Cancer risk in men exposed in utero to diethylstilbestrol.

PubMed

Strohsnitter, W C; Noller, K L; Hoover, R N; Robboy, S J; Palmer, J R; Titus-Ernstoff, L; Kaufman, R H; Adam, E; Herbst, A L; Hatch, E E

2001-04-04

An association between prenatal diethylstilbestrol (DES) exposure and cancer in men, especially testicular cancer, has been suspected, but findings from case-control studies have been inconsistent. This study was conducted to investigate the association between prenatal DES exposure and cancer risk in men via prospective follow-up. A total of 3613 men whose prenatal DES exposure status was known were followed from 1978 through 1994. The overall and site-specific cancer incidence rates among the DES-exposed men were compared with those of the unexposed men in the study and with population-based rates. The relative rate (RR) was used to assess the strength of the association between prenatal DES exposure and cancer development. All statistical tests were two-sided. Overall cancer rates among DES-exposed men were similar to those among unexposed men (RR = 1.07; 95% confidence interval [CI] = 0.58 to 1.96) and to national rates (RR = 0.99; 95% CI = 0.65 to 1.44). Testicular cancer may be elevated among DES-exposed men, since the RRs for testicular cancer were 3.05 (95% CI = 0.65 to 22.0) times those of unexposed men in the study and 2.04 (95% CI = 0.82 to 4.20) times those of males in the population-based rates. The higher rate of testicular cancer in the DES-exposed men is, however, also compatible with a chance observation. To date, men exposed to DES in utero do not appear to have an increased risk of most cancers. It remains uncertain, however, whether prenatal DES exposure is associated with testicular cancer.

[Reproductive performance of DES-exposed-female progeny. Consequences of diethylstilbestrol in women whose mothers ingested the substance during pregnancy].

PubMed

Veridiano, N P; Delke, I; Rogers, J; Tancer, M L

1982-05-01

Between October 1973-October 1979, 613 women who had been exposed to diethylstilbestrol (DES) in utero were observed at the Brookdale Medical Center; 106 of these patients were observed for problems related to pregnancy. Most patients were between 17-27 years of age, and 39% were unmarried; 70 were in their 1st pregnancy. Results of the 1st pregnancy were 52 induced abortions, 3 pregnancies still ongoing at the time of the study; of the remaining 51 pregnancies, 32 terminated in delivery; there was a 37% of fetal wastage, mostly due to early delivery. 36 of the original 106 patients had a 2nd pregnancy; in this group there were 7 abortions and only 22 deliveries. 11 patients had a 3rd pregnancy, and 5 a 4th pregnancy; these patients were able to bring their pregnancy to term. In total there were 159 pregnancies, and a high percentage of fetal loss, mostly between the 13th and 28th week of pregnancy. It is well known that many women who have been exposed to DES in utero present modifications of the aspect, shape, and size of the uterine cavity, which causes difficulties in bringing a pregnancy to term. The article reviews the published literature on the subject.

Diethylstilbestrol-Induced Mouse Hypospadias: “Window of Susceptibility”

PubMed Central

Sinclair, Adriane Watkins; Cao, Mei; Baskin, Laurence; Cunha, Gerald R.

2016-01-01

Hypospadias, an abnormality affecting the penile urethra, is one of the most prevalent congenital malformations afflicting human males. The morphology of hypospadias is markedly different in humans versus mice reflecting substantial differences in penile development in humans and mice. Estrogens such as diethylstilbestrol (DES) elicit mouse penile malformations, but the types of penile abnormalities differ depending on whether DES treatment is prenatal or neonatal. To define the actual “window of susceptibility” to the adverse effects of DES, pregnant mice and their neonatal pups were injected subcutaneously with 200ng/gbw DES every other day from embryonic day 12 to 18 (DES E12-E18), postnatal day 0 to 10 (DES P0-P10), embryonic day 12 to postnatal day 10 (DES E12 to P10), postnatal day 5 to 15 (DES P5 to P15), and postnatal day 10 to 20 (DES P10 to P20). Aged-matched controls received sesame oil vehicle. After euthanasia at 10, 15, 20 and 60 days, penises were analyzed by gross morphology, histology and morphometry. Penises of all 5 groups of DES-treated mice were reduced in size, which was confirmed by morphometric analysis of internal penile structures. The most profound effects were seen in the DES E12-P10, DES P0-P10, and DES P5-P15 groups, thus defining a DES “programming window”. For all parameters, DES treatment from P10-P20 showed the most mild of effects. Adverse effects of DES on the MUMP cartilage and erectile bodies observed shortly after the last DES injection reverted to normality in the DES P5-P15, but not in the E12-P10 and P0-P10 groups, in which MUMP cartilage and erectile body malformations persisted into adulthood, again emphasizing a “window of susceptibility” in the early neonatal period. PMID:26810244

Neonatal diethylstilbestrol exposure alters the metabolic profile of uterine epithelial cells

PubMed Central

Yin, Yan; Lin, Congxing; Veith, G. Michael; Chen, Hong; Dhandha, Maulik; Ma, Liang

2012-01-01

SUMMARY Developmental exposure to diethylstilbestrol (DES) causes reproductive tract malformations, affects fertility and increases the risk of clear cell carcinoma of the vagina and cervix in humans. Previous studies on a well-established mouse DES model demonstrated that it recapitulates many features of the human syndrome, yet the underlying molecular mechanism is far from clear. Using the neonatal DES mouse model, the present study uses global transcript profiling to systematically explore early gene expression changes in individual epithelial and mesenchymal compartments of the neonatal uterus. Over 900 genes show differential expression upon DES treatment in either one or both tissue layers. Interestingly, multiple components of peroxisome proliferator-activated receptor-γ (PPARγ)-mediated adipogenesis and lipid metabolism, including PPARγ itself, are targets of DES in the neonatal uterus. Transmission electron microscopy and Oil-Red O staining further demonstrate a dramatic increase in lipid deposition in uterine epithelial cells upon DES exposure. Neonatal DES exposure also perturbs glucose homeostasis in the uterine epithelium. Some of these neonatal DES-induced metabolic changes appear to last into adulthood, suggesting a permanent effect of DES on energy metabolism in uterine epithelial cells. This study extends the list of biological processes that can be regulated by estrogen or DES, and provides a novel perspective for endocrine disruptor-induced reproductive abnormalities. PMID:22679223

DES daughters in France: experts' points of view on the various genital, uterine and obstetric pathologies, and in utero DES exposure.

PubMed

Clement, R; Guilbaud, E; Barrios, L; Rougé-Maillart, C; Jousset, N; Rodat, O

2014-10-01

Compensation of diethylstilbestrol exposure depends on the judicial system. In France, girls having been exposed to diethylstilbestrol are currently being compensated, and each exposure victim is being evaluated. Fifty-nine expert evaluations were studied to determine the causal relation between exposure to diethylstilbestrol and the pathologies attributable to diethylstilbestrol. The following were taken into consideration: age at the first signs of the pathology; age of the sufferer at the time of evaluation; the pathologies grouped into five categories: fertility disorders - cancers - mishaps during pregnancy - psychosomatic complaints - pathologies of "3rd generation DES victims"; submission of proof of DES exposure; the degree of causality determined (direct, indirect, ruled out). 61% of the cases related to fertility disorders, 28.8% to cancer pathologies (clear-cell adenocarcinoma), 18.6% to mishaps during pregnancy, 8.5% to disorders resulting from preterm delivery, and 3.4% to psychosomatic disorders. Some cases involved a combination of two types of complaints. Indirect causality was determined in 47.1% of the cases involving primary sterility, in 66.7% involving secondary sterility, and in 5 out of 6 cases of total sterility. There is direct causality between in utero diethylstilbestrol exposure and vaginal or cervical clear cell adenocarcinoma. Causality is indirect in the case of disorders linked to prematurity in third generation victims. Causality was determined by the experts on the basis of scientific criteria which attribute the presenting pathologies to diethylstilbestrol exposure. When other risk factors come into play, or when exposure is indirect (third generation), this causality is diminished. © IMechE 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

Ultrasensitive competitive method-based electrochemiluminescence immunosensor for diethylstilbestrol detection based on Ru(bpy)32+ as luminophor encapsulated in metal-organic frameworks UiO-67.

PubMed

Dong, Xue; Zhao, Guanhui; Liu, Li; Li, Xuan; Wei, Qin; Cao, Wei

2018-07-01

In this work, Ru(bpy) 3 2+ encapsulated in metal-organic frameworks (MOFs) UiO-67 (Ru(bpy) 3 2+ /UiO-67) as luminophor was easily prepared and firstly applied in constructing an electrochemiluminescence (ECL) immunosensor to efficiently estimate diethylstilbestrol (DES). The competitive method-based ECL immunosensor platform was fabricated by amino-silicon dioxide which possesses large surface area. The poriness of UiO-67 was splendid so that Ru(bpy) 3 2+ could be easily encapsulated. Ru(bpy) 3 2+ /UiO-67 with excellent ECL luminescence signal existed large specific surface area for easily labeled with antibodies. DES competed with bovine serum albumin-diethylstilbestrol (BSA-DES) for binding to antibody-specific sites in the constructed immunosensor. However DES was micromolecule, which was easier to bond to antibodies than BSA-DES. The ECL signal was gradually decreases with the increase of the concentration of DES. Under optimal conditions, the proposed immunosensor exhibited a wide linear range from 0.01 pg mL -1 to 50 ng mL -1 with a low detetion limit of 3.27 fg mL -1 (S/N = 3). The novel fabricated immunosensor with interference immunity and high stability may cause an attractive approach for the other targets determination. Copyright © 2018 Elsevier B.V. All rights reserved.

Concurrent primaries of vaginal clear cell adenocarcinoma and endometrial adenocarcinoma in a 39-year old woman with in utero diethylstilbestrol exposure.

PubMed

Keller, C; Nanda, R; Shannon, R L; Amit, A; Kaplan, A L

2001-01-01

Diethylstilbestrol (DES) was used widely in the late 1940s in an attempt to prevent adverse pregnancy outcomes. In 1971 the US Food and Drug Administration proscribed its use for pregnancy support secondary to its association with clear cell adenocarcinoma of the vagina. Several studies in animal models demonstrated an association with endometrial cancer among offspring following in utero DES exposure. To date, there is only one case report of endometrial cancer in women exposed to DES in utero. We present the first case, to our knowledge, of a woman exposed to DES in utero who presented with double primaries of clear cell cancer of the vagina concomitant with endometrial cancer.

Prenatal diethylstilbestrol exposure and reproductive hormones in premenopausal women.

PubMed

Wise, L A; Troisi, R; Hatch, E E; Titus, L J; Rothman, K J; Harlow, B L

2015-06-01

Diethylstilbestrol (DES), a synthetic estrogen widely prescribed to pregnant women in the mid-1900s, is a potent endocrine disruptor. Prenatal DES exposure has been associated with reproductive disorders in women, but little is known about its effects on endogenous hormones. We assessed the association between prenatal DES exposure and reproductive hormones among participants from the Harvard Study of Moods and Cycles (HSMC), a longitudinal study of premenopausal women aged 36-45 years from Massachusetts (1995-1999). Prenatal DES exposure was reported at baseline (43 DES exposed and 782 unexposed). Early follicular-phase concentrations of follicle-stimulating hormone (FSH), luteinizing hormone (LH) and estradiol were measured at baseline and every 6 months during 36 months of follow-up. Inhibin B concentrations were measured through 18 months. We used multivariable logistic and repeated-measures linear regression to estimate odds ratios (OR) and percent differences in mean hormone values (β), respectively, comparing DES exposed with unexposed women, adjusted for potential confounders. DES-exposed women had lower mean concentrations of estradiol (pg/ml) (β=-15.6%, 95% confidence interval (CI): -26.5%, -3.2%) and inhibin B (pg/ml) (β=-20.3%, CI: -35.1%, -2.3%), and higher mean concentrations of FSH (IU/I) (β=12.2%, CI: -1.5%, 27.9%) and LH (IU/I) (β=10.4%, CI: -7.2%, 31.3%), than unexposed women. ORs for the association of DES with maximum FSH>10 IU/I and minimum inhibin B<45 pg/ml--indicators of low ovarian reserve--were 1.90 (CI: 0.86, 4.22) and 4.00 (CI: 0.88-18.1), respectively. Prenatal DES exposure was associated with variation in concentrations of FSH, estradiol and inhibin B among women of late reproductive age.

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

PubMed

Yang, Lihua; Lin, Li; Weng, Shaoping; Feng, Zhiqin; Luan, Tiangang

2008-10-01

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 (17beta-estradiol, estrone and testosterone) levels and hispathological pictures showed that NP (10 microg/L) and DES could exert estrogenic effects through indirect mechanisms [i.e. increased estrogens levels (up to two times) and decreased androgen level in serum (down to 20-30%)], which might subsequently induce vitellogenin synthesis in liver. Environmental realistic concentrations of NP might be on the verge of inducing significant estrogenic effects in male silver carps. High amounts of NP and DES might be accumulated in fish serum, and the uptake by fish was possibly responsible for their quick attenuation in experimental tank water. NP and DES might have different metabolic mechanisms, the estrogenic effects of DES were more significant than those of NP.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hao, Chan-Juan; Cheng, Xue-Jia; Xia, Hong-Fei, E-mail: hongfeixia@yahoo.com.cn

Epidemiology studies indicate that exposure to endocrine disruptors during developmental “window” contributes to adipogenesis and the development of obesity. Implication of endocrine disruptor such as diethylstilbestrol (DES) on adipose tissue development has been poorly investigated. Here we evaluated the effects of DES on adipocyte differentiation in vitro and in vivo, and explored potential mechanism involved in its action. DES induced 3T3-L1 preadipocyte differentiation in a dose-dependent manner, and activated the expression of estrogen receptor (ER) and peroxisome proliferator-acivated receptor (PPAR) γ as well as its target genes required for adipogenesis in vitro. ER mediated the enhancement of DES-induced PPARγ activity.more » 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.« less

Effects of postnatal administration of diethylstilbestrol on puberty and thyroid function in male rats.

PubMed

Shin, Jae-Ho; Kim, Tae Sung; Kang, Il Hyun; Kang, Tae Seok; Moon, Hyun Ju; Han, Soon-Young

2009-10-01

To examine the effects of diethylstilbestrol (DES) on male pubertal development and thyroid function, juvenile male Sprague-Dawley rats were given DES daily by oral intubation at doses of 10, 20 and 40 microg/kg/day from postnatal day 33 for 20 days. Prepuce separation was significantly delayed at the dose of 20 microg/kg/day and above in the DES-treated rats. DES treatment induced a significant reduction in the weights of testes, epididymides, the ventral prostate, seminal vesicles plus coagulating glands and fluid, levator ani bulbocavernosus muscles, Cowper's glands and the glans penis. The weights of the liver and adrenals increased in the DES-treated animals. DES caused a dose-dependent reduction in germ cells; in particular the spermatids were mainly affected. The serum levels of testosterone and luteinizing hormone were significantly reduced in the DES-treated groups, but that of estradiol decreased. No differences were observed in the serum thyroxine levels of the control and DES-treated groups. In microscopic observation of the DES-treated animals, degeneration of germ cells and tubular atrophy in the testis were noted, but there were no microscopic changes in the thyroid. These results indicate that DES affected the pubertal development of juvenile male rats and that its mode of action may be related to alterations in hormone levels.

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

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

PubMed

Mattson, Marifran; Basu, Ambar

2010-07-01

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

Hypermethylation of Homeobox A10 by in Utero Diethylstilbestrol Exposure: An Epigenetic Mechanism for Altered Developmental Programming

PubMed Central

Bromer, Jason G.; Wu, Jie; Zhou, Yuping; Taylor, Hugh S.

2009-01-01

Diethylstilbestrol (DES) is a nonsteroidal estrogen that induces developmental anomalies of the female reproductive tract. The homeobox gene HOXA10 controls uterine organogenesis, and its expression is altered after in utero DES exposure. We hypothesized that an epigenetic mechanism underlies DES-mediated alterations in HOXA10 expression. We analyzed the expression pattern and methylation profile of HOXA10 after DES exposure. Expression of HOXA10 is increased in human endometrial cells after DES exposure, whereas Hoxa10 expression is repressed and shifted caudally from its normal location in mice exposed in utero. Cytosine guanine dinucleotide methylation frequency in the Hoxa10 intron was higher in DES-exposed offspring compared with controls (P = 0.017). The methylation level of Hoxa10 was also higher in the caudal portion of the uterus after DES exposure at the promoter and intron (P < 0.01). These changes were accompanied by increased expression of DNA methyltransferases 1 and 3b. No changes in methylation were observed after in vitro or adult DES exposure. DES has a dual mechanism of action as an endocrine disruptor; DES functions as a classical estrogen and directly stimulates HOXA10 expression with short-term exposure, however, in utero exposure results in hypermethylation of the HOXA10 gene and long-term altered HOXA10 expression. We identify hypermethylation as a novel mechanism of DES-induced altered developmental programming. PMID:19299448

Effects of In Utero Exposure to Bisphenol A or Diethylstilbestrol on the Adult Male Reproductive System

PubMed Central

LaRocca, Jessica; Boyajian, Alanna; Brown, Caitlin; Smith, Stuart Duncan; Hixon, Mary

2011-01-01

The objective of this study was to determine if in utero exposure to Bisphenol A (BPA) induced reproductive tract abnormalities in the adult male testis. Using the C57/Bl6 mouse, we examined sex-organ weights, anogenital distance (AGD), and testis histopathology in adult males exposed in utero via oral gavage to sesame oil, 50 μg/kg BPA, 1,000 μg/kg BPA, or 2 μg/kg diethylstilbestrol (DES) as a positive control from gestational days 10–16. No changes in sperm production or germ cell apoptosis were observed in adult testes following exposure to either chemical. Adult mRNA levels of genes associated with sexual maturation and differentiation, GATA4 and ID2, were significantly lower only in DES-exposed testes. In summary, the data indicate no gross alterations in spermatogenesis following in utero exposure to BPA or DES. At the molecular level, in utero exposure to DES, but not BPA, leads to decreased mRNA expression of genes associated with Sertoli cell differentiation. PMID:21922642

SIX1 oncoprotein is necessary for abnormal uterine basal cell development in mice exposed neonatally to DES.

EPA Science Inventory

Exposing female mice on neonatal days 1-5 to the synthetic estrogen diethylstilbestrol (DES) results in high incidence of uterine carcinoma. However, the biological mechanisms driving DES-induced carcinogenesis remain unclear. We previously showed that the sine oculis homeobox ho...

SIX1 oncoprotein is necessary for abnormal uterine basal cell development in mice exposed neonatally to DES

EPA Science Inventory

In a classical model of latent hormonal carcinogenesis, exposing female mice on neonatal days 1-5 to the synthetic estrogen diethylstilbestrol (DES; 1 mg/kg/day) results in high incidence of uterine carcinoma. However, the biological mechanisms driving DES-induced carcinogenesis ...

Neonatal exposure to diethylstilbestrol alters expression of DNA methyltransferases and methylation of genomic DNA in the mouse uterus.

PubMed

Sato, Koji; Fukata, Hideki; Kogo, Yasushi; Ohgane, Jun; Shiota, Kunio; Mori, Chisato

2009-01-01

Perinatal exposure to diethylstilbestrol (DES) can have numerous adverse effects on the reproductive organs later in life, such as vaginal clear-cell adenocarcinoma. Epigenetic processes including DNA methylation may be involved in the mechanisms. We subcutaneously injected DES to neonatal C57BL/6 mice. At days 5, 14, and 30, expressions of DNA methyltransferases (Dnmts) Dnmt1, Dnmt3a, and Dnmt3b, and transcription factors Sp1 and Sp3 were examined. We also performed restriction landmark genomic scanning (RLGS) to detect aberrant DNA methylation. Real-time RT-PCR revealed that expressions of Dnmt1, Dnmt3b, and Sp3 were decreased at day 5 in DES-treated mice, and that those of Dnmt1, Dnmt3a, and Sp1 were also decreased at day 14. RLGS analysis revealed that 5 genomic loci were demethylated, and 5 other loci were methylated by DES treatment. Two loci were cloned, and differential DNA methylation was quantified. Our results indicated that DES altered the expression levels of Dnmts and DNA methylation.

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

PubMed

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

2015-01-01

It is quite important to develop convenient and rapid analytical methods for trace levels of endocrine disruptors because they heavily affect health and reproduction of humans and animals. Herein, graphene was easily prepared via one-step exfoliation using N-methyl-2-pyrrolidone as solvent, and then used to construct an electrochemical sensor for highly-sensitive detection of diethylstilbestrol (DES) and estradiol (E2). On the surface of prepared graphene film, two independent and greatly-increased oxidation waves were observed at 0.28V and 0.49V for DES and E2. The remarkable signal enlargements indicated that the detection sensitivity was improved significantly. The influences of pH value, amount of graphene and accumulation time on the oxidation signals of DES and E2 were discussed. As a result, a highly-sensitive and rapid electrochemical method was newly developed for simultaneous detection of DES and E2. The values of detection limit were evaluated to be 10.87 nM and 4.9 nM for DES and E2. Additionally, this new method was successfully used in lake water samples and the accuracy was satisfactory. Copyright © 2014 Elsevier B.V. All rights reserved.

Simultaneous determination of environmental estrogens: Diethylstilbestrol and estradiol using Cu-BTC frameworks-sensitized electrode.

PubMed

Ji, Liudi; Wang, Yanying; Wu, Kangbing; Zhang, Weikang

2016-10-01

It is quite important to monitor environmental estrogens in a rapid, sensitive, simple and cost-effective manner due to their wide existence and high toxicity. Using 1,3,5-Benzenetricarboxylic acid (H3BTC) as the ligand and copper ions as the center, Cu-BTC frameworks with surface area of 654.6m(2)/g were prepared, and then used to construct a novel electrochemical sensing platform for diethylstilbestrol (DES) and estradiol (E2). On the surface of Cu-BTC frameworks, two oxidation waves at 0.26V and 0.45V are observed for DES and E2, and the oxidation signals are improved greatly. The prepared Cu-BTC frameworks not only enhance the accumulation efficiency of DES and E2, but also improve their electron transfer ability. The influences of pH value, modification amount of Cu-BTC and accumulation time were examined. As a result, a highly-sensitive, rapid and convenient electrochemical method was developed for the simultaneous determination of DES and E2, with detection limit of 2.7nM and 1.1nM. The practical applications manifest this new sensing system is accurate and feasible. Copyright © 2016 Elsevier B.V. All rights reserved.

Cellular and molecular effects of developmental exposure to diethylstilbestrol: implications for other environmental estrogens.

PubMed Central

Newbold, R

1995-01-01

Concerns have been raised regarding the role of environmental and dietary estrogens as possible contributors to an increased incidence of various abnormalities in estrogen-target tissues of both sexes. These abnormalities include breast cancer, endometriosis, fibroids, and uterine adenocarcinoma in females, as well as alterations in sex differentiation, decreased sperm concentrations, benign prostatic hyperplasia, prostatic cancer, testicular cancer, and reproductive problems in males. Whether these concerns are valid remains to be determined; however, studies with the potent synthetic estrogen diethylstilbestrol (DES) suggest that exogenous estrogen exposure during critical stages of development can result in permanent cellular and molecular alterations in the exposed organism. These alterations manifest themselves in the female and male as structural, functional, or long-term pathological changes including neoplasia. Although DES has potent estrogenic activity, it may be used as a model compound to study the effects of weaker environmental estrogens, many of which may fit into the category of endocrine disruptors. PMID:8593881

Diallyl sulfide inhibits diethylstilbestrol-induced lipid peroxidation in breast tissue of female ACI rats: implications in breast cancer prevention.

PubMed

Gued, Lisa R; Thomas, Ronald D; Green, Mario

2003-01-01

Diallyl sulfide (DAS) is a component of garlic and prevents cancer in several animal models in various organs. The chemopreventive effects of DAS are attributed to modulation of enzymes to alter the bioactivation of xenobiotics. Diethylstilbestrol (DES) is a synthetic estrogen that causes breast cancer in female ACI rats subsequent to metabolism with concurrent free radical production. This study assessed the effect of DAS on DES-induced reactive oxygen species (ROS) using lipid peroxidation as an empirical endpoint. We have demonstrated that acute exposure to DES results in a significant increase in lipid hydroperoxides (LPH) in breast tissue and DAS attenuated DES-induced LPH concentrations. Two-week exposure to DES caused significant increases in LPH concentrations in breast and liver tissues. DES-induced LPH concentrations were decreased by coadministration of DAS at this time point. There were no statistical differences in the concentrations of LPH in breast and liver tissues of rats treated for 4/6 weeks with DAS/DES. These results demonstrate that DAS inhibits the production of ROS which suggests that DAS effectively inhibits DES bioactivation in female ACI rats which may have implications for chemopreventive intervention strategies. Our results suggest that garlic consumption might be useful for the prevention of human breast cancers.

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.

Clear cell adenocarcinoma of cervix in 1-year-old girl without in utero exposure to diethylstilbestrol: an uncommon tumour at an uncommon age and site.

PubMed

Arora, Aditi; Rastogi, Anurag; Neyaz, Azfar; Husain, Nuzhat

2017-03-16

Adenocarcinoma of cervix constitutes about 10-15% cases of carcinoma cervix. Clear cell variant is even a rarer variant of adenocarcinoma. It rarely occurs in the paediatric age group and a known risk factor is in utero exposure to diethylstilbestrol (DES). We report here a case of primary cervical tumour in a 1-year-old girl, which was initially suspected to be an embryonal rhabdomyosarcoma botryoides. Histopathology with immunohistochemical analysis revealed clear cell adenocarcinoma. There was no maternal history of DES intake during pregnancy. We discuss the histopathological characteristics and clinical course of this unusual tumour. 2017 BMJ Publishing Group Ltd.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Henry, E.C.

1984-01-01

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

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

PubMed Central

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

1976-01-01

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

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Oumeddour, Abdelkader; CNRS, UMR 6293, GReD, F-63171 Aubiere; INSERM, UMR 1103, GReD, F-63171 Aubiere

Highlights: • Part of the neonatal effect of DES on testis needs the presence of Lxrα/β. • Some DES-induced pathways are blocked in Lxr-deficient mice. • Lxr-deficient mice analysis defines DES-target genes protected by Lxr. - Abstract: Liver X receptors LXRα (NR1H3) and LXRβ (NR1H2) are transcription factors belonging to the nuclear receptor superfamily, activated by specific oxysterols, oxidized derivatives of cholesterol. These receptors are involved in the regulation of testis physiology. Lxr-deficient mice pointed to the physiological roles of these nuclear receptors in steroid synthesis, lipid homeostasis and germ cell apoptosis and proliferation. Diethylstilbestrol (DES) is a synthetic estrogenmore » considered as an endocrine disruptor that affects the functions of the testis. Various lines of evidences have made a clear link between estrogens, their nuclear receptors ERα (NR3A1) and ERβ (NR3A2), and Lxrα/β. As LXR activity could also be regulated by the nuclear receptor small heterodimer partner (SHP, NR0A2) and DES could act through SHP, we wondered whether LXR could be targeted by estrogen-like endocrine disruptors such as DES. For that purpose, wild-type and Lxr-deficient mice were daily treated with 0.75 μg DES from days 1 to 5 after birth. The effects of DES were investigated at 10 or 45 days of age. We demonstrated that DES induced a decrease of the body mass at 10 days only in the Lxr-deficient mice suggesting a protective effect of Lxr. We defined three categories of DES-target genes in testis: those whose accumulation is independent of Lxr; those whose accumulation is enhanced by the lack of both Lxrα/β; those whose accumulation is repressed by the absence of Lxrα/β. Lipid accumulation is also modified by neonatal DES injection. Lxr-deficient mice present different lipid profiles, demonstrating that DES could have its effects in part due to Lxrα/β. Altogether, our study shows that both nuclear receptors Lxrα and Lxrβ are

Delayed adverse effects of neonatal exposure to diethylstilbestrol and their dose dependency in female rats.

PubMed

Yoshida, Midori; Takahashi, Miwa; Inoue, Kaoru; Hayashi, Seigo; Maekawa, Akihiko; Nishikawa, Akiyoshi

2011-08-01

Neonatal exposure to estrogenic chemicals causes irreversible complex damage to the hypothalamus-pituitary-gonadal axis and reproductive system in females. Some lesions are noted after maturation as delayed adverse effects. We investigated the characteristics and dose dependence of delayed effects using female rats neonatally exposed to diethylstilbestrol (DES). Female Donryu rats were subcutaneously injected with a single dose of DES of 0 (control), 0.15, 1.5, 15, 150, or 1,500 µg/kg bw after birth. All except the lowest dose had estrogenic activity in a uterotrophic assay. All rats at 1500 µg/kg and some at 150 µg/kg showed abnormal morphologies in the genital tract, indicating they were androgenized before maturation. Although no morphological abnormalities were noted at 15 µg/kg or lower, onset of persistent estrus was significantly accelerated in the 1.5, 15, and 150 µg/kg groups with dose dependency, and the latest onset was from seventeen to twenty-one weeks of age at 1.5 µg/kg. The neonatal exposure to DES increased uterine adenocarcinoma development only at 150 µg/kg, although uterine anomalies were detected at 1,500 µg/kg. These results indicate that neonatal exposure to DES, which exerts estrogenic activity in vivo, induces delayed adverse effects in female rats in a dose-dependent manner. Early onset of persistent estrus appears to be the most sensitive parameter.

Removal and Biodegradation of 17β-Estradiol and Diethylstilbestrol by the Freshwater Microalgae Raphidocelis subcapitata

PubMed Central

Chen, Qi; Sun, Kaifeng; Sun, Dong; Wu, Xiaoqing; Duan, Shunshan

2018-01-01

Natural steroidal and synthetic non-steroidal estrogens such as 17β-estradiol (E2) and diethylstilbestrol (DES) have been found in natural water, which can potentially endanger public health and aquatic ecosystems. The removal and biodegradation of E2 and DES by Raphidocelis subcapitata were studied in bacteria-free cultures exposed to single and mixture treatments at different concentrations for 96 h. The results showed that R. subcapitata exhibited a rapid and strong ability to remove E2 and DES in both single and mixture treatments by biodegradation. At the end of 96 h, the removal percentage of single E2 and DES achieved 82.0%, 80.4%, 74.6% and 89.9%, 73.4%, 54.1% in 0.1, 0.5, and 1.5 mg·L−1, respectively. With the exception of the 0.1 mg·L−1 treatment at 96 h, the removal capacity of E2 was more efficient than that of DES by R. subcapitata. Furthermore, the removal percentage of mixture E2 and DES achieved 88.5%, 82.9%, 84.3% and 87.2%, 71.8%, 51.1% in 0.1, 0.5, and 1.5 mg·L−1, respectively. The removal percentage of mixed E2 was significantly higher than that of the single E2. The presence of DES could accelerate the removal of E2 from the mixture treatments in equal concentrations. In addition, the removal was mainly attributed to the biodegradation or biotransformation process by the microalgae cells rather than simple sorption and accumulation in the cells. The microalgae R. subcapitata demonstrated a high capability for the removal of the E2 and DES indicating future prospects for its application. PMID:29510598

Detection of chromosomal aberrations by fluorescence in situ hybridization in cervicovaginal biopsies from women exposed to diethylstilbestrol in utero.

PubMed

Hajek, R A; King, D W; Hernández-Valero, M A; Kaufman, R H; Liang, J C; Chilton, J A; Edwards, C L; Wharton, J T; Jones, L A

2006-01-01

Epidemiologic studies have associated estrogens with human neoplasms such as those in the endometrium, cervix, vagina, breast, and liver. Perinatal exposure to natural (17beta-estradiol [17beta-E(2)]) and synthetic (diethylstilbestrol [DES]) estrogens induces neoplastic changes in humans and rodents. Previous studies demonstrated that neonatal 17beta-E(2) treatment of mice results in increased nuclear DNA content of cervicovaginal epithelium that precedes histologically evident neoplasia. In order to determine whether this effect was associated with chromosomal changes in humans, the frequencies of trisomy of chromosomes 1, 7, 11, and 17 were evaluated by the fluorescence in situ hybridization (FISH) technique in cervicovaginal tissue from 19 DES-exposed and 19 control women. The trisomic frequencies were significantly elevated in 4 of the 19 (21%) DES-exposed patients. One patient presented with trisomy of chromosomes 1, 7, and 11, while trisomy of chromosome 7 was observed in one patient. There were two patients with trisomy of chromosome 1. Trisomy of chromosomes 1, 7, 11, and 17 was not observed in the cervicovaginal tissue taken from control patients. These data suggest that DES-induced chromosomal trisomy may be an early event in the development of cervicovaginal neoplasia in humans.

Altered gene expression patterns during the initiation and promotion stages of neonatally diethylstilbestrol-induced hyperplasia/dysplasia/neoplasia in the hamster uterus.

PubMed

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

2014-12-01

Neonatal treatment of hamsters with diethylstilbestrol (DES) induces uterine hyperplasia/dysplasia/neoplasia (endometrial adenocarcinoma) in adult animals. We subsequently determined that the neonatal DES exposure event directly and permanently disrupts the developing hamster uterus (initiation stage) so that it responds abnormally when it is stimulated with estrogen in adulthood (promotion stage). To identify candidate molecular elements involved in progression of the disruption/neoplastic process, we performed: (1) immunoblot analyses and (2) microarray profiling (Affymetrix Gene Chip System) on sets of uterine protein and RNA extracts, respectively, and (3) immunohistochemical analysis on uterine sections; all from both initiation stage and promotion stage groups of animals. Here we report that: (1) progression of the neonatal DES-induced hyperplasia/dysplasia/neoplasia phenomenon in the hamster uterus involves a wide spectrum of specific gene expression alterations and (2) the gene products involved and their manner of altered expression differ dramatically during the initiation vs. promotion stages of the phenomenon. Copyright © 2014 Elsevier Inc. All rights reserved.

Factors Associated with a Lack of Pap Smear Utilization in Women Exposed In Utero to Diethylstilbestrol

PubMed Central

Camp, Elizabeth A.; Prehn, Angela W.; Shen, Ji; Herbst, Arthur L.; Strohsnitter, William C.; Hobday, Christopher D.; Robboy, Stanley J.

2015-01-01

Abstract Background: Women in the1940s–1960s were prescribed diethylstilbestrol (DES), a nonsteroidal estrogen, to prevent miscarriages, but the practice was terminated after it was discovered that the daughters so exposed in utero were at increased risk for developing clear cell adenocarcinoma (CCA) of the vagina or cervix at early ages. Pap smear screening is one of the principal methods used to identify tumor development and is necessary in this group of women to maintain their health. Currently, little is known about the factors associated with nonutilization of this screening tool in this high-risk population of women. Methods: National cohort data from the National Cancer Institute (NCI) DES Combined Cohort Follow-up Study during 1994, 1997, 2001, and 2006 were used to determine which factors were associated with Pap smear screening nonutilization in 2006 among DES-exposed and unexposed women. Self-reported questionnaire data from 2,861 DES-exposed and 1,027 unexposed women were analyzed using binary logistic regression models. Results: DES exposure, not having a previous gynecologic dysplasia diagnosis, lack of insurance, originating cohort, increasing age, and previous screening behavior were all factors associated with not reporting a Pap smear examination in the 2006 questionnaire, although college education reduced nonutilization. Conclusions: Understanding which factors are associated with not acquiring a screening exam can help clinicians better identify which DES-exposed women are at risk for nonutilization and possibly tailor their standard of care to aid in the early detection of cervical and vaginal adenocarcinomas in this high-risk group. PMID:25768943

Association of diethylstilbestrol exposure in utero with cryptorchidism, testicular hypoplasia and semen abnormalities.

PubMed

Gill, W B; Schumacher, G F; Bibbo, M; Straus, F H; Schoenberg, H W

1979-07-01

Epididymal cysts and/or hypoplastic testes have been found in 31.5 per cent of 308 men exposed to diethylstilbestrol in utero, compared to 7.8 per cent of 307 placebo-exposed controls. Analyses of the spermatozoa have revealed severe pathological changes (Eliasson score greater than 10) in 134 diethylstilbestrol-exposed men (18 per cent) and 87 placebo-exposed men (8 per cent). Further investigation of the 26 diethylstilbestrol-exposed men with testicular hypoplasia has revealed that 65 per cent had a history of cryptorchidism. Only 1 of the 6 placebo-exposed controls with testicular hypoplasia had a history of testicular maldescent. Although none of our Diekmann's lying-in study group has had carcinoma to date one must keep in mind the reported increased risk of testicular carcinoma in testes that are or were cryptorchid. A 25-year-old man who was not part of the study group was treated recently by us for a testicular carcinoma ( mixed anaplastic seminoma plus embryonal cell carcinoma) and he had a history of diethylstilbestrol exposure in utero and cryptorchidism.

Organizational effects of diethylstilbestrol on brain vasotocin and sexual behavior in male quail.

PubMed

Viglietti-Panzica, Carla; Montoncello, Barbara; Mura, Elena; Pessatti, Marzia; Panzica, GianCarlo

2005-04-15

In Japanese quail, we previously described a sexual dimorphism of the parvocellular vasotocin system of the limbic region that, as the reproductive behavior, is steroid-sensitive and is organized during embryonic life by the exposure to estradiol. We verified in this study whether diethylstilbestrol, a chemical xenoestrogen, has analogous organizational effects on the vasotocin system of limbic regions and on copulatory behavior of male Japanese quail. We injected in the yolk sac of 3 day-old quail embryos diethylstilbestrol or estradiol benzoate (a treatment which suppresses male copulatory behavior in adulthood and reduces vasotocin innervation), or sesame oil (control). No further hormonal manipulations were performed after hatching. Sexual behavior was recorded in males at the age of 6 weeks. Estradiol- and diethylstilbestrol-treated males exhibited a total suppression of copulatory behavior. After behavioral tests, all males were sacrificed and brain sections processed for vasotocin immunocytochemistry. Significant decrease in the density of vasotocin immunoreactivity was detected in the medial preoptic nucleus, in the bed nucleus of stria terminalis, and in the lateral septum of diethylstilbestrol-treated males. The magnocellular vasotocin neurons were, in contrast, not affected. In conclusion, the present data demonstrate that embryonic treatment with diethylstilbestrol induces a full sex reversal of behavioral phenotype as well as a significant decrease of vasotocin expression in the preoptic-limbic region in male Japanese quail. Therefore, the parvocellular vasotocin system could represent an optimal model to investigate the effects of pollutants on neural circuits controlling reproductive functions.

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

PubMed Central

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

2014-01-01

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

Adverse health outcomes in women exposed in utero to diethylstilbestrol.

PubMed

Hoover, Robert N; Hyer, Marianne; Pfeiffer, Ruth M; Adam, Ervin; Bond, Brian; Cheville, Andrea L; Colton, Theodore; Hartge, Patricia; Hatch, Elizabeth E; Herbst, Arthur L; Karlan, Beth Y; Kaufman, Raymond; Noller, Kenneth L; Palmer, Julie R; Robboy, Stanley J; Saal, Robert C; Strohsnitter, William; Titus-Ernstoff, Linda; Troisi, Rebecca

2011-10-06

Before 1971, several million women were exposed in utero to diethylstilbestrol (DES) given to their mothers to prevent pregnancy complications. Several adverse outcomes have been linked to such exposure, but their cumulative effects are not well understood. We combined data from three studies initiated in the 1970s with continued long-term follow-up of 4653 women exposed in utero to DES and 1927 unexposed controls. We assessed the risks of 12 adverse outcomes linked to DES exposure, including cumulative risks to 45 years of age for reproductive outcomes and to 55 years of age for other outcomes, and their relationships to the baseline presence or absence of vaginal epithelial changes, which are correlated with a higher dose of, and earlier exposure to, DES in utero. Cumulative risks in women exposed to DES, as compared with those not exposed, were as follows: for infertility, 33.3% vs. 15.5% (hazard ratio, 2.37; 95% confidence interval [CI], 2.05 to 2.75); spontaneous abortion, 50.3% vs. 38.6% (hazard ratio, 1.64; 95% CI, 1.42 to 1.88); preterm delivery, 53.3% vs. 17.8% (hazard ratio, 4.68; 95% CI, 3.74 to 5.86); loss of second-trimester pregnancy, 16.4% vs. 1.7% (hazard ratio, 3.77; 95% CI, 2.56 to 5.54); ectopic pregnancy, 14.6% vs. 2.9% (hazard ratio, 3.72; 95% CI, 2.58 to 5.38); preeclampsia, 26.4% vs. 13.7% (hazard ratio 1.42; 95% CI, 1.07 to 1.89); stillbirth, 8.9% vs. 2.6% (hazard ratio, 2.45; 95% CI, 1.33 to 4.54); early menopause, 5.1% vs. 1.7% (hazard ratio, 2.35; 95% CI, 1.67 to 3.31); grade 2 or higher cervical intraepithelial neoplasia, 6.9% vs. 3.4% (hazard ratio, 2.28; 95% CI, 1.59 to 3.27); and breast cancer at 40 years of age or older, 3.9% vs. 2.2% (hazard ratio, 1.82; 95% CI, 1.04 to 3.18). For most outcomes, the risks among exposed women were higher for those with vaginal epithelial changes than for those without such changes. In utero exposure of women to DES is associated with a high lifetime risk of a broad spectrum of adverse health outcomes

Incidence rates and risks of diethylstilbestrol-related clear-cell adenocarcinoma of the vagina and cervix: Update after 40-year follow-up.

PubMed

Huo, Dezheng; Anderson, Diane; Palmer, Julie R; Herbst, Arthur L

2017-09-01

Women exposed to diethylstilbestrol (DES) in utero are at increased risk for the development of vaginal and cervical clear cell adenocarcinoma (CCA) at younger age. It is unknown if a second peak will occur in later life, the ages when CCA developed spontaneously in the pre-DES era. The complete epidemiologic curve of CCA has not been reported, yet. We reviewed 720 cases of CCA from the CCA registry at the University of Chicago through 2014. Incidence rates and cumulative risks for CCA were calculated based on white women born in the U.S. from 1948 through 1971. In 420 CCA cases there was documented evidence of prenatal DES exposure. 80% were among those between ages 15 and 31 but some occurred as late as age 55. A small second peak occurred around age 42. The risk of DES-related CCA was highest in the 1951-1956 birth cohort and this birth cohort effect closely correlated with DES prescriptions over time in the U.S. (r=0.98, P=0.005). By age 50, the cumulative risk of CCA was 1 per 750 exposed women. CCA cases without evidence of DES exposure had similar ages, year of diagnosis, and birth cohort patterns as the documented DES-exposed cases, suggesting that some negative cases were exposed. Their inclusion raises the cumulative risk of CCA to 1 per 520. With the largest data available, our results confirmed the association between prenatal DES exposure and clear cell adenocarcinoma. The study also refines the risks of DES-related CCA. Copyright © 2017 Elsevier Inc. All rights reserved.

The in vitro effect of nonylphenol, propranolol, and diethylstilbestrol on quality parameters and oxidative stress in sterlet (Acipenser ruthenus) spermatozoa.

PubMed

Shaliutina, Olena; Shaliutina-Kolešová, Anna; Lebeda, Ievgen; Rodina, Marek; Gazo, Ievgeniia

2017-09-01

The sturgeon is a highly endangered fish mostly due to over-fishing, habitat destruction, and water pollution. Nonylphenol (NP), propranolol (PN), and diethylstilbestrol (DES) are multifunctional xenobiotic compounds used in a variety of commercial and industrial products. The mechanism by which these xenobiotic compounds interfere with fish reproduction is not fully elucidated. This study assessed the effect of NP, PN, and DES on motility parameters, membrane integrity, and oxidative/antioxidant status in sterlet Acispenser ruthenus spermatozoa. Spermatozoa were incubated with several concentrations of target substances for 1h. Motility rate and velocity of spermatozoa decreased in the presence of xenobiotics in a dose-dependent manner compared with controls. A significant decrease in membrane integrity was recorded with exposure to 5μM of NP, 25μM of PN, and 50μM of DES. After 1h exposure at higher tested concentrations NP (5-25μM), PN (25-100μM), and DES (50-200μM), oxidative stress was apparent, as reflected by significantly higher levels of protein and lipid oxidation and significantly greater superoxide dismutase activity. The results demonstrated that NP, PN, and DES can induce reactive oxygen species stress in fish spermatozoa, which could impair sperm quality and the antioxidant defence system and decrease the percentage of intact sperm cells. Copyright © 2017 Elsevier Ltd. All rights reserved.

Developmental Exposure to Diethylstilbestrol Alters Uterine Gene Expression That May Be Associated With Uterine Neoplasia Later in Life

PubMed Central

Newbold, Retha R.; Jefferson, Wendy N.; Grissom, Sherry F.; Padilla-Banks, Elizabeth; Snyder, Ryan J.; Lobenhofer, Edward K.

2008-01-01

Previously, we described a mouse model where the well-known reproductive carcinogen with estrogenic activity, diethylstilbestrol (DES), caused uterine adenocarcinoma following neonatal treatment. Tumor incidence was dose-dependent reaching >90% by 18 mo following neonatal treatment with 1000 μg/kg/d of DES. These tumors followed the initiation/promotion model of hormonal carcinogenesis with developmental exposure as initiator, and exposure to ovarian hormones at puberty as the promoter. To identify molecular pathways involved in DES-initiation events, uterine gene expression profiles were examined in prepubertal mice exposed to DES (1, 10, or 1000 μg/kg/d) on days 1–5 and compared to controls. Of more than 20 000 transcripts, approximately 3% were differentially expressed in at least one DES treatment group compared to controls; some transcripts demonstrated dose–responsiveness. Assessment of gene ontology annotation revealed alterations in genes associated with cell growth, differentiation, and adhesion. When expression profiles were compared to published studies of uteri from 5-d-old DES-treated mice, or adult mice treated with 17β estradiol, similarities were seen suggesting persistent differential expression of estrogen responsive genes following developmental DES exposure. Moreover, several altered genes were identified in human uterine adenocarcinomas. Four altered genes [lactotransferrin (Ltf), transforming growth factor beta inducible (Tgfb1), cyclin D1 (Ccnd1), and secreted frizzled-related protein 4 (Sfrp4)], selected for real-time RT-PCR analysis, correlated well with the directionality of the microarray data. These data suggested altered gene expression profiles observed 2 wk after treatment ceased, were established at the time of developmental exposure and maybe related to the initiation events resulting in carcinogenesis. PMID:17394237

Developmental exposure to diethylstilbestrol alters uterine gene expression that may be associated with uterine neoplasia later in life.

PubMed

Newbold, Retha R; Jefferson, Wendy N; Grissom, Sherry F; Padilla-Banks, Elizabeth; Snyder, Ryan J; Lobenhofer, Edward K

2007-09-01

Previously, we described a mouse model where the well-known reproductive carcinogen with estrogenic activity, diethylstilbestrol (DES), caused uterine adenocarcinoma following neonatal treatment. Tumor incidence was dose-dependent reaching >90% by 18 mo following neonatal treatment with 1000 microg/kg/d of DES. These tumors followed the initiation/promotion model of hormonal carcinogenesis with developmental exposure as initiator, and exposure to ovarian hormones at puberty as the promoter. To identify molecular pathways involved in DES-initiation events, uterine gene expression profiles were examined in prepubertal mice exposed to DES (1, 10, or 1000 microg/kg/d) on days 1-5 and compared to controls. Of more than 20 000 transcripts, approximately 3% were differentially expressed in at least one DES treatment group compared to controls; some transcripts demonstrated dose-responsiveness. Assessment of gene ontology annotation revealed alterations in genes associated with cell growth, differentiation, and adhesion. When expression profiles were compared to published studies of uteri from 5-d-old DES-treated mice, or adult mice treated with 17beta estradiol, similarities were seen suggesting persistent differential expression of estrogen responsive genes following developmental DES exposure. Moreover, several altered genes were identified in human uterine adenocarcinomas. Four altered genes [lactotransferrin (Ltf), transforming growth factor beta inducible (Tgfb1), cyclin D1 (Ccnd1), and secreted frizzled-related protein 4 (Sfrp4)], selected for real-time RT-PCR analysis, correlated well with the directionality of the microarray data. These data suggested altered gene expression profiles observed 2 wk after treatment ceased, were established at the time of developmental exposure and maybe related to the initiation events resulting in carcinogenesis. (c) 2007 Wiley-Liss, Inc.

Clear cell adenocarcinoma of the ovary associated with in utero diethylstilbestrol exposure: case report and clinical overview.

PubMed

Dasanu, Constantin A; Herzog, Thomas J

2009-01-01

Clear cell adenocarcinoma of the vagina and cervix were previously shown to be tumors occurring in female offspring exposed prenatally to diethylstilbestrol. This report describes the first clinical case of clear cell adenocarcinoma of the ovary linked to early diethylstilbestrol exposure in utero. A 45-year-old woman presented with a self-discovered lump in the lower abdominal quadrant. She underwent surgery and staging that revealed clear cell adenocarcinoma confined to the left ovary. Foci of high-grade squamous neoplastic proliferation, inflammation, and a paratubal cyst were also present on the pathology specimen. Medical records established unequivocally that the patient's mother received diethylstilbestrol therapy throughout the pregnancy. Our case is consistent with clear cell adenocarcinoma, probably related to diethylstilbestrol exposure in utero. It reinforces the need for continued vigilance in individuals prenatally exposed to this drug.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhu, Liangliang; Xiao, Ling; Xia, Yangliu

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 μM, 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 themore » presence of DES (0–6.25 μM), K{sub m} values for E2-17-O-glucuronidation are located in the range of 7.2–7.4 μM, while V{sub max} values range from 0.38 to 1.54 nmol/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 μM) can elevate V{sub max} from 0.016 to 0.81 nmol/min/mg, while lifting K{sub m} in a much lesser extent from 4.4 to 11 μM. Activation of E2-17-O-glucuronidation is well described by a two binding site model, with K{sub A}, α, and β values of 0.077 ± 0.18 μM, 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. - Highlights: • E2-3-O-glucuronidation in HLM is inhibited when co-incubated with DES. • E2-17-O-glucuronidation in HLM is stimulated when co-incubated with DES. • Acceleration of E2-17-O-glucuronidationin in HLM by DES is via

Diethylstilbestrol induces vaginal adenosis by disrupting SMAD/RUNX1-mediated cell fate decision in the Müllerian duct epithelium.

PubMed

Laronda, Monica M; Unno, Kenji; Ishi, Kazutomo; Serna, Vanida A; Butler, Lindsey M; Mills, Alea A; Orvis, Grant D; Behringer, Richard R; Deng, Chuxia; Sinha, Satrajit; Kurita, Takeshi

2013-09-01

Women exposed to diethylstilbestrol (DES) in utero frequently develop vaginal adenosis, from which clear cell adenocarcinoma can arise. Despite decades of extensive investigation, the molecular pathogenesis of DES-associated vaginal adenosis remains elusive. Here we report that DES induces vaginal adenosis by inhibiting the BMP4/Activin A-regulated vaginal cell fate decision through a downregulation of RUNX1. BMP4 and Activin A produced by vaginal mesenchyme synergistically activated the expression of ΔNp63, thus deciding vaginal epithelial cell fate in the Müllerian duct epithelial cells (MDECs) via direct binding of SMADs on the highly conserved 5' sequence of ΔNp63. Therefore, mice in which Smad4 was deleted in MDECs failed to express ΔNp63 in vaginal epithelium and developed adenosis. This SMAD-dependent ΔNp63 activation required RUNX1, a binding partner of SMADs. Conditional deletion of Runx1 in the MDECs induced adenosis in the cranial portion of vagina, which mimicked the effect of developmental DES-exposure. Furthermore, neonatal DES exposure downregulated RUNX1 in the fornix of the vagina, where DES-associated adenosis is frequently found. This observation strongly suggests that the downregulation of RUNX1 is the cause of vaginal adenosis. However, once cell fate was determined, the BMP/Activin-SMAD/RUNX1 signaling pathway became dispensable for the maintenance of ΔNp63 expression in vaginal epithelium. Instead, the activity of the ΔNp63 locus in vaginal epithelium was maintained by a ΔNp63-dependent mechanism. This is the first demonstration of a molecular mechanism through which developmental chemical exposure causes precancerous lesions by altering cell fate. Copyright © 2013 Elsevier Inc. All rights reserved.

Diethylstilbestrol induces vaginal adenosis by disrupting SMAD/RUNX1-mediated cell fate decision in the Müllerian duct epithelium

PubMed Central

Laronda, Monica M.; Unno, Kenji; Ishi, Kazutomo; Serna, Vanida A.; Butler, Lindsey M.; Mills, Alea A.; Orvis, Grant D.; Behringer, Richard R.; Deng, Chuxia; Sinha, Satrajit; Kurita, Takeshi

2013-01-01

Women exposed to diethylstilbestrol (DES) in utero frequently develop vaginal adenosis, from which clear cell adenocarcinoma can arise. Despite decades of extensive investigation, the molecular pathogenesis of DES-associated vaginal adenosis remains elusive. Here we report that DES induces vaginal adenosis by inhibiting the BMP4/Activin A-regulated vaginal cell fate decision through a downregulation of RUNX1. BMP4 and Activin A produced by vaginal mesenchyme synergistically activated the expression of ΔNp63, thus deciding vaginal epithelial cell fate in the Müllerian duct epithelial cells (MDECs) via direct binding of SMADs on the highly conserved 5′sequence of ΔNp63. Therefore, mice in which Smad4 was deleted in MDECs failed to express ΔNp63 in vaginal epithelium and developed adenosis. This SMAD-dependent ΔNp63 activation required RUNX1, a binding partner of SMADs. Conditional deletion of Runx1 in the MDECs induced adenosis in the cranial portion of vagina, which mimicked the effect of developmental DES-exposure. Furthermore, neonatal DES exposure downregulated RUNX1 in the fornix of the vagina, where DES-associated adenosis is frequently found. This observation strongly suggests that the downregulation of RUNX1 is the cause of vaginal adenosis. However, once cell fate was determined, the BMP/Activin-SMAD/RUNX1 signaling pathway became dispensable for the maintenance of ΔNp63 expression in vaginal epithelium. Instead, the activity of the ΔNp63 locus in vaginal epithelium was maintained by a ΔNp63-dependent mechanism. This is the first demonstration of a molecular mechanism through which developmental chemical exposure causes precancerous lesions by altering cell fate. PMID:23830984

Menarche, menopause, years of menstruation, and the incidence of osteoporosis: the influence of prenatal exposure to diethylstilbestrol.

PubMed

Parker, Samantha E; Troisi, Rebecca; Wise, Lauren A; Palmer, Julie R; Titus-Ernstoff, Linda; Strohsnitter, William C; Hatch, Elizabeth E

2014-02-01

Estrogen is critical for bone formation and growth in women. Estrogen exposures occur throughout life, including prenatally, and change with reproductive events, such as menarche and menopause. The objective of this study was to investigate the association between age at menarche, age at menopause, and years of menstruation with incidence of osteoporosis and assess the impact of prenatal exposure to diethylstilbestrol (DES), a synthetic estrogen, on such associations. Participants were 5573 women in the National Cancer Institute Combined Cohort Study of DES (1994-2006). Data on reproductive history and medical conditions were collected through questionnaires at baseline in 1994 and subsequently in 1997, 2001, and 2006. Age-stratified Cox regression models were used to calculate multivariable incidence rate ratios (IRRs) and 95% confidence intervals (CIs). Effect measure modification by prenatal DES exposure was assessed using cubic restricted spline regression models. Osteoporosis was the main outcome measure. The IRRs for osteoporosis incidence with age at menarche less than 11 years and age at menopause of 50 years or younger were 0.82 (CI 0.59, 1.14) and 0.61 (CI 0.40, 0.92), respectively. Fewer than 25 years of menstruation was associated with an increased incidence of osteoporosis (IRR 1.80; CI 1.14, 2.86) compared with 35 years or more of menstruation. Associations were stronger among women who had not been prenatally exposed to DES. Our data support the hypothesis that lifetime cumulative exposure to estrogens is protective against osteoporosis. Furthermore, prenatal exposure to estrogen appears to modify these associations, although the mechanism by which this occurs is unknown.

Exposure to diethylstilbestrol during pregnancy modulates microRNA expression profile in mothers and fetuses reflecting oncogenic and immunological changes.

PubMed

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

2015-05-01

Prenatal exposure to diethylstilbestrol (DES) is known to cause an increased susceptibility to a wide array of clinical disorders in humans. Previous studies from our laboratory demonstrated that prenatal exposure to DES induces thymic atrophy and apoptosis in the thymus. In the current study, we investigated if such effects on the thymus result from alterations in the expression of microRNA (miR). To that end, pregnant C57BL/6 mice who were exposed to DES and miR profiles in thymocytes of both the mother and fetuses on postnatal day 3 (gestation day 17) were studied. Of the 609 mouse miRs examined, we noted 59 altered miRs that were common for both mothers and fetuses, whereas 107 altered miRs were specific to mothers only and 101 altered miRs were specific to fetuses only. Upon further analyses in the fetuses, we observed that DES-mediated changes in miR expression may regulate genes involved in important functions, such as apoptosis, autophagy, toxicity, and cancer. Of the miRs that showed decreased expression following DES treatment, miR-18b and miR-23a were found to possess complementary sequences and binding affinity for 3' untranslated regions of the Fas ligand (FasL) and Fas, respectively. Transfection studies confirmed that DES-mediated downregulation of miR-18b and miR-23a led to increased FasL and Fas expression. These data demonstrated that prenatal DES exposure can cause alterations in miRs, leading to changes in the gene expression, specifically, miR-mediated increased expression in FasL and Fas causing apoptosis and thymic atrophy. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

Diethylstilbestrol activates CatSper and disturbs progesterone actions in human spermatozoa.

PubMed

Zou, Qian-Xing; Peng, Zhen; Zhao, Qing; Chen, Hou-Yang; Cheng, Yi-Min; Liu, Qing; He, Yuan-Qiao; Weng, Shi-Qi; Wang, Hua-Feng; Wang, Tao; Zheng, Li-Ping; Luo, Tao

2017-02-01

Is diethylstilbestrol (DES), a prototypical endocrine-disrupting chemical (EDC), able to induce physiological changes in human spermatozoa and affect progesterone actions? DES promoted Ca 2+ flux into human spermatozoa by activating the cation channel of sperm (CatSper) and suppressed progesterone-induced Ca 2+ signaling, tyrosine phosphorylation and sperm functions. DES significantly impairs the male reproductive system both in fetal and postnatal exposure. Although various EDCs affect human spermatozoa in a non-genomic manner, the effect of DES on human spermatozoa remains unknown. Sperm samples from normozoospermic donors were exposed in vitro to a range of DES concentrations with or without progesterone at 37°C in a 5% CO 2 incubator to mimic the putative exposure to this toxicant in seminal plasma and the female reproductive tract fluids. The incubation time varied according to the experimental protocols. All experiments were repeated at least five times using different individual sperm samples. Human sperm intracellular calcium concentrations ([Ca 2+ ] i ) were monitored with a multimode plate reader following sperm loading with Ca 2+ indicator Fluo-4 AM, and the whole-cell patch-clamp technique was performed to record CatSper and alkalinization-activated sperm K + channel (KSper) currents. Sperm viability and motility parameters were assessed by an eosin-nigrosin staining kit and a computer-assisted semen analysis system, respectively. The ability of sperm to penetrate into viscous media was examined by penetration into 1% methylcellulose. The sperm acrosome reaction was measured using chlortetracycline staining. The level of tyrosine phosphorylation was determined by western blot assay. DES exposure rapidly increased human sperm [Ca 2+ ] i dose dependently and even at an environmentally relevant concentration (100 pM). The elevation of [Ca 2+ ] i was derived from extracellular Ca 2+ influx and mainly mediated by CatSper. Although DES did not affect sperm

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Haddad, Rami, E-mail: rami.haddad@mail.mcgill.ca; Division of Experimental Medicine, Department of Medicine, McGill University, 850 Sherbrooke Street, Montréal, Québec, Canada H3A 1A2; Kasneci, Amanda, E-mail: amanda.kasneci@mail.mcgill.ca

2013-01-01

Pregnant women, and thus their fetuses, are exposed to many endocrine disruptor compounds (EDCs). Fetal cardiomyocytes express sex hormone receptors making them potentially susceptible to re-programming by estrogenizing EDCs. Diethylstilbestrol (DES) is a proto-typical, non-steroidal estrogen. We hypothesized that changes in adult cardiac structure/function after gestational exposure to the test compound DES would be a proof in principle for the possibility of estrogenizing environmental EDCs to also alter the fetal heart. Vehicle (peanut oil) or DES (0.1, 1.0 and 10.0 μg/kg/da.) was orally delivered to pregnant C57bl/6n dams on gestation days 11.5–14.5. At 3 months, male progeny were left sedentarymore » 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. �

Diethylstilbestrol in fish tissue determined through subcritical fluid extraction and with GC-MS

NASA Astrophysics Data System (ADS)

Qiao, Qinghui; Shi, Nianrong; Feng, Xiaomei; Lu, Jie; Han, Yuqian; Xue, Changhu

2016-06-01

As the key point in sex hormone analysis, sample pre-treatment technology has attracted scientists' attention all over the world, and the development trend of sample preparation forwarded to faster and more efficient technologies. Taking economic and environmental concerns into account, subcritical fluid extraction as a faster and more efficient method has stood out as a sample pre-treatment technology. This new extraction technology can overcome the shortcomings of supercritical fluid and achieve higher extraction efficiency at relatively low pressures and temperatures. In this experiment, a simple, sensitive and efficient method has been developed for the determination of diethylstilbestrol (DES) in fish tissue using subcritical 1,1,1,2-tetrafluoroethane (R134a) extraction in combination with gas chromatography-mass spectrometry (GC-MS). After extraction, freezing-lipid filtration was utilized to remove fatty co-extract. Further purification steps were performed with C18 and NH2 solid phase extraction (SPE). Finally, the analyte was derived by heptafluorobutyric anhydride (HFBA), followed by GC-MS analysis. Response surface methodology (RSM) was employed to optimizing the extraction condition, and the optimized was as follows: extraction pressure, 4.3 MPa; extraction temperature, 26°C; amount of co-solvent volume, 4.7 mL. Under this condition, at a spiked level of 1, 5, 10 μg kg-1, the mean recovery of DES was more than 90% with relative standard deviations (RSDs) less than 10%. Finally, the developed method has been successfully used to analyzing the real samples.

Litigation involving DES.

PubMed

Rheingold, P D

1976-01-01

Focus is on the diethylstilbestrol (DES) litigation which has resulted from the 1971 discovery that this synthetic estrogen can cause cancer in the daughters of women who used the drug during pregnancy in an effort to prevent threatened abortion. Possibly 100 suits are pending at this time in which DES daughters claim injuries. In most of these vaginal or cervical cancer has appeared -- with or without a hysterectomy having been performed. Several women died from cancer. The fact that the use of DES occurred many years ago is the legal hurdle most troublesome to lawyers. The average women coming to a lawyer's office today has a mother who used some form of DES, perhaps in 1955. Few drugstores have records today of the prescriptions which they filled 20 years ago. It has been estimated that over the 1950-1970 period more than 200 different companies manufactured or "tabletized" under their own name DES plus a variety of similar synthetic estrogens promoted for the prevention of threatened abortion. A further hurdle caused by the passage of time is that even the records of the physicians are frequently lost. A final problem created by the age of the cases is statute of limitations. If the actual manufacturer of the DES cannot be identified, this is generally the end of the lawyer's interest in the case. The chance of the plaintiff winning may be increased if the action against all the manufacturers is a class action. Most of the pending DES suits are against the manufacturer and not against the doctor. Thus far no DES case has been tried to completion. Several have been settled by the manufacturers on the eve of the trial, generally for less than the full sum that a cancer victim would expect to receive.

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

PubMed Central

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

2014-01-01

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

Menarche, Menopause, Years of Menstruation, and the Incidence of Osteoporosis: The Influence of Prenatal Exposure to Diethylstilbestrol

PubMed Central

Troisi, Rebecca; Wise, Lauren A.; Palmer, Julie R.; Titus-Ernstoff, Linda; Strohsnitter, William C.; Hatch, Elizabeth E.

2014-01-01

Context: Estrogen is critical for bone formation and growth in women. Estrogen exposures occur throughout life, including prenatally, and change with reproductive events, such as menarche and menopause. Objective: The objective of this study was to investigate the association between age at menarche, age at menopause, and years of menstruation with incidence of osteoporosis and assess the impact of prenatal exposure to diethylstilbestrol (DES), a synthetic estrogen, on such associations. Design, Setting, and Participants: Participants were 5573 women in the National Cancer Institute Combined Cohort Study of DES (1994–2006). Data on reproductive history and medical conditions were collected through questionnaires at baseline in 1994 and subsequently in 1997, 2001, and 2006. Age-stratified Cox regression models were used to calculate multivariable incidence rate ratios (IRRs) and 95% confidence intervals (CIs). Effect measure modification by prenatal DES exposure was assessed using cubic restricted spline regression models. Main Outcome Measure: Osteoporosis was the main outcome measure. Results: The IRRs for osteoporosis incidence with age at menarche less than 11 years and age at menopause of 50 years or younger were 0.82 (CI 0.59, 1.14) and 0.61 (CI 0.40, 0.92), respectively. Fewer than 25 years of menstruation was associated with an increased incidence of osteoporosis (IRR 1.80; CI 1.14, 2.86) compared with 35 years or more of menstruation. Associations were stronger among women who had not been prenatally exposed to DES. Conclusions: Our data support the hypothesis that lifetime cumulative exposure to estrogens is protective against osteoporosis. Furthermore, prenatal exposure to estrogen appears to modify these associations, although the mechanism by which this occurs is unknown. PMID:24248183

Maternal obesogenic diet induces endometrial hyperplasia, an early hallmark of endometrial cancer, in a diethylstilbestrol mouse model.

