroxytryptamine 4a (5-HT4a) agonist BIMU8, which is currently not available for use in

  17. 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

  18. Sigma 1 Receptor Agonists Act as Neuroprotective Drugs Through Inhibition of Inducible Nitric Oxide Synthase

    Microsoft Academic Search

    Kamila Vagnerova; Patricia D. Hurn; Anish Bhardwaj; Jeffrey R. Kirsch

    2006-01-01

    Postischemic administration of the sigma-1 agonists reduces ischemic brain injury; however, the mechanism is unclear. We hypothesized that the sigma-1 agonist ()isoform of pentazocine (P()) reduces damage in part by ameliorating cell death mediated via inducible nitric oxide synthase (iNOS) and that the ()isoform (P()) lacks this effect. We compared treatment with P() with or without the iNOS inhibitor aminoguanidine

  19. High specific activity tritium labelling of some sigma-1 receptor agonists

    Microsoft Academic Search

    David G. Ahern; Richard J. Seguin; Crist N. Filer

    The high specific activity tritiation of (+)-SKF-10,047 (1) and N,N-dimethyltryptamine (4) is described. [N-allyl-3H] (+)-SKF-10,047 (3) was prepared by Lindlar catalyst tritiation of (+)-N-propargylnormetazocine (2) and [N-methyl-3H] N,N-dimethyltryptamine (6) was synthesized by the alkylation of N-methyltryptamine (5) with [3H] methyl iodide. Both sigma-1 synthetic agonist 3 and endogenous agonist 6 have been useful in studying this receptor.

  20. Discovery of Azetidinone Acids as Conformationally-Constrained Dual PPARalpha/gamma Agonists

    SciTech Connect

    Wang, W.; Devasthale, P; Farrelly, D; Gu, L; Harrity, T; Cap, M; Chu, C; Kunselman, L; Morgan, N; et. al.

    2008-01-01

    A novel class of azetidinone acid-derived dual PPAR{alpha}/{gamma} agonists has been synthesized for the treatment of diabetes and dyslipidemia. The preferred stereochemistry in this series for binding and functional agonist activity against both PPARa and PPAR? receptors was shown to be 3S,4S. Synthesis, in vitro and in vivo activities of compounds in this series are described. A high-yielding method for N-arylation of azetidinone esters is also described.

  1. Design and synthesis of novel and potent amide linked PPARgamma/delta dual agonists.

    PubMed

    Shi, Qing; Canada, Emily J; Xu, Yanping; Warshawsky, Alan M; Etgen, Garret J; Broderick, Carol L; Clutinger, Cathleen K; Irwin, Lynnie A; Laurila, Michael E; Montrose-Rafizadeh, Chahrzad; Oldham, Brian A; Wang, Minmin; Winneroski, Leonard L; Xie, Chaoyu; York, Jeremy S; Yumibe, Nathan P; Zink, Richard W; Mantlo, Nathan

    2007-12-15

    A series of potent amide linked PPARgamma/delta dual agonists (1a) has been discovered through rational design. In the ZDF rat model of type 2 diabetes, compound (R)-3-[4-(3-{1-[(5-chloro-1,3-dimethyl-1H-indole-2-carbonyl)-amino]-ethyl}-5-fluoro-phenoxy)-2-ethyl-phenyl]-propionic acid (42) from this series has demonstrated glucose lowering efficacy comparable to the marketed PPARgamma agonist rosiglitazone with less weight gain. PMID:18029178

  2. Structure-based design of indole propionic acids as novel PPAR?\\/? co-agonists

    Microsoft Academic Search

    Bernd Kuhn; Hans Hilpert; Jörg Benz; Alfred Binggeli; Uwe Grether; Roland Humm; Hans Peter Märki; Markus Meyer; Peter Mohr

    2006-01-01

    In the quest for novel PPAR?\\/? co-agonists as putative drugs for the treatment of type 2 diabetes and dyslipidemia, we have used a structure-based design approach to identify propionic acids with a 1,5-disubstituted indole scaffold as potent PPAR?\\/? activators. Compounds 13, 24, and 28 are examples of submicromolar dual agonists with different ?\\/? EC50 ratios that are selective against the

  3. The Pharmacokinetics, Metabolism, and Tissue Residues of b-Adrenergic Agonists in Livestock1,2

    Microsoft Academic Search

    D. J. Smith

    Since the early 1980s the usefulness of dietary b-agonists to improve the efficiency of feed utilization and(or) to enhance carcass leanness in livestock species has been well documented. Less well documented are the pharmacokinetic properties, bi- otransformation pathways, and tissue residue profiles of b-agonists used to enhance leanness in experimen- tally or illegally treated animals. Pharmacokinetic data for clenbuterol, cimaterol,

  4. SAR of psilocybin analogs: discovery of a selective 5-HT 2C agonist.

    PubMed

    Sard, Howard; Kumaran, Govindaraj; Morency, Cynthia; Roth, Bryan L; Toth, Beth Ann; He, Ping; Shuster, Louis

    2005-10-15

    An SAR study of psilocybin and psilocin derivatives reveals that 1-methylpsilocin is a selective agonist at the h5-HT(2C) receptor. The corresponding phosphate derivative, 1-methylpsilocybin, shows efficacy in an animal model for obsessive-compulsive disorder, as does 4-fluoro-N,N-dimethyltryptamine. These results suggest a new area for development of novel 5-HT(2C) agonists with applications for drug discovery. PMID:16061378

  5. SAR of psilocybin analogs: Discovery of a selective 5HT 2C agonist

    Microsoft Academic Search

    Howard Sard; Govindaraj Kumaran; Cynthia Morency; Bryan L. Roth; Beth Ann Toth; Ping He; Louis Shuster

    2005-01-01

    An SAR study of psilocybin and psilocin derivatives reveals that 1-methylpsilocin is a selective agonist at the h5-HT2C receptor. The corresponding phosphate derivative, 1-methylpsilocybin, shows efficacy in an animal model for obsessive–compulsive disorder, as does 4-fluoro-N,N-dimethyltryptamine. These results suggest a new area for development of novel 5-HT2C agonists with applications for drug discovery.

  6. Measuring asthma control in group studies: do we need airway calibre and rescue ? 2-agonist use?

    Microsoft Academic Search

    E. F. JUNIPER; P. M. O'BYRNE; J. N. ROBERTS

    2001-01-01

    Collection of airway calibre and ?2-agonist data in large clinical trials and epidemiological surveys is sometimes difficult and may be an inefficient use of resources. The aim of this study was to determine whether the omission of the forced expiratory volume in 1 sec (FEV1) and ?2-agonist questions from the seven-item Asthma Control Questionnaire (ACQ) alters its measurement properties and

  7. Characterization of an sup 125 I-labeled thromboxane A2\\/prostaglandin H2 receptor agonist

    Microsoft Academic Search

    T. A. Morinelli; J. E. Jr. Oatis; A. K. Okwu; D. E. Mais; P. R. Mayeux; A. Masuda; D. R. Knapp; P. V. Halushka

    1989-01-01

    Stable synthetic mimetics of thromboxane (TX) A2 and prostaglandin (PG) H2 have been synthesized and reported to stimulate platelets and vascular smooth muscle. The synthetic agonists induce aggregation of isolated platelets and contraction of vascular tissue. The tritiated agonists (3H)U46619 and (3H)U44069 have been used in radioligand binding studies to characterize platelet and vascular smooth muscle TXA2\\/PGH2 receptors, but have

  8. Déviance et contrôle des comportements

    Microsoft Academic Search

    Lionel Honoré

    2006-01-01

    (VF)Quel rôle joue le contrôle des comportements et que devient la place de la déviance lorsque les règles s’écartent et que l’autonomie, l’initiative, le progrès constant, deviennent des principes du fonctionnement de l’entreprise et de l’organisation du travail ? Pour tenter d’apporter des éléments de réponses à cette question, nous l’étudions sous l’angle des théories de la déviance. L’objectif est,

  9. 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

  10. Pharmacological characterization of a recombinant, fluorescent somatostatin receptor agonist.

    PubMed

    Sreenivasan, Varun K A; Stremovskiy, Oleg A; Kelf, Timothy A; Heblinski, Marika; Goodchild, Ann K; Connor, Mark; Deyev, Sergey M; Zvyagin, Andrei V

    2011-09-21

    Somatostatin (SST) is a peptide neurotransmitter/hormone found in several mammalian tissue types. Apart from its natural importance, labeled SST/analogues are utilized in clinical applications such as targeting/diagnosis of neuroendocrine tumors. We report on the development and characterization of a novel, recombinant, fluorescent somatostatin analogue that has potential to elucidate somatostatin-activated cell signaling. SST was genetically fused with a monomeric-red fluorescent protein (mRFP) as the fluorescent label. The attachment of SST to mRFP had no detectable effect on its fluorescent properties. This analogue's potency to activate the endogenous and transfected somatostatin receptors was characterized using assays of membrane potential and Ca(2+) mobilization and immunocytochemistry. SST-mRFP was found to be an effective somatostatin receptor agonist, able to trigger the membrane hyperpolarization, mobilization of the intracellular Ca(2+) and receptor-ligand internalization in cells expressing somatostatin receptors. This complex represents a novel optical reporter due to its red emission spectral band suitable for in vivo imaging and tracking of the somatostatin receptor signaling pathways, affording higher resolution and sensitivity than those of the state-of-the-art radiolabeling bioassays. PMID:21823634

  11. 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

  12. Population pharmacokinetics and pharmacodynamics of peptidic erythropoiesis receptor agonist (ERA) in healthy volunteers.

    PubMed

    Woo, Sukyung; Krzyzanski, Wojciech; Duliege, Anne-Marie; Stead, Richard B; Jusko, William J

    2008-01-01

    Peptidic erythropoiesis receptor agonist is a synthetic, PEGylated peptide that can promote red blood cell production upon binding to the erythropoietin receptor. The objective of this study was to characterize the pharmacokinetics and erythropoietic effects of peptidic erythropoiesis receptor agonist in healthy volunteers. Plasma concentrations of peptidic erythropoiesis receptor agonist and pharmacodynamic responses were obtained after single intravenous injections at doses of 0.025, 0.05, and 0.1 mg/kg. Population pharmacokinetic/pharmacodynamic modeling was performed using NONMEM. Peptidic erythropoiesis receptor agonist exhibited nonlinear pharmacokinetics described by a 1-compartment model with parallel elimination by Michaelis-Menten and linear processes. A catenary, life span-based, indirect response model reflecting bone marrow erythroid and blood cells reflected the pharmacodynamics of peptidic erythropoiesis receptor agonist. A modest tolerance and rebound phenomenon in reticulocytes was modeled with negative feedback regulation related to hemoglobin. This pharmacokinetic/pharmacodynamic model well characterized the prolonged disposition, intrinsic pharmacologic parameters, and typical hematological system properties following single doses of peptidic erythropoiesis receptor agonist in normal subjects. PMID:18025524

  13. 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

  14. The good, the bad, and the ugly: agonistic behaviour in juvenile crocodilians.

    PubMed

    Brien, Matthew L; Lang, Jeffrey W; Webb, Grahame J; Stevenson, Colin; Christian, Keith A

    2013-01-01

    We examined agonistic behaviour in seven species of hatchling and juvenile crocodilians held in small groups (N?=?4) under similar laboratory conditions. Agonistic interactions occurred in all seven species, typically involved two individuals, were short in duration (5-15 seconds), and occurred between 1600-2200 h in open water. The nature and extent of agonistic interactions, the behaviours displayed, and the level of conspecific tolerance varied among species. Discrete postures, non-contact and contact movements are described. Three of these were species-specific: push downs by C. johnstoni; inflated tail sweeping by C. novaeguineae; and, side head striking combined with tail wagging by C. porosus. The two long-snouted species (C. johnstoni and G. gangeticus) avoided contact involving the head and often raised the head up out of the way during agonistic interactions. Several behaviours not associated with aggression are also described, including snout rubbing, raising the head up high while at rest, and the use of vocalizations. The two most aggressive species (C. porosus, C. novaeguineae) appeared to form dominance hierarchies, whereas the less aggressive species did not. Interspecific differences in agonistic behaviour may reflect evolutionary divergence associated with morphology, ecology, general life history and responses to interspecific conflict in areas where multiple species have co-existed. Understanding species-specific traits in agonistic behaviour and social tolerance has implications for the controlled raising of different species of hatchlings for conservation, management or production purposes. PMID:24349018

  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. Considerations when assessing antagonism in vitro: Why standardizing the agonist concentration matters.

    PubMed

    Neale, Peta A; Leusch, Frederic D L

    2015-09-01

    There is increasing recognition of the importance of assessing both agonism and antagonism in parallel for environmental samples. Cell-based in vitro assays have the advantage over receptor binding assays as they are able to differentiate between agonist and antagonist activity, but at present there is no standardized approach to assess antagonism in vitro, and in particular the competing agonist concentration can vary in the literature anywhere from half maximal to maximal effect concentrations. In this study, we investigated the influence of changing agonist concentrations in the estrogen receptor alpha (ER?), progesterone receptor (PR) and glucocorticoid receptor (GR) assays run in antagonist mode. The antagonistic effect varied by over two orders of magnitude when using the range of agonist concentrations applied in the literature, clearly indicating the need for standardization. By comparing antagonist EC50 values with different background agonist concentrations, an EC80 background agonist concentration is recommended when assessing antagonism in vitro to optimise both assay sensitivity and reproducibility. PMID:25876032

  17. Analysis of the agonist activity of fenoldopam (SKF 82526) at the vascular 5-HT2 receptor.

    PubMed Central

    Christie, M. I.; Harper, D.; Smith, G. W.

    1992-01-01

    1. The 5-HT2 receptor agonist activity of fenoldopam (SKF 82526) was characterized in the rabbit isolated aorta preparation. 2. Fenoldopam was an agonist at the vascular 5-HT2 receptor with lower affinity and efficacy than the naturally occurring agonist 5-hydroxytryptamine (5-HT). Fenoldopam had an affinity (pKA) of 5.84 +/- 0.04 and efficacy (tau) of 0.57 +/- 0.04, whereas 5-HT had a pKA of 6.65 +/- 0.12 and tau of 2.66 +/- 0.41. 3. The constrictor effects of fenoldopam and 5-HT were competitively antagonized by the 5-HT2 antagonist, ketanserin, with pKB values of 8.81 +/- 0.11 and 8.83 +/- 0.10 respectively. 4. Prior incubation with fenoldopam produced a concentration-related rightward shift of a subsequent 5-HT concentration-response curve. This inhibition was specific for 5-HT since constrictor responses to angiotensin II were unaffected. 5. This study indicates that the D1 receptor agonist, fenoldopam, acts as an agonist at the vascular 5-HT2 receptor, but with an affinity and efficacy less than that of the naturally occurring agonist, 5-HT. PMID:1361397

  18. Three-dimensional common-feature hypotheses for octopamine agonist 2-(arylimino)imidazolidines.

    PubMed

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

    2002-01-01

    Three-dimensional pharmacophore hypotheses were built from a set of 10 octopamine (OA) agonist 2-(Arylimino)imidazolidines (AIIs), 2-(Arylimino)thiazolidines (AITs) and 2-(Arylimino)oxazolidines (AIOs). Among the 10 common-featured models generated by program Catalyst/HipHop, a hypothesis including a ring aromatic (RA), a positive ionizable (PI) and three hydrophobic aliphatic (HpAl) features was considered to be important in evaluating the OA-agonist activity. Active OA agonist 2,6-Et2 AII mapped well onto all the RA, PI and HpAl features of the hypothesis. On the other hand, less active compounds were shown to be difficult to achieve the energetically favorable conformation which is found in the active molecules in order to fit the 3-D common-feature pharmacophore models. Taken together, 2,6-Et2-Ph and foramidine structures are important as OA agonists. The present studies on OA agonists demonstrate that a RA, a PI and three HpAl sites located on the molecule seem to be essential for OA-agonist activity. PMID:11738614

  19. Generalized concentration addition: a method for examining mixtures containing partial agonists.

    PubMed

    Howard, Gregory J; Webster, Thomas F

    2009-08-01

    Environmentally relevant toxic exposures often consist of simultaneous exposure to multiple agents. Methods to predict the expected outcome of such combinations are critical both to risk assessment and to an accurate judgment of whether combinations are synergistic or antagonistic. Concentration addition (CA) has commonly been used to assess the presence of synergy or antagonism in combinations of similarly acting chemicals, and to predict effects of combinations of such agents. CA has the advantage of clear graphical interpretation: Curves of constant joint effect (isoboles) must be negatively sloped straight lines if the mixture is concentration additive. However, CA cannot be directly used to assess combinations that include partial agonists, although such agents are of considerable interest. Here, we propose a natural extension of CA to a functional form that may be applied to mixtures including full agonists and partial agonists. This extended definition, for which we suggest the term "generalized concentration addition," encompasses linear isoboles with slopes of any sign. We apply this approach to the simple example of agents with dose-response relationships described by Hill functions with slope parameter n=1. The resulting isoboles are in all cases linear, with negative, zero and positive slopes. Using simple mechanistic models of ligand-receptor systems, we show that the same isobole pattern and joint effects are generated by modeled combinations of full and partial agonists. Special cases include combinations of two full agonists and a full agonist plus a competitive antagonist. PMID:19345693

  20. 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

  1. NOTE TECHNIQUE RECHERCHE DES SALMONELLA

    E-print Network

    Paris-Sud XI, Université de

    NOTE TECHNIQUE RECHERCHE DES SALMONELLA PAR IMMUNOFLUORESCENCE M. CATSARAS J. ANANI Laboratoire Salmonella, 366 prélèvements, dans 125 boucheries, pour lesquels nous avons comparé les techniques d, dus à des coliformes. Ses avantages et ses inconvénients pour la recherche des Salmonella sont

  2. How S-DES Works

    Microsoft Academic Search

    Febiana Hanani; Indri Rahmayuni

    Data Encryption Standard (DES) is one of the most widely used symmetric key cryptography algorithm. Therefore, the susceptibility of DES to different kind of attacks has been a concern since the algorithm was first made public. The problem has escalated to the point that Electronic Frontier Foundation has now built a DES cracking machine, at a cost of less than

  3. Die pharmakologische Wirkung des Ephedrins

    Microsoft Academic Search

    H. Kreitmair

    1927-01-01

    Zusammenfassung 1.Die pharmakologische Wirkung des Ephedrins wurde zu analysieren versucht durch Studium der Beeinflussung des Blutdrucks, der Herzaktion und der Gefäße, des Effekts am Atemzentrum und an den Bronchien, der Wirkung auf die Pupillenweite, auf den Darm und den Uterus, auf die Sekretion verschiedener Drüsen und den Blutzuckerspiegel.2.Es wurden folgende Wirkungen gefunden: Der Blutdruck wird erhöht durch kleine Dosen, erniedrigt

  4. 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

  5. TIC et commerce lectronique : laboratoires de la libralisation des changes et des volutions des rgles

    E-print Network

    Paris-Sud XI, Université de

    1 TIC et commerce électronique : laboratoires de la libéralisation des échanges et des évolutions/Département Sciences Economiques et Sociales Les échanges internationaux de produits TIC et le commerce électroniques à terme à l'abolition des droits de douane pour les produits de la filière TIC et les échanges

  6. Excitatory amino acid receptor subtype agonists induce feeding in the nucleus accumbens shell in rats: opioid antagonist actions and interactions with ?-opioid agonists

    Microsoft Academic Search

    Joyce A Echo; Nicole Lamonte; Garrison Christian; Vladimir Znamensky; Tsippa F Ackerman; Richard J Bodnar

    2001-01-01

    Administration of ?-opioid receptor subtype agonists into the nucleus accumbens shell elicits feeding which is dependent upon the normal function of ?-, ?- and ?-opioid receptors, D1 dopamine receptors and GABAB receptors in the nucleus accumbens shell for its full expression. Whereas the AMPA antagonist, DNQX administered into the nucleus accumbens shell elicits a transient, though intense feeding response, feeding

  7. Beneficial effect of luteal-phase GnRH agonist administration on embryo implantation after ICSI in both GnRH agonist- and antagonist-treated ovarian stimulation cycles

    Microsoft Academic Search

    Jan Tesarik; André Hazout; Raquel Mendoza-Tesarik; Nicolas Mendoza; Carmen Mendoza

    BACKGROUND: GnRH agonist was recently suggested as a novel luteal-phase support that may act at different lev- els, including the pituitary gonadotrophs, the endometrium and the embryo itself. This prospective randomized study evaluates the effect of GnRH agonist administered in the luteal phase on ICSI outcomes in both GnRH agonist- and GnRH antagonist-treated ovarian stimulation protocols. METHODS: Six hundred women

  8. LHRH agonists and the prevention of breast and ovarian cancer.

    PubMed Central

    Pike, M. C.; Ross, R. K.; Lobo, R. A.; Key, T. J.; Potts, M.; Henderson, B. E.

    1989-01-01

    Early age at natural menopause or bilateral ovariectomy substantially reduce a woman's lifetime risk of breast cancer. Reversible 'bilateral ovariectomy' can now in effect be achieved by 'high-dose' luteinising hormone releasing hormone (LHRH) agonists (LHRHAs). The harmful effects of such medical reversible bilateral ovariectomy, in particular the increased risks of coronary heart disease and osteoporosis, can in all likelihood be obviated by 'low-dose' oestrogen replacement therapy (ERT), specifically 0.625 mg of conjugated equine oestrogens (CEE) for 21 days in each 28-day treatment cycle, and such ERT use will only negate to a relatively small extent the beneficial effect of such bilateral ovariectomy on breast cancer risk. We calculate that such an LHRHA plus low-dose ERT regimen given to a premenopausal woman for 10 years will, in addition to being a most effective contraceptive, decrease her lifetime risk of breast cancer by more than 50%. We calculate that such a 10-year regimen will also decrease her risk of ovarian cancer by two-thirds. This regimen should leave endometrial cancer risk and bone metabolism unaltered, and may reduce the risk of heart disease. The addition of a 'low-dose' progestogen to the regimen for 12 days in each 28-day treatment cycle would be beneficial to the endometrium, but it will adversely affect risk factors for heart disease and it may significantly reduce the benefit of the regimen as regards breast cancer. A satisfactory compromise may be to add a low-dose progestogen for 12 days at less frequent intervals. Another possibility may be to deliver a progestogen solely to the endometrium with an intra-uterine device; the benefits of such a regimen would be a significant reduction in the incidence of breast, ovarian and endometrial cancer. PMID:2679844

  9. Gestion processuelle des rsultats : Une tude pr-et post-IFRS des dpenses de R&D des

    E-print Network

    1 « Gestion processuelle des résultats » : Une étude pré- et post-IFRS des dépenses de R&D des'adoption des normes IFRS n'a pas neutralisé la capitalisation discrétionnaire des dépenses de R&D, mais que, à. Then the paper focuses on how accounting standards used (PCG/IFRS) alter earnings management based on R

  10. Des Vents et des Jets Astrophysiques

    NASA Astrophysics Data System (ADS)

    Sauty, C.