PubMed

Owuor, Theresa O; Reid, Michaela; Reschke, Lauren; Hagemann, Ian; Greco, Suellen; Modi, Zeel; Moley, Kelle H

2018-01-01

Thirty-eight percent of US adult women are obese, meaning that more children are now born of overweight and obese mothers, leading to an increase in predisposition to several adult onset diseases. To explore this phenomenon, we developed a maternal obesity animal model by feeding mice a diet composed of high fat/ high sugar (HF/HS) and assessed both maternal diet and offspring diet on the development of endometrial cancer (ECa). We show that maternal diet by itself did not lead to ECa initiation in wildtype offspring of the C57Bl/6J mouse strain. While offspring fed a HF/HS post-weaning diet resulted in poor metabolic health and decreased uterine weight (regardless of maternal diet), it did not lead to ECa. We also investigated the effects of the maternal obesogenic diet on ECa development in a Diethylstilbestrol (DES) carcinogenesis mouse model. All mice injected with DES had reproductive tract lesions including decreased number of glands, condensed and hyalinized endometrial stroma, and fibrosis and increased collagen deposition that in some mice extended into the myometrium resulting in extensive disruption and loss of the inner and outer muscular layers. Fifty percent of DES mice that were exposed to maternal HF/HS diet developed several features indicative of the initial stages of carcinogenesis including focal glandular and atypical endometrial hyperplasia versus 0% of their Chow counterparts. There was an increase in phospho-Akt expression in DES mice exposed to maternal HF/HS diet, a regulator of persistent proliferation in the endometrium, and no difference in total Akt, phospho-PTEN and total PTEN expression. In summary, maternal HF/HS diet exposure induces endometrial hyperplasia and other precancerous phenotypes in mice treated with DES. This study suggests that maternal obesity alone is not sufficient for the development of ECa, but has an additive effect in the presence of a secondary insult such as DES.

Enhancement of blood-tumor barrier permeability by Sar-[D-Phe8]des-Arg9BK, a metabolically resistant bradykinin B1 agonist, in a rat C6 glioma model

PubMed Central

Cardoso, Ronie Cleverson; Lobão-Soares, Bruno; Bianchin, Marino Muxfeldt; Carlotti, Carlos Gilberto; Walz, Roger; Alvarez-Silva, Márcio; Trentin, Andréa Gonçalves; Nicolau, Mauro

2004-01-01

Background While it is well known that bradykinin B2 agonists increase plasma protein extravasation (PPE) in brain tumors, the bradykinin B1 agonists tested thus far are unable to produce this effect. Here we examine the effect of the selective B1 agonist bradykinin (BK) Sar-[D-Phe8]des-Arg9BK (SAR), a compound resistant to enzymatic degradation with prolonged activity on PPE in the blood circulation in the C6 rat glioma model. Results SAR administration significantly enhanced PPE in C6 rat brain glioma compared to saline or BK (p < 0.01). Pre-administration of the bradykinin B1 antagonist [Leu8]-des-Arg (100 nmol/Kg) blocked the SAR-induced PPE in the tumor area. Conclusions Our data suggest that the B1 receptor modulates PPE in the blood tumor barrier of C6 glioma. A possible role for the use of SAR in the chemotherapy of gliomas deserves further study. PMID:15458573

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

PubMed Central

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

2012-01-01

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

Prenatal exposure of mice to diethylstilbestrol disrupts T-cell differentiation by regulating Fas/Fas ligand expression through estrogen receptor element and nuclear factor-κB motifs.

PubMed

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

2012-11-01

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

Analysis of the Effect of Estrogen/Androgen Perturbation on Penile Development in Transgenic and Diethylstilbestrol-Treated Mice

PubMed Central

BLASCHKO, SARAH D.; MAHAWONG, PHITSANU; FERRETTI, MAX; CUNHA, TRISTAN J.; SINCLAIR, ADRIANE; WANG, HONG; SCHLOMER, BRUCE J.; RISBRIDGER, GAIL; BASKIN, LAURENCE S.; CUNHA, GERALD R.

2013-01-01

Because both androgens and estrogens have been implicated in penile morphogenesis, we evaluated penile morphology in transgenic mice with known imbalance of androgen and estrogen signaling using scanning electron microscopy (SEM), histology, and immunohistochemistry of androgen and estrogen receptors α/β. Penises of adult wild-type, estrogen receptor-α knockout (αERKO), estrogen receptor-β knockout (βERKO), aromatase knockout (Arom-KO), and aromatase overexpression (Arom+) mice were evaluated, as well as adult mice treated with diethylstilbestrol (DES) from birth to day 10. Adult penises were examined because the adult pattern is the endpoint of development. The urethral orifice is formed by fusion of the MUMP (male urogenital mating protuberance) with the MUMP ridge, which consists of several processes fused to each other and to the MUMP. Similarly, the internal prepuce is completed ventrally by fusion of a ventral cleft. In adult murine penises the stromal processes that form the MUMP ridge are separated from their neighbors by clefts. αERKO, βERKO, and Arom-KO mice have penises with a MUMP ridge clefting pattern similar to that of wild-type mice. In contrast, Arom+ mice and neonatally DES-treated mice exhibit profound malformations of the MUMP, MUMP ridge clefting pattern, and internal prepuce. Abnormalities observed in Arom+ and neonatally DES-treated mice correlate with the expression of estrogen receptor-beta (ERβ) in the affected structures. This study demonstrates that formation of the urethal orifice and internal prepuce is due to fusion of separate epithelial-surfaced mesenchymal elements, a process dependent upon both androgen and estrogen signaling, in which ERβ signaling is strongly implicated. PMID:23653160

A focus group study of DES daughters: implications for health care providers.

PubMed

Duke, S S; McGraw, S A; Avis, N E; Sherman, A

2000-01-01

A focus group study of women exposed to diethylstilbestrol (DES) in utero (DES daughters) was conducted to gain understanding about exposure to this drug from a patient perspective. Focus group participants reported that learning about their DES exposure was devastating; they experienced strains in their family relationships, emotional shock, a feeling that their health concerns were not appreciated by others and, to some degree, a sense of social isolation. Although many were aware of the need for special gynecological exams and high-risk prenatal care, they were frustrated by what they felt was a lack of reliable and clear information about the effects of DES exposure. Most expressed questions and anxiety about their health. Many found their communication with physicians about their DES exposure unsatisfying. They felt that physicians lacked information about the long-term health effects of DES exposure and as a result did not give them accurate information. Furthermore, they felt that physicians were dismissive of their concerns and often gave what they felt to be false reassurances. Consequently, the women developed an enduring distrust of the medical profession. The results of the study suggest implications for the delivery of health care to DES daughters. Copyright 2000 John Wiley & Sons, Ltd.

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

PubMed Central

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

2014-01-01

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

Modeling of three dimensional structure of human alpha-fetoprotein complexed with diethylstilbestrol: docking and molecular dynamics simulation study.

PubMed

Terentiev, Alexander A; Moldogazieva, Nurbubu T; Levtsova, Olga V; Maximenko, Dmitry M; Borozdenko, Denis A; Shaitan, Konstantin V

2012-04-01

It has been long experimentally demonstrated that human alpha-fetoprotein (HAFP) has an ability to bind immobilized estrogens with the most efficiency for synthetic estrogen analog - diethylstilbestrol (DES). However, the question remains why the human AFP (HAFP), unlike rodent AFP, cannot bind free estrogens. Moreover, despite the fact that AFP was first discovered more than 50 years ago and is presently recognized as a "golden standard" among onco-biomarkers, its three-dimensional (3D) structure has not been experimentally solved yet. In this work using MODELLER program, we generated 3D model of HAFP on the basis of homology with human serum albumin (HSA) and Vitamin D-binding protein (VTDB) with subsequent molecular docking of DES to the model structure and molecular dynamics (MD) simulation study of the complex obtained. The model constructed has U-shaped structure in which a cavity may be distinguished. In this cavity the putative estrogen-binding site is localized. Validation by RMSD calculation and with the use of PROCHECK program showed good quality of the model and stability of extended region of four alpha-helical structures that contains putative hormone-binding residues. Data extracted from MD simulation trajectory allow proposing two types of interactions between amino acid residues of HAFP and DES molecule: (1) hydrogen bonding with involvement of residues S445, R452, and E551; (2) hydrophobic interactions with participation of L138, M448, and M548 residues. A suggestion is made that immobilization of the hormone using a long spacer provides delivery of the estrogen molecule to the binding site and, thereby, facilitates interaction between HAFP and the hormone.

Prostate enlargement in mice due to fetal exposure to low doses of estradiol or diethylstilbestrol and opposite effects at high doses

PubMed Central

Saal, Frederick S. vom; Timms, Barry G.; Montano, Monica M.; Palanza, Paola; Thayer, Kristina A.; Nagel, Susan C.; Dhar, Minati D.; Ganjam, V. K.; Parmigiani, Stefano; Welshons, Wade V.

1997-01-01

On the basis of results of studies using high doses of estrogens, exposure to estrogen during fetal life is known to inhibit prostate development. However, it is recognized in endocrinology that low concentrations of a hormone can stimulate a tissue, while high concentrations can have the opposite effect. We report here that a 50% increase in free-serum estradiol in male mouse fetuses (released by a maternal Silastic estradiol implant) induced a 40% increase in the number of developing prostatic glands during fetal life; subsequently, in adulthood, the number of prostatic androgen receptors per cell was permanently increased by 2-fold, and the prostate was enlarged by 30% (due to hyperplasia) relative to untreated males. However, as the free serum estradiol concentration in male fetuses was increased from 2- to 8-fold, adult prostate weight decreased relative to males exposed to the 50% increase in estradiol. As a model for fetal exposure to man-made estrogens, pregnant mice were fed diethylstilbestrol (DES) from gestation days 11 to 17. Relative to controls, DES doses of 0.02, 0.2, and 2.0 ng per g of body weight per day increased adult prostate weight, whereas a 200-ng-per-g dose decreased adult prostate weight in male offspring. Our findings suggest that a small increase in estrogen may modulate the action of androgen in regulating prostate differentiation, resulting in a permanent increase in prostatic androgen receptors and prostate size. For both estradiol and DES, prostate weight first increased then decreased with dose, resulting in an inverted-U dose-response relationship. PMID:9050904

[The effect of diethylstilbestrol on inducing abdominal cryptorchidism and relevant genetic expression in rats].

PubMed

Zhang, Lin; Zheng, Xin-min; Zheng, Hang; Yang, Zhi-wei; Li, Shi-wen

2009-05-01

To study the effect of diethylstilbestrol (DES) at different doses on transabdominal testicular descent in rats and the expression of INSL3 in the testis and HOXA10 in the gubernaculum. Fifty E13.5 (embryonic day 13.5) pregnant female SD rats were randomly divided into five groups that received a subcutaneous injection of DMSO, 2.5, 5.0, 10.0 and 20.0 mg/kg DES (group A, B, C, D and E), respectively. Male offspring were killed at E19.5, and then fetal mortality, the degree of transabdominal testicular ascent (DTA) was determined by a stereomicroscope. The mRNA expressions of INSL3 in the testis and HOXA10 in the gubernaculum were determined by RT-PCR. The expression of INSL3 protein was determined by Western blotting. Male fetal mortality in group A, B, C, D, and E were 3.57%, 6.90%, 12.00%, 19.23% and 36.36%, respectively, which showed a dose-effect relationship between DES and the male fatal mortality (r=0.999, P<0.01). DTA in group B, C, D and E were (23.7+/-1.7) U, (38.8+/-1.9) U, (49.3+/-1.8) U and (58.6+/-2.1) U that were significantly larger than that in group A [(8.5+/-1.3) U] (q=46.12, 88.53, 120.44 and 141.37, respectively, P<0.01). There was also a dose-effect relationship between DES and DTA. In group B, C, D, and E, the expression of INSL3 mRNA were 0.9570+/-0.1490, 0.6760+/-0.1380, 0.0170+/-0.0040 and 0.0013+/-0.0003, respectively; the expressions of INSL3 protein were 0.8360+/-0.1520, 0.5310+/-0.1070, 0.0140+/-0.0020 and 0.0011+/-0.0003, respectively, which were significantly larger than the expression of INSL3 mRNA (1.801+/-0.126) and INSL3 protein (1.612+/-0.134) in group A (qmRNA=40.4840, 52.4402, 83.1585 and 82.0582, respectively, and qprotein=38.6151, 52.2747, 77.2756 and 76.1983, respectively, P<0.01). The expression of HOXA10 mRNA in group A, B, C, D, and E were 0.945+/-0.125, 0.940+/-0.119, 0.656+/-0.115, 0.544+/-0.118 and 0.463+/-0.114, respectively. Compared with the expression of HOXA10 mRNA in group A, the expression of group B was not

Altered microRNA expression patterns during the initiation and promotion stages of neonatal diethylstilbestrol-induced dysplasia/neoplasia in the hamster (Mesocricetus auratus) uterus.

PubMed

Padmanabhan, Ramesh; Hendry, Isabel R; Knapp, Jennifer R; Shuai, Bin; Hendry, William J

2017-10-01

Treatment of Syrian hamsters on the day of birth with the prototypical endocrine disruptor and synthetic estrogen, diethylstilbestrol (DES), leads to 100% occurrence of uterine hyperplasia/dysplasia in adulthood, a large proportion of which progress to neoplasia (endometrial adenocarcinoma). Consistent with our prior gene expression analyses at the mRNA and protein levels, we now report (based on microarray, real-time polymerase chain reaction, and in situ hybridization analyses) that progression of the neonatal DES-induced dysplasia/neoplasia phenomenon in the hamster uterus also includes a spectrum of microRNA expression alterations (at both the whole-organ and cell-specific level) that differ during the initiation (upregulated miR-21, 200a, 200b, 200c, 29a, 29b, 429, 141; downregulated miR-181a) and promotion (downregulated miR-133a) stages of the phenomenon. The biological processes targeted by those differentially expressed miRNAs include pathways in cancer and adherens junction, plus regulation of the cell cycle, apoptosis, and miRNA functions, all of which are consistent with our model system phenotype. These findings underscore the need for continued efforts to identify and assess both the classical genetic and the more recently recognized epigenetic mechanisms that truly drive this and other endocrine disruption phenomena.

Novel kinin B1 receptor agonists with improved pharmacological profiles.

PubMed

Côté, Jérôme; Savard, Martin; Bovenzi, Veronica; Bélanger, Simon; Morin, Josée; Neugebauer, Witold; Larouche, Annie; Dubuc, Céléna; Gobeil, Fernand

2009-04-01

There is some evidence to suggest that inducible kinin B1 receptors (B1R) may play beneficial and protecting roles in cardiovascular-related pathologies such as hypertension, diabetes, and ischemic organ diseases. Peptide B1R agonists bearing optimized pharmacological features (high potency, selectivity and stability toward proteolysis) hold promise as valuable therapeutic agents in the treatment of these diseases. In the present study, we used solid-phase methodology to synthesize a series of novel peptide analogues based on the sequence of Sar[dPhe(8)]desArg(9)-bradykinin, a relatively stable peptide agonist with moderate affinity for the human B1R. We evaluated the pharmacological properties of these peptides using (1) in vitro competitive binding experiments on recombinant human B1R and B2R (for index of selectivity determination) in transiently transfected human embryonic kidney 293 cells (HEK-293T cells), (2) ex vivo vasomotor assays on isolated human umbilical veins expressing endogenous human B1R, and (3) in vivo blood pressure tests using anesthetized lipopolysaccharide-immunostimulated rabbits. Key chemical modifications at the N-terminus, the positions 3 and 5 on Sar[dPhe(8)]desArg(9)-bradykinin led to potent analogues. For example, peptides 18 (SarLys[Hyp(3),Cha(5), dPhe(8)]desArg(9)-bradykinin) and 20 (SarLys[Hyp(3),Igl(5), dPhe(8)]desArg(9)-bradykinin) outperformed the parental molecule in terms of affinity, functional potency and duration of action in vitro and in vivo. These selective agonists should be valuable in future animal and human studies to investigate the potential benefits of B1R activation.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Myllymaeki, Sari; Haavisto, Tapio; Vainio, Minna

2005-04-01

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

Drug therapy in pregnancy: the lessons of diethylstilbestrol, thalidomide, and bendectin.

PubMed

Saunders, E J; Saunders, J A

1990-01-01

A pregnant woman and the fetus she carries face health risks from many sources. One risk that requires ongoing vigilance is the use of prescription drugs during pregnancy. The international health care community has been sensitized to the risks of drug use during pregnancy because of three pharmaceuticals that have caused widespread crises for mothers and their offspring. The crises that diethylstilbestrol, thalidomide, and, to a lesser extent, Bendectin have created in the past four decades are reviewed in this article. The lessons these drug crises can teach us are articulated in the belief that similar crises may be averted in the future.

Abnormal morphology of the penis in male rats exposed neonatally to diethylstilbestrol is associated with altered profile of estrogen receptor-alpha protein, but not of androgen receptor protein: a developmental and immunocytochemical study.

PubMed

Goyal, H O; Braden, T D; Williams, C S; Dalvi, P; Mansour, M M; Mansour, M; Williams, J W; Bartol, F F; Wiley, A A; Birch, L; Prins, G S

2004-05-01

Objectives of the study were to determine developmental changes in morphology and expression of androgen receptor (AR) and estrogen receptor (ER)alpha in the body of the rat penis exposed neonatally to diethylstilbestrol (DES). Male pups received DES at a dose of 10 microg per rat on alternate days from Postnatal Day 2 to Postnatal Day 12. Controls received olive oil vehicle only. Tissue samples were collected on Days 18 (prepuberty), 41 (puberty), and 120 (adult) of age. DES-induced abnormalities were evident at 18 days of age and included smaller, lighter, and thinner penis, loss of cavernous spaces and associated smooth muscle cells, and increased deposition of fat cells in the corpora cavernosa penis. Fat cells virtually filled the entire area of the corpora cavernosa at puberty and adulthood. Plasma testosterone (T) was reduced to an undetectable level, while LH was unaltered in all treated groups. AR-positive cells were ubiquitous and their profile (incidence and staining intensity) did not differ between control and treated rats of the respective age groups. Conversely, ERalpha-positive cells were limited to the stroma of corpus spongiosus in all age groups of both control and treated rats, but the expression in treated rats at 18 days was up-regulated in stromal cells of corpora cavernosa, coincident with the presence of morphological abnormalities. Hence, this study reports for the first time DES-induced developmental, morphological abnormalities in the body of the penis and suggests that these abnormalities may have resulted from decreased T and/or overexpression of ERalpha.

Mal-Development of the Penis and Loss of Fertility in Male Rats Treated Neonatally with Female Contraceptive 17α-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 17α-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 μg/kg), 100 ng, 1 μg, or 10 μg 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-μg 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

A short-term study investigating the estrogenic potency of diethylstilbesterol in the fathead minnow (Pimephales promelas)

EPA Science Inventory

Diethylstilbestrol (DES) is a synthetic estrogen that has been banned for use in humans, but still is employed in livestock and aquaculture operations in some parts of the world. Detectable concentrations of DES in effluent and surface waters have been reported to range from slig...

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

PubMed

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

2013-08-01

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

Estrogen-Induced Developmental Disorders of the Rat Penis Involve Both Estrogen Receptor (ESR)- and Androgen Receptor (AR)-Mediated Pathways1

PubMed Central

Goyal, H.O.; Braden, T.D.; Williams, C.S.; Williams, J.W.

2009-01-01

This study tested the hypothesis that the estrogen receptor (ESR) pathway, androgen receptor (AR) pathway, or both mediate estrogen-induced developmental penile disorders. Rat pups received diethylstilbestrol (DES), with or without the ESR antagonist ICI 182,780 (ICI) or the AR agonist dihydrotestosterone (DHT) or testosterone (T), from Postnatal Days 1 to 6. Testicular T concentration, penile morphology and morphometry, and/or fertility was determined at age 7, 28, or 150 days. DES treatment alone caused 90% reduction in the neonatal intratesticular T surge; this reduction was prevented by ICI coadministration, but not by DHT or T coadministration. Unlike the T surge, coadministration of ICI and coadministration of DHT or T mitigated penile deformities and loss of fertility. Generally, ICI, DHT, or T treatment alone did not alter penile morphology; however, fertility was 20% that of controls in ICI-treated rats vs. 70%–90% in DHT- or T-treated rats. The lower fertility in the rats treated with ICI alone could be due to altered sexual behavior, as these males did not deposit vaginal plugs. In conclusion, observations that both an ESR antagonist and AR agonists prevent penile deformities and infertility suggest that both pathways are involved in estrogen-induced penile disorders. Observations that coadministration of ICI, but not DHT or T, prevents the DES-induced reduction in the neonatal T surge suggest that, although ICI exerts its mitigating effect both at the level of Leydig cells and penile stromal cells, DHT and T do so only at the level of stromal cells. PMID:19420389

Prenatal Estrogens and the Development of Homosexual Orientation.

ERIC Educational Resources Information Center

Meyer-Bahlburg, Heino F. L.; And Others

1995-01-01

Examines the hypothesis that prenatal estrogens contribute to the development of human sexual orientation. Several groups of women with a history of prenatal exposure to diethylstilbestrol (DES) were compared with several samples of control women. Findings showed that more DES-exposed women than controls were rated as bisexual or homosexual,…

Structure-guided development of dual β2 adrenergic/dopamine D2 receptor agonists.

PubMed

Weichert, Dietmar; Stanek, Markus; Hübner, Harald; Gmeiner, Peter

2016-06-15

Aiming to discover dual-acting β2 adrenergic/dopamine D2 receptor ligands, a structure-guided approach for the evolution of GPCR agonists that address multiple targets was elaborated. Starting from GPCR crystal structures, we describe the design, synthesis and biological investigation of a defined set of compounds leading to the identification of the benzoxazinone (R)-3, which shows agonist properties at the adrenergic β2 receptor and substantial G protein-promoted activation at the D2 receptor. This directed approach yielded molecular probes with tuned dual activity. The congener desOH-3 devoid of the benzylic hydroxyl function was shown to be a β2 adrenergic antagonist/D2 receptor agonist with Ki values in the low nanomolar range. The compounds may serve as a promising starting point for the investigation and treatment of neurological disorders. Copyright © 2016 Elsevier Ltd. All rights reserved.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

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

1992-06-01

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

Thrombospondin-1 (TSP-1) Analogs ABT-510 and ABT-898 Inhibit Prolactinoma Growth and Recover Active Pituitary Transforming Growth Factor-β1 (TGF-β1)

PubMed Central

Recouvreux, M. Victoria; Camilletti, M. Andrea; Rifkin, Daniel B.; Becu-Villalobos, Damasia

2012-01-01

Prolactinomas are the most prevalent type of secreting pituitary tumors in humans and generally respond well to a medical therapy with dopamine agonists. However, for patients exhibiting resistance to dopaminergic drugs, alternative treatments are desired. Antiangiogenic strategies might represent a potential therapy for these tumors. Thrombospondin 1 (TSP-1) is a large multifunctional glycoprotein involved in multiple biological processes including angiogenesis, apoptosis, and activation of TGF-β1. Because tumors that overexpress TSP-1 grow more slowly, have fewer metastases, and have decreased angiogenesis, TSP-1 provides a novel target for cancer treatment. ABT-510 and ABT-898 are TSP-1 synthetic analogs that mimic its antiangiogenic action. In the present study, we explored the potential effect of ABT-510 and ABT-898 on experimental prolactinomas induced by chronic diethylstilbestrol (DES) treatment in female rats. We demonstrated that a 2-wk treatment with ABT-510 and ABT-898 counteracted the increase in pituitary size and serum prolactin levels as well as the pituitary proliferation rate induced by DES. These inhibitory effects on tumor growth could be mediated by the antiangiogenic properties of the drugs. We also demonstrated that ABT-510 and ABT-898, in addition to their described antiangiogenic effects, increased active TGF-β1 level in the tumors. We postulate that the recovery of the local cytokine activation participates in the inhibition of lactotrope function. These results place these synthetic TSP-1 analogs as potential alternative or complementary treatments in dopamine agonist-resistant prolactinomas. PMID:22700773

Thrombospondin-1 (TSP-1) analogs ABT-510 and ABT-898 inhibit prolactinoma growth and recover active pituitary transforming growth factor-β1 (TGF-β1).

PubMed

Recouvreux, M Victoria; Camilletti, M Andrea; Rifkin, Daniel B; Becu-Villalobos, Damasia; Díaz-Torga, Graciela

2012-08-01

Prolactinomas are the most prevalent type of secreting pituitary tumors in humans and generally respond well to a medical therapy with dopamine agonists. However, for patients exhibiting resistance to dopaminergic drugs, alternative treatments are desired. Antiangiogenic strategies might represent a potential therapy for these tumors. Thrombospondin 1 (TSP-1) is a large multifunctional glycoprotein involved in multiple biological processes including angiogenesis, apoptosis, and activation of TGF-β1. Because tumors that overexpress TSP-1 grow more slowly, have fewer metastases, and have decreased angiogenesis, TSP-1 provides a novel target for cancer treatment. ABT-510 and ABT-898 are TSP-1 synthetic analogs that mimic its antiangiogenic action. In the present study, we explored the potential effect of ABT-510 and ABT-898 on experimental prolactinomas induced by chronic diethylstilbestrol (DES) treatment in female rats. We demonstrated that a 2-wk treatment with ABT-510 and ABT-898 counteracted the increase in pituitary size and serum prolactin levels as well as the pituitary proliferation rate induced by DES. These inhibitory effects on tumor growth could be mediated by the antiangiogenic properties of the drugs. We also demonstrated that ABT-510 and ABT-898, in addition to their described antiangiogenic effects, increased active TGF-β1 level in the tumors. We postulate that the recovery of the local cytokine activation participates in the inhibition of lactotrope function. These results place these synthetic TSP-1 analogs as potential alternative or complementary treatments in dopamine agonist-resistant prolactinomas.

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

PubMed

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

1995-06-01

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

Screening of environmental contaminants for ecdysteroid agonist and antagonist activity using the Drosophila melanogaster B(II) cell in vitro assay.

PubMed

Dinan, L; Bourne, P; Whiting, P; Dhadialla, T S; Hutchinson, T H

2001-09-01

The B(II) bioassay was developed as a rapid and reliable tool for detecting potential insect growth regulators acting as ecdysteroid receptor (ant)agonists. Based on an ecdysteroid-responsive cell line from Drosophila melanogaster, this microplate assay is ideally suited to the evaluation of environmental contaminants as potential endocrine disrupters. Data are presented for about 80 potential environmental contaminants, including industrial chemicals, pesticides, pharmaceuticals, phytoestrogens, and vertebrate steroids, and are compared with data for known (ant)agonists. Apart from androst-4-ene-3,17-dione (a weak antagonist), vertebrate steroids were inactive at concentrations up to 10(-3) M. The vast majority of xenobiotics also showed no (ant)agonist activity. Among the industrial chemicals, antagonistic activity was observed for bisphenol A median effective concentration (EC50) of 1.0 x 10(-4) M and diethylphthalate (EC50 of 2.0 x 10(-3) M). Some organochlorine compounds also showed weak antagonistic activity, including o,p'-dichlorodiphenyldichloroethylene (DDE), p,p'-DDE, dieldrin, and lindane (EC50 of 3.0 x 10(-5) M). For lindane, bisphenol A, and diethylphthalate, activity is not associated with impurities in the samples and, for lindane and bisphenol A at least, the compounds are able to compete with ecdysteroids for the ligand binding site on the receptor complex, albeit at concentrations very much higher than those found in the environment. The only pharmaceutical showing any detectable antagonist activity was 17alpha-ethynylestradiol. In the context of recent publications on potential endocrine disruption in marine and freshwater arthropods, these findings suggest that, for some compounds (e.g., diethylstilbestrol), ecdysteroid receptor-mediated responses are unlikely to be involved in producing chronic effects. The B(II) assay has a potentially valuable role to play in distinguishing between endocrine-mediated, which normally occur at submicromolar

Estrogen-Induced Maldevelopment of the Penis Involves Down-Regulation of Myosin Heavy Chain 11 (MYH11) Expression, a Biomarker for Smooth Muscle Cell Differentiation1

PubMed Central

Okumu, L.A.; Bruinton, Sequoia; Braden, Tim D.; Simon, Liz; Goyal, Hari O.

2012-01-01

ABSTRACT Cavernous smooth muscle cells are essential components in penile erection. In this study, we investigated effects of estrogen exposure on biomarkers for smooth muscle cell differentiation in the penis. Neonatal rats received diethylstilbestrol (DES), with or without the estrogen receptor (ESR) antagonist ICI 182,780 (ICI) or the androgen receptor (AR) agonist dihydrotestosterone (DHT), from Postnatal Days 1 to 6. Tissues were collected at 7, 10, or 21 days of age. The smooth muscle cell biomarker MYH11 was studied in depth because microarray data showed it was significantly down-regulated, along with other biomarkers, in DES treatment. Quantitative real time-PCR and Western blot analyses showed 50%–80% reduction (P ≤ 0.05) in Myh11 expression in DES-treated rats compared to that in controls; and ICI and DHT coadministration mitigated the decrease. Temporally, from 7 to 21 days of age, Myh11 expression was onefold increased (P ≥ 0.05) in DES-treated rats versus threefold increased (P ≤ 0.001) in controls, implying the long-lasting inhibitory effect of DES on smooth muscle cell differentiation. Immunohistochemical localization of smooth muscle alpha actin, another biomarker for smooth muscle cell differentiation, showed fewer cavernous smooth muscle cells in DES-treated animals than in controls. Additionally, DES treatment significantly up-regulated Esr1 mRNA expression and suppressed the neonatal testosterone surge by 90%, which was mitigated by ICI coadministration but not by DHT coadministration. Collectively, results provided evidence that DES treatment in neonatal rats inhibited cavernous smooth muscle cell differentiation, as shown by down-regulation of MYH11 expression at the mRNA and protein levels and by reduced immunohistochemical staining of smooth muscle alpha actin. Both the ESR and the AR pathways probably mediate this effect. PMID:22976277

[Vaginal adenosis: A case report and literature review].

PubMed

Harimenshi, Jean-Marie; Jean-Jacques, Bastien; Michels, Jean-Jacques

2016-08-01

We report a case of vaginal adenosis in a woman of 42years. This is a rare congenital disorder since cessation of use of diethylstilbestrol (DES), usually of benign course, not to ignore in its tubo-endometrial histological form which may progress to atypical adenosis precursor of vaginal clear cell adenocarcinoma in patients exposed in utero to DES. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Binding ability of impromidine, a potent H2 agonist of histamine

NASA Astrophysics Data System (ADS)

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

1999-09-01

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

Breast Cancer Risk in American Women

MedlinePlus

... September 7, 2012. Related Resources BRCA Mutations: Cancer Risk and Genetic Testing Breast Cancer Prevention (PDQ®)–Patient Version Diethylstilbestrol (DES) and Cancer Genetics of Breast and Gynecologic Cancers (PDQ®)–Health Professional Version Mammograms Reproductive History and Cancer Risk ...

Agonist-induced modulation of inverse agonist efficacy at the beta 2-adrenergic receptor.

PubMed

Chidiac, P; Nouet, S; Bouvier, M

1996-09-01

Sustained stimulation of several G protein-coupled receptors is known to lead to a reduction in the signaling efficacy. This phenomenon, named agonist-induced desensitization, has been best studied for the beta 2-adrenergic receptor (AR) and is characterized by a decreased efficacy of beta-adrenergic agonists to stimulate the adenylyl cyclase activity. Recently, several beta-adrenergic ligands were found to inhibit the spontaneous agonist-independent activity of the beta 2AR. These compounds, termed inverse agonists, have different inhibitory efficacies, ranging from almost neutral antagonists to full inverse agonists. The current study was undertaken to determine whether, as is the case for agonists, desensitization can affect the efficacies of inverse agonists. Agonist-promoted desensitization of the human beta 2AR expressed in Sf9 cells potentiated the inhibitory actions of the inverse agonists, with the extent of the potentiation being inversely proportional to their intrinsic activity. For example, desensitization increased the inhibitory action of the weak inverse agonist labetalol by 29%, whereas inhibition of the spontaneous activity by the strong inverse agonist timolol was not enhanced by the desensitizing stimuli. Interestingly, dichloroisoproterenol acted stochastically as either a weak partial agonist or a weak inverse agonist in control conditions but always behaved as an inverse agonist after desensitization. These data demonstrate that like for agonists, the efficacies of inverse agonists can be modulated by a desensitizing treatment. Also, the data show that the initial state of the receptor can determine whether a ligand behaves as a partial agonist or an inverse agonist.

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

PubMed

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

2010-07-01

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

β2 Agonists.

PubMed

Billington, Charlotte K; Penn, Raymond B; Hall, Ian P

2017-01-01

History suggests β agonists, the cognate ligand of the β 2 adrenoceptor, have been used as bronchodilators for around 5,000 years, and β agonists remain today the frontline treatment for asthma and chronic obstructive pulmonary disease (COPD). The β agonists used clinically today are the products of significant expenditure and over 100 year's intensive research aimed at minimizing side effects and enhancing therapeutic usefulness. The respiratory physician now has a therapeutic toolbox of long acting β agonists to prophylactically manage bronchoconstriction, and short acting β agonists to relieve acute exacerbations. Despite constituting the cornerstone of asthma and COPD therapy, these drugs are not perfect; significant safety issues have led to a black box warning advising that long acting β agonists should not be used alone in patients with asthma. In addition there are a significant proportion of patients whose asthma remains uncontrolled. In this chapter we discuss the evolution of β agonist use and how the understanding of β agonist actions on their principal target tissue, airway smooth muscle, has led to greater understanding of how these drugs can be further modified and improved in the future. Research into the genetics of the β 2 adrenoceptor will also be discussed, as will the implications of individual DNA profiles on the clinical outcomes of β agonist use (pharmacogenetics). Finally we comment on what the future may hold for the use of β agonists in respiratory disease.

Prise en charge des troubles de consommation d’opioïdes en première ligne

PubMed Central

Srivastava, Anita; Kahan, Meldon; Nader, Maya

2017-01-01

obligations familiales les empêchent de se rendre à la pharmacie tous les jours, s’ils ont une affection médicale ou psychiatrique exigeant des soins réguliers de première ligne (données de niveau IV), ou encore si leur emploi exige une fonction cognitive ou un rendement psychomoteur élevés (données de niveau III). La buprénorphine-naloxone est aussi recommandée chez les patients qui présentent un risque élevé de toxicité à la méthadone, tels que les personnes âgées, les personnes qui prennent de fortes doses de benzodiazépines ou d’autres sédatifs, les gros buveurs, les personnes dont la tolérance aux opioïdes est faible et les personnes à risque de prolongement de l’intervalle QT (données de niveau III). Conclusion Il faut tenir compte des caractéristiques et des préférences individuelles des patients lors de la sélection d’un traitement de première intention par un agoniste des opioïdes. Chez les patients qui présentent un risque élevé d’abandon (adolescents et patients socialement instables), la rétention en traitement doit avoir préséance sur les autres considérations cliniques. Chez les patients qui présentent un risque élevé de toxicité (comme les usagers abusifs d’alcool ou de benzodiazépines), la sécurité a sans doute préséance. Ce qu’il importe le plus de considérer toutefois, c’est que le traitement par un agoniste des opioïdes est beaucoup plus efficace que l’approche axée sur l’abstinence. PMID:28292811

Early-life estrogen exposure and uterine pathogenesis: ?A model for gene-environment interactions

EPA Science Inventory

Aberrant cellular differentiation early in life can contribute to increased cancer risk later in life. In a classic model of this effect, female mice exposed on postnatal day (PND) 1-5 to the synthetic estrogen diethylstilbestrol (DES) have a high incidence of uterine carcinoma. ...

The cannabinoid receptor inverse agonist AM251 regulates the expression of the EGF receptor and its ligands via destabilization of oestrogen-related receptor α 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 α (ERRα), also induced EGFR and HB-EGF expression to the same extent as AM251, whereas pretreatment with the ERRα-selective agonist, biochanin A, blunted AM251 actions. AM251 promoted the degradation of ERRα protein without loss of the corresponding mRNA. Knock-down of ERRα 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 ERRα. CONCLUSIONS AND IMPLICATIONS AM251 up-regulates EGFR expression and signalling via a novel non-CB1R-mediated pathway involving destabilization of ERRα protein in selected cancer cell lines. PMID:21449913

Accretion of biopsy specimens of vaginal adenosis from patients exposed in utero to diethylstilbestrol, when transplanted to athymic nude mice.

PubMed

Pienkowski, M M; Mann, L C; Rosloniec, E F; Welsch, C W

1979-03-01

Vaginal adenosis biopsy specimens from 10 patients exposed in utero to diethylstilbestrol were transplanted for 30 days into athymic (nude) mice. Almost all grafts were recovered, and they had morphologic features closely resembling those of the original biopsy specimens, i.e., cystic, complex, and simple occult glands covered mainly with an endocervical type of epithelium showing extensive squamous metaplasia. Autoradiographic analysis of these grafts after pulse administration of [3H]thymidine into the mice revealed extensive labeling of epithelial cells. These results imply that female athymic (nude) mice are compatible hosts for accretion of the human adenosis.

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

PubMed

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

2012-04-30

The design of improved polymeric carriers to be used in the next generation of polymer therapeutics is an ongoing challenge. Biodegradable systems present potential advantages regarding safety benefit apart from the possibility to use higher molecular weight (Mw) carriers allowing PK optimization, by exploiting the enhanced permeability and retention (EPR)-mediated tumor targeting. Within this context, we previously designed pH-responsive polyacetalic systems, tert-polymers, where a drug with the adequate diol-functionality was incorporated within the polymer mainchain. The synthetic, non-steroidal estrogen, diethylstilboestrol (DES) clinically used for the treatment of advanced prostate cancer was chosen as drug. In order to improve the properties of this tert-polymer, novel polyacetalic systems as block-co-polymers, with more defined structure have been obtained. This second generation polyacetals allowed higher drug capacity than the tert-polymer, a biphasic DES release profile at acidic pH and due to its controlled amphiphilic character readily formed micelle-like structures in solution. These features result in an enhancement of conjugate therapeutic value in selected prostate cancer cell models. Exhaustive physico-chemical characterization focusing on nanoconjugate solution behavior and using advanced techniques, such as, pulsed-gradient spin-echo NMR (PGSE-NMR) and small-angle neutron scattering (SANS), has been carried out in order to demonstrate this hypothesis. Clear evidence of significantly different conformation in solution has been obtained for both polyacetals. These results demonstrate that an adequate control on molecular or supramolecular conformation in solution with polymer therapeutics is crucial in order to achieve the desired therapeutic output. Copyright © 2012 Elsevier B.V. All rights reserved.

Repellent activity of estrogenic compounds toward zoospores of the phytopathogenic fungus Aphanomyces cochlioides.

PubMed

Islam, M T; Tahara, S

2001-01-01

Screening chemical compounds, we found that a xenoestrogen, bisphenol A, showed potent repellent activity against the zoospores of Aphanomyces cochlioides. Based on this finding, we tested a number of androgenic and estrogenic compounds (e.g. testosterone, progesterone, estradiols, diethylstilbestrol, estrone, estriol, pregnenolone, dienestrol etc.) on the motility behavior of A. cochlioides zoospores. Interestingly, most of the estrogenic compounds exhibited potent repellent activity (1 microg/ml or less by the "particle method") toward the motile zoospores of A. cochlioides. We derivatized some of the estrogens and discussed the relationship between the structure of active molecules and their repellent activity. Apparently, aromatization of the A ring with a free hydroxyl group at C-3 position of a steroidal structure is necessary for higher repellent activity. Interestingly, methylation of diethylstilbestrol (DES) yielded completely different activity i.e. both mono- and di-methyl ethers of DES showed attractant activity. Moreover, the attracted zoospores were encysted and then germinated in the presence of di-methyl ether of DES. The potential usefulness of this repellent test is discussed for the detection of estrogenic activity of naturally occurring compounds, and the possible role of phytoestrogens in host/parasite interactions. So far, this will be the first report of repellent activity of estrogenic compounds toward trivial fungal zoospores.

Clear Cell Carcinoma of the Uterine Cervix: A Clinical and Pathological Analysis of 47 Patients Without Intrauterine Diethylstilbestrol Exposure.

PubMed

Yang, Li; Zheng, Aiwen; Zhang, Xiang; Fang, Xianhua; Sun, Wenyong; Chen, Yaqing

2017-06-01

The aim of this study was to summarize the clinical and pathological characteristics and to conduct prognosis analysis of patients who were diagnosed with clear cell carcinoma of the uterine cervix (CCCUC) and without a history of exposure to diethylstilbestrol. We performed a retrospective review of all the patients with CCCUC who were diagnosed and treated at Zhejiang Cancer Hospital between 1998 and 2014. Charts were reviewed for clinical and pathological characteristics, and prognosis analysis was conducted. A total of 47 patients were included. Median age was 52 years. No patient had a history of exposure to diethylstilbestrol. The International Federation of Gynecology and Obstetrics stage distribution was 55.3% (n = 26) stage I, 40.4% (n = 19) stage II, 2.1% (n = 1) stage III, and 2.1% (n = 1) stage IV. Forty-two patients (89.4%) underwent radical hysterectomy and pelvic lymphadenectomy. Pathological examination revealed deep cervical stromal invasion (greater than two thirds) in 20 patients (48.4%), pelvic lymph node (PLN) metastasis in 10 patients (23.8%), lymphovascular space involvement in 9 patients (21.4%), and ovarian metastasis in 1 patient (2.4%). Advanced tumor stage (IIB-IV), larger tumor size (>4 cm), and PLN metastasis had negative effects on progression-free survival (PFS) and overall survival (OS) (P < 0.05). Adjuvant radiation therapy alone or concurrent chemoradiation therapy after radical surgery did not affect PFS or OS in patients with risk factors (P > 0.05). International Federation of Gynecology and Obstetrics stage, tumor size, and PLN status were prognostic factors for both PFS and OS in patients with CCCUC. The long-term effects of adjuvant radiation therapy or concurrent chemoradiation therapy may be limited for CCCUC patients with risk factors. Future larger case series or clinical trials are required to confirm these findings.

Discrimination between olfactory receptor agonists and non-agonists.

PubMed

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

2014-08-11

A joint approach combining free-energy calculations and calcium-imaging assays on the broadly tuned human 1G1 olfactory receptor is reported. The free energy of binding of ten odorants was computed by means of molecular-dynamics simulations. This state function allows separating the experimentally determined eight agonists from the two non-agonists. This study constitutes a proof-of-principle for the computational deorphanization of olfactory receptors. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Negative cooperativity in binding of muscarinic receptor agonists and GDP as a measure of agonist efficacy

PubMed Central

Jakubík, J; Janíčková, H; El-Fakahany, EE; Doležal, V

2011-01-01

BACKGROUND AND PURPOSE Conventional determination of agonist efficacy at G-protein coupled receptors is measured by stimulation of guanosine-5′-γ−thiotriphosphate (GTPγS) binding. We analysed the role of guanosine diphosphate (GDP) in the process of activation of the M2 muscarinic acetylcholine receptor and provide evidence that negative cooperativity between agonist and GDP binding is an alternative measure of agonist efficacy. EXPERIMENTAL APPROACH Filtration and scintillation proximity assays measured equilibrium binding as well as binding kinetics of [35S]GTPγS and [3H]GDP to a mixture of G-proteins as well as individual classes of G-proteins upon binding of structurally different agonists to the M2 muscarinic acetylcholine receptor. KEY RESULTS Agonists displayed biphasic competition curves with the antagonist [3H]-N-methylscopolamine. GTPγS (1 µM) changed the competition curves to monophasic with low affinity and 50 µM GDP produced a similar effect. Depletion of membrane-bound GDP increased the proportion of agonist high-affinity sites. Carbachol accelerated the dissociation of [3H]GDP from membranes. The inverse agonist N-methylscopolamine slowed GDP dissociation and GTPγS binding without changing affinity for GDP. Carbachol affected both GDP association with and dissociation from Gi/o G-proteins but only its dissociation from Gs/olf G-proteins. CONCLUSIONS AND IMPLICATIONS These findings suggest the existence of a low-affinity agonist-receptor conformation complexed with GDP-liganded G-protein. Also the negative cooperativity between GDP and agonist binding at the receptor/G-protein complex determines agonist efficacy. GDP binding reveals differences in action of agonists versus inverse agonists as well as differences in activation of Gi/o versus Gs/olf G-proteins that are not identified by conventional GTPγS binding. PMID:20958290

Negative cooperativity in binding of muscarinic receptor agonists and GDP as a measure of agonist efficacy.

PubMed

Jakubík, J; Janíčková, H; El-Fakahany, E E; Doležal, V

2011-03-01

Conventional determination of agonist efficacy at G-protein coupled receptors is measured by stimulation of guanosine-5'-γ-thiotriphosphate (GTPγS) binding. We analysed the role of guanosine diphosphate (GDP) in the process of activation of the M₂ muscarinic acetylcholine receptor and provide evidence that negative cooperativity between agonist and GDP binding is an alternative measure of agonist efficacy. Filtration and scintillation proximity assays measured equilibrium binding as well as binding kinetics of [³⁵S]GTPγS and [³H]GDP to a mixture of G-proteins as well as individual classes of G-proteins upon binding of structurally different agonists to the M₂ muscarinic acetylcholine receptor. Agonists displayed biphasic competition curves with the antagonist [³H]-N-methylscopolamine. GTPγS (1 µM) changed the competition curves to monophasic with low affinity and 50 µM GDP produced a similar effect. Depletion of membrane-bound GDP increased the proportion of agonist high-affinity sites. Carbachol accelerated the dissociation of [³H]GDP from membranes. The inverse agonist N-methylscopolamine slowed GDP dissociation and GTPγS binding without changing affinity for GDP. Carbachol affected both GDP association with and dissociation from G(i/o) G-proteins but only its dissociation from G(s/olf) G-proteins. These findings suggest the existence of a low-affinity agonist-receptor conformation complexed with GDP-liganded G-protein. Also the negative cooperativity between GDP and agonist binding at the receptor/G-protein complex determines agonist efficacy. GDP binding reveals differences in action of agonists versus inverse agonists as well as differences in activation of G(i/o) versus G(s/olf) G-proteins that are not identified by conventional GTPγS binding. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

Chemical Risk Assessment: Selected Federal Agencies’ Procedures, Assumptions, and Policies

DTIC Science & Technology

2001-08-01

adverse effects of exposures to hazardous substances or situations. It is a complex but valuable set of tools for federal regulatory agencies, helping...Act DES diethylstilbestrol DOT Department of Transportation ED effective dose EPA Environmental Protection Agency EPCRA Emergency Planning and...ISO International Organization for Standardization LED lowest effective dose LOAEL lowest observed adverse effect level LOEL lowest observed effect

Lysophosphatidic Acid Promotes Cell Migration through STIM1- and Orai1-Mediated Ca2+i Mobilization and NFAT2 Activation

PubMed Central

Jans, Ralph; Mottram, Laura; Johnson, Darren L; Brown, Anna M; Sikkink, Stephen; Ross, Kehinde; Reynolds, Nick J

2013-01-01

Lysophosphatidic acid (LPA) enhances cell migration and promotes wound healing in vivo, but the intracellular signaling pathways regulating these processes remain incompletely understood. Here we investigated the involvement of agonist-induced Ca2+ entry and STIM1 and Orai1 proteins in regulating nuclear factor of activated T cell (NFAT) signaling and LPA-induced keratinocyte cell motility. As monitored by Fluo-4 imaging, stimulation with 10 μℳ LPA in 60 μℳ Ca2+o evoked Ca2+i transients owing to store release, whereas addition of LPA in physiological 1.2 mℳ Ca2+o triggered store release coupled to extracellular Ca2+ entry. Store-operated Ca2+ entry (SOCE) was blocked by the SOCE inhibitor diethylstilbestrol (DES), STIM1 silencing using RNA interference (RNAi), and expression of dominant/negative Orai1R91W. LPA induced significant NFAT activation as monitored by nuclear translocation of green fluorescent protein-tagged NFAT2 and a luciferase reporter assay, which was impaired by DES, expression of Orai1R91W, and inhibition of calcineurin using cyclosporin A (CsA). By using chemotactic migration assays, LPA-induced cell motility was significantly impaired by STIM1, CsA, and NFAT2 knockdown using RNAi. These data indicate that in conditions relevant to epidermal wound healing, LPA induces SOCE and NFAT activation through Orai1 channels and promotes cell migration through a calcineurin/NFAT2-dependent pathway. PMID:23096711

Facile screening of potential xenoestrogens by an estrogen receptor-based reusable optical biosensor.

PubMed

Liu, Lanhua; Zhou, Xiaohong; Lu, Yun; Shan, Didi; Xu, Bi; He, Miao; Shi, Hanchang; Qian, Yi

2017-11-15

The apparent increase in hormone-induced cancers and disorders of the reproductive tract has led to a growing demand for new technologies capable of screening xenoestrogens. We reported an estrogen receptor (ER)-based reusable fiber biosensor for facile screening estrogenic compounds in environment. The bioassay is based on the competition of xenoestrogens with 17β-estradiol (E 2 ) for binding to the recombinant receptor of human estrogen receptor α (hERα) protein, leaving E 2 free to bind to fluorophore-labeled anti-E 2 monoclonal antibody. Unbound anti-E 2 antibody then binds to the immobilized E 2 -protein conjugate on the fiber surface, and is detected by fluorescence emission induced by evanescent field. As expected, the stronger estrogenic activity of xenoestrogen would result in the weaker fluorescent signal. Three estrogen-agonist compounds, diethylstilbestrol (DES), 4-n-nonylphenol (NP) and 4-n-octylphenol (OP), were chosen as a paradigm for validation of this assay. The rank order of estrogenic potency determined by this biosensor was DES>OP>NP, which were consistent with the published results in numerous studies. Moreover, the E 2 -protein conjugate modified optical fiber was robust enough for over 300 sensing cycles with the signal recoveries ranging from 90% to 100%. In conclusion, the biosensor is reusable, reliable, portable and amenable to on-line operation, providing a facile, efficient and economical alternative to screen potential xenoestrogens in environment. Copyright © 2017 Elsevier B.V. All rights reserved.

Estrogens and development

DOE Office of Scientific and Technical Information (OSTI.GOV)

McLachlan, J.A.; Newbold, R.R.

1987-11-01

The normal development of the genital organs of mammals, including humans, is under hormonal control. A role for the female sex hormone estrogen in this process is still unclear. However, exposure of experimental animals or humans to the potent exogenous estrogen, diethylstilbestrol (DES), results in persistent differentiation effects. Since many chemicals in the environment are weakly estrogenic, the possibility of hormonally altered differentiation must be considered.

The epileptogenic spectrum of opiate agonists.

PubMed

Snead, O C; Bearden, L J

1982-11-01

The present authors gave mu, delta, kappa, epsilon and sigma opiate receptor agonists intracerebroventricularly to rats both singly and in combination while monitoring the electroencephalogram from cortical and depth electrodes. Dose-response curves were plotted with naloxone against the changes produced by each agonist, and the effect of a number of anticonvulsant drugs on agonist-induced seizures was ascertained. Each opiate agonist produced a different seizure pattern with a different naloxone dose-response curve and anticonvulsant profile. The order of convulsive potency was epsilon greater than delta greater than mu greater than sigma much greater than kappa. Petit mal-like seizure activity was unique to the delta agonist, leucine-enkephalin, while only the mu agonist, morphine produced generalized convulsive seizures. These experiments raise the possibility that opiate systems in the brain may be involved in the pathogenesis of a wide spectrum of seizure disorders.

Evaluation of partial beta-adrenoceptor agonist activity.

PubMed

Lipworth, B J; Grove, A

1997-01-01

A partial beta-adrenoceptor (beta-AR) agonist will exhibit opposite agonist and antagonist activity depending on the prevailing degree of adrenergic tone or the presence of a beta-AR agonist with higher intrinsic activity. In vivo partial beta-AR agonist activity will be evident at rest with low endogenous adrenergic tone, as for example with chronotropicity (beta 1/beta 2), inotropicity (beta 1) or peripheral vasodilatation and finger tremor (beta 2). beta-AR blocking drugs which have partial agonist activity may exhibit a better therapeutic profile when used for hypertension because of maintained cardiac output without increased systemic vascular resistance, along with an improved lipid profile. In the presence of raised endogenous adrenergic tone such as exercise or an exogenous full agonist, beta-AR subtype antagonist activity will become evident in terms of effects on exercise induced heart rate (beta 1) and potassium (beta 2) responses. Reduction of exercise heart rate will occur to a lesser degree in the case of a beta-adrenoceptor blocker with partial beta 1-AR agonist activity compared with a beta-adrenoceptor blocker devoid of partial agonist activity. This may result in reduced therapeutic efficacy in the treatment of angina on effort when using beta-AR blocking drugs with partial beta 1-AR agonist activity. Effects on exercise hyperkalaemia are determined by the balance between beta 2-AR partial agonist activity and endogenous adrenergic activity. For predominantly beta 2-AR agonist such as salmeterol and salbutamol, potentiation of exercise hyperkalaemia occurs. For predominantly beta 2-AR antagonists such as carteolol, either potentiation or attenuation of exercise hyperkalaemia occurs at low and high doses respectively. beta 2-AR partial agonist activity may also be expressed as antagonism in the presence of an exogenous full agonist, as for example attenuation of fenoterol induced responses by salmeterol. Studies are required to investigate whether

Differential agonist and inverse agonist profile of antipsychotics at D2L receptors coupled to GIRK potassium channels.

PubMed

Heusler, Peter; Newman-Tancredi, Adrian; Castro-Fernandez, Annabelle; Cussac, Didier

2007-03-01

The D(2) dopaminergic receptor represents a major target of antipsychotic drugs. Using the coupling of the human D(2long) (hD(2L)) receptor to G protein-coupled inward rectifier potassium (GIRK) channels in Xenopus laevis oocytes, we examined the activity of antipsychotic agents of different classes - typical, atypical, and a "new generation" of compounds, exhibiting a preferential D(2) and 5-HT(1A) receptor profile. When the hD(2L) receptor was coexpressed with GIRK channels, a series of reference compounds exhibited full agonist (dopamine, and quinpirole), partial agonist (apomorphine, (-)3-PPP, and (+)-UH232) or inverse agonist (raclopride, and L741626) properties. Sarizotan exhibited only very weak partial agonist action. At higher levels of receptor cRNA injected per oocyte, both partial agonist activity and inverse agonist properties were generally more pronounced. The inverse agonist action of L741626 was reversed by interaction with sarizotan, thus confirming the constitutive activity of wild-type hD(2L) receptors in the oocyte expression system. When antipsychotic agents were tested for their actions at the hD(2L) receptor, typical (haloperidol) as well as atypical (nemonapride, ziprasidone, and clozapine) compounds acted as inverse agonists. In contrast, among D(2)/5-HT(1A) antipsychotics, only SLV313 and F15063 behaved as inverse agonists, whilst the other members of this group (bifeprunox, SSR181507 and the recently marketed antipsychotic, aripiprazole) exhibited partial agonist properties. Thus, the X. laevis oocyte expression system highlights markedly different activity of antipsychotics at the hD(2L) receptor. These differential properties may translate to distinct therapeutic potential of these compounds.

[Dopamine agonists--clinical applications beyond Parkinson's disease].

PubMed

Kuran, Włodzimierz

2007-01-01

Contemporary experience and results of clinical trials concerning dopamine agonist application in the treatment of many different diseases (apart from Parkinson's disease) are presented in the paper. A basic clinical recommendation for agonists is restless legs syndrome. In this syndrome almost all agonists give a considerable subjective and objective improvement. Treatment of atypical parkinsonism (MSA, PSP, CBD) in the majority of patients is ineffective. The author also presents promising results of treatment with agonists in such diverse diseases as hyperkinetic syndromes, cocaine dependence, drug-resistant depression and erectile dysfunction (apomorphine). Dopamine partial agonists (e.g. aripiprazol) are recommended in the modern treatment of schizophrenia.

Kappa Opioid Receptor Agonist and Brain Ischemia

PubMed Central

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

2014-01-01

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

Adverse Effects of GLP-1 Receptor Agonists

PubMed Central

Filippatos, Theodosios D.; Panagiotopoulou, Thalia V.; Elisaf, Moses S.

2014-01-01

Glucagon-like peptide-1 (GLP-1) receptor agonists are a class of injective anti-diabetic drugs that improve glycemic control and many other atherosclerosis-related parameters in patients with type 2 diabetes (T2D). However, the use of this relatively new class of drugs may be associated with certain adverse effects. Concerns have been expressed regarding the effects of these drugs on pancreatic and thyroid tissue, since animal studies and analyses of drug databases indicate an association of GLP-1 receptor agonists with pancreatitis, pancreatic cancer, and thyroid cancer. However, several meta-analyses failed to confirm a cause-effect relation between GLP-1 receptor agonists and the development of these adverse effects. One benefit of GLP-1 receptor agonists is that they do not cause hypoglycemia when combined with metformin or thiazolidinediones, but the dose of concomitant sulphonylurea or insulin may have to be decreased to reduce the risk of hypoglycemic episodes. On the other hand, several case reports have linked the use of these drugs, mainly exenatide, with the occurrence of acute kidney injury, primarily through hemodynamic derangement due to nausea, vomiting, and diarrhea. The most common symptoms associated with the use of GLP-1 receptor agonists are gastrointestinal symptoms, mainly nausea. Other common adverse effects include injection site reactions, headache, and nasopharyngitis, but these effects do not usually result in discontinuation of the drug. Current evidence shows that GLP-1 receptor agonists have no negative effects on the cardiovascular risk of patients with T2D. Thus, GLP-1 receptor agonists appear to have a favorable safety profile, but ongoing trials will further assess their cardiovascular effects. The aim of this review is to analyze critically the available data regarding adverse events of GLP-1 receptor agonists in different anatomic systems published in Pubmed and Scopus. Whenever possible, certain differences between GLP-1

Beta-agonists and animal welfare

USDA-ARS?s Scientific Manuscript database

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

Long-term studies of dopamine agonists.

PubMed

Hubble, Jean P

2002-02-26

Dopamine agonists have long been used as adjunctive therapy for the treatment of Parkinson's disease (PD). In more recent years these drugs have also been proved safe and effective as initial therapy in lieu of levodopa in the treatment of PD. Long-term levodopa therapy is associated with motor complications, including fluctuating response patterns and dyskinesia. By initially introducing a dopamine agonist as symptomatic drug therapy, it may be possible to postpone the use of levodopa and delay or prevent the development of motor complications. Recently, four clinical trials have explored this hypothesis by comparing the long-term response and side effects of levodopa with dopamine agonist therapy. The drugs studied have included ropinirole, pramipexole, cabergoline, and pergolide. In each of these projects, the occurrence of motor complications, such as wearing off and dyskinesia, was significantly less in the subjects assigned to initiation of therapy with a dopamine agonist. The addition of levodopa could be postponed by many months or even several years. Therefore, these long-term studies of dopamine agonists support the initiation of a dopamine agonist instead of levodopa in an effort to postpone levodopa-related motor complications. This therapeutic approach may be particularly appropriate in PD patients with a long treatment horizon on the basis of age and general good health. The extension phase of the long-term study comparing pramipexole with levodopa is ongoing, and follow-up information may help to establish the value of this treatment strategy.

Evaluation of AhR-agonists and AhR-agonist activity in sediments of Liaohe River protected areas, China.

PubMed

Zhang, Yun; Ke, Xin; Gui, Shaofeng; Wu, Xiaoqiong; Wang, Chunyong; Zhang, Haijun

2017-02-15

A total of 9 sediment samples of Liaohe River protected areas were collected to evaluate aryl hydrocarbon receptor agonists (AhR-agonists) and AhR-agonist activity via chemical analysis and in vitro H4IIE cell bioassay. Results indicated that bioassay-derived 2,3,7,8-tetrachlorodibenzo-p-dioxin equivalents (Bio-TEQs) ranged from 89.1 to 251.1pg/g dry weight. Concentrations of 16 EPA polycyclic aromatic hydrocarbons (PAHs), 12 dioxin-like polychlorinated biphenyls (PCBs), and polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) ranged from 256.8 to 560.1ng/g, 79.2 to 416.2pg/g, and 199.6 to 538.4pg/g, respectively. According to potency balance analysis, TEQ chem s based on PAHs, PCBs, and PCDD/Fs could contribute 16.56% to 26.11% of Bio-TEQs. This could be explained by the potential existence of unidentified AhR-agonists and the potential non-additive interactions among AhR-agonists in sediment extracts. Through the different contributions to Bio-TEQs, this study confirms that PCDD/Fs were the main pollutants that induced significantly AhR-agonist activity in sediments of Liaohe River protected areas. Copyright © 2016. Published by Elsevier Ltd.

Modification of kindled amygdaloid seizures by opiate agonists and antagonists.

PubMed

Albertson, T E; Joy, R M; Stark, L G

1984-03-01

The effects of 19 opiate agonists and antagonists on kindled amygdaloid seizures in the rat were studied. The mu agonists tended to reduce the length of elicited afterdischarges and behavioral ranks, while markedly increasing postictal electroencephalogram spikes and behavioral arrest time. These effects were reversed by naloxone. The kappa agonists reduced behavioral rank and variably reduced afterdischarge length with a concomitant lengthening of postictal behavioral arrest time and number of electroencephalogram spikes. The putative sigma agonist, SKF 10,047, reduced afterdischarge durations only at the higher doses tested. The decreases found after the sigma agonists in postictal electroencephalogram spiking and time of behavioral arrest were not reversed by naloxone. Only the lower doses of normeperidine were found to decrease seizure thresholds. The mixed agonist/antagonists (MAA) cyclazocine and cyclorphan markedly increased seizure threshold and reduced afterdischarge duration and behavioral rank. Only the MAA pentazocine tended to increase threshold but not suprathreshold afterdischarge durations. The order of ability to modify the ictal events was MAA (selected) greater than kappa agonists greater than mu agonists greater than sigma agonists. The increase in postictal events (behavior arrest and spikes) was caused most effectively by pretreatment with mu agonist greater than kappa agonist greater than selected MAA greater than sigma agonists.(ABSTRACT TRUNCATED AT 250 WORDS)

Vecteurs Singuliers des Theories des Champs Conformes Minimales

NASA Astrophysics Data System (ADS)

Benoit, Louis

En 1984 Belavin, Polyakov et Zamolodchikov revolutionnent la theorie des champs en explicitant une nouvelle gamme de theories, les theories quantiques des champs bidimensionnelles invariantes sous les transformations conformes. L'algebre des transformations conformes de l'espace-temps presente une caracteristique remarquable: en deux dimensions elle possede un nombre infini de generateurs. Cette propriete impose de telles conditions aux fonctions de correlations qu'il est possible de les evaluer sans aucune approximation. Les champs des theories conformes appartiennent a des representations de plus haut poids de l'algebre de Virasoro, une extension centrale de l'algebre conforme du plan. Ces representations sont etiquetees par h, le poids conforme de leur vecteur de plus haut poids, et par la charge centrale c, le facteur de l'extension centrale, commune a toutes les representations d'une meme theorie. Les theories conformes minimales sont constituees d'un nombre fini de representations. Parmi celles-ci se trouvent des theories unitaires dont les representation forment la serie discrete de l'algebre de Virasoro; leur poids h a la forme h_{p,q}(m)=[ (p(m+1) -qm)^2-1] (4m(m+1)), ou p,q et m sont des entiers positifs et p+q<= m+1. L'entier m parametrise la charge centrale: c(m)=1 -{6over m(m+1)} avec n>= 2. Ces representations possedent un sous-espace invariant engendre par deux sous-representations avec h_1=h_{p,q} + pq et h_2=h_{p,q} + (m-p)(m+1-q) dont chacun des vecteurs de plus haut poids portent le nom de vecteur singulier et sont notes respectivement |Psi _{p,q}> et |Psi_{m-p,m+1-q}>. . Les theories super-conformes sont une version super-symetrique des theories conformes. Leurs champs appartiennent a des representation de plus haut poids de l'algebre de Neveu-Schwarz, une des deux extensions super -symetriques de l'algebre de Virasoro. Les theories super -conformes minimales possedent la meme structure que les theories conformes minimales. Les representations

Dopamine agonists in the treatment of Parkinson's disease.

PubMed

Bonuccelli, Ubaldo; Pavese, Nicola

2006-01-01

Dopamine agonists are highly effective as adjunctive therapy to levodopa in advanced Parkinson's disease and have rapidly gained popularity as a monotherapy in the early stages of Parkinson's disease for patients less than 65-70 years old. In the latter case, dopamine agonists are about as effective as levodopa but patients demonstrate a lower tendency to develop motor complications. However, dopamine agonists lose efficacy over time and the number of patients remaining on agonist monotherapy decreases to less than 50% after 3 years of treatment. Thus, after a few years of treatment the majority of patients who started on dopamine agonists will be administered levodopa, in a combined dopaminergic therapy, in order to achieve a better control of motor symptoms.

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.

Structure/function relationships of calcitonin analogues as agonists, antagonists, or inverse agonists in a constitutively activated receptor cell system.

PubMed

Pozvek, G; Hilton, J M; Quiza, M; Houssami, S; Sexton, P M

1997-04-01

The structure/function relationship of salmon calcitonin (sCT) analogues was investigated in heterologous calcitonin receptor (CTR) expression systems. sCT analogues with progressive amino-terminal truncations intermediate of sCT-(1-32) to sCT-(8-32) were examined for their ability to act as agonists, antagonists, or inverse agonists. Two CTR cell clones, B8-H10 and G12-E12, which express approximately 5 million and 25,000 C1b receptors/cell, respectively, were used for this study. The B8-H10 clone has an approximately 80-fold increase in basal levels of intracellular cAMP due to constitutive activation of the overexpressed receptor. In whole-cell competition binding studies, sCT-(1-32) was more potent than any of its amino-terminally truncated analogues in competition for 125I-sCT binding. In cAMP accumulation studies, sCT-(1-32) and modified analogues sCT-(2-32) and sCT-(3-32) had agonist activities. SDZ-216-710, with an amino-terminal truncation of four amino acids, behaved as a partial agonist/antagonist, whereas amino-terminal truncations of six or seven amino acid residues produced a 16-fold reduction in basal cAMP levels and attenuated the response to the agonist sCT-(1-32) in the constitutively active CTR system. This inverse agonist effect was insensitive to pertussis toxin inhibition. In contrast, the inverse agonist activity of these peptides was not observed in the nonconstitutively active CTR system, in which sCT analogues with amino-terminal truncations of four or more amino acids behaved as neutral competitive antagonists. These results suggest that the inverse agonist activity is mediated by stabilization of the inactive state of the receptor, which does not couple to G protein, and attenuates basal signaling initiated by ligand-independent activation of the effector adenylyl cyclase.

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

PubMed Central

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

2013-01-01

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

Uterine adenocarcinoma in mice treated neonatally with genistein.

PubMed

Newbold, R R; Banks, E P; Bullock, B; Jefferson, W N

2001-06-01

The developing fetus is uniquely sensitive to perturbation with estrogenic chemicals. The carcinogenic effect of prenatal exposure to diethylstilbestrol (DES) is the classic example. Because phytoestrogen use in nutritional and pharmaceutical applications for infants and children is increasing, we investigated the carcinogenic potential of genistein, a naturally occurring plant estrogen in soy, in an experimental animal model previously reported to result in a high incidence of uterine adenocarcinoma after neonatal DES exposure. Outbred female CD-1 mice were treated on days 1-5 with equivalent estrogenic doses of DES (0.001 mg/kg/day) or genistein (50 mg/kg/day). At 18 months, the incidence of uterine adenocarcinoma was 35% for genistein and 31% for DES. These data suggest that genistein is carcinogenic if exposure occurs during critical periods of differentiation. Thus, the use of soy-based infant formulas in the absence of medical necessity and the marketing of soy products designed to appeal to children should be closely examined.

Agonist-Directed Desensitization of the β2-Adrenergic Receptor

PubMed Central

Goral, Vasiliy; Jin, Yan; Sun, Haiyan; Ferrie, Ann M.; Wu, Qi; Fang, Ye

2011-01-01

The β2-adrenergic receptor (β2AR) agonists with reduced tachyphylaxis may offer new therapeutic agents with improved tolerance profile. However, receptor desensitization assays are often inferred at the single signaling molecule level, thus ligand-directed desensitization is poorly understood. Here we report a label-free biosensor whole cell assay with microfluidics to determine ligand-directed desensitization of the β2AR. Together with mechanistic deconvolution using small molecule inhibitors, the receptor desensitization and resensitization patterns under the short-term agonist exposure manifested the long-acting agonism of salmeterol, and differentiated the mechanisms of agonist-directed desensitization between a full agonist epinephrine and a partial agonist pindolol. This study reveals the cellular mechanisms of agonist-selective β2AR desensitization at the whole cell level. PMID:21541288

Sports doping: emerging designer and therapeutic β2-agonists.

PubMed

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

2013-10-21

Beta2-adrenergic agonists, or β2-agonists, are considered essential bronchodilator drugs in the treatment of bronchial asthma, both as symptom-relievers and, in combination with inhaled corticosteroids, as disease-controllers. The use of β2-agonists is prohibited in sports by the World Anti-Doping Agency (WADA) due to claimed anabolic effects, and also, is prohibited as growth promoters in cattle fattening in the European Union. This paper reviews the last seven-year (2006-2012) literature concerning the development of novel β2-agonists molecules either by modifying the molecule of known β2-agonists or by introducing moieties producing indole-, adamantyl- or phenyl urea derivatives. New emerging β2-agonists molecules for future therapeutic use are also presented, intending to emphasize their potential use for doping purposes or as growth promoters in the near future. © 2013.

Mixed Kappa/Mu Opioid Receptor Agonists: The 6β-Naltrexamines

PubMed Central

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

2011-01-01

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

Exploring the binding energy profiles of full agonists, partial agonists, and antagonists of the α7 nicotinic acetylcholine receptor.

PubMed

Tabassum, Nargis; Ma, Qianyun; Wu, Guanzhao; Jiang, Tao; Yu, Rilei

2017-09-01

Nicotinic acetylcholine receptors (nAChRs) belong to the Cys-loop receptor family and are important drug targets for the treatment of neurological diseases. However, the precise determinants of the binding efficacies of ligands for these receptors are unclear. Therefore, in this study, the binding energy profiles of various ligands (full agonists, partial agonists, and antagonists) were quantified by docking those ligands with structural ensembles of the α7 nAChR exhibiting different degrees of C-loop closure. This approximate treatment of interactions suggested that full agonists, partial agonists, and antagonists of the α7 nAChR possess distinctive binding energy profiles. Results from docking revealed that ligand binding efficacy may be related to the capacity of the ligand to stabilize conformational states with a closed C loop.

New thrombopoietin receptor agonists for platelet disorders.

PubMed

Homeida, S; Ebdon, C; Batty, P; Jackson, B; Kolade, S; Bateman, C; Peng, Y Y; Stasi, R

2012-04-01

Since thrombopoietin (TPO) was cloned in 1994, TPO receptor (TPO-R) agonists have been developed which have shown significant clinical activity in various conditions characterized by thrombocytopenia. First-generation TPO-R agonists were recombinant forms of human TPO. The clinical development of these molecules was discontinued after one of them, pegylated recombinant human megakaryocyte growth and development factor, was associated with the development of neutralizing autoantibodies cross-reacting with endogenous TPO. Second-generation TPO-R agonists are now available, which present no sequence homology to endogenous TPO. Two of these new agents, romiplostim and eltrombopag, have been granted marketing authorization for use in patients with primary immune thrombocytopenia unresponsive to conventional treatments. Clinical trials with TPO-R agonists are also ongoing in other thrombocytopenias, such as hepatitis C virus-related thrombocytopenia and the myelodysplastic syndromes. Copyright 2012 Prous Science, S.A.U. or its licensors. All rights reserved.

Sensitivity of GBM cells to cAMP agonist-mediated apoptosis correlates with CD44 expression and agonist resistance with MAPK signaling.

PubMed

Daniel, Paul M; Filiz, Gulay; Mantamadiotis, Theo

2016-12-01

In some cell types, activation of the second messenger cAMP leads to increased expression of proapoptotic Bim and subsequent cell death. We demonstrate that suppression of the cAMP pathway is a common event across many cancers and that pharmacological activation of cAMP in glioblastoma (GBM) cells leads to enhanced BIM expression and apoptosis in specific GBM cell types. We identified the MAPK signaling axis as the determinant of cAMP agonist sensitivity in GBM cells, with high MAPK activity corresponding to cAMP resistance and low activity corresponding to sensitization to cAMP-induced apoptosis. Sensitive cells were efficiently killed by cAMP agonists alone, while targeting both the cAMP and MAPK pathways in resistant GBM cells resulted in efficient apoptosis. We also show that CD44 is differentially expressed in cAMP agonist-sensitive and -resistant cells. We thus propose that CD44 may be a useful biomarker for distinguishing tumors that may be sensitive to cAMP agonists alone or cAMP agonists in combination with other pathway inhibitors. This suggests that using existing chemotherapeutic compounds in combination with existing FDA-approved cAMP agonists may fast track trials toward improved therapies for difficult-to-treat cancers, such as GBM.

Modification of opiate agonist binding by pertussis toxin

DOE Office of Scientific and Technical Information (OSTI.GOV)

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.more » 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.« less

Characterization of bradykinin receptors in human lung fibroblasts using the binding of 3[H][Des-Arg10,Leu9]kallidin and [3H]NPC17731.

PubMed

Zhang, S P; Codd, E E

1998-01-01

Bradykinin (BK) receptors are involved in pain and inflammation. Two BK receptor subtypes, B1 and B2, have been defined based on their pharmacological properties. Both B1 and B2 receptors are G-protein coupled membrane receptors. B1 receptors are present in smooth muscle tissue, whereas B2 receptors are found in both smooth muscle tissue and neurons. [Des-Arg10,Leu9]kallidin (DALKD) is a selective B1 receptor antagonist, and NPC17731 is a selective B2 receptor antagonist. To develop binding assays for the two known BK receptor subtypes, [3H]DALKD and [3H]NPC17731 were used as selective ligands for B1 and B2 receptors respectively. Both ligands bound to the CCD-16 human lung fibroblast membranes reaching equilibrium at 25 degrees C within 30 min. Binding was stable for at least 60 min. The Kd of [3H]DALKD was 0.33 nM and Bmax was 52 fmol/mg membrane protein. The Kd of [3H]NPC17731 was 0.39 nM and Bmax was 700 fmol/mg membrane protein. Competition for [3H]DALKD binding with BK receptor agonists was in the order: [des-Arg10]KD (DAKD) > KD > [des-Arg9]BK (DABK) > BK, and competition for [3H]DALKD binding with BK receptor antagonists was in the order: DALKD > [des-Arg10]Hoe 140 (DAHoe 140) > [des-Arg9,Leu8]BK (DALBK) > NPC17731 > Hoe 140 > DNMFBK, suggesting that [3H]DALKD bound selectively to B1 receptors. By contrast, competition for [3H]NPC17731 binding by BK agonists was in the order: BK > KD > DAKD > DABK, and competition for [3H]NPC17731 binding by BK antagonists was in the order: NPC17731 = Hoe 140 > DNMFBK > DAHoe 140 > DALBK > DALKD, indicating that [3H]NPC17731 labeled B2 receptors selectively. These results demonstrate that [3H]DALKD and [3H]NPC17731 can be used with CCD-16 human lung fibroblast membranes to provide a pair of binding assays for the simultaneous evaluation of B1 and B2 BK receptor subtypes.

Impact de la preparation des anodes crues et des conditions de cuisson sur la fissuration dans des anodes denses

NASA Astrophysics Data System (ADS)

Amrani, Salah

La fabrication de l'aluminium est realisee dans une cellule d'electrolyse, et cette operation utilise des anodes en carbone. L'evaluation de la qualite de ces anodes reste indispensable avant leur utilisation. La presence des fissures dans les anodes provoque une perturbation du procede l'electrolyse et une diminution de sa performance. Ce projet a ete entrepris pour determiner l'impact des differents parametres de procedes de fabrication des anodes sur la fissuration des anodes denses. Ces parametres incluent ceux de la fabrication des anodes crues, des proprietes des matieres premieres et de la cuisson. Une recherche bibliographique a ete effectuee sur tous les aspects de la fissuration des anodes en carbone pour compiler les travaux anterieurs. Une methodologie detaillee a ete mise au point pour faciliter le deroulement des travaux et atteindre les objectifs vises. La majorite de ce document est reservee pour la discussion des resultats obtenus au laboratoire de l'UQAC et au niveau industriel. Concernant les etudes realisees a l'UQAC, une partie des travaux experimentaux est reservee a la recherche des differents mecanismes de fissuration dans les anodes denses utilisees dans l'industrie d'aluminium. L'approche etait d'abord basee sur la caracterisation qualitative du mecanisme de la fissuration en surface et en profondeur. Puis, une caracterisation quantitative a ete realisee pour la determination de la distribution de la largeur de la fissure sur toute sa longueur, ainsi que le pourcentage de sa surface par rapport a la surface totale de l'echantillon. Cette etude a ete realisee par le biais de la technique d'analyse d'image utilisee pour caracteriser la fissuration d'un echantillon d'anode cuite. L'analyse surfacique et en profondeur de cet echantillon a permis de voir clairement la formation des fissures sur une grande partie de la surface analysee. L'autre partie des travaux est basee sur la caracterisation des defauts dans des echantillons d'anodes crues

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.

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

Fiabilité des structures mécaniques adaptatives: effet de la panne des actionneurs ou des capteurs sur la stabilité

NASA Astrophysics Data System (ADS)

Fall, H.; Charon, W.; Kouta, R.

2002-12-01

Ces dernières décennies, des activités significatives dans le monde étaient dirigées autour du contrôle actif. Le but de ces recherches était essentiellement d'améliorer les performances, la fiabilité et la sécurité des systèmes. Notamment dans le cas des structures soumises à des vibrations aléatoires. D'importants travaux ont été consacré à l'utilisation des “matériaux intelligents” comme capteurs et actionneurs. Cette article propose l'analyse de la fiabilité des systèmes mécaniques en étudiant les pannes des actionneurs ou des capteurs. L'effet de ces pannes sur la stabilité et la performance du système y est démontré. Les méthodologies de conception y sont rappelées. Des exemples numériques sont fournis à travers le contrôle d'un panneau sous chargement dynamique pour illustrer la méthode proposée.

Use of sub-micron sized resin particles for removal of endocrine disrupting compounds and pharmaceuticals from water and wastewater.

PubMed

Murray, Audrey; Örmeci, Banu; Lai, Edward P C

2017-01-01

Endocrine disrupting compounds (EDCs) and pharmaceuticals pose a challenge for water and wastewater treatment because they exist at very low concentrations in the presence of substances at much higher concentrations competing for adsorption sites. Sub-micron sized resin particles (approximately 300nm in diameter) (SMR) were tested to evaluate their potential as a treatment for EDCs including: 17-β estradiol (E2), 17-α ethinylestradiol (EE2), estrone (E1), bisphenol A (BPA), and diethylstilbestrol (DES) as well as 12 pharmaceuticals. SMR were able to remove 98% of spiked E2, 80% of EE2, 87% of BPA, and up to 97% of DES from water. For a 0.5ppm mixture of E2, EE2, E1, BPA and DES, the minimum removal was 24% (E2) and the maximum was 49% (DES). They were also able to remove the pharmaceuticals from deionized water and wastewater. Overall, SMR are a promising advanced treatment for removal of both EDCs and pharmaceuticals. Copyright © 2016. Published by Elsevier B.V.

Developpement des betons semi autoplacants a rheologie adaptee pour des infrastructures

NASA Astrophysics Data System (ADS)

Sotomayor Cruz, Cristian Daniel

Au cours des dernières décennies, les infrastructures canadiennes et québécoises comportent plusieurs structures en béton armé présentant des problèmes de durabilité dus aux conditions climatiques sévères, à la mauvaise conception des structures, à la qualité des matériaux, aux types des bétons choisis, aux systèmes de construction ou à l'existence d'événements incontrôlables. En ce qui concerne le choix du béton pour la construction des infrastructures, une vaste gamme de béton divisée en deux principaux types peut être utilisée: le béton conventionnel vibré (BCV) et le béton autoplaçant (BAP). Dans le cas d'un BCV, la consolidation inadéquate par vibration a été un problème récurrent, occasionnant des dommages structuraux. Ceci a conduit à une réduction de la durabilité et à une augmentation du coût d'entretien et de réparation des infrastructures. Rien que l'utilisation d'un BAP a des avantages tels que l'élimination de la vibration, la réduction des coûts de main d'oeuvre et l'amélioration de la qualité des structures, néanmoins, le coût initial d'un BAP par rapport à un BCV ne permet pas encore de généraliser son utilisation dans l'industrie de la construction. Ce mémoire présente la conception d'une nouvelle gamme de béton semi-autoplaçant pour la construction des infrastructures (BSAP-I) exigeant une vibration minimale. Il s'agit de trouver un équilibre optimal entre la rhéologie et le coût initial du nouveau béton pour conférer une bonne performance structurale et économique aux structures. Le programme expérimental établi a premièrement permis d'évaluer la faisabilité d'utilisation des BSAP-I pour la mise en place des piliers d'une infrastructure de pont à Sherbrooke. En plus, l'utilisation d'un plan d'expériences a permis l'évaluation de trois paramètres de formulation sur les propriétés des mélanges de BSAP-I à l'état frais et durci. Finalement, l'évaluation de la performance des

Mechanisms of inverse agonist action at D2 dopamine receptors

PubMed Central

Roberts, David J; Strange, Philip G

2005-01-01

Mechanisms of inverse agonist action at the D2(short) dopamine receptor have been examined. Discrimination of G-protein-coupled and -uncoupled forms of the receptor by inverse agonists was examined in competition ligand-binding studies versus the agonist [3H]NPA at a concentration labelling both G-protein-coupled and -uncoupled receptors. Competition of inverse agonists versus [3H]NPA gave data that were fitted best by a two-binding site model in the absence of GTP but by a one-binding site model in the presence of GTP. Ki values were derived from the competition data for binding of the inverse agonists to G-protein-uncoupled and -coupled receptors. Kcoupled and Kuncoupled were statistically different for the set of compounds tested (ANOVA) but the individual values were different in a post hoc test only for (+)-butaclamol. These observations were supported by simulations of these competition experiments according to the extended ternary complex model. Inverse agonist efficacy of the ligands was assessed from their ability to reduce agonist-independent [35S]GTPγS binding to varying degrees in concentration–response curves. Inverse agonism by (+)-butaclamol and spiperone occurred at higher potency when GDP was added to assays, whereas the potency of (−)-sulpiride was unaffected. These data show that some inverse agonists ((+)-butaclamol, spiperone) achieve inverse agonism by stabilising the uncoupled form of the receptor at the expense of the coupled form. For other compounds tested, we were unable to define the mechanism. PMID:15735658

Paternité des articles et intérêts concurrents : une analyse des recommandations aux auteurs des journaux traitant de pratique pharmaceutique

PubMed Central

Courbon, Ève; Tanguay, Cynthia; Lebel, Denis; Bussières, Jean-François

2014-01-01

RÉSUMÉ Contexte : La présence d’auteurs honorifiques et fantômes ainsi que les intérêts concurrents représentent des difficultés bien documentées, liées à la publication d’articles scientifiques. Il existe des lignes directrices encadrant la rédaction et la publication de manuscrits scientifiques, notamment celles de l’International Committee of Medical Journal Editors (ICMJE). Objectifs : L’objectif principal de cette étude descriptive et transversale visait à recenser les instructions portant sur la paternité des articles et les intérêts concurrents provenant des recommandations aux auteurs des journaux traitant de pratique pharmaceutique. L’objectif secondaire visait à déterminer des mesures correctrices pour une paternité des articles plus transparente. Méthode : La recherche a débuté par l’identification des journaux traitant de pratique pharmaceutique. La consultation des instructions aux auteurs des journaux a permis ensuite de recenser les recommandations destinées à éviter les problèmes de paternité des articles et d’intérêts concurrents. Finalement, les membres de l’équipe de recherche se sont consultés afin de définir des mesures correctrices possibles à l’intention des chercheurs. Résultats : Des 232 journaux traitant de pharmacie, 33 ont été définis comme traitant de pratique pharmaceutique. Un total de 24 (73 %) journaux mentionnaient suivre la politique de l’ICMJE, 14 (42 %) demandaient aux auteurs de remplir un formulaire de déclaration d’intérêts concurrents au moment de la soumission de l’article, 17 (52 %) présentaient une définition de la qualité d’auteur et 5 (15 %) demandaient de détailler les contributions de chaque auteur. Une grille de 40 critères a été élaborée pour définir l’attribution du statut d’auteur. Conclusion : Moins de la moitié des journaux demandait aux auteurs de transmettre un formulaire de déclaration des intérêts concurrents au moment de la

Activation of single heteromeric GABAA receptor ion channels by full and partial agonists

PubMed Central

Mortensen, Martin; Kristiansen, Uffe; Ebert, Bjarke; Frølund, Bente; Krogsgaard-Larsen, Povl; Smart, Trevor G

2004-01-01

The linkage between agonist binding and the activation of a GABAA receptor ion channel is yet to be resolved. This aspect was examined on human recombinant α1β2γ2S GABAA receptors expressed in human embryonic kidney cells using the following series of receptor agonists: GABA, isoguvacine, 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP), isonipecotic acid, piperidine-4-sulphonic acid (P4S), imidazole-4-acetic acid (IAA), 5-(4-piperidyl)-3-isothiazolol (thio-4-PIOL) and 5-(4-piperidyl)-3-isoxazolol (4-PIOL). Whole-cell concentration–response curves enabled the agonists to be categorized into four classes based upon their maximum responses. Single channel analyses revealed that the channel conductance of 25–27 pS was unaffected by the agonists. However, two open states were resolved from the open period distributions with mean open times reduced 5-fold by the weakest partial agonists. Using saturating agonist concentrations, estimates of the channel shutting rate, α, ranged from 200 to 600 s−1. The shut period distributions were described by three or four components and for the weakest partial agonists, the interburst shut periods increased whilst the mean burst durations and longest burst lengths were reduced relative to the full agonists. From the burst analyses, the opening rates for channel activation, β, and the total dissociation rates, k−1, for the agonists leaving the receptor were estimated. The agonist efficacies were larger for the full agonists (E ∼7−9) compared to the weak partial agonists (∼0.4–0.6). Overall, changes in agonist efficacy largely determined the different agonist profiles with contributions from the agonist affinities and the degree of receptor desensitization. From this we conclude that GABAA receptor activation does not occur in a switch-like manner since the agonist recognition sites are flexible, accommodating diverse agonist structures which differentially influence the opening and shutting rates of the ion

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. © 2014 John Wiley & Sons Ltd.

Caracterisation des melanges developpes pour le moulage basse pression des poudres metalliques (LPIM) =

NASA Astrophysics Data System (ADS)

Fareh, Fouad

Le moulage par injection basse pression des poudres metalliques est une technique de fabrication qui permet de fabriquer des pieces possedant la complexite des pieces coulees mais avec les proprietes mecaniques des pieces corroyees. Cependant, l'optimisation des etapes de deliantage et de frittage a ete jusqu'a maintenant effectuee a l'aide de melange pour lesquels la moulabilite optimale n'a pas encore ete demontree. Ainsi, la comprehension des proprietes rheologiques et de la segregation des melanges est tres limitee et cela presente le point faible du processus de LPIM. L'objectif de ce projet de recherche etait de caracteriser l'influence des liants sur le comportement rheologique des melanges en mesurant la viscosite et la segregation des melanges faible viscosite utilises dans le procede LPIM. Afin d'atteindre cet objectif, des essais rheologiques et thermogravimetriques ont ete conduits sur 12 melanges. Ces melanges ont ete prepares a base de poudre d'Inconel 718 de forme spherique (chargement solide constant a 60%) et de cires, d'agents surfactants ou epaississants. Les essais rheologiques ont ete utilises entre autre pour calculer l'indice d'injectabilite ?STV des melanges, tandis que les essais thermogravimetriques ont permis d'evaluer precisement la segregation des poudres dans les melanges. Il a ete demontre que les trois (3) melanges contenant de la cire de paraffine et de l'acide stearique presentent des indices alpha STV plus eleves qui sont avantageux pour le moulage par injection des poudres metalliques (MIM), mais segregent beaucoup trop pour que la piece fabriquee produise de bonnes caracteristiques mecaniques. A l'oppose, le melange contenant de la cire de paraffine et de l'ethylene-vinyle acetate ainsi que le melange contenant seulement de la cire de carnauba segregent peu voire pas du tout, mais possedent de tres faibles indices alphaSTV : ils sont donc difficilement injectables. Le meilleur compromis semble donc etre les melanges contenant de

Reverse Induced Fit-Driven MAS-Downstream Transduction: Looking for Metabotropic Agonists.

PubMed

Pernomian, Larissa; Gomes, Mayara S; de Paula da Silva, Carlos H Tomich; Rosa, Joaquin M C

2017-01-01

Protective effects of MAS activation have spurred clinical interests in developing MAS agonists. However, current bases that drive this process preclude that physiological concentrations of peptide MAS agonists induce an atypical signaling that does not reach the metabotropic efficacy of constitutive activation. Canonical activation of MAS-coupled G proteins is only achieved by supraphysiological concentrations of peptide MAS agonists or physiological concentrations of chemically modified analogues. These pleiotropic differences are because of two overlapped binding domains: one non-metabotropic site that recognizes peptide agonists and one metabotropic domain that recognizes modified analogues. It is feasible that supraphysiological concentrations of peptide MAS agonists undergo to chemical modifications required for binding to metabotropic domain. Receptor oligomerization enhances pharmacological parameters coupled to metabotropic signaling. The formation of receptor-signalosome complex makes the transduction of agonists more adaptive. Considering the recent identification of MAS-signalosome, we aimed to postulate the reverse induced fit hypothesis in which MAS-signalosome would trigger chemical modifications required for agonists bind to MAS metabotropic domain. Here we cover rational perspectives for developing novel metabotropic MAS agonists in the view of the reverse induced-fit hypothesis. Predicting a 3D model of MAS metabotropic domain may guide the screening of chemical modifications required for metabotropic efficacy. Pharmacophore-based virtual screening would select potential metabotropic MAS agonists from virtual libraries from human proteome. Rational perspectives that consider reverse induced fit hypothesis during MAS activation for developing metabotropic MAS agonists represents the best approach in providing MAS ligands with constitutive efficacy at physiological concentrations. Copyright© Bentham Science Publishers; For any queries, please email

La participation des enfants et des adolescents à la boxe

PubMed Central

Purcell, Laura K; LeBlanc, Claire MA

2012-01-01

RÉSUMÉ Des milliers de garçons et de filles de moins de 19 ans font de la boxe en Amérique du Nord. Même si la boxe comporte des avantages pour ceux qui y participent, y compris l’exercice, l’autodiscipline et la confiance en soi, le sport lui-même favorise et récompense des coups délibérés à la tête et au visage. Les personnes qui font de la boxe risquent de subir des blessures à la tête, au visage et au cou, y compris des traumatismes neurologiques chroniques et même fatals. Les commotions cérébrales sont l’une des principales blessures causées par la boxe. En raison du risque de blessures crâniennes et faciales, la Société canadienne de pédiatrie et l’American Academy of Pediatrics s’opposent vigoureusement à la boxe comme activité sportive pour les enfants et les adolescents. Ces organismes recommandent que les médecins s’élèvent contre la boxe auprès des jeunes et les encouragent à participer à d’autres activités dans lesquelles les coups intentionnels à la tête ne constituent pas un élément essentiel du sport.

Trial Watch: Toll-like receptor agonists for cancer therapy.

PubMed

Vacchelli, Erika; Eggermont, Alexander; Sautès-Fridman, Catherine; Galon, Jérôme; Zitvogel, Laurence; Kroemer, Guido; Galluzzi, Lorenzo

2013-08-01

Toll-like receptors (TLRs) have long been known for their ability to initiate innate immune responses upon exposure to conserved microbial components such as lipopolysaccharide (LPS) and double-stranded RNA. More recently, this family of pattern recognition receptors has been attributed a critical role in the elicitation of anticancer immune responses, raising interest in the development of immunochemotherapeutic regimens based on natural or synthetic TLR agonists. In spite of such an intense wave of preclinical and clinical investigation, only three TLR agonists are currently licensed by FDA for use in cancer patients: bacillus Calmette-Guérin (BCG), an attenuated strain of Mycobacterium bovis that operates as a mixed TLR2/TLR4 agonist; monophosphoryl lipid A (MPL), a derivative of Salmonella minnesota that functions as a potent agonist of TLR4; and imiquimod, a synthetic imidazoquinoline that activates TLR7. One year ago, in the August and September issues of OncoImmunology , we described the main biological features of TLRs and discussed the progress of clinical studies evaluating the safety and therapeutic potential of TLR agonists in cancer patients. Here, we summarize the latest developments in this exciting area of research, focusing on preclinical studies that have been published during the last 13 mo and clinical trials launched in the same period to investigate the antineoplastic activity of TLR agonists.

Membrane fluidization by alcohols inhibits DesK-DesR signalling in Bacillus subtilis.

PubMed

Vaňousová, Kateřina; Beranová, Jana; Fišer, Radovan; Jemioła-Rzemińska, Malgorzata; Matyska Lišková, Petra; Cybulski, Larisa; Strzałka, Kazimierz; Konopásek, Ivo

2018-03-01

After cold shock, the Bacillus subtilis desaturase Des introduces double bonds into the fatty acids of existing membrane phospholipids. The synthesis of Des is regulated exclusively by the two-component system DesK/DesR; DesK serves as a sensor of the state of the membrane and triggers Des synthesis after a decrease in membrane fluidity. The aim of our work is to investigate the biophysical changes in the membrane that are able to affect the DesK signalling state. Using linear alcohols (ethanol, propanol, butanol, hexanol, octanol) and benzyl alcohol, we were able to suppress Des synthesis after a temperature downshift. The changes in the biophysical properties of the membrane caused by alcohol addition were followed using membrane fluorescent probes and differential scanning calorimetry. We found that the membrane fluidization induced by alcohols was reflected in an increased hydration at the lipid-water interface. This is associated with a decrease in DesK activity. The addition of alcohol mimics a temperature increase, which can be measured isothermically by fluorescence anisotropy. The effect of alcohols on the membrane periphery is in line with the concept of the mechanism by which two hydrophilic motifs located at opposite ends of the transmembrane region of DesK, which work as a molecular caliper, sense temperature-dependent variations in membrane properties. Copyright © 2017 Elsevier B.V. All rights reserved.

Etude du processus de changement vecu par des familles ayant decide d'adopter volontairement des comportements d'attenuation des changements climatiques

NASA Astrophysics Data System (ADS)

Leger, Michel T.

Les activites humaines energivores telles l'utilisation intensive de l'automobile, la surconsommation de biens et l'usage excessif d'electricite contribuent aux changements climatiques et autres problemes environnementaux. Bien que plusieurs recherches rapportent que l'etre humain est de plus en plus conscient de ses impacts sur le climat de la planete, ces memes recherches indiquent qu'en general, les gens continuent a se comporter de facon non ecologique. Que ce soit a l'ecole ou dans la communaute, plusieurs chercheurs en education relative a l'environnement estiment qu'une personne bien intentionnee est capable d'adopter des comportements plus respectueux de l'environnement. Le but de cette these etait de comprendre le processus d'integration de comportements d'attenuation des changements climatiques dans des familles. A cette fin, nous nous sommes fixe deux objectifs : 1) decrire les competences et les procedes qui favorisent l'adoption de comportements d'attenuation des changements climatiques dans des familles et 2) decrire les facteurs et les dynamiques familiales qui facilitent et limitent l'adoption de comportements d'attenuation des changements climatiques dans des familles. Des familles ont ete invitees a essayer des comportements personnels et collectifs d'attenuation des changements climatiques de sorte a integrer des modes de vie plus ecologiques. Sur une periode de huit mois, nous avons suivi leur experience de changement afin de mieux comprendre comment se produit le processus de changement dans des familles qui decident volontairement d'adopter des comportements d'attenuation des changements climatiques. Apres leur avoir fourni quelques connaissances de base sur les changements climatiques, nous avons observe le vecu de changement des familles durant huit mois d'essais a l'aide de journaux reflexifs, d'entretiens d'explicitation et du journal du chercheur. La these comporte trois articles scientifiques. Dans le premier article, nous presentons une

Cancer immunotherapy: activating innate and adaptive immunity through CD40 agonists

PubMed Central

Beatty, Gregory L.; Li, Yan; Long, Kristen B.

2017-01-01

INTRODUCTION CD40 is a promising therapeutic target for cancer immunotherapy. In patients with advanced solid malignancies, CD40 agonists have demonstrated some anti-tumor activity and a manageable toxicity profile. A 2nd generation of CD40 agonists has now been designed with optimized Fc receptor (FcR) binding based on preclinical evidence suggesting a critical role for FcR engagement in defining the potency of CD40 agonists in vivo. AREAS COVERED We provide a comprehensive review using PubMed and Google Patent databases on the current clinical status of CD40 agonists, strategies for applying CD40 agonists in cancer therapy, and the preclinical data that supports and is guiding the future development of CD40 agonists. EXPERT COMMENTARY There is a wealth of preclinical data that provide rationale on several distinct approaches for using CD40 agonists in cancer immunotherapy. This data illustrates the need to strategically combine CD40 agonists with other clinically active treatment regimens in order to realize the full potential of activating CD40 in vivo. Thus, critical to the success of this class of immune-oncology drugs, which have the potential to restore both innate and adaptive immunosurveillance, will be the identification of biomarkers for monitoring and predicting responses as well as informing mechanisms of treatment resistance. PMID:27927088

Identification of M-CSF agonists and antagonists

DOEpatents

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

2000-02-15

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

Synthetic RORγt Agonists Enhance Protective Immunity

PubMed Central

Chang, Mi Ra; Dharmarajan, Venkatasubramanian; Doebelin, Christelle; Garcia-Ordonez, Ruben D.; Novick, Scott J.; Kuruvilla, Dana S.; Kamenecka, Theodore M.; Griffin, Patrick R.

2016-01-01

The T cell specific RORγ isoform RORγt has been shown to be the key lineage-defining transcription factor to initiate the differentiation program of TH17 and Tc17 cells, cells that have demonstrated anti-tumor efficacy. RORγt controls gene networks that enhance immunity including increased IL17 production and decreased immune suppression. Both synthetic and putative endogenous agonists of RORγt have been shown to increase the basal activity of RORγt enhancing TH17 cell proliferation. Here we show that activation of RORγt using synthetic agonists drives proliferation of TH17 cells while decreasing levels of the immune checkpoint protein PD-1, a mechanism that should enhance anti-tumor immunity while blunting tumor associated adaptive immune resistance. Interestingly, putative endogenous agonists drive proliferation of TH17 cells but do not repress PD-1. These findings suggest that synthetic agonists of RORγt should activate TC17/TH17 cells (with concomitant reduction in the Tregs population), repress PD-1, and produce IL17 in situ (a factor associated with good prognosis in cancer). Enhanced immunity and blockage of immune checkpoints has transformed cancer treatment, thus such a molecule would provide a unique approach for the treatment of cancer. PMID:26785144

Des ballons pour demain

NASA Astrophysics Data System (ADS)

Régipa, R.

A partir d'une théorie sur la détermination des formes et des contraintes globales d'un ballon de révolution, ou s'en rapprochant, une nouvelle famille de ballons a été définie. Les ballons actuels, dits de ``forme naturelle'', sont calculés en général pour une tension circonférencielle nulle. Ainsi, pour une mission donnée, la tension longitudinale et la forme de l'enveloppe sont strictement imposées. Les ballons de la nouvelle génération sont globalement cylindriques et leurs pôles sont réunis par un câble axial, chargé de transmettre une partie des efforts depuis le crochet (pôle inférieur), directement au pôle supérieur. De plus, la zone latérale cylindrique est soumise à un faible champ de tensions circonférencielles. Ainsi, deux paramètres permettent de faire évoluer la distribution des tensions et la forme de l'enveloppe: - la tension du câble de liaison entre pôles (ou la longueur de ce câble) - la tension circonférencielle moyenne désirée (ou le rayon du ballon). On peut donc calculer et réaliser: - soit des ballons de forme adaptée, comme les ballons à fond plat pour le bon fonctionnement des montgolfières infrarouge (projet MIR); - soit des ballons optimisés pour une bonne répartition des contraintes et une meilleure utilisation des matériaux d'enveloppe, pour l'ensemble des programmes stratosphériques. Il s'ensuit une économie sensible des coûts de fabrication, une fiabilité accrue du fonctionnement de ces ballons et une rendement opérationnel bien supérieur, permettant entre autres, d'envisager des vols à très haute altitude en matériaux très légers.

Magnesium ions and opioid agonists in vincristine-induced neuropathy.

PubMed

Bujalska, Magdalena; Makulska-Nowak, Helena; Gumułka, Stanisław W

2009-01-01

Neuropathic pain is difficult to treat. Classic analgesics (i.e., opioid receptor agonists) usually possess low activity. Therefore other agents such as antidepressants, anticonvulsants, and corticosteroids are used. It is commonly known that NMDA antagonists increase analgesic activity of opioids. Unfortunately, clinical use of NMDA antagonists is limited because of the relatively frequent occurrence of adverse effects e.g., memory impairment, psychomimetic effects, ataxia and motor in-coordination. Magnesium ions (Mg(2+)) are NMDA receptor blockers in physiological conditions. Therefore, in this study the effect of opioid receptor agonists and the influence of Mg(2+) on the action of opioid agonists in vincristine-induced hyperalgesia were examined. Opioid agonists such as morphine (5 mg/kg, ip), and fentanyl (0.0625 mg/kg, ip), as well as the partial agonist buprenorphine (0.075 mg/kg, ip) administered alone on 5 consecutives days did not modify the hyperalgesia in vincristine rats. In contrast, pretreatment with a low dose of magnesium sulfate (30 mg/kg, ip) resulted in a progressive increase of the analgesic action of all three investigated opioids. After discontinuation of drug administration, the effect persisted for several days.

TLR9 agonist protects mice from radiation-induced gastrointestinal syndrome.

PubMed

Saha, Subhrajit; Bhanja, Payel; Liu, Laibin; Alfieri, Alan A; Yu, Dong; Kandimalla, Ekambar R; Agrawal, Sudhir; Guha, Chandan

2012-01-01

Radiation-induced gastrointestinal syndrome (RIGS) is due to the clonogenic loss of crypt cells and villi depopulation, resulting in disruption of mucosal barrier, bacterial invasion, inflammation and sepsis. Intestinal macrophages could recognize invading bacterial DNA via TLR9 receptors and transmit regenerative signals to the neighboring crypt. We therefore investigated whether systemic administration of designer TLR9 agonist could ameliorate RIGS by activating TLR9. Male C57Bl6 mice were distributed in four experimental cohorts, whole body irradiation (WBI) (8.4-10.4 Gy), TLR9 agonist (1 mg/kg s.c.), 1 h pre- or post-WBI and TLR9 agonist+WBI+iMyd88 (pretreatment with inhibitory peptide against Myd88). Animals were observed for survival and intestine was harvested for histological analysis. BALB/c mice with CT26 colon tumors in abdominal wall were irradiated with 14 Gy single dose of whole abdominal irradiation (AIR) for tumor growth study. Mice receiving pre-WBI TLR9 agonist demonstrated improvement of survival after 10.4 Gy (p<0.03), 9.4 Gy (p<0.008) and 8.4 Gy (p<0.002) of WBI, compared to untreated or iMyd88-treated controls. Post-WBI TLR9 agonist mitigates up to 8.4 Gy WBI (p<0.01). Histological analysis and xylose absorption test demonstrated significant structural and functional restitution of the intestine in WBI+TLR9 agonist cohorts. Although, AIR reduced tumor growth, all animals died within 12 days from RIGS. TLR9 agonist improved the survival of mice beyond 28 days post-AIR (p<0.008) with significant reduction of tumor growth (p<0.0001). TLR9 agonist treatment could serve both as a prophylactic or mitigating agent against acute radiation syndrome and also as an adjuvant therapy to increase the therapeutic ratio of abdominal Radiation Therapy for Gastro Intestinal malignancies.

Maladie des vibrations

PubMed Central

Shen, Shixin (Cindy); House, Ronald A.

2017-01-01

Résumé Objectif Permettre aux médecins de famille de comprendre l’épidémiologie, la pathogenèse, les symptômes, le diagnostic et la prise en charge de la maladie des vibrations, une maladie professionnelle importante et courante au Canada. Sources d’information Une recherche a été effectuée sur MEDLINE afin de relever les recherches et comptes rendus portant sur la maladie des vibrations. Une recherche a été effectuée sur Google dans le but d’obtenir la littérature grise qui convient au contexte canadien. D’autres références ont été tirées des articles relevés. Message principal La maladie des vibrations est une maladie professionnelle répandue touchant les travailleurs de diverses industries qui utilisent des outils vibrants. La maladie est cependant sous-diagnostiquée au Canada. Elle compte 3 éléments : vasculaire, sous la forme d’un phénomène de Raynaud secondaire; neurosensoriel; et musculosquelettique. Aux stades les plus avancés, la maladie des vibrations entraîne une invalidité importante et une piètre qualité de vie. Son diagnostic exige une anamnèse minutieuse, en particulier des antécédents professionnels, un examen physique, des analyses de laboratoire afin d’éliminer les autres diagnostics, et la recommandation en médecine du travail aux fins d’investigations plus poussées. La prise en charge consiste à réduire l’exposition aux vibrations, éviter les températures froides, abandonner le tabac et administrer des médicaments. Conclusion Pour assurer un diagnostic rapide de la maladie des vibrations et améliorer le pronostic et la qualité de vie, les médecins de famille devraient connaître cette maladie professionnelle courante, et pouvoir obtenir les détails pertinents durant l’anamnèse, recommander les patients aux cliniques de médecine du travail et débuter les demandes d’indemnisation de manière appropriée. PMID:28292812

Etat des lieux des soins de premier recours des malades mentaux à Antananarivo : étude rétrospective

PubMed Central

Bakohariliva, Hasina Andrianarivony; Rafehivola, Imisanavalona Hanitrinihaja; Raobelle, Evah Norotiana; Raharivelo, Adeline; Rajaonarison, Bertille Hortense

2018-01-01

Résumé Religion et guérisseurs traditionnels occupent encore une place prépondérante dans la prise en charge des maladies mentales à Madagascar. Ainsi, nous nous sommes fixés comme objectif d'établir un état des lieux sur les soins de premier recours des malades mentaux. Nous avons mené une étude rétrospective descriptive s'étalant sur une période de 16 mois allant de janvier 2014 en avril 2015 au sein du service de psychiatrie du CHU de Befelatanana à Antananarivo. La prévalence des psychoses était de 25%. Le genre féminin (53%), l'ethnie merina (77%), les étudiants (45%), le niveau d'étude secondaire (40%), les célibataires (72%), la religion protestante (45%), ainsi que le niveau socio-économique moyen (57,5%) étaient prédominants. Dans les paramètres cliniques, le mode de début brutal (52%), le premier recours à la religion (40%), la présence d'antécédents des cas similaire (90%), étaient majoritaires. La schizophrénie était la pathologie la plus rencontrée dans la moitié des cas. Le délai d'amélioration en cas de traitement religieux et traditionnels était dans la moitié des cas de plus de 10 jours d'hospitalisation. Les patients ayant reçu une prise en charge psychiatrique en premier recours, étaient améliorés dans 75 % cas en moins de 10jours. Le retard du recours aux soins psychiatriques est une réalité à Madagascar qui aggrave le pronostic des psychoses. PMID:29632623

TOXICITY OF AHR AGONISTS TO FISH EARLY LIFE STAGES

EPA Science Inventory

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

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.

Electrophysiological Perspectives on the Therapeutic Use of Nicotinic Acetylcholine Receptor Partial AgonistsS⃞

PubMed Central

Trocmé-Thibierge, Caryn; Guendisch, Daniela; Al Rubaiy, Shehd Abdullah Abbas; Bloom, Stephen A.

2011-01-01

Partial agonist therapies rely variously on two hypotheses: the partial agonists have their effects through chronic low-level receptor activation or the partial agonists work by decreasing the effects of endogenous or exogenous full agonists. The relative significance of these activities probably depends on whether acute or chronic effects are considered. We studied nicotinic acetylcholine receptors (nAChRs) expressed in Xenopus laevis oocytes to test a model for the acute interactions between acetylcholine (ACh) and weak partial agonists. Data were best-fit to a basic competition model that included an additional factor for noncompetitive inhibition. Partial agonist effects were compared with the nAChR antagonist bupropion in prolonged bath application experiments that were designed to mimic prolonged drug exposure typical of therapeutic drug delivery. A primary effect of prolonged application of nicotine was to decrease the response of all nAChR subtypes to acute applications of ACh. In addition, nicotine, cytisine, and varenicline produced detectable steady-state activation of α4β2* [(α4)2(β2)3, (α4)3(β2)2, and (α4)2(β2)2α5)] receptor subtypes that was not seen with other test compounds. Partial agonists produced no detectable steady-state activation of α7 nAChR, but seemed to show small potentiation of ACh-evoked responses; however, “run-up” of α7 ACh responses was also sometimes observed under control conditions. Potential off-target effects of the partial agonists therefore included the modulation of α7 responses by α4β2 partial agonists and decreases in α4β2* responses by α7-selective agonists. These data indicate the dual effects expected for α4β2* partial agonists and provide models and insights for utility of partial agonists in therapeutic development. PMID:21285282

Agonist-Specific Recruitment of Arrestin Isoforms Differentially Modify Delta Opioid Receptor Function

PubMed Central

Perroy, Julie; Walwyn, Wendy M.; Smith, Monique L.; Vicente-Sanchez, Ana; Segura, Laura; Bana, Alia; Kieffer, Brigitte L.; Evans, Christopher J.

2016-01-01

Ligand-specific recruitment of arrestins facilitates functional selectivity of G-protein-coupled receptor signaling. Here, we describe agonist-selective recruitment of different arrestin isoforms to the delta opioid receptor in mice. A high-internalizing delta opioid receptor agonist (SNC80) preferentially recruited arrestin 2 and, in arrestin 2 knock-outs (KOs), we observed a significant increase in the potency of SNC80 to inhibit mechanical hyperalgesia and decreased acute tolerance. In contrast, the low-internalizing delta agonists (ARM390, JNJ20788560) preferentially recruited arrestin 3 with unaltered behavioral effects in arrestin 2 KOs. Surprisingly, arrestin 3 KO revealed an acute tolerance to these low-internalizing agonists, an effect never observed in wild-type animals. Furthermore, we examined delta opioid receptor–Ca2+ channel coupling in dorsal root ganglia desensitized by ARM390 and the rate of resensitization was correspondingly decreased in arrestin 3 KOs. Live-cell imaging in HEK293 cells revealed that delta opioid receptors are in pre-engaged complexes with arrestin 3 at the cell membrane and that ARM390 strengthens this membrane interaction. The disruption of these complexes in arrestin 3 KOs likely accounts for the altered responses to low-internalizing agonists. Together, our results show agonist-selective recruitment of arrestin isoforms and reveal a novel endogenous role of arrestin 3 as a facilitator of resensitization and an inhibitor of tolerance mechanisms. SIGNIFICANCE STATEMENT Agonists that bind to the same receptor can produce highly distinct signaling events and arrestins are a major mediator of this ligand bias. Here, we demonstrate that delta opioid receptor agonists differentially recruit arrestin isoforms. We found that the high-internalizing agonist SNC80 preferentially recruits arrestin 2 and knock-out (KO) of this protein results in increased efficacy of SNC80. In contrast, low-internalizing agonists (ARM390 and JNJ20788560

Determination des Parametres Atmospheriques des Etoiles Naines Blanches de Type DB

NASA Astrophysics Data System (ADS)

Beauchamp, Alain

1995-01-01

Les etoiles naines blanches dont les spectres visibles sont domines par des raies fortes d'helium neutre sont subdivisees en trois classes, DB (raies d'helium neutre seulement), DBA (raies d'helium neutre et d'hydrogene) et DBZ (raies d'helium neutre et d'elements lourds). Nous analysons trois echantillons de spectres observes de ces types de naines blanches. Les echantillons consistent, respectivement, de 48 spectres dans le domaine du visible (3700-5100 A). 24 dans l'ultraviolet (1200-3100 A) et quatre dans la partie rouge du visible (5100-6900) A). Parmi les objets de l'echantillon visible, nous identifions quatre nouvelles DBA, ainsi que deux nouvelles DBZ, auparavant classees DB. L'analyse nous permet de determiner spectroscopiquement les parametres atmospheriques, soit la temperature effective, la gravite de surface, ainsi que l'abondance relative de l'hydrogene, N(H)/N(He), dans le cas des DBA. Pour les objets plus chauds que ~15,000 K, la gravite de surface determinee est fiable, et nous obtenons les masses stellaires avec une relation masse -rayon theorique. Les exigences propres a l'analyse de ces objets ont requis d'importantes ameliorations dans la modelisation de leurs atmospheres et distributions de flux de radiation emis par ces derniers. Nous avons inclus dans les modeles d'atmospheres, pour la premiere fois a notre connaissance, les effets dus a la molecule He_sp{2 }{+}, ainsi que l'equation d'etat de Hummer et Mihalas (1988), qui tient compte des perturbations entre particules dans le calcul des populations des differents niveaux atomiques. Nous traitons la convection dans le cadre de la theorie de la longueur de melange. Trois grilles de modeles d'atmospheres a l'ETL (equilibre thermodynamique local) ont ete produites, pour un ensemble de temperatures effectives, gravites de surface et abondances d'hydrogene couvrant les proprietes des etoiles de nos echantillons; elles sont caracterisees par differentes parametrisations appelees, respectivement

Differential effects of AMPK agonists on cell growth and metabolism

PubMed Central

Vincent, Emma E.; Coelho, Paula P.; Blagih, Julianna; Griss, Takla; Viollet, Benoit; Jones, Russell G.

2016-01-01

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

Lack of cocaine-like discriminative-stimulus effects of σ-receptor agonists in rats.

PubMed

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

2011-09-01

Previous studies demonstrated the effectiveness of selective σ-receptor (σR) agonists [1,3-di-o-tolylguanidine (DTG), PRE-084] as reinforcers in rats trained to self-administer cocaine. Similar to cocaine, these drugs increased nucleus accumbens shell dopamine levels, and effects of DTG, but not PRE-084, on dopamine seemed to be mediated by σRs. In addition, σR antagonists blocked self-administration of σR agonists, but were inactive against reinforcing and neurochemical effects of cocaine. Thus, pharmacologically distinct mechanisms likely underlie the reinforcing and neurochemical effects of σR agonists and cocaine. This study further examined the cocaine-like effects of σR agonists in rats trained to discriminate injections of cocaine from saline to assess the similarity of their subjective effects. Standard dopamine-uptake inhibitors (WIN 35,428, methylphenidate), but neither σR agonist (PRE-084, DTG), produced full cocaine-like discriminative-stimulus effects. The lack of effects of σR agonists was obtained regardless of route of administration (intraperitoneal, subcutaneous, or intravenous) or pretreatment time (5 or 30 min before sessions). The present results demonstrate differences in the discriminative-stimulus effects of cocaine and selective σR agonists, indicating that an overlap of subjective effects is not necessary for σR agonist self-administration. The previously found differences in neurochemical effects of cocaine and σR agonists may contribute to their different subjective effects.

Lack of Cocaine-Like Discriminative-Stimulus Effects of σ Receptor Agonists in Rats

PubMed Central

Hiranita, Takato; Soto, Paul L.; Tanda, Gianluigi; Katz, Jonathan L.

2013-01-01

Previous studies demonstrated effectiveness of selective sigma-receptor (σR) agonists (DTG, PRE-084) as reinforcers in rats trained to self-administer cocaine. Like cocaine, these drugs increased nucleus accumbens shell dopamine levels, and effects of DTG, but not PRE-084, on dopamine appeared to be mediated by σRs. Additionally, σR antagonists blocked self-administration of σR agonists, but were inactive against reinforcing and neurochemical effects of cocaine. Thus pharmacologically distinct mechanisms likely underlie the reinforcing and neurochemical effects of σR agonists and cocaine. The present study further examined the cocaine-like effects of σR agonists in rats trained to discriminate injections of cocaine from saline to assess the similarity of their subjective effects. Standard dopamine-uptake inhibitors (WIN 35,428, methylphenidate), but neither σR agonist (PRE-084, DTG) produced full cocaine-like discriminative-stimulus effects. The lack of effects of σR agonists was obtained regardless of route of administration (i.p., s.c. or i.v.) or pretreatment time (5- or 30-min before sessions). The present results demonstrate differences in the discriminative-stimulus effects of cocaine and selective σR agonists, indicating that an overlap of subjective effects is not necessary for σR agonist self-administration. The previously found differences in neurochemical effects of cocaine and σR agonists may contribute to their different subjective effects. PMID:21808192

Pharmacological characterization of the new histamine H4 receptor agonist VUF 8430

PubMed Central

Lim, Herman D; Adami, Maristella; Guaita, Elena; Werfel, Thomas; Smits, Rogier A; de Esch, Iwan JP; Bakker, Remko A; Gutzmer, Ralf; Coruzzi, Gabriella; Leurs, Rob

2009-01-01

Background and purpose: We compare the pharmacological profiles of a new histamine H4 receptor agonist 2-(2-guanidinoethyl)isothiourea (VUF 8430) with that of a previously described H4 receptor agonist, 4-methylhistamine. Experimental approach: Radioligand binding and functional assays were performed using histamine H4 receptors expressed in mammalian cell lines. Compounds were also evaluated ex vivo in monocyte-derived dendritic cells endogenously expressing H4 receptors and in vivo in anaesthetized rats for gastric acid secretion activity. Key results: Both VUF 8430 and 4-methylhistamine were full agonists at human H4 receptors with lower affinity at rat and mouse H4 receptors. Both compounds induced chemotaxis of monocyte-derived dendritic cells. VUF 8430 also showed reasonable affinity and was a full agonist at the H3 receptor. Agmatine is a metabolite of arginine, structurally related to VUF 8430, and was a H4 receptor agonist with micromolar affinity. At histamine H3 receptors, agmatine was a full agonist, whereas 4-methylhistamine was an agonist only at high concentrations. Both VUF 8430 and agmatine were inactive at H1 and H2 receptors, whereas 4-methylhistamine is as active as histamine at H2 receptors. In vivo, VUF 8430 only caused a weak secretion of gastric acid mediated by H2 receptors, whereas 4-methylhistamine, dimaprit, histamine and amthamine, at equimolar doses, induced 2.5- to 6-fold higher output than VUF 8430. Conclusions and implications: Our results suggest complementary use of 4-methylhistamine and VUF 8430 as H4 receptor agonists. Along with H4 receptor antagonists, both agonists can serve as useful pharmacological tools in studies of histamine H4 receptors. PMID:19413569

Mouse hypospadias: A critical examination and definition

PubMed Central

Sinclair, Adriane Watkins; Cao, Mei; Shen, Joel; Cooke, Paul; Risbridger, Gail; Baskin, Laurence; Cunha, Gerald R.

2016-01-01

Hypospadias is a common malformation whose etiology is based upon perturbation of normal penile development. The mouse has been previously used as a model of hypospadias, despite an unacceptably wide range of definitions for this malformation. The current paper presents objective criteria and a definition of mouse hypospadias. Accordingly, diethylstilbestrol (DES) induced penile malformations were examined at 60 days postnatal (P60) in mice treated with DES over the age range of 12 days embryonic to 20 days postnatal (E12 to P20). DES-induced hypospadias involves malformation of the urethral meatus, which is most severe in DES E12-P10, DES P0-P10 and DES P5-P15 groups and less so or absent in the other treatment groups. A frenulum-like ventral tether between the penis and the prepuce was seen in the most severely affected DES-treated mice. Internal penile morphology was also altered in the DES E12-P10, DES P0-P10 and DES P5-P15 groups (with little effect in the other DES treatment groups). Thus, adverse effects of DES are a function of the period of DES treatment and most severe in the P0 to P10 period. In “estrogen mutant mice” (NERKI, βERKO, αERKO and AROM+) hypospadias was only seen in AROM+ male mice having genetically-engineered elevation is serum estrogen. Significantly, mouse hypospadias was only seen distally at and near the urethral meatus where epithelial fusion events are known to take place and never in the penile midshaft, where urethral formation occurs via an entirely different morphogenetic process. PMID:27068029

Differential effects of AMPK agonists on cell growth and metabolism.

PubMed

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

2015-07-01

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

Etude numerique et experimentale de la reponse vibro-acoustique des structures raidies a des excitations aeriennes et solidiennes

NASA Astrophysics Data System (ADS)

Mejdi, Abderrazak

Les fuselages des avions sont generalement en aluminium ou en composite renforces par des raidisseurs longitudinaux (lisses) et transversaux (cadres). Les raidisseurs peuvent etre metalliques ou en composite. Durant leurs differentes phases de vol, les structures d'avions sont soumises a des excitations aeriennes (couche limite turbulente : TBL, champs diffus : DAF) sur la peau exterieure dont l'energie acoustique produite se transmet a l'interieur de la cabine. Les moteurs, montes sur la structure, produisent une excitation solidienne significative. Ce projet a pour objectifs de developper et de mettre en place des strategies de modelisations des fuselages d'avions soumises a des excitations aeriennes et solidiennes. Tous d'abord, une mise a jour des modeles existants de la TBL apparait dans le deuxieme chapitre afin de mieux les classer. Les proprietes de la reponse vibro-acoustique des structures planes finies et infinies sont analysees. Dans le troisieme chapitre, les hypotheses sur lesquelles sont bases les modeles existants concernant les structures metalliques orthogonalement raidies soumises a des excitations mecaniques, DAF et TBL sont reexamines en premier lieu. Ensuite, une modelisation fine et fiable de ces structures est developpee. Le modele est valide numeriquement a l'aide des methodes des elements finis (FEM) et de frontiere (BEM). Des tests de validations experimentales sont realises sur des panneaux d'avions fournis par des societes aeronautiques. Au quatrieme chapitre, une extension vers les structures composites renforcees par des raidisseurs aussi en composites et de formes complexes est etablie. Un modele analytique simple est egalement implemente et valide numeriquement. Au cinquieme chapitre, la modelisation des structures raidies periodiques en composites est beaucoup plus raffinee par la prise en compte des effets de couplage des deplacements planes et transversaux. L'effet de taille des structures finies periodiques est egalement pris en

Differential agonist sensitivity of glycine receptor α2 subunit splice variants

PubMed Central

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

2004-01-01

The glycine receptor (GlyR) α2A and α2B splice variants differ by a dual, adjacent amino acid substitution from α2AV58,T59 to α2BI58,A59 in the N-terminal extracellular domain. Comparing the effects of the GlyR agonists, glycine, β-alanine and taurine, on the GlyR α2 isoforms, revealed a significant increase in potency for all three agonists at the α2B variant. The sensitivities of the splice variants to the competitive antagonist, strychnine, and to the biphasic modulator Zn2+, were comparable. In contrast, the allosteric inhibitor picrotoxin was more potent on GlyR α2A compared to GlyR α2B receptors. Coexpression of α2A or α2B subunits with the GlyR β subunit revealed that the higher agonist potencies observed with the α2B homomer were retained for the α2Bβ heteromer. The identical sensitivity to strychnine combined with a reduction in the maximum current induced by the partial agonist taurine at the GlyR α2A homomer, suggested that the changed sensitivity to agonists is in accordance with a modulation of agonist efficacy rather than agonist affinity. An effect on agonist efficacy was also supported by using a structural model of the GlyR, localising the region of splice variation to the proposed docking region between GlyR loop 2 and the TM2-3 loop, an area associated with channel activation. The existence of a spasmodic mouse phenotype linked to a GlyR α1A52S mutation, the equivalent position to the source of the α2 splice variation, raises the possibility that the GlyR α2 splice variants may be responsible for distinct roles in neuronal function. PMID:15302677

Radiolabelled D2 agonists as prolactinoma imaging agents

DOE Office of Scientific and Technical Information (OSTI.GOV)

Otto, C.A.

1989-08-01

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

Etude de l'amelioration de la qualite des anodes par la modification des proprietes du brai

NASA Astrophysics Data System (ADS)

Bureau, Julie

La qualite des anodes produites se doit d'etre bonne afin d'obtenir de l'aluminium primaire tout en reduisant le cout de production du metal, la consommation d'energie et les emissions environnementales. Or, l'obtention des proprietes finales de l'anode necessite une liaison satisfaisante entre le coke et le brai. Toutefois, la matiere premiere actuelle n'assure pas forcement la compatibilite entre le coke et le brai. Une des solutions les plus prometteuses, pour ameliorer la cohesion entre ces deux materiaux, est la modification des proprietes du brai. L'objectif de ce travail consiste a modifier les proprietes du brai par l'ajout d'additifs chimiques afin d'ameliorer la mouillabilite du coke par le brai modifie pour produire des anodes de meilleure qualite. La composition chimique du brai est modifiee en utilisant des tensioactifs ou agents de modification de surface choisis dans le but d'enrichir les groupements fonctionnels susceptibles d'ameliorer la mouillabilite. L'aspect economique, l'empreinte environnementale et l'impact sur la production sont consideres dans la selection des additifs chimiques. Afin de realiser ce travail, la methodologie consiste a d'abord caracteriser les brais non modifies, les additifs chimiques et les cokes par la spectroscopie infrarouge a transformee de Fourier (FTIR) afin d'identifier les groupements chimiques presents. Puis, les brais sont modifies en ajoutant un additif chimique afin de possiblement modifier ses proprietes. Differentes quantites d'additif sont ajoutees afin d'examiner l'effet de la variation de la concentration sur les proprietes du brai modifie. La methode FTIR permet d'evaluer la composition chimique des brais modifies afin de constater si l'augmentation de la concentration d'additif enrichit les groupements fonctionnels favorisant l'adhesion coke/brai. Ensuite, la mouillabilite du coke par le brai est observee par la methode goutte- sessile. Une amelioration de la mouillabilite par la modification a l'aide d

Evaluation of novel synthetic TLR7/8 agonists as vaccine adjuvants

PubMed Central

Smith, Alyson J.; Li, Yufeng; Bazin, Hélène G.; St-Jean, Julien R.; Larocque, Daniel; Evans, Jay T.; Baldridge, Jory R.

2016-01-01

Small-molecule adjuvants that boost and direct adaptive immunity provide a powerful means to increase the effectiveness of vaccines. Through rational design several novel imidazoquinoline and oxoadenine TLR7/8 agonists, each with unique molecular modifications, were synthesized and assessed for their ability to augment adaptive immunity. All agonists bound human TLR7 and TLR8 and induced maturation of both human mDCs and pDCs. All agonists prompted production of type I interferon and/or proinflammatory cytokines, albeit with varying potencies. In most in vitro assays, the oxoadenine class of agonists proved more potent than the imidazoquinolines. Therefore, an optimized oxoadenine TLR7/8 agonist that demonstrated maximal activity in the in vitro assays was further assessed in a vaccine study with the CRM197 antigen in a porcine model. Antigen-specific antibody production was greatly enhanced in a dose dependent manner, with antibody titers increased 800-fold compared to titers from pigs vaccinated with the non-adjuvanted vaccine. Moreover, pigs vaccinated with antigen containing the highest dose of adjuvant promoted a 13-fold increase in the percentage of antigen-specific CD3+/CD8+ T cells over pigs vaccinated with antigen alone. Together this work demonstrates the promise of these novel TLR7/8 agonists as effective human vaccine adjuvants. PMID:27402566

Muscarinic agonists for the treatment of cognition in schizophrenia.

PubMed

Sellin, Angela K; Shad, Mujeeb; Tamminga, Carol

2008-11-01

It is widely accepted that cholinergic activity at muscarinic receptors is required to maintain cognitive functions, including learning and memory. Memory domains are especially impaired in schizophrenia, which may explain difficulties in psychosocial rehabilitation of individuals with this illness. However, little is known about the mechanism of this impairment. To understand our current knowledge, we reviewed the literature since 1990 via a PubMed search for the terms "muscarinic", "schizophrenia", "cognition", "memory", "learning", and "agonist" in combination. We found 89 basic science/laboratory studies, case reports/series, case-control studies, cross-sectional studies, standardized controlled animal trials, standardized controlled human trials, and reviews. Although further research is required to fully understand the neuropharmacology of the cholinergic system in cognitive function in schizophrenia, we have examined the data currently available. In general, these data suggest that agonist activity at acetylcholine muscarinic type 1 (M1) receptors would enhance memory and learning in schizophrenia. We present an overview of likely side effects of muscarinic agonists. We outline the anticholinergic activity of several available antipsychotics and review the available M1 muscarinic agonists.

FXR agonist activity of conformationally constrained 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; Madauss, Kevin P; Marr, Harry B; McFadyen, Robert B; Miller, Aaron B; Navas, Frank; Parks, Derek J; Spearing, Paul K; Todd, Dan; Williams, Shawn P; Bruce Wisely, G

2009-08-15

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.

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

PubMed

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

2014-01-14

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 TGFβ. 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 α3) 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.

D1 receptor agonist improves sleep-wake parameters in experimental parkinsonism.