    Plasma outflows from a central gravitating object are a widespread phenomenon in astrophysics. They include the solar and stellar winds, jets from Young Stellar Objects, jets from compact stellar objects and extra-galactic jets associated with Active Galactic Nuclei and quasars. Beyond this huge zoology, a common theoretical ground exists. The aim of this review is to present qualitatively the various theories of winds (Part 1) and how different astrophysical domains interplay. A more or less complete catalog of the ideas proposed for explaining the acceleration and the morphologies of winds and jets is intended. All this part avoids getting into any mathematical formalism. Some macroscopic properties of such outflows may be described by solving the time-independent and axisymmetric magnetohydrodynamic equations. This formalism, underlying most of the theories, is presented in Part 2. It helps to introduce quantitatively the free integrals that such systems possess. Those integrals play an important role in the basic physics of acceleration and collimation, in particular the mass loss rate, the angular momentum loss rate and the energy of the magnetic rotator. Most of the difficulty in modelling flows lies in the necessity to cross critical points, characteristic of non linear equations. The physical nature and the location of such critical points is debated because they are the clue towards the resolution. We thus introduce the notions of topology and critical points (Parts 3 and 4) from the simplest hydrodynamic and spherically symmetric case to the most sophisticated, MHD and axisymmetric cases. Particular attention is given to self-similar models which allows to give some general and simple ideas on the problem due to their semi-analytical treatment. With the use of these notions, a more quantitative comparison of the various models is given (Parts 3 and 4), especially on the shape of the flows. It is thus shown that magnetic collimation of winds into jets is a well expected result from the theory. Although, collimation may be conical, paraboloidal or cylindrical (Part 4), cylindrical collimation is the more likely to occur. The shape of outflows may then be used as a tool to predict physical conditions on the flows or on their source. L'éjection continue de plasma autour d'objets massifs est un phénomène largement répandu en astrophysique, que ce soit sous la forme du vent solaire, de vents stellaires, de jets d'étoiles en formation, de jets stellaires autour d'objets compacts ou de jets extra-galactiques. Cette zoologie diversifiée fait pourtant l'objet d'un commun effort de modélisation. Le but de cette revue est d'abord de présenter qualitativement le développement, depuis leur origine, des diverses théories de vents (Partie 1) et l'inter disciplinarité dans ce domaine. Il s'agit d'une énumération, plus ou moins exhaustive, des idées proposées pour expliquer l'accélération et la morphologie des vents et des jets, accompagnée d'une présentation sommaire des aspects observationnels. Cette partie s'abstient de tout aspect faisant appel au formalisme mathématique. Ces écoulements peuvent être décrits, au moins partiellement, en résolvant les équations magnétohydrodynamiques, axisymétriques et stationnaires. Ce formalisme, à la base de la plupart des théories, est exposé dans la Partie 2. Il permet d'introduire quantitativement les intégrales premières qu'un tel système possède. Ces dernières sont amenées à jouer un rôle important dans la compréhension des phénomènes d'accélération ou de collimation, en particulier le taux de perte de masse, le taux de perte de moment angulaire ou l'énergie du rotateur magnétique. La difficulté de modélisation réside dans l'existence de points critiques, propres aux équations non linéaires, qu'il faut franchir. La nature physique et la localisation de ces points critiques fait l'objet d'un débat important car ils sont la clef de voute de la résolution. Nous introduisons donc la notion de topologie des points critiques (Parties 3 et 4

  11. Agonist activity of N-desmethylclozapine at delta-opioid receptors of human frontal cortex.

    PubMed

    Olianas, Maria C; Dedoni, Simona; Ambu, Rossano; Onali, Pierluigi

    2009-04-01

    The clozapine metabolite N-desmethylclozapine (NDMC) has been recently shown to act at different neurotransmitter receptors and to display both antagonist and agonist activities. We have previously reported that in cells over-expressing the recombinant delta-opioid receptor NDMC behaved as partial agonist with high intrinsic activity, but its action at the receptors naturally expressed in human brain remained to be investigated. In the present study, we examined whether NDMC was able to bind to and activate delta-opioid receptors in membranes of post-mortem human frontal cortex. In radioligand binding assays, NDMC competition curves displayed high- (K(i)=26 nM) and low-affinity (K(i)=3 microM) components, whose proportion was regulated by guanine nucleotides in an agonist-like fashion. In functional assays, NDMC stimulated [(35)S]GTPgammaS binding (EC(50)=905 nM) and inhibited cyclic AMP formation (EC(50)=590 nM) as effectively as delta-opioid agonists, whereas clozapine was much less potent and efficacious and clozapine N-oxide was completely inactive. The NDMC agonist activity was potently antagonized by the delta-opioid antagonist naltrindole, but not by the micro-opioid receptor antagonist CTAP (D-phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH(2)) or the kappa-opioid antagonist nor-binaltorphimine. Moreover, blockade of either acetylcholine muscarinic, dopamine D(2) or serotonin 5HT(1A) receptors failed to affect NDMC agonist activity. These data demonstrate that at clinically relevant concentrations NDMC behaves as an efficacious agonist at delta-opioid receptors of human frontal cortex. PMID:19239909

  12. Glucagon-like peptide-1 receptor agonist administration suppresses both water and saline intake in rats

    PubMed Central

    McKay, Naomi J.; Daniels, Derek

    2013-01-01

    Glucagon-like peptide-1 (GLP-1) plays an important role in energy homeostasis. Injections of GLP-1 receptor (GLP-1R) agonists suppress food intake, and endogenous GLP-1 is released when nutrients enter the gut. There is also growing evidence that the GLP-1 system is involved in the regulation of body fluid homeostasis. GLP-1R agonists suppress water intake independent of their effects on food intake. It is unknown, however, whether this suppressive effect of GLP-1R agonists extends to saline intake. Accordingly, we tested the effect of the GLP-1R agonists liraglutide (0.05 µg) and exendin-4 (0.05 µg) on water and saline intakes stimulated either by angiotensin II (AngII) or by water deprivation with partial rehydration (WD-PR). Each agonist suppressed AngII-induced water intake; however, only exendin-4 suppressed saline intake. WD-PR-induced water and saline intakes were both attenuated by each agonist. Analysis of drinking microstructure after WD-PR found a reliable effect of the agonists on burst number. Furthermore, exendin-4 conditioned a robust taste avoidance to saccharine; however, there was no similar effect of liraglutide. To evaluate the relevance of the conditioned taste avoidance, we tested whether inducing visceral malaise by injection of lithium chloride (LiCl) suppressed fluid intake. Injection of LiCl did not suppress water or saline intakes. Overall, these results indicate that the fluid intake suppression by GLP-1R activation is not selective to water intake, is a function of post-ingestive feedback, and is not secondary to visceral malaise. PMID:23957745

  13. Glucagon-like peptide-1 receptor agonist administration suppresses both water and saline intake in rats.

    PubMed

    McKay, N J; Daniels, D

    2013-10-01

    Glucagon-like peptide-1 (GLP-1) plays an important role in energy homeostasis. Injections of GLP-1 receptor (GLP-1R) agonists suppress food intake, and endogenous GLP-1 is released when nutrients enter the gut. There is also growing evidence that the GLP-1 system is involved in the regulation of body fluid homeostasis. GLP-1R agonists suppress water intake independent of their effects on food intake. It is unknown, however, whether this suppressive effect of GLP-1R agonists extends to saline intake. Accordingly, we tested the effect of the GLP-1R agonists liraglutide (0.05 ?g) and exendin-4 (0.05 ?g) on water and saline intake, as stimulated either by angiotensin II (AngII) or by water deprivation with partial rehydration (WD-PR). Each agonist suppressed AngII-induced water intake; however, only exendin-4 suppressed saline intake. WD-PR-induced water and saline intakes were both attenuated by each agonist. Analysis of drinking microstructure after WD-PR found a reliable effect of the agonists on burst number. Furthermore, exendin-4 conditioned a robust taste avoidance to saccharine; however, there was no similar effect of liraglutide. To evaluate the relevance of the conditioned taste avoidance, we tested whether inducing visceral malaise by injection of lithium chloride (LiCl) suppressed fluid intake. Injection of LiCl did not suppress water or saline intakes. Overall, these results indicate that the fluid intake suppression by GLP-1R activation is not selective to water intake, is a function of post-ingestive feedback, and is not secondary to visceral malaise. PMID:23957745

  14. Evaluation of Computational Docking to Identify Pregnane X Receptor Agonists in the ToxCast Database

    PubMed Central

    Kortagere, Sandhya; Krasowski, Matthew D.; Reschly, Erica J.; Venkatesh, Madhukumar; Mani, Sridhar; Ekins, Sean

    2010-01-01

    Background The pregnane X receptor (PXR) is a key transcriptional regulator of many genes [e.g., cytochrome P450s (CYP2C9, CYP3A4, CYP2B6), MDR1] involved in xenobiotic metabolism and excretion. Objectives As part of an evaluation of different approaches to predict compound affinity for nuclear hormone receptors, we used the molecular docking program GOLD and a hybrid scoring scheme based on similarity weighted GoldScores to predict potential PXR agonists in the ToxCast database of pesticides and other industrial chemicals. We present some of the limitations of different in vitro systems, as well as docking and ligand-based computational models. Methods Each ToxCast compound was docked into the five published crystallographic structures of human PXR (hPXR), and 15 compounds were selected based on their consensus docking scores for testing. In addition, we used a Bayesian model to classify the ToxCast compounds into PXR agonists and nonagonists. hPXR activation was determined by luciferase-based reporter assays in the HepG2 and DPX-2 human liver cell lines. Results We tested 11 compounds, of which 6 were strong agonists and 2 had weak agonist activity. Docking results of additional compounds were compared with data reported in the literature. The prediction sensitivity of PXR agonists in our sample ToxCast data set (n = 28) using docking and the GoldScore was higher than with the hybrid score at 66.7%. The prediction sensitivity for PXR agonists using GoldScore for the entire ToxCast data set (n = 308) compared with data from the NIH (National Institutes of Health) Chemical Genomics Center data was 73.8%. Conclusions Docking and the GoldScore may be useful for prioritizing large data sets prior to in vitro testing with good sensitivity across the sample and entire ToxCast data set for hPXR agonists. PMID:20558333

  15. Human pregnane X receptor antagonists and agonists define molecular requirements for different binding sites.

    PubMed

    Ekins, Sean; Chang, Cheng; Mani, Sridhar; Krasowski, Matthew D; Reschly, Erica J; Iyer, Manisha; Kholodovych, Vladyslav; Ai, Ni; Welsh, William J; Sinz, Michael; Swaan, Peter W; Patel, Rachana; Bachmann, Kenneth

    2007-09-01

    The pregnane X receptor (PXR) is an important transcriptional regulator of the expression of xenobiotic metabolism and transporter genes. The receptor is promiscuous, binding many structural classes of molecules that act as agonists at the ligand-binding domain, triggering up-regulation of genes, increasing the metabolism and excretion of therapeutic agents, and causing drug-drug interactions. It has been suggested that human PXR antagonists represent a means to counteract such interactions. Several azoles have been hypothesized to bind the activation function-2 (AF-2) surface on the exterior of PXR when agonists are concurrently bound in the ligand-binding domain. In the present study, we have derived novel computational models for PXR agonists using different series of imidazoles, steroids, and a set of diverse molecules with experimental PXR agonist binding data. We have additionally defined a novel pharmacophore for the steroidal agonist site. All agonist pharmacophores showed that hydrophobic features are predominant. In contrast, a qualitative comparison with the corresponding PXR antagonist pharmacophore models using azoles and biphenyls showed that they are smaller and hydrophobic with increased emphasis on hydrogen bonding features. Azole antagonists were docked into a proposed hydrophobic binding pocket on the outer surface at the AF-2 site and fitted comfortably, making interactions with key amino acids involved in charge clamping. Combining computational and experimental data for different classes of molecules provided strong evidence for agonists and antagonists binding distinct regions on PXR. These observations bear significant implications for future discovery of molecules that are more selective and potent antagonists. PMID:17576789

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

    PubMed

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

    2013-04-26

    Although TRPV1 and TRPM8 agonists (vanilloid capsaicin and menthol, respectively) at high concentrations inhibit action potential conduction, it remains to be unknown whether TRPA1 agonists have a similar action. The present study examined the actions of TRPA1 agonists, cinnamaldehyde (CA) and allyl isothiocyanate (AITC), which differ in chemical structure from each other, on compound action potentials (CAPs) recorded from the frog sciatic nerve by using the air-gap method. CA and AITC concentration-dependently reduced the peak amplitude of the CAP with the IC50 values of 1.2 and 1.5mM, respectively; these activities were resistant to a non-selective TRP antagonist ruthenium red or a selective TRPA1 antagonist HC-030031. The CA and AITC actions were distinct in property; the latter but not former action was delayed in onset and partially reversible, and CA but not AITC increased thresholds to elicit CAPs. A CAP inhibition was seen by hydroxy-?-sanshool (by 60% at 0.05 mM), which activates both TRPA1 and TRPV1 channels, a non-vanilloid TRPV1 agonist piperine (by 20% at 0.07 mM) and tetrahydrolavandulol (where the six-membered ring of menthol is opened; IC50=0.38 mM). It is suggested that TRPA1 agonists as well as TRPV1 and TRPM8 agonists have an ability to inhibit nerve conduction without TRP activation, although their agonists are quite different in chemical structure from each other. PMID:23537660

  17. 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

  18. Agonist self-inhibition at the nicotinic acetylcholine receptor a nonspecific action

    SciTech Connect

    Forman, S.A.; Firestone, L.L.; Miller, K.W.

    1987-05-19

    Agonist concentration-response relationships at nicotinic postsynaptic receptors were established by measuring /sup 86/Rb/sup +/ efflux from acetylcholine receptor rich native Torpedo membrane vesicles under three different conditions: (1) integrated net ion efflux (in 10 s) from untreated vesicles, (2) integrated net efflux from vesicles in which most acetylcholine sites were irreversibly blocked with ..cap alpha..-bungarotoxin, and (3) initial rates of efflux (5-100 ms) from vesicles that were partially blocked with ..cap alpha..-bungarotoxin. Exposure to acetylcholine, carbamylcholine, suberyldicholine, phenyltrimethylammonium, or (-)-nicotine over 10/sup 8/-fold concentration ranges results in bell-shaped ion flux response curves due to stimulation of acetylcholine receptor channel opening at low concentrations and inhibition of channel function at 60-2000 times higher concentrations. Concentrations of agonists that inhibit their own maximum /sup 86/Rb/sup +/ efflux by 50% (K/sub B/ values) are 110, 211, 3.0, 39, and 8.9 mM, respectively, for the agonists listed above. For acetylcholine and carbamylcholine, K/sub B/ values determined from both 10-s and 15-ms efflux measurements are the same, indicating that the rate of agonist-induced desensitization increases to maximum at concentrations lower than those causing self-inhibition. For all partial and full agonists studied, Hill coefficients for self-inhibition are close to 1.0. Concentrations of agonists up to 8 times K/sub B/ did not change the order parameter reported by a spin-labeled fatty acid incorporated in Torpedo membranes. The authors conclude that agonist self-inhibition cannot be attributed to a general nonspecific membrane perturbation. Instead, these results are consistent with a saturable site of action either at the lipid-protein interface or on the acetylcholine receptor protein itself.

  19. 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

  20. Detection of glucocorticoid receptor agonists in effluents from sewage treatment plants in Japan.

    PubMed

    Suzuki, Go; Sato, Kentaro; Isobe, Tomohiko; Takigami, Hidetaka; Brouwer, Abraham; Nakayama, Kei

    2015-09-15

    Glucocorticoids (GCs) are widely used as anti-inflammatory drugs. Our previous study demonstrated that several GCs such as cortisol and dexamethasone (Dex) were frequently detected in effluents collected from Japanese sewage treatment plants (STPs) in 2012. In this study, we used the GC-Responsive Chemical-Activated LUciferase gene eXpression (GR-CALUX) assay to elucidate GC receptor (GR) agonistic activities of ten pure synthetic GCs and selected STP effluents in Japan for assessment of the risks associated with the presence of GR agonists. The tested GCs demonstrated dose-dependent agonistic effects in the GR-CALUX assay and their EC50 values were calculated for estimation of relative potencies (REPs) compared to Dex. The GR agonistic potency was in the rank of: clobetasol propionate>clobetasone butyrate>betamethasone 17-valerate>difluprednate>betamethasone 17,21-dipropionate>Dex>betamethasone>6?-methylprednisolone>prednisolone>cortisol. The GR agonistic activity in STP effluents as measured in Dex-equivalent (Dex-EQ) activities ranged from <3.0-78ngL(-1) (median: 29ngL(-1), n=50). To evaluate the contribution of the target GCs, theoretical Dex-EQs were calculated by multiplying the concentrations of each GC by its respective REP. Our calculation of Dex-EQ contribution for individual GR agonists indicated that the well-known GCs cortisol and Dex should not be given priority for subsequent in vivo testing, monitoring and removal experiments, but rather the highly potent synthetic GCs clobetasol propionate and betamethasone 17-valerate (REP=28 and 3.1) as well as other unidentified compounds are important GR agonists in STP effluents in Japan. PMID:25965047

  1. Find novel dual-agonist drugs for treating type 2 diabetes by means of cheminformatics

    PubMed Central

    Liu, Lei; Ma, Ying; Wang, Run-Ling; Xu, Wei-Ren; Wang, Shu-Qing; Chou, Kuo-Chen

    2013-01-01

    The high prevalence of type 2 diabetes mellitus in the world as well as the increasing reports about the adverse side effects of the existing diabetes treatment drugs have made developing new and effective drugs against the disease a very high priority. In this study, we report ten novel compounds found by targeting peroxisome proliferator-activated receptors (PPARs) using virtual screening and core hopping approaches. PPARs have drawn increasing attention for developing novel drugs to treat diabetes due to their unique functions in regulating glucose, lipid, and cholesterol metabolism. The reported compounds are featured with dual functions, and hence belong to the category of dual agonists. Compared with the single PPAR agonists, the dual PPAR agonists, formed by combining the lipid benefit of PPAR? agonists (such as fibrates) and the glycemic advantages of the PPAR? agonists (such as thiazolidinediones), are much more powerful in treating diabetes because they can enhance metabolic effects while minimizing the side effects. This was observed in the studies on molecular dynamics simulations, as well as on absorption, distribution, metabolism, and excretion, that these novel dual agonists not only possessed the same function as ragaglitazar (an investigational drug developed by Novo Nordisk for treating type 2 diabetes) did in activating PPAR? and PPAR?, but they also had more favorable conformation for binding to the two receptors. Moreover, the residues involved in forming the binding pockets of PPAR? and PPAR? among the top ten compounds are explicitly presented, and this will be very useful for the in-depth conduction of mutagenesis experiments. It is anticipated that the ten compounds may become potential drug candidates, or at the very least, the findings reported here may stimulate new strategies or provide useful insights for designing new and more powerful dual-agonist drugs for treating type 2 diabetes. PMID:23630413

  2. BULLITIONS NUIT DES SCIENCES

    E-print Network

    Gutkin, Boris

    partenariat avec TV5MONDE, Le Monde.fr, France culture Plus et l'Institut français, l'ENS a aussi souhaité de l'événement et des débats animés par Mohamed Kaci (TV5MONDE). Plusieurs thèmes seront abordés : la partager cette nuit avec le plus grand nombre, grâce à un plateau web-tv diffusé en direct dans le monde

  3. COMPORTEMENT SCURITAIRE DES

    E-print Network

    Paris-Sud XI, Université de

    , Robert Latour 1 Résumé Abstract Des données fournies par 109 utilisateurs de systèmes informatiques ont.., CA et Robert Latour L. SC. Com., C.S.E. stat., professeurs agrégés (avec la collaboration de Jacques-5633 Courrier électronique : andre.peres@hec.ca et robert.latour@hec.ca halshs-00587496,version1-20Apr2011

  4. Bilan des turbulences

    Microsoft Academic Search

    Françoise Milewski; Hervé Péléraux; Olivier Passet; Christine Rifflart; Jean-Marc Daniel

    1994-01-01

    [eng] Turbulences' check-up Département des diagnostics Western economies began their recovery one year ago, but it is still difficult to foresee jobs and capacities creations on the near term. National situations exhibit quite varied imprints of indebtedness and disindebtedness waves brought about by the deregulations and monetary policies. Continental Europe, Germany excepted, has achieved the curbing of corporate failures, but

  5. Injectabilite des coulis de ciment dans des milieux fissures

    NASA Astrophysics Data System (ADS)

    Mnif, Thameur

    Le travail presente ici est un bilan du travaux de recherche effectues sur l'injectabilite des coulis de ciment dans lu milieux fissures. Un certain nombre de coulis a base de ciment Portland et microfin ont ete selectionnes afin de caracteriser leur capacite a penetrer des milieux fissures. Une partie des essais a ete menee en laboratoire. L'etude rheologique des differents melanges a permis de tester l'influence de l'ajout de superplastifiant et/ou de fumee de silice sur la distribution granulometrique des coulis et par consequent sur leur capacite a injecter des colonnes de sable simulant un milieu fissure donne. La classe granulometrique d'un coulis, sa stabilite et sa fluidite sont apparus comme les trois facteurs principaux pour la reussite d'une injection. Un facteur de finesse a ete defini au cours de cette etude: base sur la classe granulometrique du ciment et sa stabilite, il peut entrer dans la formulation theorique du debit d'injection avant application sur chantier. La deuxieme et derniere partie de l'etude presente les resultats de deux projets de recherche sur l'injection realises sur chantier. L'injection de dalles de beton fissurees a permis le suivi de l'evolution des pressions avec la distance au point d'injection. L'injection de murs de maconnerie a caractere historique a montre l'importance de la definition de criteres de performance des coulis a utiliser pour traiter un milieu donne et pour un objectif donne. Plusieurs melanges peuvent ainsi etre predefinis et mis a disposition sur le chantier. La complementarite des ciments traditionnels et des ciments microfins devient alors un atout important. Le choix d'utilisation de ces melanges est fonction du terrain rencontre. En conclusion, cette recherche etablit une methodologie pour la selection des coulis a base de ciment et des pressions d'injection en fonction de l'ouverture des fissures ou joints de construction.

  6. ECOLE DOCTORALE Savoirs scientifiques : pistmologie, histoire des

    E-print Network

    Paris-Sud XI, Université de

    1 ECOLE DOCTORALE Savoirs scientifiques : épistémologie, histoire des sciences, didactique des-DIDEROT, PARIS 7 & DOCTEUR DE L'UNIVERSITE VIRTUELLE DE TUNIS Spécialité : Didactique des mathématiques Présentée'enseignement sur les possibilités d'apprentissage des étudiants Cas des notions ensemblistes fonctionnelles dans la

  7. EVALUATION DES INTERFACES UTILISATEUR : TAXONOMIE ET RECOMMANDATIONS

    E-print Network

    Nigay, Laurence

    'Assurance Qualité se pratique à façon, en fonction des ressources et des objectifs. A chaque cas, sa méthode. Nous Méthodes candidates Résultats souhaités Figure 1 : Choix d'une méthode d'évaluation en fonction des coûts (appel à des experts pratiquant par exemple la technique structurée des ``cognitive walkthrough'' [LEWIS

  8. 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

  9. Design and synthesis of silicon-containing fatty acid amide derivatives as novel peroxisome proliferator-activated receptor (PPAR) agonists.

    PubMed

    Kajita, Daisuke; Nakamura, Masaharu; Matsumoto, Yotaro; Ishikawa, Minoru; Hashimoto, Yuichi; Fujii, Shinya

    2015-08-15

    We recently reported that diphenylsilane structure can function as a cis-stilbene mimetic. Here, we investigate whether silyl functionality can also serve as a mimetic of aliphatic cis-olefin. We designed and synthesized various silyl derivatives of oleoylethanolamide (OEA: 8), an endogenous cis-olefin-containing PPAR? agonist, and evaluated their PPAR?/?/? agonistic activity. We found that diethylsilyl derivative 20 exhibited PPAR?/? agonistic activity, and we also obtained a PPAR?-selective agonist, 32. Our results suggest that incorporation of silyl functionality is a useful option for structural development of biologically active compounds. PMID:26071639

  10. Synthetic agonists of Toll-like receptors 7, 8 and 9.

    PubMed

    Agrawal, S; Kandimalla, E R

    2007-12-01

    TLRs (Toll-like receptors) are a family of innate immune receptors that induce protective immune responses against infections. Single-stranded viral RNA and bacterial DNA containing unmethylated CpG motifs are the ligands for TLR7 and TLR8 and 9 respectively. We have carried out extensive structure-activity relationship studies of DNA- and RNA-based compounds to elucidate the impact of nucleotide motifs and structures on these TLR-mediated immune responses. These studies have led us to design novel DNA- and RNA-based compounds, which act as potent agonists of TLR9 and TLR7 and 8 respectively. These novel synthetic agonists produce different immune response profiles depending on the structures and nucleotide motifs present in them. The ability to modulate TLR-mediated immune responses with these novel DNA- and RNA-based agonists in a desired fashion may allow targeting a broad range of diseases, including cancers, asthma, allergies and infections, alone or in combination with other therapeutic agents, and their use as adjuvants with vaccines. IMO-2055, our first lead candidate, is a TLR9 agonist that is currently in clinical evaluation in oncology patients. A second candidate, IMO-2125, is also a TLR9 agonist that has been shown to induce high and sustained levels of IFN (interferon) in non-human primates and is being evaluated in HepC-infected human subjects. PMID:18031246

  11. ADRP/ADFP and Mal1 expression are increased in macrophages treated with TLR agonists.

    PubMed

    Feingold, Kenneth R; Kazemi, Mahmood R; Magra, Amy L; McDonald, Carol M; Chui, Lisa G; Shigenaga, Judy K; Patzek, Sophie M; Chan, Zoe W; Londos, Constantine; Grunfeld, Carl

    2010-03-01

    Activation of macrophages by TLR agonists enhances foam cell formation, but the underlying mechanisms are not understood. We examined the effects of TLR agonists on ADRP/ADFP, a protein associated with forming lipid droplets, and Mal1 a fatty acid-binding protein, in two mouse macrophage cell lines and human monocytes. Low doses of LPS, a TLR4 agonist increased both mRNA and protein levels of ADRP/ADFP and Mal1 in RAW 264.7 macrophages. Following pretreatment with Intralipid, fatty acids, or acetyl-LDL to increase triglyceride or cholesterol ester storage, LPS treatment still increased ADRP/ADFP and Mal1 mRNA levels. LPS also induced ADRP/ADFP and Mal1 in J774 macrophages and ADRP/ADFP in human monocytes. Zymosan, a fungal product that activates TLR2, poly-I:C, a viral mimetic that activates TLR3, and imiquimod, a TLR7 agonist, also increased ADRP/ADFP. Zymosan, but not poly-I:C or imiquimod, induced Mal1. In contrast, neither gene was induced by TNFalpha, IL-1beta, IL-6, or interferon-gamma. Thus TLR agonists induce ADRP/ADFP and Mal1, which likely contributes to macrophage triglyceride and cholesterol ester storage leading to foam cell formation. PMID:19748622

  12. Novel non-indolic melatonin receptor agonists differentially entrain endogenous melatonin rhythm and increase its amplitude.

    PubMed

    Drijfhout, W J; de Vries, J B; Homan, E J; Brons, H F; Copinga, S; Gruppen, G; Beresford, I J; Hagan, R M; Grol, C J; Westerink, B H

    1999-10-15

    In this study we have examined the ability of melatonin and four synthetic melatonin receptor agonists to entrain endogenous melatonin secretion in rats, free running in constant darkness. The circadian melatonin profile was measured by trans-pineal microdialysis, which not only reveals the time of onset and end of production (phase), but also the amplitude of the rhythm. Exogenous melatonin given at the onset of subjective darkness (clock time 12 h) was effective to entrain endogenous melatonin production. Only one agonist, 2-chloroacetamido-8-methoxytetralin (AH-017), mimicked this action. Two other agonists, 4-methoxy-2-(methylene propylamide)indan (GG-012) and N-[2-[2,3,7,8-tetrahydro-1H-furo(2, 3-g)indol-1-yl]ethyl]acetamide (GR196429), induced a phase-delay under free running conditions, possibly by increasing tau (tau) period. One agonist, 2-acetamido-8-methoxytetralin (AH-001) did not show any phase effect on the free running rhythm. Unexpectedly, all melatonin receptor agonists increased the amplitude of melatonin secretion. The amount of the increase varied from just below the level of significance (AH-001) to an approximately 2-fold increase (GG-012 and GR196429). This is in clear contrast to entrainment with melatonin, which significantly decreased the amplitude. It is hypothesized that entrainment and effects on amplitude of melatonin secretion are mediated by different mechanisms which can be differentially modulated using specific ligands. PMID:10556666

  13. 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.