PubMed

Hyacinthe, Carole; Barraud, Quentin; Tison, François; Bezard, Erwan; Ghorayeb, Imad

2014-03-01

Both excessive daytime sleepiness (EDS) and rapid eye movement (REM) sleep deregulation are part of Parkinson's disease (PD) non-motor symptoms and may complicate dopamine replacement therapy. We report here that dopamine agonists act differentially on sleep architecture in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine macaque monkey. Continuous sleep and wake electroencephalographic monitoring revealed no effect of the selective dopamine D2 receptor agonist quinpirole on EDS, whereas the selective dopamine D1 receptor agonist SKF38393 efficiently alleviated EDS and restored REM sleep to baseline values. The present results question the relevance of abandoning D1 receptor agonist treatment in PD as it might actually improve sleep-related disorders. Copyright © 2013 Elsevier Inc. All rights reserved.

Quantification des besoins en intrants antipaludiques: contribution à l'actualisation des hypothèses pour la quantification des intrants de prise en charge des cas de paludisme grave en République Démocratique du Congo

PubMed Central

Likwela, Joris Losimba; Otokoye, John Otshudiema

2015-01-01

Les formes graves de paludisme à Plasmodium falciparum sont une cause majeure de décès des enfants de moins de 5 ans en Afrique Sub-saharienne. Un traitement rapide dépend de la disponibilité de médicaments appropriés au niveau des points de prestation de service. La fréquence des ruptures de stock des commodités antipaludiques, en particuliers celles utilisées pour le paludisme grave, avait nécessité une mise à jour des hypothèses de quantification. Les données issues de la collecte de routine du PNLP de 2007 à 2012 ont été comparées à celles rapportés par d'autres pays africains et utilisées pour orienter les discussions au cours d'un atelier organisé par le PNLP et ses partenaires techniques et financiers afin de dégager un consensus national. La proportion des cas de paludisme rapportés comme grave en RDC est resté autour d'une médiane de 7% avec un domaine de variation de 6 à 9%. Hormis la proportion rapportée au Kenya (2%), les pays africains ont rapporté une proportion de cas grave variant entre 5 et 7%. Il apparaît que la proportion de 1% précédemment utilisée pour la quantification en RDC a été sous-estimée dans le contexte de la gestion des cas graves sur terrain. Un consensus s'est dégagé autour de la proportion de 5% étant entendu que des efforts de renforcement des capacités seraient déployés afin d'améliorer le diagnostic au niveau des points de prestation des services. PMID:26213595

Characterization of the hypothermic effects of imidazoline I2 receptor agonists in rats

PubMed Central

Thorn, David A; An, Xiao-Fei; Zhang, Yanan; Pigini, Maria; Li, Jun-Xu

2012-01-01

BACKGROUND AND PURPOSE Imidazoline I2 receptors have been implicated in several CNS disorders. Although several I2 receptor agonists have been described, no simple and sensitive in vivo bioassay is available for studying I2 receptor ligands. This study examined I2 receptor agonist-induced hypothermia as a functional in vivo assay of I2 receptor agonism. EXPERIMENTAL APPROACH Different groups of rats were used to examine the effects of I2 receptor agonists on the rectal temperature and locomotion. The pharmacological mechanisms were investigated by combining I2 receptor ligands and different antagonists. KEY RESULTS All the selective I2 receptor agonists examined (2-BFI, diphenyzoline, phenyzoline, CR4056, tracizoline, BU224 and S22687, 3.2–56 mg·kg–1, i.p.) dose-dependently and markedly decreased the rectal temperature (hypothermia) in rats, with varied duration of action. Pharmacological mechanism of the observed hypothermia was studied by combining the I2 receptor agonists (2-BFI, BU224, tracizoline and diphenyzoline) with imidazoline I2 receptor/ α2 adrenoceptor antagonist idazoxan, selective I1 receptor antagonist efaroxan, α2 adrenoceptor antagonist/5-HT1A receptor agonist yohimbine. Idazoxan but not yohimbine or efaroxan attenuated the hypothermic effects of 2-BFI, BU224, tracizoline and diphenyzoline, supporting the I2 receptor mechanism. In contrast, both idazoxan and yohimbine attenuated hypothermia induced by the α2 adrenoceptor agonist clonidine. Among all the I2 receptor agonists studied, only S22687 markedly increased the locomotor activity in rats. CONCLUSIONS AND IMPLICATIONS Imidazoline I2 receptor agonists can produce hypothermic effects, which are primarily mediated by I2 receptors. These data suggest that I2 receptor agonist-induced hypothermia is a simple and sensitive in vivo assay for studying I2 receptor ligands. PMID:22324428

Agonist activation of α7 nicotinic acetylcholine receptors via an allosteric transmembrane site

PubMed Central

Gill, JasKiran K.; Savolainen, Mari; Young, Gareth T.; Zwart, Ruud; Sher, Emanuele; Millar, Neil S.

2011-01-01

Conventional nicotinic acetylcholine receptor (nAChR) agonists, such as acetylcholine, act at an extracellular “orthosteric” binding site located at the interface between two adjacent subunits. Here, we present evidence of potent activation of α7 nAChRs via an allosteric transmembrane site. Previous studies have identified a series of nAChR-positive allosteric modulators (PAMs) that lack agonist activity but are able to potentiate responses to orthosteric agonists, such as acetylcholine. It has been shown, for example, that TQS acts as a conventional α7 nAChR PAM. In contrast, we have found that a compound with close chemical similarity to TQS (4BP-TQS) is a potent allosteric agonist of α7 nAChRs. Whereas the α7 nAChR antagonist metyllycaconitine acts competitively with conventional nicotinic agonists, metyllycaconitine is a noncompetitive antagonist of 4BP-TQS. Mutation of an amino acid (M253L), located in a transmembrane cavity that has been proposed as being the binding site for PAMs, completely blocks agonist activation by 4BP-TQS. In contrast, this mutation had no significant effect on agonist activation by acetylcholine. Conversely, mutation of an amino acid located within the known orthosteric binding site (W148F) has a profound effect on agonist potency of acetylcholine (resulting in a shift of ∼200-fold in the acetylcholine dose-response curve), but had little effect on the agonist dose-response curve for 4BP-TQS. Computer docking studies with an α7 homology model provides evidence that both TQS and 4BP-TQS bind within an intrasubunit transmembrane cavity. Taken together, these findings provide evidence that agonist activation of nAChRs can occur via an allosteric transmembrane site. PMID:21436053

Illegal use of beta-adrenergic agonists: European Community.

PubMed

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

1998-01-01

The use of veterinary medicinal products within the European Community is governed by a series of directives and regulations that describe the requirements for safety, quality, and efficacy of these products. Veterinary therapeutic use of beta-agonists has only been approved in the case of clenbuterol for bronchodilatation in horses and calves and for tocolysis in cows. No beta-agonists have been permitted in the European Community for growth-promoting purposes in farm animals. Surveillance for the presence of residues of veterinary agents in food-producing animals and meat is regulated by the Directive 86/469/EEC containing specific guidelines for sampling procedures on farms and in slaughterhouses. The level and frequency of sampling is dependent on the category of compounds and animal species. When positive samples have been identified (above certain action levels), sampling intensity is increased. Results of monitoring programs in EU member states during 1992 and 1993 for the occurrence of residues of beta-agonists in food-producing animals vary substantially with respect to the percentages of positive samples, ranging from 0 to 7%. The variability is partly explained by differences in sampling strategies, detection methods, and action levels applied. Identification of the proper matrices for sampling and detection of beta-agonists is important. In the case of clenbuterol, hair and choroid retinal tissue are appropriate tissues because clenbuterol accumulates in these matrices. A clear decrease in the use of clenbuterol in cattle has been observed in The Netherlands, Germany, Northern Ireland, and Spanish Basque Country over the last 3 yr. This is partly due to intensified surveillance activities at farms and slaughterhouses by governmental agencies and production sector organizations. There are data on human intoxication following consumption of liver or meat from cattle treated with beta-agonists. At the concentrations of clenbuterol measured in contaminated

Agonist-Antagonist Interaction at the Cholinergic Receptor of Denervated Diaphragm,

DTIC Science & Technology

A study has been made of the cholinergic receptor induced by chronic denervation in the rat diaphragm. The agonists acetylcholine, carbachol and...muscle cells. Supramaximally effective doses of agonists caused desensitization of the preparation; however, there was no cross tachyphylaxis between acetylcholine and carbachol . (Author)

Different skeletal effects of the peroxisome proliferator activated receptor (PPAR)α agonist fenofibrate and the PPARγ agonist pioglitazone

PubMed Central

Syversen, Unni; Stunes, Astrid K; Gustafsson, Björn I; Obrant, Karl J; Nordsletten, Lars; Berge, Rolf; Thommesen, Liv; Reseland, Janne E

2009-01-01

Background All the peroxisome proliferator activated receptors (PPARs) are found to be expressed in bone cells. The PPARγ agonist rosiglitazone has been shown to decrease bone mass in mice and thiazolidinediones (TZDs) have recently been found to increase bone loss and fracture risk in humans treated for type 2 diabetes mellitus. The aim of the study was to examine the effect of the PPARα agonist fenofibrate (FENO) and the PPARγ agonist pioglitazone (PIO) on bone in intact female rats. Methods Rats were given methylcellulose (vehicle), fenofibrate or pioglitazone (35 mg/kg body weight/day) by gavage for 4 months. BMC, BMD, and body composition were measured by DXA. Histomorphometry and biomechanical testing of excised femurs were performed. Effects of the compounds on bone cells were studied. Results The FENO group had higher femoral BMD and smaller medullary area at the distal femur; while trabecular bone volume was similar to controls. Whole body BMD, BMC, and trabecular bone volume were lower, while medullary area was increased in PIO rats compared to controls. Ultimate bending moment and energy absorption of the femoral shafts were reduced in the PIO group, while similar to controls in the FENO group. Plasma osteocalcin was higher in the FENO group than in the other groups. FENO stimulated proliferation and differentiation of, and OPG release from, the preosteoblast cell line MC3T3-E1. Conclusion We show opposite skeletal effects of PPARα and γ agonists in intact female rats. FENO resulted in significantly higher femoral BMD and lower medullary area, while PIO induced bone loss and impairment of the mechanical strength. This represents a novel effect of PPARα activation. PMID:19331671

Identification of novel selective V2 receptor non-peptide agonists.

PubMed

Del Tredici, Andria L; Vanover, Kim E; Knapp, Anne E; Bertozzi, Sine M; Nash, Norman R; Burstein, Ethan S; Lameh, Jelveh; Currier, Erika A; Davis, Robert E; Brann, Mark R; Mohell, Nina; Olsson, Roger; Piu, Fabrice

2008-10-30

Peptides with agonist activity at the vasopressin V(2) receptor are used clinically to treat fluid homeostasis disorders such as polyuria and central diabetes insipidus. Of these peptides, the most commonly used is desmopressin, which displays poor bioavailability as well as potent activity at the V(1b) receptor, with possible stress-related adverse effects. Thus, there is a strong need for the development of small molecule chemistries with selective V(2) receptor agonist activity. Using the functional cell-based assay Receptor Selection and Amplification Technology (R-SAT((R))), a screening effort identified three small molecule chemotypes (AC-94544, AC-88324, and AC-110484) with selective agonist activity at the V(2) receptor. One of these compounds, AC-94544, displayed over 180-fold selectivity at the V(2) receptor compared to related vasopressin and oxytocin receptors and no activity at 28 other G protein-coupled receptors (GPCRs). All three compounds also showed partial agonist activity at the V(2) receptor in a cAMP accumulation assay. In addition, in a rat model of central diabetes insipidus, AC-94544 was able to significantly reduce urine output in a dose-dependent manner. Thus, AC-94544, AC-88324, and AC-110484 represent novel opportunities for the treatment of disorders associated with V(2) receptor agonist deficiency.

The estrogen receptor antagonist ICI 182,780 can act both as an agonist and an inverse agonist when estrogen receptor α AF-2 is modified

PubMed Central

Movérare-Skrtic, Sofia; Börjesson, Anna E.; Farman, Helen H.; Sjögren, Klara; Windahl, Sara H.; Lagerquist, Marie K.; Andersson, Annica; Stubelius, Alexandra; Carlsten, Hans; Gustafsson, Jan-Åke; Ohlsson, Claes

2014-01-01

The bone-sparing effect of estrogen is primarily mediated via estrogen receptor (ER) α, which stimulates target gene transcription through two activation functions (AFs), AF-1 in the N-terminal and AF-2 in the ligand-binding domain. It was recently demonstrated that the ER antagonist ICI 182,780 (ICI) acts as an ER agonist in uterus of mice with mutations in the ERα AF-2. To evaluate the estrogen-like effects of ICI in different tissues, ovariectomized wild-type mice and mice with mutations in the ERα AF-2 (ERαAF-20) were treated with ICI, estradiol, or vehicle for 3 wk. Estradiol increased the trabecular and cortical bone mass as well as the uterine weight, whereas it reduced fat mass, thymus weight, and the growth plate height in wild-type but not in ERαAF-20 mice. Although ICI had no effect in wild-type mice, it exerted tissue-specific effects in ERαAF-20 mice. It acted as an ERα agonist on trabecular bone mass and uterine weight, whereas no effect was seen on cortical bone mass, fat mass, or thymus weight. Surprisingly, a pronounced inverse agonistic activity was seen on the growth plate height, resulting in enhanced longitudinal bone growth. In conclusion, ICI uses ERα AF-1 in a tissue-dependent manner in mice lacking ERαAF-2, resulting in no effect, agonistic activity, or inverse agonistic activity. We propose that ERα lacking AF-2 is constitutively active in the absence of ligand in the growth plate, enabling ICI to act as an inverse agonist. PMID:24395795

The estrogen receptor antagonist ICI 182,780 can act both as an agonist and an inverse agonist when estrogen receptor α AF-2 is modified.

PubMed

Movérare-Skrtic, Sofia; Börjesson, Anna E; Farman, Helen H; Sjögren, Klara; Windahl, Sara H; Lagerquist, Marie K; Andersson, Annica; Stubelius, Alexandra; Carlsten, Hans; Gustafsson, Jan-Åke; Ohlsson, Claes

2014-01-21

The bone-sparing effect of estrogen is primarily mediated via estrogen receptor (ER) α, which stimulates target gene transcription through two activation functions (AFs), AF-1 in the N-terminal and AF-2 in the ligand-binding domain. It was recently demonstrated that the ER antagonist ICI 182,780 (ICI) acts as an ER agonist in uterus of mice with mutations in the ERα AF-2. To evaluate the estrogen-like effects of ICI in different tissues, ovariectomized wild-type mice and mice with mutations in the ERα AF-2 (ERαAF-2(0)) were treated with ICI, estradiol, or vehicle for 3 wk. Estradiol increased the trabecular and cortical bone mass as well as the uterine weight, whereas it reduced fat mass, thymus weight, and the growth plate height in wild-type but not in ERαAF-2(0) mice. Although ICI had no effect in wild-type mice, it exerted tissue-specific effects in ERαAF-2(0) mice. It acted as an ERα agonist on trabecular bone mass and uterine weight, whereas no effect was seen on cortical bone mass, fat mass, or thymus weight. Surprisingly, a pronounced inverse agonistic activity was seen on the growth plate height, resulting in enhanced longitudinal bone growth. In conclusion, ICI uses ERα AF-1 in a tissue-dependent manner in mice lacking ERαAF-2, resulting in no effect, agonistic activity, or inverse agonistic activity. We propose that ERα lacking AF-2 is constitutively active in the absence of ligand in the growth plate, enabling ICI to act as an inverse agonist.

Evaluation of novel synthetic TLR7/8 agonists as vaccine adjuvants.

PubMed

Smith, Alyson J; Li, Yufeng; Bazin, Hélène G; St-Jean, Julien R; Larocque, Daniel; Evans, Jay T; Baldridge, Jory R

2016-08-05

Small-molecule adjuvants that boost and direct adaptive immunity provide a powerful means to increase the effectiveness of vaccines. Through rational design several novel imidazoquinoline and oxoadenine TLR7/8 agonists, each with unique molecular modifications, were synthesized and assessed for their ability to augment adaptive immunity. All agonists bound human TLR7 and TLR8 and induced maturation of both human mDCs and pDCs. All agonists prompted production of type I interferon and/or proinflammatory cytokines, albeit with varying potencies. In most in vitro assays, the oxoadenine class of agonists proved more potent than the imidazoquinolines. Therefore, an optimized oxoadenine TLR7/8 agonist that demonstrated maximal activity in the in vitro assays was further assessed in a vaccine study with the CRM197 antigen in a porcine model. Antigen-specific antibody production was greatly enhanced in a dose dependent manner, with antibody titers increased 800-fold compared to titers from pigs vaccinated with the non-adjuvanted vaccine. Moreover, pigs vaccinated with antigen containing the highest dose of adjuvant promoted a 13-fold increase in the percentage of antigen-specific CD3(+)/CD8(+) T cells over pigs vaccinated with antigen alone. Together this work demonstrates the promise of these novel TLR7/8 agonists as effective human vaccine adjuvants. Copyright © 2016 Elsevier Ltd. All rights reserved.

Les effets des interfaces sur les proprietes magnetiques et de transport des multicouches nickel/iron et cobalt/silver

NASA Astrophysics Data System (ADS)

Veres, Teodor

Cette these est consacree a l'etude de l'evolution structurale des proprietes magnetiques et de transport des multicouches Ni/Fe et nanostructures a base de Co et de l'Ag. Dans une premiere partie, essentiellement bibliographique, nous introduisons quelques concepts de base relies aux proprietes magnetiques et de transport des multicouches metalliques. Ensuite, nous presentons une breve description des methodes d'analyse des resultats. La deuxieme partie est consacree a l'etude des proprietes magnetiques et de transport des multicouches ferromagnetiques/ferromagnetiques Ni/Fe. Nous montrerons qu'une interpretation coherente de ces proprietes necessite la prise en consideration des effets des interfaces. Nous nous attacherons a mettre en evidence, a evaluer et a etudier les effets de ces interfaces ainsi que leur evolution, et ce, suite a des traitements thermiques tel que le depot a temperature elevee et l'irradiation ionique. Les analyses correlees de la structure et de la magnetoresistance nous permettront d'emettre des conclusions sur l'influence des couches tampons entre l'interface et le substrat ainsi qu'entre les couches elles-memes sur le comportement magnetique des couches F/F. La troisieme partie est consacree aux systemes a Magneto-Resistance Geante (MRG) a base de Co et Ag. Nous allons etudier l'evolution de la microstructure suite a l'irradiation avec des ions Si+ ayant une energie de 1 MeV, ainsi que les effets de ces changements sur le comportement magnetique. Cette partie debutera par l'analyse des proprietes d'une multicouche hybride, intermediaire entre les multicouches et les materiaux granulaires. Nous analyserons a l'aide des mesures de diffraction, de relaxation superparamagnetique et de magnetoresistance, les evolutions structurales produites par l'irradiation ionique. Nous etablirons des modeles qui nous aideront a interpreter les resultats pour une serie des multicouches qui couvrent un large eventail de differents comportements magnetiques

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…

Caracterisation des proprietes acoustiques des materiaux poreux a cellules ouvertes et a matrice rigide ou souple

NASA Astrophysics Data System (ADS)

Salissou, Yacoubou

L'objectif global vise par les travaux de cette these est d'ameliorer la caracterisation des proprietes macroscopiques des materiaux poreux a structure rigide ou souple par des approches inverses et indirectes basees sur des mesures acoustiques faites en tube d'impedance. La precision des approches inverses et indirectes utilisees aujourd'hui est principalement limitee par la qualite des mesures acoustiques obtenues en tube d'impedance. En consequence, cette these se penche sur quatre problemes qui aideront a l'atteinte de l'objectif global precite. Le premier probleme porte sur une caracterisation precise de la porosite ouverte des materiaux poreux. Cette propriete en est une de passage permettant de lier la mesure des proprietes dynamiques acoustiques d'un materiau poreux aux proprietes effectives de sa phase fluide decrite par les modeles semi-phenomenologiques. Le deuxieme probleme traite de l'hypothese de symetrie des materiaux poreux selon leur epaisseur ou un index et un critere sont proposes pour quantifier l'asymetrie d'un materiau. Cette hypothese est souvent source d'imprecision des methodes de caracterisation inverses et indirectes en tube d'impedance. Le critere d'asymetrie propose permet ainsi de s'assurer de l'applicabilite et de la precision de ces methodes pour un materiau donne. Le troisieme probleme vise a mieux comprendre le probleme de transmission sonore en tube d'impedance en presentant pour la premiere fois un developpement exact du probleme par decomposition d'ondes. Ce developpement permet d'etablir clairement les limites des nombreuses methodes existantes basees sur des tubes de transmission a 2, 3 ou 4 microphones. La meilleure comprehension de ce probleme de transmission est importante puisque c'est par ce type de mesures que des methodes permettent d'extraire successivement la matrice de transfert d'un materiau poreux et ses proprietes dynamiques intrinseques comme son impedance caracteristique et son nombre d'onde complexe. Enfin, le

Endogenous cannabinoid receptor agonists inhibit neurogenic inflammations in guinea pig airways.

PubMed

Yoshihara, Shigemi; Morimoto, Hiroshi; Ohori, Makoto; Yamada, Yumi; Abe, Toshio; Arisaka, Osamu

2005-09-01

Although neurogenic inflammation via the activation of C fibers in the airway must have an important role in the pathogenesis of asthma, their regulatory mechanism remains uncertain. The pharmacological profiles of endogenous cannabinoid receptor agonists on the activation of C fibers in airway tissues were investigated and the mechanisms how cannabinoids regulate airway inflammatory reactions were clarified. The effects of endogenous cannabinoid receptor agonists on electrical field stimulation-induced bronchial smooth muscle contraction, capsaicin-induced bronchoconstriction and capsaicin-induced substance P release in guinea pig airway tissues were investigated. The influences of cannabinoid receptor antagonists and K+ channel blockers to the effects of cannabinoid receptor agonists on these respiratory reactions were examined. Both endogenous cannabinoid receptor agonists, anandamide and palmitoylethanolamide, inhibited electrical field stimulation-induced guinea pig bronchial smooth muscle contraction, but not neurokinin A-induced contraction. A cannabinoid CB2 antagonist, SR 144528, reduced the inhibitory effect of endogenous agonists, but not a cannabinoid CB1 antagonist, SR 141716A. Inhibitory effects of agonists were also reduced by the pretreatment of large conductance Ca2+ -activated K+ channel (maxi-K+ channel) blockers, iberiotoxin and charybdotoxin, but not by other K+ channel blockers, dendrotoxin or glibenclamide. Anandamide and palmitoylethanolamide blocked the capsaicin-induced release of substance P-like immunoreactivity from guinea pig airway tissues. Additionally, intravenous injection of palmitoylethanolamide dose-dependently inhibited capsaicin-induced guinea pig bronchoconstriction, but not neurokinin A-induced reaction. However, anandamide did not reduce capsaicin-induced guinea pig bronchoconstriction. These findings suggest that endogenous cannabinoid receptor agonists inhibit the activation of C fibers via cannabinoid CB2 receptors and

Partial agonist therapy in schizophrenia: relevance to diminished criminal responsibility.

PubMed

Gavaudan, Gilles; Magalon, David; Cohen, Julien; Lançon, Christophe; Léonetti, Georges; Pélissier-Alicot, Anne-Laure

2010-11-01

Pathological gambling (PG), classified in the DSM-IV among impulse control disorders, is defined as inappropriate, persistent gaming for money with serious personal, family, and social consequences. Offenses are frequently committed to obtain money for gambling. Pathological gambling, a planned and structured behavioral disorder, has often been described as a complication of dopamine agonist treatment in patients with Parkinson's disease. It has never been described in patients with schizophrenia receiving dopamine agonists. We present two patients with schizophrenia, previously treated with antipsychotic drugs without any suggestion of PG, who a short time after starting aripiprazole, a dopamine partial agonist, developed PG and criminal behavior, which totally resolved when aripiprazole was discontinued. Based on recent advances in research on PG and adverse drug reactions to dopamine agonists in Parkinson's disease, we postulate a link between aripiprazole and PG in both our patients with schizophrenia and raise the question of criminal responsibility. © 2010 American Academy of Forensic Sciences.

Binary agonist surface patterns prime platelets for downstream adhesion in flowing whole blood.

PubMed

Eichinger, Colin D; Hlady, Vladimir

2017-04-28

As platelets encounter damaged vessels or biomaterials, they interact with a complex milieu of surface-bound agonists, from exposed subendothelium to adsorbed plasma proteins. It has been shown that an upstream, surface-immobilized agonist is capable of priming platelets for enhanced adhesion downstream. In this study, binary agonists were integrated into the upstream position of flow cells and the platelet priming response was measured by downstream adhesion in flowing whole blood. A nonadditive response was observed in which platelets transiently exposed to two agonists exhibited greater activation and downstream adhesion than that from the sum of either agonist alone. Antibody blocking of one of the two upstream agonists eliminated nonadditive activation and downstream adhesion. Crosstalk between platelet activation pathways likely led to a synergistic effect which created an enhanced activation response in the platelet population. The existence of synergy between platelet priming pathways is a concept that has broad implications for the field of biomaterials hemocompatibility and platelet activity testing.

Cholinergic agonists increase intracellular calcium concentration in guinea pig vestibular hair cells.

PubMed

Han, W; Zhang, S; Han, D; Jiang, S; Yang, W

2001-07-01

To better understand the cholinergic receptors in vestibular hair cells (VHC) and their subtypes, and to investigate the effects of cholinergic agonists on intracellular calcium concentration ([Ca2+]i) in guinea pig VHCs. VHCs were isolated from guinea pig crista ampullaris by enzymatic and mechanical methods. The effect of cholinergic agonists on [Ca2+]i was examined using laser scanning confocal microscopy and the Ca2+ sensitive dye Fluo-3. The results showed that the addition of acetylcholine (ACh) and carbachol (CCh), muscamic and nicotinic agonists, induced [Ca2+]i increases in all the VHCs, whereas acetylcholine bromide (ACh-Br), a nicotinic agonist, induced the [Ca2+]i increase in only a small percentage of VHCs. The ACh or CCh-induced Ca2+ response could be partially suppressed by atropine. In the presence of 0.1 mmol/L atropine, the amplitudes of ACh or CCh-induced [Ca2+]i responses became significantly smaller than those in atropine free medium (P < 0.01). The results suggest the existence of cholinergic receptors in guinea pig VHCs. It is the muscamic agonists rather than nicontic receptors that dominate [Ca2+]i variation. Atropine can suppress muscamic agonist-induced Ca2+ responses.

Le role du phytoplancton de petite taille (<20 mum) dans les variations des proprietes optiques des eaux du Saint-Laurent

NASA Astrophysics Data System (ADS)

Mas, Sebastien

Les mesures satellitaires de couleur des oceans sont largement determinees par les proprietes optiques inherentes (IOPs) des eaux de surface. D'autre part, le phytoplancton de petite taille (<20 mum) est le plus souvent dominant dans les oceans, et peut donc etre une source importante de variation des IOPs dans les oceans. Dans ce contexte, le but principal de ce doctorat etait de definir l'impact du phytoplancton (<20 mum) sur les variations des proprietes optiques de l'Estuaire et du Golfe du Saint-Laurent (Canada). Afin d'atteindre cet objectif, il etait necessaire de determiner en milieu controle les facteurs de variabilite des proprietes optiques cellulaires et des IOPs du phytoplancton (<20 mum) des eaux du Saint-Laurent, et d'evaluer la contribution du phytoplancton (<20 mum) aux proprietes optiques totales des eaux du Saint-Laurent. Des experiences en laboratoire ont montre que les variations des proprietes optiques des cellules phytoplanctoniques soumises a un cycle jour-nuit, ainsi qu'a des changements concomitants d'intensite lumineuse, peuvent contribuer significativement a la variabilite des proprietes optiques observee en milieu naturel. D'autres experiences ont, quant a elles, mis en evidence que les variations des proprietes optiques des cellules phytoplanctoniques dues aux phases de croissance peuvent alterer les IOPs des oceans, particulierement pendant les periodes de floraison. De plus, la presence de bacteries et de particules detritiques peut egalement affecter la variabilite des IOPs totales, notamment la diffusion. Au printemps, dans l'Estuaire et le Golfe du Saint-Laurent, la contribution du phytoplancton <20 mum aux IOPs presentait des differences regionales evidentes pour les proprietes d'absorption et de diffusion. En plus de la variabilite spatiale, les proprietes optiques cellulaires presentaient des variations journalieres, et ce particulierement pour le picophytoplancton. Enfin, la plupart des differences observees dans les

PPARgamma agonists inhibit TGF-beta-PKA signaling in glomerulosclerosis.

PubMed

Zou, Rong; Xu, Gang; Liu, Xiao-cheng; Han, Min; Jiang, Jing-jing; Huang, Qian; He, Yong; Yao, Ying

2010-01-01

To study the probable mechanisms of the anti-glomerulosclerosis effects induced by peroxisome proliferator-activated receptor gamma (PPARgamma) agonists in rat intraglomerular mesangial cells (MCs). Cells were transfected with the pTAL-PPRE-tk-Luc(+) plasmid and then treated with different concentrations of PPARgamma agonist, either troglitazone or telmisartan, for the indicated times. Promega luciferase assays were subsequently used for the detection of PPARgamma activation. Protein expression levels were assessed by Western blot, and PepTag assays were used for the non-radioactive detection of protein kinase A (PKA) activity. The deposition of alpha-smooth muscle actin (alpha-SMA) and p-cyclic AMP responsive element binding protein (pCREB) were analyzed by confocal laser scanning. Both troglitazone and telmisartan remarkably inhibit the PKA activation and pCREB expression that is stimulated by TGF-beta. The PPARgamma agonists also inhibited alpha-SMA and collagen IV protein expression by blocking PKA activation. PPARgamma ligands effectively suppress the activation of MCs and the accumulation of collagen IV stimulated by TGF-beta in vitro. The renal protection provided by PPARgamma agonists is partly mediated via their blockade of TGF-beta/PKA signaling.

Adenosine-A1 Receptor Agonist Induced Hyperalgesic Priming Type II

PubMed Central

Araldi, Dioneia; Ferrari, Luiz F.; Levine, Jon D.

2016-01-01

We have recently shown that repeated exposure of the peripheral terminal of the primary afferent nociceptor to the mu-opioid receptor (MOR) agonist DAMGO ([D-Ala2, N-Me-Phe4, Gly5-ol]-Enkephalin acetate salt) induces a model of the transition to chronic pain that we have termed Type II hyperalgesic priming. Similar to Type I hyperalgesic priming, there is a markedly prolonged response to subsequent administration of proalgesic cytokines, prototypically prostaglandin E2 (PGE2). However, Type II hyperalgesic priming differs from Type I in being rapidly induced, protein kinase A (PKA), rather than PKCε dependent, not reversed by a protein translation inhibitor, occurring in female as well as in male rats, and isolectin B4-negative neuron dependent. We report that as with the repeated injection of a MOR agonist, the repeated administration of an agonist at the A1-adenosine receptor, also a Gi-protein coupled receptor, N6-Cyclopentyladenosine (CPA), also produces priming similar to DAMGO-induced Type II hyperalgesic priming. In this study we demonstrate that priming induced by repeated exposure to this A1-adenosine receptor agonist shares the same mechanisms as MOR-agonist induced priming. However, the prolongation of PGE2 hyperalgesia induced by repeated administration of CPA depends on G-protein αi subunit activation, differently from DAMGO-induced Type II priming, in which it depends on the β/γ subunit. These data implicate a novel form of Gi-protein signaling pathway in the Type II hyperalgesic priming induced by repeated administration of an agonist at A1-adenosine receptor to the peripheral terminal of the nociceptor. PMID:26588695

Effect of beta-agonists on LAM progression and treatment.

PubMed

Le, Kang; Steagall, Wendy K; Stylianou, Mario; Pacheco-Rodriguez, Gustavo; Darling, Thomas N; Vaughan, Martha; Moss, Joel

2018-01-30

Lymphangioleiomyomatosis (LAM), a rare disease of women, is associated with cystic lung destruction resulting from the proliferation of abnormal smooth muscle-like LAM cells with mutations in the tuberous sclerosis complex (TSC) genes TSC1 and/or TSC2 The mutant genes and encoded proteins are responsible for activation of the mechanistic target of rapamycin (mTOR), which is inhibited by sirolimus (rapamycin), a drug used to treat LAM. Patients who have LAM may also be treated with bronchodilators for asthma-like symptoms due to LAM. We observed stabilization of forced expiratory volume in 1 s over time in patients receiving sirolimus and long-acting beta-agonists with short-acting rescue inhalers compared with patients receiving only sirolimus. Because beta-agonists increase cAMP and PKA activity, we investigated effects of PKA activation on the mTOR pathway. Human skin TSC2 +/- fibroblasts or LAM lung cells incubated short-term with isoproterenol (beta-agonist) showed a sirolimus-independent increase in phosphorylation of S6, a downstream effector of the mTOR pathway, and increased cell growth. Cells incubated long-term with isoproterenol, which may lead to beta-adrenergic receptor desensitization, did not show increased S6 phosphorylation. Inhibition of PKA blocked the isoproterenol effect on S6 phosphorylation. Thus, activation of PKA by beta-agonists increased phospho-S6 independent of mTOR, an effect abrogated by beta-agonist-driven receptor desensitization. In agreement, retrospective clinical data from patients with LAM suggested that a combination of bronchodilators in conjunction with sirolimus may be preferable to sirolimus alone for stabilization of pulmonary function.

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

PubMed

Randáková, Alena; Dolejší, Eva; Rudajev, Vladimír; Zimčík, 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. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Opioid-receptor subtype agonist-induced enhancements of sucrose intake are dependent upon sucrose concentration.

PubMed

Ruegg, H; Yu, W Z; Bodnar, R J

1997-07-01

Selective mu ([D-Ala2, N-Me-Phe4, Gly-ol5]-enkephalin (DAMGO)), delta1 ([D-Pen2, D-Pen5]-enkephalin (DPDPE)), delta2 ([D-Ala2, Glu4]-Deltorphin (Delt II)), kappa1 (U50488H) and kappa3 (naloxone benzoylhydrazone (NalBzOH)) opioid agonists each stimulate food intake in rats. Whereas studies with selective opioid antagonists implicate mu and kappa1 receptors in the mediation of sucrose intake, studies with selective opioid agonists implicate mu and delta receptors in the mediation of saccharin intake. The present study determined if specific delta1, delta2, kappa1, kappa3 and mu opioid-receptor subtype agonists produced similar alterations in sucrose intake as a function of sucrose concentration (0.5%, 2.5%, 10%) across a 1-h time-course. Each of these agonists significantly increased sucrose intake with variations in pattern, magnitude, and consistency as a function of sucrose concentration. Whereas the mu opioid agonist, DAMGO, and the delta1 opioid agonist, DPDPE, each enhanced sucrose intake at higher (2.5%, 10%), but not lower (0.5%), concentrations, the delta2 opioid agonist, Delt II, increased sucrose intake at lower (0.5%, 2.5%), but not higher (10%), concentrations. Kappa opioid agonists produced less consistent effects. The kappa1 opioid agonist, U50488H, increased sucrose intake at high (10%) concentrations and decreased sucrose intake at low (0.5%) concentrations, and the kappa3 opioid agonist, NalBzOH, inconsistently increased sucrose intake at the 0.5% (20 microg) and 10% (1 microg) concentrations. Thus, these data further implicate mu, delta1, and delta2 opioid mediation of palatable intake, particularly of its orosensory characteristics.

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

PubMed

Howard, Gregory J; Webster, Thomas F

2009-08-07

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.

Mouse hypospadias: A critical examination and definition.

PubMed

Sinclair, Adriane Watkins; Cao, Mei; Shen, Joel; Cooke, Paul; Risbridger, Gail; Baskin, Laurence; Cunha, Gerald R

2016-12-01

Hypospadias is a common malformation whose etiology is based upon perturbation of normal penile development. The mouse has been previously used as a model of hypospadias, despite an unacceptably wide range of definitions for this malformation. The current paper presents objective criteria and a definition of mouse hypospadias. Accordingly, diethylstilbestrol (DES) induced penile malformations were examined at 60 days postnatal (P60) in mice treated with DES over the age range of 12 days embryonic to 20 days postnatal (E12-P20). DES-induced hypospadias involves malformation of the urethral meatus, which is most severe in DES E12-P10, DES P0-P10 and DES P5-P15 groups, and less so or absent in the other treatment groups. A frenulum-like ventral tether between the penis and the prepuce was seen in the most severely affected DES-treated mice. Internal penile morphology was also altered in the DES E12-P10, DES P0-P10 and DES P5-P15 groups (with little effect in the other DES treatment groups). Thus, adverse effects of DES are a function of the period of DES treatment and most severe in the P0-P10 period. In "estrogen mutant mice" (NERKI, βERKO, αERKO and AROM+) hypospadias was only seen in AROM+ male mice having genetically-engineered elevation is serum estrogen. Significantly, mouse hypospadias was only seen distally at and near the urethral meatus where epithelial fusion events are known to take place and never in the penile midshaft, where urethral formation occurs via an entirely different morphogenetic process. Copyright © 2016 International Society of Differentiation. Published by Elsevier B.V. All rights reserved.

Interaction between the mu-agonist dermorphin and the delta-agonist [D-Ala2, Glu4]deltorphin in supraspinal antinociception and delta-opioid receptor binding.

PubMed Central

Negri, L.; Improta, G.; Lattanzi, R.; Potenza, R. L.; Luchetti, F.; Melchiorri, P.

1995-01-01

1. In rats, the interaction between the mu-opioid agonist dermorphin and the delta-opioid agonist [D-Ala2, Glu4]deltorphin was studied in binding experiments to delta-opioid receptors and in the antinociceptive test to radiant heat. 2. When injected i.c.v., doses of [D-Ala2, Glu4]deltorphin higher than 20 nmol produced antinociception in the rat tail-flick test to radiant heat. Lower doses were inactive. None of the doses tested elicited the maximum achievable response. This partial antinociception was accomplished with an in vivo occupancy of more than 97% of brain delta-opioid receptors and of 17% of mu-opioid receptors. Naloxone (0.1 mg kg-1, s.c.), and naloxonazine (10 mg kg-1, i.v., 24 h before), but not the selective delta-opioid antagonist naltrindole, antagonized the antinociception. 3. In vitro competitive inhibition studies in rat brain membranes showed that [D-Ala2, Glu4]deltorphin displaced [3H]-naltrindole from two delta-binding sites of high and low affinity. The addition of 100 microM Gpp[NH]p produced a three fold increase in the [D-Ala2, Glu4]deltorphin Ki value for both binding sites. The addition of 10 nM dermorphin increased the Ki value of the delta-agonist for the high affinity site five times. When Gpp[NH]p was added to the incubation medium together with 10 nM dermorphin, the high affinity Ki of the delta-agonist increased 15 times. 4. Co-administration into the rat brain ventricles of subanalgesic doses of dermorphin and [D-Ala2, Glu4]deltorphin resulted in synergistic antinociceptive responses. 5. Pretreatment with naloxone or with the non-equilibrium mu-antagonists naloxonazine and beta-funaltrexamine completely abolished the antinociceptive response of the mu-delta agonist combinations. 6. Pretreatment with the delta-opioid antagonists naltrindole and DALCE reduced the antinociceptive response of the dermorphin-[D-Ala2, Glu4]deltorphin combinations to a value near that observed after the mu-agonist alone. At the dosage used, naltrindole

Small-molecule agonists for the glucagon-like peptide 1 receptor

PubMed Central

Knudsen, Lotte Bjerre; Kiel, Dan; Teng, Min; Behrens, Carsten; Bhumralkar, Dilip; Kodra, János T.; Holst, Jens J.; Jeppesen, Claus B.; Johnson, Michael D.; de Jong, Johannes Cornelis; Jorgensen, Anker Steen; Kercher, Tim; Kostrowicki, Jarek; Madsen, Peter; Olesen, Preben H.; Petersen, Jacob S.; Poulsen, Fritz; Sidelmann, Ulla G.; Sturis, Jeppe; Truesdale, Larry; May, John; Lau, Jesper

2007-01-01

The peptide hormone glucagon-like peptide (GLP)-1 has important actions resulting in glucose lowering along with weight loss in patients with type 2 diabetes. As a peptide hormone, GLP-1 has to be administered by injection. Only a few small-molecule agonists to peptide hormone receptors have been described and none in the B family of the G protein coupled receptors to which the GLP-1 receptor belongs. We have discovered a series of small molecules known as ago-allosteric modulators selective for the human GLP-1 receptor. These compounds act as both allosteric activators of the receptor and independent agonists. Potency of GLP-1 was not changed by the allosteric agonists, but affinity of GLP-1 for the receptor was increased. The most potent compound identified stimulates glucose-dependent insulin release from normal mouse islets but, importantly, not from GLP-1 receptor knockout mice. Also, the compound stimulates insulin release from perfused rat pancreas in a manner additive with GLP-1 itself. These compounds may lead to the identification or design of orally active GLP-1 agonists. PMID:17213325

The desA and desB genes from Clostridium scindens ATCC 35704 encode steroid-17,20-desmolase.

PubMed

Devendran, Saravanan; Mythen, Sean M; Ridlon, Jason M

2018-06-01

Clostridium scindens is a gut microbe capable of removing the side-chain of cortisol, forming 11β-hydro-xyandrostenedione. A cortisol-inducible operon ( desABCD ) was previously identified in C. scindens ATCC 35704 by RNA-Seq. The desC gene was shown to encode a cortisol 20α-hydroxysteroid dehydrogenase (20α-HSDH). The desD encodes a protein annotated as a member of the major facilitator family, predicted to function as a cortisol transporter. The desA and desB genes are annotated as N-terminal and C-terminal transketolases, respectively. We hypothesized that the DesAB forms a complex and has steroid-17,20-desmolase activity. We cloned the desA and desB genes from C. scindens ATCC 35704 in pETDuet for overexpression in Escherichia coli The purified recombinant DesAB was determined to be a 142 ± 5.4 kDa heterotetramer. We developed an enzyme-linked continuous spectrophotometric assay to quantify steroid-17,20-desmolase. This was achieved by coupling DesAB-dependent formation of 11β-hydroxyandrostenedione with the NADPH-dependent reduction of the steroid 17-keto group by a recombinant 17β-HSDH from the filamentous fungus, Cochliobolus lunatus The pH optimum for the coupled assay was 7.0 and kinetic constants using cortisol as substrate were K m of 4.96 ± 0.57 µM and k cat of 0.87 ± 0.076 min -1 Substrate-specificity studies revealed that rDesAB recognized substrates regardless of 11β-hydroxylation, but had an absolute requirement for 17,21-dihydroxy 20-ketosteroids. Copyright © 2018 Devendran et al.

beta-Adrenoceptor agonists enhance 5-hydroxytryptamine-mediated behavioural responses.

PubMed Central

Cowen, P. J.; Grahame-Smith, D. G.; Green, A. R.; Heal, D. J.

1982-01-01

The beta-adrenoceptor agonists, salbutamol, terbutaline and clenbuterol, were investigated for their effect on 5-hydroxytryptamine-mediated (5-HT) hyperactivity. 2 The lipophilic beta-adrenoceptor agonist, clenbuterol (5 mg/kg) enhanced the behaviours induced by quipazine (25 mg/kg), including headweaving, forepaw treading and hind-limb abduction and thus increased automated activity recording. Clenbuterol (5 mg/kg) also enhanced the hyperactivity syndrome produced by the 5-HT agonist, 5-methoxy N,N-dimethyltryptamine (2 mg/kg) and the combination of tranylcypromine (10 mg/kg) and L-tryptophan (50 mg/kg). Salbutamol and terbutaline potentiated quipazine-induced hyperactivity only when given at the higher dose of 20 mg/kg. 3 The effect of clenbuterol in enhancing quipazine hyperactivity was blocked by the centrally acting beta 1-adrenoceptor antagonist, metoprolol (5 mg/kg), but not by the beta 2-adrenoceptor antagonist, butoxamine (5 mg/kg) or the peripherally acting beta 1-adrenoceptor antagonist, atenolol (5 mg/kg). 4 Clenbuterol (5 mg/kg) did not enhance the circling responses produced by methamphetamine (0.5 mg/kg) in unilateral nigrostriatal-lesioned rats. 5 The results suggest that beta-adrenoceptor agonists in common with some established antidepressant treatments produce enhancement of 5-HT-mediated behavioural responses. PMID:6124294

Long-acting beta 2-agonists in chronic obstructive pulmonary disease.

PubMed

Llewellyn-Jones, Carol

2002-01-01

Until recently, the use of long-acting beta 2-agonists in chronic obstructive pulmonary disease has been understated. There is now evidence that they may offer benefits beyond bronchodilation. This article reviews the management of chronic obstructive pulmonary disease and looks at the place of long-acting beta 2-agonists as a first-line treatment option.

Importance of agonists in alpha-adrenoceptor classification and localisation of alpha1-adrenoceptors in human prostate.

PubMed

McGrath, J C; Naghadeh, M A; Pediani, J D; Mackenzie, J F; Daly, C J

1999-01-01

alpha-Adrenoceptor blocker drugs are commonly used in the clinical (non-surgical) treatment of BPH. alpha1-adrenoceptors were originally sub-divided using agonists but, subsequently, were sub-divided using only antagonists in ligand-ligand interactions, which did not require agonists at all. Ultimately, proof that adrenoceptors are functional receptors for the natural ligands, noradrenaline and adrenaline, requires that agonists be used. The earlier excitement engendered by finding varying agonist potency series in different tissues has not been revisited to place it in the context of current concepts of alpha1-adrenoceptor subtypes. This review will consider the advantages and limitations of different agonists for the study of alpha1-adrenoceptor subtypes including 'extreme' examples where the archetypal alpha1-adrenoceptor agonist phenylephrine activates alpha2-adrenoceptors and others where UK14304, often the alpha2-adrenoceptor agonist of choice, activates alpha1-adrenoceptors. New work will also be presented showing the interaction between agonists and the fluorescent alpha1-adrenoceptor antagonist QAPB. This introduces the novel point of view of studying the displacement of antagonists by agonists. Possible errors in antagonist classification arising from complexity in the actions of agonists and the recently developed method of fluorescent ligand binding on isolated living human prostatic smooth muscle cells will be discussed.

Effets des electrons secondaires sur l'ADN

NASA Astrophysics Data System (ADS)

Boudaiffa, Badia

Les interactions des electrons de basse energie (EBE) representent un element important en sciences des radiations, particulierement, les sequences se produisant immediatement apres l'interaction de la radiation ionisante avec le milieu biologique. Il est bien connu que lorsque ces radiations deposent leur energie dans la cellule, elles produisent un grand nombre d'electrons secondaires (4 x 104/MeV), qui sont crees le long de la trace avec des energies cinetiques initiales bien inferieures a 20 eV. Cependant, il n'y a jamais eu de mesures directes demontrant l'interaction de ces electrons de tres basse energie avec l'ADN, du principalement aux difficultes experimentales imposees par la complexite du milieu biologique. Dans notre laboratoire, les dernieres annees ont ete consacrees a l'etude des phenomenes fondamentaux induits par impact des EBE sur differentes molecules simples (e.g., N2, CO, O2, H2O, NO, C2H 4, C6H6, C2H12) et quelques molecules complexes dans leur phase solide. D'autres travaux effectues recemment sur des bases de l'ADN et des oligonucleotides ont montre que les EBE produisent des bris moleculaires sur les biomolecules. Ces travaux nous ont permis d'elaborer des techniques pour mettre en evidence et comprendre les interactions fondamentales des EBE avec des molecules d'interet biologique, afin d'atteindre notre objectif majeur d'etudier l'effet direct de ces particules sur la molecule d'ADN. Les techniques de sciences des surfaces developpees et utilisees dans les etudes precitees peuvent etre etendues et combinees avec des methodes classiques de biologie pour etudier les dommages de l'ADN induits par l'impact des EBE. Nos experiences ont montre l'efficacite des electrons de 3--20 eV a induire des coupures simple et double brins dans l'ADN. Pour des energies inferieures a 15 eV, ces coupures sont induites par la localisation temporaire d'un electron sur une unite moleculaire de l'ADN, ce qui engendre la formation d'un ion negatif transitoire

Flow-injection chemiluminescence method to detect a β2 adrenergic agonist.

PubMed

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

2015-02-01

A new method for the detection of β2 adrenergic agonists was developed based on the chemiluminescence (CL) reaction of β2 adrenergic agonist with potassium ferricyanide-luminol CL. The effect of β2 adrenergic agonists including isoprenaline hydrochloride, salbutamol sulfate, terbutaline sulfate and ractopamine on the CL intensity of potassium ferricyanide-luminol was discovered. Detection of the β2 adrenergic agonist was carried out in a flow system. Using uniform design experimentation, the influence factors of CL were optimized. The optimal experimental conditions were 1 mmol/L of potassium ferricyanide, 10 µmol/L of luminol, 1.2 mmol/L of sodium hydroxide, a flow speed of 2.6 mL/min and a distance of 1.2 cm from 'Y2 ' to the flow cell. The linear ranges and limit of detection were 10-100 and 5 ng/mL for isoprenaline hydrochloride, 20-100 and 5 ng/mL for salbutamol sulfate, 8-200 and 1 ng/mL for terbutaline sulfate, 20-100 and 4 ng/mL for ractopamine, respectively. The proposed method allowed 200 injections/h with excellent repeatability and precision. It was successfully applied to the determination of three β2 adrenergic agonists in commercial pharmaceutical formulations with recoveries in the range of 96.8-98.5%. The possible CL reaction mechanism of potassium ferricyanide-luminol-β2 adrenergic agonist was discussed from the UV/vis spectra. Copyright © 2014 John Wiley & Sons, Ltd.

Update in TSH Receptor Agonists and Antagonists

PubMed Central

Neumann, Susanne

2012-01-01

The physiological role of the TSH receptor (TSHR) as a major regulator of thyroid function is well understood, but TSHRs are also expressed in multiple normal extrathyroidal tissues, and the physiological roles of TSHRs in these tissues are unclear. Moreover, TSHRs play a major role in several pathological conditions including hyperthyroidism, hypothyroidism, and thyroid tumors. Small molecule, “drug-like” TSHR agonists, neutral antagonists, and inverse agonists may be useful as probes of TSHR function in extrathyroidal tissues and as leads to develop drugs for several diseases of the thyroid. In this Update, we review the most recent findings regarding the development and use of these small molecule TSHR ligands. PMID:23019348

Targeted Delivery of LXR Agonist Using a Site-Specific Antibody-Drug Conjugate.

PubMed

Lim, Reyna K V; Yu, Shan; Cheng, Bo; Li, Sijia; Kim, Nam-Jung; Cao, Yu; Chi, Victor; Kim, Ji Young; Chatterjee, Arnab K; Schultz, Peter G; Tremblay, Matthew S; Kazane, Stephanie A

2015-11-18

Liver X receptor (LXR) agonists have been explored as potential treatments for atherosclerosis and other diseases based on their ability to induce reverse cholesterol transport and suppress inflammation. However, this therapeutic potential has been hindered by on-target adverse effects in the liver mediated by excessive lipogenesis. Herein, we report a novel site-specific antibody-drug conjugate (ADC) that selectively delivers a LXR agonist to monocytes/macrophages while sparing hepatocytes. The unnatural amino acid para-acetylphenylalanine (pAcF) was site-specifically incorporated into anti-CD11a IgG, which binds the α-chain component of the lymphocyte function-associated antigen 1 (LFA-1) expressed on nearly all monocytes and macrophages. An aminooxy-modified LXR agonist was conjugated to anti-CD11a IgG through a stable, cathepsin B cleavable oxime linkage to afford a chemically defined ADC. The anti-CD11a IgG-LXR agonist ADC induced LXR activation specifically in human THP-1 monocyte/macrophage cells in vitro (EC50-27 nM), but had no significant effect in hepatocytes, indicating that payload delivery is CD11a-mediated. Moreover, the ADC exhibited higher-fold activation compared to a conventional synthetic LXR agonist T0901317 (Tularik) (3-fold). This novel ADC represents a fundamentally different strategy that uses tissue targeting to overcome the limitations of LXR agonists for potential use in treating atherosclerosis.

Evaluation of peroxisome proliferator-activated receptor agonists on interleukin-5-induced eosinophil differentiation

PubMed Central

Smith, Steven G; Hill, Mike; Oliveria, John-Paul; Watson, Brittany M; Baatjes, Adrian J; Dua, Benny; Howie, Karen; Campbell, Heather; Watson, Rick M; Sehmi, Roma; Gauvreau, Gail M

2014-01-01

Peroxisome proliferator-activated receptor (PPAR) agonists have been suggested as novel therapeutics for the treatment of inflammatory lung disease, such as allergic asthma. Treatment with PPAR agonists has been shown to inhibit airway eosinophilia in murine models of allergic asthma, which can occur through several mechanisms including attenuated generation of chemoattractants (e.g. eotaxin) and decreased eosinophil migrational responses. In addition, studies report that PPAR agonists can inhibit the differentiation of several cell types. To date, no studies have examined the effects of PPAR agonists on interleukin-5 (IL-5) -induced eosinophil differentiation from haemopoietic progenitor cells. Non-adherent mononuclear cells or CD34+ cells isolated from the peripheral blood of allergic subjects were grown for 2 weeks in Methocult® cultures with IL-5 (10 ng/ml) and IL-3 (25 ng/ml) in the presence of 1–1000 nm PPARα agonist (GW9578), PPARβ/δ agonist (GW501516), PPARγ agonist (rosiglitazone) or diluent. The number of eosinophil/basophil colony-forming units (Eo/B CFU) was quantified by light microscopy. The signalling mechanism involved was assessed by phosphoflow. Blood-extracted CD34+ cells cultured with IL-5 or IL-5 + IL-3 formed Eo/B CFU, which were significantly inhibited by rosiglitazone (100 nm, P < 0·01) but not GW9578 or GW501516. In addition, rosglitazone significantly inhibited IL-5-induced phosphorylation of extracellular signal-regulated kinase 1/2. We observed an inhibitory effect of rosiglitazone on eosinophil differentiation in vitro, mediated by attenuation of the extracellular signal-regulated kinase 1/2 signalling pathway. These findings indicate that the PPARγ agonist can attenuate tissue eosinophilia by interfering with local differentiative responses. PMID:24628018

β-Agonist-mediated Relaxation of Airway Smooth Muscle Is Protein Kinase A-dependent*

PubMed Central

Morgan, Sarah J.; Deshpande, Deepak A.; Tiegs, Brian C.; Misior, Anna M.; Yan, Huandong; Hershfeld, Alena V.; Rich, Thomas C.; Panettieri, Reynold A.; An, Steven S.; Penn, Raymond B.

2014-01-01

Inhaled β-agonists are effective at reversing bronchoconstriction in asthma, but the mechanism by which they exert this effect is unclear and controversial. PKA is the historically accepted effector, although this assumption is made on the basis of associative and not direct evidence. Recent studies have asserted that exchange protein activated by cAMP (Epac), not PKA, mediates the relaxation of airway smooth muscle (ASM) observed with β-agonist treatment. This study aims to clarify the role of PKA in the prorelaxant effects of β-agonists on ASM. Inhibition of PKA activity via expression of the PKI and RevAB peptides results in increased β-agonist-mediated cAMP release, abolishes the inhibitory effect of isoproterenol on histamine-induced intracellular calcium flux, and significantly attenuates histamine-stimulated MLC-20 phosphorylation. Analyses of ASM cell and tissue contraction demonstrate that PKA inhibition eliminates most, if not all, β-agonist-mediated relaxation of contracted smooth muscle. Conversely, Epac knockdown had no effect on the regulation of contraction or procontractile signaling by isoproterenol. These findings suggest that PKA, not Epac, is the predominant and physiologically relevant effector through which β-agonists exert their relaxant effects. PMID:24973219

Self-Administration of Cocaine Induces Dopamine-Independent Self-Administration of Sigma Agonists

PubMed Central

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

2013-01-01

Sigma1 receptors (σ1Rs) are intracellularly mobile chaperone proteins implicated in several disease processes, as well as psychiatric disorders and substance abuse. Here we report that although selective σ1R 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 σ1R agonist. In contrast, after subjects self-administered cocaine σ1R 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 σ1R agonists, extinguished when injections were discontinued, and reconditioned when σ1R agonists again followed responses. Experience with food reinforcement was ineffective as an inducer of σ1R 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 σR 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 σ1R agonists, and that the mechanism underlying these reinforcing effects is dopamine independent. It is further suggested that induced σ1R 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

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 (σ(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 σ(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 σ(1)R agonist. In contrast, after subjects self-administered cocaine σ(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 σ(1)R agonists, extinguished when injections were discontinued, and reconditioned when σ(1)R agonists again followed responses. Experience with food reinforcement was ineffective as an inducer of σ(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 σR 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 σ(1)R agonists, and that the mechanism underlying these reinforcing effects is dopamine independent. It is further suggested that induced σ(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.

Perinatal development of conjugative enzyme systems.

PubMed Central

Lucier, G W

1976-01-01

The problems and priorities involved in studying the role of conjugagive enzymes in developmental pharmacology are discussed and evaluated. The relative rates of UDP glucuronyltransferase and beta-glucuronidase were studied during perinatal development in hepatic and extrahepatic tissues to determine the net balance of glucuronidation or deglucuronidation at different developmental stages. In general, deglucuronidation predominated over glucuronidation in fetal tissues whereas the converse was evident in adults. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), an extremely toxic contaminant of some organochlorine compounds, was shown to be a potent inducer of some hepatic and extrahepatic drug-metabolizing enzymes. TCDD, administered during gestation, induced the postnatal activities of p-nitrophenol glucuronyltransferase and benzpyrene hydroxylase in rats. Foster mother experiments revealed that the postnatal induction was caused primarily by newborn exposure to TCDD in the mother's milk. Tissue distribution experiments with TCDD-14C confirmed these findings. Although TCDD induced non-steroid glucuronidation, no significant effects were evident on the postnatal development of steroid glucuronidation. The synthetic estrogen diethylstilbestrol (DES) is metabolized primarily by glucuronidation. The postnatal development of DES glucuronidation, like the steroid pathway, was not affected by gestational TCDD treatment. The fetal distribution of DES and DES-glucuronide, at different stages of development, correlated well with the perinatal development of steroid glucuronyltransferase activity. PMID:829487

Aircraft Disinsection: A Guide for Military and Civilian Air Carriers (Desinsectisation des aeronefs: Un guide a l’intention des responsables des transports aeriens civils et militaires)

DTIC Science & Technology

1996-04-01

regulations. - Ceratitis capitata (Mediterranean fruit fly). Quarantine regulations generally reduce - Rhagoletis pomonella (Apple maggot). the chances of a...d’insectes nuisibles dans un pays, en 6vitant des risques pour la sant6 des 6quipages, pour la s~curit6 de 1’a~ronef et pour l’industrie. Ce rapport examine 1...diffrrents officiels responsables de la r~glementation des insectes nuisibles introduits, de l’inscription des pesticides et de leur utilisation en

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

Extrinsic factors regulate partial agonist efficacy of strychnine-sensitive glycine receptors

PubMed Central

Farroni, Jeffrey S; McCool, Brian A

2004-01-01

Background Strychnine-sensitive glycine receptors in many adult forebrain regions consist of alpha2 + beta heteromeric channels. This subunit composition is distinct from the alpha1 + beta channels found throughout the adult spinal cord. Unfortunately, the pharmacology of forebrain alpha2beta receptors are poorly defined compared to 'neonatal' alpha2 homomeric channels or 'spinal' alpha1beta heteromers. In addition, the pharmacologic properties of native alpha2beta glycine receptors have been generally distinct from receptors produced by heterologous expression. To identify subtype-specific pharmacologic tools for the forebrain alpha2beta receptors, it is important to identify a heterologous expression system that closely resembles these native glycine-gated chloride channels. Results While exploring pharmacological properties of alpha2beta glycine receptors compared to alpha2-homomers, we found that distinct heterologous expression systems appeared to differentially influence partial agonist pharmacology. The β-amino acid taurine possessed 30–50% efficacy for alpha2-containing receptor isoforms when expressed in HEK 293 cells. However, taurine efficacy was dramatically reduced in L-cell fibroblasts. Similar results were obtained for β-alanine. The efficacy of these partial agonists was also strongly reduced by the beta subunit. There were no significant differences in apparent strychnine affinity values calculated from concentration-response data between expression systems or subunit combinations. Nor did relative levels of expression correlate with partial agonist efficacy when compared within or between several different expression systems. Finally, disruption of the tubulin cytoskeleton reduced the efficacy of partial agonists in a subunit-dependent, but system-independent, fashion. Conclusions Our results suggest that different heterologous expression systems can dramatically influence the agonist pharmacology of strychnine-sensitive glycine receptors. In

Extrinsic factors regulate partial agonist efficacy of strychnine-sensitive glycine receptors.

PubMed

Farroni, Jeffrey S; McCool, Brian A

2004-08-09

Strychnine-sensitive glycine receptors in many adult forebrain regions consist of alpha2 + beta heteromeric channels. This subunit composition is distinct from the alpha1 + beta channels found throughout the adult spinal cord. Unfortunately, the pharmacology of forebrain alpha2beta receptors are poorly defined compared to 'neonatal' alpha2 homomeric channels or 'spinal' alpha1beta heteromers. In addition, the pharmacologic properties of native alpha2beta glycine receptors have been generally distinct from receptors produced by heterologous expression. To identify subtype-specific pharmacologic tools for the forebrain alpha2beta receptors, it is important to identify a heterologous expression system that closely resembles these native glycine-gated chloride channels. While exploring pharmacological properties of alpha2beta glycine receptors compared to alpha2-homomers, we found that distinct heterologous expression systems appeared to differentially influence partial agonist pharmacology. The beta-amino acid taurine possessed 30-50% efficacy for alpha2-containing receptor isoforms when expressed in HEK 293 cells. However, taurine efficacy was dramatically reduced in L-cell fibroblasts. Similar results were obtained for beta-alanine. The efficacy of these partial agonists was also strongly reduced by the beta subunit. There were no significant differences in apparent strychnine affinity values calculated from concentration-response data between expression systems or subunit combinations. Nor did relative levels of expression correlate with partial agonist efficacy when compared within or between several different expression systems. Finally, disruption of the tubulin cytoskeleton reduced the efficacy of partial agonists in a subunit-dependent, but system-independent, fashion. Our results suggest that different heterologous expression systems can dramatically influence the agonist pharmacology of strychnine-sensitive glycine receptors. In the systems examine here

Do agonistic motives matter more than anger? Three studies of cardiovascular risk in adolescents.

PubMed

Ewart, Craig K; Elder, Gavin J; Smyth, Joshua M; Sliwinski, Martin J; Jorgensen, Randall S

2011-09-01

Three motivational profiles have been associated with recurring psychological stress in low-income youth and young adults: Striving to control others (agonistic striving), striving to control the self (transcendence striving), and not asserting control (dissipated striving). Agonistic striving has been associated with elevated ambulatory blood pressure during daily activities. Three studies tested the hypotheses that: (1) agonistic striving is associated with poor anger regulation, and (2) agonistic striving and poor anger regulation interactively elevate blood pressure. Motivational profiles, anger regulation, and ambulatory blood pressure were assessed in a multiethnic sample of 264 urban youth. (1) anger regulation/recovery during laboratory challenge; (2) anger/blood pressure during daily activities (48 hours). Replication of the profiles in distant cities showed they occur with similar frequency across differences of region, race, and gender. Analyses controlling for body size, race, and gender revealed that individuals with the agonistic striving profile had higher ambulatory pressure, especially during social encounters. They became more openly angry and aggressive when challenged but did not exhibit difficulty regulating anger in the laboratory, nor did they feel angrier during monitoring. However, individuals with the agonistic striving profile who did display poor anger regulation in the lab had the highest blood pressure; deficient self-regulatory capability amplified the positive association between agonistic striving and cardiovascular risk in both genders and all ethnic groups. Although anger is thought to increase cardiovascular risk, present findings suggest that anger and elevated blood pressure are coeffects of agonistic struggles to control others.

Etude des phenomenes dynamiques ultrarapides et des caracteristiques impulsionnelles d'emission terahertz du supraconducteur YBCO

NASA Astrophysics Data System (ADS)

Savard, Stephane

Les premieres etudes d'antennes a base de supraconducteurs a haute temperature critique emettant une impulsion electromagnetique dont le contenu en frequence se situe dans le domaine terahertz remontent a 1996. Une antenne supraconductrice est formee d'un micro-pont d'une couche mince supraconductrice sur lequel un courant continu est applique. Un faisceau laser dans le visible est focalise sur le micro-pont et place le supraconducteur dans un etat hors-equilibre ou des paires sont brisees. Grace a la relaxation des quasiparticules en surplus et eventuellement de la reformation des paires supraconductrices, nous pouvons etudier la nature de la supraconductivite. L'analyse de la cinetique temporelle du champ electromagnetique emis par une telle antenne terahertz supraconductrice s'est averee utile pour decrire qualitativement les caracteristiques de celle-ci en fonction des parametres d'operation tels que le courant applique, la temperature et la puissance d'excitation. La comprehension de l'etat hors-equilibre est la cle pour comprendre le fonctionnement des antennes terahertz supraconductrices a haute temperature critique. Dans le but de comprendre ultimement cet etat hors-equilibre, nous avions besoin d'une methode et d'un modele pour extraire de facon plus systematique les proprietes intrinseques du materiau qui compose l'antenne terahertz a partir des caracteristiques d'emission de celle-ci. Nous avons developpe une procedure pour calibrer le spectrometre dans le domaine temporel en utilisant des antennes terahertz de GaAs bombarde aux protons H+ comme emetteur et detecteur. Une fois le montage calibre, nous y avons insere une antenne emettrice dipolaire de YBa 2Cu3O7-delta . Un modele avec des fonctions exponentielles de montee et de descente du signal est utilise pour lisser le spectre du champ electromagnetique de l'antenne de YBa 2Cu3O7-delta, ce qui nous permet d'extraire les proprietes intrinseques de ce dernier. Pour confirmer la validite du modele

Developpement d'une methode calorimetrique de mesure des pertes ac pour des rubans supraconducteurs a haute temperature critique

NASA Astrophysics Data System (ADS)

Dolez, Patricia

Le travail de recherche effectue dans le cadre de ce projet de doctorat a permis la mise au point d'une methode de mesure des pertes ac destinee a l'etude des supraconducteurs a haute temperature critique. Pour le choix des principes de cette methode, nous nous sommes inspires de travaux anterieurs realises sur les supraconducteurs conventionnels, afin de proposer une alternative a la technique electrique, presentant lors du debut de cette these des problemes lies a la variation du resultat des mesures selon la position des contacts de tension sur la surface de l'echantillon, et de pouvoir mesurer les pertes ac dans des conditions simulant la realite des futures applications industrielles des rubans supraconducteurs: en particulier, cette methode utilise la technique calorimetrique, associee a une calibration simultanee et in situ. La validite de la methode a ete verifiee de maniere theorique et experimentale: d'une part, des mesures ont ete realisees sur des echantillons de Bi-2223 recouverts d'argent ou d'alliage d'argent-or et comparees avec les predictions theoriques donnees par Norris, nous indiquant la nature majoritairement hysteretique des pertes ac dans nos echantillons; d'autre part, une mesure electrique a ete realisee in situ dont les resultats correspondent parfaitement a ceux donnes par notre methode calorimetrique. Par ailleurs, nous avons compare la dependance en courant et en frequence des pertes ac d'un echantillon avant et apres qu'il ait ete endommage. Ces mesures semblent indiquer une relation entre la valeur du coefficient de la loi de puissance modelisant la dependance des pertes avec le courant, et les inhomogeneites longitudinales du courant critique induites par l'endommagement. De plus, la variation en frequence montre qu'au niveau des grosses fractures transverses creees par l'endommagement dans le coeur supraconducteur, le courant se partage localement de maniere a peu pres equivalente entre les quelques grains de matiere

Evaluation of peroxisome proliferator-activated receptor agonists on interleukin-5-induced eosinophil differentiation.

PubMed

Smith, Steven G; Hill, Mike; Oliveria, John-Paul; Watson, Brittany M; Baatjes, Adrian J; Dua, Benny; Howie, Karen; Campbell, Heather; Watson, Rick M; Sehmi, Roma; Gauvreau, Gail M

2014-07-01

Peroxisome proliferator-activated receptor (PPAR) agonists have been suggested as novel therapeutics for the treatment of inflammatory lung disease, such as allergic asthma. Treatment with PPAR agonists has been shown to inhibit airway eosinophilia in murine models of allergic asthma, which can occur through several mechanisms including attenuated generation of chemoattractants (e.g. eotaxin) and decreased eosinophil migrational responses. In addition, studies report that PPAR agonists can inhibit the differentiation of several cell types. To date, no studies have examined the effects of PPAR agonists on interleukin-5 (IL-5) -induced eosinophil differentiation from haemopoietic progenitor cells. Non-adherent mononuclear cells or CD34(+) cells isolated from the peripheral blood of allergic subjects were grown for 2 weeks in Methocult(®) cultures with IL-5 (10 ng/ml) and IL-3 (25 ng/ml) in the presence of 1-1000 nm PPARα agonist (GW9578), PPARβ/δ agonist (GW501516), PPARγ agonist (rosiglitazone) or diluent. The number of eosinophil/basophil colony-forming units (Eo/B CFU) was quantified by light microscopy. The signalling mechanism involved was assessed by phosphoflow. Blood-extracted CD34(+) cells cultured with IL-5 or IL-5 + IL-3 formed Eo/B CFU, which were significantly inhibited by rosiglitazone (100 nm, P < 0·01) but not GW9578 or GW501516. In addition, rosglitazone significantly inhibited IL-5-induced phosphorylation of extracellular signal-regulated kinase 1/2. We observed an inhibitory effect of rosiglitazone on eosinophil differentiation in vitro, mediated by attenuation of the extracellular signal-regulated kinase 1/2 signalling pathway. These findings indicate that the PPARγ agonist can attenuate tissue eosinophilia by interfering with local differentiative responses. © 2014 John Wiley & Sons Ltd.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Matsushita, Akitomo; Ohtsubo, Sena; Fujita, Tsugumi

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

Cartographie des disques

NASA Astrophysics Data System (ADS)

Hameury, Jean-Marie

2001-01-01

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

Antimitogenic effect of bitter taste receptor agonists on airway smooth muscle cells

PubMed Central

Sharma, Pawan; Panebra, Alfredo; Pera, Tonio; Tiegs, Brian C.; Hershfeld, Alena; Kenyon, Lawrence C.

2015-01-01

Airway remodeling is a hallmark feature of asthma and chronic obstructive pulmonary disease. Clinical studies and animal models have demonstrated increased airway smooth muscle (ASM) mass, and ASM thickness is correlated with severity of the disease. Current medications control inflammation and reverse airway obstruction effectively but have limited effect on remodeling. Recently we identified the expression of bitter taste receptors (TAS2R) on ASM cells, and activation with known TAS2R agonists resulted in ASM relaxation and bronchodilation. These studies suggest that TAS2R can be used as new therapeutic targets in the treatment of obstructive lung diseases. To further establish their effectiveness, in this study we aimed to determine the effects of TAS2R agonists on ASM growth and promitogenic signaling. Pretreatment of healthy and asthmatic human ASM cells with TAS2R agonists resulted in a dose-dependent inhibition of ASM proliferation. The antimitogenic effect of TAS2R ligands was not dependent on activation of protein kinase A, protein kinase C, or high/intermediate-conductance calcium-activated K+ channels. Immunoblot analyses revealed that TAS2R agonists inhibit growth factor-activated protein kinase B phosphorylation without affecting the availability of phosphatidylinositol 3,4,5-trisphosphate, suggesting TAS2R agonists block signaling downstream of phosphatidylinositol 3-kinase. Furthermore, the antimitogenic effect of TAS2R agonists involved inhibition of induced transcription factors (activator protein-1, signal transducer and activator of transcription-3, E2 factor, nuclear factor of activated T cells) and inhibition of expression of multiple cell cycle regulatory genes, suggesting a direct inhibition of cell cycle progression. Collectively, these findings establish the antimitogenic effect of TAS2R agonists and identify a novel class of receptors and signaling pathways that can be targeted to reduce or prevent airway remodeling as well as

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

Structure and biological activity of endogenous and synthetic agonists of GPR119

NASA Astrophysics Data System (ADS)

Tyurenkov, I. N.; Ozerov, A. A.; Kurkin, D. V.; Logvinova, E. O.; Bakulin, D. A.; Volotova, E. V.; Borodin, D. D.

2018-02-01

A G-protein-coupled receptor, GPR119, is a promising pharmacological target for a new class of hypoglycaemic drugs with an original mechanism of action, namely, increase in the glucose-dependent incretin and insulin secretion. In 2005, the first ligands were found and in the subsequent years, a large number of GPR119 agonists were synthesized in laboratories in various countries; the safest and most promising agonists have entered phase I and II clinical trials as agents for the treatment of type 2 diabetes mellitus and obesity. The review describes the major endogenous GPR119 agonists and the main trends in the design and modification of synthetic structures for increasing the hypoglycaemic activity. The data on synthetic agonists are arranged according to the type of the central core of the molecules. The bibliography includes 104 references.

β-Agonist-mediated relaxation of airway smooth muscle is protein kinase A-dependent.

PubMed

Morgan, Sarah J; Deshpande, Deepak A; Tiegs, Brian C; Misior, Anna M; Yan, Huandong; Hershfeld, Alena V; Rich, Thomas C; Panettieri, Reynold A; An, Steven S; Penn, Raymond B

2014-08-15

Inhaled β-agonists are effective at reversing bronchoconstriction in asthma, but the mechanism by which they exert this effect is unclear and controversial. PKA is the historically accepted effector, although this assumption is made on the basis of associative and not direct evidence. Recent studies have asserted that exchange protein activated by cAMP (Epac), not PKA, mediates the relaxation of airway smooth muscle (ASM) observed with β-agonist treatment. This study aims to clarify the role of PKA in the prorelaxant effects of β-agonists on ASM. Inhibition of PKA activity via expression of the PKI and RevAB peptides results in increased β-agonist-mediated cAMP release, abolishes the inhibitory effect of isoproterenol on histamine-induced intracellular calcium flux, and significantly attenuates histamine-stimulated MLC-20 phosphorylation. Analyses of ASM cell and tissue contraction demonstrate that PKA inhibition eliminates most, if not all, β-agonist-mediated relaxation of contracted smooth muscle. Conversely, Epac knockdown had no effect on the regulation of contraction or procontractile signaling by isoproterenol. These findings suggest that PKA, not Epac, is the predominant and physiologically relevant effector through which β-agonists exert their relaxant effects. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Do Agonistic Motives Matter More Than Anger? Three Studies of Cardiovascular Risk in Adolescents

PubMed Central

Ewart, Craig K.; Elder, Gavin J.; Smyth, Joshua M.; Sliwinski, Martin J.; Jorgensen, Randall S.

2011-01-01

Objective Three motivational profiles have been associated with recurring psychological stress in low-income youth and young adults: Striving to control others (agonistic striving), striving to control the self (transcendence striving), and not asserting control (dissipated striving); Agonistic Striving has been associated with elevated ambulatory blood pressure during daily activities. Three studies tested the hypotheses that: (1) Agonistic Striving is associated with poor anger regulation, and (2) Agonistic Striving and poor anger regulation interactively elevate blood pressure. Design Motivational profiles, anger regulation, and ambulatory blood pressure were assessed in a multiethnic sample of 264 urban youth. Main outcome measures (1) Anger regulation/recovery during laboratory challenge; (2) anger / blood pressure during daily activities (48 hours). Results and conclusion Replication of the profiles in distant cities showed they occur with similar frequency across differences of region, race, and gender. Analyses controlling for body size, race, and gender revealed that individuals with the Agonistic Striving profile had higher ambulatory pressure, especially during social encounters. They became more openly angry and aggressive when challenged, but did not exhibit difficulty regulating anger in the laboratory, nor did they feel more angry during monitoring. However, individuals with the Agonistic Striving profile who did display poor anger regulation in the lab had the highest blood pressure; deficient self-regulatory capability amplified the positive association between Agonistic Striving and cardiovascular risk in both genders and all ethnic groups. Although anger is thought to increase cardiovascular risk, present findings suggest that anger and elevated blood pressure are co-effects of agonistic struggles to control others. PMID:21534673

Bitter taste receptor agonists alter mitochondrial function and induce autophagy in airway smooth muscle cells.

PubMed

Pan, Shi; Sharma, Pawan; Shah, Sushrut D; Deshpande, Deepak A

2017-07-01

Airway remodeling, including increased airway smooth muscle (ASM) mass, is a hallmark feature of asthma and COPD. We previously identified the expression of bitter taste receptors (TAS2Rs) on human ASM cells and demonstrated that known TAS2R agonists could promote ASM relaxation and bronchodilation and inhibit mitogen-induced ASM growth. In this study, we explored cellular mechanisms mediating the antimitogenic effect of TAS2R agonists on human ASM cells. Pretreatment of ASM cells with TAS2R agonists chloroquine and quinine resulted in inhibition of cell survival, which was largely reversed by bafilomycin A1, an autophagy inhibitor. Transmission electron microscope studies demonstrated the presence of double-membrane autophagosomes and deformed mitochondria. In ASM cells, TAS2R agonists decreased mitochondrial membrane potential and increased mitochondrial ROS and mitochondrial fragmentation. Inhibiting dynamin-like protein 1 (DLP1) reversed TAS2R agonist-induced mitochondrial membrane potential change and attenuated mitochondrial fragmentation and cell death. Furthermore, the expression of mitochondrial protein BCL2/adenovirus E1B 19-kDa protein-interacting protein 3 (Bnip3) and mitochondrial localization of DLP1 were significantly upregulated by TAS2R agonists. More importantly, inhibiting Bnip3 mitochondrial localization by dominant-negative Bnip3 significantly attenuated cell death induced by TAS2R agonist. Collectively the TAS2R agonists chloroquine and quinine modulate mitochondrial structure and function, resulting in ASM cell death. Furthermore, Bnip3 plays a central role in TAS2R agonist-induced ASM functional changes via a mitochondrial pathway. These findings further establish the cellular mechanisms of antimitogenic effects of TAS2R agonists and identify a novel class of receptors and pathways that can be targeted to mitigate airway remodeling as well as bronchoconstriction in obstructive airway diseases. Copyright © 2017 the American Physiological

Cholecystokinin type B receptor antagonist PD-136,450 is a partial secretory agonist in the stomach and a full agonist in the pancreas of the rat.

PubMed Central

Schmassmann, A; Garner, A; Flogerzi, B; Hasan, M Y; Sanner, M; Varga, L; Halter, F

1994-01-01

Gastrin (cholecystokinin type B (CCK-B)) receptor antagonists may help to elucidate the physiological role of gastrin, have therapeutic potential as acid antisecretory drugs, and may be of use as adjuvant therapy for gastrin sensitive tumours. In binding studies, the gastrin receptor antagonist PD-136,450 had at least 1000 fold greater affinity for gastrin (CCK-B) than CCK-A receptors. In this study the biological activity of PD-136,450 was evaluated in conscious and anaesthetised rats. PD-136,450 antagonised gastrin stimulated acid secretion after subcutaneous (IC50: 0.28 mumol/kg; conscious rats) and intravenous (IC50: 0.17 mumol/kg; anaesthetised rats) administration. In basal secreting fistula animals, the compound stimulated acid output to 30 (5)% of the maximal response to gastrin. Stimulant activity was not caused by gastrin release. As an agonist PD-136,450 was about 350 times less potent than gastrin-17 on a molar basis. In addition, PD-136,450 was a powerful agonist of pancreatic secretion in anaesthetised rats. The specific gastrin antagonist L-365,260 inhibited the (partial) agonist activity of PD-136,450 in the stomach and the specific CCK-A receptor antagonist L-364,718 inhibited the agonist activity of PD-136,450 in the pancreas. It is concluded that the agonist effect of PD-136,450 is mediated via interaction with the gastrin (CCK-B) receptor in the stomach and the CCK-A receptor in the pancreas. PMID:8307482

3D-Pharmacophore Identification for κ-Opioid Agonists Using Ligand-Based Drug-Design Techniques

NASA Astrophysics Data System (ADS)

Yamaotsu, Noriyuki; Hirono, Shuichi

A selective κ-opioid receptor (KOR) agonist might act as a powerful analgesic without the side effects of μ-opioid receptor-selective drugs such as morphine. The eight classes of known KOR agonists have different chemical structures, making it difficult to construct a pharmacophore model that takes them all into account. Here, we summarize previous efforts to identify the pharmacophore for κ-opioid agonists and propose a new three-dimensional pharmacophore model that encompasses the κ-activities of all classes. This utilizes conformational sampling of agonists by high-temperature molecular dynamics and pharmacophore extraction through a series of molecular superpositions.

The Influence of Gender, Age, Matriline and Hierarchical Rank on Individual Social Position, Role and Interactional Patterns in Macaca sylvanus at 'La Forêt des Singes': A Multilevel Social Network Approach.

PubMed

Sosa, Sebastian

2016-01-01

A society is a complex system composed of individuals that can be characterized by their own attributes that influence their behaviors. In this study, a specific analytical protocol based on social network analysis was adopted to investigate the influence of four attributes (gender, age, matriline, and hierarchical rank) on affiliative (allogrooming) and agonistic networks in a non-human primate species, Macaca sylvanus, at the park La Forêt des Singes in France. The results show significant differences with respect to the position (i.e., centric, peripheral) and role (i.e., implication in the network cohesiveness) of an individual within a social network and hence interactional patterns. Females are more central, more active, and have a denser ego network in the affiliative social network tan males; thus, they contribute in a greater way to the cohesive structure of the network. High-ranking individuals are likely to receive fewer agonistic behaviors than low-ranking individuals, and high-ranking females receive more allogrooming. I also observe homophily for affiliative interactions regarding all attributes and homophily for agonistic interactions regarding gender and age. Revealing the positions, the roles, and the interactional behavioral patterns of individuals can help understand the mechanisms that shape the overall structure of a social network.

Effets perturbateurs endocriniens des pesticides organochlores.

PubMed

Charlier, C; Plomteux, G

2002-01-01

Xenoestrogens such organochlorine pesticides are known to induce changes in reproductive development, function or behaviour in wildlife. Because these compounds are able to modify the estrogens metabolism, or to compete with estradiol for binding to the estrogen receptor, it may be possible that these products affect the risk of developing impaired fertility, precocious puberty or some kinds of cancer in man. Le plus ancien récit de lutte contre la pollution remonte à une légende indienne racontant que la divinité Sing-bonga était incommodée par les émanations des fours dans lesquels les Asuras fondaient leurs métaux (1). Evidemment depuis, la problématique n-a cessé de s-accroître et la contamination de la Terre par de nombreux polluants est devenue aujourd-hui un problème majeur de notre Société. La protection de notre environnement est une question capitale qui doit être respectée malgré la pression économique actuelle et qui ne cessera de croître au cours des prochaines années même si l-identification objective et indiscutable de ce qui est essentiel - donc devant être prioritairement garanti sur la planète - est difficile à cerner (2). « Un oiseau en mauvais état ne pond pas de bons oeufs » disait un proverbe grec. Mais ce n-est qu-à partir de la seconde moitié du XXème siècle que les toxicologues ont commencé à identifier les effets qu-avaient entraînés à l-échelle mondiale les pollutions émises aux XIXème siècle sur la faune sauvage et sur le cheptel (3). L-histoire contemporaine des pesticides industriels commence vers 1874 (synthèse des organochlorés) et se poursuit tout au long de ces 2 siècles en passant par la synthèse des organophosphorés (1950), des carbamates (1970) et des pyréthroïdes (1975) (4). Le dichlorodiphényltrichloroéthane (DDT) a été synthétisé pour la première fois par un étudiant en cours de préparation de sa thèse de doctorat : Othmer Zeidler. La production, reprise par les

The glycine transport inhibitor sarcosine is an inhibitory glycine receptor agonist.

PubMed

Zhang, Hai Xia; Lyons-Warren, Ariel; Thio, Liu Lin

2009-01-01

Sarcosine is an endogenous amino acid that is a competitive inhibitor of the type I glycine transporter (GlyT1), an N-methyl-d-aspartate receptor (NMDAR) co-agonist, and an important intermediate in one-carbon metabolism. Its therapeutic potential for schizophrenia further underscores its clinical importance. The structural similarity between sarcosine and glycine and sarcosine's ability to serve as an NMDAR co-agonist led us to examine whether sarcosine is also an agonist at the inhibitory glycine receptor (GlyR). We examined this possibility using whole-cell recordings from cultured embryonic mouse hippocampal neurons and found that sarcosine evoked a dose-dependent, strychnine sensitive, Cl(-) current that cross-inhibited glycine currents. Sarcosine evoked this current with Li(+) in the extracellular solution to block GlyT1, in neurons treated with the essentially irreversible GlyT1 inhibitor N[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)propyl]sarcosine (NFPS), and in neurons plated in the absence of glia. These results indicate that the sarcosine currents did not result from GlyT1 inhibition or heteroexchange. We conclude that sarcosine is a GlyR agonist.

Differential profile of typical, atypical and third generation antipsychotics at human 5-HT7a receptors coupled to adenylyl cyclase: detection of agonist and inverse agonist properties.

PubMed

Rauly-Lestienne, Isabelle; Boutet-Robinet, Elisa; Ailhaud, Marie-Christine; Newman-Tancredi, Adrian; Cussac, Didier

2007-10-01

5-HT(7) receptors are present in thalamus and limbic structures, and a possible role of these receptors in the pathology of schizophrenia has been evoked. In this study, we examined binding affinity and agonist/antagonist/inverse agonist properties at these receptors of a large series of antipsychotics, i.e., typical, atypical, and third generation compounds preferentially targeting D(2) and 5-HT(1A) sites. Adenylyl cyclase (AC) activity was measured in HEK293 cells stably expressing the human (h) 5-HT(7a) receptor isoform. 5-HT and 5-CT increased cyclic adenosine monophosphate level by about 20-fold whereas (+)-8-OH-DPAT, the antidyskinetic agent sarizotan, and the novel antipsychotic compound bifeprunox exhibited partial agonist properties at h5-HT(7a) receptors stimulating AC. Other compounds antagonized 5-HT-induced AC activity with pK (B) values which correlated with their pK (i) as determined by competition binding vs [(3)H]5-CT. The selective 5-HT(7) receptor ligand, SB269970, was the most potent antagonist. For antipsychotic compounds, the following rank order of antagonism potency (pK (B)) was ziprasidone > tiospirone > SSR181507 > or = clozapine > or = olanzapine > SLV-314 > SLV-313 > or = aripiprazole > or = chlorpromazine > nemonapride > haloperidol. Interestingly, pretreatment of HEK293-h5-HT(7a) cells with forskolin enhanced basal AC activity and revealed inverse agonist properties for both typical and atypical antipsychotics as well as for aripiprazole. In contrast, other novel antipsychotics exhibited diverse 5-HT(7a) properties; SLV-313 and SLV-314 behaved as quasi-neutral antagonists, SSR181507 acted as an inverse agonist, and bifeprunox as a partial agonist, as mentioned above. In conclusion, the differential properties of third generation antipsychotics at 5-HT(7) receptors may influence their antipsychotic profile.

Platelet-activating factor receptor agonists mediate xeroderma pigmentosum A photosensitivity.

PubMed

Yao, Yongxue; Harrison, Kathleen A; Al-Hassani, Mohammed; Murphy, Robert C; Rezania, Samin; Konger, Raymond L; Travers, Jeffrey B

2012-03-16

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-α 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.

Identification des parametres du moteur de l'avion Cessna Citation X pour la phase de croisiere a partir des tests en vol et a base des reseaux de neurones =

NASA Astrophysics Data System (ADS)

Zaag, Mahdi

La disponibilite des modeles precis des avions est parmi les elements cles permettant d'assurer leurs ameliorations. Ces modeles servent a ameliorer les commandes de vol et de concevoir de nouveaux systemes aerodynamiques pour la conception des ailes deformables des avions. Ce projet consiste a concevoir un systeme d'identification de certains parametres du modele du moteur de l'avion d'affaires americain Cessna Citation X pour la phase de croisiere a partir des essais en vol. Ces essais ont ete effectues sur le simulateur de vol concu et fabrique par CAE Inc. qui possede le niveau D de la dynamique de vol. En effet, le niveau D est le plus haut niveau de precision donne par l'autorite federale de reglementation FAA de l'aviation civile aux Etats-Unis. Une methodologie basee sur les reseaux de neurones optimises a l'aide d'un algorithme intitule le "grand deluge etendu" est utilisee dans la conception de ce systeme d'identification. Plusieurs tests de vol pour differentes altitudes et differents nombres de Mach ont ete realises afin de s'en servir comme bases de donnees pour l'apprentissage des reseaux de neurones. La validation de ce modele a ete realisee a l'aide des donnees du simulateur. Malgre la nonlinearite et la complexite du systeme, les parametres du moteur ont ete tres bien predits pour une enveloppe de vol determinee. Ce modele estime pourrait etre utilise pour des analyses de fonctionnement du moteur et pourrait assurer le controle de l'avion pendant cette phase de croisiere. L'identification des parametres du moteur pourrait etre realisee aussi pour les autres phases de montee et de descente afin d'obtenir son modele complet pour toute l'enveloppe du vol de l'avion Cessna Citation X (montee, croisiere, descente). Cette methode employee dans ce travail pourrait aussi etre efficace pour realiser un modele pour l'identification des coefficients aerodynamiques du meme avion a partir toujours des essais en vol. None None None

Induction of selective blood-tumor barrier permeability and macromolecular transport by a biostable kinin B1 receptor agonist in a glioma rat model.

PubMed

Côté, Jérôme; Bovenzi, Veronica; Savard, Martin; Dubuc, Céléna; Fortier, Audrey; Neugebauer, Witold; Tremblay, Luc; Müller-Esterl, Werner; Tsanaclis, Ana-Maria; Lepage, Martin; Fortin, David; Gobeil, Fernand

2012-01-01

Treatment of malignant glioma with chemotherapy is limited mostly because of delivery impediment related to the blood-brain tumor barrier (BTB). B1 receptors (B1R), inducible prototypical G-protein coupled receptors (GPCR) can regulate permeability of vessels including possibly that of brain tumors. Here, we determine the extent of BTB permeability induced by the natural and synthetic peptide B1R agonists, LysdesArg(9)BK (LDBK) and SarLys[dPhe(8)]desArg(9)BK (NG29), in syngeneic F98 glioma-implanted Fischer rats. Ten days after tumor inoculation, we detected the presence of B1R on tumor cells and associated vasculature. NG29 infusion increased brain distribution volume and uptake profiles of paramagnetic probes (Magnevist and Gadomer) at tumoral sites (T(1)-weighted imaging). These effects were blocked by B1R antagonist and non-selective cyclooxygenase inhibitors, but not by B2R antagonist and non-selective nitric oxide synthase inhibitors. Consistent with MRI data, systemic co-administration of NG29 improved brain tumor delivery of Carboplatin chemotherapy (ICP-Mass spectrometry). We also detected elevated B1R expression in clinical samples of high-grade glioma. Our results documented a novel GPCR-signaling mechanism for promoting transient BTB disruption, involving activation of B1R and ensuing production of COX metabolites. They also underlined the potential value of synthetic biostable B1R agonists as selective BTB modulators for local delivery of different sized-therapeutics at (peri)tumoral sites.

Elaboration de nouvelles approches micromecaniques pour l'optimisation des performances mecaniques des materiaux heterogenes

NASA Astrophysics Data System (ADS)

Aboutajeddine, Ahmed

Les modeles micromecaniques de transition d'echelles qui permettent de determiner les proprietes effectives des materiaux heterogenes a partir de la microstructure sont consideres dans ce travail. L'objectif est la prise en compte de la presence d'une interphase entre la matrice et le renforcement dans les modeles micromecaniques classiques, de meme que la reconsideration des approximations de base de ces modeles, afin de traiter les materiaux multiphasiques. Un nouveau modele micromecanique est alors propose pour tenir compte de la presence d'une interphase elastique mince lors de la determination des proprietes effectives. Ce modele a ete construit grace a l'apport de l'equation integrale, des operateurs interfaciaux de Hill et de la methode de Mori-Tanaka. Les expressions obtenues pour les modules globaux et les champs dans l'enrobage sont de nature analytique. L'approximation de base de ce modele est amelioree par la suite dans un nouveau modele qui s'interesse aux inclusions enrobees avec un enrobage mince ou epais. La resolution utilisee s'appuie sur une double homogeneisation realisee au niveau de l'inclusion enrobee et du materiau. Cette nouvelle demarche, permettra d'apprehender completement les implications des approximations de la modelisation. Les resultats obtenus sont exploites par la suite dans la solution de l'assemblage de Hashin. Ainsi, plusieurs modeles micromecaniques classiques d'origines differentes se voient unifier et rattacher, dans ce travail, a la representation geometrique de Hashin. En plus de pouvoir apprecier completement la pertinence de l'approximation de chaque modele dans cette vision unique, l'extension correcte de ces modeles aux materiaux multiphasiques est rendue possible. Plusieurs modeles analytiques et explicites sont alors proposee suivant des solutions de differents ordres de l'assemblage de Hashin. L'un des modeles explicite apparait comme une correction directe du modele de Mori-Tanaka, dans les cas ou celui ci echoue a

Relation entre les caractéristiques des table-bancs et les mesures anthropométriques des écoliers au Benin

PubMed Central

Falola, Stève Marjelin; Gouthon, Polycarpe; Falola, Jean-Marie; Fiogbe, Michel Armand; Nigan, Issiako Bio

2014-01-01

Introduction Le mobilier scolaire et la posture assise en classe sont souvent impliqués dans l'apparition des douleurs rachidiennes, influant de fait sur la qualité des tâches réalisées par les apprenants. Aucune étude n'a encore vérifié le degré d'adéquation entre les caractéristiques du mobilier et celles des écoliers au Bénin. L'objectif de cette étude transversale est donc de déterminer la relation entre les dimensions des table-bancs utilisées en classe et les mesures anthropométriques des écoliers au Bénin. Methods Elle a été réalisée avec un échantillon probabiliste de 678 écoliers, âgés de 4 à 17 ans. Les mesures anthropométriques des écoliers et les mensurations relatives aux longueurs, largeurs et hauteurs des table-bancs ont été mesurées, puis intégrées aux équations proposées dans la littérature. Les pourcentages des valeurs situées hors des limitesacceptables, dérivées de l'application des équations ont été calculés. Results La largeur et la hauteur des table-bancs utilisées par les écoliers étaient plus élevées (p < 0,05) que les valeurs de référence recommandées par les structures officielles de contrôle et de production des mobiliers scolaires au Bénin. Quel que soit le sexe, il y avait une inadéquation entre la largeur du banc et la longueur fesse-poplité, puis entre la hauteur de la table et la distance coude-bancdes écoliers. Conclusion Les résultats suggèrent de prendre en compte l’évolution des mesures anthropométriques des écoliers dans la confection des table-bancs, afin de promouvoir de bonnes postures assises en classe et de réduire le risque de troubles du rachis. PMID:25317232

The therapeutic potential of nicotinic acetylcholine receptor agonists for pain control.

PubMed

Decker, M W; Meyer, M D; Sullivan, J P

2001-10-01

Due to the limitations of currently available analgesics, a number of novel alternatives are currently under investigation, including neuronal nicotinic acetylcholine receptor (nAChR) agonists. During the 1990s, the discovery of the antinociceptive properties of the potent nAChR agonist epibatidine in rodents sparked interest in the analgesic potential of this class of compounds. Although epibatidine also has several mechanism-related toxicities, the identification of considerable nAChR diversity suggested that the toxicities and therapeutic actions of the compound might be mediated by distinct receptor subtypes. Consistent with this view, a number of novel nAChR agonists with antinociceptive activity and improved safety profiles in preclinical models have now been identified, including A-85380, ABT-594, DBO-83, SIB-1663 and RJR-2403. Of these, ABT-594 is the most advanced and is currently in Phase II clinical evaluation. Nicotinically-mediated antinociception has been demonstrated in a variety of rodent pain models and is likely mediated by the activation of descending inhibitory pathways originating in the brainstem with the predominant high-affinity nicotine site in brain, the alpha4beta2 subtype, playing a critical role. Thus, preclinical findings suggest that nAChR agonists have the potential to be highly efficacious treatments in a variety of pain states. However, clinical proof-of-principle studies will be required to determine if nAChR agonists are active in pathological pain.

The Influence of Gender, Age, Matriline and Hierarchical Rank on Individual Social Position, Role and Interactional Patterns in Macaca sylvanus at ‘La Forêt des Singes’: A Multilevel Social Network Approach

PubMed Central

Sosa, Sebastian

2016-01-01

A society is a complex system composed of individuals that can be characterized by their own attributes that influence their behaviors. In this study, a specific analytical protocol based on social network analysis was adopted to investigate the influence of four attributes (gender, age, matriline, and hierarchical rank) on affiliative (allogrooming) and agonistic networks in a non-human primate species, Macaca sylvanus, at the park La Forêt des Singes in France. The results show significant differences with respect to the position (i.e., centric, peripheral) and role (i.e., implication in the network cohesiveness) of an individual within a social network and hence interactional patterns. Females are more central, more active, and have a denser ego network in the affiliative social network tan males; thus, they contribute in a greater way to the cohesive structure of the network. High-ranking individuals are likely to receive fewer agonistic behaviors than low-ranking individuals, and high-ranking females receive more allogrooming. I also observe homophily for affiliative interactions regarding all attributes and homophily for agonistic interactions regarding gender and age. Revealing the positions, the roles, and the interactional behavioral patterns of individuals can help understand the mechanisms that shape the overall structure of a social network. PMID:27148137

Profil épidémiologique des tumeurs malignes primitives des glandes salivaires : à propos de 154 cas

PubMed Central

Setti, Khadija; Mouanis, Mohamed; Moumni, Abdelmounim; Maher, Mostafa; Harmouch, Amal

2014-01-01

Introduction Les tumeurs des glandes salivaires sont des tumeurs rares représentant 3à 5% des tumeurs de la tête et du cou. La classification de l'OMS 2005 distingue les tumeurs épithéliales, les tumeurs mésenchymateuses, les tumeurs hématologiques et les tumeurs secondaires. Méthodes Notre travail consiste en une étude rétrospective réalisée sur une période de 10 ans allant de janvier 2002 à janvier 2012. Les critères d'inclusion étaient: l'âge, le sexe, le siège de la tumeur et le type histologique. Résultats L'incidence annuelle des tumeurs malignes primitives des glandes salivaires dans notre série était de 15 cas par an. Cent cinquante quatre cas de tumeurs malignes primitives des glandes salivaires ont été colligés sans prédominance de sexe (78 femmes (50,6%) et 76 hommes (49,4%)). La moyenne d'âge était de 60 ans avec des extrêmes de 4 et 83 ans et un pic de fréquence entre 51et 70 ans. Deux tiers des cas (65%) avaient une localisation au niveau des glandes principales avec 66 cas au niveau de la parotide (43%) et 34 cas au niveau de la glande sous maxillaire (22%). Cinquante quatre patients avaient une tumeur maligne des glandes salivaires accessoires (35%) dont 61% au niveau du palais. Aucun cas de tumeur maligne de la glande sublinguale n'a été recensé dans notre étude. Le type histologique prédominant dans notre série était le carcinome adénoïde kystique et retrouvé chez 43 patients (27,9%), suivi de l'adénocarcinome sans autre indication chez 37 patients (24%) puis du carcinome mucoépidermoïde chez 16 patients (10,4%) et de l'adénocarcinome polymorphe de bas grade également chez 16 patients (10. 4%). Conclusion Les tumeurs malignes des glandes salivaires représentent un ensemble hétérogène de maladies de caractérisation complexe et de fréquence variable. PMID:25120861

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

PubMed

Fernández-García, José Carlos; Colomo, Natalia; Tinahones, Francisco José

2014-01-01

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

Using XML to encode TMA DES metadata.

PubMed

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

2011-01-01

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

Using XML to encode TMA DES metadata

PubMed Central

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

2011-01-01

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

Comparative gene expression profiles induced by PPAR{gamma} and PPAR{alpha}/{gamma} agonists in rat hepatocytes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rogue, Alexandra; Universite de Rennes 1, 35065 Rennes Cedex; Biologie Servier, 45520 Gidy

2011-07-01

Species-differential toxic effects have been described with PPAR{alpha} and PPAR{gamma} agonists between rodent and human liver. PPAR{alpha} agonists (fibrates) are potent hypocholesterolemic agents in humans while they induce peroxisome proliferation and tumors in rodent liver. By contrast, PPAR{gamma} agonists (glitazones) and even dual PPAR{alpha}/{gamma} agonists (glitazars) have caused idiosyncratic hepatic and nonhepatic toxicities in human without evidence of any damage in rodent during preclinical studies. The mechanisms involved in such differences remain largely unknown. Several studies have identified the major target genes of PPAR{alpha} agonists in rodent liver while no comprehensive analysis has been performed on gene expression changes inducedmore » by PPAR{gamma} and dual PPAR{alpha}/{gamma} agonists. Here, we investigated transcriptomes of rat hepatocytes after 24 h treatment with two PPAR{gamma} (troglitazone and rosiglitazone) and two PPAR{alpha}/{gamma} (muraglitazar and tesaglitazar) agonists. Although, hierarchical clustering revealed a gene expression profile characteristic of each PPAR agonist class, only a limited number of genes was specifically deregulated by glitazars. Functional analyses showed that many genes known as PPAR{alpha} targets were also modulated by both PPAR{gamma} and PPAR{alpha}/{gamma} agonists and quantitative differences in gene expression profiles were observed between these two classes. Moreover, most major genes modulated in rat hepatocytes were also found to be deregulated in rat liver after tesaglitazar treatment. Taken altogether, these results support the conclusion that differential toxic effects of PPAR{alpha} and PPAR{gamma} agonists in rodent liver do not result from transcriptional deregulation of major PPAR target genes but rather from qualitative and/or quantitative differential responses of a small subset of genes.« less

Les soins aux enfants et aux adolescents des familles des militaires canadiens : les considérations particulières

PubMed Central

Rowan-Legg, Anne

2017-01-01

Résumé Les familles des militaires font face à de nombreux facteurs de stress, tels que les réinstallations fréquentes, les longues pério des de séparation familiale, l’isolement géographique du réseau de soutien de la famille élargie et le déploiement en zones très dangereuses. Les enfants et les adolescents des familles des militaires vivent les mêmes trajectoires développementales et motivationnelles que leurs homologues civils, mais ils sont également aux prises avec des pressions et des facteurs de stress liés à leur développement qui sont inhabituels et qui leur sont imposés par les exigences de la vie militaire. Les effets de la vie militaire sur les familles et les enfants commencent à être admis et mieux caractérisés. Il est essentiel de comprendre les préoccupations propres aux enfants et aux adolescents des familles des militaires et de mobiliser les ressources nécessaires pour les soutenir afin de répondre à leurs besoins en matière de santé.

Lignes directrices canadiennes sur l’utilisation sécuritaire et efficace des opioïdes pour la douleur chronique non cancéreuse

PubMed Central

Kahan, Meldon; Wilson, Lynn; Mailis-Gagnon, Angela; Srivastava, Anita

2011-01-01

Résumé Objectif Présenter aux médecins de famille un résumé clinique pratique sur la prescription d’opioïdes à des populations particulières en se fondant sur les recommandations faites dans les lignes directrices canadiennes sur l’utilisation sécuritaire et efficace des opioïdes pour la douleur chronique non cancéreuse. Qualité des données Pour produire les lignes directrices, les chercheurs ont effectué une synthèse critique de la littérature médicale en insistant plus précisément sur les études de l’efficacité et de la sécurité des opioïdes dans des populations particulières. Message principal Les médecins de famille peuvent atténuer les risques de surdose, de sédation, d’usage abusif et de dépendance grâce à des stratégies adaptées à l’âge et à l’état de santé des patients. Dans le cas de patients à risque de dépendance, on devrait réserver les opioïdes aux douleurs nociceptives ou neuropathiques bien définies qui n’ont pas répondu aux traitements de première intention. Il faut procéder lentement au titrage des opioïdes, avec des dispensations fréquentes et une étroite surveillance pour dépister tout signe d’usage abusif. Une dépendance aux opioïdes suspectée est prise en charge au moyen d’une thérapie structurée aux opioïdes, d’un traitement à la méthadone ou à la buprénorphine ou encore d’un traitement fondé sur l’abstinence. Les patients souffrant de troubles de l’humeur ou d’anxiété ont tendance à avoir une réponse analgésique atténuée aux opioïdes, sont à risque plus élevé d’usage abusif et prennent souvent des sédatifs qui interagissent défavorablement avec les opioïdes. Il faut prendre des précautions semblables à celles utilisées avec d’autres patients à risque élevé. Il faut faire un sevrage progressif si la douleur du patient demeure sévère même avec un essai adéquat de thérapie aux opioïdes. Chez les personnes âgées, la s

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

PubMed Central

2010-01-01

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

L'astronomie des Anciens

NASA Astrophysics Data System (ADS)

Nazé, Yaël

2009-04-01

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

The Role of Agonistic Striving in the Association Between Cortisol and High Blood Pressure.

PubMed

Ewart, Craig K; Elder, Gavin J; Jorgensen, Randall S; Fitzgerald, Sheila T

2017-05-01

A social action theory of chronic stress proposes that agonistic striving (seeking to influence or control others) impairs cardiovascular health by magnifying the impact of high adversity-induced cortisol levels on blood pressure. We tested three predictions of social action theory: (1) the social action theory taxonomy of regulatory strivings characterizes young adults from high-adversity neighborhoods; (2) high cortisol levels predict high blood pressure more reliably in the subgroup with the agonistic striving profile than in subgroups with other profiles; (3) the association of higher cortisol and higher blood pressure with agonistic striving is not explained by negative affect (depressive symptoms/dysphoria, anger, hostility). Participants were young adults (N = 198, mean [SD] age = 32 [3.4] years); 71% female; 65% black) from disadvantaged urban neighborhoods. Motive profiles (including agonistic strivings) were assessed using the Social Competence Interview. Cortisol levels were derived from saliva samples; blood pressure level was obtained during two days of ambulatory monitoring. Psychological measures of negative affect were assessed using questionnaires. The predicted taxonomy of regulatory strivings was replicated in this sample; the interaction between cortisol and motive profile was significant (F(2, 91) = 6.72, p = .002); analyses of simple effects disclosed that higher cortisol levels predicted higher ambulatory blood pressure only in individuals who exhibited agonistic striving. Depressive symptoms/dysphoria, trait anger, and hostility were not correlated with agonistic striving, cortisol, or blood pressure. Agonistic striving may represent a distinctive (and novel) social-cognitive mechanism of toxic stress and cardiovascular risk.

Determination of beta-agonists in swine hair by μFIA and chemiluminescence.

PubMed

Chen, Xu; Luo, Yong; Shi, Bo; Gao, Zhigang; Du, Yuguang; Liu, Xianming; Zhao, Weijie; Lin, Bingcheng

2015-04-01

β-Agonists are a group of illegal feed additives. In this paper, it was found that the light emission produced by the oxidation of luminol by potassium ferricyanide was enhanced by the β-agonists (ractopamine, salbutamol, and terbutaline). Based on chemiluminescence phenomenon, a novel, rapid, and sensitive microflow injection analysis system on a microfluidic glass chip was established for determination of the β-agonists. The chip was fabricated from two glass plates (64 mm × 32 mm) with microchannels of 200 μm width and 100 μm depth. The detection limits were achieved at 2.0 × 10(-8) mol/L of ractopamine, 1.0 × 10(-8) mol/L of terbutaline and 5.0 × 10(-7) mol/L of salbutamol. In this report, our method was applied for determination of the β-agonists in swine hair from three different sources with satisfactory results. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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.

Antimitogenic effect of bitter taste receptor agonists on airway smooth muscle cells.

PubMed

Sharma, Pawan; Panebra, Alfredo; Pera, Tonio; Tiegs, Brian C; Hershfeld, Alena; Kenyon, Lawrence C; Deshpande, Deepak A

2016-02-15

Airway remodeling is a hallmark feature of asthma and chronic obstructive pulmonary disease. Clinical studies and animal models have demonstrated increased airway smooth muscle (ASM) mass, and ASM thickness is correlated with severity of the disease. Current medications control inflammation and reverse airway obstruction effectively but have limited effect on remodeling. Recently we identified the expression of bitter taste receptors (TAS2R) on ASM cells, and activation with known TAS2R agonists resulted in ASM relaxation and bronchodilation. These studies suggest that TAS2R can be used as new therapeutic targets in the treatment of obstructive lung diseases. To further establish their effectiveness, in this study we aimed to determine the effects of TAS2R agonists on ASM growth and promitogenic signaling. Pretreatment of healthy and asthmatic human ASM cells with TAS2R agonists resulted in a dose-dependent inhibition of ASM proliferation. The antimitogenic effect of TAS2R ligands was not dependent on activation of protein kinase A, protein kinase C, or high/intermediate-conductance calcium-activated K(+) channels. Immunoblot analyses revealed that TAS2R agonists inhibit growth factor-activated protein kinase B phosphorylation without affecting the availability of phosphatidylinositol 3,4,5-trisphosphate, suggesting TAS2R agonists block signaling downstream of phosphatidylinositol 3-kinase. Furthermore, the antimitogenic effect of TAS2R agonists involved inhibition of induced transcription factors (activator protein-1, signal transducer and activator of transcription-3, E2 factor, nuclear factor of activated T cells) and inhibition of expression of multiple cell cycle regulatory genes, suggesting a direct inhibition of cell cycle progression. Collectively, these findings establish the antimitogenic effect of TAS2R agonists and identify a novel class of receptors and signaling pathways that can be targeted to reduce or prevent airway remodeling as well as

Implementation Cryptography Data Encryption Standard (DES) and Triple Data Encryption Standard (3DES) Method in Communication System Based Near Field Communication (NFC)

NASA Astrophysics Data System (ADS)

Ratnadewi; Pramono Adhie, Roy; Hutama, Yonatan; Saleh Ahmar, A.; Setiawan, M. I.

2018-01-01

Cryptography is a method used to create secure communication by manipulating sent messages during the communication occurred so only intended party that can know the content of that messages. Some of the most commonly used cryptography methods to protect sent messages, especially in the form of text, are DES and 3DES cryptography method. This research will explain the DES and 3DES cryptography method and its use for stored data security in smart cards that working in the NFC-based communication system. Several things that will be explained in this research is the ways of working of DES and 3DES cryptography method in doing the protection process of a data and software engineering through the creation of application using C++ programming language to realize and test the performance of DES and 3DES cryptography method in encrypted data writing process to smart cards and decrypted data reading process from smart cards. The execution time of the entering and the reading process data using a smart card DES cryptography method is faster than using 3DES cryptography.

Effects of oxytocin on serotonin 1B agonist-induced autism-like behavior in mice.

PubMed

Lawson, Sarah K; Gray, Andrew C; Woehrle, Nancy S

2016-11-01

Social impairments in autism remain poorly understood and without approved pharmacotherapies. Novel animals models are needed to elucidate mechanisms and evaluate novel treatments for the social deficits in autism. Recently, serotonin 1B receptor (5-HT1B) agonist challenge in mice was shown to induce autism-like behaviors including perseveration, reduced prepulse inhibition, and delayed alternation deficits. However, the effects of 5-HT1B agonists on autism-related social behaviors in mice remain unknown. Here, we examine the effects of 5-HT1B agonist challenge on sociability and preference for social novelty in mice. We also examine the effects of 5-HT1B agonist treatment on average rearing duration, a putative rodent measure of non-selective attention. Non-selective attention is an associated feature of autism that is also not well understood. We show that 5-HT1B receptor activation reduces sociability, preference for social novelty, and rearing in mice. In addition, we examine the ability of oxytocin, an off-label treatment for the social impairments in autism, to reverse 5-HT1B agonist-induced social and attention deficits in mice. We show that oxytocin restores social novelty preference in mice treated with a 5-HT1B agonist. We also show that oxytocin attenuates 5-HT1B agonist-induced sociability and rearing deficits in mice. Our results suggest that 5-HT1B agonist challenge provides a useful pharmacological mouse model for aspects of autism, and implicate 5-HT1B in autism social and attention deficits. Moreover, our findings suggest that oxytocin may treat the social deficits in autism through a mechanism involving 5-HT1B. Copyright © 2016 Elsevier B.V. All rights reserved.

Systematic review: cardiovascular safety profile of 5-HT(4) agonists developed for gastrointestinal disorders.

PubMed

Tack, J; Camilleri, M; Chang, L; Chey, W D; Galligan, J J; Lacy, B E; Müller-Lissner, S; Quigley, E M M; Schuurkes, J; De Maeyer, J H; Stanghellini, V

2012-04-01

The nonselective 5-HT(4) receptor agonists, cisapride and tegaserod have been associated with cardiovascular adverse events (AEs). To perform a systematic review of the safety profile, particularly cardiovascular, of 5-HT(4) agonists developed for gastrointestinal disorders, and a nonsystematic summary of their pharmacology and clinical efficacy. Articles reporting data on cisapride, clebopride, prucalopride, mosapride, renzapride, tegaserod, TD-5108 (velusetrag) and ATI-7505 (naronapride) were identified through a systematic search of the Cochrane Library, Medline, Embase and Toxfile. Abstracts from UEGW 2006-2008 and DDW 2008-2010 were searched for these drug names, and pharmaceutical companies approached to provide unpublished data. Retrieved articles on pharmacokinetics, human pharmacodynamics and clinical data with these 5-HT(4) agonists, are reviewed and summarised nonsystematically. Articles relating to cardiac safety and tolerability of these agents, including any relevant case reports, are reported systematically. Two nonselective 5-HT(4) agonists had reports of cardiovascular AEs: cisapride (QT prolongation) and tegaserod (ischaemia). Interactions with, respectively, the hERG cardiac potassium channel and 5-HT(1) receptor subtypes have been suggested to account for these effects. No cardiovascular safety concerns were reported for the newer, selective 5-HT(4) agonists prucalopride, velusetrag, naronapride, or for nonselective 5-HT(4) agonists with no hERG or 5-HT(1) affinity (renzapride, clebopride, mosapride). 5-HT(4) agonists for GI disorders differ in chemical structure and selectivity for 5-HT(4) receptors. Selectivity for 5-HT(4) over non-5-HT(4) receptors may influence the agent's safety and overall risk-benefit profile. Based on available evidence, highly selective 5-HT(4) agonists may offer improved safety to treat patients with impaired GI motility. © 2012 Blackwell Publishing Ltd.

Systematic review: cardiovascular safety profile of 5-HT4 agonists developed for gastrointestinal disorders

PubMed Central

Tack, J; Camilleri, M; Chang, L; Chey, W D; Galligan, J J; Lacy, B E; Müller-Lissner, S; Quigley, E M M; Schuurkes, J; Maeyer, J H; Stanghellini, V

2012-01-01

Summary Background The nonselective 5-HT4 receptor agonists, cisapride and tegaserod have been associated with cardiovascular adverse events (AEs). Aim To perform a systematic review of the safety profile, particularly cardiovascular, of 5-HT4 agonists developed for gastrointestinal disorders, and a nonsystematic summary of their pharmacology and clinical efficacy. Methods Articles reporting data on cisapride, clebopride, prucalopride, mosapride, renzapride, tegaserod, TD-5108 (velusetrag) and ATI-7505 (naronapride) were identified through a systematic search of the Cochrane Library, Medline, Embase and Toxfile. Abstracts from UEGW 2006–2008 and DDW 2008–2010 were searched for these drug names, and pharmaceutical companies approached to provide unpublished data. Results Retrieved articles on pharmacokinetics, human pharmacodynamics and clinical data with these 5-HT4 agonists, are reviewed and summarised nonsystematically. Articles relating to cardiac safety and tolerability of these agents, including any relevant case reports, are reported systematically. Two nonselective 5-HT4 agonists had reports of cardiovascular AEs: cisapride (QT prolongation) and tegaserod (ischaemia). Interactions with, respectively, the hERG cardiac potassium channel and 5-HT1 receptor subtypes have been suggested to account for these effects. No cardiovascular safety concerns were reported for the newer, selective 5-HT4 agonists prucalopride, velusetrag, naronapride, or for nonselective 5-HT4 agonists with no hERG or 5-HT1 affinity (renzapride, clebopride, mosapride). Conclusions 5-HT4 agonists for GI disorders differ in chemical structure and selectivity for 5-HT4 receptors. Selectivity for 5-HT4 over non-5-HT4 receptors may influence the agent's safety and overall risk–benefit profile. Based on available evidence, highly selective 5-HT4 agonists may offer improved safety to treat patients with impaired GI motility. PMID:22356640

Beta2-adrenoceptor agonists for dysmenorrhoea.

PubMed

Fedorowicz, Zbys; Nasser, Mona; Jagannath, Vanitha A; Beaman, Jessica H; Ejaz, Kiran; van Zuuren, Esther J

2012-05-16

Dysmenorrhoea is a common gynaecological complaint that can affect as many as 50% of premenopausal women, 10% of whom suffer severely enough to be rendered incapacitated for one to three days during each menstrual cycle. Primary dysmenorrhoea is where women suffer from menstrual pain but lack any pathology in their pelvic anatomy. Beta2-adrenoceptor agonists have been used in the treatment of women with primary dysmenorrhoea but their effects are unclear. To determine the effectiveness and safety of beta2-adrenoceptor agonists in the treatment of primary dysmenorrhoea. We searched the Cochrane Menstrual Disorders and Subfertility Group Specialised Register; CENTRAL (The Cochrane Library 2011, Issue 8); MEDLINE; EMBASE; PsycINFO and the EBM Reviews databases. The last search was on 22 August 2011. Randomised controlled trials comparing beta2-adrenoceptor agonists with placebo or no treatment, each other or any other conventional treatment in women of reproductive age with primary dysmenorrhoea. Two review authors independently assessed trial quality and extracted the data. Five trials involving 187 women with an age range of 15 to 40 years were included. Oral isoxsuprine was compared with placebo in two trials; terbutaline oral spray, ritodrine chloride and oral hydroxyphenyl-orciprenalin were compared with placebo in a further three trials. Clinical diversity in the studies in terms of the interventions being evaluated, assessments at different time points and the use of different assessment tools mitigated against pooling of outcome data across studies in order to provide a summary estimate of effect for any of the comparisons. Only one study, with unclear risk of bias, reported pain relief with a combination of isoxsuprine, acetaminophen and caffeine. None of the other studies reported any significant clinical difference in effectiveness between the intervention and placebo. Adverse effects were reported with all of these medications in up to a quarter of the

Targeting GLP-1 receptor trafficking to improve agonist efficacy.

PubMed

Jones, Ben; Buenaventura, Teresa; Kanda, Nisha; Chabosseau, Pauline; Owen, Bryn M; Scott, Rebecca; Goldin, Robert; Angkathunyakul, Napat; Corrêa, Ivan R; Bosco, Domenico; Johnson, Paul R; Piemonti, Lorenzo; Marchetti, Piero; Shapiro, A M James; Cochran, Blake J; Hanyaloglu, Aylin C; Inoue, Asuka; Tan, Tricia; Rutter, Guy A; Tomas, Alejandra; Bloom, Stephen R

2018-04-23

Glucagon-like peptide-1 receptor (GLP-1R) activation promotes insulin secretion from pancreatic beta cells, causes weight loss, and is an important pharmacological target in type 2 diabetes (T2D). Like other G protein-coupled receptors, the GLP-1R undergoes agonist-mediated endocytosis, but the functional and therapeutic consequences of modulating GLP-1R endocytic trafficking have not been clearly defined. Here, we investigate a series of biased GLP-1R agonists with variable propensities for GLP-1R internalization and recycling. Compared to a panel of FDA-approved GLP-1 mimetics, compounds that retain GLP-1R at the plasma membrane produce greater long-term insulin release, which is dependent on a reduction in β-arrestin recruitment and faster agonist dissociation rates. Such molecules elicit glycemic benefits in mice without concomitant increases in signs of nausea, a common side effect of GLP-1 therapies. Our study identifies a set of agents with specific GLP-1R trafficking profiles and the potential for greater efficacy and tolerability as T2D treatments.

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

PubMed

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

2009-06-01

Phenolic beta(2)-adrenoreceptor agonists salbutamol, fenoterol, and terbutaline relax smooth muscle cells that relieve acute airway bronchospasm associated with asthma. Why their use sometimes fails to relieve bronchospasm and why the drugs appear to be less effective in patients with severe asthma exacerbations remains unclear. We show that in the presence of hydrogen peroxide, both myeloperoxidase, secreted by activated neutrophils present in inflamed airways, and lactoperoxidase, which is naturally present in the respiratory system, catalyze oxidation of these beta(2)-agonists. Azide, cyanide, thiocyanate, ascorbate, glutathione, and methimazole inhibited this process, while methionine was without effect. Inhibition by ascorbate and glutathione was associated with their oxidation to corresponding radical species by the agonists' derived phenoxyl radicals. Using electron paramagnetic resonance (EPR), we detected free radical metabolites from beta(2)-agonists by spin trapping with 2-methyl-2-nitrosopropane (MNP). Formation of these radicals was inhibited by pharmacologically relevant concentrations of methimazole and dapsone. In alkaline buffers, radicals from fenoterol and its structural analogue, metaproteronol, were detected by direct EPR. Analysis of these spectra suggests that oxidation of fenoterol and metaproterenol, but not terbutaline, causes their transformation through intramolecular cyclization by addition of their amino nitrogen to the aromatic ring. Together, these results indicate that phenolic beta(2)-agonists function as substrates for airway peroxidases and that the resulting products differ in their structural and functional properties from their parent compounds. They also suggest that these transformations can be modulated by pharmacological approaches using appropriate peroxidase inhibitors or alternative substrates. These processes may affect therapeutic efficacy and also play a role in adverse reactions of the beta(2)-agonists.

NOP Receptor Mediates Anti-analgesia Induced by Agonist-Antagonist Opioids

PubMed Central

Gear, Robert W.; Bogen, Oliver; Ferrari, Luiz F.; Green, Paul G.; Levine, Jon D.

2014-01-01

Clinical studies have shown that agonist-antagonist opioid analgesics that produce their analgesic effect via action on the kappa-opioid receptor, produce a delayed-onset anti-analgesia in men but not women, an effect blocked by co-administration of a low dose of naloxone. We now report the same time-dependent anti-analgesia and its underlying mechanism in an animal model. Using the Randall-Selitto paw-withdrawal assay in male rats, we found that nalbuphine, pentazocine, and butorphanol each produced analgesia during the first hour followed by anti-analgesia starting at ~90 minutes after administration in males but not females, closely mimicking its clinical effects. As observed in humans, co-administration of nalbuphine with naloxone in a dose ratio of 12.5:1 blocked anti-analgesia but not analgesia. Administration of the highly selective kappa-opioid receptor agonist U69,593 produced analgesia without subsequent anti-analgesia, and confirmed by the failure of the selective kappa antagonist nor-binaltorphimine to block nalbuphine-induced anti-analgesia, indicating that anti-analgesia is not mediated by kappa-opioid receptors. We therefore tested the role of other receptors in nalbuphine anti-analgesia. Nociceptin/orphanin FQ (NOP) and sigma-1 and sigma-2 receptors were chosen on the basis of their known anti-analgesic effects and receptor binding studies. The selective NOP receptor antagonists, JTC801, and J113397, but not the sigma receptor antagonist, BD 1047, antagonized nalbuphine anti-analgesia. Furthermore, the NOP receptor agonist NNC 63-0532 produced anti-analgesia with the same delay in onset observed with the three agonist-antagonists, but without producing preceding analgesia and this anti-analgesia was also blocked by naloxone. These results strongly support the suggestion that clinically used agonist-antagonists act at the NOP receptor to produce anti-analgesia. PMID:24188792

Progesterone receptor isoforms, agonists and antagonists differentially reprogram estrogen signaling

PubMed Central

Singhal, Hari; Greene, Marianne E.; Zarnke, Allison L.; Laine, Muriel; Al Abosy, Rose; Chang, Ya-Fang; Dembo, Anna G.; Schoenfelt, Kelly; Vadhi, Raga; Qiu, Xintao; Rao, Prakash; Santhamma, Bindu; Nair, Hareesh B.; Nickisch, Klaus J.; Long, Henry W.; Becker, Lev; Brown, Myles; Greene, Geoffrey L.

2018-01-01

Major roadblocks to developing effective progesterone receptor (PR)-targeted therapies in breast cancer include the lack of highly-specific PR modulators, a poor understanding of the pro- or anti-tumorigenic networks for PR isoforms and ligands, and an incomplete understanding of the cross talk between PR and estrogen receptor (ER) signaling. Through genomic analyses of xenografts treated with various clinically-relevant ER and PR-targeting drugs, we describe how the activation or inhibition of PR differentially reprograms estrogen signaling, resulting in the segregation of transcriptomes into separate PR agonist and antagonist-mediated groups. These findings address an ongoing controversy regarding the clinical utility of PR agonists and antagonists, alone or in combination with tamoxifen, for breast cancer management. Additionally, the two PR isoforms PRA and PRB, bind distinct but overlapping genomic sites and interact with different sets of co-regulators to differentially modulate estrogen signaling to be either pro- or anti-tumorigenic. Of the two isoforms, PRA inhibited gene expression and ER chromatin binding significantly more than PRB. Differential gene expression was observed in PRA and PRB-rich patient tumors and PRA-rich gene signatures had poorer survival outcomes. In support of antiprogestin responsiveness of PRA-rich tumors, gene signatures associated with PR antagonists, but not PR agonists, predicted better survival outcomes. The better patient survival associated with PR antagonists versus PR agonists treatments was further reflected in the higher in vivo anti-tumor activity of therapies that combine tamoxifen with PR antagonists and modulators. This study suggests that distinguishing common effects observed due to concomitant interaction of another receptor with its ligand (agonist or antagonist), from unique isoform and ligand-specific effects will inform the development of biomarkers for patient selection and translation of PR

The convulsive and electroencephalographic changes produced by nonpeptidic delta-opioid agonists in rats: comparison with pentylenetetrazol.

PubMed

Jutkiewicz, Emily M; Baladi, Michelle G; Folk, John E; Rice, Kenner C; Woods, James H

2006-06-01

delta-Opioid agonists produce convulsions and antidepressant-like effects in rats. It has been suggested that the antidepressant-like effects are produced through a convulsant mechanism of action either through overt convulsions or nonconvulsive seizures. This study evaluated the convulsive and seizurogenic effects of nonpeptidic delta-opioid agonists at doses that previously were reported to produce antidepressant-like effects. In addition, delta-opioid agonist-induced electroencephalographic (EEG) and behavioral changes were compared with those produced by the chemical convulsant pentylenetetrazol (PTZ). For these studies, EEG changes were recorded using a telemetry system before and after injections of the delta-opioid agonists [(+)-4-[(alphaR)-alpha-[(2S,5R)-2,5-dimethyl-4-(2-propenyl)-1-piperazinyl]-(3-methoxyphenyl)methyl]-N,N-diethylbenz (SNC80) and [(+)-4-[alpha(R)-alpha-[(2S,5R)-2,5-dimethyl-4-(2-propenyl)-1-piperazinyl]-(3-hydroxyphenyl)methyl]-N,N-diethylbenzamide [(+)-BW373U86]. Acute administration of nonpeptidic delta-opioid agonists produced bilateral ictal and paroxysmal spike and/or sharp wave discharges. delta-Opioid agonists produced brief changes in EEG recordings, and tolerance rapidly developed to these effects; however, PTZ produced longer-lasting EEG changes that were exacerbated after repeated administration. Studies with antiepileptic drugs demonstrated that compounds used to treat absence epilepsy blocked the convulsive effects of nonpeptidic delta-opioid agonists. Overall, these data suggest that delta-opioid agonist-induced EEG changes are not required for the antidepressant-like effects of these compounds and that neural circuitry involved in absence epilepsy may be related to delta-opioid agonist-induced convulsions. In terms of therapeutic development, these data suggest that it may be possible to develop delta-opioid agonists devoid of convulsive properties.

The Glycine Transport Inhibitor Sarcosine Is an Inhibitory Glycine Receptor Agonist

PubMed Central

Zhang, Hai Xia; Lyons-Warren, Ariel; Thio, Liu Lin

2009-01-01

Summary Sarcosine is an endogenous amino acid that is a competitive inhibitor of the type I glycine transporter (GlyT1), an N-methyl-D-aspartate receptor (NMDAR) co-agonist, and an important intermediate in one-carbon metabolism. Its therapeutic potential for schizophrenia further underscores its clinical importance. The structural similarity between sarcosine and glycine and sarcosine's ability to serve as an NMDAR co-agonist led us to examine whether sarcosine is also an agonist at the inhibitory glycine receptor (GlyR). We examined this possibility using whole-cell recordings from cultured embryonic mouse hippocampal neurons and found that sarcosine evoked a dose-dependent, strychnine sensitive, Cl- current that cross-inhibited glycine currents. Sarcosine evoked this current with Li+ in the extracellular solution to block GlyT1, in neurons treated with the essentially irreversible GlyT1 inhibitor N[3-(4′-fluorophenyl)-3-(4′-phenylphenoxy)propyl]sarcosine (NFPS), and in neurons plated in the absence of glia. These results indicate that the sarcosine currents did not result from GlyT1 inhibition or heteroexchange. We conclude that sarcosine is a GlyR agonist. PMID:19619564

PPAR agonists regulate brain gene expression: relationship to their effects on ethanol consumption.