  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. ?2-Adrenoceptor agonists are required for development of the asthma phenotype in a murine model.

    PubMed

    Thanawala, Vaidehi J; Forkuo, Gloria S; Al-Sawalha, Nour; Azzegagh, Zoulikha; Nguyen, Long P; Eriksen, Jason L; Tuvim, Michael J; Lowder, Thomas W; Dickey, Burton F; Knoll, Brian J; Walker, Julia K L; Bond, Richard A

    2013-02-01

    ?(2)-Adrenoceptor (?2AR) agonists are the most effective class of bronchodilators and a mainstay of asthma management. The first potent ?2AR agonist discovered and widely used in reversing the airway constriction associated with asthma exacerbation was the endogenous activator of the ?2AR, epinephrine. In this study, we demonstrate that activation of the ?2AR by epinephrine is paradoxically required for development of the asthma phenotype. In an antigen-driven model, mice sensitized and challenged with ovalbumin showed marked elevations in three cardinal features of the asthma phenotype: inflammatory cells in their bronchoalveolar lavage fluid, mucin over production, and airway hyperresponsiveness. However, genetic depletion of epinephrine using mice lacking the enzyme to synthesize epinephrine, phenylethanolamine N-methyltransferase, or mice that had undergone pharmacological sympathectomy with reserpine to deplete epinephrine, had complete attenuation of these three cardinal features of the asthma phenotype. Furthermore, administration of the long-acting ?2AR agonist, formoterol, a drug currently used in asthma treatment, to phenylethanolamine N-methyltransferase-null mice restored the asthma phenotype. We conclude that ?2AR agonist-induced activation is needed for pathogenesis of the asthma phenotype. These findings also rule out constitutive signaling by the ?2AR as sufficient to drive the asthma phenotype, and may help explain why chronic administration of ?2AR agonists, such as formoterol, have been associated with adverse outcomes in asthma. These data further support the hypothesis that chronic asthma management may be better served by treatment with certain "?-blockers." PMID:23204390

  16. ?2-Adrenoceptor Agonists Are Required for Development of the Asthma Phenotype in a Murine Model

    PubMed Central

    Thanawala, Vaidehi J.; Forkuo, Gloria S.; Al-Sawalha, Nour; Azzegagh, Zoulikha; Nguyen, Long P.; Eriksen, Jason L.; Tuvim, Michael J.; Lowder, Thomas W.; Dickey, Burton F.; Knoll, Brian J.; Walker, Julia K. L.

    2013-01-01

    ?2-Adrenoceptor (?2AR) agonists are the most effective class of bronchodilators and a mainstay of asthma management. The first potent ?2AR agonist discovered and widely used in reversing the airway constriction associated with asthma exacerbation was the endogenous activator of the ?2AR, epinephrine. In this study, we demonstrate that activation of the ?2AR by epinephrine is paradoxically required for development of the asthma phenotype. In an antigen-driven model, mice sensitized and challenged with ovalbumin showed marked elevations in three cardinal features of the asthma phenotype: inflammatory cells in their bronchoalveolar lavage fluid, mucin over production, and airway hyperresponsiveness. However, genetic depletion of epinephrine using mice lacking the enzyme to synthesize epinephrine, phenylethanolamine N-methyltransferase, or mice that had undergone pharmacological sympathectomy with reserpine to deplete epinephrine, had complete attenuation of these three cardinal features of the asthma phenotype. Furthermore, administration of the long-acting ?2AR agonist, formoterol, a drug currently used in asthma treatment, to phenylethanolamine N-methyltransferase–null mice restored the asthma phenotype. We conclude that ?2AR agonist–induced activation is needed for pathogenesis of the asthma phenotype. These findings also rule out constitutive signaling by the ?2AR as sufficient to drive the asthma phenotype, and may help explain why chronic administration of ?2AR agonists, such as formoterol, have been associated with adverse outcomes in asthma. These data further support the hypothesis that chronic asthma management may be better served by treatment with certain “?-blockers.” PMID:23204390

  17. Action of kappa and Delta opioid agonists on premotor cardiac vagal neurons in the nucleus ambiguus.

    PubMed

    Wang, X; Dergacheva, O; Griffioen, K J S; Huang, Z-G; Evans, C; Gold, A; Bouairi, E; Mendelowitz, D

    2004-01-01

    Both enkephalin and dynorphin containing fibers are in close proximity to neurons in the nucleus ambiguus, including cardiac vagal neurons. Microinjection of Delta and kappa agonists into the nucleus ambiguus have been shown to evoke decreases in heart rate. Yet little is known about the mechanisms by which Delta and kappa opioid receptors alter the activity of cardiac vagal neurons. This study tests whether kappa and Delta opioid agonists can alter the activity of cardiac vagal neurons by modulating likely opioid targets including voltage gated calcium currents, and both glycinergic and GABA) neurotransmission to cardiac vagal neurons. Cardiac vagal neurons were identified in vitro by a fluorescent tracer and studied using patch clamp techniques. Neither the kappa agonist spiradoline or the Delta agonist [D-Pen(2), D-Pen(5)]enkephalin (DPDPE) modulated the voltage gated calcium currents in cardiac vagal neurons. DPDPE also did not alter either glycinergic or GABAergic synaptic neurotransmission. Spiradoline did not change GABAergic synaptic inputs, but did significantly inhibit glycinergic synaptic inputs to cardiac vagal neurons. At a concentration of 1 microM, spiradoline inhibited the amplitude of glycinergic events, and at a concentration of 5 microM, spiradoline inhibited both glycinergic amplitude and frequency. Spiradoline also inhibited both the amplitude and frequency of glycinergic miniature inhibitory post-synaptic currents, indicating kappa agonists likely act at both presynaptic and postsynaptic sites to inhibit glycinergic neurotransmission to cardiac vagal neurons. PMID:15489045

  18. Action of agonists and antagonists at muscarinic receptors present on ileum and atria in vitro.

    PubMed Central

    Clague, R. U.; Eglen, R. M.; Strachan, A. C.; Whiting, R. L.

    1985-01-01

    The action of 'selective' agonists and antagonists at muscarinic receptors mediating ileal contractions, and the rate and force of atrial contractions has been assessed. The effect of nicotinic receptor stimulation, catecholamine release and acetylcholinesterase (AChE) action on muscarinic activity has also been assessed. The nicotinic actions of carbachol did not affect its agonist potency nor the antagonist affinity data obtained when this agonist was used in atrial and ileal preparations. Antagonist data indicated that muscarinic receptors mediating the rate and force of atrial contractions did not differ. Differences in agonist potencies at these two muscarinic receptors were attributable to either differences in intrinsic efficacy or susceptibility to the action of acetylcholinesterase. The small differences in agonist potency observed between atrial and ileal muscarinic receptors were considered not sufficient to indicate receptor heterogeneity. The pirenzepine affinity data indicated that all three receptors are of the M2 type. Affinity data using secoverine and 4-diphenyl-acetoxy-N-methyl piperidine methiodide indicated that ileal and atrial muscarinic receptors differ. Data obtained using gallamine, pancuronium and stercuronium cannot be regarded as indicative of receptor affinity since the antagonism is not competitive; it did nonetheless corroborate the conclusion that ileal and atrial muscarinic receptors are different. PMID:3876860

  19. 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

  20. 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.

  1. Inhibitory effects of sigma-2 receptor agonists on T lymphocyte activation.

    PubMed

    Iñiguez, Miguel A; Punzón, Carmen; Nieto, Raquel; Burgueño, Javier; Vela, José M; Fresno, Manuel

    2013-01-01

    Sigma (?) receptor ligands are essentially known for their effects on the nervous system although recent studies have shown their potential effects modulating some other pathophysiological processes as cell proliferation, cancer, and the immune response. Here, we have analyzed the actions of ?-1 and ?-2 receptors ligands on T cell activation. Our results show that treatment of Jurkat T cells with ?-2 agonists decreased the induction of the expression of Interleukin (IL)-2, Tumor necrosis factor (TNF)-?, and Cyclooxygenase (COX)-2 by activated T cells in a dose-dependent manner. These effects take place at the transcriptional level since ?-2 agonists BD-737 and CB-184 diminished the activity of the promoters of those genes. Those immunosuppressive effects could be attributable to interference with transcription factor activation. Induced transcription mediated by Nuclear factor (NF)-?B or Nuclear Factor of Activated T cells (NFAT) was inhibited by ?-2 agonists. These effects seem to be specific for ?-2 agonists as no significant effects on T cell activation by ?-1 ligands PRE-084 and BD-1063 were found. Our results provide new insights into the immunomodulatory actions of ? ligands and describe a new property of ?-2 agonists, through inhibition of activation of transcription factors as NFAT by which these compounds are regulating gene expression. This may have important consequences on the possible therapeutic use of those compounds. PMID:23494519

  2. Gonadotropin-releasing hormone: an update review of the antagonists versus agonists.

    PubMed

    Van Poppel, Hein; Klotz, Laurence

    2012-07-01

    Gonadotropin-releasing hormone agonists and antagonists provide androgen-deprivation therapy for prostate cancer. Unlike agonists, gonadotropin-releasing hormone antagonists have a direct mode of action to block pituitary gonadotropin-releasing hormone receptors. There are two licensed gonadotropin-releasing hormone antagonists, degarelix and abarelix. Of these, degarelix is the more extensively studied and has been documented to be more effective than the well-established, first-line agonist, leuprolide, in terms of substantially faster onset of castration, faster suppression of prostate-specific antigen, no risk for testosterone surge or clinical flare, and improved prostate-specific antigen progression-free survival, suggesting a delay in castration resistance. Other than minor injection-site reactions, degarelix is generally well tolerated, without systemic allergic reactions and with most adverse events consistent with androgen suppression or the underlying condition. In conclusion, degarelix provides a rational, first-line androgen-deprivation therapy suitable for the treatment of prostate cancer, with faster onset of castration than with agonists, and no testosterone surge. Furthermore, data suggest that degarelix improves disease control compared with leuprolide, and might delay the onset of castration-resistant disease. In view of these clinical benefits and the lack of need for concomitant anti-androgen treatment, gonadotropin-releasing hormone antagonists might replace gonadotropin-releasing hormone agonists as first-line androgen-deprivation therapy in the future. PMID:22416801

  3. Behavioral effects of the novel potent cannabinoid CB1 agonist AM 4054.

    PubMed

    McLaughlin, Peter J; Thakur, Ganesh A; Vemuri, V Kiran; McClure, Evan D; Brown, Cara M; Winston, Keisha M; Wood, Jodianne T; Makriyannis, Alexandros; Salamone, John D

    2013-08-01

    Due to the ubiquity of the CB1 cannabinoid receptor throughout the nervous system, as well as the many potential therapeutic uses of CB1 agonist-based interventions, it is desirable to synthesize novel probes of the CB1 receptor. Here, the acute behavioral effects of systemic (i.p.) administration of the putative novel CB1 full agonist AM 4054 were tested in rats. In Experiment 1, a dose range (0.15625-1.25 mg/kg) of AM 4054 produced effects consistent with CB1 agonism in the cannabinoid tetrad of tasks in rats, including induction of analgesia, catalepsy, hypothermia, and locomotor suppression. These effects were reversed with the CB1-selective inverse agonist AM 251 in Experiment 2, indicating that AM 4054 produced CB1 receptor-mediated effects. Analysis of open-field activity indicated that the reduction in locomotion is more consistent with general motor slowing than anxiogenesis. AM 4054 (0.0625-0.5 mg/kg) also dose-dependently reduced fixed-ratio 5 (FR5) operant responding for food in Experiment 3, and microanalysis of the timing and rate of lever pressing indicated a pattern of suppression similar to other CB1 agonists. Minimum doses of AM 4054 (0.125-0.3125 mg/kg) required to produce significant effects in these behavioral assays were lower than those of many CB1 agonists. It is likely that AM 4054 is a potent pharmacological tool for assessment of cannabinoid receptor function. PMID:23603029

  4. Diffusion model in ion channel gating. Extension to agonist-activated ion channels.

    PubMed Central

    Oswald, R E; Millhauser, G L; Carter, A A

    1991-01-01

    Previously, we described a model which treats ion channel gating as a discrete diffusion problem. In the case of agonist-activated channels at high agonist concentration, the model predicts that the closed lifetime probability density function from single channel recording approximates a power law with an exponent of -3/2 (Millhauser, G. L., E. E. Salpeter, and R. E. Oswald. 1988a. Proc. Natl. Acad. Sci. USA. 85: 1503-1507). This prediction is consistent with distributions derived from a number of ligand-gated channels at high agonist concentration (Millhauser, G. L., E. E. Salpeter, and R. E. Oswald. 1988b. Biophys. J. 54: 1165-1168.) but does not describe the behavior of ion channels at low activator concentrations. We examine here an extension of this model to include an agonist binding step. This extended model is consistent with the closed time distributions generated from the BC3H-1 nicotinic acetylcholine receptor for agonist concentrations varying over three orders of magnitude. PMID:1714303

  5. 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.

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

    E-print Network

    Boyer, Edmond

    , LTH, ACTH) et les distinguant du groupe des cellules à contenu glycoprotidique (FSH, LH, TSH). b) Bleu distribution très hétérogène des cellules TSH, à l'abondance des cellules ACTH, ces trois dernières catégories

  7. DEVELOPMENT AND IN VITRO CHARACTERIZATION OF A NOVEL BIFUNCTIONAL MU-AGONIST/DELTA-ANTAGONIST OPIOID TETRAPEPTIDE

    PubMed Central

    Purington, Lauren C.; Sobczyk-Kojiro, Katarzyna; Pogozheva, Irina D.; Traynor, John R.; Mosberg, Henry I.

    2011-01-01

    The development of tolerance to and dependence on opioid analgesics greatly reduces their long-term usefulness. Previous studies have demonstrated that co-administration of a mu opioid receptor (MOR) agonist and delta opioid receptor (DOR) antagonist can decrease MOR agonist induced tolerance and dependence development after chronic exposure. Clinically, a single ligand displaying multiple efficacies (e.g. MOR agonism concurrently with DOR antagonism) would be of increased value over two drugs administered simultaneously. Guided by modeling of receptor-ligand complexes we have developed a series of potent non-selective opioid tetrapeptides that have differing efficacy at MOR and DOR. In particular, our lead peptide (KSK-103) binds with equal affinity to MOR and DOR but acts as a MOR agonist with similar efficacy but greater potency than morphine and a DOR antagonist in cellular assays measuring both G protein stimulation and adenylyl cyclase inhibition. PMID:21958158

  8. Basal phosphorylation of mu opioid receptor is agonist modulated and Ca2+-dependent.

    PubMed

    Wang, Z; Arden, J; Sadée, W

    1996-05-27

    The mu opioid receptor was shown to be phosphorylated at a basal rate in the absence of agonist, measured in permeabilized HEK293 cells transfected with an epitope tagged mu receptor (EE-mu) [Arden, J., Segredo, V., Wang, Z., Lameh, J. and Sadee, W. (1995) J. Neurochem. 65, 1636-1645]. In the present study, basal phosphorylation was found to be Ca2+ dependent; however, several inhibitors of protein kinase C and Ca2+-calmodulin dependent kinases failed to affect basal mu receptor phosphorylation. Thus, the basal mu receptor phosphorylating activity differed from the main kinases involved in receptor regulation. The general kinase inhibitor H7 (100 microM) suppressed basal mu receptor phosphorylation. Pretreatment with the agonist morphine, followed by drug removal, resulted in a sustained increase of basal mu receptor phosphorylation. The gradual agonist dependent modulation of basal mu receptor phosphorylation suggests a novel regulatory mechanism which may play a role in narcotic tolerance and dependence. PMID:8654566

  9. PPAR? AGONISTS AS THERAPEUTICS FOR THE TREATMENT OF ALZHEIMER’S DISEASE

    PubMed Central

    Landreth, Gary; Jiang, Qingguang; Mandrekar, Shweta; Heneka, Michael

    2008-01-01

    Alzheimer’s Disease is characterized by the deposition of ?-amyloid within the brain parenchyma and is accompanied by the impairment of neuronal metabolism and function, leading to extensive neuronal loss. The disease involves the perturbation of synaptic function, energy and lipid metabolism. The development of amyloid plaques results in the induction of microglial-mediated inflammatory response. The nuclear receptor PPAR? is a ligand-activated transcription factor whose biological actions are to regulate glucose and lipid metabolism and suppress inflammatory gene expression. Thus, agonists of this receptor represent an attractive therapeutic target for AD. There is now an extensive body of evidence that has demonstrated the efficacy of PPAR? agonists in ameliorating disease–related pathology and improved learning and memory in animal models of AD. Recent clinical trials of the PPAR? agonist rosiglitazone have shown significant improvement in memory and cognition in AD patients. Thus, PPAR? represents an important new therapeutic target in treating AD. PMID:18625459

  10. Anticancer Role of PPAR? Agonists in Hematological Malignancies Found in the Vasculature, Marrow, and Eyes

    PubMed Central

    Simpson-Haidaris, P. J.; Pollock, S. J.; Ramon, S.; Guo, N.; Woeller, C. F.; Feldon, S. E.; Phipps, R. P.

    2010-01-01

    The use of targeted cancer therapies in combination with conventional chemotherapeutic agents and/or radiation treatment has increased overall survival of cancer patients. However, longer survival is accompanied by increased incidence of comorbidities due, in part, to drug side effects and toxicities. It is well accepted that inflammation and tumorigenesis are linked. Because peroxisome proliferator-activated receptor (PPAR)-? agonists are potent mediators of anti-inflammatory responses, it was a logical extension to examine the role of PPAR? agonists in the treatment and prevention of cancer. This paper has two objectives: first to highlight the potential uses for PPAR? agonists in anticancer therapy with special emphasis on their role when used as adjuvant or combined therapy in the treatment of hematological malignancies found in the vasculature, marrow, and eyes, and second, to review the potential role PPAR? and/or its ligands may have in modulating cancer-associated angiogenesis and tumor-stromal microenvironment crosstalk in bone marrow. PMID:20204067

  11. Discovery of novel indazole derivatives as dual angiotensin II antagonists and partial PPAR? agonists.

    PubMed

    Lamotte, Yann; Faucher, Nicolas; Sançon, Julien; Pineau, Olivier; Sautet, Stéphane; Fouchet, Marie-Hélène; Beneton, Véronique; Tousaint, Jean-Jacques; Saintillan, Yannick; Ancellin, Nicolas; Nicodeme, Edwige; Grillot, Didier; Martres, Paul

    2014-02-15

    Identification of indazole derivatives acting as dual angiotensin II type 1 (AT1) receptor antagonists and partial peroxisome proliferator-activated receptor-? (PPAR?) agonists is described. Starting from Telmisartan, we previously described that indole derivatives were very potent partial PPAR? agonists with loss of AT1 receptor antagonist activity. Design, synthesis and evaluation of new central scaffolds led us to the discovery of pyrrazolopyridine then indazole derivatives provided novel series possessing the desired dual activity. Among the new compounds, 38 was identified as a potent AT1 receptor antagonist (IC50=0.006 ?M) and partial PPAR? agonist (EC50=0.25 ?M, 40% max) with good oral bioavailability in rat. The dual pharmacology of compound 38 was demonstrated in two preclinical models of hypertension (SHR) and insulin resistance (Zucker fa/fa rat). PMID:24462665

  12. Total synthesis and dual PPAR?/? agonist effects of amorphastilbol and its synthetic derivatives.

    PubMed

    Kim, Taejung; Lee, Woojung; Jeong, Kyu Hyuk; Song, Jung Ho; Park, Soon-Hye; Choi, Pilju; Kim, Su-Nam; Lee, Seokjoon; Ham, Jungyeob

    2012-06-15

    Amorphastilbol (APH-1), isolated from a Robinia pseudoacacia var. umbraculifer [corrected] seed extract, is a biologically interesting natural trans-stilbene compound with dual peroxisome proliferator-activated receptor (PPAR) ?/? agonist activity. After total synthesis of APH-1 and its derivatives by Pd-catalyzed Suzuki-Miyaura cross-coupling of a common (E)-styryl bromide intermediate and various aromatic trifluoroborate compounds, we biologically evaluated APH-2-APH-12 for PPAR agonist activity. APH-4 and APH-11 were effective PPAR?/? transcriptional activators, compared with APH-1. Therefore, we suggest that APH-4 and APH-11 are novel dual PPAR?/? agonists and are potentially useful for treating type 2 diabetes by enhancing glucose and lipid metabolism. PMID:22579420

  13. 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.

  14. 2-Aminoalkyl nicotinamide derivatives as pure inverse agonists of the ghrelin receptor.

    PubMed

    Takahashi, Bitoku; Funami, Hideaki; Iwaki, Takehiko; Maruoka, Hiroshi; Nagahira, Asako; Koyama, Makoto; Kamiide, Yoshiyuki; Matsuo, Tsuyoshi; Muto, Tsuyoshi; Annoura, Hirokazu

    2015-07-01

    New inverse agonists of the ghrelin receptor (ghrelinR) were obtained through high-throughput screening and subsequent structural modification of 2-aminoalkyl nicotinamide derivatives. The key structural feature to improve in vitro activity was the introduction of a diazabicyclo ring at the 5-position of the pyridine ring. The final product showed potent inverse agonist activity and, despite its low brain permeability, reduced food intake in both normal and obese mice. These results implied that peripheral ghrelinR activity is important for appetite control and that a peripheral ghrelinR inverse agonist could be an anti-obesity drug with reduced risk of central nervous system (CNS)-related side effects. PMID:25981690

  15. PPAR{alpha} agonists up-regulate organic cation transporters in rat liver cells

    SciTech Connect

    Luci, Sebastian [Institute of Agricultural and Nutritional Sciences, Martin-Luther-University Halle-Wittenberg, Emil-Abderhalden-Strasse 26, D-06108 Halle (Germany); Geissler, Stefanie [Institute of Agricultural and Nutritional Sciences, Martin-Luther-University Halle-Wittenberg, Emil-Abderhalden-Strasse 26, D-06108 Halle (Germany); Koenig, Bettina [Institute of Agricultural and Nutritional Sciences, Martin-Luther-University Halle-Wittenberg, Emil-Abderhalden-Strasse 26, D-06108 Halle (Germany); Koch, Alexander [Institute of Agricultural and Nutritional Sciences, Martin-Luther-University Halle-Wittenberg, Emil-Abderhalden-Strasse 26, D-06108 Halle (Germany); Stangl, Gabriele I. [Institute of Agricultural and Nutritional Sciences, Martin-Luther-University Halle-Wittenberg, Emil-Abderhalden-Strasse 26, D-06108 Halle (Germany); Hirche, Frank [Institute of Agricultural and Nutritional Sciences, Martin-Luther-University Halle-Wittenberg, Emil-Abderhalden-Strasse 26, D-06108 Halle (Germany); Eder, Klaus [Institute of Agricultural and Nutritional Sciences, Martin-Luther-University Halle-Wittenberg, Emil-Abderhalden-Strasse 26, D-06108 Halle (Germany)]. E-mail: klaus.eder@landw.uni-halle.de

    2006-11-24

    It has been shown that clofibrate treatment increases the carnitine concentration in the liver of rats. However, the molecular mechanism is still unknown. In this study, we observed for the first time that treatment of rats with the peroxisome proliferator activated receptor (PPAR)-{alpha} agonist clofibrate increases hepatic mRNA concentrations of organic cation transporters (OCTNs)-1 and -2 which act as transporters of carnitine into the cell. In rat hepatoma (Fao) cells, treatment with WY-14,643 also increased the mRNA concentration of OCTN-2. mRNA concentrations of enzymes involved in carnitine biosynthesis were not altered by treatment with the PPAR{alpha} agonists in livers of rats and in Fao cells. We conclude that PPAR{alpha} agonists increase carnitine concentrations in livers of rats and cells by an increased uptake of carnitine into the cell but not by an increased carnitine biosynthesis.

  16. Ghrelin agonist does not foster insulin resistance but improves cognition in an Alzheimer's disease mouse model.

    PubMed

    Kunath, Nicolas; van Groen, Thomas; Allison, David B; Kumar, Ashish; Dozier-Sharpe, Monique; Kadish, Inga

    2015-01-01

    The orexigenic hormone ghrelin, a potential antagonist of the insulin system, ensures sufficient serum glucose in times of fasting. In the race for new therapeutics for diabetes, one focus of study has been antagonizing the ghrelin system in order to improve glucose tolerance. We provide evidence for a differential role of a ghrelin agonist on glucose homeostasis in an Alzheimer's disease mouse model fed a high-glycemic index diet as a constant challenge for glucose homeostasis. The ghrelin agonist impaired glucose tolerance immediately after administration but not in the long term. At the same time, the ghrelin agonist improved spatial learning in the mice, raised their activity levels, and reduced their body weight and fat mass. Immunoassay results showed a beneficial impact of long-term treatment on insulin signaling pathways in hippocampal tissue. The present results suggest that ghrelin might improve cognition in Alzheimer's disease via a central nervous system mechanism involving insulin signaling. PMID:26090621

  17. Les mtiers des langues trangres

    E-print Network

    Jeanjean, Louis

    individuel, en groupe, en face à face ou à distance, par téléphone ou en ligne. Il doit être en mesure de s'adapter à des publics sans cesse renouvelé, il faut alors faire preuve de capacités de communication et d'adaptation enseigner les termes de la vie quotidienne à des migrants ou un français plus technique s'il s'adresse à des

  18. V-Durabilit des cramiques et des verres Ce chapitre se propose de traiter de la tenue long terme des cramiques et des verres.