PubMed

Ferguson, Laura B; Most, Dana; Blednov, Yuri A; Harris, R Adron

2014-11-01

Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that act as ligand-activated transcription factors. Although prescribed for dyslipidemia and type-II diabetes, PPAR agonists also possess anti-addictive characteristics. PPAR agonists decrease ethanol consumption and reduce withdrawal severity and susceptibility to stress-induced relapse in rodents. However, the cellular and molecular mechanisms facilitating these properties have yet to be investigated. We tested three PPAR agonists in a continuous access two-bottle choice (2BC) drinking paradigm and found that tesaglitazar (PPARα/γ; 1.5 mg/kg) and fenofibrate (PPARα; 150 mg/kg) decreased ethanol consumption in male C57BL/6J mice while bezafibrate (PPARα/γ/β; 75 mg/kg) did not. We hypothesized that changes in brain gene expression following fenofibrate and tesaglitazar treatment lead to reduced ethanol drinking. We studied unbiased genomic profiles in areas of the brain known to be important for ethanol dependence, the prefrontal cortex (PFC) and amygdala, and also profiled gene expression in liver. Genomic profiles from the non-effective bezafibrate treatment were used to filter out genes not associated with ethanol consumption. Because PPAR agonists are anti-inflammatory, they would be expected to target microglia and astrocytes. Surprisingly, PPAR agonists produced a strong neuronal signature in mouse brain, and fenofibrate and tesaglitazar (but not bezafibrate) targeted a subset of GABAergic interneurons in the amygdala. Weighted gene co-expression network analysis (WGCNA) revealed co-expression of treatment-significant genes. Functional annotation of these gene networks suggested that PPAR agonists might act via neuropeptide and dopaminergic signaling pathways in the amygdala. Our results reveal gene targets through which PPAR agonists can affect alcohol consumption behavior. Copyright © 2014 Elsevier Ltd. All rights reserved.

Suppression of atherosclerosis by synthetic REV-ERB agonist

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sitaula, Sadichha; Billon, Cyrielle; Kamenecka, Theodore M.

2015-05-08

The nuclear receptors for heme, REV-ERBα and REV-ERBβ, play important roles in the regulation of metabolism and inflammation. Recently it was demonstrated that reduced REV-ERBα expression in hematopoetic cells in LDL receptor null mice led to increased atherosclerosis. We sought to determine if synthetic REV-ERB agonists that we have developed might have the ability to suppress atherosclerosis in this model. A previously characterized synthetic REV-ERB agonist, SR9009, was used to determine if activation of REV-ERB activity would affect atherosclerosis in LDL receptor deficient mice. Atherosclerotic plaque size was significantly reduced (p < 0.05) in mice administered SR9009 (100 mg/kg) for seven weeks comparedmore » to control mice (n = 10 per group). SR9009 treatment of bone marrow-derived mouse macrophages (BMDM) reduced the polarization of BMDMs to proinflammatory M1 macrophage while increasing the polarization of BMDMs to anti-inflammatory M2 macrophages. Our results suggest that pharmacological targeting of REV-ERBs may be a viable therapeutic option for treatment of atherosclerosis. - Highlights: • Synthetic REV-ERB agonist treatment reduced atherosclerosis in a mouse model. • Pharmacological activation of REV-ERB decreased M1 macrophage polarization. • Pharmacological activation of REV-ERB increased M2 macrophage polarization.« less

Pharmacological characterization of ATPM [(-)-3-aminothiazolo[5,4-b]-N-cyclopropylmethylmorphinan hydrochloride], a novel mixed kappa-agonist and mu-agonist/-antagonist that attenuates morphine antinociceptive tolerance and heroin self-administration behavior.

PubMed

Wang, Yu-Jun; Tao, Yi-Min; Li, Fu-Ying; Wang, Yu-Hua; Xu, Xue-Jun; Chen, Jie; Cao, Ying-Lin; Chi, Zhi-Qiang; Neumeyer, John L; Zhang, Ao; Liu, Jing-Gen

2009-04-01

ATPM [(-)-3-amino-thiazolo[5,4-b]-N-cyclopropylmethylmorphinan hydrochloride] was found to have mixed kappa- and mu-opioid activity and identified to act as a full kappa-agonist and a partial mu-agonist by in vitro binding assays. The present study was undertaken to characterize its in vivo effects on morphine antinociceptive tolerance in mice and heroin self-administration in rats. ATPM was demonstrated to yield more potent antinociceptive effects than (-)U50,488H (trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide). It was further found that the antinociceptive effects of ATPM were mediated by kappa- and mu-, but not delta-opioid, receptors. In addition to its agonist profile on the mu-receptor, ATPM also acted as a mu-antagonist, as measured by its inhibition of morphine-induced antinociception. It is more important that ATPM had a greater ratio of the ED(50) value of sedation to that of antinociception than (-)U50,488 (11.8 versus 3.7), indicative of a less sedative effect than (-)U50,488H. In addition, ATPM showed less potential to develop antinociceptive tolerance relative to (-)U50,488H and morphine. Moreover, it dose-dependently inhibited morphine-induced antinociceptive tolerance. Furthermore, it was found that chronic treatment of rats for 8 consecutive days with ATPM (0.5 mg/kg s.c.) produced sustained decreases in heroin self-administration. (-)U50,488H (2 mg/kg s.c.) also produced similar inhibitory effect. Taken together, our findings demonstrated that ATPM, a novel mixed kappa-agonist and mu-agonist/-antagonist, could inhibit morphine-induced antinociceptive tolerance, with less potential to develop tolerance and reduce heroin self-administration with less sedative effect. kappa-Agonists with some mu-activity appear to offer some advantages over selective kappa-agonists for the treatment of heroin abuse.

PPAR agonists reduce steatosis in oleic acid-overloaded HepaRG cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rogue, Alexandra; Université de Rennes 1, Faculté des Sciences Pharmaceutiques et Biologiques, 35043 Rennes Cedex; Biologie Servier, Gidy

2014-04-01

Although non-alcoholic fatty liver disease (NAFLD) is currently the most common form of chronic liver disease there is no pharmacological agent approved for its treatment. Since peroxisome proliferator-activated receptors (PPARs) are closely associated with hepatic lipid metabolism, they seem to play important roles in NAFLD. However, the effects of PPAR agonists on steatosis that is a common pathology associated with NAFLD, remain largely controversial. In this study, the effects of various PPAR agonists, i.e. fenofibrate, bezafibrate, troglitazone, rosiglitazone, muraglitazar and tesaglitazar on oleic acid-induced steatotic HepaRG cells were investigated after a single 24-hour or 2-week repeat treatment. Lipid vesicles stainedmore » by Oil-Red O and triglycerides accumulation caused by oleic acid overload, were decreased, by up to 50%, while fatty acid oxidation was induced after 2-week co-treatment with PPAR agonists. The greatest effects on reduction of steatosis were obtained with the dual PPARα/γ agonist muraglitazar. Such improvement of steatosis was associated with up-regulation of genes related to fatty acid oxidation activity and down-regulation of many genes involved in lipogenesis. Moreover, modulation of expression of some nuclear receptor genes, such as FXR, LXRα and CAR, which are potent actors in the control of lipogenesis, was observed and might explain repression of de novo lipogenesis. Conclusion: Altogether, our in vitro data on steatotic HepaRG cells treated with PPAR agonists correlated well with clinical investigations, bringing a proof of concept that drug-induced reversal of steatosis in human can be evaluated in in vitro before conducting long-term and costly in vivo studies in animals and patients. - Highlights: • There is no pharmacological agent approved for the treatment of NAFLD. • This study demonstrates that PPAR agonists can reduce fatty acid-induced steatosis. • Some nuclear receptors appear to be potent actors in the

Agemone mexicana flavanones; apposite inverse agonists of the β2-adrenergic receptor in asthma treatment.

PubMed

Eniafe, Gabriel O; Metibemu, Damilohun S; Omotuyi, Olaposi I; Ogunleye, Adewale J; Inyang, Olumide K; Adelakun, Niyi S; Adeniran, Yakubu O; Adewumi, Bamidele; Enejoh, Ojochenemi A; Osunmuyiwa, Joseph O; Shodehinde, Sidiqat A; Oyeneyin, Oluwatoba E

2018-01-01

Asthma is an inflammatory disease of the airway that poses a major threat to human health. With increase industrialization in the developed and developing countries, the incidence of asthma is on the rise. The β2-adrenergic receptor is an important target in designing anti-asthmatic drugs. The synthetic agonists of the β2-adrenergic receptor used over the years proved effective, but with indispensable side effects, thereby limiting their therapeutic use on a long-term scale. Inverse agonists of this receptor, although initially contraindicated, had been reported to have long-term beneficial effects. Phytochemicals from Agemone mexicana were screened against the human β2-adrenergic receptor in the agonist, inverse agonist, covalent agonist, and the antagonist conformations. Molecular docking of the phyto-constituents showed that the plant constituents bind better to the inverse agonist bound conformation of the protein, and revealed two flavanones; eriodictyol and hesperitin, with lower free energy (ΔG) values and higher affinities to the inverse agonist bound receptor than the co-crystallized ligand. Eriodictyol and hesperitin bind with the glide score of -10.684 and - 9.958 kcal/mol respectively, while the standard compound ICI-118551, binds with glide score of -9.503 kcal/mol. Further interaction profiling at the protein orthosteric site and ADME/Tox screening confirmed the drug-like properties of these compounds.

Discovery of Peripheral κ-Opioid Receptor Agonists as Novel Analgesics.

PubMed

Suzuki, Shinya; Sugawara, Yuji; Inada, Hideaki; Tsuji, Riichiro; Inoue, Atsushi; Tanimura, Ryuji; Shimozono, Rieko; Konno, Mitsuhiro; Ohyama, Tomofumi; Higashi, Eriko; Sakai, Chizuka; Kawai, Koji

2017-01-01

κ-Opioid receptor agonists with high selectivity over the μ-opioid receptor and peripheral selectivity are attractive targets in the development of drugs for pain. We have previously attempted to create novel analgesics with peripheral selective κ-opioid receptor agonist on the basis of TRK-820. In this study, we elucidated the biological properties of 17-hydroxy-cyclopropylmethyl and 10α-hydroxy derivatives. These compounds were found to have better κ-opioid receptor selectivity and peripheral selectivity than TRK-820.

Relations de Dispersion et Diffusion des Glueballs et des Mesons dans la Theorie de Jauge U(1)(2+1) Compacte

NASA Astrophysics Data System (ADS)

Ahmed, Chaara El Mouez

Nous avons etudie les relations de dispersion et la diffusion des glueballs et des mesons dans le modele U(1)_{2+1} compact. Ce modele a ete souvent utilise comme un simple modele de la chromodynamique quantique (QCD), parce qu'il possede le confinement ainsi que les etats de glueballs. Par contre, sa structure mathematique est beaucoup plus simple que la QCD. Notre methode consiste a diagonaliser l'Hamiltonien de ce modele dans une base appropriee de graphes et sur reseau impulsion, afin de generer les relations de dispersion des glueballs et des mesons. Pour la diffusion, nous avons utilise la methode dependante du temps pour calculer la matrice S et la section efficace de diffusion des glueballs et des mesons. Les divers resultats obtenus semblent etre en accord avec les travaux anterieurs de Hakim, Alessandrini et al., Irving et al., qui eux, utilisent plutot la theorie des perturbations en couplage fort, et travaillent sur un reseau espace-temps.

Choline as an agonist: determination of its agonistic potency on cholinergic receptors.

PubMed

Ulus, I H; Millington, W R; Buyukuysal, R L; Kiran, B K

1988-07-15

These experiments examined the potency of choline as a cholinergic agonist at both muscarinic and nicotinic receptors in rat brain and peripheral tissues. Choline stimulated the contraction of isolated smooth muscle preparations of the stomach fundus, urinary bladder and trachea and reduced the frequency of spontaneous contractions of the right atrium at high micromolar and low millimolar concentrations. The potency of choline to elicit a biological response varied markedly among these tissues; EC50 values ranged between 0.41 mM in the fundus to 14.45 mM in the atrium. Choline also displaced [3H]quinuclidinyl benzilate binding in a concentration-dependent manner although, again, its potency varied among different brain regions (Ki = 1.2 to 3.5 mM) and peripheral tissues (Ki = 0.28 to 3.00 mM). Choline exhibited a comparable affinity for nicotinic receptors. It stimulated catecholamine release from the vascularly perfused adrenal gland (EC50 = 1.3 mM) and displaced L-[3H]nicotine binding to membrane preparations of brain and peripheral tissues (Ki = 0.38 to 1.17 mM). However, the concentration of choline required to bind to cholinergic receptors in most tissues was considerably higher than serum levels either in controls (8-13 microM) or following the administration of choline chloride (200 microM). These results clearly demonstrate that choline is a weak cholinergic agonist. Its potency is too low to account for the central nervous system effects produced by choline administration, although the direct activation of cholinergic receptors in several peripheral tissues may explain some of its side effects.

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.

Evaluation d’une grille de supervision des laboratoires des leishmanioses cutanées au Maroc

PubMed Central

El Mansouri, Bouchra; Amarir, Fatima; Hajli, Yamina; Fellah, Hajiba; Sebti, Faiza; Delouane, Bouchra; Sadak, Abderrahim; Adlaoui, El Bachir; Rhajaoui, Mohammed

2017-01-01

Introduction Afin d’évaluer une grille de contrôle standardisée de laboratoire de diagnostic des leishmanioses, comme nouveau outil de supervision. Méthodes Un essai pilote a été pratiqué sur sept laboratoires provinciaux, appartenant à quatre provinces au Maroc, en suivant l’évolution de leurs performances tous les deux ans, entre l’année 2006 et 2014. Cette étude détaille la situation des laboratoires provinciaux avant et après la mise en œuvre de la grille de supervision. Au total vingt et une grille sont analysées. Résultats En 2006, les résultats ont montré clairement une insuffisance des performances des laboratoires: besoin en formation (41.6%), personnel pratiquant le prélèvement cutané (25%), pénurie en matériels et réactifs (65%), gestions documentaire et local non conformes (85%). Différentes actions correctives ont été menées par le Laboratoire National de Référence des Leishmanioses (LNRL) durant la période d’étude. En 2014, le LNRL a enregistré une nette amélioration des performances des laboratoires. Les besoins en matière de formation, qualité du prélèvement, dotation en matériels et réactifs ont été comblés et une coordination efficace s’est établie entre le LNRL et les laboratoires provinciaux. Conclusion Ceci montre l'efficacité de la grille comme outil de supervision de grande qualité, et comme pierre angulaire de tout progrès qui doit être obtenu dans les programmes de lutte contre les leishmanioses. PMID:29187922

Identification et prise en charge des femmes ayant des antécédents familiaux de cancer du sein

PubMed Central

Heisey, Ruth; Carroll, June C.

2016-01-01

Résumé Objectif Résumer les meilleures données portant sur les stratégies d’identification et de prise en charge des femmes qui présentent des antécédents familiaux de cancer du sein. Sources d’information Une recherche a été effectuée sur PubMed à l’aide des mots-clés anglais suivants : breast cancer, guidelines, risk, family history, management et magnetic resonance imaging screening, entre 2000 et 2016. La plupart des données sont de niveau II. Message principal Une bonne anamnèse familiale est essentielle lors de l’évaluation du risque de cancer du sein afin d’identifier les femmes qui sont candidates à une recommandation en counseling génétique pour un éventuel test génétique. On peut sauver des vies en offrant aux femmes porteuses d’une mutation au gène BRCA des interventions chirurgicales de réduction des risques (mastectomie bilatérale prophylactique, salpingo-ovariectomie bilatérale). Il faut encourager toutes les femmes qui présentent des antécédents familiaux de cancer du sein à demeurer actives et à limiter leur consommation d’alcool à moins de 1 verre par jour; certaines femmes sont admissibles à la chimioprévention. Il faut offrir aux femmes dont le risque à vie de cancer du sein est de 20 à 25 % ou plus un dépistage poussé par imagerie par résonance magnétique en plus d’une mammographie. Conclusion Une vie saine et la chimioprévention (chez les candidates) pourraient réduire l’incidence du cancer du sein; le dépistage poussé pourrait entraîner une détection plus précoce. Le fait d’aiguiller des femmes porteuses d’une mutation au BRCA vers la chirurgie de réduction des risques sauve des vies. PMID:27737991

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 μ-opioid receptor (μ-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 μ-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 μ-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

Note des Éditeurs scientifiques

NASA Astrophysics Data System (ADS)

Averbuch, P.

Cette série d'articles est une revue de résultats expérimentaux sur différents "fluides" moléculaires, dans lesquels la cohésion est due à des forces de Van der Waals et à des liaisons hydrogène, l'eau étant un de ces fluides. Ces résultats sont présentés de façon à justifier expérimentalement un modèle original, non extensif, des propriétés de ces fluides, et l'ensemble se présente sous la forme de trois articles décrivant le modèle, suivis chacun par un article le comparant aux résultats expérimentaux publiés par de nombreux auteurs. Le caractère non extensif des propriétés physiques des fluides est choquant, contraire à beaucoup d'idées établies, il semble n'avoir en sa faveur qu'un argument, la comparaison avec un nombre de résultats expérimentaux assez grand pour que l'effet du hasard soit difficilement soupçonnable. En particulier, les écarts entre des résultats de mesures faits par des auteurs différents dans des conditions différentes sont expliqués, le sérieux et la compétence des différents expérimentateurs ne sont plus mis en doute : mais l'interprétation de ces résultats avec un modèle extensif non adapté est seule mise en cause. Les modèles extensifs étant utilisés systématiquement, au delà des expériences de physiciens, dans les calculs d'ingénieurs, et dans la modélisation d'appareils qui fonctionnent et de phénomènes naturels observés par tout le monde, il fallait expliquer pourquoi on pouvait renoncer à l'extensivité. Les raisons du succès pratique des modèles extensifs sont données, d'abord dans le cas des nématiques, puis dans celui des liquides ordinaires, et c'est ce qui rend l'ensemble cohérent, tant avec les mesures physiques fines qu'avec les observations quotidiennes. Il n'en reste pas moins que si l'interprétation donnée dans cette série d'articles est généralisable, une justification théorique du modèle utilisé devient nécessaire. Pour ce qui est des propriétés d

Applications of Composite Materials in Helicopter Construction (Les Applications des Materiaux Composite dans la Construction des Helicopteres),

DTIC Science & Technology

1983-11-21

TRANSLATION TITLE: APPLICATIONS OF COMPOSITE MATERIALS IN HELICOPTER CONSTRUCTION LES APPLICATIONS DES MATERTAUX COMWSITE DANS LA CONSTRUCTION DES...International Symposium on Design and Use of Kevlar in Aircraft, Geneva, 12 October 1982 [Beziac, Gilbert;* Les applications des mat6riaux composite...the pilot’s orders to the engine and the rotors. --Rear rotor Conventional or "faired propeller" type with its overall pitch control --Vibration

Activation of muscle nicotinic acetylcholine receptor channels by nicotinic and muscarinic agonists

PubMed Central

Akk, Gustav; Auerbach, Anthony

1999-01-01

The dose-response parameters of recombinant mouse adult neuromuscular acetylcholine receptor channels (nAChR) activated by carbamylcholine, nicotine, muscarine and oxotremorine were measured. Rate constants for agonist association and dissociation, and channel opening and closing, were estimated from single-channel kinetic analysis.The dissociation equilibrium constants were (mM): ACh (0.16)carbamylcholine (5.1)>oxotremorine M (0.6)>nicotine (0.5)>muscarine (0.15).Rat neuronal α4β2 nAChR can be activated by all of the agonists. However, detailed kinetic analysis was impossible because the recordings lacked clusters representing the activity of a single receptor complex. Thus, the number of channels in the patch was unknown and the activation rate constants could not be determined.Considering both receptor affinity and agonist efficacy, muscarine and oxotremorine are significant agonists of muscle-type nAChR. The results are discussed in terms of structure-function relationships at the nAChR transmitter binding site. PMID:10602325

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

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.

Receptor-selective, peptidase-resistant agonists at neurokinin NK-1 and NK-2 receptors: new tools for investigating neurokinin function.

PubMed

Hagan, R M; Ireland, S J; Jordan, C C; Beresford, I J; Deal, M J; Ward, P

1991-06-01

The pharmacological profiles of two novel neurokinin agonists have been investigated. delta Ava[L-Pro9,N-MeLeu10]SP(7-11) (GR73632) and [Lys3,Gly8-R-gamma-lactam-Leu9] NKA(3-10) (GR64349) are potent and selective agonists at NK-1 and NK-2 receptors respectively. In the guinea-pig isolated trachea preparation, contractions induced by these agonists were largely unaffected by inclusion of peptidase inhibitors in the bathing medium, indicating that these agonists are resistant to metabolism by peptidases. In the anaesthetised guinea-pig, both agonists were more potent bronchoconstrictor agents than either NKA or the SP analogue, SP methylester. In the anaesthetised rat, the NK-1 agonist, GR73632 was more potent than SP, NKA or NKB at causing the histamine-independent extravasation of plasma proteins into the skin after intradermal administration. The NK-2 agonist, GR64349 and the NK-3 agonist, senktide were without significant effect in this model. These agonists are useful tools for characterizing neurokinin receptor-mediated actions both in vitro and in vivo.

Ligand-based receptor tyrosine kinase partial agonists: New paradigm for cancer drug discovery?

PubMed

Riese, David J

2011-02-01

INTRODUCTION: Receptor tyrosine kinases (RTKs) are validated targets for oncology drug discovery and several RTK antagonists have been approved for the treatment of human malignancies. Nonetheless, the discovery and development of RTK antagonists has lagged behind the discovery and development of agents that target G-protein coupled receptors. In part, this is because it has been difficult to discover analogs of naturally-occurring RTK agonists that function as antagonists. AREAS COVERED: Here we describe ligands of ErbB receptors that function as partial agonists for these receptors, thereby enabling these ligands to antagonize the activity of full agonists for these receptors. We provide insights into the mechanisms by which these ligands function as antagonists. We discuss how information concerning these mechanisms can be translated into screens for novel small molecule- and antibody-based antagonists of ErbB receptors and how such antagonists hold great potential as targeted cancer chemotherapeutics. EXPERT OPINION: While there have been a number of important key findings into this field, the identification of the structural basis of ligand functional specificity is still of the greatest importance. While it is true that, with some notable exceptions, peptide hormones and growth factors have not proven to be good platforms for oncology drug discovery; addressing the fundamental issues of antagonistic partial agonists for receptor tyrosine kinases has the potential to steer oncology drug discovery in new directions. Mechanism based approaches are now emerging to enable the discovery of RTK partial agonists that may antagonize both agonist-dependent and -independent RTK signaling and may hold tremendous promise as targeted cancer chemotherapeutics.

The Therapeutic Potential of Nociceptin/Orphanin FQ Receptor Agonists as Analgesics without Abuse Liability

PubMed Central

2012-01-01

Although mu opioid (MOP) receptor agonists are the most commonly used analgesics for the treatment of moderate to severe pain in the clinic, the side effects of MOP agonists such as abuse liability limit their value as a medication. Research to identify novel analgesics without adverse effects is pivotal to advance the health care of humans. The nociceptin/orphanin FQ peptide (NOP) receptor, the fourth opioid receptor subtype, mediates distinctive actions in nonhuman primates which suggests the possibility that activity at this receptor may result in strong analgesia in the absence of virtually all of the side effects associated with MOP agonists. The present review highlights the recent progress of pharmacological studies of NOP-related ligands in primates. Selective NOP agonists, either peptidic or nonpeptidic, produce full analgesia in various assays in primates, when delivered systemically or intrathecally. Yet small molecule NOP agonists do not serve as reinforcers, indicating a lack of abuse liability. Given that NOP agonists have low abuse liability and that coactivation of NOP and MOP receptors produces synergistic antinociception, it is worth developing bifunctional NOP/MOP ligands. The outcomes of these studies and recent developments provide new perspectives to establish a translational bridge for understanding the biobehavioral functions of NOP receptors in primates and for facilitating the development of NOP-related ligands as a new generation of analgesics without abuse liability in humans. PMID:23421672

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

PubMed

Fernández-García, José Carlos; Colomo, Natalia; Tinahones, Francisco José

2014-09-01

Glucagon-like peptide-1 (GLP-1) receptor agonists are a new group of drugs for the treatment of type 2 diabetes mellitus (DM2). In the present article, we review the available evidence on the efficacy of GLP-1 receptor agonists as glucose-lowering agents, their place in therapeutic algorithms, and the clinical factors associated with a favorable treatment response. Finally, we describe the clinical characteristics of patients who may benefit from these drugs. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

Occurrence and removal of phenolic endocrine disrupting chemicals in the water treatment processes

NASA Astrophysics Data System (ADS)

Lv, Xuemin; Xiao, Sanhua; Zhang, Gang; Jiang, Pu; Tang, Fei

2016-03-01

This paper evaluated the occurrence and removal efficiency of four selected phenolic endocrine disrupting chemicals (bisphenol A (BPA), octylphenol (OP), nonylphenol (NP) and diethylstilbestrol (DES)) in two drinking waterworks in Jiangsu province which take source water from Taihu Lake. The recombined yeast estrogen screen (YES) and liquid chromatography tandem mass spectrometry (LC-MS/MS) were applied to assess the estrogenicity and detect the estrogens in the samples. The estrogen equivalents (EEQs) ranged from nd (not detected) to 2.96 ng/L, and the estrogenic activities decreased along the processes. Among the 32 samples, DES prevailed in all samples, with concentrations ranging 1.46-12.0 ng/L, BPA, OP and NP were partially detected, with concentrations ranging from nd to 17.73 ng/L, nd to 0.49 ng/L and nd to 3.27 ng/L, respectively. DES was found to be the main contributor to the estrogenicity (99.06%), followed by NP (0.62%), OP (0.23%) and BPA (0.09%). From the observation of treatment efficiency, the advanced treatment processes presented much higher removal ratio in reducing DES, the biodegradation played an important role in removing BPA, ozonation and pre-oxidation showed an effective removal on all the four estrogens; while the conventional ones can also reduce all the four estrogens.

Occurrence and removal of phenolic endocrine disrupting chemicals in the water treatment processes

PubMed Central

Lv, Xuemin; Xiao, Sanhua; Zhang, Gang; Jiang, Pu; Tang, Fei

2016-01-01

This paper evaluated the occurrence and removal efficiency of four selected phenolic endocrine disrupting chemicals (bisphenol A (BPA), octylphenol (OP), nonylphenol (NP) and diethylstilbestrol (DES)) in two drinking waterworks in Jiangsu province which take source water from Taihu Lake. The recombined yeast estrogen screen (YES) and liquid chromatography tandem mass spectrometry (LC-MS/MS) were applied to assess the estrogenicity and detect the estrogens in the samples. The estrogen equivalents (EEQs) ranged from nd (not detected) to 2.96 ng/L, and the estrogenic activities decreased along the processes. Among the 32 samples, DES prevailed in all samples, with concentrations ranging 1.46–12.0 ng/L, BPA, OP and NP were partially detected, with concentrations ranging from nd to 17.73 ng/L, nd to 0.49 ng/L and nd to 3.27 ng/L, respectively. DES was found to be the main contributor to the estrogenicity (99.06%), followed by NP (0.62%), OP (0.23%) and BPA (0.09%). From the observation of treatment efficiency, the advanced treatment processes presented much higher removal ratio in reducing DES, the biodegradation played an important role in removing BPA, ozonation and pre-oxidation showed an effective removal on all the four estrogens; while the conventional ones can also reduce all the four estrogens. PMID:26953121

Etude spectroscopique des collisions moleculaires (hydrogene-azote et hydrogene-oxygene) a des energies de quelques MeV

NASA Astrophysics Data System (ADS)

Plante, Jacinthe

1998-09-01

Les resultats presentes ici proviennent d'une etude systematique portant sur les collisions a vitesse constante, entre les projectiles d'hydrogene (H+, H2+ et H3+ a 1 MeV/nucleon) et deux cibles gazeuses (N2 et O2), soumises a differentes pressions. Les collisions sont analysees a l'aide des spectres d'emission (de 400 A a 6650 A) et des graphiques intensite/pression. Les spectres ont revele la presence des raies d'azote atomique, d'azote moleculaire, d'oxygene atomique, d'oxygene moleculaire et d'hydrogene atomique. Les raies d'hydrogene sont observees seulement avec les projectiles H2+ et H3+. Donc les processus responsables de la formation de ces raies sont des mecanismes de fragmentation des projectiles. Pour conclure, il existe une difference notable entre les projectiles et les differentes pressions. Les raies d'azote et d'oxygene augmentent selon la pression et les raies d'hydrogene atomique presentent une relation non lineaire avec la pression.

Effect of vibration frequency on agonist and antagonist arm muscle activity.

PubMed

Rodríguez Jiménez, Sergio; Benítez, Adolfo; García González, Miguel A; Moras Feliu, Gerard; Maffiuletti, Nicola A

2015-06-01

This study aimed to assess the effect of vibration frequency (f out) on the electromyographic (EMG) activity of the biceps brachii (BB) and triceps brachii (TB) muscles when acting as agonist and antagonist during static exercises with different loads. Fourteen healthy men were asked to hold a vibratory bar as steadily as possible for 10 s during lying row (pulling) and bench press (pushing) exercise at f out of 0 (non-vibration condition), 18, 31 and 42 Hz with loads of 20, 50, and 80 % of the maximum sustainable load (MSL). The root mean square of the EMG activity (EMGRMS) of the BB and TB muscles was expressed as a function of the maximal EMGRMS for respective muscles to characterize agonist activation and antagonist coactivation. We found that (1) agonist activation was greater during vibration (42 Hz) compared to non-vibration exercise for the TB but not for the BB muscle (p < 0.05); (2) antagonist activation was greater during vibration compared to non-vibration exercise for both BB (p < 0.01) and TB (p < 0.05) muscles; (3) the vibration-induced increase in antagonist coactivation was proportional to vibration f out in the range 18-42 Hz and (4) the vibration-induced increase in TB agonist activation and antagonist coactivation occurred at all loading conditions in the range 20-80 % MSL. The use of high vibration frequencies within the range of 18-42 Hz can maximize TB agonist activation and antagonist activation of both BB and TB muscles during upper limb vibration exercise.

DES Science Portal: II- Creating Science-Ready Catalogs

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fausti Neto, Angelo; et al.

We present a novel approach for creating science-ready catalogs through a software infrastructure developed for the Dark Energy Survey (DES). We integrate the data products released by the DES Data Management and additional products created by the DES collaboration in an environment known as DES Science Portal. Each step involved in the creation of a science-ready catalog is recorded in a relational database and can be recovered at any time. We describe how the DES Science Portal automates the creation and characterization of lightweight catalogs for DES Year 1 Annual Release, and show its flexibility in creating multiple catalogs withmore » different inputs and configurations. Finally, we discuss the advantages of this infrastructure for large surveys such as DES and the Large Synoptic Survey Telescope. The capability of creating science-ready catalogs efficiently and with full control of the inputs and configurations used is an important asset for supporting science analysis using data from large astronomical surveys.« less

Signal Use by Octopuses in Agonistic Interactions.

PubMed

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

2016-02-08

Cephalopods show behavioral parallels to birds and mammals despite considerable evolutionary distance [1, 2]. Many cephalopods produce complex body patterns and visual signals, documented especially in cuttlefish and squid, where they are used both in camouflage and a range of interspecific interactions [1, 3-5]. Octopuses, in contrast, are usually seen as solitary and asocial [6, 7]; their body patterns and color changes have primarily been interpreted as camouflage and anti-predator tactics [8-12], though the familiar view of the solitary octopus faces a growing list of exceptions. Here, we show by field observation that in a shallow-water octopus, Octopus tetricus, a range of visible displays are produced during agonistic interactions, and these displays correlate with the outcome of those interactions. Interactions in which dark body color by an approaching octopus was matched by similar color in the reacting octopus were more likely to escalate to grappling. Darkness in an approaching octopus met by paler color in the reacting octopus accompanied retreat of the paler octopus. Octopuses also displayed on high ground and stood with spread web and elevated mantle, often producing these behaviors in combinations. This study is the first to document the systematic use of signals during agonistic interactions among octopuses. We show prima facie conformity of our results to an influential model of agonistic signaling [13]. These results suggest that interactions have a greater influence on octopus evolution than has been recognized and show the importance of convergent evolution in behavioral traits. Copyright © 2016 Elsevier Ltd. All rights reserved.

Characterization of 12 GnRH peptide agonists - a kinetic perspective.

PubMed

Nederpelt, Indira; Georgi, Victoria; Schiele, Felix; Nowak-Reppel, Katrin; Fernández-Montalván, Amaury E; IJzerman, Adriaan P; Heitman, Laura H

2016-01-01

Drug-target residence time is an important, yet often overlooked, parameter in drug discovery. Multiple studies have proposed an increased residence time to be beneficial for improved drug efficacy and/or longer duration of action. Currently, there are many drugs on the market targeting the gonadotropin-releasing hormone (GnRH) receptor for the treatment of hormone-dependent diseases. Surprisingly, the kinetic receptor-binding parameters of these analogues have not yet been reported. Therefore, this project focused on determining the receptor-binding kinetics of 12 GnRH peptide agonists, including many marketed drugs. A novel radioligand-binding competition association assay was developed and optimized for the human GnRH receptor with the use of a radiolabelled peptide agonist, [(125) I]-triptorelin. In addition to radioligand-binding studies, a homogeneous time-resolved FRET Tag-lite™ method was developed as an alternative assay for the same purpose. Two novel competition association assays were successfully developed and applied to determine the kinetic receptor-binding characteristics of 12 high-affinity GnRH peptide agonists. Results obtained from both methods were highly correlated. Interestingly, the binding kinetics of the peptide agonists were more divergent than their affinities with residence times ranging from 5.6 min (goserelin) to 125 min (deslorelin). Our research provides new insights by incorporating kinetic, next to equilibrium, binding parameters in current research and development that can potentially improve future drug discovery targeting the GnRH receptor. © 2015 The British Pharmacological Society.

Adenosine A2A receptor agonists with potent antiplatelet activity.

PubMed

Fuentes, Eduardo; Fuentes, Manuel; Caballero, Julio; Palomo, Iván; Hinz, Sonja; El-Tayeb, Ali; Müller, Christa E

2018-05-01

Selected adenosine A 2A receptor agonists (PSB-15826, PSB-12404, and PSB-16301) have been evaluated as new antiplatelet agents. In addition, radioligand-binding studies and receptor-docking experiments were performed in order to explain their differential biological effects on a molecular level. Among the tested adenosine derivatives, PSB-15826 was the most potent compound to inhibit platelet aggregation (EC 50 0.32 ± 0.05 µmol/L) and platelet P-selectin cell-surface localization (EC 50 0.062 ± 0.2 µmol/L), and to increase intraplatelets cAMP levels (EC 50 0.24 ± 0.01 µmol/L). The compound was more active than CGS21680 (EC 50 0.97±0.07 µmol/L) and equipotent to NECA (EC 50 0.31 ± 0.05 µmol/L) in platelet aggregation induced by ADP. In contrast to the results from cAMP assays, K i values determined in radioligand-binding studies were not predictive of the A 2A agonists' antiplatelet activity. Docking studies revealed the key molecular determinants of this new family of adenosine A 2A receptor agonists: differences in activities are related to π-stacking interactions between the ligands and the residue His264 in the extracellular loop of the adenosine A 2A receptor which may result in increased residence times. In conclusion, these results provide an improved understanding of the requirements of antiplatelet adenosine A 2A receptor agonists.

Using the verona coding definitions of emotional sequences (VR-CoDES) and health provider responses (VR-CoDES-P) in the dental context.

PubMed

Wright, Alice; Humphris, Gerry; Wanyonyi, Kristina L; Freeman, Ruth

2012-10-01

To show if cues, concerns and provider responses (defined in VR-CoDES and VR-CoDES-P manuals) are present, can be reliably coded and require additional advice for adoption in a dental context. Thirteen patients in a dental practice setting were videoed with either their dentist or hygienist and dental nurse present in routine treatment sessions. All utterances were coded using the Verona systems: VR-CoDES and the VR-CoDES-P. Rates of cue, concerns and provider responses described and reliability tested. The VR-CoDES and VR-CoDES-P were successfully applied in the dental context. The intra-rater ICCs for the detection of cues and concerns and provider response were acceptable and above 0.75. A similar satisfactory result was found for the inter-rater reliability. The VR-CoDES and the VR-CoDES-P are applicable in the dental setting with minor supporting guidelines and show evidence of reliable coding. The VR-CoDES and the VR-CoDES-P may be helpful tools for analysing patient cues and concerns and the dental professionals' responses in the dental context. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Rational design of orally-active, pyrrolidine-based progesterone receptor partial agonists

DOE Office of Scientific and Technical Information (OSTI.GOV)

Thompson, Scott K.; Washburn, David G.; Frazee, James S.

2010-09-03

Using the X-ray crystal structure of an amide-based progesterone receptor (PR) partial agonist bound to the PR ligand binding domain, a novel PR partial agonist class containing a pyrrolidine ring was designed. Members of this class of N-alkylpyrrolidines demonstrate potent and highly selective partial agonism of the progesterone receptor, and one of these analogs was shown to be efficacious upon oral dosing in the OVX rat model of estrogen opposition.

Reticulation des fibres lignocellulosiques

NASA Astrophysics Data System (ADS)

Landrevy, Christel

Pour faire face à la crise économique la conception de papier à valeur ajoutée est développée par les industries papetières. Le but de se projet est l'amélioration des techniques actuelles de réticulation des fibres lignocellulosiques de la pâte à papier visant à produire un papier plus résistant. En effet, lors des réactions de réticulation traditionnelles, de nombreuses liaisons intra-fibres se forment ce qui affecte négativement l'amélioration anticipée des propriétés physiques du papier ou du matériau produit. Pour éviter la formation de ces liaisons intra-fibres, un greffage sur les fibres de groupements ne pouvant pas réagir entre eux est nécessaire. La réticulation des fibres par une réaction de « click chemistry » appelée cycloaddition de Huisgen entre un azide et un alcyne vrai, catalysée par du cuivre (CuAAC) a été l'une des solutions trouvée pour remédier à ce problème. De plus, une adaptation de cette réaction en milieux aqueux pourrait favoriser son utilisation en milieu industriel. L'étude que nous désirons entreprendre lors de ce projet vise à optimiser la réaction de CuAAC et les réactions intermédiaires (propargylation, tosylation et azidation) sur la pâte kraft, en milieu aqueux. Pour cela, les réactions ont été adaptées en milieu aqueux sur la cellulose microcristalline afin de vérifier sa faisabilité, puis transférée à la pâte kraft et l'influence de différents paramètres comme le temps de réaction ou la quantité de réactifs utilisée a été étudiée. Dans un second temps, une étude des différentes propriétés conférées au papier par les réactions a été réalisée à partir d'une série de tests papetiers optiques et physiques. Mots Clés Click chemistry, Huisgen, CuAAC, propargylation, tosylation, azidation, cellulose, pâte kraft, milieu aqueux, papier.

6'-Guanidinonaltrindole (6'-GNTI) is a G protein-biased κ-opioid receptor agonist that inhibits arrestin recruitment.

PubMed

Rives, Marie-Laure; Rossillo, Mary; Liu-Chen, Lee-Yuan; Javitch, Jonathan A

2012-08-03

κ-Opioid receptor (KOR) agonists do not activate the reward pathway stimulated by morphine-like μ-opioid receptor (MOR) agonists and thus have been considered to be promising nonaddictive analgesics. However, KOR agonists produce other adverse effects, including dysphoria, diuresis, and constipation. The therapeutic promise of KOR agonists has nonetheless recently been revived by studies showing that their dysphoric effects require arrestin recruitment, whereas their analgesic effects do not. Moreover, KOR agonist-induced antinociceptive tolerance observed in vivo has also been proposed to be correlated to the ability to induce arrestin-dependent phosphorylation, desensitization, and internalization of the receptor. The discovery of functionally selective drugs that are therapeutically effective without the adverse effects triggered by the arrestin pathway is thus an important goal. We have identified such an extreme G protein-biased KOR compound, 6'-guanidinonaltrindole (6'-GNTI), a potent partial agonist at the KOR receptor for the G protein activation pathway that does not recruit arrestin. Indeed, 6'-GNTI functions as an antagonist to block the arrestin recruitment and KOR internalization induced by other nonbiased agonists. As an extremely G protein-biased KOR agonist, 6'-GNTI represents a promising lead compound in the search for nonaddictive opioid analgesic as its signaling profile suggests that it will be without the dysphoria and other adverse effects promoted by arrestin recruitment and its downstream signaling.

Induction of Selective Blood-Tumor Barrier Permeability and Macromolecular Transport by a Biostable Kinin B1 Receptor Agonist in a Glioma Rat Model

PubMed Central

Côté, Jérôme; Bovenzi, Veronica; Savard, Martin; Dubuc, Céléna; Fortier, Audrey; Neugebauer, Witold; Tremblay, Luc; Müller-Esterl, Werner; Tsanaclis, Ana-Maria; Lepage, Martin; Fortin, David; Gobeil, Fernand

2012-01-01

Treatment of malignant glioma with chemotherapy is limited mostly because of delivery impediment related to the blood-brain tumor barrier (BTB). B1 receptors (B1R), inducible prototypical G-protein coupled receptors (GPCR) can regulate permeability of vessels including possibly that of brain tumors. Here, we determine the extent of BTB permeability induced by the natural and synthetic peptide B1R agonists, LysdesArg9BK (LDBK) and SarLys[dPhe8]desArg9BK (NG29), in syngeneic F98 glioma-implanted Fischer rats. Ten days after tumor inoculation, we detected the presence of B1R on tumor cells and associated vasculature. NG29 infusion increased brain distribution volume and uptake profiles of paramagnetic probes (Magnevist and Gadomer) at tumoral sites (T 1-weighted imaging). These effects were blocked by B1R antagonist and non-selective cyclooxygenase inhibitors, but not by B2R antagonist and non-selective nitric oxide synthase inhibitors. Consistent with MRI data, systemic co-administration of NG29 improved brain tumor delivery of Carboplatin chemotherapy (ICP-Mass spectrometry). We also detected elevated B1R expression in clinical samples of high-grade glioma. Our results documented a novel GPCR-signaling mechanism for promoting transient BTB disruption, involving activation of B1R and ensuing production of COX metabolites. They also underlined the potential value of synthetic biostable B1R agonists as selective BTB modulators for local delivery of different sized-therapeutics at (peri)tumoral sites. PMID:22629405

Estradiol agonists inhibit human LoVo colorectal-cancer cell proliferation and migration through p53.

PubMed

Hsu, Hsi-Hsien; Kuo, Wei-Wen; Ju, Da-Tong; Yeh, Yu-Lan; Tu, Chuan-Chou; Tsai, Ying-Lan; Shen, Chia-Yao; Chang, Sheng-Huang; Chung, Li-Chin; Huang, Chih-Yang

2014-11-28

To investigate the effects of 17β-estradiol via estrogen receptors (ER) or direct administration of ER agonists on human colorectal cancer. LoVo cells were established from the Bioresource Collection and Research Center and cultured in phenol red-free DMEM (Sigma, United States). To investigate the effects of E2 and/or ER selective agonists on cellular proliferation, LoVo colorectal cells were treated with E2 or ER-selective agonists for 24 h and 48 h and subjected to the MTT (Sigma) assay to find the concentration. And investigate the effects of E2 and/or ER selective agonists on cell used western immunoblotting to find out the diversification of signaling pathways. In order to observe motility and migration the wound healing assay and a transwell chamber (Neuro Probe) plate were tased. For a quantitative measure, we counted the number of migrating cells to the wound area post-wounding for 24 h. We further examined the cellular migration-regulating factors urokinase-type plasminogen activator (u-PA), tissue-type plasminogen activator (t-PA) and matrix metalloproteinase (MMP)-9 in human LoVo cells so gelatin zymography that we used and gelatinolytic activity was visualized by Coomassie blue staining. And these results are presented as means ± SE, and statistical comparisons were made using Student's t-test. The structure was first compared with E2 and ER agonists. We then treated the LoVo cells with E2 and ER agonists (10(-8) mol/L) for 24 h and 48 h and subsequently measured the cell viability using MTT assay. Our results showed that treatment with 17β-estradiol and/or ER agonists in human LoVo colorectal cancer cells activated p53 and then up-regulated p21 and p27 protein levels, subsequently inhibiting the downstream target gene, cyclin D1, which regulates cell proliferation. Taken together, our findings demonstrate the anti-tumorigenesis effects of 17β-estradiol and/or ER agonists and suggest that these compounds may prove to be a potential alternative

Minimisation des inductances propres des condensateurs à film métallisé

NASA Astrophysics Data System (ADS)

Joubert, Ch.; Rojat, G.; Béroual, A.

1995-07-01

In this article, we examine the different factors responsible for the equivalent series inductance in metallized capacitors and we propose structures for capacitors that reduce this inductance. After recalling the structure of metallized capacitors we compare, by experimental measurements, the inductance due to the winding and that one added by the connections. The latter can become preponderant. In order to explain the experimental evolution of the winding impedance vs. frequency, we describe an analytical model which gives the current density in the winding and its impedance. This model enables us to determine the self resonant frequency for different types of capacitors. From where, we can infer the influence of the height of capacitors and their internal and external radius upon performances, It appears that to reduce the equivalent series inductance, it is better to use flat windings and annular windings. Dans cet article nous examinons les différents facteurs responsables de l'inductance équivalente série dans les condensateurs à film métallisé et proposons des géométries de condensateurs qui réduisent cette inductance. Après avoir rappelé la structure des condensateurs à film métallisé, nous comparons, par des mesures expérimentales, l'inductance due au bobinage et l'inductance ajoutée par les connexions. Cette dernière peut devenir prépondérante. Afin d'expliquer l'évolution de l'impédance du bobinage en fonction de la fréquence, nous décrivons un modèle analytique qui donne la densité du courant dans le bobinage et l'impédance de ce dernier. En outre, ce modèle permet de déterminer la fréquence de résonance série de divers types de condensateurs ce qui permet de déduire l'influence de la hauteur des condensateurs et de leurs rayons interne et externe sur les performances. Il apparaît ainsi que, pour diminuer l'inductance équivalente série, il vaut mieux employer des bobinages plats et des bobinages annulaires.

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

PubMed

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

2013-01-01

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

Comparative Gene Expression Profiles Induced by PPARγ and PPARα/γ Agonists in Human Hepatocytes

PubMed Central

Rogue, Alexandra; Lambert, Carine; Jossé, Rozenn; Antherieu, Sebastien; Spire, Catherine; Claude, Nancy; Guillouzo, André

2011-01-01

Background Several glitazones (PPARγ agonists) and glitazars (dual PPARα/γ agonists) have been developed to treat hyperglycemia and, simultaneously, hyperglycemia and dyslipidemia, respectively. However, most have caused idiosyncratic hepatic or extrahepatic toxicities through mechanisms that remain largely unknown. Since the liver plays a key role in lipid metabolism, we analyzed changes in gene expression profiles induced by these two types of PPAR agonists in human hepatocytes. Methodology/Principal Findings Primary human hepatocytes and the well-differentiated human hepatoma HepaRG cells were exposed to different concentrations of two PPARγ (troglitazone and rosiglitazone) and two PPARα/γ (muraglitazar and tesaglitazar) agonists for 24 h and their transcriptomes were analyzed using human pangenomic Agilent microarrays. Principal Component Analysis, hierarchical clustering and Ingenuity Pathway Analysis® revealed large inter-individual variability in the response of the human hepatocyte populations to the different compounds. Many genes involved in lipid, carbohydrate, xenobiotic and cholesterol metabolism, as well as inflammation and immunity, were regulated by both PPARγ and PPARα/γ agonists in at least a number of human hepatocyte populations and/or HepaRG cells. Only a few genes were selectively deregulated by glitazars when compared to glitazones, indicating that PPARγ and PPARα/γ agonists share most of their target genes. Moreover, some target genes thought to be regulated only in mouse or to be expressed in Kupffer cells were also found to be responsive in human hepatocytes and HepaRG cells. Conclusions/Significance This first comprehensive analysis of gene regulation by PPARγ and PPARα/γ agonists favor the conclusion that glitazones and glitazars share most of their target genes and induce large differential changes in gene profiles in human hepatocytes depending on hepatocyte donor, the compound class and/or individual compound, thereby

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

Structure of an agonist-bound ionotropic glutamate receptor.

PubMed

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

2014-08-29

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 cross-links to probe domain interactions that are important for iGluR gating events. The combination of structural information, kinetic modeling, and biochemical and electrophysiological experiments provides insight into the mechanism of iGluR gating. Copyright © 2014, American Association for the Advancement of Science.

AMPK and PPARδ agonists are exercise mimetics

PubMed Central

Narkar, Vihang A.; Downes, Michael; Yu, Ruth T.; Embler, Emi; Wang, Yong-Xu; Banayo, Ester; Mihaylova, Maria M.; Nelson, Michael C.; Zou, Yuhua; Juguilon, Henry; Kang, Heonjoong; Shaw, Reuben; Evans, Ronald M.

2008-01-01

SUMMARY The benefits of endurance exercise on general health make it desirable to identify orally active agents that would mimic or potentiate the effects of exercise to treat metabolic diseases. Although certain natural compounds, such as reseveratrol, have endurance-enhancing activities, their exact metabolic targets remain elusive. We therefore tested the effect of pathway-specific drugs on endurance capacities of mice in a treadmill running test. We found that PPARβ/δ agonist and exercise training synergistically increase oxidative myofibers and running endurance in adult mice. Because training activates AMPK and PGC1α, we then tested whether the orally active AMPK agonist AICAR might be sufficient to overcome the exercise requirement. Unexpectedly, even in sedentary mice, 4 weeks of AICAR treatment alone induced metabolic genes and enhanced running endurance by 44%. These results demonstrate that AMPK-PPARδ pathway can be targeted by orally active drugs to enhance training adaptation or even to increase endurance without exercise. PMID:18674809

Antagonism of methoxyflurane-induced anesthesia in rats by benzodiazepine inverse agonists.

PubMed

Miller, D W; Yourick, D L; Tessel, R E

1989-11-28

Injection of the partial benzodiazepine inverse agonist Ro15-4513 (1-32 mg/kg i.p.) or nonconvulsant i.v. doses of the full benzodiazepine inverse agonist beta-CCE immediately following cessation of exposure of rats to an anesthetic concentration of methoxyflurane significantly antagonized the duration of methoxyflurane anesthesia as measured by recovery of the righting reflex and/or pain sensitivity. This antagonism was inhibited by the benzodiazepine antagonist Ro15-1788 at doses which alone did not alter the duration of methoxyflurane anesthesia. In addition, high-dose Ro15-4513 pretreatment (32 mg/kg) antagonized the induction and duration of methoxyflurane anesthesia but was unable to prevent methoxyflurane anesthesia or affect the induction or duration of anesthesia induced by the dissociative anesthetic ketamine (100 mg/kg). These findings indicate that methoxyflurane anesthesia can be selectively antagonized by the inverse agonistic action of Ro15-4513 and beta-CCE.

Alpha-2 adrenergic agonists for the prevention of cardiac complications among adults undergoing surgery.

PubMed

Duncan, Dallas; Sankar, Ashwin; Beattie, W Scott; Wijeysundera, Duminda N

2018-03-06

The surgical stress response plays an important role on the pathogenesis of perioperative cardiac complications. Alpha-2 adrenergic agonists attenuate this response and may help prevent postoperative cardiac complications. To determine the efficacy and safety of α-2 adrenergic agonists for reducing mortality and cardiac complications in adults undergoing cardiac surgery and non-cardiac surgery. We searched CENTRAL (2017, Issue 4), MEDLINE (1950 to April Week 4, 2017), Embase (1980 to May 2017), the Science Citation Index, clinical trial registries, and reference lists of included articles. We included randomized controlled trials that compared α-2 adrenergic agonists (i.e. clonidine, dexmedetomidine or mivazerol) against placebo or non-α-2 adrenergic agonists. Included trials had to evaluate the efficacy and safety of α-2 adrenergic agonists for preventing perioperative mortality or cardiac complications (or both), or measure one or more relevant outcomes (i.e. death, myocardial infarction, heart failure, acute stroke, supraventricular tachyarrhythmia and myocardial ischaemia). Two authors independently assessed trial quality, extracted data and independently performed computer entry of abstracted data. We contacted study authors for additional information. Adverse event data were gathered from the trials. We evaluated included studies using the Cochrane 'Risk of bias' tool, and the quality of the evidence underlying pooled treatment effects using GRADE methodology. Given the clinical heterogeneity between cardiac and non-cardiac surgery, we analysed these subgroups separately. We expressed treatment effects as pooled risk ratios (RR) with 95% confidence intervals (CI). We included 47 trials with 17,039 participants. Of these studies, 24 trials only included participants undergoing cardiac surgery, 23 only included participants undergoing non-cardiac surgery and eight only included participants undergoing vascular surgery. The α-2 adrenergic agonist studied

Virtual identification of novel PPARα/γ dual agonists by scaffold hopping of saroglitazar.

PubMed

Jia, Wen-Qing; Jing, Zhi; Liu, Xin; Feng, Xiao-Yan; Liu, Ya-Ya; Wang, Shu-Qing; Xu, Wei-Ren; Liu, Jian-Wen; Cheng, Xian-Chao

2017-10-28

The thiazolidinedione class PPARγ agonists as antidiabetic agents are restricted in clinical use because of the side effects such as edema, weight gain, and heart failure. The single and selective agonism of PPARγ is the main cause of side effects. The multi-target cooperative PPARα/γ dual agonist development is a hot topic in the antidiabetic medicinal chemistry field. Saroglitazar is the first approved PPARα/γ dual agonist, available in India for the treatment of diabetic dyslipidemia. It got rid of these side effects. With the aim of finding more protent PPARα/γ dual agonists, the scaffold hopping was used to replace α-o phenylpropionic acid skeleton of saroglitazar with L-tyrosine skeleton. Then, the structural modification was carried out designing 72 compounds. Considering the importance of chirality, opposite configuration of 72 compounds was also studied. 12 compounds with better -cdocker energy were screened by molecular docking. Subsequently, the pharmacokinetic properties and toxicity evaluated by ADMET prediction, 11 of them showed better properties. Comp#L-17-1 and comp#L-3-1 were regarded as representatives to study the binding stability by molecular dynamics (MD) simulations. The MD simulation results of comp#L-17-1-PPARs (α, γ) and comp#L-3-1-PPARs (α, γ) provided structure reference for the research and development of novel PPARα/γ dual agonists.

Combined ovulation triggering with GnRH agonist and hCG in IVF patients.

PubMed

Kasum, Miro; Kurdija, Kristijan; Orešković, Slavko; Čehić, Ermin; Pavičić-Baldani, Dinka; Škrgatić, Lana

2016-11-01

The aim of the review is to analyse the combination of a gonadotrophin releasing hormone (GnRH) agonist with a human chorionic gonadotrophin (hCG) trigger, for final oocyte maturation in in vitro fertilisation (IVF) cycles. The concept being a ''dual trigger'' combines a single dose of the GnRH agonist with a reduced or standard dosage of hCG at the time of triggering. The use of a GnRH agonist with a reduced dose of hCG in high responders demonstrated luteal phase support with improved pregnancy rates, similar to those after conventional hCG and a low risk of ovarian hyperstimulation syndrome (OHSS). The administration of a GnRH agonist and a standard hCG in normal responders, demonstrated significantly improved live-birth rates and a higher number of embryos of excellent quality, or cryopreserved embryos. The concept of the ''double trigger" represents a combination of a GnRH agonist and a standard hCG, when used 40 and 34 h prior to ovum pick-up, respectively. The use of the ''double trigger" has been successfully offered in the treatment of empty follicle syndrome and in patients with a history of immature oocytes retrieved or with low/poor oocytes yield. Further prospective studies are required to confirm the aforementioned observations prior to clinical implementation.

Antineoplastic Effects of PPARγ Agonists, with a Special Focus on Thyroid Cancer.

PubMed

Ferrari, Silvia Martina; Materazzi, Gabriele; Baldini, Enke; Ulisse, Salvatore; Miccoli, Paolo; Antonelli, Alessandro; Fallahi, Poupak

2016-01-01

Peroxisome Proliferator-Activated Receptor-γ (PPARγ) is a ligand-activated nuclear hormone receptor that functions as transcription factor and plays an important role in lipid metabolism and insulin sensitization. Recent studies have shown that PPARγ is overexpressed in many tumor types, including cancers of breast, lung, pancreas, colon, glioblastoma, prostate and thyroid differentiated/anaplastic cancers. These data suggest a role of PPARγ in tumor development and/or progression. PPARγ is emerging as a growth-limiting and differentiation-promoting factor, and it exerts a tumor suppressor role. Moreover, naturally-occurring and synthetic PPARγ agonists promote growth inhibition and apoptosis. Thiazolidinediones (TZDs) are synthetic agonists of PPARγ that were developed to treat type II diabetes. These compounds also display anticancer effects which appear mainly to be independent of their PPARγ agonist activity. Various preclinical and clinical studies strongly suggest a role for TZDs both alone and in combination with existing chemotherapeutic agents, for the treatment of cancer. Differentiation therapy involves the use of agents with the ability to induce differentiation in cells that have lost this ability, i.e. cancer cells, targeting pathways capable of re-activating blocked terminal differentiation programs. PPARγ agonists have been shown to induce differentiation in solid tumors such as thyroid differentiated/ anaplastic cancers and sarcomas. However, emerging data suggest that chronic use of TZDs is associated with increased risk of adverse cardiovascular events. The exploration of newer PPARγ agonists can help in unveiling the underlying mechanisms of these drugs, providing new molecules that are able to treat cancer, without increasing the cardiovascular risk of neoplastic patients.

Apport des neutrons à l'analyse structurale des composés partiellement désordonnés

NASA Astrophysics Data System (ADS)

Cousson, A.

2003-02-01

La cristallographie est un outil extrêmement puissant qui pourrait être utilisé par de nombreux scientifiques dont les sujets de recherche sont en fait très éloignés. L'évolution des techniques ces dernières années a relégué par exemple la cristallographie des rayons X des petites molécules à un rôle mineur, un rôle de service. Certains ont même le sentiment semble-t-il que toutes les connaissances sont contenues dans de multiples logiciels capables par eux-mêmes de conduire une analyse structurale à un résultat correct unique. Il est souhaitable que chacun soit capable de réaliser l'étude structurale du composé qui l'intéresse et bien entendu nécessaire de comprendre ce que l'on fait, la qualité des résultats et leur analyse en dépend. L'objet de cette présentation est de montrer l'apport spécifique de la diffraction de neutrons sur monocristaux à l'étude du désordre, en particulier des atomes d'hydrogène, et ses conséquences sur la compréhension des propriétés physiques, à partir de développements et d'exemples récents.

PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR (PPAR) AGONISTS AS PROMISING NEW MEDICATIONS FOR DRUG ADDICTION: PRECLINICAL EVIDENCE

PubMed Central

Foll, Bernard Le; Ciano, Patricia Di; Panlilio, Leigh V.; Goldberg, Steven R.; Ciccocioppo, Roberto

2013-01-01

This review examines the growing literature on the role of peroxisome proliferator-activated receptors (PPARs) in addiction. There are two subtypes of PPAR receptors that have been studied in addiction: PPAR-α and PPAR-γ. The role of each PPAR subtype in common models of addictive behavior, mainly pre-clinical models, is summarized. In particular, studies are reviewed that investigated the effects of PPAR-α agonists on relapse, sensitization, conditioned place preference, withdrawal and drug intake, and effects of PPAR-γ agonists on relapse, withdrawal and drug intake. Finally, studies that investigated the effects of PPAR agonists on neural pathways of addiction are reviewed. Taken together this preclinical data indicates that PPAR agonists are promising new medications for drug addiction treatment. PMID:23614675

Apport des moyens endoscopiques dans la dilatation des sténoses caustiques de l’œsophage

PubMed Central

Seydou, Togo; Abdoulaye, Ouattara Moussa; xing, Li; Zi, Sanogo Zimogo; sekou, Koumaré; Wen, Yang Shang; Ibrahim, Sankare; Sekou, Toure Cheik Ahmed; Boubacar, Maiga Ibrahim; Saye, Jacque; Jerome, Dakouo Dodino; Dantoumé, Toure Ousmane; Sadio, Yena

2016-01-01

Introduction Toutes les sténoses symptomatiques de l’œsophage peuvent être dilatées par voie endoscopique. Nous évaluons l'apport des moyens endoscopiques dans la prise en charge de la dilatation œsophagienne pour sténose caustique de l’œsophage (SCO) au Mali. Méthodes IL s'agissait d'une étude descriptive et prospective réalisée dans le service de chirurgie thoracique à l'hôpital du Mali. Au total 46 dossiers cliniques de patients on été enregistrés et subdivisés en 4 groupes en fonction de la topographie des lésions cicatricielles. Le nombre de cas d'assistance endoscopique réalisé a été déterminé afin de comprendre l'apport des moyens endoscopiques dans le succès de la dilatation des SCO. Pour les 2 différentes méthodes de dilatation utilisées, le résultat du traitement et le coût ont comparés. Résultats La FOGD a été utilisée dans 19 cas (41.30%) de dilatation avec la bougie de Savary Guillard et dans 47.82% des cas dans la dilatation de Lerut. La vidéo-laryngoscopie a été utilisé 58.69% des cas de dilatation à la bougie de Lerut. Le passage de guide métallique et / ou de fil-guide a été réalisée dans 39.13% avec la vidéo laryngoscopie et dans 58.68% avec la FOGD. Dans la comparaison des deux méthodes, il existe une différence significative dans la survenue des complications (p=0.04075), l'anesthésie générale (p=0.02287), l'accessibilité à la méthode (p=0.04805) et la mortalité (p=0.00402). Conclusion La SCO est une pathologie grave et sous évaluée au Mali. Les moyens endoscopiques contribuent considérablement au succès de la dilatation œsophagienne pour sténose caustique dans les différentes méthodes utilisées. PMID:27200129

Reports of pathological gambling, hypersexuality, and compulsive shopping associated with dopamine receptor agonist drugs.

PubMed

Moore, Thomas J; Glenmullen, Joseph; Mattison, Donald R

2014-12-01

Severe impulse control disorders involving pathological gambling, hypersexuality, and compulsive shopping have been reported in association with the use of dopamine receptor agonist drugs in case series and retrospective patient surveys. These agents are used to treat Parkinson disease, restless leg syndrome, and hyperprolactinemia. To analyze serious adverse drug event reports about these impulse control disorders received by the US Food and Drug Administration (FDA) and to assess the relationship of these case reports with the 6 FDA-approved dopamine receptor agonist drugs. We conducted a retrospective disproportionality analysis based on the 2.7 million serious domestic and foreign adverse drug event reports from 2003 to 2012 extracted from the FDA Adverse Event Reporting System. Cases were selected if they contained any of 10 preferred terms in the Medical Dictionary for Regulatory Activities (MedDRA) that described the abnormal behaviors. We used the proportional reporting ratio (PRR) to compare the proportion of target events to all serious events for the study drugs with a similar proportion for all other drugs. We identified 1580 events indicating impulse control disorders from the United States and 21 other countries:710 fordopamine receptor agonist drugs and 870 for other drugs. The dopamine receptor agonist drugs had a strong signal associated with these impulse control disorders (n = 710; PRR = 277.6, P < .001). The association was strongest for the dopamine agonists pramipexole (n = 410; PRR = 455.9, P < .001) and ropinirole (n = 188; PRR = 152.5, P < .001), with preferential affinity for the dopamine D3 receptor. A signal was also seen for aripiprazole, an antipsychotic classified as a partial agonist of the D3 receptor (n = 37; PRR = 8.6, P < .001). Our findings confirm and extend the evidence that dopamine receptor agonist drugs are associated with these specific impulse control disorders. At present

Evolution of the Bifunctional Lead μ Agonist / δ Antagonist Containing the Dmt-Tic Opioid Pharmacophore.

PubMed

Balboni, Gianfranco; Salvadori, Severo; Trapella, Claudio; Knapp, Brian I; Bidlack, Jean M; Lazarus, Lawrence H; Peng, Xuemei; Neumeyer, John L

2010-02-17

Based on a renewed importance recently attributed to bi- or multifunctional opioids, we report the synthesis and pharmacological evaluation of some analogues derived from our lead μ agonist / δ antagonist, H-Dmt-Tic-Gly-NH-Bzl. Our previous studies focused on the importance of the C-teminal benzyl function in the induction of such bifunctional activity. The introduction of some substituents in the para position of the phenyl ring (-Cl, -CH(3), partially -NO(2), inactive -NH(2)) was found to give a more potent μ agonist / antagonist effect associated with a relatively unmodified δ antagonist activity (pA(2) = 8.28-9.02). Increasing the steric hindrance of the benzyl group (using diphenylmethyl and tetrahydroisoquinoline functionalities) substantially maintained the μ agonist and δ antagonist activities of the lead compound. Finally and quite unexpectedly D-Tic2, considered as a wrong opioid message now; inserted into the reference compound in lieu of L-Tic, provided a μ agonist / δ agonist better than our reference ligand (H-Dmt-Tic-Gly-NH-Ph) and was endowed with the same pharmacological profile.

Pharmacological characterization of 30 human melanocortin-4 receptor polymorphisms with the endogenous proopiomelanocortin-derived agonists, synthetic agonists, and the endogenous agouti-related protein antagonist.