    E-print Network

    V- Durabilité des céramiques et des verres Ce chapitre se propose de traiter de la tenue à long terme des céramiques et des verres. A partir d'exemples présentés dans une première partie, une démarche dans une démarche de conception fiabiliste de composants contenant des verres ou/et des céramiques. V.1

  19. Potentiation of cytotoxic chemotherapy by growth hormone-releasing hormone agonists

    PubMed Central

    Jaszberenyi, Miklos; Rick, Ferenc G.; Popovics, Petra; Block, Norman L.; Zarandi, Marta; Cai, Ren-Zhi; Vidaurre, Irving; Szalontay, Luca; Jayakumar, Arumugam R.; Schally, Andrew V.

    2014-01-01

    The dismal prognosis of malignant brain tumors drives the development of new treatment modalities. In view of the multiple activities of growth hormone-releasing hormone (GHRH), we hypothesized that pretreatment with a GHRH agonist, JI-34, might increase the susceptibility of U-87 MG glioblastoma multiforme (GBM) cells to subsequent treatment with the cytotoxic drug, doxorubicin (DOX). This concept was corroborated by our findings, in vivo, showing that the combination of the GHRH agonist, JI-34, and DOX inhibited the growth of GBM tumors, transplanted into nude mice, more than DOX alone. In vitro, the pretreatment of GBM cells with JI-34 potentiated inhibitory effects of DOX on cell proliferation, diminished cell size and viability, and promoted apoptotic processes, as shown by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide proliferation assay, ApoLive-Glo multiplex assay, and cell volumetric assay. Proteomic studies further revealed that the pretreatment with GHRH agonist evoked differentiation decreasing the expression of the neuroectodermal stem cell antigen, nestin, and up-regulating the glial maturation marker, GFAP. The GHRH agonist also reduced the release of humoral regulators of glial growth, such as FGF basic and TGF?. Proteomic and gene-expression (RT-PCR) studies confirmed the strong proapoptotic activity (increase in p53, decrease in v-myc and Bcl-2) and anti-invasive potential (decrease in integrin ?3) of the combination of GHRH agonist and DOX. These findings indicate that the GHRH agonists can potentiate the anticancer activity of the traditional chemotherapeutic drug, DOX, by multiple mechanisms including the induction of differentiation of cancer cells. PMID:24379381

  20. Time-Dependent Protection of CB2 Receptor Agonist in Stroke

    PubMed Central

    Yu, Seong-Jin; Reiner, David; Shen, Hui; Wu, Kou-Jen; Liu, Qing-Rong; Wang, Yun

    2015-01-01

    Recent studies have indicated that type 2 cannabinoid receptor (CB2R) agonists reduce neurodegeneration after brain injury through anti-inflammatory activity. The purpose of this study was to examine the time-dependent interaction of CB2R and inflammation in stroke brain. Adult male rats were subjected to right middle cerebral artery occlusion (MCAo). CB2R mRNA expression was significantly elevated >20 fold on day 2, peaked >40-fold on day 5, and normalized on day 10 post-stroke. Inflammatory markers IBA1 and TLR4 were significantly upregulated 15 fold until day 5 after MCAo. Because of the delayed upregulation of CB2R and IBA1, we next treated animals daily with CB2R agonist AM1241 or anti-inflammatory PPAR-? agonist pioglitazone from 2 to 5 days after MCAo. Delayed treatment with pioglitazone significantly reduced abnormal neurological scores and body asymmetry as well as brain infarction in stroke animals. No behavioral improvement or reduction in brain infarction was found in animals receiving AM1241. Pioglitazone, but not AM1241, significantly reduced IBA1 expression in the stroke cortex, suggesting that delayed treatment with AM1241 failed to alter ischemia-mediated IBA-1 upregulation. In contrast, pretreatment with AM1241 significantly reduced brain infarction and neurological deficits. In conclusion, our data support a time-dependent neuroprotection of CB2 agonist in an animal model of stroke. Delayed post- treatment with PPAR-? agonist induced behavioral recovery and microglial suppression; early treatment with CB2R agonist suppressed neurodegeneration in stroke animals. PMID:26186541

  1. 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

  2. ?2-Adrenergic receptor agonist administration promotes counter-regulatory responses and recovery from hypoglycaemia in rats

    PubMed Central

    Szepietowska, Barbara; Zhu, Wanling; Sherwin, Robert S.

    2013-01-01

    Aims/hypothesis We have previously reported that local activation of ?2-adrenergic receptors (B2ARs) in the ventromedial hypothalamus (VMH) enhances hypoglycaemic counter-regulation. This study examines whether peripheral delivery of a selective B2AR agonist could also promote counter-regulatory responses and thereby has potential therapeutic value to limit hypoglycaemia risk. Methods Conscious male Sprague–Dawley rats received an intra-arterial injection of the B2AR specific agonist, formoterol, or a control solution either before a hyperinsulinaemic–hypoglycaemic clamp study or immediately before recovery from insulin-induced hypoglycaemia. In addition, the capacity of a VMH-targeted microinjection of a B2AR antagonist to limit the anti-insulin effect of the B2AR agonist was assessed. Results Systemic delivery of B2AR agonist markedly reduced the exogenous glucose infusion rate (GIR) required during the hypoglycaemic clamp study. This effect was mediated by blockade of insulin’s inhibitory effect on endogenous glucose production. Local blockade of B2ARs within the VMH using a specific antagonist partially diminished the effect of systemic activation of B2ARs during hypoglycaemia at least in part by diminishing the adrenaline (epinephrine) response to hypoglycaemia. Peripheral B2AR agonist injection also enhanced glucose recovery from insulin-induced hypoglycaemia. Conclusions/interpretation Systemic B2AR agonist administration acts to limit insulin-induced hypoglycaemia by offsetting insulin’s inhibitory effect on hepatic glucose production. This effect appears to be predominately mediated via a direct effect on liver B2ARs, but a small stimulatory effect on B2ARs within the VMH cannot be excluded. Our data suggest that formoterol may have therapeutic value to limit the risk of hypoglycaemia in patients with diabetes. PMID:23933834

  3. Identification of an extracellular segment of the oxytocin receptor providing agonist-specific binding epitopes.

    PubMed Central

    Hawtin, S R; Howard, H C; Wheatley, M

    2001-01-01

    The effects of the peptide hormone oxytocin are mediated by oxytocin receptors (OTRs) expressed by the target tissue. The OTR is a member of the large family of G-protein-coupled receptors. Defining differences between the interaction of agonists and antagonists with the OTR at the molecular level is of fundamental importance, and is addressed in this study. Using truncated and chimaeric receptor constructs, we establish that a small 12-residue segment in the distal portion of the N-terminus of the human OTR provides important epitopes which are required for agonist binding. In contrast, this segment does not contribute to the binding site for antagonists, whether peptide or non-peptide. It does, however, have a role in agonist-induced OTR signalling. Oxytocin is also an agonist at the vasopressin V(1a) receptor (V(1a)R). A chimaeric receptor (V(1a)R(N)-OTR) was engineered in which the N-terminus of the OTR was substituted by the corresponding, but unrelated, sequence from the N-terminus of the V(1a)R. We show that the V(1a)R N-terminus present in V(1a)R(N)-OTR fully restored both agonist binding and intracellular signalling to a dysfunctional truncated OTR construct. The N-terminal segment does not, however, contribute to receptor-selective agonism between the OTR and the V(1a)R. Our data establish a key role for the distal N-terminus of the OTR in providing agonist-specific binding epitopes. PMID:11171127

  4. 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

  5. Pungency of TRPV1 agonists is directly correlated with kinetics of receptor activation and lipophilicity.

    PubMed

    Ursu, Daniel; Knopp, Kelly; Beattie, Ruth E; Liu, Bin; Sher, Emanuele

    2010-09-01

    TRPV1 (transient receptor potential vanilloid 1) is a ligand-gated ion channel expressed predominantly in nociceptive primary afferents that plays a key role in pain processing. In vivo activation of TRPV1 receptors by natural agonists like capsaicin is associated with a sharp and burning pain, frequently described as pungency. To elucidate the mechanisms underlying pungency we investigated a series of TRPV1 agonists that included both pungent and non-pungent compounds covering a large range of potencies. Pungency of capsaicin, piperine, arvanil, olvanil, RTX (resiniferatoxin) and SDZ-249665 was evaluated in vivo, by determining the increase in the number of eye wipes caused by direct instillation of agonist solutions into the eye. Agonist-induced calcium fluxes were recorded using the FLIPR technique in a recombinant, TRPV1-expressing cell line. Current-clamp recordings were performed in rat DRG (dorsal root ganglia) neurons in order to assess the consequences of TRPV1 activation on neuronal excitability. Using the eye wipe assay the following rank of pungency was obtained: capsaicin>piperine>RTX>arvanil>olvanil>SDZ-249665. We found a strong correlation between kinetics of calcium flux, pungency and lipophilicity of TRPV1 agonists. Current-clamp recordings confirmed that the rate of receptor activation translates in the ability of agonists to generate action potentials in sensory neurons. We have demonstrated that the lipophilicity of the compounds is directly related to the kinetics of TRPV1 activation and that the latter influences their ability to trigger action potentials in sensory neurons and, ultimately, pungency. PMID:20576527

  6. Differential gene expression in mouse primary hepatocytes exposed to the peroxisome proliferator-activated receptor ? agonists

    PubMed Central

    Guo, Lei; Fang, Hong; Collins, Jim; Fan, Xiao-hui; Dial, Stacey; Wong, Alex; Mehta, Kshama; Blann, Ernice; Shi, Leming; Tong, Weida; Dragan, Yvonne P

    2006-01-01

    Background Fibrates are a unique hypolipidemic drugs that lower plasma triglyceride and cholesterol levels through their action as peroxisome proliferator-activated receptor alpha (PPAR?) agonists. The activation of PPAR? leads to a cascade of events that result in the pharmacological (hypolipidemic) and adverse (carcinogenic) effects in rodent liver. Results To understand the molecular mechanisms responsible for the pleiotropic effects of PPAR? agonists, we treated mouse primary hepatocytes with three PPAR? agonists (bezafibrate, fenofibrate, and WY-14,643) at multiple concentrations (0, 10, 30, and 100 ?M) for 24 hours. When primary hepatocytes were exposed to these agents, transactivation of PPAR? was elevated as measured by luciferase assay. Global gene expression profiles in response to PPAR? agonists were obtained by microarray analysis. Among differentially expressed genes (DEGs), there were 4, 8, and 21 genes commonly regulated by bezafibrate, fenofibrate, and WY-14,643 treatments across 3 doses, respectively, in a dose-dependent manner. Treatments with 100 ?M of bezafibrate, fenofibrate, and WY-14,643 resulted in 151, 149, and 145 genes altered, respectively. Among them, 121 genes were commonly regulated by at least two drugs. Many genes are involved in fatty acid metabolism including oxidative reaction. Some of the gene changes were associated with production of reactive oxygen species, cell proliferation of peroxisomes, and hepatic disorders. In addition, 11 genes related to the development of liver cancer were observed. Conclusion Our results suggest that treatment of PPAR? agonists results in the production of oxidative stress and increased peroxisome proliferation, thus providing a better understanding of mechanisms underlying PPAR? agonist-induced hepatic disorders and hepatocarcinomas. PMID:17118139

  7. Optimizing gonadotropin-releasing hormone agonist therapy in women with endometriosis.

    PubMed

    Olive, David L

    2004-01-01

    Endometriosis is a highly prevalent disease among women of reproductive age. While many treatments are available, one of the most widely utilized is treatment with gonadotropin-releasing hormone (GnRH) agonists. These agents work by producing a profound suppression of gonadotropin secretion by the pituitary, resulting in a hypoestrogenic state and subsequent diminution of endometriosis lesions. The GnRH agonists on the market have been shown to work quite well in reducing all pain symptoms associated with endometriosis, including dysmenorrhea, dyspareunia, and noncyclic pelvic pain. However, there is no evidence to suggest that this treatment is of value in endometriosis-associated infertility. Conflicting data exist regarding the role of GnRH agonists in the treatment of endometriomas, but the bulk of the evidence suggests a low degree of efficacy. GnRH agonists are often initiated with the onset of menses, but a more rapid response is observed with mid-luteal administration. A limit of 6 months per treatment course is required due to loss of bone mineral density during therapy, but this can be extended via the addition of 'add-back' therapy. Such adjunctive regimens demonstrated to maintain efficacy and reduce adverse effects include progestogen alone or a low-dose combination of estrogen and progestogen. Retreatment with these drugs is supported by limited data. The use of GnRH agonists as surgical adjuncts has been studied by several investigators. Their use preoperatively has not been shown to be of value. Similarly, 3 months of postoperative administration has failed to enhance treatment. However, 6 months of postoperative GnRH agonists appear to improve the duration of relief of pain symptoms. Future studies will need to focus on the role of these agents when used for repeated courses, in young women, and in conjunction with assisted reproduction. PMID:15743104

  8. Attenuation of HIV-1 replication in macrophages by cannabinoid receptor 2 agonists

    PubMed Central

    Ramirez, Servio H.; Reichenbach, Nancy L.; Fan, Shongshan; Rom, Slava; Merkel, Steven F.; Wang, Xu; Ho, Wen-zhe; Persidsky, Yuri

    2013-01-01

    Infiltrating monocytes and macrophages play a crucial role in the progression of HIV-1 infection in the CNS. Previous studies showed that activation of the CB2 can attenuate inflammatory responses and affect HIV-1 infectivity in T cells and microglia. Here, we report that CB2 agonists can also act as immunomodulators on HIV-1-infected macrophages. First, our findings indicated the presence of elevated levels of CB2 expression on monocytes/macrophages in perivascular cuffs of postmortem HIV-1 encephalitic cases. In vitro analysis by FACS of primary human monocytes revealed a step-wise increase in CB2 surface expression in monocytes, MDMs, and HIV-1-infected MDMs. We next tested the notion that up-regulation of CB2 may allow for the use of synthetic CB2 agonist to limit HIV-1 infection. Two commercially available CB2 agonists, JWH133 and GP1a, and a resorcinol-based CB2 agonist, O-1966, were evaluated. Results from measurements of HIV-1 RT activity in the culture media of 7 day-infected cells showed a significant decrease in RT activity when the CB2 agonist was present. Furthermore, CB2 activation also partially inhibited the expression of HIV-1 pol. CB2 agonists did not modulate surface expression of CXCR4 or CCR5 detected by FACS. We speculate that these findings indicate that prevention of viral entry is not a central mechanism for CB2-mediated suppression in viral replication. However, CB2 may affect the HIV-1 replication machinery. Results from a single-round infection with the pseudotyped virus revealed a marked decrease in HIV-1 LTR activation by the CB2 ligands. Together, these results indicate that CB2 may offer a means to limit HIV-1 infection in macrophages. PMID:23463725

  9. The potency of different serotonergic agonists in counteracting opioid evoked cardiorespiratory disturbances

    PubMed Central

    Dutschmann, M.; Waki, H.; Manzke, T.; Simms, A. E.; Pickering, A. E.; Richter, D. W.; Paton, J. F. R.

    2009-01-01

    Serotonin receptor (5-HTR) agonists that target 5-HT4(a)R and 5-HT1AR can reverse ?-opioid receptor (?-OR)-evoked respiratory depression. Here, we have tested whether such rescuing by serotonin agonists also applies to the cardiovascular system. In working heart–brainstem preparations in situ, we have recorded phrenic nerve activity, thoracic sympathetic chain activity (SCA), vascular resistance and heart rate (HR) and in conscious rats, diaphragmatic electromyogram, arterial blood pressure (BP) and HR via radio-telemetry. In addition, the distribution of 5-HT4(a)R and 5-HT1AR in ponto-medullary cardiorespiratory networks was identified using histochemistry. Systemic administration of the ?-OR agonist fentanyl in situ decreased HR, vascular resistance, SCA and phrenic nerve activity. Subsequent application of the 5-HT1AR agonist 8-OH-DPAT further enhanced bradycardia, but partially compensated the decrease in vascular resistance, sympathetic activity and restored breathing. By contrast, the 5-HT4(a)R agonist RS67333 further decreased vascular resistance, HR and sympathetic activity, but partially rescued breathing. In conscious rats, administration of remifentanyl caused severe respiratory depression, a decrease in mean BP accompanied by pronounced bradyarrhythmia. 8-OH-DPAT restored breathing and prevented the bradyarrhythmia; however, BP and HR remained below baseline. In contrast, RS67333 further suppressed cardiovascular functions in vivo and only partially recovered breathing in some cases. The better recovery of ?-OR cardiorespiratory disturbance by 5-HT1AR than 5-HT4(a)R is supported by the finding that 5-HT1AR was more densely expressed in key brainstem nuclei for cardiorespiratory control compared with 5-HT4(a)R. We conclude that during treatment of severe pain, 5-HT1AR agonists may provide a useful tool to counteract opioid-mediated cardiorespiratory disturbances. PMID:19651661

  10. Chemotherapie des metastasierten Nierenzellkarzinoms

    Microsoft Academic Search

    Hans-Joachim Beck; C. Huber

    1998-01-01

    Die Lebenserwartung des Patienten mit metastasiertem Nierenzellkarzinom (NZK) ist kurz, so liegt die 5-Jahresüberlebenszeit\\u000a im Stadium IV mit Fernmetastasen unter 10% [5]. Dennoch existiert eine kleine Gruppe von Patienten, die durch günstigeren\\u000a Spontanverlauf und lange Überlebenszeiten charakterisiert ist. Desweiteren kommt es beim NZK zu immer wieder beschriebenen\\u000a Spontanremissionen [12], die jedoch in den wenigen einschlägigen Studien mehrheitlich unter 1% liegen.  

  11. Seltene Tumoren des Integuments

    Microsoft Academic Search

    U. Hofmann; A. Stein; H. Helmbach; A. Philipp; D. Schadendorf

    1999-01-01

    An der Haut manifestieren sich die hufigsten Malignome des Menschen, die epidermalen Plattenepithel- und Basalzellkarzinome,\\u000a sowie auch maligne Melanome mit steigender Inzidenz. Darber hinausgehend sind eine betrchtliche Zahl weiterer, verschiedenartigster,\\u000a jedoch vergleichsweise seltener Tumore am Integument zu beobachten. Das vor allem histologisch bunte Bild resultiert aus Gewebsanteilen\\u000a meso- und ektodermalen Ursprungs, welche in ausgesprochener Differenzierungsvielfalt die Haut und Unterhaut konstituieren.

  12. Strukturanalyse des Hämoglobin Köln

    Microsoft Academic Search

    R. W. Carrell; H. Lehmann; W. Pribilla

    1967-01-01

    Zusammenfassung Obwohl das Hb Köln zuerst in Deutschland bei einer Familie aus Köln gefunden wurde, gelang die Aufklärung der molekularen Strukturanomalie erstmalig bei einer aus Glasgow stammenden Familie, die einige deutsche Vorfahren hat. Es konnte mit verschiedenen Methoden gezeigt werden, daß Hb Köln folgende Struktur hat: a2ß2 98 Val?Met. Die in dieser Arbeit dargestellten Untersuchungen zeigen, daß die Strukturanomalie des

  13. Studies on the synthesis and opioid agonistic activities of mitragynine-related indole alkaloids: discovery of opioid agonists structurally different from other opioid ligands.

    PubMed

    Takayama, Hiromitsu; Ishikawa, Hayato; Kurihara, Mika; Kitajima, Mariko; Aimi, Norio; Ponglux, Dhavadee; Koyama, Fumi; Matsumoto, Kenjiro; Moriyama, Tomoyuki; Yamamoto, Leonard T; Watanabe, Kazuo; Murayama, Toshihiko; Horie, Syunji

    2002-04-25

    Mitragynine (1) is a major alkaloidal component in the Thai traditional medicinal herb, Mitragyna speciosa, and has been proven to exhibit analgesic activity mediated by opioid receptors. By utilizing this natural product as a lead compound, synthesis of some derivatives, evaluations of the structure-activity relationship, and surveys of the intrinsic activities and potencies on opioid receptors were performed with guinea pig ileum. The affinities of some compounds for mu-, delta-, and kappa-receptors were determined in a receptor binding assay. The essential structural moieties in the Corynanthe type indole alkaloids for inducing the opioid agonistic activity were also clarified. The oxidative derivatives of mitragynine, i.e., mitragynine pseudoindoxyl (2) and 7-hydroxymitragynine (12), were found as opioid agonists with higher potency than morphine in the experiment with guinea pig ileum. In addition, 2 induced an analgesic activity in the tail flick test in mice. PMID:11960505

  14. 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

  15. 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

  16. Activation of a common potassium channel in molluscan neurones by glutamate, dopamine and muscarinic agonist.

    PubMed Central

    Bolshakov VYu; Gapon, S A; Katchman, A N; Magazanik, L G

    1993-01-01

    1. The potassium currents evoked in isolated and identified neurones of molluscan pedal ganglia by either glutamate, dopamine or the muscarinic agonist F-2268 were investigated using voltage and patch clamp techniques. 2. Potassium currents induced by either dopamine or F-2268 could be blocked by pertussis toxin, as well as by a prolonged intracellular injection of the G protein inhibitor, GDP-beta-S. Loading the neurones with the G protein activator, GppNHp, on the other hand, induced a potassium current. This current was not additive to the currents evoked by agonist application. 3. Intracellular injection of the calcium buffer BAPTA failed to affect any of the agonist-induced currents, although it effectively blocked the after-hyperpolarization following directly evoked action potentials. 4. The activity of the potassium channels seen in cell-attached patches was greatly enhanced by application to the bath of either glutamate, dopamine, or F-2268. 5. The only effect of an addition of agonists to the bath was to increase the open probability (Po) of the K+ channel already active in the control conditions. The identity of the spontaneously active and agonist-activated channels was concluded from the identity of their channel conductances, rectification properties and current amplitudes. 6. Phorbol-12,13-dibutyrate, when applied to the bath, induced an increase in open time and caused an increase in Po, as did the agonists. Staurosporine completely prevented changes of Po induced by the phorbol ester but not those induced by the agonists. 7. The same inwardly rectifying potassium channel may be opened by both the receptor-linked G protein (with glutamate, dopamine, F-2268) and by protein kinase C (with phorbol ester) activation. 8. Strong evidence was obtained against the involvement of any known secondary messenger systems (formation of nucleotides, phosphoinositide turnover and subsequent activation of protein kinase C, formation of nitric oxide, metabolism of arachidonic acid) in the transduction mechanism of F-2268-, dopamine- and glutamate-induced responses. 9. Since none of the known secondary messenger systems seems to affect the activation by agonists applied to receptors outside the patch of channels located under the patch electrode, it appears that some as yet undescribed linking system must exist that could connect the spatially separated receptor-G protein complex and the potassium channel. PMID:7902868

  17. Disease modification of breast cancer-induced bone remodeling by cannabinoid 2 receptor agonists.

    PubMed

    Lozano-Ondoua, Alysia N; Hanlon, Katherine E; Symons-Liguori, Ashley M; Largent-Milnes, Tally M; Havelin, Josh J; Ferland, Henry L; Chandramouli, Anupama; Owusu-Ankomah, Mabel; Nikolich-Zugich, Tijana; Bloom, Aaron P; Jimenez-Andrade, Juan Miguel; King, Tamara; Porreca, Frank; Nelson, Mark A; Mantyh, Patrick W; Vanderah, Todd W

    2013-01-01

    Most commonly originating from breast malignancies, metastatic bone cancer causes bone destruction and severe pain. Although novel chemotherapeutic agents have increased life expectancy, patients are experiencing higher incidences of fracture, pain, and drug-induced side effects; furthermore, recent findings suggest that patients are severely undertreated for their cancer pain. Strong analgesics, namely opiates, are first-line therapy in alleviating cancer-related pain despite the severe side effects, including enhanced bone destruction with sustained administration. Bone resorption is primarily treated with bisphosphonates, which are associated with highly undesirable side effects, including nephrotoxicity and osteonecrosis of the jaw. In contrast, cannabinoid receptor 2 (CB(2) ) receptor-specific agonists have been shown to reduce bone loss and stimulate bone formation in a model of osteoporosis. CB(2) agonists produce analgesia in both inflammatory and neuropathic pain models. Notably, mixed CB(1) /CB(2) agonists also demonstrate a reduction in ErbB2-driven breast cancer progression. Here we demonstrate for the first time that CB(2) agonists reduce breast cancer-induced bone pain, bone loss, and breast cancer proliferation via cytokine/chemokine suppression. Studies used the spontaneously-occurring murine mammary cell line (66.1) implanted into the femur intramedullary space; measurements of spontaneous pain, bone loss, and cancer proliferation were made. The systemic administration of a CB(2) agonist, JWH015, for 7 days significantly attenuated bone remodeling, assuaged spontaneous pain, and decreased primary tumor burden. CB(2) -mediated effects in vivo were reversed by concurrent treatment with a CB(2) antagonist/inverse agonist but not with a CB(1) antagonist/inverse agonist. In vitro, JWH015 reduced cancer cell proliferation and inflammatory mediators that have been shown to promote pain, bone loss, and proliferation. Taken together, these results suggest CB(2) agonists as a novel treatment for breast cancer-induced bone pain, in which disease modifications include a reduction in bone loss, suppression of cancer growth, attenuation of severe bone pain, and increased survival without the major side effects of current therapeutic options. PMID:22903605

  18. Structure-activity relationship in PAF-acether. 3. Hydrophobic contribution to agonistic activity.

    PubMed

    Godfroid, J J; Broquet, C; Jouquey, S; Lebbar, M; Heymans, F; Redeuilh, C; Steiner, E; Michel, E; Coeffier, E; Fichelle, J

    1987-05-01

    The synthesis of some selected PAF-acether homologues with an alkoxy-chain length from C1 to C20 in position 1 is described. All agonist activities are closely correlated among themselves and with the calculated fatty-chain hydrophobicity. After a discussion on recent published results and comparison with our data, we conclude that the ether oxide function is absolutely essential at the glycerol 1-position for potent agonist activity and that potency correlates well with hydrophobicity parameters. We indicate the importance of steric and configurational constraints. PMID:3572968

  19. Differential Effects of Allosteric M1 Muscarinic Acetylcholine Receptor Agonists on Receptor Activation, Arrestin 3 Recruitment, and Receptor Downregulation

    PubMed Central

    2010-01-01

    Muscarinic acetylcholine receptors (mAChRs) are drug targets for multiple neurodegenerative and neuropsychiatric disorders, but the full therapeutic potential of mAChR-targeted drugs has not been realized, mainly because of a lack of subtype-selective agonists. Recent advances have allowed the development of highly selective agonists that bind to an allosteric site on the M1 mAChR that is spatially distinct from the orthosteric acetylcholine binding site, but less is known about the profile of intracellular signals activated by orthosteric versus allosteric M1 mAChR agonists. We investigated the activation and regulatory mechanisms of two structurally distinct allosteric M1 mAChR agonists, AC260584 and TBPB. We show that allosteric agonists potently activate multiple signal transduction pathways linked to the M1 mAChR receptor but, compared to orthosteric agonists, much less efficiently recruit arrestin 3, a protein involved in the regulation of G-protein coupled receptor signaling. Consistent with decreased arrestin recruitment, both allosteric agonists showed blunted responses in measurements of receptor desensitization, internalization, and downregulation. These results advance the understanding of mAChR biology and may shed light on unanticipated differences in the pharmacology of orthosteric versus allosteric agonists that might be capitalized upon for drug development for the treatment of CNS diseases. PMID:20835371

  20. 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

  1. Elimination of rat spinal substance P receptor bearing neurons dissociates cardiovascular and nocifensive responses to nicotinic agonists

    Microsoft Academic Search

    Imran M. Khan; Chris V. Wart; Erin A. Singletary; Shanaka Stanislaus; Tom Deerinck; Tony L. Yaksh; Morton P. Printz

    2008-01-01

    Intrathecal (IT) delivery of nicotinic agonists evokes dose dependent nocifensive behavior and cardiovascular responses. Previous studies suggested that these effects may be attenuated by the loss of substance P positive (sP(+)) primary afferents. To further characterize these cell systems, we examined the effect of selectively destroying neurokinin 1 receptor bearing (NK1-r(+)) dorsal horn neurons on IT nicotinic agonist evoked responses.