PubMed

Xiang, Zhimin; Proneth, Bettina; Dirain, Marvin L; Litherland, Sally A; Haskell-Luevano, Carrie

2010-06-08

The melanocortin-4 receptor (MC4R) is a G-protein-coupled receptor (GPCR) that is expressed in the central nervous system and has a role in regulating feeding behavior, obesity, energy homeostasis, male erectile response, and blood pressure. Since the report of the MC4R knockout mouse in 1997, the field has been searching for links between this genetic biomarker and human obesity and type 2 diabetes. More then 80 single nucleotide polymorphisms (SNPs) have been identified from human patients, both obese and nonobese controls. Many significant studies have been performed examining the pharmacological characteristics of these hMC4R SNPs in attempts to identify a molecular defects/insights that might link a genetic factor to the obese phenotype observed in patients possessing these mutations. Our laboratory has previously reported the pharmacological characterization of 40 of these polymorphic hMC4 receptors with multiple endogenous and synthetic ligands. The goal of the current study is to perform a similar comprehensive side-by-side characterization of 30 additional human hMC4R with single nucleotide polymorphisms using multiple endogenous agonists [alpha-, beta-, and gamma(2)-melanocyte stimulating hormones (MSH) and adrenocorticotropin (ACTH)], the antagonist agouti-related protein hAGRP(87-132), and synthetic agonists [NDP-MSH, MTII, and the tetrapeptide Ac-His-dPhe-Arg-Trp-NH(2) (JRH887-9)]. These in vitro data, in some cases, provide a putative molecular link between dysfunctional hMC4R's and human obesity. These 30 hMC4R SNPs include R7H, R18H, R18L, S36Y, P48S, V50M, F51L, E61K, I69T, D90N, S94R, G98R, I121T, A154D, Y157S, W174C, G181D, F202L, A219 V, I226T, G231S, G238D, N240S, C271R, S295P, P299L, E308K, I317V, L325F, and 750DelGA. All but the N240S hMC4R were identified in obese patients. Additionally, we have characterized a double I102T/V103I hMC4R. In addition to the pharmacological characterization, the hMC4R variants were evaluated for cell surface

Fissuration en relaxation des aciers inoxydables austénitiques au voisinage des soudures

NASA Astrophysics Data System (ADS)

Auzoux, Q.; Allais, L.; Gourgues, A. F.; Pineau, A.

2003-03-01

Des fissures intergranulaires peuvent se développer au voisinage des soudures des aciers inoxydables austénitiques lorsqu'ils sont réchauffés dans le domaine de température compris entre 500^{circ}C et 700^{circ}C. A ces températures, les contraintes résiduelles post-soudage se relaxent par déformation viscoplastique. Il peut arriver que ces zones proches de la soudure soient tellement fragiles, qu'elles ne puissent accommoder cette faible déformation. Afin de préciser quelles peuvent être les modifications microstructurales qui conduisent à une telle fragilisation, on a examiné les microstructures de ces zones et révélé ainsi un écrouissage résiduel, responsable d'une forte élévation de la dureté. On a pu reproduire par hypertrempe puis laminage entre 400^{circ}C et 600^{circ}C une microstructure similaire. Des essais mécaniques (traction, fluage, relaxation, sur éprouvettes lisses et pré-fissurées) ont été réalisés à 550^{circ}C et à 600^{circ}C sur ces zones affectées simulées et sur un état de référence hypertrempé. Ils ont montré que l'écrouissage diminuait la ductilité dans le domaine de rupture intergranulaire, sans modifier qualitativement le mécanisme d'endommagement. Pendant la pré-déformation les incompatibilités de déformation entre grains conduiraient à l'existence de contraintes locales élevées qui favoriseraient la germination des cavités intergranulaires.

Synthesis and pharmacological characterization of beta2-adrenergic agonist enantiomers: zilpaterol.

PubMed

Kern, Christopher; Meyer, Thorsten; Droux, Serge; Schollmeyer, Dieter; Miculka, Christian

2009-03-26

The beta-adrenergic agonist 1 (zilpaterol) is used as production enhancer in cattle. Binding experiments of separated enantiomers on recombinant human beta(2)-adrenergic and mu-opioid receptors and functional studies showed that the (-)-1 enantiomer accounts for essentially all the beta(2)-adrenergic agonist activity and that it exhibits less affinity toward the mu-opioid receptor than (+)-1, which is a mu-opioid receptor antagonist. X-ray crystallography revealed the absolute configuration of (-)-1 to be 6R,7R.

Comparaison des effets des irradiations γ, X et UV dans les fibres optiques

NASA Astrophysics Data System (ADS)

Girard, S.; Ouerdane, Y.; Baggio, J.; Boukenter, A.; Meunier, J.-P.; Leray, J.-L.

2005-06-01

Les fibres optiques présentent de nombreux avantages incitant à les intégrer dans des applications devant résister aux environnements radiatifs associés aux domaines civil, spatial ou militaire. Cependant, leur exposition à un rayonnement entraîne la création de défauts ponctuels dans la silice amorphe pure ou dopée qui constitue les différentes parties de la fibre optique. Ces défauts causent, en particulier, une augmentation transitoire de l'atténuation linéique des fibres optiques responsable de la dégradation voire de la perte du signal propagé dans celles-ci. Dans cet article, nous comparons les effets de deux types d'irradiation: une impulsion X et une dose γ cumulée. Les effets de ces irradiations sont ensuite comparés avec ceux induits par une insolation ultraviolette (244 nm) sur les propriétés d'absorption des fibres optiques. Nous montrons qu'il existe des similitudes entre ces différentes excitations et qu'il est possible, sous certaines conditions, d'utiliser celles-ci afin d'évaluer la capacité de certaines fibres optiques à fonctionner dans un environnement nucléaire donné.

Toll-like receptor 7 agonists are potent and rapid bronchodilators in guinea pigs

PubMed Central

Kaufman, Elad H.; Fryer, Allison D.; Jacoby, David B.

2011-01-01

Background Respiratory tract viral infections result in asthma exacerbations. Toll-like receptor (TLR) 7 is a receptor for viral single-stranded RNA and is expressed at high levels in the lungs. Objective Because TLR7 polymorphisms are associated with asthma, we examined the effects of TLR7 agonists in guinea pig airways. Methods We induced bronchoconstriction in guinea pigs in vivo by means of electrical stimulation of the vagus nerve or intravenous administration of acetylcholine and measured the effect of a TLR7 agonist administered intravenously. We induced contraction of airway smooth muscle in segments of isolated guinea pig tracheas in vitro and measured the effect of TLR7 agonists, antagonists, and pharmacologic inhibitors of associated signaling pathways administered directly to the bath. Results TLR7 agonists acutely inhibited bronchoconstriction in vivo and relaxed contraction of airway smooth muscle in vitro within minutes of administration. Airway relaxation induced by the TLR7 agonist R837 (imiquimod) was partially blocked with a TLR7 antagonist and was also blocked by inhibitors of large-conductance, calcium-activated potassium channels; prostaglandin synthesis; and nitric oxide generation. Another TLR7 agonist, 21-mer single-stranded phosphorothioated polyuridylic acid (PolyUs), mediated relaxation that was completely blocked by a TLR7 antagonist. Conclusions These data demonstrate a novel protective mechanism to limit bronchoconstriction and maintain airflow during respiratory tract viral infections. The fast time frame is inconsistent with canonical TLR7 signaling. R837 mediates bronchodilation by means of TLR7-dependent and TLR7-independent mechanisms, whereas PolyUs does so through only the TLR7-dependent mechanism. TLR7-independent mechanisms involve prostaglandins and large-conductance, calcium-activated potassium channels, whereas TLR7-dependent mechanisms involve nitric oxide. TLR7 is an attractive therapeutic target for its ability to

Gonadotropin-releasing Hormone Agonists, Orchiectomy, and Risk of Cardiovascular Disease: Semi-ecologic, Nationwide, Population-based Study.

PubMed

Thomsen, Frederik Birkebæk; Sandin, Fredrik; Garmo, Hans; Lissbrant, Ingela Franck; Ahlgren, Göran; Van Hemelrijck, Mieke; Adolfsson, Jan; Robinson, David; Stattin, Pär

2017-12-01

In observational studies, men with prostate cancer treated with gonadotropin-releasing hormone (GnRH) agonists had a higher risk of cardiovascular disease (CVD) compared to men who had undergone orchiectomy. However, selection bias may have influenced the difference in risk. To investigate the association of type of androgen deprivation therapy (ADT) with risk of CVD while minimising selection bias. Semi-ecologic study of 6556 men who received GnRH agonists and 3330 men who underwent orchiectomy as primary treatment during 1992-1999 in the Prostate Cancer Database Sweden 3.0. We measured the proportion of men who received GnRH agonists as primary treatment in 580 experimental units defined by healthcare provider, diagnostic time period, and age at diagnosis. Incident or fatal CVD events in units with high and units with low use of GnRH agonists were compared. Net and crude probabilities were also analysed. The risk of CVD was similar between units with the highest and units with the lowest proportion of GnRH agonist use (relative risk 1.01, 95% confidence interval [CI] 0.93-1.11). Accordingly, there was no difference in the net probability of CVD after GnRH agonist compared to orchiectomy (hazard ratio 1.02, 95% CI 0.96-1.09). The 10-yr crude probability of CVD was 0.56 (95% CI 0.55-0.57) for men on GnRH agonists and 0.52 (95% CI 0.50-0.54) for men treated with orchiectomy. The main limitation was the nonrandom allocation to treatment, with younger men with lower comorbidity and less advanced cancer more likely to receive GnRH agonists. Our data do not support previous observations that GnRH agonists increase the risk of CVD in comparison to orchiectomy. We found a similar risk of cardiovascular disease between medical and surgical treatment as androgen deprivation therapy for prostate cancer. Copyright © 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Dendritic cells tolerized with adenosine A2AR agonist attenuate acute kidney injury

PubMed Central

Li, Li; Huang, Liping; Ye, Hong; Song, Steven P.; Bajwa, Amandeep; Lee, Sang Ju; Moser, Emily K.; Jaworska, Katarzyna; Kinsey, Gilbert R.; Day, Yuan J.; Linden, Joel; Lobo, Peter I.; Rosin, Diane L.; Okusa, Mark D.

2012-01-01

DC-mediated NKT cell activation is critical in initiating the immune response following kidney ischemia/reperfusion injury (IRI), which mimics human acute kidney injury (AKI). Adenosine is an important antiinflammatory molecule in tissue inflammation, and adenosine 2A receptor (A2AR) agonists protect kidneys from IRI through their actions on leukocytes. In this study, we showed that mice with A2AR-deficient DCs are more susceptible to kidney IRI and are not protected from injury by A2AR agonists. In addition, administration of DCs treated ex vivo with an A2AR agonist protected the kidneys of WT mice from IRI by suppressing NKT production of IFN-γ and by regulating DC costimulatory molecules that are important for NKT cell activation. A2AR agonists had no effect on DC antigen presentation or on Tregs. We conclude that ex vivo A2AR–induced tolerized DCs suppress NKT cell activation in vivo and provide a unique and potent cell-based strategy to attenuate organ IRI. PMID:23093781

Neurotransmitter agonists inhibit inositol phosphate formation in the brain of bupropione-treated rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Butler, P.D.; Hungund, B.; Suckow, R.

1986-03-05

Bupropione is a chemically unique antidepressant whose mechanism of action is not known. In this study they have evaluated the effect of chronic treatment with bupropione on the receptor-mediated release of inositol phosphates (IP) from brain slices in rats. Animals were implanted with Alzet osmotic pumps that delivered bupropione at a constant rate (40mg/kg/day) for 2 weeks. Cross-chopped slices of cerebral cortex from control and drug-treated rats were prelabelled with myo-/sup 3/H-inositol in HEPES buffer containing 11 mM LiCl. Accumulation of IP was measured in the presence and absence of the following agonists: Carbamylcholine (100..mu..m); norepinephrine (5..mu..M) and serotonin (10..mu..M).more » All agonists stimulated release of IP from slices of control animals but appeared to inhibit IP release in bupropione-treated rats. These results indicate that a phospholipase C inhibitor may appear following the activation of this enzyme by the agonist, and that the agonist-induced formation of the apparent inhibitor may be markedly enhanced after treatment with bupropione.« less

Vers des boites quantiques a base de graphene

NASA Astrophysics Data System (ADS)

Branchaud, Simon

Le graphene est un materiau a base de carbone qui est etudie largement depuis 2004. De tres nombreux articles ont ete publies tant sur les proprietes electroniques, qu'optiques ou mecaniques de ce materiel. Cet ouvrage porte sur l'etude des fluctuations de conductance dans le graphene, et sur la fabrication et la caracterisation de nanostructures gravees dans des feuilles de ce cristal 2D. Des mesures de magnetoresistance a basse temperature ont ete faites pres du point de neutralite de charge (PNC) ainsi qu'a haute densite electronique. On trouve deux origines aux fluctuations de conductance pres du PNC, soit des oscillations mesoscopiques provenant de l'interference quantique, et des fluctuations dites Hall quantique apparaissant a plus haut champ (>0.5T), semblant suivre les facteurs de remplissage associes aux monocouches de graphene. Ces dernieres fluctuations sont attribuees a la charge d'etats localises, et revelent un precurseur a l'effet Hall quantique, qui lui, ne se manifeste pas avant 2T. On arrive a extraire les parametres caracterisant l'echantillon a partir de ces donnees. A la fin de cet ouvrage, on effectue des mesures de transport dans des constrictions et ilots de graphene, ou des boites quantiques sont formees. A partir de ces mesures, on extrait les parametres importants de ces boites quantiques, comme leur taille et leur energie de charge.

Differential effects of subtype-specific nicotinic acetylcholine receptor agonists on early and late hippocampal LTP.

PubMed

Kroker, Katja S; Rast, Georg; Rosenbrock, Holger

2011-12-05

Brain nicotinic acetylcholine receptors are involved in several neuropsychiatric disorders, e.g. Alzheimer's and Parkinson's diseases, Tourette's syndrome, schizophrenia, depression, autism, attention deficit hyperactivity disorder, and anxiety. Currently, approaches selectively targeting the activation of specific nicotinic acetylcholine receptors are in clinical development for treatment of memory impairment of Alzheimer's disease patients. These are α4β2 and α7 nicotinic acetylcholine receptor agonists which are believed to enhance cholinergic and glutamatergic neurotransmission, respectively. In order to gain a better insight into the mechanistic role of these two nicotinic acetylcholine receptors in learning and memory, we investigated the effects of the α4β2 nicotinic acetylcholine receptor agonist TC-1827 and the α7 nicotinic acetylcholine receptor partial agonist SSR180711 on hippocampal long-term potentiation (LTP), a widely accepted cellular experimental model of memory formation. Generally, LTP is distinguished in an early and a late form, the former being protein-synthesis independent and the latter being protein-synthesis dependent. TC-1827 was found to increase early LTP in a bell-shaped dose dependent manner, but did not affect late LTP. In contrast, the α7 nicotinic acetylcholine receptor partial agonist SSR180711 showed enhancing effects on both early and late LTP in a bell-shaped manner. Furthermore, SSR180711 not only increased early LTP, but also transformed it into late LTP, which was not observed with the α4β2 nicotinic acetylcholine receptor agonist. Therefore, based on these findings α7 nicotinic acetylcholine receptor (partial) agonists appear to exhibit stronger efficacy on memory improvement than α4β2 nicotinic acetylcholine receptor agonists. Copyright © 2011 Elsevier B.V. All rights reserved.

Dopamine agonist 3-PPP fails to protect against MPTP-induced toxicity.

PubMed

Muralikrishnan, Dhanasekaran; Ebadi, Manuchair; Brown-Borg, Holly M

2004-02-01

We investigated the neuroprotective effect of the dopamine agonist, 3-PPP [3-(3-hydroxyphenyl)-N-propylpiperidine] against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity. MPTP (30 mg/kg, i.p., twice, 16 h apart) causes significant dopamine depletion in nucleus caudatus putamen (NCP) by 1 week. 3-PPP had no effect on the monoamine oxidase-B activity (MAO-B) activity in NCP. 3-PPP did not affect dopamine uptake, whereas mazindol significantly blocked the uptake of dopamine dose dependently. MPTP-induced behavioral changes in mice were not reduced by pretreatment with 3-PPP. This dopamine agonist did not prevent dopamine depletion caused by MPTP. MPP+ (20 microM) significantly inhibited the cell proliferation of SH-SY5Y dopaminergic neuronal cells. 3-PPP had no effect on the SH-SY5Y neuronal cell growth in culture and did not block the MPP(+)-induced cytotoxicity. This study shows that the dopamine agonist 3-PPP failed to protect against MPTP-induced dopaminergic neurotoxicity.

GnRH agonist versus GnRH antagonist in ovarian stimulation: is the emperor naked?

PubMed

Orvieto, R; Rabinson, J; Meltzer, S; Homburg, R; Anteby, E; Zohav, E

2006-01-01

The aim of the study was to evaluate the influence of type of GnRH-analog used during controlled ovarian hyperstimulation (COH) on the outcome of in vitro fertilization (IVF) cycles. All consecutive women aged < or = 35 years admitted to our IVF unit from January 2001 to December 2004 were enrolled in the study. Only patients undergoing up to their third IVF cycle attempt were included. Ovarian stimulation characteristics, number of oocytes retrieved, number of embryos transferred, and clinical pregnancy rate were compared between women given GnRH-agonist or GnRH-antagonist during COH. Four hundred and eighty-seven consecutive IVF cycles were evaluated, 226 in the agonist group and 261 in the antagonist group. A clinical pregnancy was achieved in 93 patients in the agonist group (pregnancy rate 41.2% per cycle) and 66 patients in the antagonist grup (pregnancy rate 25.3%); this difference was statistically significant (p < 0.01). The agonist group also used significantly more gonadotropin ampoules, required longer stimulation, and had higher estradiol levels on the day of human chorionic gonadotropin administration. The midluteal long GhRH-agonist suppressive protocol should be the protocol of choice in young patients in their first three IVF cycle attempts.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

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

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

Determination dans les Installations au Sol des Parametres Aerodynamiques de Stabilite des Aeronefs (Determination in Ground Facilities of Aerodynamic Stability Parameters of Aircraft),

DTIC Science & Technology

1979-06-01

7 INTRODUCTION ...................................................................................... 12 CHAPITRE I : ELEMENTS DE DYNAMIQUE...daone Ie texts. 12 INTRODUCTION La ddtermination des ddrivdes adrodynamiques de stabilitd, en soufflerie et au tunnel de tir, aur des maquettes...ddtection des forces eat effectuds de fegon classiqus depuis plus de vingt ana par des barreaux d’acier dquipds de jauges de contrainte, gdndralament en

Identification of PPARgamma Partial Agonists of Natural Origin (I): Development of a Virtual Screening Procedure and In Vitro Validation

PubMed Central

Guasch, Laura; Sala, Esther; Castell-Auví, Anna; Cedó, Lidia; Liedl, Klaus R.; Wolber, Gerhard; Muehlbacher, Markus; Mulero, Miquel; Pinent, Montserrat; Ardévol, Anna; Valls, Cristina; Pujadas, Gerard; Garcia-Vallvé, Santiago

2012-01-01

Background Although there are successful examples of the discovery of new PPARγ agonists, it has recently been of great interest to identify new PPARγ partial agonists that do not present the adverse side effects caused by PPARγ full agonists. Consequently, the goal of this work was to design, apply and validate a virtual screening workflow to identify novel PPARγ partial agonists among natural products. Methodology/Principal Findings We have developed a virtual screening procedure based on structure-based pharmacophore construction, protein-ligand docking and electrostatic/shape similarity to discover novel scaffolds of PPARγ partial agonists. From an initial set of 89,165 natural products and natural product derivatives, 135 compounds were identified as potential PPARγ partial agonists with good ADME properties. Ten compounds that represent ten new chemical scaffolds for PPARγ partial agonists were selected for in vitro biological testing, but two of them were not assayed due to solubility problems. Five out of the remaining eight compounds were confirmed as PPARγ partial agonists: they bind to PPARγ, do not or only moderately stimulate the transactivation activity of PPARγ, do not induce adipogenesis of preadipocyte cells and stimulate the insulin-induced glucose uptake of adipocytes. Conclusions/Significance We have demonstrated that our virtual screening protocol was successful in identifying novel scaffolds for PPARγ partial agonists. PMID:23226391

Regulation of p53 Stability and Apoptosis by a ROR Agonist

PubMed Central

Wang, Yongjun; Solt, Laura A.; Kojetin, Douglas J.; Burris, Thomas P.

2012-01-01

Activation of p53 function leading to cell-cycle arrest and/or apoptosis is a promising strategy for development of anti-cancer therapeutic agents. Here, we describe a novel mechanism for stabilization of p53 protein expression via activation of the orphan nuclear receptor, RORα. We demonstrate that treatment of cancer cells with a newly described synthetic ROR agonist, SR1078, leads to p53 stabilization and induction of apoptosis. These data suggest that synthetic ROR agonists may hold utility in the treatment of cancer. PMID:22509368

Regulation of p53 stability and apoptosis by a ROR agonist.

PubMed

Wang, Yongjun; Solt, Laura A; Kojetin, Douglas J; Burris, Thomas P

2012-01-01

Activation of p53 function leading to cell-cycle arrest and/or apoptosis is a promising strategy for development of anti-cancer therapeutic agents. Here, we describe a novel mechanism for stabilization of p53 protein expression via activation of the orphan nuclear receptor, RORα. We demonstrate that treatment of cancer cells with a newly described synthetic ROR agonist, SR1078, leads to p53 stabilization and induction of apoptosis. These data suggest that synthetic ROR agonists may hold utility in the treatment of cancer.

Discovery of 3-aryl-4-isoxazolecarboxamides as TGR5 receptor agonists.

PubMed

Evans, Karen A; Budzik, Brian W; Ross, Sean A; Wisnoski, David D; Jin, Jian; Rivero, Ralph A; Vimal, Mythily; Szewczyk, George R; Jayawickreme, Channa; Moncol, David L; Rimele, Thomas J; Armour, Susan L; Weaver, Susan P; Griffin, Robert J; Tadepalli, Sarva M; Jeune, Michael R; Shearer, Todd W; Chen, Zibin B; Chen, Lihong; Anderson, Donald L; Becherer, J David; De Los Frailes, Maite; Colilla, Francisco Javier

2009-12-24

A series of 3-aryl-4-isoxazolecarboxamides identified from a high-throughput screening campaign as novel, potent small molecule agonists of the human TGR5 G-protein coupled receptor is described. Subsequent optimization resulted in the rapid identification of potent exemplars 6 and 7 which demonstrated improved GLP-1 secretion in vivo via an intracolonic dose coadministered with glucose challenge in a canine model. These novel TGR5 receptor agonists are potentially useful therapeutics for metabolic disorders such as type II diabetes and its associated complications.

Lignes directrices canadiennes sur l’utilisation sécuritaire et efficace des opioïdes pour la douleur chronique non cancéreuse

PubMed Central

Kahan, Meldon; Mailis-Gagnon, Angela; Wilson, Lynn; Srivastava, Anita

2011-01-01

Résumé Objectif Présenter aux médecins de famille un résumé clinique pratique des lignes directrices canadiennes sur l’utilisation sécuritaire et efficace des opioïdes pour la douleur chronique non cancéreuse, produites par le National Opioid Use Guideline Group. Qualité des données Pour produire les lignes directrices, les chercheurs ont effectué une synthèse critique de la littérature médicale sur l’efficacité et l’innocuité des opioïdes pour la douleur chronique non cancéreuse et ont rédigé une série de recommandations. Un panel de 49 cliniciens experts de toutes les régions du Canada ont passé en revue l’ébauche et ont atteint un consensus sur 24 recommandations. Message principal Il est recommandé de faire un dépistage du risque de dépendance avant de prescrire des opioïdes. On recommande des opioïdes faibles (codéine et tramadol) pour une douleur de légère à modérée qui n’a pas répondu aux traitements de première intention. On peut essayer l’oxycodone, l’hydromorphone et la morphine chez les patients qui n’ont pas eu de soulagement avec des opioïdes plus faibles. Une faible dose initiale et une lente hausse du titrage sont recommandées, ainsi qu’une étroite surveillance du patient qu’on a d’abord renseigné. Les médecins doivent surveiller l’apparition de complications comme l’apnée du sommeil. La dose optimale est celle qui améliore le fonctionnement ou atténue les cotes d’évaluation de la douleur d’au moins 30 %. Pour la grande majorité des patients, la dose optimale sera bien en deçà de l’équivalent de 200 mg de morphine par jour. On recommande le sevrage progressif pour les patients qui n’ont pas répondu à un essai d’opioïdes adéquat. Conclusion Les opioïdes jouent un rôle important dans la prise en charge de la douleur chronique non cancéreuse, mais il faut en prescrire avec prudence pour limiter les dommages potentiels. Les nouvelles lignes directrices

Peroxidative Metabolism of β2-Agonists Salbutamol and Fenoterol and Their Analogs

PubMed Central

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

2009-01-01

Phenolic β2-adrenoreceptor agonists salbutamol, fenoterol and terbutaline relax smooth muscle cells that relieve acute airway bronchospasm associated with asthma. Why their use sometimes fails to relieve bronchospasm, and why the drugs appear to be less effective in patients with severe asthma exacerbations, remains unclear. We show that in the presence of hydrogen peroxide, both myeloperoxidase, secreted by activated neutrophils present in inflamed airways, and lactoperoxidase, which is naturally present in the respiratory system, catalyze oxidation of these β2-agonists. Azide, cyanide, thiocyanate, ascorbate, glutathione, and methimazole inhibited this process, while methionine was without effect. Inhibition by ascorbate and glutathione was associated with their oxidation to corresponding radical species by the agonists’-derived phenoxyl radicals. Using electron paramagnetic resonance (EPR), we detected free radical metabolites from β2-agonists by spin trapping with 2-methyl-2-nitrosopropane (MNP). Formation of these radicals was inhibited by pharmacologically-relevant concentrations of methimazole and dapsone. In alkaline buffers radicals from fenoterol and its structural analog, metaproteronol, were detected by direct EPR. Analysis of these spectra suggests that oxidation of fenoterol and metaproterenol, but not terbutaline, causes their transformation through intramolecular cyclization by addition of their amino nitrogen to the aromatic ring. Together, these results indicate that phenolic β2-agonists function as substrates for airway peroxidases and that the resulting products differ in their structural and functional properties from their parent compounds. They also suggest that these transformations can be modulated by pharmacological approaches using appropriate peroxidase inhibitors or alternative substrates. These processes may affect therapeutic efficacy and also play a role in adverse reactions of the β2-agonists. PMID:19462961

Oxytocin and Vasopressin Agonists and Antagonists as Research Tools and Potential Therapeutics

PubMed Central

Manning, M; Misicka, A; Olma, A; Bankowski, K; Stoev, S; Chini, B; Durroux, T; Mouillac, B; Corbani, M; Guillon, G

2012-01-01

We recently reviewed the status of peptide and nonpeptide agonists and antagonists for the V1a, V1b and V2 receptors for arginine vasopressin (AVP) and the oxytocin receptor for oxytocin (OT). In the present review, we update the status of peptides and nonpeptides as: (i) research tools and (ii) therapeutic agents. We also present our recent findings on the design of fluorescent ligands for V1b receptor localisation and for OT receptor dimerisation. We note the exciting discoveries regarding two novel naturally occurring analogues of OT. Recent reports of a selective VP V1a agonist and a selective OT agonist point to the continued therapeutic potential of peptides in this field. To date, only two nonpeptides, the V2/V1a antagonist, conivaptan and the V2 antagonist tolvaptan have received Food and Drug Administration approval for clinical use. The development of nonpeptide AVP V1a, V1b and V2 antagonists and OT agonists and antagonists has recently been abandoned by Merck, Sanofi and Pfizer. A promising OT antagonist, Retosiban, developed at Glaxo SmithKline is currently in a Phase II clinical trial for the prevention of premature labour. A number of the nonpeptide ligands that were not successful in clinical trials are proving to be valuable as research tools. Peptide agonists and antagonists continue to be very widely used as research tools in this field. In this regard, we present receptor data on some of the most widely used peptide and nonpeptide ligands, as a guide for their use, especially with regard to receptor selectivity and species differences. PMID:22375852

Discovery of novel acetanilide derivatives as potent and selective beta3-adrenergic receptor agonists.

PubMed

Maruyama, Tatsuya; Onda, Kenichi; Hayakawa, Masahiko; Matsui, Tetsuo; Takasu, Toshiyuki; Ohta, Mitsuaki

2009-06-01

In the search for potent and selective human beta3-adrenergic receptor (AR) agonists as potential drugs for the treatment of obesity and noninsulin-dependent (type II) diabetes, a novel series of acetanilide-based analogues were prepared and their biological activities were evaluated at the human beta3-, beta2-, and beta1-ARs. Among these compounds, 2-pyridylacetanilide (2f), pyrimidin-2-ylacetanilide (2u), and pyrazin-2-ylacetanilide (2v) derivatives exhibited potent agonistic activity at the beta3-AR with functional selectivity over the beta1- and beta2-ARs. In particular, compound 2u was found to be the most potent and selective beta3-AR agonist with an EC(50) value of 0.11 microM and no agonistic activity for either the beta1- or beta2-AR. In addition, 2f, 2u, and 2v showed significant hypoglycemic activity in a rodent diabetic model.

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.

Newspapers and Newspaper Ink Contain Agonists for the Ah Receptor

PubMed Central

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

2010-01-01

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 [3H]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

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

Neonatal (+)-methamphetamine exposure in rats alters adult locomotor responses to dopamine D1 and D2 agonists and to a glutamate NMDA receptor antagonist, but not to serotonin agonists

PubMed Central

Graham, Devon L.; Amos-Kroohs, Robyn M.; Braun, Amanda A.; Grace, Curtis E.; Schaefer, Tori L.; Skelton, Matthew R.; Williams, Michael T.; Vorhees, Charles V.

2015-01-01

Neonatal exposure to (+)-methamphetamine (Meth) results in long-term behavioural abnormalities but its developmental mechanisms are unknown. In a series of experiments, rats were treated from post-natal days (PD) 11–20 (stage that approximates human development from the second to third trimester) with Meth or saline and assessed using locomotor activity as the readout following pharmacological challenge doses with dopamine, serotonin and glutamate agonists or antagonists during adulthood. Exposure to Meth early in life resulted in an exaggerated adult locomotor hyperactivity response to the dopamine D1 agonist SKF-82958 at multiple doses, a high dose only under-response activating effect of the D2 agonist quinpirole, and an exaggerated under-response to the activating effect of the N-methyl-D-aspartic acid (NMDA) receptor antagonist, MK-801. No change in locomotor response was seen following challenge with the 5-HT releaser p-chloroamphetamine or the 5-HT2/3 receptor agonist, quipazine. These are the first data to show that PD 11-20 Meth exposure induces long-lasting alterations to dopamine D1, D2 and glutamate NMDA receptor function and may suggest how developmental Meth exposure leads to many of its long-term adverse effects. PMID:22391043

Gonadotropin-releasing Hormone Agonist Overuse: Urologists’ Response to Reimbursement and Characteristics Associated with Persistent Overuse

PubMed Central

Ellis, Shellie D.; Nielsen, Matthew E.; Carpenter, William R.; Jackson, George L.; Wheeler, Stephanie B.; Liu, Huan; Weinberger, Morris

2015-01-01

BACKGROUND Medicare reimbursement cuts have been associated with declining Gonadotropin-releasing Hormone (GnRH) agonist overuse in localized prostate cancer. Medical school affiliation and foreign training have been associated with persistent overuse. However, physician-level prescribing changes and the practice type of persistent overusers have not been examined. We sought to describe physician-level changes in GnRH agonist overuse and test the association of time in practice and solo practice type with GnRH agonist overuse. METHODS We matched American Medical Association physician data for 2,138 urologists to SEER–Medicare data for 12,943 men diagnosed with early stage and lower grade adenocarcinoma of the prostate between 2000 and 2007. We conducted a population-based, retrospective study using multi-level modeling to control for patient and provider characteristics. RESULTS Three distinct patterns of GnRH agonist overuse were observed. Urologists’ time in practice was not associated with GnRH agonist overuse (OR 0.89; 95% CI 0.75–1.05).However, solo practice type (OR 1.65; 95% CI 1.34–2.02), medical school affiliation (OR 0.65; 95% CI 0.55–0.77), and patient race were. Compared to non-Hispanic whites, non-Hispanic blacks (OR 1.76; 95% CI 1.37–2.27), Hispanics (OR 1.41; 95% CI 1.12–1.79) and men of “other” race (OR 1.44; 95% CI 1.04–1.99) had greater odds of receiving unnecessary GnRH agonists. CONCLUSIONS GnRH agonist overuse remains high among some urologists who may be professionally isolated and difficult to reach. These urologists treat more vulnerable populations, which may contribute to health disparities in prostate cancer treatment quality. Nonetheless, these findings provide guidance to develop interventions to address overuse in prostate cancer. PMID:25849354

A molecular characterization of the agonist binding site of a nematode cys-loop GABA receptor

PubMed Central

Kaji, Mark D; Kwaka, Ariel; Callanan, Micah K; Nusrat, Humza; Desaulniers, Jean-Paul; Forrester, Sean G

2015-01-01

Background and Purpose Cys-loop GABA receptors represent important targets for human chemotherapeutics and insecticides and are potential targets for novel anthelmintics (nematicides). However, compared with insect and mammalian receptors, little is known regarding the pharmacological characteristics of nematode Cys-loop GABA receptors. Here we have investigated the agonist binding site of the Cys-loop GABA receptor UNC-49 (Hco-UNC-49) from the parasitic nematode Haemonchus contortus. Experimental Approach We used two-electrode voltage-clamp electrophysiology to measure channel activation by classical GABA receptor agonists on Hco-UNC-49 expressed in Xenopus laevis oocytes, along with site-directed mutagenesis and in silico homology modelling. Key Results The sulphonated molecules P4S and taurine had no effect on Hco-UNC-49. Other classical Cys-loop GABAA receptor agonists tested on the Hco-UNC-49B/C heteromeric channel had a rank order efficacy of GABA > trans-4-aminocrotonic acid > isoguvacine > imidazole-4-acetic acid (IMA) > (R)-(−)-4-amino-3-hydroxybutyric acid [R(−)-GABOB] > (S)-(+)-4-amino-3-hydroxybutyric acid [S(+)-GABOB] > guanidinoacetic acid > isonipecotic acid > 5-aminovaleric acid (DAVA) (partial agonist) > β-alanine (partial agonist). In silico ligand docking revealed some variation in binding between agonists. Mutagenesis of a key serine residue in binding loop C to threonine had minimal effects on GABA and IMA but significantly increased the maximal response to DAVA and decreased twofold the EC50 for R(−)- and S(+)-GABOB. Conclusions and Implications The pharmacological profile of Hco-UNC-49 differed from that of vertebrate Cys-loop GABA receptors and insect resistance to dieldrin receptors, suggesting differences in the agonist binding pocket. These findings could be exploited to develop new drugs that specifically target GABA receptors of parasitic nematodes. PMID:25850584

Metformin sensitizes triple-negative breast cancer to proapoptotic TRAIL receptor agonists by suppressing XIAP expression.

PubMed

Strekalova, Elena; Malin, Dmitry; Rajanala, Harisha; Cryns, Vincent L

2017-06-01

Despite robust antitumor activity in diverse preclinical models, TNF-related apoptosis-inducing ligand (TRAIL) receptor agonists have not demonstrated efficacy in clinical trials, underscoring the need to identify agents that enhance their activity. We postulated that the metabolic stress induced by the diabetes drug metformin would sensitize breast cancer cells to TRAIL receptor agonists. Human triple (estrogen receptor, progesterone receptor, and HER2)-negative breast cancer (TNBC) cell lines were treated with TRAIL receptor agonists (monoclonal antibodies or TRAIL peptide), metformin, or the combination. The effects on cell survival, caspase activation, and expression of TRAIL receptors and the antiapoptotic protein XIAP were determined. In addition, XIAP was silenced by RNAi in TNBC cells and the effects on sensitivity to TRAIL were determined. The antitumor effects of metformin, TRAIL, or the combination were evaluated in an orthotopic model of metastatic TNBC. Metformin sensitized diverse TNBC cells to TRAIL receptor agonists. Metformin selectively enhanced the sensitivity of transformed breast epithelial cells to TRAIL receptor agonist-induced caspase activation and apoptosis with little effect on untransformed breast epithelial cells. These effects of metformin were accompanied by robust reductions in the protein levels of XIAP, a negative regulator of TRAIL-induced apoptosis. Silencing XIAP in TNBC cells mimicked the TRAIL-sensitizing effects of metformin. Metformin also enhanced the antitumor effects of TRAIL in a metastatic murine TNBC model. Our findings indicate that metformin enhances the activity of TRAIL receptor agonists, thereby supporting the rationale for additional translational studies combining these agents.

Molecular interactions of agonist and inverse agonist ligands at serotonin 5-HT2C G protein-coupled receptors: computational ligand docking and molecular dynamics studies validated by experimental mutagenesis results

NASA Astrophysics Data System (ADS)

Córdova-Sintjago, Tania C.; Liu, Yue; Booth, Raymond G.

2015-02-01

To understand molecular determinants for ligand activation of the serotonin 5-HT2C G protein-coupled receptor (GPCR), a drug target for obesity and neuropsychiatric disorders, a 5-HT2C homology model was built according to an adrenergic β2 GPCR (β2AR) structure and validated using a 5-HT2B GPCR crystal structure. The models were equilibrated in a simulated phosphatidyl choline membrane for ligand docking and molecular dynamics studies. Ligands included (2S, 4R)-(-)-trans-4-(3'-bromo- and trifluoro-phenyl)-N,N-dimethyl-1,2,3,4-tetrahydronaphthalene-2-amine (3'-Br-PAT and 3'-CF3-PAT), a 5-HT2C agonist and inverse agonist, respectively. Distinct interactions of 3'-Br-PAT and 3'-CF3-PAT at the wild-type (WT) 5-HT2C receptor model were observed and experimental 5-HT2C receptor mutagenesis studies were undertaken to validate the modelling results. For example, the inverse agonist 3'-CF3-PAT docked deeper in the WT 5-HT2C binding pocket and altered the orientation of transmembrane helices (TM) 6 in comparison to the agonist 3'-Br-PAT, suggesting that changes in TM orientation that result from ligand binding impact function. For both PATs, mutation of 5-HT2C residues S3.36, T3.37, and F5.47 to alanine resulted in significantly decreased affinity, as predicted from modelling results. It was concluded that upon PAT binding, 5-HT2C residues T3.37 and F5.47 in TMs 3 and 5, respectively, engage in inter-helical interactions with TMs 4 and 6, respectively. The movement of TMs 5 and 6 upon agonist and inverse agonist ligand binding observed in the 5-HT2C receptor modelling studies was similar to movements reported for the activation and deactivation of the β2AR, suggesting common mechanisms among aminergic neurotransmitter GPCRs.

Co-administration of delta- and mu-opioid receptor agonists promotes peripheral opioid receptor function

PubMed Central

Schramm, Cicely L.; Honda, Christopher N.

2010-01-01

Enhancement of peripheral opioid analgesia following tissue injury or inflammation in animal models is well-documented, but clinical results of peripheral opioid therapy remain inconsistent. Previous studies in the central nervous system have shown that co-administration of μ- and δ-opioid receptor agonists can enhance analgesic outcomes; however, less is known about the functional consequences of opioid receptor interactions in the periphery. The present study examines the effects of intraplantar injection of the μ- and δ-opioid receptor agonists, morphine and deltorphin, alone and in combination on behavioral tests of nociception in naïve rats and on potassium-evoked release of CGRP from sciatic nerves of naïve rats. Neither drug alone affected nociceptive behaviors or CGRP release. Two separate measures of mechanical nociceptive sensitivity remained unchanged after co-administration of the two drugs. In contrast, when deltorphin was co-injected with morphine, dose-dependent and peripherally-restricted increases in paw withdrawal latencies to radiant heat were observed. Similarly, concentration-dependent inhibition of CGRP release was observed when deltorphin and morphine were administered in sequence prior to potassium stimulation. However, no inhibition was observed when morphine was administered prior to deltorphin. All combined opioid effects were blocked by co-application of antagonists. Deltorphin exposure also enhanced the in vivo and in vitro effects of another μ-opioid receptor agonist, DAMGO. Together, these results suggest that under normal conditions, δ-opioid receptor agonists enhance the effect of μ-opioid receptor agonists in the periphery, and local co-administration of δ- and μ-opioid receptor agonists may improve results of peripheral opioid therapy for the treatment of pain. PMID:20970925

Drugs for metabolic conditions and prostate cancer death in men on GnRH agonists.

PubMed

Bosco, Cecilia; Wong, Chloe; Garmo, Hans; Crawley, Danielle; Holmberg, Lars; Hammar, Niklas; Adolfsson, Jan; Stattin, Pär; Van Hemelrijck, Mieke

2018-02-01

To evaluate whether drugs for metabolic conditions influence prostate cancer-specific mortality in men starting gonadotrophin-releasing hormone (GnRH) agonists, as it is unclear whether metabolic syndrome and its related drugs is affecting treatment response in men with prostate cancer on GnRH agonists. We selected all men receiving GnRH agonists as primary treatment in the Prostate Cancer data Base Sweden (PCBaSe) (n = 9267). Use of drugs for metabolic conditions (i.e. anti-diabetes, anti-dyslipidaemia, and antihypertension) in relation to all-cause, cardiovascular disease (CVD), and prostate cancer-specific death were studied using multivariate Cox proportional hazard and Fine and Gray competing regression models. In all, 6322 (68%) men used at least one drug for a metabolic condition at GnRH agonist initiation: 46% on antihypertensive drugs only, 32% on drugs for dyslipidaemia and hypertension, and ~10% on drugs for more than two metabolic conditions. Cox models indicated a weak increased risk of prostate cancer death in men who were on drugs for hypertension only (hazard ratio [HR] 1.12, 95% confidence interval [CI] 1.03-1.23) or drugs for hyperglycaemia (HR 1.19, 95% CI 1.06-1.35) at GnRH agonist initiation. However, upon taking into account competing risk from CVD death, none of the drugs for metabolic conditions were associated with an increased risk of prostate cancer death. We did not find evidence for a better or worse response to GnRH agonists in men with prostate cancer who were also on drugs for hypertension, dyslipidaemia, or hyperglycaemia. © 2017 The Authors BJU International © 2017 BJU International Published by John Wiley & Sons Ltd.

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

PubMed Central

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

2010-01-01

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

Assembly of high-affinity insulin receptor agonists and antagonists from peptide building blocks

PubMed Central

Schäffer, Lauge; Brissette, Renee E.; Spetzler, Jane C.; Pillutla, Renuka C.; Østergaard, Søren; Lennick, Michael; Brandt, Jakob; Fletcher, Paul W.; Danielsen, Gillian M.; Hsiao, Ku-Chuan; Andersen, Asser S.; Dedova, Olga; Ribel, Ulla; Hoeg-Jensen, Thomas; Hansen, Per Hertz; Blume, Arthur J.; Markussen, Jan; Goldstein, Neil I.

2003-01-01

Insulin is thought to elicit its effects by crosslinking the two extracellular α-subunits of its receptor, thereby inducing a conformational change in the receptor, which activates the intracellular tyrosine kinase signaling cascade. Previously we identified a series of peptides binding to two discrete hotspots on the insulin receptor. Here we show that covalent linkage of such peptides into homodimers or heterodimers results in insulin agonists or antagonists, depending on how the peptides are linked. An optimized agonist has been shown, both in vitro and in vivo, to have a potency close to that of insulin itself. The ability to construct such peptide derivatives may offer a path for developing agonists or antagonists for treatment of a wide variety of diseases. PMID:12684539

Pharmacological Characterization of 30 Human Melanocortin-4 Receptor Polymorphisms with the Endogenous Proopiomelanocortin Derived Agonists, Synthetic Agonists, and the Endogenous Agouti-Related Protein (AGRP) Antagonist

PubMed Central

Xiang, Zhimin; Proneth, Bettina; Dirain, Marvin L.; Litherland, Sally A.; Haskell-Luevano, Carrie

2010-01-01

The melanocortin-4 receptor (MC4R) is a G-protein coupled receptor (GPCR) that is expressed in the central nervous system and has a role in regulating feeding behavior, obesity, energy homeostasis, male erectile response, and blood pressure. Since the report of the MC4R knockout mouse in 1997, the field has been searching for links between this genetic bio marker and human obesity and type 2 diabetes. More then 80 single nucleotide polymorphisms (SNPs) have been identified from human patients, both obese and non-obese controls. Many significant studies have been performed examining the pharmacological characteristics of these hMC4R SNPs in attempts to identify a molecular defects/insights that might link a genetic factor to the obese phenotype observed in patients possessing these mutations. Our laboratory has previously reported the pharmacological characterization of 40 of these polymorphic hMC4 receptors with multiple endogenous and synthetic ligands. The goal of the current study is to perform a similar comprehensive side-by-side characterization of 30 additional human hMC4R with single nucleotide polymorphisms using multiple endogenous agonists [α-, β, γ2-melanocyte stimulating hormones (MSH) and adrenocorticotropin (ACTH)], the antagonist agouti-related protein hAGRP(87-132), and synthetic agonists [NDP-MSH, MTII, and the tetrapeptide Ac-His-DPhe-Arg-Trp-NH2 (JRH887-9)]. These in vitro data, in some cases, provide a putative molecular link between dysfunctional hMC4R's and human obesity. These 30 hMC4R SNPs include R7H, R18H, R18L, S36Y, P48S, V50M, F51L, E61K, I69T, D90N, S94R, G98R, I121T, A154D, Y157S, W174C, G181D, F202L, A219V, I226T, G231S, G238D, N240S, C271R, S295P, P299L, E308K, I317V, L325F and 750DelGA. All but the N240S hMC4R were identified in obese patients. Additionally, we have characterized a double I102T/V103I hMC4R. In addition to the pharmacological characterization, the hMC4R variants were evaluated for cell surface expression by flow

LHRH Agonists for the Treatment of Prostate Cancer: 2012

PubMed Central

Lepor, Herbert; Shore, Neal D

2012-01-01

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

Heritable victimization and the benefits of agonistic relationships

PubMed Central

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

2010-01-01

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

Treatment of Obesity-Related Complications with Novel Classes of Naturally Occurring PPAR Agonists

PubMed Central

Bassaganya-Riera, Josep; Guri, Amir J.; Hontecillas, Raquel

2011-01-01

The prevalence of obesity and its associated comorbidities has grown to epidemic proportions in the US and worldwide. Thus, developing safe and effective therapeutic approaches against these widespread and debilitating diseases is important and timely. Activation of peroxisome proliferator-activated receptors (PPARs) α, γ, and δ through several classes of pharmaceuticals can prevent or treat a variety of metabolic and inflammatory diseases, including type II diabetes (T2D). Thus, PPARs represent important molecular targets for developing novel and better treatments for a wide range of debilitating and widespread obesity-related diseases and disorders. However, available PPAR γ agonistic drugs such as Avandia have significant adverse side effects, including weight gain, fluid retention, hepatotoxicity, and congestive heart failure. An alternative to synthetic agonists of PPAR γ is the discovery and development of naturally occurring and safer nutraceuticals that may be dual or pan PPAR agonists. The purpose of this paper is to summarize the health effects of three plant-derived PPAR agonists: abscisic acid (ABA), punicic acid (PUA), and catalpic acid (CAA) in the prevention and treatment of chronic inflammatory and metabolic diseases and disorders. PMID:21253508

Treatment of Obesity-Related Complications with Novel Classes of Naturally Occurring PPAR Agonists.

PubMed

Bassaganya-Riera, Josep; Guri, Amir J; Hontecillas, Raquel

2011-01-01

The prevalence of obesity and its associated comorbidities has grown to epidemic proportions in the US and worldwide. Thus, developing safe and effective therapeutic approaches against these widespread and debilitating diseases is important and timely. Activation of peroxisome proliferator-activated receptors (PPARs) α, γ, and δ through several classes of pharmaceuticals can prevent or treat a variety of metabolic and inflammatory diseases, including type II diabetes (T2D). Thus, PPARs represent important molecular targets for developing novel and better treatments for a wide range of debilitating and widespread obesity-related diseases and disorders. However, available PPAR γ agonistic drugs such as Avandia have significant adverse side effects, including weight gain, fluid retention, hepatotoxicity, and congestive heart failure. An alternative to synthetic agonists of PPAR γ is the discovery and development of naturally occurring and safer nutraceuticals that may be dual or pan PPAR agonists. The purpose of this paper is to summarize the health effects of three plant-derived PPAR agonists: abscisic acid (ABA), punicic acid (PUA), and catalpic acid (CAA) in the prevention and treatment of chronic inflammatory and metabolic diseases and disorders.

Modulation Effect of Peroxisome Proliferator-Activated Receptor Agonists on Lipid Droplet Proteins in Liver.

PubMed

Zhu, Yun-Xia; Zhang, Ming-Liang; Zhong, Yuan; Wang, Chen; Jia, Wei-Ping

2016-01-01

Peroxisome proliferator-activated receptor (PPAR) agonists are used for treating hyperglycemia and type 2 diabetes. However, the mechanism of action of these agonists is still under investigation. The lipid droplet-associated proteins FSP27/CIDEC and LSDP5, regulated directly by PPARγ and PPARα, are associated with hepatic steatosis and insulin sensitivity. Here, we evaluated the expression levels of FSP27/CIDEC and LSDP5 and the regulation of these proteins by consumption of a high-fat diet (HFD) or administration of PPAR agonists. Mice with diet-induced obesity were treated with the PPARγ or PPARα agonist, pioglitazone or fenofibrate, respectively. Liver tissues from db/db diabetic mice and human were also collected. Interestingly, FSP27/CIEDC was expressed in mouse and human livers and was upregulated in obese C57BL/6J mice. Fenofibrate treatment decreased hepatic triglyceride (TG) content and FSP27/CIDEC protein expression in mice fed an HFD diet. In mice, LSDP5 was not detected, even in the context of insulin resistance or treatment with PPAR agonists. However, LSDP5 was highly expressed in humans, with elevated expression observed in the fatty liver. We concluded that fenofibrate greatly decreased hepatic TG content and FSP27/CIDEC protein expression in mice fed an HFD, suggesting a potential regulatory role for fenofibrate in the amelioration of hepatic steatosis.

New-generation 5-HT4 receptor agonists: potential for treatment of gastrointestinal motility disorders.

PubMed

Manabe, Noriaki; Wong, Banny S; Camilleri, Michael

2010-06-01

Gastrointestinal (GI) dysmotility is an important mechanism in functional GI disorders (FGIDs) including constipation, irritable bowel syndrome, functional dyspepsia, and gastroparesis. 5-hydroxytryptamine(4) (5-HT(4)) receptors are targets for the treatment of GI motility disorders. However, older 5-HT(4) receptor agonists had limited clinical success because they were associated with changes in the function of the cardiac HERG potassium channel. We conducted a PubMed search using the following key words alone or in combination: 5-HT(4), safety, toxicity, pharmacokinetics, pharmacodynamics, clinical trial, cardiac, hERG, arrhythmia, potassium current, elderly, prucalopride, ATI-7505, and velusetrag (TD-5108), to review mechanisms of action, clinical efficacy, safety and tolerability of three new-generation 5-HT(4) receptor agonists. Prucalopride, ATI-7505, and velusetrag (TD-5108) are highly selective, high-affinity 5-HT(4) receptor agonists that are devoid of action on other receptors within their therapeutic range. Their efficacy has been demonstrated in pharmacodynamic studies which demonstrate acceleration of colonic transit and, to a variable degree, in clinical trials that significantly relieve chronic constipation. Currently available evidence shows that the new 5-HT(4) receptor agonists have safe cardiac profiles. New-generation 5-HT(4) receptor agonists and future drugs targeting organ-specific splice variants are promising approaches to treat GI dysmotility, particularly colonic diseases.

Antinociceptive action of NOP and opioid receptor agonists in the mouse orofacial formalin test.

PubMed

Rizzi, A; Ruzza, C; Bianco, S; Trapella, C; Calo', G

2017-08-01

Nociceptin/orphanin FQ (N/OFQ) modulates several biological functions, including pain transmission via selective activation of a specific receptor named NOP. The aim of this study was the investigation of the antinociceptive properties of NOP agonists and their interaction with opioids in the trigeminal territory. The orofacial formalin (OFF) test in mice was used to investigate the antinociceptive potential associated to the activation of NOP and opioid receptors. Mice subjected to OFF test displayed the typical biphasic nociceptive response and sensitivity to opioid and NSAID drugs. Mice knockout for the NOP gene displayed a robust pronociceptive phenotype. The NOP selective agonist Ro 65-6570 (0.1-1mgkg -1 ) and morphine (0.1-10mgkg -1 ) elicited dose dependent antinociceptive effects in the OFF with the alkaloid showing larger effects; the isobologram analysis of their actions demonstrated an additive type of interaction. The mixed NOP/opioid receptor agonist cebranopadol elicited potent (0.01-0.1mgkg -1 ) and robust antinociceptive effects. In the investigated dose range, all drugs did not modify the motor performance of the mice in the rotarod test. Collectively the results of this study demonstrated that selective NOP agonists and particularly mixed NOP/opioid agonists are worthy of development as innovative drugs to treat painful conditions of the trigeminal territory. Copyright © 2017 Elsevier Inc. All rights reserved.

5-Functionalized indazoles as glucocorticoid receptor agonists.

PubMed

Bai, Mei; Carr, Grant; Deorazio, Russell J; Friedrich, Thomas D; Dobritsa, Svetlana; Fitzpatrick, Kevin; Guzzo, Peter R; Kitchen, Douglas B; Lynch, Michael A; Peace, Denise; Sajad, Mohammed; Usyatinsky, Alexander; Wolf, Mark A

2010-05-15

An indazole based series of glucocorticoid receptor agonists is reported. The SAR exploration of this scaffold yielded compounds with nanomolar affinity for the glucocorticoid receptor with indications of selectivity for the preferred transrepression mechanism; in vivo efficacy was observed in the mouse LPS induced TNFalpha model for compound 28. Copyright 2010 Elsevier Ltd. All rights reserved.

Development of novel neurokinin 3 receptor (NK3R) selective agonists with resistance to proteolytic degradation.

PubMed

Misu, Ryosuke; Oishi, Shinya; Yamada, Ai; Yamamura, Takashi; Matsuda, Fuko; Yamamoto, Koki; Noguchi, Taro; Ohno, Hiroaki; Okamura, Hiroaki; Ohkura, Satoshi; Fujii, Nobutaka

2014-10-23

Neurokinin B (NKB) regulates the release of gonadotropin-releasing hormone (GnRH) via activation of the neurokinin-3 receptor (NK3R). We evaluated the biological stability of NK3R selective agonists to develop novel NK3R agonists to regulate reproductive functions. On the basis of degradation profiles, several peptidomimetic derivatives were designed. The modification of senktide with (E)-alkene dipeptide isostere generated a novel potent NK3R agonist with high stability and prolonged bioactivity.

Des recommandations probantes pour surveiller l’innocuité des antipsychotiques de deuxième génération chez les enfants et les adolescents

PubMed Central

Pringsheim, Tamara; Panagiotopoulos, Constadina; Davidson, Jana; Ho, Josephine

2012-01-01

HISTORIQUE : Au Canada, l’utilisation d’antipsychotiques, notamment les antipsychotiques de deuxième génération (ADG), a augmenté de façon considérable depuis cinq ans chez les enfants ayant des troubles de santé mentale. Ces médicaments ont le potentiel de causer de graves complications métaboliques et neurologiques lorsqu’on les utilise de manière chronique. OBJECTIF : Synthétiser les données probantes relatives aux effets secondaires métaboliques et neurologiques précis associés à l’usage d’ADG chez les enfants et fournir des recommandations probantes sur la surveillance de ces effets secondaires. MÉTHODOLOGIE : Les auteurs ont procédé à une analyse systématique des essais cliniques contrôlés des ADG auprès d’enfants. Ils ont fait des recommandations à l’égard de la surveillance de l’innocuité des ADG d’après un modèle de classification fondé sur le système GRADE (système de notation de l’évaluation et de l’élaboration des recommandations). Lorsque les données probantes n’étaient pas suffisantes, ils fondaient leurs recommandations sur le consensus et l’avis d’experts. Un groupe consensuel multidisciplinaire a analysé toutes les données probantes pertinentes et est parvenu à un consensus à l’égard des recommandations. RÉSULTATS : Les recommandations probantes portant sur la surveillance de l’innocuité des ADG figurent dans les présentes lignes directrices. Les auteurs indiquent la qualité des recommandations relatives à des examens physiques et tests de laboratoire précis à l’égard de chaque ADG à des moments déterminés. CONCLUSION : De multiples essais aléatoires et contrôlés ont permis d’évaluer l’efficacité de bon nombre des ADG utilisés pour traiter les troubles de santé mentale en pédiatrie. Toutefois, leurs avantages ne sont pas sans risques : on observe à la fois des effets secondaires métaboliques et neurologiques chez les enfants traités au moyen d�

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.

PPAR-γ Agonists As Antineoplastic Agents in Cancers with Dysregulated IGF Axis

PubMed Central

Vella, Veronica; Nicolosi, Maria Luisa; Giuliano, Stefania; Bellomo, Maria; Belfiore, Antonino; Malaguarnera, Roberta

2017-01-01

It is now widely accepted that insulin resistance and compensatory hyperinsulinemia are associated to increased cancer incidence and mortality. Moreover, cancer development and progression as well as cancer resistance to traditional anticancer therapies are often linked to a deregulation/overactivation of the insulin-like growth factor (IGF) axis, which involves the autocrine/paracrine production of IGFs (IGF-I and IGF-II) and overexpression of their cognate receptors [IGF-I receptor, IGF-insulin receptor (IR), and IR]. Recently, new drugs targeting various IGF axis components have been developed. However, these drugs have several limitations including the occurrence of insulin resistance and compensatory hyperinsulinemia, which, in turn, may affect cancer cell growth and survival. Therefore, new therapeutic approaches are needed. In this regard, the pleiotropic effects of peroxisome proliferator activated receptor (PPAR)-γ agonists may have promising applications in cancer prevention and therapy. Indeed, activation of PPAR-γ by thiazolidinediones (TZDs) or other agonists may inhibit cell growth and proliferation by lowering circulating insulin and affecting key pathways of the Insulin/IGF axis, such as PI3K/mTOR, MAPK, and GSK3-β/Wnt/β-catenin cascades, which regulate cancer cell survival, cell reprogramming, and differentiation. In light of these evidences, TZDs and other PPAR-γ agonists may be exploited as potential preventive and therapeutic agents in tumors addicted to the activation of IGF axis or occurring in hyperinsulinemic patients. Unfortunately, clinical trials using PPAR-γ agonists as antineoplastic agents have reached conflicting results, possibly because they have not selected tumors with overactivated insulin/IGF-I axis or occurring in hyperinsulinemic patients. In conclusion, the use of PPAR-γ agonists in combined therapies of IGF-driven malignancies looks promising but requires future developments. PMID:28275367

Local administration of a hedgehog agonist accelerates fracture healing in a mouse model

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kashiwagi, Miki; Division of Clinical Biotechnology, The University of Tokyo Graduate School of Medicine, Bunkyo-ku, Tokyo, 113-0033; Hojo, Hironori

Bone fracture healing is processed through multiple biological stages including the transition from cartilaginous callus to bony callus formation. Because of its specific, temporal and indispensable functions demonstrated by mouse genetic studies, Hedgehog (Hh) signaling is one of the most potent signaling pathways involved in these processes, but the effect of Hh-signaling activation by small compounds on the repair process had not yet been addressed. Here we examined therapeutic effects of local and one shot-administration of the Hh agonist known as smoothened agonist (SAG) on bone fracture healing in a mouse model. A quantitative analysis with three-dimensional micro-computed tomography showedmore » that SAG administration increased the size of both the cartilaginous callus and bony callus at 14 days after the surgery. A histological analysis showed that SAG administration increased the number of cells expressing a proliferation marker and a chondrocyte marker in cartilaginous callus as well as the cells expressing an osteoblast marker in bony callus. These results indicate that the SAG administration resulted in an enhancement of callus formation during bone fracture healing, which is at least in part mediated by an increase in chondrocyte proliferation in cartilaginous callus and the promotion of bone formation in bony callus. Therapeutic strategies with a SAG-mediated protocol may thus be useful for the treatment of bone fractures. - Highlights: • Local administration of a Hh agonist accelerates callus formation. • The Hh agonist administration promotes chondrocyte proliferation in the soft callus. • The Hh agonist administration increases osteoblast formation in the hard callus.« less

Comparison of the release of microRNAs and extracellular vesicles from platelets in response to different agonists.

PubMed

Ambrose, Ashley R; Alsahli, Mohammed A; Kurmani, Sameer A; Goodall, Alison H

2018-07-01

On activation platelets release microRNAs and extracellular vesicles (EV) into circulation. The release of EV from platelets has been shown to be dependent on the agonist; in this study, we investigated whether the microRNA profile or EV released from platelets was also agonist specific. Washed platelets from healthy subjects were maximally stimulated with agonists specific for the receptors for collagen (Glycoprotein VI (GPVI)), thrombin (PAR1/PAR4), or ADP (P2Y1/P2Y12) with/without inhibiting secondary mediators, using aspirin to block cyclooxygenase-1 and apyrase to remove ADP. The released microRNAs were profiled using TaqMan microRNA microarray cards. Platelet-derived EV (pdEV) were characterized by size (Nanoparticle Tracking Analysis, NTA), for procoagulant activity (Annexin-V binding and support of thrombin generation), and for the EV markers CD63 and HSP70. Platelet activation triggered the release of 57-79 different microRNAs, dependent upon agonist, with a core of 46 microRNAs observed with all agonists. There was a high level of correlation between agonists (r 2  > 0.98; p < 0.0001 for all), and with the microRNA content of the parent platelets (r 2  > 0.98; p < 0.0001). The 46 microRNAs seen in all samples are predicted to have significant effects on the translation of proteins involved in endocytosis, cell cycle control, and differentiation. MiR-223-3p was the most abundant in all samples and has previously been implicated in myeloid lineage development and demonstrated to have anti-inflammatory effects. Stimulation through GPVI produced a pdEV population with significantly more procoagulant activity than the other agonists. Apyrase significantly reduced microRNA and pdEV release, while aspirin had little effect. These data suggest that all tested agonists trigger the release of a similar microRNA profile while the procoagulant activity of the pdEV was agonist dependent. ADP was shown to play an important role in the release of both micro

Influence du comportement des accompagnants sur le vécu des patients admis pour hémorragies digestives hautes au CHU campus de Lomé (Togo)

PubMed Central

Bagny, Aklesso; Dusabe, Angelique; Bouglouga, Oumboma; Lawson-ananisoh, Mawuli Late; Kaaga, Yeba Laconi; Djibril, Mohaman Awalou; Soedje, Kokou Mensah; Dassa, Simliwa Kolou; Redah, Datouda

2014-01-01

Introduction L'hémorragie digestive haute est une urgence, qui constitue souvent pour les patients un danger mortel suscitant inquiétude et agitation. Dans cet état, le patient dépend de ses accompagnants pour ses soins et pour honorer le traitement; mais souvent, il a été observé une discordance entre l'urgence et les comportements des accompagnants. Le but de cette étude était de décrire les facteurs socioéconomiques et psychologiques pouvant influencer les comportements des accompagnants des patients admis pour HDH, estimer l'indice de relation entre ces comportements et les facteurs associés d'une part et le vécu des patients admis pour HDH d'autre part. Méthodes Il s'agit d'une étude prospective menée de Septembre 2010 à Juin 2011 (soit 10 mois). Nous avions utilisé l'entretien semi-dirigé et l'observation directe pour collecter nos données, ces dernières avaient été traitées par les méthodes statistiques et d'analyse de contenu. Résultats Dans la présente étude, les comportements des accompagnants des patients admis pour HDH sont en majorité marqués par l'abandon (84%) et le manque de sollicitude (80,2%). Ces comportements sont souvent stimulés par les facteurs socioéconomiques tels que les difficultés économiques (83,2%), des conflits intrafamiliaux (85,1%) et des représentations (maladie incurable ou envoûtement) de la maladie par les accompagnants (73,3%) des cas. Quant aux patients, ils vivent ces comportements comme étant des menaces de mort ou des rejets (77,20%) et comme étant une dévalorisation ou une humiliation de la part de leurs accompagnants (70,30%). Les résultats confirment l'existence de lien significatif entre les comportements des accompagnants et les facteurs socio économiques, entre les comportements des accompagnants et des facteurs psychologiques, et entre le vécu des patients admis pour l'HDH et les comportements des accompagnants. Conclusion Des études ultérieures devraient aborder les points

Beta agonists in livestock feed: status, health concerns, and international trade.

PubMed

Centner, T J; Alvey, J C; Stelzleni, A M

2014-09-01

Since the U.S. Food and Drug Administration approved ractopamine hydrochloride and zilpaterol hydrochloride in animal feeds, usage of those compounds has been a topic of worldwide debate. Ractopamine and zilpaterol are β-adrenergic agonists used as veterinary drugs to increase weight gain in certain animals raised for food. The Joint FAO/WHO Expert Committee on Food Additives (JECFA) established maximum residue limits for ractopamine, which were adopted by the Codex Alimentarius Commission (Codex). No maximum residue limits for zilpaterol have been adopted by JECFA, and new reports of animal mobility issues confront the use of this feed additive. However, many countries disagree with the Codex standards and are restricting or banning meat products containing β agonists. The bans by major importers of U.S. meat products have prompted some to advocate that the United States use the World Trade Organization dispute settlement body. This paper looks at the developments to provide a fuller accounting of what the issues may mean to U.S. firms selling meat products containing residues of β agonists.