  2. The first X-ray crystal structure of the glucocorticoid receptor bound to a non-steroidal agonist

    SciTech Connect

    Madauss, Kevin P.; Bledsoe, Randy K.; Mclay, Iain; Stewart, Eugene L.; Uings, Iain J.; Weingarten, Gordon; Williams, Shawn P. (GSKNC); (GSK)

    2009-07-23

    The amino-pyrazole 2,6-dichloro-N-ethyl benzamide 1 is a selective GR agonist with dexamethasone-like in vitro potency. Its X-ray crystal structure in the GR LBD (Glucocorticoid ligand-binding domain) is described and compared to other reported structures of steroidal GR agonists in the GR LBD (3E7C).

  3. Immunity, Vol. 13, 475484, October, 2000, Copyright 2000 by Cell Press Conversion of a T Cell Antagonist into an Agonist

    E-print Network

    Harrison, Stephen C.

    Signaling This view is supported by the data of Lyons et al. (1996), in which the binding of the mouse TCR 2B4 to the mouse class II MHC I-Ek complexed with six altered peptides (one agonist, two weak ligand disso-alanine (P6A), an antagonist, is nearly identical to the ciating the fastest and the agonist

  4. 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

  5. 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

  6. 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.

  7. Le temps des unes et le temps des autres

    E-print Network

    Paris-Sud XI, Université de

    Le temps des unes et le temps des autres ans une journée tout le monde dispose de vingt-quatre heures. De quelle manière le temps est-il compté, quantifié et analysé selon les institutions ? Les temps. Dans les couples, hommes et femmes se ressemblent dans leur usage du temps sauf dans deux

  8. Facult des arts et des sciences Dpartement de sciences biologiques

    E-print Network

    Parrott, Lael

    i Faculté des arts et des sciences Département de sciences biologiques Plan de cours Politique sur étudiants de déposer leur copie d'examen et de libérer la salle. Ex : examen d'une durée de 1h45 ou de 2h45 2014 2h45 B-442 Les examens comportent deux parties: une série de 30 questions objectives et 2

  9. Facult des arts et des sciences Dpartement de sciences biologiques

    E-print Network

    Parrott, Lael

    i Faculté des arts et des sciences Département de sciences biologiques Plan de cours Politique sur étudiants de déposer leur copie d'examen et de libérer la salle. Ex : examen d'une durée de 1h45 ou de 2h45 examens comportent deux parties: une série de 30 questions objectives et 2-3 questions de synthèse ou d

  10. Rles indirects des microtubules dans la morphogense nuclaire des spermatides

    E-print Network

    Paris-Sud XI, Université de

    Rôles indirects des microtubules dans la morphogenèse nucléaire des spermatides J.-L. COURTENS. Summary. The indirect roles of microtubules in the nuclear morphogenesis of spermatids. The depolymerization of the microtubules of the spermatid manchette was effective for 4 to 5 h in rat, starting 30 min

  11. Plan de cours Facult des arts et des sciences

    E-print Network

    Parrott, Lael

    'analyse phylogénétique. Les 3 domaines du vivant: Archées, Eubactéries et Eucaryotes. Origine évolutive des Eucaryotes leurs niches écologiques. Éléments de contenu : Chapitre 6 - Origine évolutive des Végétaux. Végétaux et al. 2005 et de Campbell et al. 2012) #12;CALENDRIER Date Local Pavillon Contenu Mer. 8 mai 1409 A

  12. Exploration des Ondelettes en Prtraitement des Documents Anciens Anis Kricha

    E-print Network

    Paris-Sud XI, Université de

    Exploration des Ondelettes en Prétraitement des Documents Anciens Anis Kricha 1 ­ Amina Ghardallou de numérisation posent un axe de recherche très récent particulièrement pour les documents anciens présente une étape incontournable pour la restauration et le nettoyage d'un document. Elle permet d

  13. FACULTE DES ARTS ET DES SCIENCES DEPARTEMENT DE PHYSIQUE

    E-print Network

    Parrott, Lael

    FACULT´E DES ARTS ET DES SCIENCES D´EPARTEMENT DE PHYSIQUE AUTOMNE 2013 PLAN DE COURS Sigle du cours: PHY 1234 Titre du cours: Introduction `a la physique num´erique Nombre de cr´edits: 3 Professeur est offert principalement aux ´etudiant(e)s inscrit(e)s au premier cycle en physique et au programme

  14. PD 158771, a potential antipsychotic agent with D2/D3 partial agonist and 5-HT(1A) agonist actions. II. Preclinical behavioral effects.

    PubMed

    Corbin, A E; Meltzer, L T; Ninteman, F W; Wiley, J N; Christoffersen, C L; Wustrow, D J; Wise, L D; Pugsley, T A; Heffner, T G

    2000-04-27

    PD 158771 has been described in receptor binding and biochemical tests as a partial agonist at dopamine (DA) D2 and D3 receptors as well as an agonist at serotonin (5-HT)(1A) receptors. The present studies describe the profile of PD 158771 in rodent and primate behavioral tests. PD 158771 reduced spontaneous locomotor activity in mice (ED(50)=0.38 mg/kg, i.p.) and rats (ED(50) = 1.2 mg/kg, i.p. and 0.16 mg/kg, s.c.), and reduced amphetamine-stimulated locomotion in mice (ED(50) = 0.13 mg/kg, i.p.). At relatively higher doses up to 3 mg/kg, s.c. in rats, PD 158771 did not produce locomotor stimulation or induce stereotypy, indicating a lack of postsynaptic DA agonist activity. PD 158771 reduced apomorphine stimulated locomotion in rats at a dose 4.6-fold greater than those that reduced spontaneous locomotor activity, indicating weak postsynaptic DA antagonist actions; results consistent with a partial agonist profile. PD 158771 produced anxiolytic-like effects in the water-lick (Vogel) conflict test, effects possibly due to the 5-HT(1A) activity. However, PD 158771 was inactive in the water wheel behavioral despair model in rats, indicating lack of antidepressant properties. Similar to known antipsychotics, PD 158771 produced a potent and long-lasting inhibition of conditioned avoidance responding in squirrel monkeys. In contrast to standard antipsychotics, and similar to clozapine, PD 158771 did not cause catalepsy in rats at a dose 20-fold higher than the ED(50) dose for locomotor inhibition. PD 158771 also had a somewhat lower liability than haloperidol to produce extrapyramidal dysfunction in squirrel and cebus monkeys sensitized to the dystonic effects of haloperidol. The data indicate that PD 158771 is a DA partial agonist with weak intrinsic activity that selectively activates brain DA autoreceptors. PD 158771 produced behavioral effects consistent with potential antipsychotic and anxiolytic efficacy, and has an improved profile in the extrapyramidal side effect model when compared to certain currently available antipsychotic agents. PMID:10760363

  15. Rekonstruktion des Gesichts bei Verbrennungen

    Microsoft Academic Search

    Michael Steen

    2003-01-01

    Zusammenfassung Die Rekonstruktion des Gesichts bei Schwerbrandverletzten ist ein komplexer Bereich, bei dem schon die primäre Versorgung und Transplantationstechnik wesentlichen Einfluss auf das Endergebnis haben. Neben funktionellen Rekonstruktionen bei Narbenkontrakturen, Ektropion und inkomplettem Lidschluss, narbiger Begrenzung der Mundöffnung und Verlegungen des Naseneingangs finden heute auch Techniken Anwendung, welche vorrangig aus der ästhetischen Chirurgie bekannt sind. Beispiele dafür sind Haartransplantationen, Glättung

  16. 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

  17. HABILITATION `A DIRIGER DES RECHERCHES

    E-print Network

    Paris-Sud XI, Université de

    HABILITATION `A DIRIGER DES RECHERCHES PR´ESENT´EE `A L'UNIVERSIT´E CLAUDE BERNARD LYON I INSTITUT dilogarithme de Rogers . . . . . . . . . . . . . . . 19 2.4 Carquois et cat´egories d cambriens et ´equivalences d´eriv´ees . . . . . . . . . . . . 23 2.7 Cat´egorification des op

  18. La pertinence informationnelle des chiffres comptables aprs l'adoption des Mise en vidence du rle des facteurs institutionnels

    E-print Network

    Paris-Sud XI, Université de

    1 La pertinence informationnelle des chiffres comptables après l'adoption des IFRS Mise en évidence informationnelle additionnelle des chiffres comptables due à l'adoption des IFRS. Les tests empiriques ont porté financière (Dyck et Zingales 2007) et les différences entre les normes locales et les IFRS (Bae et al. 2008

  19. POSTES DE GRAVURE HUMIDE MANUELS Ce sont des postes scuriss qui permettent le traitement manuel des plaquettes dans des rcipients

    E-print Network

    Ingrand, François

    POSTES DE GRAVURE HUMIDE MANUELS Ce sont des postes sécurisés qui permettent le traitement manuel des plaquettes dans des récipients contenant le réactif de gravure humide CARACTERISTIQUES PRINCIPALES conduire une gravure humide (attaque chimique) du matériau concerné dans des récipients adaptés posés sur

  20. Les marchs des investisseurs institutionnels sont-ils efficients : cas des fonds de pension et des unit trusts britanniques

    E-print Network

    Paris-Sud XI, Université de

    Les marchés des investisseurs institutionnels sont-ils efficients : cas des fonds de pension et des, nous proposons d'étudier la persistance de la performance de deux échantillons de fonds (de pension et long terme, et en investissant sur le marché des actions, les fonds de pension ne semblent pas avoir

  1. 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...

  2. Profil psychopharmacologique d'un nouvel agoniste Dopaminergique, le RU 24213

    Microsoft Academic Search

    J. R. Boissier; C. Dumont; J. Laurent; C. Oberlander

    1980-01-01

    The psychopharmacological properties of RU 24213 were compared to those of other dopaminergic agonists (apomorphine, dexamphetamine, bromocriptine and l-dopa) in various behavioural tests. In naive mice the drug reduced the locomotor hyperactivity in the primary exploratory phase and produced stimulation in the subsequent stabilized activity period. In rats it provoked dose-related stereotypies, specially gnawing and sniffing. It delayed the cataleptic

  3. Preclinical evaluation of SMM-189, a cannabinoid receptor 2-specific inverse agonist

    PubMed Central

    Presley, Chaela; Abidi, Ammaar; Suryawanshi, Satyendra; Mustafa, Suni; Meibohm, Bernd; Moore, Bob M

    2015-01-01

    Cannabinoid receptor 2 agonists and inverse agonists are emerging as new therapeutic options for a spectrum of autoimmune-related disease. Of particular interest, is the ability of CB2 ligands to regulate microglia function in neurodegenerative diseases and traumatic brain injury. We have previously reported the receptor affinity of 3?,5?-dichloro-2,6-dihydroxy-biphenyl-4-yl)-phenyl-methanone (SMM-189) and the characterization of the beneficial effects of SMM-189 in the mouse model of mild traumatic brain injury. Herein, we report the further characterization of SMM-189 as a potent and selective CB2 inverse agonist, which acts as a noncompetitive inhibitor of CP 55,940. The ability of SMM-189 to regulate microglial activation, in terms of chemokine expression and cell morphology, has been determined. Finally, we have determined that SMM-189 possesses acceptable biopharmaceutical properties indicating that the triaryl class of CB2 inverse agonists are viable compounds for continued preclinical development for the treatment of neurodegenerative disorders and traumatic brain injury. PMID:26196013

  4. Mapping the Agonist Binding Site of the GABAA Receptor: Evidence for a b-Strand

    Microsoft Academic Search

    Andrew J. Boileau; Amy R. Evers; Anson F. Davis; Cynthia Czajkowski

    1999-01-01

    GABAA receptors, along with the receptors for acetylcholine, glycine, and serotonin, are members of a ligand-gated ion channel superfamily (Ortells and Lunt, 1995). Because of the paucity of crystallographic information for these ligand-gated channels, little is known about the structure of their binding sites or how agonist binding is transduced into channel gating. We used the substituted cysteine accessibility method

  5. 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

  6. THE IMMUNOMODULATORY EFFECTS OF CLONIDINE, AN ALPHA-2-ADRENERGIC AGONIST, IN LAYING HENS

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The ability of the sympathetic nervous system to regulate chicken immune functions was examined. Clonidine, an alpha-2 adrenergic receptor agonist, was administrated at 2.5, 5.0 or 10.0 mg/L in the drinking water of White Leghorn hens at 48 wks of age. The hens were randomly housed in conventional c...

  7. Synthesis and evaluation of a conditionally-silent agonist for the ?7 nicotinic acetylcholine receptor

    PubMed Central

    Chojnacka, Kinga; Papke, Roger L.; Horenstein, Nicole A.

    2013-01-01

    We introduce the term ‘silent agonists’ to describe ligands that can place the ?7 nicotinic acetylcholine receptor (nAChR) into a desensitized state with little or no apparent activation of the ion channel, forming a complex that can subsequently generate currents when treated with an allosteric modulator. KC-1 (5?-phenylanabaseine) was synthesized and identified as a new silent agonist for the ?7 nAChR; it binds to the receptor but does not activate ?7 nAChR channel opening when applied alone, and its agonism is revealed by co-application with the type II positive allosteric modulator PNU-120596 in the Xenopus oocyte system. The concise synthesis was accomplished in three steps with the C–C bonds formed via Pd-catalyzed mono-arylation and organolithium coupling with N-Boc piperidinone. Comparative structural analyses indicate that a positive charge, an H-bond acceptor, and an aryl ring in a proper arrangement are needed to constitute one class of silent agonist for the ?7 nAChR. Because silent agonists may act on signaling pathways not involving ion channel opening, this class of ?7 nAChR ligands may constitute a new alternative for the development of ?7 nAChR therapeutics. PMID:23746476

  8. Basal phosphorylation of ? opioid receptor is agonist modulated and Ca 2+-dependent

    Microsoft Academic Search

    Zaijie Wang; James Arden; Wolfgang Sadee

    1996-01-01

    The ? opioid receptor was shown to be phosphorylated at a basal rate in the absence of agonist, measured in permeabilized HEK293 cells transfected with an epitope tagged ? receptor (EE-?) [Arden, J., Segredo, V., Wang, Z., Lameh, J. and Sadée, W. (1995) J. Neurochem. 65, 1636–1645]. In the present study, basal phosphorylation was found to be Ca2+ dependent; however,

  9. Changes in agonist EMG activation level during MVC cannot explain early strength improvement

    Microsoft Academic Search

    Andreas Holtermann; Karin Roeleveld; Beatrix Vereijken; Gertjan Ettema

    2005-01-01

    A substantial gain in strength is often observed in the early phase of resistance training. The aim of this study was to address whether improved strength in the early phase of resistance training, can be attributed to increased activation, or to intra-muscular changes of the agonist muscle during maximal isometric torque production. Fourteen male subjects trained maximal isometric dorsiflexion during

  10. The effects of an orally administered cholinergic agonist on REM sleep in major depression

    Microsoft Academic Search

    Michael L Perlis; Michael T Smith; Henry J Orff; Patrick J Andrews; J. Christian Gillin; Donna E Giles

    2002-01-01

    Background: Centrally active cholinergic agents such as arecoline and physostigmine shorten rapid eye movement (REM) latency, reduce REM interval times, or both and do so preferentially in patients with depression. We tested an orally administered cholinergic agonist (donepezil HCL 10 mg [Aricept]) to determine whether this agent also alters REM timing in depressed patients (n = 8) compared with age-

  11. Separation and peroxisome proliferator-activated receptor-? agonist activity evaluation of synthetic racemic bavachinin enantiomers.

    PubMed

    Du, Guoxin; Feng, Li; Yang, Zhuo; Shi, Jiye; Huang, Cheng; Guo, Fujiang; Li, Bo; Zhu, Weiliang; Li, Yiming

    2015-06-15

    Bavachinin, isolated from Psoralea corylifolia seeds, has been reported to demonstrate peroxisome proliferator-activated receptor-? (PPAR-?) agonist activity. However, isolated bavachinin is actually a mixture of S and R configurations, with an enantiomeric excess value of approximately 24.3%. For further study on the structure-activity relationships of bavachinin, investigating the PPAR-? agonist activity of the two enantiomers is crucial. Considering the limited availability, racemic bavachinin was prepared in this study using chemical synthesis. The enantiomers of racemic bavachinin were then separated using supercritical fluid chromatography. This concise strategy yielded (S)- and (R)-bavachinin in optical purity as high as ?97.5%. The PPAR-? agonist activity of the two enantiomers was evaluated using a time-resolved fluorescence resonance energy transfer-based competitive binding assay method; IC50 values of (S)- and (R)-bavachinin were 616.7 and 471.2nM, respectively. The interaction between the compounds and PPAR-? was further explored using a molecular docking method. This study suggests that (S)- and (R)-bavachinin demonstrate similar PPAR-? agonist activities. PMID:25978962

  12. 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.

  13. Intermittent etidronate partially prevents bone loss in hirsute hyperandrogenic women treated with GnRH agonist

    Microsoft Academic Search

    N. Zamberlan; R. Castello; D. Gatti; M. Rossini; V. Braga; E. Fracassi; S. Adami

    1997-01-01

    Treatment with gonadotropin-releasing hormone (GnRH) agonist leads to enhanced bone turnover and accelerated bone loss in premenopausal women with endometriosis, uterine leiomyomatomas and hirsutism. Sodium etidronate is a powerful inhibitor of bone resorption which has been proven efficacious in the prevention and treatment of postmenopausal osteoporosis. The objective of this study was to evaluate the skeletal effects of 6 months

  14. The transcriptional PPAR?/? network in human macrophages defines a unique agonist-induced activation state

    PubMed Central

    Adhikary, Till; Wortmann, Annika; Schumann, Tim; Finkernagel, Florian; Lieber, Sonja; Roth, Katrin; Toth, Philipp M.; Diederich, Wibke E.; Nist, Andrea; Stiewe, Thorsten; Kleinesudeik, Lara; Reinartz, Silke; Müller-Brüsselbach, Sabine; Müller, Rolf

    2015-01-01

    Peroxisome proliferator-activated receptor ?/? (PPAR?/?) is a lipid ligand-inducible transcription factor with established metabolic functions, whereas its anti-inflammatory function is poorly understood. To address this issue, we determined the global PPAR?/?-regulated signaling network in human monocyte-derived macrophages. Besides cell type-independent, canonical target genes with metabolic and immune regulatory functions we identified a large number of inflammation-associated NF?B and STAT1 target genes that are repressed by agonists. Accordingly, PPAR?/? agonists inhibited the expression of multiple pro-inflammatory mediators and induced an anti-inflammatory, IL-4-like morphological phenotype. Surprisingly, bioinformatic analyses also identified immune stimulatory effects. Consistent with this prediction, PPAR?/? agonists enhanced macrophage survival under hypoxic stress and stimulated CD8+ T cell activation, concomitantly with the repression of immune suppressive target genes and their encoded products CD274 (PD-1 ligand), CD32B (inhibitory Fc? receptor IIB) and indoleamine 2,3-dioxygenase 1 (IDO-1), as well as a diminished release of the immune suppressive IDO-1 metabolite kynurenine. Comparison with published data revealed a significant overlap of the PPAR?/? transcriptome with coexpression modules characteristic of both anti-inflammatory and pro-inflammatory cytokines. Our findings indicate that PPAR?/? agonists induce a unique macrophage activation state with strong anti-inflammatory but also specific immune stimulatory components, pointing to a context-dependent function of PPAR?/? in immune regulation. PMID:25934804

  15. Melatonin, sleep, and circadian rhythms: rationale for development of specific melatonin agonists

    E-print Network

    Gillette, Martha U.

    Review Melatonin, sleep, and circadian rhythms: rationale for development of specific melatonin agonists Fred W. Tureka,*, Martha U. Gilletteb a Department of Neurobiology and Physiology, Center for Sleep and Circadian Biology, Northwestern University, 2205 Tech Drive, Hogan Hall 2-160, Evanston, IL

  16. J Physiol 587.21 (2009) pp 50455072 5045 Agonist and blocking actions of choline

    E-print Network

    Colquhoun, David

    2009-01-01

    and tetramethylammonium on human muscle acetylcholine receptors Remigijus Lape, Paraskevi Krashia, David Colquhoun and by tetramethylammonium (TMA). Channel block by the agonist was incorporated into the mechanisms that were fitted of the mean; TMA, tetramethylammonium. Introduction Block of nicotinic ion channels is ubiquitous. It has been

  17. Differentiation of ?, ?, and ? opioid receptor agonists based on pharmacophore development and computed physicochemical properties

    Microsoft Academic Search

    Marta Filizola; Hugo O. Villar; Gilda H. Loew

    2001-01-01

    Compounds that bind with significant affinity to the opioid receptor types, d, µ, and ?, with different combinations of activation and inhibition at these three receptors could be promising behaviorally selective agents. Working on this hypothesis, the chemical moieties common to three different sets of opioid receptor agonists with significant affinity for each of the three receptor types d, µ,

  18. Considerations on the recognition of the D1 receptor by agonists

    Microsoft Academic Search

    Ibon Alkorta; Hugo O. Villar

    1993-01-01

    A model of the mechanism for recognition of the D1 receptor has been developed. Conformational analysis for 10 agonists from diverse chemical families was carried out as a first step toward the characterization of the bioactive form. First, maximum structural overlap of the features common to all ligands allowed a simple identification of the candidate bioactive form for each ligand.

  19. Opiate Agonists Activate Feeding in Limax: Comparison of In Vivo and In Vitro Effects

    Microsoft Academic Search

    M. Wong; K. Delaney; A. Gelperin

    1991-01-01

    The neural control system for feeding in the terrestrial mollusc Limax maximus is modulated by at least two major families of peptides. Sequence homology between one of the peptides known to modulate Limax feeding and some members of the opioid peptide family suggested that opioid peptides might also modulate Limax feeding. Experiments with the mu agonist morphine and the kappa

  20. 2-Arachidonyl glyceryl ether, an endogenous agonist of the cannabinoid CB1 receptor

    E-print Network

    Vogel, Zvi

    2-Arachidonyl glyceryl ether, an endogenous agonist of the cannabinoid CB1 receptor Lumi´r Hanus, the only known endocannabinoid in the ester series. We report now an example of a third, ether-type endocannabinoid, 2-arachidonyl glyceryl ether (noladin ether), isolated from porcine brain. The structure

  1. ACCELERATED COMMUNICATION Di(2-ethylhexyl) phthalate Is a Highly Potent Agonist for the

    E-print Network

    Omiecinski, Curtis

    the common plasticizer, di(2- ethylhexyl) phthalate (DEHP), as a highly potent and uniquely selective agonist of CAR2. Results from reporter transactivation and mammalian two-hybrid assays reveal that DEHP activates mouse, rat, and marmoset models of DEHP toxicity cannot accurately profile potential human toxic- ity

  2. Therapeutic potential of vanilloid receptor TRPV1 agonists and antagonists as analgesics: Recent advances and setbacks.

    PubMed

    Wong, Gilbert Y; Gavva, Narender R

    2009-04-01

    The vanilloid receptor TRPV1 is a homotetrameric, non-selective cation channel abundantly expressed in the nociceptors (c-fibers). TRPV1 is considered as a highly validated pain target because, i) its agonists such as capsaicin cause desensitization of TRPV1 channels that relieves pain behaviors in preclinical species, and ii) its antagonists relieve pain behaviors in rodent models of inflammation, osteoarthritis, and cancer. Hence, both agonists and antagonists of TRPV1 are being evaluated as potential analgesics in clinical trials. Clinical trial results of TRPV1 agonists such as resiniferatoxin in interstitial cystitis, NGX 4010 in post-herpetic neuralgia, and 4975 (Adlea) in osteoarthritis, bunionectomy, and Morton's neuroma have been reported. Similarly, clinical trial results of TRPV1 antagonists such as SB-705498 and AMG 517 have also been published recently. Overall, some molecules (e.g., capsaicin) demonstrated potential analgesia in certain conditions (postsurgical pain, postherpetic neuralgia, pain in diabetic neuropathy, osteoarthritis, bunionectomy, and Morton's neuroma), whereas others fell out of the clinic due to on-target liabilities or failed to demonstrate efficacy. This review summarizes recent advances and setbacks of TRPV1 agonists and antagonists in the clinic and predicts future directions. PMID:19150372

  3. Pharmacodynamics of TRPV1 Agonists in a Bioassay Using Human PC-3 Cells

    PubMed Central

    Jiménez, Marcel; Clavé, Pere

    2014-01-01

    Purpose. TRPV1 is a multimodal channel mainly expressed in sensory neurons. We aimed to explore the pharmacodynamics of the TRPV1 agonists, capsaicin, natural capsaicinoids, and piperine in an in vitro bioassay using human PC-3 cells and to examine desensitization and the effect of the specific antagonist SB366791. Methods. PC-3 cells expressing TRPV1 were incubated with Fluo-4. Fluorescence emission changes following exposition to agonists with and without preincubation with antagonists were assessed and referred to maximal fluorescence following the addition of ionomycin. Concentration-response curves were fitted to the Hill equation. Results. Capsaicin and piperine had similar pharmacodynamics (Emax 204.8 ± 184.3% piperine versus 176.6 ± 35.83% capsaicin, P = 0.8814, Hill coefficient 0.70 ± 0.50 piperine versus 1.59 ± 0.86 capsaicin, P = 0.3752). In contrast, capsaicinoids had lower Emax (40.99 ± 6.14% capsaicinoids versus 176.6 ± 35.83% capsaicin, P < 0.001). All the TRPV1 agonists showed significant desensitization after the second exposition and their effects were strongly inhibited by SB366791. Conclusion. TRPV1 receptor is successfully stimulated by capsaicin, piperine, and natural capsaicinoids. These agonists present desensitization and their effect is significantly reduced by a TRPV1-specific antagonist. In addition, PC-3 cell bioassays proved useful in the study of TRPV1 pharmacodynamics. PMID:24688365

  4. Preclinical evaluation of SMM-189, a cannabinoid receptor 2-specific inverse agonist.

    PubMed

    Presley, Chaela; Abidi, Ammaar; Suryawanshi, Satyendra; Mustafa, Suni; Meibohm, Bernd; Moore, Bob M

    2015-08-01

    Cannabinoid receptor 2 agonists and inverse agonists are emerging as new therapeutic options for a spectrum of autoimmune-related disease. Of particular interest, is the ability of CB2 ligands to regulate microglia function in neurodegenerative diseases and traumatic brain injury. We have previously reported the receptor affinity of 3',5'-dichloro-2,6-dihydroxy-biphenyl-4-yl)-phenyl-methanone (SMM-189) and the characterization of the beneficial effects of SMM-189 in the mouse model of mild traumatic brain injury. Herein, we report the further characterization of SMM-189 as a potent and selective CB2 inverse agonist, which acts as a noncompetitive inhibitor of CP 55,940. The ability of SMM-189 to regulate microglial activation, in terms of chemokine expression and cell morphology, has been determined. Finally, we have determined that SMM-189 possesses acceptable biopharmaceutical properties indicating that the triaryl class of CB2 inverse agonists are viable compounds for continued preclinical development for the treatment of neurodegenerative disorders and traumatic brain injury. PMID:26196013

  5. ?2-Adrenoceptor agonists alleviate neuropathic allodynia in mice after chronic treatment

    PubMed Central

    Choucair-Jaafar, Nada; Yalcin, Ipek; Rodeau, Jean-Luc; Waltisperger, Elisabeth; Freund-Mercier, Marie-José; Barrot, Michel

    2009-01-01

    Background and purpose: Antidepressants are a first-line treatment against neuropathic pain. We previously demonstrated that ?2-adrenoceptors are necessary for antidepressants to exert their anti-allodynic action. The aim of the present study was to assess whether ?2-adrenoceptor agonists could be sufficient to alleviate neuropathic allodynia. Experimental approach: We used a murine model of neuropathy induced by unilateral sciatic nerve cuffing in C57BL/6J mice. We previously demonstrated that this animal model is sensitive to chronic, but not to acute, treatment with antidepressant drugs, which is clinically relevant. The mechanical allodynia was evaluated using the von Frey filaments. Key results: We showed that chronic but not acute treatment with the ?-adrenoceptor agonists, bambuterol, isoprenaline, fenoterol, salbutamol, salmeterol, terbutaline or ritodrine suppressed mechanical allodynia. We confirmed that the action of these ?-adrenoceptor agonists was mediated through ?2-adrenoceptors by blocking it with intraperitoneal or intrathecal, but not intracerebroventricular or intraplantar, injections of the antagonist ICI118551. We also showed that chronic treatments with the ?-adrenoceptor antagonists, propranolol or ICI118551 did not suppress the allodynia. Conclusions and implications: Our data show that chronic treatment with ?-adrenoceptor agonists has the same antiallodynic properties as treatments with antidepressant drugs. This study was, however, conducted in an animal model, and a clinical validation will be required to confirm the value of the present findings in patients. PMID:19912227

  6. Analgesic tolerance to microinjection of the ?-opioid agonist DAMGO into the ventrolateral periaqueductal gray

    PubMed Central

    Meyer, Paul J.; Fossum, Erin N.; Ingram, Susan L.; Morgan, Michael M.

    2007-01-01

    Repeated administration of the relatively low-efficacy ?-opioid receptor agonist morphine induces tolerance to its antinociceptive effects. High-efficacy agonists such as D-Ala2NMePhe4,Gly-ol5 (DAMGO) have been shown to be less effective at producing tolerance, suggesting that different neural mechanisms underlie tolerance to these agonists. However, the correlation between agonist efficacy and tolerance development has not been examined within the ventrolateral periaqueductal gray (vPAG), a brain area known to be crucial for the development of morphine tolerance. The current studies examined whether tolerance to DAMGO occurs within the vPAG, and whether repeated treatment with DAMGO into the vPAG alters the development of morphine tolerance. The results showed that repeated vPAG microinjections of DAMGO induced robust tolerance and cross-tolerance to morphine. Further, co-administration of a low dose of DAMGO with morphine potentiated morphine tolerance. These findings indicate that similar mechanisms underlie tolerance to morphine and DAMGO within the vPAG. PMID:17445843

  7. New ?-adrenergic agonists used illicitly as growth promoters in animal breeding: chemical and pharmacodynamic studies

    Microsoft Academic Search

    Gabriela Mazzanti; Claudia Daniele; Gianpiero Boatto; Giuliana Manca; Gianfranco Brambilla; Alberto Loizzo

    2003-01-01

    Clenbuterol and ?-adrenergic receptor agonist drugs are illegally used as growth promoters in animal production. Pharmacologically active residues in edible tissues led to intoxication outbreaks in several countries. Pressure of official controls pulsed synthesis of new compounds to escape analytical procedures. We report two new compounds named ‘A’ and ‘G4’, found in feeding stuffs. Chemical structure was studied through nuclear

  8. Accessory Cell Mediated Activation of Porcine NK Cells by TLR7 and TLR8 Agonists

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The induction of innate immune responses by toll-like receptor (TLR) agonists is the subject of intense investigation in many different species. In large part, this reflects the potential of such compounds to be effective vaccine adjuvants. For that reason, we analyzed the activation of innate cells...

  9. Platelet-activating Factor Receptor Agonists Mediate Xeroderma Pigmentosum A Photosensitivity*

    PubMed Central

    Yao, Yongxue; Harrison, Kathleen A.; Al-Hassani, Mohammed; Murphy, Robert C.; Rezania, Samin; Konger, Raymond L.; Travers, Jeffrey B.

    2012-01-01

    To date, oxidized glycerophosphocholines (Ox-GPCs) with platelet-activating factor (PAF) activity produced non-enzymatically have not been definitively demonstrated to mediate any known disease processes. Here we provide evidence that these Ox-GPCs play a pivotal role in the photosensitivity associated with the deficiency of the DNA repair protein xeroderma pigmentosum type A (XPA). It should be noted that XPA-deficient cells are known to have decreased antioxidant defenses. These studies demonstrate that treatment of human XPA-deficient fibroblasts with the pro-oxidative stressor ultraviolet B (UVB) radiation resulted in increased reactive oxygen species and PAF receptor (PAF-R) agonistic activity in comparison with gene-corrected cells. The UVB irradiation-generated PAF-R agonists were inhibited by antioxidants. UVB irradiation of XPA-deficient (Xpa?/?) mice also resulted in increased PAF-R agonistic activity and skin inflammation in comparison with control mice. The increased UVB irradiation-mediated skin inflammation and TNF-? production in Xpa?/? mice were blocked by systemic antioxidants and by PAF-R antagonists. Structural characterization of PAF-R-stimulating activity in UVB-irradiated XPA-deficient fibroblasts using mass spectrometry revealed increased levels of sn-2 short-chain Ox-GPCs along with native PAF. These studies support a critical role for PAF-R agonistic Ox-GPCs in the pathophysiology of XPA photosensitivity. PMID:22303003

  10. The transcriptional PPAR?/? network in human macrophages defines a unique agonist-induced activation state.

    PubMed

    Adhikary, Till; Wortmann, Annika; Schumann, Tim; Finkernagel, Florian; Lieber, Sonja; Roth, Katrin; Toth, Philipp M; Diederich, Wibke E; Nist, Andrea; Stiewe, Thorsten; Kleinesudeik, Lara; Reinartz, Silke; Müller-Brüsselbach, Sabine; Müller, Rolf

    2015-05-26

    Peroxisome proliferator-activated receptor ?/? (PPAR?/?) is a lipid ligand-inducible transcription factor with established metabolic functions, whereas its anti-inflammatory function is poorly understood. To address this issue, we determined the global PPAR?/?-regulated signaling network in human monocyte-derived macrophages. Besides cell type-independent, canonical target genes with metabolic and immune regulatory functions we identified a large number of inflammation-associated NF?B and STAT1 target genes that are repressed by agonists. Accordingly, PPAR?/? agonists inhibited the expression of multiple pro-inflammatory mediators and induced an anti-inflammatory, IL-4-like morphological phenotype. Surprisingly, bioinformatic analyses also identified immune stimulatory effects. Consistent with this prediction, PPAR?/? agonists enhanced macrophage survival under hypoxic stress and stimulated CD8(+) T cell activation, concomitantly with the repression of immune suppressive target genes and their encoded products CD274 (PD-1 ligand), CD32B (inhibitory Fc? receptor IIB) and indoleamine 2,3-dioxygenase 1 (IDO-1), as well as a diminished release of the immune suppressive IDO-1 metabolite kynurenine. Comparison with published data revealed a significant overlap of the PPAR?/? transcriptome with coexpression modules characteristic of both anti-inflammatory and pro-inflammatory cytokines. Our findings indicate that PPAR?/? agonists induce a unique macrophage activation state with strong anti-inflammatory but also specific immune stimulatory components, pointing to a context-dependent function of PPAR?/? in immune regulation. PMID:25934804

  11. A combined ligand- and structure-based virtual screening protocol identifies submicromolar PPAR? partial agonists.

    PubMed

    Vidovi?, Dušica; Busby, Scott A; Griffin, Patrick R; Schürer, Stephan C

    2011-01-01

    Peroxisome proliferator-activated receptor ? (PPAR?) is involved in expression of genes that control glucose and lipid metabolism. PPAR? is the molecular target of the thiazolidinedione (TZD) class of antidiabetic drugs. However, despite their clinical use these drugs are associated with numerous adverse effects, which are related to their full activation of PPAR? transcriptional responses. PPAR? partial agonists are the focus of development efforts towards second-generation PPAR? modulators with favorable pharmacology, potent insulin sensitization without the severe full agonists' adverse effects. In order to identify novel PPAR? partial agonist lead compounds, we developed a virtual screening protocol based on three-dimensional ligand-shape similarity and docking. Prioritization gave 235 compounds for experimental screening from the National Institutes of Health (NIH) Molecular Libraries Small Molecule Repository (MLSMR)-a chemical library containing 340?000 compounds. Seven novel potent partial agonists were confirmed in cell-based transactivation and competitive binding assays. Our results illustrate a well-designed virtual screening campaign successfully identifying novel lead compounds as potential entry points for the development of antidiabetic drugs. PMID:21162086

  12. The effects of cage enrichment on agonistic behaviour and dominance in male laboratory rats ( Rattus norvegicus)

    Microsoft Academic Search

    Usama A. Abou-Ismail

    2011-01-01

    This experiment was carried out to investigate the effects of enriching laboratory cages on agonistic interaction and dominance of rats. In a series of three replicates, 48 rats were housed in groups of four in either ‘standard’ or ‘enriched’ cages for 6 weeks. Successful aggressive and defensive behaviour that ended up in a clear winner and loser were sampled in

  13. Conformationally constrained farnesoid X receptor (FXR) agonists: heteroaryl replacements of the naphthalene.

    PubMed

    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, Frank; Parks, Derek J; Smalley, Terrence L; Spearing, Paul K; Todd, Dan; Williams, Shawn P; Wisely, G Bruce

    2011-02-15

    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. PMID:21256005

  14. Serotonin4 (5-HT4) Receptor Agonists Are Putative Antidepressants with a Rapid Onset of Action

    E-print Network

    Kharasch, Evan

    protein and neurogenesis in the hippocampus. In contrast, a 3 day treatment with the SSRI cit- alopram intake consecutive to a chronic mild stress. These findings point out 5-HT4 receptor agonists and clinicians, the mood improvement starts only after 3­6 weeks of AD treatment. Similarly, in animal behavioral

  15. The two-state model of receptor activation: The agonist and the efficacy

    Microsoft Academic Search

    Tracy Lynn Blevins

    1999-01-01

    The Two State model describes how drugs activate receptors by inducing or supporting a conformational change in the receptor from “off” to “on”. The beta 2 adrenergic receptor system is the model system which was used to formalize the concept of two states, and the mechanism of hormone agonist stimulation of this receptor is similar to ligand activation of other

  16. A radial distribution function approach to predict A 2B agonist effect of adenosine analogues

    Microsoft Academic Search

    Maykel Pérez González; Carmen Terán; Yagamare Fall; Marta Teijeira; Pedro Besada

    2005-01-01

    The radial distribution function (RDF) approach has been applied to the study of the A2B agonist effect of a set of 89 adenosine analogues reported with this activity. A model able to describe more than 70% of the variance in the experimental activity was developed with the use of the mentioned approach. In contrast, none of the eleven different approaches

  17. Characterization of supraspinal antinociceptive actions of opiod delta agonists in the rat

    Microsoft Academic Search

    Michael H. Ossipov; Carl J. Kovelowski; Michael L. Nichols; Victor J. Hruby; Frank Porreca

    1995-01-01

    Supraspinally mediated antinociception has been clearly established for agonists acting via both ?- and ?-opioid receptors. The present experiments were undertaken to further characterize the role of supraspinal opioid ? receptors in the mediation of antinociception in rats and to examine the possible role of putative ?1- and ?2-opioid receptors in the antinociceptive effect. Cannulae directed at the right lateral

  18. Combined Effects of PPAR ? Agonists and Epidermal Growth Factor Receptor Inhibitors in Human Proximal Tubule Cells.

    PubMed

    Pegg, Katherine; Zhang, Jie; Pollock, Carol; Saad, Sonia

    2013-01-01

    We aimed to determine whether epidermal growth factor receptor (EGFR) inhibition, in addition to a peroxisome proliferator-activated receptor gamma (PPAR ? ) agonist, prevents high-glucose-induced proximal tubular fibrosis, inflammation, and sodium and water retention in human proximal tubule cells exposed to normal glucose; high glucose; high glucose with the PPAR ? agonist pioglitazone or with the P-EGFR inhibitor, gefitinib; or high glucose with both pioglitazone and gefitinib. We have shown that high glucose increases AP-1 and NF ? B binding activity, downstream phosphorylation of EGFR and Erk1/2, and fibronectin and collagen IV expression. Pioglitazone reversed these effects but upregulated NHE3 and AQP1 expression. Gefitinib inhibited high glucose induced fibronectin and collagen IV, and EGFR and Erk1/2 phosphorylation and reversed pioglitazone-induced increases in NHE3 and AQP1 expression. Our data suggests that combination of an EGFR inhibitor and a PPAR ? agonist mitigates high-glucose-induced fibrosis and inflammation and reverses the upregulation of transporters and channels involved in sodium and water retention in human proximal tubule cells. Hence EGFR blockade may hold promise, not only in limiting tubulointerstitial pathology in diabetic nephropathy, but also in limiting the sodium and water retention observed in patients with diabetes and exacerbated by PPAR ? agonists. PMID:23533381

  19. Predicted structure of agonist-bound glucagon-like peptide 1 receptor, a class

    E-print Network

    Goddard III, William A.

    Predicted structure of agonist-bound glucagon-like peptide 1 receptor, a class B G protein and Process Simulation Center (139-74), California Institute of Technology, Pasadena, CA 91125 Contributed by William A. Goddard III, October 18, 2012 (sent for review July 9, 2012) The glucagon-like peptide 1

  20. Do agonistic interactions underlie the segregation and relative abundances between two Loxosceles species (Araneae: Sicariidae)?

    PubMed

    Fischer, Marta L; Diniz, Suzana; Vasconcellos-Neto, João

    2014-05-01

    The medically important spiders Loxosceles intermedia Mello-Leitão and Loxosceles laeta (Nicolet) are segregated in Curitiba, southern Brazil, where L. intermedia is more abundant and widespread than L. laeta. Because they share similar microhabitat preferences and wander in search of web sites, agonistic encounters are likely to occur. The purposes of this study were to describe agonistic interactions and interpret their consequences for the relative abundances and spatial segregation of L. intermedia and L. laeta. Experimental contests were performed between residents and intruders. Asymmetries between contestants included sex, age, species, weight, and residence status. Nine behavioral categories were defined. Through discriminant analyses, it was possible to differentiate spider sex, species, and residence based on their agonistic behaviors. Intruders, juveniles, and L. intermedia individuals were better characterized by exploratory behaviors, whereas L. laeta females were differentiated by aggressiveness. By performing a multiple logistic regression, with winning or defeat as a dependent variable of sex, age, species, size, weight, and residence, it was possible to say that residents and L. intermedia individuals had the highest winning odds in contests, whereas juveniles had lower winning odds than adults. Advantages of the prior residence may help to explain the predominance of L. laeta in old colonization sites, whereas the higher winning odds of L. intermedia and less aggressive behavior toward conspecifics may lead to a successful establishment of dense populations in new sites. A better understanding of agonistic interactions as a mechanism of spacing, segregation, and species replacement among spiders may be helpful for control purposes. PMID:24897847

  1. 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

  2. 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.

  3. 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...

  4. Quantitative structure–Activity studies of octopaminergic agonists and antagonists against nervous system of Locusta migratoria

    Microsoft Academic Search

    Eiichi Kuwano; C PAN; K SHINKAI; J TOMITA; E TANIGUCHI; M ETO

    1998-01-01

    The quantitative structure–activity relationship (QSAR) of octopaminergic agonists and antagonists against the thoracic nerve cord of the migratory locust, Locusta migratoria L., was analyzed using physicochemical parameters and regression analysis. The hydrophobic effect, dipole moment, and shape index were important in terms of Ki: the more hydrophobic, the greater dipole moment, and the smaller shape index of the molecules, the

  5. 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

  6. Anim. Behav., 1995, 49, 71-79 Resource quality afkcts the agonistic behaviour of territorial salamanders

    E-print Network

    Gabor, Caitlin - Department of Biology, Texas State University

    salamanders CAITLIN R. GABOR & ROBERT G. JAEGER Department of Biology, University of Southwestern Louisiana-backed salamanders, Plethodon cinereus, function as exclusive feeding areas,becauseprey are limited in availability resource is one of the dominant factors affecting agonistic behaviour for terrestrial salamanders. We

  7. Identification of Novel Synthetic Toll-like Receptor 2 Agonists by High Throughput Screening*

    E-print Network

    Hergenrother, Paul J.

    and adaptive immune responses fol- lowing infection. Drugs that target TLRs are of considerable interest as responses of profes- sional antigen-presenting cells essential for generating effec- tive adaptive immunity TLR2 agonists that may be of therapeutic benefit. Cellular innate immune responses drive the immediate

  8. Use of Street Methadone in Italian Heroin Addicts Presenting for Opioid Agonist Treatment

    Microsoft Academic Search

    Icro Maremmani; Matteo Pacini; Pier Paolo Pani; Dina Popovic; Anna Romano; Angelo G. I. Maremmani; Joseph Deltito; Giulio Perugi

    2009-01-01

    It is commonly assumed that people who are addicted to certain substances would abuse any substance. This position has never been supported by validly collected and analyzed research data. In this study, the authors examine the use of street methadone by heroin addicts seeking their first agonist opioid treatment in a clinical setting. Fifty-four heroin addicts who resorted to street

  9. The ?7 nAChR selective agonists as drug candidates for Alzheimer's disease.

    PubMed

    Fan, Huaimeng; Gu, Ruoxu; Wei, Dongqing

    2015-01-01

    The nicotinic acetylcholine receptors (nAChRs) are ion channels distribute in the central or peripheral nervous system. They are receptors of the neurotransmitter acetylcholine and activation of them by agonists mediates synaptic transmission in the neuron and muscle contraction in the neuromuscular junction. Current studies reveal relationship between the nAChRs and the learning and memory as well as cognation deficit in various neurological disorders such as Alzheimer's disease, Parkinson's disease, schizophrenia and drug addiction. There are various subtypes in the nAChR family and the ?7 nAChR is one of the most abundant subtypes in the brain. The ?7 nAChR is significantly reduced in the patients of Alzheimer's disease and is believed to interact with the A? amyloid. A? amyloid is co-localized with ?7 nAChR in the senile plaque and interaction between them induces neuron apoptosis and reduction of the ?7 nAChR expression. Treatment with ?7 agonist in vivo shows its neuron protective and procognation properties and significantly improves the learning and memory ability of the animal models. Therefore, the ?7 nAChR agonists are excellent drug candidates for Alzheimer's disease and we summarized here the current agonists that have selectivity of the ?7 nAChR over the other nAChR, introduced recent molecular modeling works trying to explain the molecular mechanism of their selectivity and described the design of novel allosteric modulators in our lab. PMID:25387975

  10. ?-Opioid receptor agonists inhibit migraine-related hyperalgesia, aversive state and cortical spreading depression in mice

    PubMed Central

    Pradhan, Amynah A; Smith, Monique L; Zyuzin, Jekaterina; Charles, Andrew

    2014-01-01

    Background and Purpose Migraine is an extraordinarily common brain disorder for which treatment options continue to be limited. Agonists that activate the ?-opioid receptor may be promising for the treatment of migraine as they are highly effective for the treatment of chronic rather than acute pain, do not induce hyperalgesia, have low abuse potential and have anxiolytic and antidepressant properties. The aim of this study was to investigate the therapeutic potential of ?-opioid receptor agonists for migraine by characterizing their effects in mouse migraine models. Experimental Approach Mechanical hypersensitivity was assessed in mice treated with acute and chronic doses of nitroglycerin (NTG), a known human migraine trigger. Conditioned place aversion to NTG was also measured as a model of migraine-associated negative affect. In addition, we assessed evoked cortical spreading depression (CSD), an established model of migraine aura, in a thinned skull preparation. Key Results NTG evoked acute and chronic mechanical and thermal hyperalgesia in mice, as well as conditioned place aversion. Three different ?-opioid receptor agonists, SNC80, ARM390 and JNJ20788560, significantly reduced NTG-evoked hyperalgesia. SNC80 also abolished NTG-induced conditioned place aversion, suggesting that ?-opioid receptor activation may also alleviate the negative emotional state associated with migraine. We also found that SNC80 significantly attenuated CSD, a model that is considered predictive of migraine preventive therapies. Conclusions and Implications These data show that ?-opioid receptor agonists modulate multiple basic mechanisms associated with migraine, indicating that ?-opioid receptors are a promising therapeutic target for this disorder. PMID:24467301

  11. Synthesis and pharmacological evaluation of 6-aminonicotinic acid analogues as novel GABA(A) receptor agonists.

    PubMed

    Petersen, Jette G; Sørensen, Troels; Damgaard, Maria; Nielsen, Birgitte; Jensen, Anders A; Balle, Thomas; Bergmann, Rikke; Frølund, Bente

    2014-09-12

    A series of 6-aminonicotinic acid analogues have been synthesized and pharmacologically characterized at native and selected recombinant GABA(A) receptors. 6-Aminonicotinic acid (3) as well as 2- and 4-alkylated analogues (9-11, 14-16) display low to mid-micromolar GABA(A)R binding affinities to native GABA(A) receptors (K(i) 1.1-24 ?M). The tetrahydropyridine analogue of 3 (22) shows low-nanomolar affinity (K(i) 0.044 ?M) and equipotency as an agonist to GABA itself as well as the standard GABA(A) agonist isoguvacine. Cavities surrounding the core of the GABA binding pocket were predicted by molecular interaction field calculations and docking studies in a ?1?2?2 GABA(A) receptor homology model, and were confirmed by affinities of substituted analogues of 3. The tight steric requirements observed for the remarkably few GABA(A)R agonists reported to date is challenged by our findings. New openings for agonist design are proposed which potentially could facilitate the exploration of different pharmacological profiles within the GABA(A)R area. PMID:25038482

  12. Hierarchical virtual screening: identification of potential high-affinity and selective ?(3)-adrenergic receptor agonists.