Differential epileptogenic potentials of selective mu and delta opiate receptor agonists.

PubMed

Haffmans, J; Dzoljic, M R

1983-01-01

By using electroencephalographic (EEG) and electromyographic recordings in anaesthetized and free-moving rats, two opioid peptides, known as selective agonists for mu and delta opiate receptors, respectively, were examined for their epileptogenic properties. The delta receptor peptide (DSTLE, 4.6-18.6 nmol, intraventricularly, ivt), a putative delta opiate agonist, produced a dose-related increase of myoclonic contractions (MC) with epileptic discharges in anaesthetized rats and severe wet dog shakes, with occasionally falling down, in free-moving animals. Morphiceptin, a specific mu opiate agonist, used in equimolar doses and under the same experimental conditions, had a significantly less pronounced effect on the number of MC and epileptiform EEG phenomena. Similarly, DSTLE (18.6 nmol) injected in the CA2 area of the hippocampus, a region with a nearly equal distribution of mu and delta opiate receptors, induced epileptic discharges in anaesthetized and free-moving rats, while an equimolar dose of morphiceptin had no significant effect. It is suggested that the epileptiform activity of opioid peptides is mainly due to an activation of delta opiate receptors in the central nervous system.

Biphasic Effect of Melanocortin Agonists on Metabolic Rate and Body Temperature

PubMed Central

Lute, Beth; Jou, William; Lateef, Dalya M.; Goldgof, Margalit; Xiao, Cuiying; Piñol, Ramón A.; Kravitz, Alexxai V.; Miller, Nicole R.; Huang, Yuning George; Girardet, Clemence; Butler, Andrew A.; Gavrilova, Oksana; Reitman, Marc L.

2014-01-01

Summary The melanocortin system regulates metabolic homeostasis and inflammation. Melanocortin agonists have contradictorily been reported to both increase and decrease metabolic rate and body temperature. We find two distinct physiologic responses occurring at similar doses. Intraperitoneal administration of the nonselective melanocortin agonist MTII causes a melanocortin-4 receptor (Mc4r) mediated hypermetabolism/hyperthermia. This is preceded by a profound, transient hypometabolism/hypothermia that is preserved in mice lacking any one of Mc1r, Mc3r, Mc4r, or Mc5r. Three other melanocortin agonists also caused hypothermia, which is actively achieved via seeking a cool environment, vasodilation, and inhibition of brown adipose tissue thermogenesis. These results suggest that the hypometabolic/hypothermic effect of MTII is not due to a failure of thermoregulation. The hypometabolism/hypothermia was prevented by dopamine antagonists and MTII selectively activated arcuate nucleus dopaminergic neurons; these neurons may contribute to the hypometabolism/hypothermia. We propose that the hypometabolism/hypothermia is a regulated response, potentially beneficial during extreme physiologic stress. PMID:24981835

Stimulants as specific inducers of dopamine-independent σ 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 σ agonists mediated by their selective actions at σ1 receptors (σ1Rs), 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 μ-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 σ1R 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 σ1R 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 σR 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 μg/kg) nor by the opioid antagonist (-)-naltrexone (1.0-10 mg/kg), whereas these antagonists were active against d

Stimulants as Specific Inducers of Dopamine-Independent σ 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 σ agonists mediated by their selective actions at σ1 receptors (σ1Rs), 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 μ-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 σ1R 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 σ1R 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 σR 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 μg/kg) nor by the opioid antagonist (−)-naltrexone (1.0–10 mg/kg), whereas these antagonists were active

A Small Molecule Inverse Agonist for the Human Thyroid-Stimulating Hormone Receptor

PubMed Central

Neumann, Susanne; Huang, Wenwei; Eliseeva, Elena; Titus, Steve; Thomas, Craig J.; Gershengorn, Marvin C.

2010-01-01

Small molecule inverse agonists for the TSH receptor (TSHR) may be used as probes of the role of basal (or agonist-independent or constitutive) signaling and may have therapeutic potential as orally active drugs to inhibit basal signaling in patients with thyroid cancer and in some patients with hyperthyroidism. We describe the first small-molecule ligand [1;2-(3-((2,6-dimethylphenoxy)methyl)-4-methoxyphenyl)-3-(furan-2-ylmethyl)-2,3-dihydroquinazolin-4(1H)-one] that exhibits inverse agonist properties at TSHR. 1 inhibits basal and TSH-stimulated signaling, measured as cAMP production, by TSHRs in HEK-EM 293 cells stably expressing wild-type TSHRs; the antagonism of TSH-mediated signaling is competitive. 1 also inhibits basal signaling by wild-type TSHRs, and four constitutively active mutants of TSHR expressed transiently in HEK-EM 293 cells. 1 was active under more physiologically relevant conditions in primary cultures of human thyrocytes expressing endogenous TSHRs where it inhibited basal levels of mRNA transcripts for thyroglobulin, thyroperoxidase, sodium iodide symporter, and TSHR. These data serve as proof of principle that small, drug-like molecules can inhibit basal signaling by TSHR. We suggest that this small molecule is a lead compound for the development of higher-potency inverse agonists that can be used as probes of TSHR biology with therapeutic potential. PMID:20427476

Comparative Review of Approved Melatonin Agonists for the Treatment of Circadian Rhythm Sleep-Wake Disorders.

PubMed

Williams, Wilbur P Trey; McLin, Dewey E; Dressman, Marlene A; Neubauer, David N

2016-09-01

Circadian rhythm sleep-wake disorders (CRSWDs) are characterized by persistent or recurrent patterns of sleep disturbance related primarily to alterations of the circadian rhythm system or the misalignment between the endogenous circadian rhythm and exogenous factors that affect the timing or duration of sleep. These disorders collectively represent a significant unmet medical need, with a total prevalence in the millions, a substantial negative impact on quality of life, and a lack of studied treatments for most of these disorders. Activation of the endogenous melatonin receptors appears to play an important role in setting the circadian clock in the suprachiasmatic nucleus of the hypothalamus. Therefore, melatonin agonists, which may be able to shift and/or stabilize the circadian phase, have been identified as potential therapeutic candidates for the treatment of CRSWDs. Currently, only one melatonin receptor agonist, tasimelteon, is approved for the treatment of a CRSWD: non-24-hour sleep-wake disorder (or non-24). However, three additional commercially available melatonin receptor agonists-agomelatine, prolonged-release melatonin, and ramelteon-have been investigated for potential use for treatment of CRSWDs. Data indicate that these melatonin receptor agonists have distinct pharmacologic profiles that may help clarify their clinical use in CRSWDs. We review the pharmacokinetic and pharmacodynamic properties of these melatonin agonists and summarize their efficacy profiles when used for the treatment of CRSWDs. Further studies are needed to determine the therapeutic potential of these melatonin agonists for most CRSWDs. © 2016 Vanda Pharmaceuticals, Inc. Pharmacotherapy published by Wiley Periodicals, Inc. on behalf of Pharmacotherapy Publications, Inc.

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; Navas, Frank; 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.

Differential activation of G-proteins by mu-opioid receptor agonists.

PubMed

Saidak, Zuzana; Blake-Palmer, Katherine; Hay, Debbie L; Northup, John K; Glass, Michelle

2006-03-01

We investigated the ability of the activated mu-opioid receptor (MOR) to differentiate between myristoylated G(alphai1) and G(alphaoA) type G(alpha) proteins, and the maximal activity of a range of synthetic and endogenous agonists to activate each G(alpha) protein. Membranes from HEK293 cells stably expressing transfected MOR were chaotrope extracted to denature endogenous G-proteins and reconstituted with specific purified G-proteins. The G(alpha) subunits were generated in bacteria and were demonstrated to be recognised equivalently to bovine brain purified G(alpha) protein by CB(1) cannabinoid receptors. The ability of agonists to catalyse the MOR-dependent GDP/[(35)S]GTP(gamma)S exchange was then compared for G(alphai1) and G(alphaoA). Activation of MOR by DAMGO produced a high-affinity saturable interaction for G(alphaoA) (K(m)=20+/-1 nM) but a low-affinity interaction with G(alphai1) (K(m)=116+/-12 nM). DAMGO, met-enkephalin and leucine-enkephalin displayed maximal G(alpha) activation among the agonists evaluated. Endomorphins 1 and 2, methadone and beta-endorphin activated both G(alpha) to more than 75% of the maximal response, whereas fentanyl partially activated both G-proteins. Buprenorphine and morphine demonstrated a statistically significant difference between the maximal activities between G(alphai1) and G(alphaoA). Interestingly, DAMGO, morphine, endomorphins 1 and 2, displayed significant differences in the potencies for the activation of the two G(alpha). Differences in maximal activity and potency, for G(alphai1) versus G(alphaoA), are both indicative of agonist selective activation of G-proteins in response to MOR activation. These findings may provide a starting point for the design of drugs that demonstrate greater selectivity between these two G-proteins and therefore produce a more limited range of effects.

Differential activation of G-proteins by μ-opioid receptor agonists

PubMed Central

Saidak, Zuzana; Blake-Palmer, Katherine; Hay, Debbie L; Northup, John K; Glass, Michelle

2006-01-01

We investigated the ability of the activated μ-opioid receptor (MOR) to differentiate between myristoylated Gαi1 and GαoA type Gα proteins, and the maximal activity of a range of synthetic and endogenous agonists to activate each Gα protein. Membranes from HEK293 cells stably expressing transfected MOR were chaotrope extracted to denature endogenous G-proteins and reconstituted with specific purified G-proteins. The Gα subunits were generated in bacteria and were demonstrated to be recognised equivalently to bovine brain purified Gα protein by CB1 cannabinoid receptors. The ability of agonists to catalyse the MOR-dependent GDP/[35S]GTPγS exchange was then compared for Gαi1 and GαoA. Activation of MOR by DAMGO produced a high-affinity saturable interaction for GαoA (Km=20±1 nM) but a low-affinity interaction with Gαi1 (Km=116±12 nM). DAMGO, met-enkephalin and leucine-enkephalin displayed maximal Gα activation among the agonists evaluated. Endomorphins 1 and 2, methadone and β-endorphin activated both Gα to more than 75% of the maximal response, whereas fentanyl partially activated both G-proteins. Buprenorphine and morphine demonstrated a statistically significant difference between the maximal activities between Gαi1 and GαoA. Interestingly, DAMGO, morphine, endomorphins 1 and 2, displayed significant differences in the potencies for the activation of the two Gα. Differences in maximal activity and potency, for Gαi1 versus GαoA, are both indicative of agonist selective activation of G-proteins in response to MOR activation. These findings may provide a starting point for the design of drugs that demonstrate greater selectivity between these two G-proteins and therefore produce a more limited range of effects. PMID:16415903

Scramjet Thermal Management (Tenue thermique des superstatoreacteurs)

DTIC Science & Technology

2010-09-01

RTO-EN-AVT-185 13 - 1 Scramjet Thermal Management (Tenue thermique des superstatoréacteurs) Marc BOUCHEZ MBDA France Rond-point Marcel...SPEED PROPULSION: ENGINE DESIGN – INTEGRATION AND THERMAL MANAGEMENT” fut donné à l’Institut Von Karman en septembre 2010 et à l’Université Wright de ...Dayton (Ohio, USA) en décembre 2010. Le présent cours aborde la tenue thermique. Il est basé sur des informations publiées, et des détails

Characterization of 12 GnRH peptide agonists – a kinetic perspective

PubMed Central

Nederpelt, Indira; Georgi, Victoria; Schiele, Felix; Nowak‐Reppel, Katrin; Fernández‐Montalván, Amaury E.; IJzerman, Adriaan P.

2015-01-01

Background and Purpose Drug‐target residence time is an important, yet often overlooked, parameter in drug discovery. Multiple studies have proposed an increased residence time to be beneficial for improved drug efficacy and/or longer duration of action. Currently, there are many drugs on the market targeting the gonadotropin‐releasing hormone (GnRH) receptor for the treatment of hormone‐dependent diseases. Surprisingly, the kinetic receptor‐binding parameters of these analogues have not yet been reported. Therefore, this project focused on determining the receptor‐binding kinetics of 12 GnRH peptide agonists, including many marketed drugs. Experimental Approach A novel radioligand‐binding competition association assay was developed and optimized for the human GnRH receptor with the use of a radiolabelled peptide agonist, [125I]‐triptorelin. In addition to radioligand‐binding studies, a homogeneous time‐resolved FRET Tag‐lite™ method was developed as an alternative assay for the same purpose. Key Results Two novel competition association assays were successfully developed and applied to determine the kinetic receptor‐binding characteristics of 12 high‐affinity GnRH peptide agonists. Results obtained from both methods were highly correlated. Interestingly, the binding kinetics of the peptide agonists were more divergent than their affinities with residence times ranging from 5.6 min (goserelin) to 125 min (deslorelin). Conclusions and Implications Our research provides new insights by incorporating kinetic, next to equilibrium, binding parameters in current research and development that can potentially improve future drug discovery targeting the GnRH receptor. PMID:26398856

Targeting alpha-7 nicotinic neurotransmission in schizophrenia: A novel agonist strategy

PubMed Central

Deutsch, Stephen I.; Schwartz, Barbara L.; Schooler, Nina R.; Brown, Clayton H.; Rosse, Richard B.; Rosse, Stephanie M.

2013-01-01

Alpha7 nicotinic acetylcholine receptor (α7 nAChR) agonists may be valuable treatments for negative symptoms and cognitive impairment in schizophrenia. Unfortunately, chronic exposure to an agonist may reduce the receptor’s sensitivity. Therefore, we combined CDP-choline, a dietary source of the direct agonist choline, with galantamine, a positive allosteric modulator (PAM) of nicotinic acetylcholine receptors, to improve the efficiency of transducing the choline signal and, possibly, preserve the receptor in a sensitive state. We conducted a single-site, double-blind randomized clinical trial comparing galantamine/CDP-choline to placebos in schizophrenia patients with negative symptoms who were receiving second generation antipsychotics. Forty-three subjects received galantamine and CDP-choline or matching placebos for 16 weeks. The primary outcome measure was the 5-item Marder negative-symptoms factor of the Positive and Negative Syndrome Scale (PANSS). Cognition and functioning were also assessed. Trial completion was high; 79%. There was no significant treatment effect on negative symptoms, other PANSS symptom factors, or the MATRICS Cognitive Consensus Battery. There were significant treatment effects in overall functioning and a test of free verbal recall. Three subjects discontinued treatment in the active treatment group for gastro-intestinal adverse events (AE). The most common AE for galantamine/CDP-choline was abdominal pain; for placebo it was headache and sweating. Although there was no significant treatment effect on negative symptoms, the direction of effect mirrored the effects on a cognitive measure and overall functioning. Further study of α7 nAChR agonist/PAMs are warranted in larger studies that will have greater power. PMID:23768813

The Case for the Use of PPARγ Agonists as an Adjunctive Therapy for Cerebral Malaria

PubMed Central

Serghides, Lena

2012-01-01

Cerebral malaria is a severe complication of Plasmodium falciparum infection associated with high mortality even when highly effective antiparasitic therapy is used. Adjunctive therapies that modify the pathophysiological processes caused by malaria are a possible way to improve outcome. This review focuses on the utility of PPARγ agonists as an adjunctive therapy for the treatment of cerebral malaria. The current knowledge of PPARγ agonist use in malaria is summarized. Findings from experimental CNS injury and disease models that demonstrate the potential for PPARγ agonists as an adjunctive therapy for cerebral malaria are also discussed. PMID:21772838

Classification of 13 DES supernova with OzDES

NASA Astrophysics Data System (ADS)

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

2018-01-01

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

Classification of 26 DES supernova with OzDES

NASA Astrophysics Data System (ADS)

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

2018-01-01

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

Classification of 25 DES supernova with OzDES

NASA Astrophysics Data System (ADS)

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

2018-01-01

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

Classification of 18 DES supernova with OzDES

NASA Astrophysics Data System (ADS)

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

2018-06-01

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

Classification of 17 DES supernova with OzDES

NASA Astrophysics Data System (ADS)

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

2017-09-01

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

Small-molecule agonists for the thyrotropin receptor stimulate thyroid function in human thyrocytes and mice

PubMed Central

Neumann, Susanne; Huang, Wenwei; Titus, Steve; Krause, Gerd; Kleinau, Gunnar; Alberobello, Anna Teresa; Zheng, Wei; Southall, Noel T.; Inglese, James; Austin, Christopher P.; Celi, Francesco S.; Gavrilova, Oksana; Thomas, Craig J.; Raaka, Bruce M.; Gershengorn, Marvin C.

2009-01-01

Seven-transmembrane-spanning receptors (7TMRs) are prominent drug targets. However, small-molecule ligands for 7-transmembrane-spanning receptors for which the natural ligands are large, heterodimeric glycoprotein hormones, like thyroid-stimulating hormone (TSH; thyrotropin), have only recently been reported, and none are approved for human use. We have used quantitative high-throughput screening to identify a small-molecule TSH receptor (TSHR) agonist that was modified to produce a second agonist with increased potency. We show that these agonists are highly selective for human TSHR versus other glycoprotein hormone receptors and interact with the receptor's serpentine domain. A binding pocket within the transmembrane domain was defined by docking into a TSHR homology model and was supported by site-directed mutagenesis. In primary cultures of human thyrocytes, both TSH and the agonists increase mRNA levels for thyroglobulin, thyroperoxidase, sodium iodide symporter, and deiodinase type 2, and deiodinase type 2 enzyme activity. Moreover, oral administration of the agonist stimulated thyroid function in mice, resulting in increased serum thyroxine and thyroidal radioiodide uptake. Thus, we discovered a small molecule that activates human TSHR in vitro, is orally active in mice, and could be a lead for development of drugs to use in place of recombinant human TSH in patients with thyroid cancer. PMID:19592511

Discovery of N-(4-aryl-5-aryloxy-thiazol-2-yl)-amides as potent RORγt inverse agonists.

PubMed

Wang, Yonghui; Yang, Ting; Liu, Qian; Ma, Yingli; Yang, Liuqing; Zhou, Ling; Xiang, Zhijun; Cheng, Ziqiang; Lu, Sijie; Orband-Miller, Lisa A; Zhang, Wei; Wu, Qianqian; Zhang, Kathleen; Li, Yi; Xiang, Jia-Ning; Elliott, John D; Leung, Stewart; Ren, Feng; Lin, Xichen

2015-09-01

A novel series of N-(4-aryl-5-aryloxy-thiazol-2-yl)-amides as RORγt inverse agonists was discovered. Binding mode analysis of a RORγt partial agonist (2c) revealed by co-crystal structure in RORγt LBD suggests that the inverse agonists do not directly interfere with the interaction between H12 and the RORγt LBD. Detailed SAR exploration led to identification of potent RORγt inverse agonists such as 3m with a pIC50 of 8.0. Selected compounds in the series showed reasonable activity in Th17 cell differentiation assay as well as low intrinsic clearance in mouse liver microsomes. Copyright © 2015 Elsevier Ltd. All rights reserved.

Influence des défauts de la structure du verre sur la résistance mécanique des fibres optiques

NASA Astrophysics Data System (ADS)

Chmel, A.; Baptizmanski, V. V.; Kharshak, A. A.

1992-12-01

For silica (pure and doped) optical fibers prepared from preforms irradiated by thermal neutrons and Ar^+ ions, the measurements of lifetime under transverse stress were carried out. It is found that the neutron bombardment leads to decrease of the lifetime and the strength of fiber while the ion implantation results in increasing of these parameters. The influence of particle irradiation on the glass strength is explained by the generation of structural defects which were observed by the infrared an Raman spectroscopy methods. The direction of the change of mechanical properties of fibers is determined by the type of defects and their distribution in the cross-section of fiber. Des préformes de fibres optiques de silice ont été exposées à un bombardement par des faisceaux de neutrons thermiques et d'ions Ar^+ à énergie de 40 keV afin d'engendrer des défauts de la structure respectivement dans le volume ou dans la couche superficielle des échantillons. Les fibres obtenues des préformes irradiées et non irradiées ont été mises en charge de flexion. On a déterminé leur temps de rupture sous diverses contraintes de traction sur la surface extérieure de la fibre en flexion. On a observé une diminution du temps de rupture des fibres après le bombardement neutronique et une augmentation après l'implantation ionique. L'analyse de la nature des défauts en faisant appel à la spectroscopie infrarouge et Raman a fait ressortir que l'irradiation aux ions entraînait essentiellement des liaisons chimiques dans une fine couche superficielle de l'échantillon alors que l'irradiation aux neutrons occasionnait une déformation des zones du réseau silicique dans toute la section de la préforme et de la fibre. L'amélioration de la résistance mécanique s'explique par une augmentation de la mobilité des éléments structuraux de la matrice de verre par suite d'une rupture partielle des liaisons chimiques et sa diminution par l'apparition de concentrateurs

Agonist Met antibodies define the signalling threshold required for a full mitogenic and invasive program of Kaposi's Sarcoma cells.

PubMed

Bardelli, Claudio; Sala, Marilena; Cavallazzi, Umberto; Prat, Maria

2005-09-09

We previously showed that the Kaposi Sarcoma line KS-IMM express a functional Met tyrosine kinase receptor, which, upon HGF stimulation, activates motogenic, proliferative, and invasive responses. In this study, we investigated the signalling pathways activated by HGF, as well as by Met monoclonal antibodies (Mabs), acting as full or partial agonists. The full agonist Mab mimics HGF in all biological and biochemical aspects. It elicits the whole spectrum of responses, while the partial agonist Mab induces only wound healing. These differences correlated with a more prolonged and sustained tyrosine phosphorylation of the receptor and MAPK evoked by HGF and by the full agonist Mab, relative to the partial agonist Mab. Since Gab1, JNK and PI 3-kinase are activated with same intensity and kinetics by HGF and by the two agonist antibodies, it is concluded that level and duration of MAPK activation by Met receptor are crucial for the induction of a full HGF-dependent mitogenic and invasive program in KS cells.

Etude de la dynamique des porteurs dans des nanofils de silicium par spectroscopie terahertz

NASA Astrophysics Data System (ADS)

Beaudoin, Alexandre

Ce memoire presente une etude des proprietes de conduction electrique et de la dynamique temporelle des porteurs de charges dans des nanofils de silicium sondes par rayonnement terahertz. Les cas de nanofils de silicium non intentionnellement dopes et dopes type n sont compares pour differentes configurations du montage experimental. Les mesures de spectroscopie terahertz en transmission montre qu'il est possible de detecter la presence de dopants dans les nanofils via leur absorption du rayonnement terahertz (˜ 1--12 meV). Les difficultes de modelisation de la transmission d'une impulsion electromagnetique dans un systeme de nanofils sont egalement discutees. La detection differentielle, une modification au systeme de spectroscopie terahertz, est testee et ses performances sont comparees au montage de caracterisation standard. Les instructions et des recommendations pour la mise en place de ce type de mesure sont incluses. Les resultats d'une experience de pompe optique-sonde terahertz sont egalement presentes. Dans cette experience, les porteurs de charge temporairement crees suite a l'absorption de la pompe optique (lambda ˜ 800 nm) dans les nanofils (les photoporteurs) s'ajoutent aux porteurs initialement presents et augmentent done l'absorption du rayonnement terahertz. Premierement, l'anisotropie de l'absorption terahertz et de la pompe optique par les nanofils est demontree. Deuxiemement, le temps de recombinaison des photoporteurs est etudie en fonction du nombre de photoporteurs injectes. Une hypothese expliquant les comportements observes pour les nanofils non-dopes et dopes-n est presentee. Troisiemement, la photoconductivite est extraite pour les nanofils non-dopes et dopes-n sur une plage de 0.5 a 2 THz. Un lissage sur la photoconductivite permet d'estimer le nombre de dopants dans les nanofils dopes-n. Mots-cles: nanofil, silicium, terahertz, conductivite, spectroscopie, photoconductivite.

ICI 204448: a kappa-opioid agonist with limited access to the CNS.

PubMed Central

Shaw, J. S.; Carroll, J. A.; Alcock, P.; Main, B. G.

1989-01-01

1. A number of compounds were evaluated in an attempt to identify a kappa-opioid receptor agonist with limited access to the central nervous system. 2. Quaternary derivatives of the kappa-opioid agonists tifluadom, U-50488H and ethylketocyclazocine were essentially devoid of opioid activity in a range of isolated tissue preparations. 3. A novel compound - ICI 204448 - is described which produced a potent and naloxone-reversible inhibition of electrically-evoked contraction of the guinea-pig ileum, mouse vas deferens and rabbit vas deferens preparations. ICI 204448 was shown to displace the binding of the kappa-opioid ligand [3H]-bremazocine from guinea-pig cerebellum membranes. 4. Ex vivo binding studies in mice showed ICI 204448 to be well absorbed following subcutaneous administration. The brain levels achieved by ICI 20448 were substantially lower than those produced by kappa-agonists such as U-50488H and tifluadom. 5. A good correlation was found for a range of opioids between lipophilicity and degree of CNS penetration. PMID:2568146

Cell type-specific regulation of beta2-adrenoceptor mRNA by agonists.

PubMed

Danner, S; Lohse, M J

1997-07-16

Prolonged agonist stimulation of beta2-adrenoceptors results in receptor down-regulation which is often paralleled by a reduction of the corresponding mRNA. In this study, we investigated the agonist-dependent regulation of beta2-adrenoceptor mRNA in DDT1-MF2 smooth muscle cells and C6 glioma cells. In DDT1-MF2 cells the half-life of the mRNA was 12 h in monolayer compared to 2 h in suspension cultures. Under both conditions, the agonist isoproterenol reduced this half-life by a factor of 2. In contrast, in C6 glioma cells isoproterenol had no effect on the mRNA stability, even though it reduced mRNA levels by approximately 50%. Isoproterenol-induced downregulation of beta2-adrenoceptor mRNA was completely blocked in C6 cells by the presence of a protein synthesis inhibitor, while this was not so in DDT1-MF2-cells. These data show that beta2-adrenoceptor downregulation occurs via cell-type specific mechanisms.

Clinical use of deslorelin (GnRH agonist) in companion animals: a review.

PubMed

Lucas, X

2014-10-01

Over the years, many contraceptive medications have been developed for companion animals, but many secondary adverse effects have limited their use. A major advancement was achieved with the use of gonadotropin-releasing hormone (GnRH) analogues, mainly GnRH agonists, which mimic the effects of native GnRH. The development of effective low-dose, slow-release implants with potent agonists such as deslorelin (Suprelorin®, Virbac) have allowed their use to become widespread in recent years, with many potential benefits in companion animals. While the major application of deslorelin was initially male contraception, due to its two differing actions, either the stimulation of oestrus or the sterilization of fertility, its use has been increasing in the bitch as well. The aim of this study is to review the applications of deslorelin GnRH agonist implants in companion animal, such as dogs, cats and some exotic pets. © 2014 Blackwell Verlag GmbH.

Appraisal of unimodal cues during agonistic interactions in Maylandia zebra

PubMed Central

Ben Ammar, Imen; Fernandez, Marie S.A.; Boyer, Nicolas; Attia, Joël; Fonseca, Paulo J.; Amorim, M. Clara P.; Beauchaud, Marilyn

2017-01-01

Communication is essential during social interactions including animal conflicts and it is often a complex process involving multiple sensory channels or modalities. To better understand how different modalities interact during communication, it is fundamental to study the behavioural responses to both the composite multimodal signal and each unimodal component with adequate experimental protocols. Here we test how an African cichlid, which communicates with multiple senses, responds to different sensory stimuli in a social relevant scenario. We tested Maylandia zebra males with isolated chemical (urine or holding water coming both from dominant males), visual (real opponent or video playback) and acoustic (agonistic sounds) cues during agonistic interactions. We showed that (1) these fish relied mostly on the visual modality, showing increased aggressiveness in response to the sight of a real contestant but no responses to urine or agonistic sounds presented separately, (2) video playback in our study did not appear appropriate to test the visual modality and needs more technical prospecting, (3) holding water provoked territorial behaviours and seems to be promising for the investigation into the role of the chemical channel in this species. Our findings suggest that unimodal signals are non-redundant but how different sensory modalities interplay during communication remains largely unknown in fish. PMID:28785523

Use of ß-adrenergic agonists in hybrid catfish

USDA-ARS?s Scientific Manuscript database

Ractopamine hydrochloride (RH) is a potent ß-adrenergic agonist that has been used in some species of fish to improve growth performance and dress out characteristics. While this metabolic modifier has been shown to have positive effects on growth of fish, little research has focused on the mechani...

Design and Discovery of Functionally Selective Serotonin 2C (5-HT2C) Receptor Agonists.

PubMed

Cheng, Jianjun; McCorvy, John D; Giguere, Patrick M; Zhu, Hu; Kenakin, Terry; Roth, Bryan L; Kozikowski, Alan P

2016-11-10

On the basis of the structural similarity of our previous 5-HT 2C agonists with the melatonin receptor agonist tasimelteon and the putative biological cross-talk between serotonergic and melatonergic systems, a series of new (2,3-dihydro)benzofuran-based compounds were designed and synthesized. The compounds were evaluated for their selectivity toward 5-HT 2A , 5-HT 2B , and 5-HT 2C receptors in the calcium flux assay with the ultimate goal to generate selective 5-HT 2C agonists. Selected compounds were studied for their functional selectivity by comparing their transduction efficiency at the G protein signaling pathway versus β-arrestin recruitment. The most functionally selective compound (+)-7e produced weak β-arrestin recruitment and also demonstrated less receptor desensitization compared to serotonin in both calcium flux and phosphoinositide (PI) hydrolysis assays. We report for the first time that selective 5-HT 2C agonists possessing weak β-arrestin recruitment can produce distinct receptor desensitization properties.

Simulations of Biased Agonists in the β2 Adrenergic Receptor with Accelerated Molecular Dynamics

PubMed Central

2013-01-01

The biased agonism of the G protein-coupled receptors (GPCRs), where in addition to a traditional G protein-signaling pathway a GPCR promotes intracellular signals though β-arrestin, is a novel paradigm in pharmacology. Biochemical and biophysical studies have suggested that a GPCR forms a distinct ensemble of conformations signaling through the G protein and β-arrestin. Here we report on the dynamics of the β2 adrenergic receptor bound to the β-arrestin and G protein-biased agonists and the empty receptor to further characterize the receptor conformational changes caused by biased agonists. We use conventional and accelerated molecular dynamics (aMD) simulations to explore the conformational transitions of the GPCR from the active state to the inactive state. We found that aMD simulations enable monitoring of the transition within the nanosecond time scale while capturing the known microscopic characteristics of the inactive states, such as the ionic lock, the inward position of F6.44, and water clusters. Distinct conformational states are shown to be stabilized by each biased agonist. In particular, in simulations of the receptor with the β-arrestin-biased agonist N-cyclopentylbutanepherine, we observe a different pattern of motions in helix 7 when compared to simulations with the G protein-biased agonist salbutamol that involves perturbations of the network of interactions within the NPxxY motif. Understanding the network of interactions induced by biased ligands and the subsequent receptor conformational shifts will lead to development of more efficient drugs. PMID:23879802

Methodes iteratives paralleles: Applications en neutronique et en mecanique des fluides

NASA Astrophysics Data System (ADS)

Qaddouri, Abdessamad

Dans cette these, le calcul parallele est applique successivement a la neutronique et a la mecanique des fluides. Dans chacune de ces deux applications, des methodes iteratives sont utilisees pour resoudre le systeme d'equations algebriques resultant de la discretisation des equations du probleme physique. Dans le probleme de neutronique, le calcul des matrices des probabilites de collision (PC) ainsi qu'un schema iteratif multigroupe utilisant une methode inverse de puissance sont parallelises. Dans le probleme de mecanique des fluides, un code d'elements finis utilisant un algorithme iteratif du type GMRES preconditionne est parallelise. Cette these est presentee sous forme de six articles suivis d'une conclusion. Les cinq premiers articles traitent des applications en neutronique, articles qui representent l'evolution de notre travail dans ce domaine. Cette evolution passe par un calcul parallele des matrices des PC et un algorithme multigroupe parallele teste sur un probleme unidimensionnel (article 1), puis par deux algorithmes paralleles l'un mutiregion l'autre multigroupe, testes sur des problemes bidimensionnels (articles 2--3). Ces deux premieres etapes sont suivies par l'application de deux techniques d'acceleration, le rebalancement neutronique et la minimisation du residu aux deux algorithmes paralleles (article 4). Finalement, on a mis en oeuvre l'algorithme multigroupe et le calcul parallele des matrices des PC sur un code de production DRAGON ou les tests sont plus realistes et peuvent etre tridimensionnels (article 5). Le sixieme article (article 6), consacre a l'application a la mecanique des fluides, traite la parallelisation d'un code d'elements finis FES ou le partitionneur de graphe METIS et la librairie PSPARSLIB sont utilises.

A cannabinoid 2 receptor agonist attenuates bone cancer-induced pain and bone loss

PubMed Central

Lozano, Alysia; Wright, Courtney; Vardanyan, Anna; King, Tamara; Largent-Milnes, Tally M.; Nelson, Mark; Jimenez-Andrade, Juan Miguel; Mantyh, Patrick W; Vanderah, Todd W.

2010-01-01

Aims Cannabinoid CB2 agonists have been shown to alleviate behavioral signs of inflammatory and neuropathic pain in animal models. AM1241, a CB2 agonist, does not demonstrate central nervous system side-effects seen with CB1 agonists such as hypothermia and catalepsy. Metastatic bone cancer causes severe pain in patients and is treated with analgesics such as opiates. Recent reports suggest that sustained opiates can produce paradoxical hyperalgesic actions and enhance bone destruction in a murine model of bone cancer. In contrast, CB2 selective agonists have been shown to reduce bone loss associated with a model of osteoporosis. Here we tested whether a CB2 agonist administered over a 7 day period inhibits bone cancer-induced pain as well as attenuates cancer-induced bone degradation. Main Methods A murine bone cancer model was used in which osteolytic sarcoma cells were injected into the intramedullary space of the distal end of the femur. Behavioral and radiographic image analysis was performed at days 7, 10 and 14 after injection of tumor cells into the femur. Key Findings Osteolytic sarcoma within the femur produced spontaneous and touch evoked behavioral signs of pain within the tumor-bearing limb. The systemic administration of AM1241 acutely or for 7 days significantly attenuated spontaneous and evoked pain in the inoculated limb. Sustained AM1241 significantly reduced bone loss and decreased the incidence of cancer-induced bone fractures. Significance These findings suggest a novel therapy for cancer-induced bone pain, bone loss and bone fracture while lacking many unwanted side effects seen with current treatments for bone cancer pain. PMID:20176037

Agonistic Human Antibodies Binding to Lecithin-Cholesterol Acyltransferase Modulate High Density Lipoprotein Metabolism*

PubMed Central

Gunawardane, Ruwanthi N.; Fordstrom, Preston; Piper, Derek E.; Masterman, Stephanie; Siu, Sophia; Liu, Dongming; Brown, Mike; Lu, Mei; Tang, Jie; Zhang, Richard; Cheng, Janet; Gates, Andrew; Meininger, David; Chan, Joyce; Carlson, Tim; Walker, Nigel; Schwarz, Margrit; Delaney, John; Zhou, Mingyue

2016-01-01

Drug discovery opportunities where loss-of-function alleles of a target gene link to a disease-relevant phenotype often require an agonism approach to up-regulate or re-establish the activity of the target gene. Antibody therapy is increasingly recognized as a favored drug modality due to multiple desirable pharmacological properties. However, agonistic antibodies that enhance the activities of the target enzymes are rarely developed because the discovery of agonistic antibodies remains elusive. Here we report an innovative scheme of discovery and characterization of human antibodies capable of binding to and agonizing a circulating enzyme lecithin cholesterol acyltransferase (LCAT). Utilizing a modified human LCAT protein with enhanced enzymatic activity as an immunogen, we generated fully human monoclonal antibodies using the XenoMouseTM platform. One of the resultant agonistic antibodies, 27C3, binds to and substantially enhances the activity of LCAT from humans and cynomolgus macaques. X-ray crystallographic analysis of the 2.45 Å LCAT-27C3 complex shows that 27C3 binding does not induce notable structural changes in LCAT. A single administration of 27C3 to cynomolgus monkeys led to a rapid increase of plasma LCAT enzymatic activity and a 35% increase of the high density lipoprotein cholesterol that was observed up to 32 days after 27C3 administration. Thus, this novel scheme of immunization in conjunction with high throughput screening may represent an effective strategy for discovering agonistic antibodies against other enzyme targets. 27C3 and other agonistic human anti-human LCAT monoclonal antibodies described herein hold potential for therapeutic development for the treatment of dyslipidemia and cardiovascular disease. PMID:26644477

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.

Pharmacologic Treatment with GABAB Receptor Agonist of Methamphetamine-Induced Cognitive Impairment in Mice

PubMed Central

Mizoguchi, Hiroyuki; Yamada, Kiyofumi

2011-01-01

Methamphetamine (METH) is a highly addictive drug, and addiction to METH has increased to epidemic proportions worldwide. Chronic use of METH causes psychiatric symptoms, such as hallucinations and delusions, and long-term cognitive deficits, which are indistinguishable from paranoid schizophrenia. The GABA receptor system is known to play a significant role in modulating the dopaminergic neuronal system, which is related to behavioral changes induced by drug abuse. However, few studies have investigated the effects of GABA receptor agonists on cognitive deficits induced by METH. In the present review, we show that baclofen, a GABA receptor agonist, is effective in treating METH-induced impairment of object recognition memory and prepulse inhibition (PPI) of the startle reflex, a measure of sensorimotor gating in mice. Acute and repeated treatment with METH induced a significant impairment of PPI. Furthermore, repeated but not acute treatment of METH resulted in a long-lasting deficit of object recognition memory. Baclofen, a GABAB receptor agonist, dose-dependently ameliorated the METH-induced PPI deficits and object recognition memory impairment in mice. On the other hand, THIP, a GABAA receptor agonist, had no effect on METH-induced cognitive deficits. These results suggest that GABAB receptors may constitute a putative new target in treating cognitive deficits in chronic METH users. PMID:21886573

Des Moines metropolitan area ITS strategic plan

DOT National Transportation Integrated Search

1998-08-19

The Des Moines Area Metropolitan Organization (MPO) completed an early deployment study for the Des Moines metropolitan area in late 1997. The purpose of the study was to develop a strategic plan for Intelligent Transportation Systems (ITS) deploymen...

Alcohol Screening among Opioid Agonist Patients in a Primary Care Clinic and an Opioid Treatment Program.

PubMed

Klimas, Jan; Muench, John; Wiest, Katharina; Croff, Raina; Rieckman, Traci; McCarty, Dennis

2015-01-01

Problem alcohol use is associated with adverse health and economic outcomes, especially among people in opioid agonist treatment. Screening, brief intervention, and referral to treatment (SBIRT) are effective in reducing alcohol use; however, issues involved in SBIRT implementation among opioid agonist patients are unknown. To assess identification and treatment of alcohol use disorders, we reviewed clinical records of opioid agonist patients screened for an alcohol use disorder in a primary care clinic (n = 208) and in an opioid treatment program (n = 204) over a two-year period. In the primary care clinic, 193 (93%) buprenorphine patients completed an annual alcohol screening and six (3%) had elevated AUDIT scores. In the opioid treatment program, an alcohol abuse or dependence diagnosis was recorded for 54 (27%) methadone patients. Practitioner focus groups were completed in the primary care (n = 4 physicians) and the opioid treatment program (n = 11 counselors) to assess experience with and attitudes towards screening opioid agonist patients for alcohol use disorders. Focus groups suggested that organizational, structural, provider, patient, and community variables hindered or fostered alcohol screening. Alcohol screening is feasible among opioid agonist patients. Effective implementation, however, requires physician training and systematic changes in workflow.

Agonist-induced conformational changes in the G-protein-coupling domain of the β2 adrenergic receptor

PubMed Central

Ghanouni, Pejman; Steenhuis, Jacqueline J.; Farrens, David L.; Kobilka, Brian K.

2001-01-01

The majority of extracellular physiologic signaling molecules act by stimulating GTP-binding protein (G-protein)-coupled receptors (GPCRs). To monitor directly the formation of the active state of a prototypical GPCR, we devised a method to site specifically attach fluorescein to an endogenous cysteine (Cys-265) at the cytoplasmic end of transmembrane 6 (TM6) of the β2 adrenergic receptor (β2AR), adjacent to the G-protein-coupling domain. We demonstrate that this tag reports agonist-induced conformational changes in the receptor, with agonists causing a decline in the fluorescence intensity of fluorescein-β2AR that is proportional to the biological efficacy of the agonist. We also find that agonists alter the interaction between the fluorescein at Cys-265 and fluorescence-quenching reagents localized to different molecular environments of the receptor. These observations are consistent with a rotation and/or tilting of TM6 on agonist activation. Our studies, when compared with studies of activation in rhodopsin, indicate a general mechanism for GPCR activation; however, a notable difference is the relatively slow kinetics of the conformational changes in the β2AR, which may reflect the different energetics of activation by diffusible ligands. PMID:11353823

A Novel Aminotetralin-Type Serotonin (5-HT) 2C Receptor-Specific Agonist and 5-HT2A Competitive Antagonist/5-HT2B Inverse Agonist with Preclinical Efficacy for Psychoses

PubMed Central

Morgan, Drake; Felsing, Daniel; Kondabolu, Krishnakanth; Rowland, Neil E.; Robertson, Kimberly L.; Sakhuja, Rajeev; Booth, Raymond G.

2014-01-01

Development of 5-HT2C agonists for treatment of neuropsychiatric disorders, including psychoses, substance abuse, and obesity, has been fraught with difficulties, because the vast majority of reported 5-HT2C selective agonists also activate 5-HT2A and/or 5-HT2B receptors, potentially causing hallucinations and/or cardiac valvulopathy. Herein is described a novel, potent, and efficacious human 5-HT2C receptor agonist, (−)-trans-(2S,4R)-4-(3′[meta]-bromophenyl)-N,N-dimethyl-1,2,3,4-tetrahydronaphthalen-2-amine (−)-MBP), that is a competitive antagonist and inverse agonist at human 5-HT2A and 5-HT2B receptors, respectively. (−)-MBP has efficacy comparable to the prototypical second-generation antipsychotic drug clozapine in three C57Bl/6 mouse models of drug-induced psychoses: the head-twitch response elicited by [2,5]-dimethoxy-4-iodoamphetamine; hyperlocomotion induced by MK-801 [(5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate (dizocilpine maleate)]; and hyperlocomotion induced by amphetamine. (−)-MBP, however, does not alter locomotion when administered alone, distinguishing it from clozapine, which suppresses locomotion. Finally, consumption of highly palatable food by mice was not increased by (−)-MBP at a dose that produced at least 50% maximal efficacy in the psychoses models. Compared with (−)-MBP, the enantiomer (+)-MBP was much less active across in vitro affinity and functional assays using mouse and human receptors and also translated in vivo with comparably lower potency and efficacy. Results indicate a 5-HT2C receptor-specific agonist, such as (−)-MBP, may be pharmacotherapeutic for psychoses, without liability for obesity, hallucinations, heart disease, sedation, or motoric disorders. PMID:24563531

Evaluation des Connaissances-Attitudes-Pratiques des populations des districts sanitaires de Benoye, Laoukassy, Moundou et N’Djaména Sud sur la rage canine au Tchad

PubMed Central

Mindekem, Rolande; Lechenne, Monique; Alfaroukh, Idriss Oumar; Moto, Daugla Doumagoum; Zinsstag, Jakob; Ouedraogo, Laurent Tinoaga; Salifou, Sahidou

2017-01-01

Introduction La rage canine demeure une préoccupation en Afrique comme au Tchad. La présente étude vise à évaluer les Connaissances-Attitudes-Pratiques des populations pour la prise en charge appropriée des personnes exposées et une lutte efficace. Méthodes C’était une étude transversale descriptive réalisée en juillet et septembre dans quatre districts sanitaires au Tchad en 2015. Les données ont été collectées à l’aide d’un questionnaire auprès des ménages recrutés suivant un sondage aléatoire à 3 degrés. Résultats C’était 2428 personnes enquêtées avec un niveau maximum primaire (54,12%). L’âge moyen était de 36 ± 13,50 ans. Ils étaient cultivateurs (35,17%), commerçants (18,04%), ménagères (12,81%). La rage était définie comme une maladie transmise du chien à l’homme (41,43%), une altération du cerveau (41,27%), une sous-alimentation (10,26%). Le chat était faiblement connu réservoir (13,84%) et vecteur (19,77%) ainsi que la griffure comme moyen de transmission (4,61%) et la vaccination du chat comme mesure préventive (0,49%). Les premiers soins en cas de morsure à domicile étaient les pratiques traditionnelles (47,69%), le lavage des plaies (19,48%) ou aucune action entreprise (20,43%). Les ménages consultaient la santé humaine (78,50%), la santé animale (5,35%) et les guérisseurs traditionnels (27%). Conclusion La communication en rapport avec des premiers soins à la maison en cas de morsure, la connaissance du chat comme réservoir et vecteur, celle de la griffure comme moyen de transmission et la promotion de la consultation des services vétérinaires en cas de morsure sont nécessaires. PMID:28761600

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-1α, 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 PPARα 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

DES Science Portal: Computing Photometric Redshifts

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gschwend, Julia

An important challenge facing photometric surveys for cosmological purposes, such as the Dark Energy Survey (DES), is the need to produce reliable photometric redshifts (photo-z). The choice of adequate algorithms and configurations and the maintenance of an up-to-date spectroscopic database to build training sets, for example, are challenging tasks when dealing with large amounts of data that are regularly updated and constantly growing. In this paper, we present the first of a series of tools developed by DES, provided as part of the DES Science Portal, an integrated web-based data portal developed to facilitate the scientific analysis of the data,more » while ensuring the reproducibility of the analysis. We present the DES Science Portal photometric redshift tools, starting from the creation of a spectroscopic sample to training the neural network photo-z codes, to the final estimation of photo-zs for a large photometric catalog. We illustrate this operation by calculating well calibrated photo-zs for a galaxy sample extracted from the DES first year (Y1A1) data. The series of processes mentioned above is run entirely within the Portal environment, which automatically produces validation metrics, and maintains the provenance between the different steps. This system allows us to fine tune the many steps involved in the process of calculating photo-zs, making sure that we do not lose the information on the configurations and inputs of the previous processes. By matching the DES Y1A1 photometry to a spectroscopic sample, we define different training sets that we use to feed the photo-z algorithms already installed at the Portal. Finally, we validate the results under several conditions, including the case of a sample limited to i<22.5 with the color properties close to the full DES Y1A1 photometric data. This way we compare the performance of multiple methods and training configurations. The infrastructure presented here is an effcient way to test several methods

Monitoring of PAEMs and beta-agonists in urine for a small group of experimental subjects and PAEs and beta-agonists in drinking water consumed by the same subjects.

PubMed

Liou, Saou-Hsing; Yang, Gordon C C; Wang, Chih-Lung; Chiu, Yu-Han

2014-07-30

This 5-month study contains two parts: (1) to monitor the concentrations of 11 phthalate esters metabolites (PAEMs) and two beta-agonists in human urine samples collected from a small group of consented participants including 16 females and five males; and (2) to analyze the residues of phthalate esters (PAEs) and beta-agonists in various categories of drinking water consumed by the same group of subjects. Each category of human urine and drinking water had 183 samples of its own. The analytical results showed that nine PAEMs were detected in human urine and eight PAEs were detected in drinking water samples. It was found that average concentrations of PAEMs increased as the age increased, but no significant difference between sexes. Further, using the principal component analysis, the loadings of age effect were found to be two times greater than that of gender effect in terms of four DEHP metabolites. Regarding beta-agonists of concern (i.e., ractopamine and salbutamol), they were neither detected in human urine nor drinking water samples in this study. Copyright © 2014 Elsevier B.V. All rights reserved.

Optimisation des proprietes fonctionnelles des alliages a memoire de forme suite a l'application de traitements thermomecaniques

NASA Astrophysics Data System (ADS)

Demers, Vincent

L'objectif de ce projet est de determiner les conditions de laminage et la temperature de traitement thermique maximisant les proprietes fonctionnelles de l'alliage a memoire de forme Ti-Ni. Les specimens sont caracterises par des mesures de calorimetrie, de microscopie optique, de gene ration de contrainte, de deformation recuperable et des essais mecaniques. Pour un cycle unique, l'utilisation d'un taux d'ecrouissage e=1.5 obtenu avec l'application d'une force de tension FT = 0.1sigma y et d'une huile minerale resulte en un echantillon droit, sans microfissure et qui apres un recuit a 400°C, produit un materiau nanostructure manifestant des proprietes fonctionnelles deux fois plus grandes que le meme materiau ayant une structure polygonisee. Pour des cycles repetes, les memes conditions de laminage sont valables mais le niveau de deformation optimal est situe entre e=0.75-2, et depend particulierement du mode de sollicitation, du niveau de stabilisation et du nombre de cycles a la rupture requis par l'application.

Effects of bezafibrate, PPAR pan-agonist, and GW501516, PPARdelta agonist, on development of steatohepatitis in mice fed a methionine- and choline-deficient diet.

PubMed

Nagasawa, Tatsuya; Inada, Yoichi; Nakano, Shigeru; Tamura, Toru; Takahashi, Tetsuaki; Maruyama, Kazuyasu; Yamazaki, Yoshinobu; Kuroda, Junji; Shibata, Nobuo

2006-04-24

We evaluated the effects of bezafibrate, a peroxisome proliferator-activated receptor (PPAR) pan-agonist, and GW501516, a PPARdelta agonist, on mice fed a methionine- and choline-deficient (MCD) diet, a model of non-alcholic steatohepatitis (NASH), to investigate (a) the efficacy of bezafibrate against non-alcholic steatohepatitis and (b) the relation between non-alcholic steatohepatitis and the functional role of PPARdelta. Bezafibrate (50 or 100 mg/kg/day) and GW501516 (10 mg/kg/day) were administered by gavage once a day for 5 weeks. Hepatic lipid contents, plasma triglyceride, high density lipoprotein (HDL)-cholesterol and alanine aminotransferase (ALT) concentrations were evaluated, as were histopathological changes in the liver and hepatic mRNA expression levels. Bezafibrate and GW501516 inhibited the MCD-diet-induced elevations of hepatic triglyceride and thiobarbituric acid-reactants contents and the histopathological increases in fatty droplets within hepatocytes, liver inflammation and number of activated hepatic stellate cells. In this model, bezafibrate and GW501516 increased the levels of hepatic mRNAs associated with fatty acid beta-oxidation [acyl-CoA oxidase (ACO), carnitine palmitoyltransferase-1 (CPT-1), liver-fatty acid binding protein (L-FABP) and peroxisomal ketothiolase], and reduced the levels of those associated with inflammatory cytokines or chemokine [transforming growth factor (TGF)-beta1, interleukin (IL)-6, IL-1beta, monocyte chemoattractant protein (MCP)-1, tumor necrosis factor (TNF) alpha and nuclear factor (NF)-kappaB1]. In addition, bezafibrate characteristically reduced the elevation in the level of plasma ALT, but enhanced that in plasma adiponectin and increased the mRNA expression levels of its receptors (adiponectin receptors 1 and 2). These results suggest that (a) bezafibrate (especially) and GW501516 might improve hepatic steatosis via an improvement in fatty acid beta-oxidation and a direct prevention of inflammation, (b

Integration des sciences et de la langue: Creation et experimentation d'un modele pedagogique pour ameliorer l'apprentissage des sciences en milieu francophone minoritaire

NASA Astrophysics Data System (ADS)

Cormier, Marianne

Les faibles resultats en sciences des eleves du milieu francophone minoritaire, lors d'epreuves au plan national et international, ont interpelle la recherche de solutions. Cette these avait pour but de creer et d'experimenter un modele pedagogique pour l'enseignement des sciences en milieu linguistique minoritaire. En raison de la presence de divers degres de francite chez la clientele scolaire de ce milieu, plusieurs elements langagiers (l'ecriture, la discussion et la lecture) ont ete integres a l'apprentissage scientifique. Nous avions recommande de commencer le processus d'apprentissage avec des elements langagiers plutot informels (redaction dans un journal, discussions en dyades...) pour progresser vers des activites langagieres plus formelles (redaction de rapports ou d'explications scientifiques). En ce qui a trait a l'apprentissage scientifique, le modele preconisait une demarche d'evolution conceptuelle d'inspiration socio-constructiviste tout en s'appuyant fortement sur l'apprentissage experientiel. Lors de l'experimentation du modele, nous voulions savoir si celui-ci provoquait une evolution conceptuelle chez les eleves, et si, simultanement, le vocabulaire scientifique de ces derniers s'enrichissait. Par ailleurs, nous cherchions a comprendre comment les eleves vivaient leurs apprentissages dans le cadre de ce modele pedagogique. Une classe de cinquieme annee de l'ecole de Grande-Digue, dans le Sud-est du Nouveau-Brunswick, a participe a la mise a l'essai du modele en etudiant les marais sales locaux. Lors d'entrevues initiales, nous avons remarque que les connaissances des eleves au sujet des marais sales etaient limitees. En effet, s'ils etaient conscients que les marais etaient des lieux naturels, ils ne pouvaient pas necessairement les decrire avec precision. Nous avons egalement constate que les eleves utilisaient surtout des mots communs (plantes, oiseaux, insectes) pour decrire le marais. Les resultats obtenus indiquent que les eleves ont

Hypotensive effects of ghrelin receptor agonists mediated through a novel receptor.

PubMed

Callaghan, Brid; Kosari, Samin; Pustovit, Ruslan V; Sartor, Daniela M; Ferens, Dorota; Ban, Kung; Baell, Jonathan; Nguyen, Trung V; Rivera, Leni R; Brock, James A; Furness, John B

2014-03-01

Some agonists of ghrelin receptors cause rapid decreases in BP. The mechanisms by which they cause hypotension and the pharmacology of the receptors are unknown. The effects of ligands of ghrelin receptors were investigated in rats in vivo, on isolated blood vessels and on cells transfected with the only molecularly defined ghrelin receptor, growth hormone secretagogue receptor 1a (GHSR1a). Three agonists of GHSR1a receptors, ulimorelin, capromorelin and CP464709, caused a rapid decrease in BP in the anaesthetized rat. The effect was not reduced by either of two GHSR1a antagonists, JMV2959 or YIL781, at doses that blocked effects on colorectal motility, in vivo. The rapid hypotension was not mimicked by ghrelin, unacylated ghrelin or the unacylated ghrelin receptor agonist, AZP531. The early hypotension preceded a decrease in sympathetic nerve activity. Early hypotension was not reduced by hexamethonium or by baroreceptor (sino-aortic) denervation. Ulimorelin also relaxed isolated segments of rat mesenteric artery, and, less potently, relaxed aorta segments. The vascular relaxation was not reduced by JMV2959 or YIL781. Ulimorelin, capromorelin and CP464709 activated GHSR1a in transfected HEK293 cells at nanomolar concentrations. JMV2959 and YIL781 both antagonized effects in these cells, with their pA2 values at the GHSR1a receptor being 6.55 and 7.84. Our results indicate a novel vascular receptor or receptors whose activation by ulimorelin, capromorelin and CP464709 lowered BP. This receptor is activated by low MW GHSR1a agonists, but is not activated by ghrelin. © 2013 The British Pharmacological Society.

Hypotensive effects of ghrelin receptor agonists mediated through a novel receptor

PubMed Central

Callaghan, Brid; Kosari, Samin; Pustovit, Ruslan V; Sartor, Daniela M; Ferens, Dorota; Ban, Kung; Baell, Jonathan; Nguyen, Trung V; Rivera, Leni R; Brock, James A; Furness, John B

2014-01-01

BACKGROUND AND PURPOSE Some agonists of ghrelin receptors cause rapid decreases in BP. The mechanisms by which they cause hypotension and the pharmacology of the receptors are unknown. EXPERIMENTAL APPROACH The effects of ligands of ghrelin receptors were investigated in rats in vivo, on isolated blood vessels and on cells transfected with the only molecularly defined ghrelin receptor, growth hormone secretagogue receptor 1a (GHSR1a). KEY RESULTS Three agonists of GHSR1a receptors, ulimorelin, capromorelin and CP464709, caused a rapid decrease in BP in the anaesthetized rat. The effect was not reduced by either of two GHSR1a antagonists, JMV2959 or YIL781, at doses that blocked effects on colorectal motility, in vivo. The rapid hypotension was not mimicked by ghrelin, unacylated ghrelin or the unacylated ghrelin receptor agonist, AZP531. The early hypotension preceded a decrease in sympathetic nerve activity. Early hypotension was not reduced by hexamethonium or by baroreceptor (sino-aortic) denervation. Ulimorelin also relaxed isolated segments of rat mesenteric artery, and, less potently, relaxed aorta segments. The vascular relaxation was not reduced by JMV2959 or YIL781. Ulimorelin, capromorelin and CP464709 activated GHSR1a in transfected HEK293 cells at nanomolar concentrations. JMV2959 and YIL781 both antagonized effects in these cells, with their pA2 values at the GHSR1a receptor being 6.55 and 7.84. CONCLUSIONS AND IMPLICATIONS Our results indicate a novel vascular receptor or receptors whose activation by ulimorelin, capromorelin and CP464709 lowered BP. This receptor is activated by low MW GHSR1a agonists, but is not activated by ghrelin. PMID:24670149

GPR40 partial agonists and AgoPAMs: Differentiating effects on glucose and hormonal secretions in the rodent

PubMed Central

Pachanski, Michele J.; Kirkland, Melissa E.; Kosinski, Daniel T.; Mane, Joel; Cheewatrakoolpong, Boonlert; Xue, Jiyan; Szeto, Daphne; Forrest, Gail; Miller, Corin; Bunzel, Michelle; Plummer, Christopher W.; Chobanian, Harry R.; Miller, Michael W.; Souza, Sarah; Thomas-Fowlkes, Brande S.; Ogawa, Aimie M.; Weinglass, Adam B.; Di Salvo, Jerry; Li, Xiaoyan; Feng, Yue; Tatosian, Daniel A.; Howard, Andrew D.; Colletti, Steven L.

2017-01-01

GPR40 agonists are effective antidiabetic agents believed to lower glucose through direct effects on the beta cell to increase glucose stimulated insulin secretion. However, not all GPR40 agonists are the same. Partial agonists lower glucose through direct effects on the pancreas, whereas GPR40 AgoPAMs may incorporate additional therapeutic effects through increases in insulinotrophic incretins secreted by the gut. Here we describe how GPR40 AgoPAMs stimulate both insulin and incretin secretion in vivo over time in diabetic GK rats. We also describe effects of AgoPAMs in vivo to lower glucose and body weight beyond what is seen with partial GPR40 agonists in both the acute and chronic setting. Further comparisons of the glucose lowering profile of AgoPAMs suggest these compounds may possess greater glucose control even in the presence of elevated glucagon secretion, an unexpected feature observed with both acute and chronic treatment with AgoPAMs. Together these studies highlight the complexity of GPR40 pharmacology and the potential additional benefits AgoPAMs may possess above partial agonists for the diabetic patient. PMID:29053717

Impaired β-arrestin recruitment and reduced desensitization by non-catechol agonists of the D1 dopamine receptor.

PubMed

Gray, David L; Allen, John A; Mente, Scot; O'Connor, Rebecca E; DeMarco, George J; Efremov, Ivan; Tierney, Patrick; Volfson, Dmitri; Davoren, Jennifer; Guilmette, Edward; Salafia, Michelle; Kozak, Rouba; Ehlers, Michael D

2018-02-14

Selective activation of dopamine D1 receptors (D1Rs) has been pursued for 40 years as a therapeutic strategy for neurologic and psychiatric diseases due to the fundamental role of D1Rs in motor function, reward processing, and cognition. All known D1R-selective agonists are catechols, which are rapidly metabolized and desensitize the D1R after prolonged exposure, reducing agonist response. As such, drug-like selective D1R agonists have remained elusive. Here we report a novel series of selective, potent non-catechol D1R agonists with promising in vivo pharmacokinetic properties. These ligands stimulate adenylyl cyclase signaling and are efficacious in a rodent model of Parkinson's disease after oral administration. They exhibit distinct binding to the D1R orthosteric site and a novel functional profile including minimal receptor desensitization, reduced recruitment of β-arrestin, and sustained in vivo efficacy. These results reveal a novel class of D1 agonists with favorable drug-like properties, and define the molecular basis for catechol-specific recruitment of β-arrestin to D1Rs.

Etude de la performance des radars hautes-frequences CODAR et WERA pour la mesure des courants marins en presence partielle de glace de mer

NASA Astrophysics Data System (ADS)

Kamli, Emna

Les radars hautes-frequences (RHF) mesurent les courants marins de surface avec une portee pouvant atteindre 200 kilometres et une resolution de l'ordre du kilometre. Cette etude a pour but de caracteriser la performance des RHF, en terme de couverture spatiale, pour la mesure des courants de surface en presence partielle de glace de mer. Pour ce faire, les mesures des courants de deux radars de type CODAR sur la rive sud de l'estuaire maritime du Saint-Laurent, et d'un radar de type WERA sur la rive nord, prises pendant l'hiver 2013, ont ete utilisees. Dans un premier temps, l'aire moyenne journaliere de la zone ou les courants sont mesures par chaque radar a ete comparee a l'energie des vagues de Bragg calculee a partir des donnees brutes d'acceleration fournies par une bouee mouillee dans la zone couverte par les radars. La couverture des CODARs est dependante de la densite d'energie de Bragg, alors que la couverture du WERA y est pratiquement insensible. Un modele de fetch appele GENER a ete force par la vitesse du vent predite par le modele GEM d'Environnement Canada pour estimer la hauteur significative ainsi que la periode modale des vagues. A partir de ces parametres, la densite d'energie des vagues de Bragg a ete evaluee pendant l'hiver a l'aide du spectre theorique de Bretschneider. Ces resultats permettent d'etablir la couverture normale de chaque radar en absence de glace de mer. La concentration de glace de mer, predite par le systeme canadien operationnel de prevision glace-ocean, a ete moyennee sur les differents fetchs du vent selon la direction moyenne journaliere des vagues predites par GENER. Dans un deuxieme temps, la relation entre le ratio des couvertures journalieres obtenues pendant l'hiver 2013 et des couvertures normales de chaque radar d'une part, et la concentration moyenne journaliere de glace de mer d'autre part, a ete etablie. Le ratio des couvertures decroit avec l'augmentation de la concentration de glace de mer pour les deux types

Combined sodium ion sensitivity in agonist binding and internalization of vasopressin V1b receptors.

PubMed

Koshimizu, Taka-Aki; Kashiwazaki, Aki; Taniguchi, Junichi

2016-05-03

Reducing Na(+) in the extracellular environment may lead to two beneficial effects for increasing agonist binding to cell surface G-protein coupled receptors (GPCRs): reduction of Na(+)-mediated binding block and reduce of receptor internalization. However, such combined effects have not been explored. We used Chinese Hamster Ovary cells expressing vasopressin V1b receptors as a model to explore Na(+) sensitivity in agonist binding and receptor internalization. Under basal conditions, a large fraction of V1b receptors is located intracellularly, and a small fraction is in the plasma membrane. Decreases in external Na(+) increased cell surface [(3)H]AVP binding and decreased receptor internalization. Substitution of Na(+) by Cs(+) or NH4(+) inhibited agonist binding. To suppress receptor internalization, the concentration of NaCl, but not of CsCl, had to be less than 50 mM, due to the high sensitivity of the internalization machinery to Na(+) over Cs(+). Iso-osmotic supplementation of glucose or NH4Cl maintained internalization of the V1b receptor, even in a low-NaCl environment. Moreover, iodide ions, which acted as a counter anion, inhibited V1b agonist binding. In summary, we found external ionic conditions that could increase the presence of high-affinity state receptors at the cell surface with minimum internalization during agonist stimulations.

Combined sodium ion sensitivity in agonist binding and internalization of vasopressin V1b receptors

PubMed Central

Koshimizu, Taka-aki; Kashiwazaki, Aki; Taniguchi, Junichi

2016-01-01

Reducing Na+ in the extracellular environment may lead to two beneficial effects for increasing agonist binding to cell surface G-protein coupled receptors (GPCRs): reduction of Na+-mediated binding block and reduce of receptor internalization. However, such combined effects have not been explored. We used Chinese Hamster Ovary cells expressing vasopressin V1b receptors as a model to explore Na+ sensitivity in agonist binding and receptor internalization. Under basal conditions, a large fraction of V1b receptors is located intracellularly, and a small fraction is in the plasma membrane. Decreases in external Na+ increased cell surface [3H]AVP binding and decreased receptor internalization. Substitution of Na+ by Cs+ or NH4+ inhibited agonist binding. To suppress receptor internalization, the concentration of NaCl, but not of CsCl, had to be less than 50 mM, due to the high sensitivity of the internalization machinery to Na+ over Cs+. Iso-osmotic supplementation of glucose or NH4Cl maintained internalization of the V1b receptor, even in a low-NaCl environment. Moreover, iodide ions, which acted as a counter anion, inhibited V1b agonist binding. In summary, we found external ionic conditions that could increase the presence of high-affinity state receptors at the cell surface with minimum internalization during agonist stimulations. PMID:27138239