    PubMed

    Saxena, A K; Roy, K K

    2012-07-01

    The hierarchical virtual screening (HVS) study, consisting of pharmacophore modelling, docking and VS of the generated focussed virtual library, has been carried out to identify novel high-affinity and selective ?(3)-adrenergic receptor (?-AR) agonists. The best pharmacophore model, comprising one H-bond donor, two hydrophobes, one positive ionizable and one negative ionizable feature, was developed based on a training set of 51 ?(3)-AR agonists using the pharmacophore generation protocol implemented in Discovery Studio. The model was further validated with the test set, external set and ability of the pharmacophoric features to complement the active site amino acids of the homology modelled ?(3)-AR developed using MODELLER software. The focussed virtual library was generated using the structure-based insights gained from our earlier reported comprehensive study focussing on the structural basis of ?-AR subtype selectivity of representative agonists and antagonists. The HVS with the sequential use of the best pharmacophore model and homology modelled ?(3)-AR in the screening of the generated focussed library has led to the identification of potential virtual leads as novel high-affinity and selective ?(3)-AR agonists. PMID:22452658

  13. Toll-like receptor 7 agonists: chemical feature based pharmacophore identification and molecular docking studies.

    PubMed

    Yu, Hui; Jin, Hongwei; Sun, Lidan; Zhang, Liangren; Sun, Gang; Wang, Zhanli; Yu, Yongchun

    2013-01-01

    Chemical feature based pharmacophore models were generated for Toll-like receptors 7 (TLR7) agonists using HypoGen algorithm, which is implemented in the Discovery Studio software. Several methods tools used in validation of pharmacophore model were presented. The first hypothesis Hypo1 was considered to be the best pharmacophore model, which consists of four features: one hydrogen bond acceptor, one hydrogen bond donor, and two hydrophobic features. In addition, homology modeling and molecular docking studies were employed to probe the intermolecular interactions between TLR7 and its agonists. The results further confirmed the reliability of the pharmacophore model. The obtained pharmacophore model (Hypo1) was then employed as a query to screen the Traditional Chinese Medicine Database (TCMD) for other potential lead compounds. One hit was identified as a potent TLR7 agonist, which has antiviral activity against hepatitis virus in vitro. Therefore, our current work provides confidence for the utility of the selected chemical feature based pharmacophore model to design novel TLR7 agonists with desired biological activity. PMID:23526932

  14. New mechanism-based anticancer drugs that act as orphan nuclear receptor agonists 

    E-print Network

    Chintharlapalli, Sudhakar Reddy

    2007-09-17

    and KU7 cells, the PPAR�³ agonists induced caveolin-1 expression and this induction was significantly downregulated after cotreatment with the PPAR�³ antagonist GW9662. Since overexpression of caveolin-1 is known to suppress cancer cell and tumor...

  15. Inhibitory GTP binding protein G/sub i/ regulates US -adrenoceptor affinity towards US -agonists

    SciTech Connect

    Marbach, I.; Levitzki, A.

    1987-05-01

    Treatment of S-49 lymphoma cell membranes with pertussis toxin (PT) causes a three-fold reduction of US -adrenoceptor (US AR) affinity towards isoproterenol. A similar treatment with cholera toxin (CT) does not cause such a modulation. The effects were studied by the detailed analysis of SVI-cyanopindolol (CYP) binding curves in the absence and presence of increasing agonist concentrations. Thus, the authors were able to compare in detail the effects of G/sub s/ and G/sub i/ on the agonist-associated state of the US AR. In contrast to these findings, PT treatment does not have any effect on the displacement of SVI-CYP by (-)isoproterenol. These results demonstrate that the inhibitory GTP protein G/sub i/ modulates the US AR affinity towards US -agonists. This might be due to the association of G/sub i/ with the agonist-bound US AR x G/sub s/ x C complex within the membrane. This hypothesis, as well as others, is under investigation.

  16. Identification of surrogate agonists and antagonists for orphan G-protein-coupled receptor GPR139.

    PubMed

    Hu, Liaoyuan A; Tang, Pauline M; Eslahi, Nima K; Zhou, Tian; Barbosa, Joseph; Liu, Qingyun

    2009-08-01

    GPR139 is an orphan G-protein-coupled receptor (GPCR) that is expressed nearly exclusively in the central nervous system and may play a role in the control of locomotor activity. The signal transduction pathway and pharmacological function of GPR139, however, are still controversial due to the lack of natural or synthetic ligands. The authors report the characterization of human GPR139 signaling pathway and identification of surrogate agonists and antagonists. In both transient and stable transfections of HEK293F cells, overexpression of GPR139 increased basal intracellular cAMP concentrations compared to control cells. Furthermore, forskolin and isoproterenol-stimulated cAMP responses were enhanced in GPR139-expressing cells, suggesting that GPR139 is predominantly coupled to Galpha(s). The authors screened a large library of small molecules for compounds that increase cAMP levels in GPR139-expressing cells and identified a compound with GPR139 agonist activity. This compound increased cAMP production specifically in cells expressing GPR139 but not in cells expressing its highly homologous receptor GPR142. Furthermore, this compound did not induce calcium mobilization in GPR139 cells, indicating no Galpha(q)-mediated response. In addition, antagonist screening with the identified agonist yielded 2 classes of compounds as antagonists. The identification of surrogate agonists and antagonists of human GPR139 provides important tools for further study of this orphan GPCR. PMID:19525486

  17. Journal of Steroid Biochemistry & Molecular Biology 77 (2001) 229238 Common phytochemicals are ecdysteroid agonists and antagonists

    E-print Network

    McLachlan, John

    2001-01-01

    -gene assay and a cell differentiation assay of an ecdysone-responsive cell line, Cl.8+. We tested rutin in insects). None of the phytochemicals tested were ecdysone agonists in the reporter-gene assay,6]. Most significantly, aromatase * Corresponding author. Present address: Department of Biological

  18. Agonist\\/antagonist modulation in a series of 2-aryl benzimidazole H 4 receptor ligands

    Microsoft Academic Search

    Brad M. Savall; James P. Edwards; Jennifer D. Venable; Daniel J. Buzard; Robin Thurmond; Michael Hack; Patricia McGovern

    2010-01-01

    The present work details the transformation of a series of human histamine H4 agonists into potent functional antagonists. Replacement of the aminopyrrolidine diamine functionality with a 5,6-fused pyrrolopiperidine ring system led to an antagonist. The dissection of this fused diamine led to the eventual replacement with heterocycles. The incorporation of histamine as the terminal amine led to a very potent

  19. 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

  20. Peroxisome proliferator-activated receptor agonists modulate neuropathic pain: a link to chemokines?

    PubMed Central

    Freitag, Caroline M.; Miller, Richard J.

    2014-01-01

    Chronic pain presents a widespread and intractable medical problem. While numerous pharmaceuticals are used to treat chronic pain, drugs that are safe for extended use and highly effective at treating the most severe pain do not yet exist. Chronic pain resulting from nervous system injury (neuropathic pain) is common in conditions ranging from multiple sclerosis to HIV-1 infection to type II diabetes. Inflammation caused by neuropathy is believed to contribute to the generation and maintenance of neuropathic pain. Chemokines are key inflammatory mediators, several of which (MCP-1, RANTES, MIP-1?, fractalkine, SDF-1 among others) have been linked to chronic, neuropathic pain in both human conditions and animal models. The important roles chemokines play in inflammation and pain make them an attractive therapeutic target. Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear receptors known for their roles in metabolism. Recent research has revealed that PPARs also play a role in inflammatory gene repression. PPAR agonists have wide-ranging effects including inhibition of chemokine expression and pain behavior reduction in animal models. Experimental evidence suggests a connection between the pain ameliorating effects of PPAR agonists and suppression of inflammatory gene expression, including chemokines. In early clinical research, one PPAR? agonist, palmitoylethanolamide (PEA), shows promise in relieving chronic pain. If this link can be better established, PPAR agonists may represent a new drug therapy for neuropathic pain. PMID:25191225

  1. 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

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

    E-print Network

    Paris-Sud XI, Université de

    the kidney water reabsorption through binding and activating V2 receptor subtype. AVP also plays a crucial ; pharmacology ; Receptors, G-Protein-Coupled ; agonists ; antagonists & inhibitors ; metabolism ; Receptors localization and% [1 2] trafficking, receptor molecular structural analysis and developing new receptor

  3. The effect of agonistic interactions on the heart rate of group-housed sows

    Microsoft Academic Search

    Jeremy N. Marchant; Michael T. Mendl; Andrew R. Rudd; Donald M. Broom

    1995-01-01

    Inter-sow aggression can be a major welfare problem in group-housing systems and can also affect productivity. This experiment investigated the effect of different types of agonistic interaction using heart rate as an indicator of physiological response. The heart rates of nine Large White × Landrace sows housed in a large group with an electronic sow feeder system, were monitored during

  4. 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.…

  5. Primary Macrophage Chemotaxis Induced by Cannabinoid Receptor 2 Agonists Occurs Independently of the CB2 Receptor

    PubMed Central

    Taylor, Lewis; Christou, Ivy; Kapellos, Theodore S.; Buchan, Alice; Brodermann, Maximillian H.; Gianella-Borradori, Matteo; Russell, Angela; Iqbal, Asif J.; Greaves, David R.

    2015-01-01

    Activation of CB2 has been demonstrated to induce directed immune cell migration. However, the ability of CB2 to act as a chemoattractant receptor in macrophages remains largely unexplored. Using a real-time chemotaxis assay and a panel of chemically diverse and widely used CB2 agonists, we set out to examine whether CB2 modulates primary murine macrophage chemotaxis. We report that of 12 agonists tested, only JWH133, HU308, L-759,656 and L-759,633 acted as macrophage chemoattractants. Surprisingly, neither pharmacological inhibition nor genetic ablation of CB2 had any effect on CB2 agonist-induced macrophage chemotaxis. As chemotaxis was pertussis toxin sensitive in both WT and CB2-/- macrophages, we concluded that a non-CB1/CB2, Gi/o-coupled GPCR must be responsible for CB2 agonist-induced macrophage migration. The obvious candidate receptors GPR18 and GPR55 could not mediate JWH133 or HU308-induced cytoskeletal rearrangement or JWH133-induced ?-arrestin recruitment in cells transfected with either receptor, demonstrating that neither are the unidentified GPCR. Taken together our results conclusively demonstrate that CB2 is not a chemoattractant receptor for murine macrophages. Furthermore we show for the first time that JWH133, HU308, L-759,656 and L-759,633 have off-target effects of functional consequence in primary cells and we believe that our findings have wide ranging implications for the entire cannabinoid field. PMID:26033291

  6. 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. PMID:25859173

  7. Continuous Inhalation of Ipratropium Bromide for Acute Asthma Refractory to ?2-agonist Treatment.

    PubMed

    Koumbourlis, Anastassios C; 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. PMID:25859173

  8. Unusual compulsive behaviors primarily related to dopamine agonist therapy in Parkinson's disease and multiple system atrophy

    Microsoft Academic Search

    Andrew McKeon; Keith A. Josephs; Kevin J. Klos; Kathleen Hecksel; James H. Bower; J. Michael Bostwick; J. Eric Ahlskog

    2007-01-01

    Unusual compulsive behaviors (weighing, card and video game playing, fishing, gardening, intense interest in established hobbies, locking and unlocking doors, repetitive dressing and undressing) occurred in relation to dopamine agonist therapy (six patients) and levodopa therapy (one patient) in seven patients with parkinsonism (seven Parkinson's disease, one multiple system atrophy). These behaviors occurred in tandem with pathological gambling, hypersexuality, compulsive

  9. 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...

  10. ?2 Agonists Enhance the Efficacy of Simultaneous Enzyme Replacement Therapy in Murine Pompe Disease

    PubMed Central

    Koeberl, Dwight D.; Li, Songtao; Dai, Jian; Thurberg, Beth L.; Bali, Deeksha; Kishnani, Priya S.

    2011-01-01

    Enzyme replacement therapy (ERT) with recombinant human acid ?-glucosidase (rhGAA) has improved clinical outcomes in patients with Pompe disease; however, the response of skeletal muscle and the central nervous system to ERT has been attenuated. The poor response of skeletal muscle to ERT has been attributed to the low abundance of the cation-independent mannose-6-phosphate receptor (CI-MPR), which mediates receptor-mediated uptake of rhGAA. Hence the ability of adjunctive therapy with ?2-agonists to increase CI-MPR expression in skeletal muscle was evaluated during ERT in murine Pompe disease with regard to reversal of neuromuscular involvement. Mice with Pompe disease were treated with weekly rhGAA injections (20 mg/kg) and a selective ?2-agonist, either albuterol (30 mg/l in drinking water) or low-dose clenbuterol (6 mg/l in drinking water). Biochemical correction was enhanced by ?2-agonist treatment in both muscle and the cerebellum, indicating that adjunctive therapy could enhance efficacy from ERT in Pompe disease with regard to neuromuscular involvement. Intriguingly, clenbuterol slightly reduced muscle glycogen content independent of CI-MPR expression, as demonstrated in CI-MPR knockout/GAA knockout mice that were otherwise resistant to ERT. Thus, adjunctive therapy with ?2 agonists might improve the efficacy of ERT in Pompe disease and possibly other lysosomal storage disorders through enhancing receptor-mediated uptake of recombinant lysosomal enzymes. PMID:22154081

  11. The PPAR alpha agonist gemfibrozil is an ineffective treatment for spinal cord injured mice

    Microsoft Academic Search

    Akshata Almad; A. Todd Lash; Ping Wei; Amy E. Lovett-Racke; Dana M. McTigue

    2011-01-01

    Peroxisome Proliferator Activated Receptor (PPAR)-? is a key regulator of lipid metabolism and recent studies reveal it also regulates inflammation in several different disease models. Gemfibrozil, an agonist of PPAR-?, is a FDA approved drug for hyperlipidemia and has been shown to inhibit clinical signs in a rodent model of multiple sclerosis. Since many studies have shown improved outcome from

  12. EFFECT OF CHRONIC TREATMENT WITH THE GONADOTROPHIN-RELEASING HORMONE AGONIST AZAGLY-NAFARELIN ON BASAL CONCENTRATIONS OF LH IN PREPUBERTAL BULLS

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Infusion of GnRH agonists for extended periods inhibits pulsatile LH release, but enhances testicular function of bulls. The reason long-term infusion of GnRH agonist enhances testosterone (T) concentration in blood of cattle treated for extended periods with GnRH agonists has not been delineated. T...

  13. PHI 1901 : Pense rationnelle et argumentation Dpartement de philosophie, Facult des arts et des sciences

    E-print Network

    Parrott, Lael

    PHI 1901 : Pensée rationnelle et argumentation Département de philosophie, Faculté des arts et des rationalité et de l'importance de l'argumentation. Analyse du concept, de la définition et de la proposition, acceptabilité des prémisses, nécessité et suffisance. Étude des sophismes et des erreurs de raisonnements

  14. Evaluation des proprits thermiques de surface de la neige par assimilation des

    E-print Network

    Ribes, Aurélien

    simulations Crocus/forçage ERA-interim, les réanalyses ERA-interim et les données MODIS. #12;Plan I. Cycles, des simulations Crocus et des réanalyses ERA-interim IV. Conclusion et travaux envisagés #12;I. Cycles partir des données MODIS, des simulations Crocus et des réanalyses ERA-iterim #12;Cartes mensuelles de

  15. Gestion des terminologies riches : l'exemple des et Mathieu MANGEOT

    E-print Network

    Paris-Sud XI, Université de

    Gestion des terminologies riches : l'exemple des acronymes Ying ZHANG 1 et Mathieu MANGEOT 1 (1 ______________________________________________________________________________________________________________ La gestion des terminologies pose encore des problèmes, en particulier pour des constructions____________________________________________________________________________________________________________ Complex terminologies management ­ the case of acronyms Terminology management is still problematic

  16. FRET-Based Detection of M1 Muscarinic Acetylcholine Receptor Activation by Orthosteric and Allosteric Agonists

    PubMed Central

    Markovic, Danijela; Holdich, Jonathan; Al-Sabah, Suleiman; Mistry, Rajendra; Krasel, Cornelius; Mahaut-Smith, Martyn P.; Challiss, R. A. John

    2012-01-01

    Background and Objective Muscarinic acetylcholine receptors (mAChRs) are 7-transmembrane, G protein-coupled receptors that regulate a variety of physiological processes and represent potentially important targets for therapeutic intervention. mAChRs can be stimulated by full and partial orthosteric and allosteric agonists, however the relative abilities of such ligands to induce conformational changes in the receptor remain unclear. To gain further insight into the actions of mAChR agonists, we have developed a fluorescently tagged M1 mAChR that reports ligand-induced conformational changes in real-time by changes in Förster resonance energy transfer (FRET). Methods Variants of CFP and YFP were inserted into the third intracellular loop and at the end of the C-terminus of the mouse M1 mAChR, respectively. The optimized FRET receptor construct (M1-cam5) was expressed stably in HEK293 cells. Results The variant CFP/YFP-receptor chimera expressed predominantly at the plasma membrane of HEK293 cells and displayed ligand-binding affinities comparable with those of the wild-type receptor. It also retained an ability to interact with G?q/11 proteins and to stimulate phosphoinositide turnover, ERK1/2 phosphorylation and undergo agonist-dependent internalization. Addition of the full agonist methacholine caused a reversible decrease in M1 FRET (FEYFP/FECFP) that was prevented by atropine pre-addition and showed concentration-dependent amplitude and kinetics. Partial orthosteric agonists, arecoline and pilocarpine, as well as allosteric agonists, AC-42 and 77-LH-28-1, also caused atropine-sensitive decreases in the FRET signal, which were smaller in amplitude and significantly slower in onset compared to those evoked by methacholine. Conclusion The M1 FRET-based receptor chimera reports that allosteric and orthosteric agonists induce similar conformational changes in the third intracellular loop and/or C-terminus, and should prove to be a valuable molecular reagent for pharmacological and structural investigations of M1 mAChR activation. PMID:22272263

  17. Stimulants as Specific Inducers of Dopamine-Independent ? Agonist Self-Administration in Rats

    PubMed Central

    Hiranita, Takato; Soto, Paul L.; Tanda, Gianluigi; Kopajtic, Theresa A.

    2013-01-01

    A previous study showed that cocaine self-administration induced dopamine-independent reinforcing effects of ? agonists mediated by their selective actions at ?1 receptors (?1Rs), which are intracellularly mobile chaperone proteins implicated in abuse-related effects of stimulants. The present study assessed whether the induction was specific to self-administration of cocaine. Rats were trained to self-administer the dopamine releaser, d-methamphetamine (0.01–0.32 mg/kg per injection), the ?-opioid receptor agonist, heroin (0.001–0.032 mg/kg per injection), and the noncompetitive N-methyl-d-aspartate receptor/channel antagonist ketamine (0.032–1.0 mg/kg per injection). As with cocaine, self-administration of d-methamphetamine induced reinforcing effects of the selective ?1R agonists PRE-084 [2-(4-morpholinethyl)1-phenylcyclohexanecarboxylate hydrochloride] and (+)-pentazocine (0.032–1.0 mg/kg per injection, each). In contrast, neither self-administration of heroin nor ketamine induced PRE-084 or (+)-pentazocine (0.032–10 mg/kg per injection, each) self-administration. Although the ?1R agonists did not maintain responding in subjects with histories of heroin or ketamine self-administration, substitution for those drugs was obtained with appropriate agonists (e.g., remifentanil, 0.1–3.2 µg/kg per injection, for heroin and (5S,10R)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine ((+)-MK 801; dizocilpine), 0.32–10.0 µg/kg per injection, for ketamine). The ?R antagonist N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamine dihydrobromide (BD 1008; 1.0–10 mg/kg) dose-dependently blocked PRE-084 self-administration but was inactive against d-methamphetamine, heroin, and ketamine. In contrast, PRE-084 self-administration was affected neither by the dopamine receptor antagonist (+)-butaclamol (10–100 ?g/kg) nor by the opioid antagonist (?)-naltrexone (1.0–10 mg/kg), whereas these antagonists were active against d-methamphetamine and heroin self-administration, respectively. The results indicate that experience specifically with indirect-acting dopamine agonists induces reinforcing effects of previously inactive ?1R agonists. It is further suggested that induced ?1R reinforcing mechanisms may play an essential role in treatment-resistant stimulant abuse, suggesting new approaches for the development of effective medications for its treatment. PMID:23908387

  18. Stimulants as specific inducers of dopamine-independent ? agonist self-administration in rats.

    PubMed

    Hiranita, Takato; Soto, Paul L; Tanda, Gianluigi; Kopajtic, Theresa A; Katz, Jonathan L

    2013-10-01

    A previous study showed that cocaine self-administration induced dopamine-independent reinforcing effects of ? agonists mediated by their selective actions at ?1 receptors (?1Rs), which are intracellularly mobile chaperone proteins implicated in abuse-related effects of stimulants. The present study assessed whether the induction was specific to self-administration of cocaine. Rats were trained to self-administer the dopamine releaser, d-methamphetamine (0.01-0.32 mg/kg per injection), the ?-opioid receptor agonist, heroin (0.001-0.032 mg/kg per injection), and the noncompetitive N-methyl-d-aspartate receptor/channel antagonist ketamine (0.032-1.0 mg/kg per injection). As with cocaine, self-administration of d-methamphetamine induced reinforcing effects of the selective ?1R agonists PRE-084 [2-(4-morpholinethyl)1-phenylcyclohexanecarboxylate hydrochloride] and (+)-pentazocine (0.032-1.0 mg/kg per injection, each). In contrast, neither self-administration of heroin nor ketamine induced PRE-084 or (+)-pentazocine (0.032-10 mg/kg per injection, each) self-administration. Although the ?1R agonists did not maintain responding in subjects with histories of heroin or ketamine self-administration, substitution for those drugs was obtained with appropriate agonists (e.g., remifentanil, 0.1-3.2 µg/kg per injection, for heroin and (5S,10R)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine ((+)-MK 801; dizocilpine), 0.32-10.0 µg/kg per injection, for ketamine). The ?R antagonist N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamine dihydrobromide (BD 1008; 1.0-10 mg/kg) dose-dependently blocked PRE-084 self-administration but was inactive against d-methamphetamine, heroin, and ketamine. In contrast, PRE-084 self-administration was affected neither by the dopamine receptor antagonist (+)-butaclamol (10-100 ?g/kg) nor by the opioid antagonist (-)-naltrexone (1.0-10 mg/kg), whereas these antagonists were active against d-methamphetamine and heroin self-administration, respectively. The results indicate that experience specifically with indirect-acting dopamine agonists induces reinforcing effects of previously inactive ?1R agonists. It is further suggested that induced ?1R reinforcing mechanisms may play an essential role in treatment-resistant stimulant abuse, suggesting new approaches for the development of effective medications for its treatment. PMID:23908387

  19. 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.

  20. Formation et intgration Mise jour des dossiers

    E-print Network

    Spino, Claude

    Formation et intégration Mise à jour des dossiers du personnel Intégration des nouveaux employés les moyennes et grandes entreprises, ainsi que dans les domaines publics et de la consultation privée affaires permet aux étudiants d'acquérir des connaissances et des qualités propres au domaine de la gestion

  1. Gntique formelle des pigmentations humaines variations continues

    E-print Network

    Boyer, Edmond

    Génétique formelle des pigmentations humaines à variations continues : beaucoup d'hypothèses, peu et de mesures sont actuellement disponibles concer- nant la biochimie des pigments humains, leur génétique physiologique, les répartitions mondiales des pigmentations de la peau et des cheveux. La

  2. ACTION DES ANTIBIOTIQUES SUR PORCELETS ALLAITS

    E-print Network

    Boyer, Edmond

    VII. - ACTION DES ANTIBIOTIQUES SUR PORCELETS ALLAITÉS E. SALMON LEGAGNEUR M. MICHEL Station de. - Technique de distribution. C. - Animaux. D. - Dosage des antibiotiques. E. - Etude des flores intestinales : a) mortalité ; b) diarrhées ; c) régularité. D. - Étude des flores intestinales : a) Examen

  3. Comparative toxicity of three ecdysone agonist insecticides against the Mediterranean flour moth.

    PubMed

    Hami, M; Taibi, F; Smagghe, G; Soltani-Mazouni, N

    2005-01-01

    The Mediterranean flour moth, Ephestia Kuehniella Zeller (Lepidoptera: Pyralidae), is an important pest in stored products worldwide, and is one of the major pests in flour mills in Algeria. Because environmental consideration, alternative approaches to neurotoxic insecticides, as well as safe, effective, and sound integrated pest management strategies are developed pest control agents such as the insect growth regulator (IGRs). Among these IGRs, the bisacylhydrazine derivatives are nonsteroidal ecdysterold agonists that mimic the action of moulting hormones and induce a precocious and incomplete moult in several insect orders. In topical bioassays using the pupae of E. kuehniella, three ecdysteroid agonists: RH-5849, the first bisaclhydrazine ecdysone agonist and two analogs, RH-5992 (tebufenozide) and RH-0345 (halofenozide), were evaluated on the reproduction under laboratory conditions. In a first series of experiments, the efficacy of these compounds was tested. These compounds exhibited insecticidal activity and the duration of pupal development was reduced with a dose-response relationship. Among the three tested compounds, tebufenozide (LD50 = 0.005 microg) appeared the most potent ecdysteroid agonist against E. kuehniella (RH-5849: LD50 = 0.05 microg and RH-0345: LD50 = 5.10 microg). In a second series of experiments, the effects of the ecdysone agonists (LD50) were investigated on the reproduction. Data showed that the three compounds affected growth of ovaries as evidenced by morphometric measurements of the ovaries from newly emerged adult females. In addition, the thickness of the chorion from basal oocytes was reduced only by RH-5992 and RH-0345. However, electron microscopic observations revealed that the three compounds had no significant effect on the fine structure of chorion. Finally, measurements of ovarian ecdysteroids' production by an enzyme immunoassay showed an increase in the hormonal amounts recorded in treated series compared to control series. PMID:16628915

  4. Natural product agonists of peroxisome proliferator-activated receptor gamma (PPAR?): a review.

    PubMed

    Wang, Limei; Waltenberger, Birgit; Pferschy-Wenzig, Eva-Maria; Blunder, Martina; Liu, Xin; Malainer, Clemens; Blazevic, Tina; Schwaiger, Stefan; Rollinger, Judith M; Heiss, Elke H; Schuster, Daniela; Kopp, Brigitte; Bauer, Rudolf; Stuppner, Hermann; Dirsch, Verena M; Atanasov, Atanas G

    2014-11-01

    Agonists of the nuclear receptor PPAR? are therapeutically used to combat hyperglycaemia associated with the metabolic syndrome and type 2 diabetes. In spite of being effective in normalization of blood glucose levels, the currently used PPAR? agonists from the thiazolidinedione type have serious side effects, making the discovery of novel ligands highly relevant. Natural products have proven historically to be a promising pool of structures for drug discovery, and a significant research effort has recently been undertaken to explore the PPAR?-activating potential of a wide range of natural products originating from traditionally used medicinal plants or dietary sources. The majority of identified compounds are selective PPAR? modulators (SPPARMs), transactivating the expression of PPAR?-dependent reporter genes as partial agonists. Those natural PPAR? ligands have different binding modes to the receptor in comparison to the full thiazolidinedione agonists, and on some occasions activate in addition PPAR? (e.g. genistein, biochanin A, sargaquinoic acid, sargahydroquinoic acid, resveratrol, amorphastilbol) or the PPAR?-dimer partner retinoid X receptor (RXR; e.g. the neolignans magnolol and honokiol). A number of in vivo studies suggest that some of the natural product activators of PPAR? (e.g. honokiol, amorfrutin 1, amorfrutin B, amorphastilbol) improve metabolic parameters in diabetic animal models, partly with reduced side effects in comparison to full thiazolidinedione agonists. The bioactivity pattern as well as the dietary use of several of the identified active compounds and plant extracts warrants future research regarding their therapeutic potential and the possibility to modulate PPAR? activation by dietary interventions or food supplements. PMID:25083916

  5. Allosteric activation of the follicle-stimulating hormone (FSH) receptor by selective, nonpeptide agonists.

    PubMed

    Yanofsky, Stephen D; Shen, Emily S; Holden, Frank; Whitehorn, Erik; Aguilar, Barbara; Tate, Emily; Holmes, Christopher P; Scheuerman, Randall; MacLean, Derek; Wu, May M; Frail, Donald E; López, Francisco J; Winneker, Richard; Arey, Brian J; Barrett, Ronald W

    2006-05-12

    The pituitary glycoprotein hormones, luteinizing hormone and follicle-stimulating hormone (FSH), act through their cognate receptors to initiate a series of coordinated physiological events that results in germ cell maturation. Given the importance of FSH in regulating folliculogenesis and fertility, the development of FSH mimetics has been sought to treat infertility. Currently, purified and recombinant human FSH are the only FSH receptor (FSH-R) agonists available for infertility treatment. By screening unbiased combinatorial chemistry libraries, using a cAMP-responsive luciferase reporter assay, we discovered thiazolidinone agonists (EC50's = 20 microm) of the human FSH-R. Subsequent analog library screening and parallel synthesis optimization resulted in the identification of a potent agonist (EC50 = 2 nm) with full efficacy compared with FSH that was FSH-R-selective and -dependent. The compound mediated progesterone production in Y1 cells transfected with the human FSH-R (EC50 = 980 nm) and estradiol production from primary rat ovarian granulosa cells (EC50 = 10.5 nm). This and related compounds did not compete with FSH for binding to the FSH-R. Use of human FSH/thyroid-stimulating hormone (TSH) receptor chimeras suggested a novel mechanism for receptor activation through a binding site independent of the natural hormone binding site. This study is the first report of a high affinity small molecule agonist that activates a glycoprotein hormone receptor through an allosteric mechanism. The small molecule FSH receptor agonists described here could lead to an oral alternative to the current parenteral FSH treatments used clinically to induce ovarian stimulation for both in vivo and in vitro fertilization therapy. PMID:16540466

  6. An Accessory Agonist Binding Site Promotes Activation of ?4?2* Nicotinic Acetylcholine Receptors.

    PubMed

    Wang, Jingyi; Kuryatov, Alexander; Sriram, Aarati; Jin, Zhuang; Kamenecka, Theodore M; Kenny, Paul J; Lindstrom, Jon

    2015-05-29

    Neuronal nicotinic acetylcholine receptors containing ?4, ?2, and sometimes other subunits (?4?2* nAChRs) regulate addictive and other behavioral effects of nicotine. These nAChRs exist in several stoichiometries, typically with two high affinity acetylcholine (ACh) binding sites at the interface of ?4 and ?2 subunits and a fifth accessory subunit. A third low affinity ACh binding site is formed when this accessory subunit is ?4 but not if it is ?2. Agonists selective for the accessory ACh site, such as 3-[3-(3-pyridyl)-1,2,4-oxadiazol-5-yl]benzonitrile (NS9283), cannot alone activate a nAChR but can facilitate more efficient activation in combination with agonists at the canonical ?4?2 sites. We therefore suggest categorizing agonists according to their site selectivity. NS9283 binds to the accessory ACh binding site; thus it is termed an accessory site-selective agonist. We expressed (?4?2)2 concatamers in Xenopus oocytes with free accessory subunits to obtain defined nAChR stoichiometries and ?4/accessory subunit interfaces. We show that ?2, ?3, ?4, and ?6 accessory subunits can form binding sites for ACh and NS9283 at interfaces with ?4 subunits, but ?2 and ?4 accessory subunits cannot. To permit selective blockage of the accessory site, ?4 threonine 126 located on the minus side of ?4 that contributes to the accessory site, but not the ?4?2 sites, was mutated to cysteine. Alkylation of this cysteine with a thioreactive reagent blocked activity of ACh and NS9283 at the accessory site. Accessory agonist binding sites are promising drug targets. PMID:25869137

  7. Natural product agonists of peroxisome proliferator-activated receptor gamma (PPAR?): a review

    PubMed Central

    Wang, Limei; Waltenberger, Birgit; Pferschy-Wenzig, Eva-Maria; Blunder, Martina; Liu, Xin; Malainer, Clemens; Blazevic, Tina; Schwaiger, Stefan; Rollinger, Judith M.; Heiss, Elke H.; Schuster, Daniela; Kopp, Brigitte; Bauer, Rudolf; Stuppner, Hermann; Dirsch, Verena M.; Atanasov, Atanas G.

    2014-01-01

    Agonists of the nuclear receptor PPAR? are therapeutically used to combat hyperglycaemia associated with the metabolic syndrome and type 2 diabetes. In spite of being effective in normalization of blood glucose levels, the currently used PPAR? agonists from the thiazolidinedione type have serious side effects, making the discovery of novel ligands highly relevant. Natural products have proven historically to be a promising pool of structures for drug discovery, and a significant research effort has recently been undertaken to explore the PPAR?-activating potential of a wide range of natural products originating from traditionally used medicinal plants or dietary sources. The majority of identified compounds are selective PPAR? modulators (SPPARMs), transactivating the expression of PPAR?-dependent reporter genes as partial agonists. Those natural PPAR? ligands have different binding modes to the receptor in comparison to the full thiazolidinedione agonists, and on some occasions activate in addition PPAR? (e.g. genistein, biochanin A, sargaquinoic acid, sargahydroquinoic acid, resveratrol, amorphastilbol) or the PPAR?-dimer partner retinoid X receptor (RXR; e.g. the neolignans magnolol and honokiol). A number of in vivo studies suggest that some of the natural product activators of PPAR? (e.g. honokiol, amorfrutin 1, amorfrutin B, amorphastilbol) improve metabolic parameters in diabetic animal models, partly with reduced side effects in comparison to full thiazolidinedione agonists. The bioactivity pattern as well as the dietary use of several of the identified active compounds and plant extracts warrants future research regarding their therapeutic potential and the possibility to modulate PPAR? activation by dietary interventions or food supplements. PMID:25083916

  8. Nuclear receptors and autoimmune disease: the potential of PPAR agonists to treat multiple sclerosis.

    PubMed

    Racke, Michael K; Gocke, Anne R; Muir, Mark; Diab, Asim; Drew, Paul D; Lovett-Racke, Amy E

    2006-03-01

    Experimental autoimmune encephalomyelitis (EAE) is a T-cell-mediated, autoimmune disorder characterized by central nervous system inflammation and demyelination, features reminiscent of the human disease, multiple sclerosis (MS). Prior work in the EAE model has suggested that encephalitogenic T cells are of the T helper (Th)-1 phenotype. Our group has performed several studies in the EAE model that suggest that a strategy for treating autoimmune disorders is to convert the pathogenic cells from the Th1 to Th2 phenotype. Peroxisome proliferator-activated receptors (PPARs) are members of a nuclear hormone receptor superfamily that include receptors for steroids, retinoids, and thyroid hormone, all of which are known to affect the immune response. Recently, we examined the role of PPARgamma in EAE and observed that administration of the PPARgamma agonist 15-deoxy-Delta(12,14) prostaglandin J2 exerted a significant therapeutic effect predominantly by inhibiting the activation and expansion of encephalitogenic T cells. One potential advantage in studying PPARalpha agonists is that they have been very well tolerated when used in humans to treat conditions such as elevated triglycerides. Building on prior work in immune deviation and with PPAR agonists, we have demonstrated that PPARalpha agonists can alter the cytokine phenotype of myelin-reactive T cells, alter their encephalitogenicity, and be useful in the treatment of EAE. The fact that PPARalpha agonists have been used as therapeutic agents in humans to treat metabolic conditions for over 25 years with little toxicity makes them attractive candidates for use as adjunctive therapies in MS. PMID:16484546

  9. Agonists with supraphysiological efficacy at the muscarinic M2 ACh receptor

    PubMed Central

    Schrage, R; Seemann, WK; Klöckner, J; Dallanoce, C; Racké, K; Kostenis, E; De Amici, M; Holzgrabe, U; Mohr, K

    2013-01-01

    Background and Purpose Artificial agonists may have higher efficacy for receptor activation than the physiological agonist. Until now, such ‘superagonism’ has rarely been reported for GPCRs. Iperoxo is an extremely potent muscarinic receptor agonist. We hypothesized that iperoxo is a ‘superagonist’. Experimental Approach Signalling of iperoxo and newly synthesized structural analogues was compared with that of ACh at label-free M2 muscarinic receptors applying whole cell dynamic mass redistribution, measurement of G-protein activation, evaluation of cell surface agonist binding and computation of operational efficacies. Key Results In CHO-hM2 cells, iperoxo significantly exceeds ACh in Gi/Gs signalling competence. In the orthosteric loss-of-function mutant M2-Y1043.33A, the maximum effect of iperoxo is hardly compromised in contrast to ACh. ‘Superagonism’ is preserved in the physiological cellular context of MRC-5 human lung fibroblasts. Structure–signalling relationships including iperoxo derivatives with either modified positively charged head group or altered tail suggest that ‘superagonism’ of iperoxo is mechanistically based on parallel activation of the receptor protein via two orthosteric interaction points. Conclusion and Implications Supraphysiological agonist efficacy at muscarinic M2 ACh receptors is demonstrated for the first time. In addition, a possible underlying molecular mechanism of GPCR ‘superagonism’ is provided. We suggest that iperoxo-like orthosteric GPCR activation is a new avenue towards a novel class of receptor activators. Linked Article This article is commented on by Langmead and Christopoulos, pp. 353–356 of this issue. To view this commentary visit http://dx.doi.org/10.1111/bph.12142 PMID:23062057

  10. Agonist-selective endocytosis of mu opioid receptor by neurons in vivo.

    PubMed Central

    Sternini, C; Spann, M; Anton, B; Keith, D E; Bunnett, N W; von Zastrow, M; Evans, C; Brecha, N C

    1996-01-01

    Opiate alkaloids are potent analgesics that exert multiple pharmacological effects in the nervous system by activating G protein-coupled receptors. Receptor internalization upon stimulation may be important for desensitization and resensitization, which affect cellular responsiveness to ligands. Here, we investigated the agonist-induced internalization of the mu opioid receptor (MOR) in vivo by using the guinea pig ileum as a model system and immunohistochemistry with an affinity-purified antibody to the C terminus of rat MOR. Antibody specificity was confirmed by the positive staining of human embryonic kidney 293 cells transfected with epitope-tagged MOR cDNA, by the lack of staining of cells transfected with the delta or kappa receptor cDNA, and by the abolition of staining when the MOR antibody was preadsorbed with the MOR peptide fragment. Abundant MOR immunoreactivity (MOR-IR) was localized to the cell body, dendrites, and axonal processes of myenteric neurons. Immunostaining was primarily confined to the plasma membrane of cell bodies and processes. Within 15 min of an intraperitoneal injection of the opiate agonist etorphine, intense MOR-IR was present in vesicle-like structures, which were identified as endosomes by confocal microscopy. At 30 min, MOR-IR was throughout the cytoplasm and in perinuclear vesicles. MOR-IR was still internalized at 120 min. Agonist-induced endocytosis was completely inhibited by the opiate antagonist naloxone. Interestingly, morphine, a high-affinity MOR agonist, did not cause detectable internalization, but it partially inhibited the etorphine-induced MOR endocytosis. These results demonstrate the occurrence of agonist-selective MOR endocytosis in neurons naturally expressing this receptor in vivo and suggest the existence of different mechanisms regulating cellular responsiveness to ligands. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 PMID:8799185

  11. K+ efflux agonists induce NLRP3 inflammasome activation independently of Ca2+ signaling.

    PubMed

    Katsnelson, Michael A; Rucker, L Graham; Russo, Hana M; Dubyak, George R

    2015-04-15

    Perturbation of intracellular ion homeostasis is a major cellular stress signal for activation of NLRP3 inflammasome signaling that results in caspase-1-mediated production of IL-1? and pyroptosis. However, the relative contributions of decreased cytosolic K(+) concentration versus increased cytosolic Ca(2+) concentration ([Ca(2+)]) remain disputed and incompletely defined. We investigated roles for elevated cytosolic [Ca(2+)] in NLRP3 activation and downstream inflammasome signaling responses in primary murine dendritic cells and macrophages in response to two canonical NLRP3 agonists (ATP and nigericin) that facilitate primary K(+) efflux by mechanistically distinct pathways or the lysosome-destabilizing agonist Leu-Leu-O-methyl ester. The study provides three major findings relevant to this unresolved area of NLRP3 regulation. First, increased cytosolic [Ca(2+)] was neither a necessary nor sufficient signal for the NLRP3 inflammasome cascade during activation by endogenous ATP-gated P2X7 receptor channels, the exogenous bacterial ionophore nigericin, or the lysosomotropic agent Leu-Leu-O-methyl ester. Second, agonists for three Ca(2+)-mobilizing G protein-coupled receptors (formyl peptide receptor, P2Y2 purinergic receptor, and calcium-sensing receptor) expressed in murine dendritic cells were ineffective as activators of rapidly induced NLRP3 signaling when directly compared with the K(+) efflux agonists. Third, the intracellular Ca(2+) buffer, BAPTA, and the channel blocker, 2-aminoethoxydiphenyl borate, widely used reagents for disruption of Ca(2+)-dependent signaling pathways, strongly suppressed nigericin-induced NLRP3 inflammasome signaling via mechanisms dissociated from their canonical or expected effects on Ca(2+) homeostasis. The results indicate that the ability of K(+) efflux agonists to activate NLRP3 inflammasome signaling can be dissociated from changes in cytosolic [Ca(2+)] as a necessary or sufficient signal. PMID:25762778

  12. Absorptionsspektrum des Sehpurpurs und des Sehgelb. „Nachbleichung des Sehgelb im Dunkeln“

    Microsoft Academic Search

    Yuji Hosoya

    1934-01-01

    Zusammenfassung Eine photoelektrische Versuchsanordnung, die aus einer Selen-Sperrschichtphotozelle, einemMollschen Spiegelgalvanometer und einem Monochromator besteht, ist sehr geeignet das Absorptionsspektrum der photosensiblen Substanz der Netzhaut ohne die Gefahr der Bleichung während der Messung zu bestimmen. Mit diesen Meßgeräten wurde die spektrale Absorption des mit früheren, sowie neuerlich von mir benutzten Extraktionsmitteln hergestellten Sehpurpurs und des Sehgelb genauer und viel schneller als

  13. 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 ?

  14. Activation of Cyclic AMP Synthesis by Full and Partial Beta-Adrenergic Receptor Agonists in Chicken Skeletal Muscle Cells

    NASA Technical Reports Server (NTRS)

    Young, R. B.; Bridge, K. Y.; Cureri, Peter A. (Technical Monitor)

    2002-01-01

    Several beta-adrenergic receptor (bAR) agonists are known to cause hypertrophy of skeletal muscle tissue. Accordingly, 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 concentrations were approximately 15-fold weaker than isoproterenol in stimulating the rate of cAMP synthesis. When cimaterol and clenbuterol were added to culture media at concentrations known to cause significant muscle hypertrophy in animals, there was no detectable effect on stimulation of cAMP synthesis. Finally, these same levels of cimaterol and clenbuterol did not antagonize the stimulation of cAMP by either epinephrine or isoproterenol.

  15. Activation of Cyclic AMP Synthesis by Full and Partial Beta-Adrenergic Receptor Agonists in Chicken Skeletal Muscle Cells

    NASA Technical Reports Server (NTRS)

    Young, R. B.; Bridge, K. Y.

    2003-01-01

    Several beta-adrenergic receptor (bAR) agonists are known to cause hypertrophy of skeletal muscle tissue. Accordingly, 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 concentrations were approximately 15-fold weaker than isoproterenol in stimulating the rate of CAMP synthesis. When cimaterol and clenbuterol were added to culture media at concentrations known to cause significant muscle hypertrophy in animals, there was no detectable effect on stimulation of CAMP synthesis. Finally, these same levels of cimaterol and clenbuterol did not antagonize the stimulation of CAMP by either epinephrine or isoproterenol.

  16. Agonists of growth hormone-releasing hormone stimulate self-renewal of cardiac stem cells and promote their survival

    PubMed Central

    Florea, Victoria; Majid, Sonia S.; Kanashiro-Takeuchi, Rosemeire M.; Cai, Ren-Zhi; Block, Norman L.; Schally, Andrew V.; Hare, Joshua M.; Rodrigues, Claudia O.

    2014-01-01

    The beneficial effects of agonists of growth hormone-releasing hormone receptor (GHRH-R) in heart failure models are associated with an increase in the number of ckit+ cardiac stem cells (CSCs). The goal of the present study was to determine the presence of GHRH-R in CSCs, the effect of GHRH-R agonists on their proliferation and survival, and the mechanisms involved. We investigated the expression of GHRH-R in CSCs of different species and the effect of GHRH-R agonists on their cell proliferation and survival. GHRH-R is expressed in ckit+ CSCs isolated from mouse, rat, and pig. Treatment of porcine CSCs with the GHRH-R agonist JI-38 significantly increased the rate of cell division. Similar results were observed with other GHRH-R agonists, MR-356 and MR-409. JI-38 exerted a protective effect on survival of porcine CSCs under conditions of oxidative stress induced by exposure to hydrogen peroxide. Treatment with JI-38 before exposure to peroxide significantly reduced cell death. A similar effect was observed with MR-356. Addition of GHRH-R agonists to porcine CSCs induced activation of ERK and AKT pathways as determined by increased expression of phospho-ERK and phospho-AKT. Inhibitors of ERK and AKT pathways completely reversed the effect of GHRH-R agonists on CSC proliferation. Our findings extend the observations of the expression of GHRH-R by CSCs and demonstrate that GHRH-R agonists have a direct effect on proliferation and survival of CSCs. These results support the therapeutic use of GHRH-R agonists for stimulating endogenous mechanisms for myocardial repair or for preconditioning of stem cells before transplantation. PMID:25404316

  17. Addition of gonadotropin releasing hormone agonist for luteal phase support in in-vitro fertilization: an analysis of 2739 cycles

    PubMed Central

    ?im?ek, Erhan; K?l?çda?, Esra Bulgan; Aytaç, P?nar Ça?lar; Çoban, Gonca; ?im?ek, Seda Yüksel; Çok, Tayfun; Haydardedeo?lu, Bülent

    2015-01-01

    Objective Luteal phase is defective in in vitro fertilization (IVF) cycles, and many regimens were tried for the very best luteal phase support (LPS). Gonadotropin releasing hormone (GnRH) agonist use, which was administered as an adjunct to the luteal phase support in IVF cycles, was suggested to improve pregnancy outcome measures in certain randomized studies. We analyzed the effects of addition of GnRH agonist to standard progesterone luteal support on pregnancy outcome measures, particularly the live birth rates. Material and Methods This is a retrospective cohort study, including 2739 IVF cycles. Long GnRH agonist and antagonist stimulation IVF cycles with cleavage-stage embryo transfer were included. Cycles were divided into two groups: Group A included cycles with single-dose GnRH agonist plus progesterone LPS and Group B included progesterone only LPS. Live birth rates were the primary outcome measures of the analysis. Miscarriage rates and multiple pregnancy rates were the secondary outcome measures. Results Live birth rates were not statistically different in GnRH agonist plus progesterone (Group A) and progesterone only (Group B) groups in both the long agonist and antagonist stimulation arms (40.8%/41.2% and 32.8%/34.4%, p<0.05 respectively). Moreover, pregnancy rates, implantation rates, and miscarriage rates were found to be similar between groups. Multiple pregnancy rates in antagonist cycles were significantly higher in Group A than those in Group B (12.0% and 6.9%, respectively). Conclusion A beneficial effect of a single dose of GnRH agonist administration as a luteal phase supporting agent is yet to be determined because of the wide heterogeneity of data present in literature. Well-designed randomized clinical studies are required to clarify any effect of luteal GnRH agonist addition on pregnancy outcome measures with different doses, timing, and administration routes of GnRH agonists. PMID:26097392

  18. Synthesis and biological activities of some new dibenzopyranones and dibenzopyrans: search for potential oestrogen receptor agonists and antagonists.

    PubMed

    Pandey, Jaya; Jha, Ashok K; Hajela, K

    2004-05-01

    Continuing our search for newer oestrogen agonists or antagonists and extending our work on the exploration of benzopyran related compounds, some new tricyclic molecules bridged between the active molecules of 3,4-diaryl chroman and 2,3-diaryl benzopyrans have been synthesised. Structural modifications at different positions with elements known to impart agonist or antagonist activities have been carried out to prepare the desired molecules. The target compounds were screened for their anti-osteoporotic (agonist) and anti-uterotrophic (antagonist) activities and were found to be moderately active. PMID:15080923

  19. Synthesis and evaluation of 8-oxoadenine derivatives as potent Toll-like receptor 7 agonists with high water solubility.

    PubMed

    Nakamura, Tomoaki; Wada, Hiroki; Kurebayashi, Hirotaka; McInally, Tom; Bonnert, Roger; Isobe, Yoshiaki

    2013-02-01

    We report the discovery of novel series of highly potent TLR7 agonists based on 8-oxoadenines, 1 and 2 by introducing and optimizing various tertiary amines onto the N(9)-position of the adenine moiety. The introduction of the amino group resulted in not only improved water solubility but also enhanced TLR7 agonistic activity. In particular compound 20 (DSR-6434) indicated an optimal balance between the agonistic potency and high water solubility. It also demonstrated a strong antitumor effect in vivo by intravenous administration in a tumor bearing mice model. PMID:23265901

  20. GnRH agonist for triggering final oocyte maturation in patients at risk of ovarian hyperstimulation syndrome: still a controversy?

    Microsoft Academic Search

    S. Kol; I. Solt

    2008-01-01

    Purpose  An update on the subject of ovarian hyperstimulation syndrome (OHSS) prevention with GnRH agonist ovulation trigger.\\u000a \\u000a \\u000a \\u000a Methods  Review of pertinent English language studies published during the past 4 years.\\u000a \\u000a \\u000a \\u000a Results  Randomized prospective studies support the notion that agonist trigger completely eliminates OHSS. Conflicting results regarding\\u000a on going pregnancy rate probably reflect different approaches to luteal phase support. Embryos obtained and frozen after agonist