Science.gov

Sample records for agonist muscimol mus

  1. The GABAA receptor agonist muscimol induces an age- and region-dependent form of long-term depression in the mouse striatum.

    PubMed

    Zhang, Xiaoqun; Yao, Ning; Chergui, Karima

    2016-09-01

    Several forms of long-term depression (LTD) of glutamatergic synaptic transmission have been identified in the dorsal striatum and in the nucleus accumbens (NAc). Such experience-dependent synaptic plasticity might play important roles in reward-related learning. The GABAA receptor agonist muscimol was recently found to trigger a long-lasting depression of glutamatergic synaptic transmission in the NAc of adolescent mice, but the mechanisms that underlie this novel form of LTD were not studied. Here we examined the effect of muscimol applied in the perfusion solution on the amplitude of field excitatory postsynaptic potentials/population spikes (fEPSP/PSs) in mouse brain slices. We found that muscimol depressed the fEPSP/PS in the NAc of adolescent mice but not adult mice, through both postsynaptic and presynaptic mechanisms. Indeed, muscimol altered the fEPSP/PS paired-pulse ratio, depolarized the membrane of projection neurons, and decreased the frequency, but not amplitude, of spontaneous excitatory postsynaptic currents in the NAc of adolescent mice. The LTD induced by muscimol likely involved endocannabinoids, metabotropic glutamate receptors (mGluRs), but not TRPV1 receptors. Muscimol-LTD was occluded by prior induction of LTD through low-frequency stimulation (LFS) of the slice, demonstrating a common pathway in the induction of LFS-LTD and muscimol-LTD. We also found that muscimol induced a form of LTD in the dorsolateral striatum of adult but not adolescent mice. This LTD was mediated by endocannabinoids but did not involve mGluRs or TRPV1 receptors. These results identify a novel form of synaptic plasticity, and its mechanisms of induction, which is age and region dependent. These findings may contribute to a better understanding of the increased susceptibility of the adolescent brain to long-term synaptic changes in regions associated with reward mechanisms. PMID:27531838

  2. The GABA[subscript A] Receptor Agonist Muscimol Induces an Age- and Region-Dependent Form of Long-Term Depression in the Mouse Striatum

    ERIC Educational Resources Information Center

    Zhang, Xiaoqun; Yao, Ning; Chergui, Karima

    2016-01-01

    Several forms of long-term depression (LTD) of glutamatergic synaptic transmission have been identified in the dorsal striatum and in the nucleus accumbens (NAc). Such experience-dependent synaptic plasticity might play important roles in reward-related learning. The GABA[subscript A] receptor agonist muscimol was recently found to trigger a…

  3. Intraocular Injection of Muscimol Induces Illusory Motion Reversal in Goldfish

    PubMed Central

    Lee, Sang-Yoon

    2009-01-01

    Induced activation of the gamma-aminobutyric acidA (GABAA) receptor in the retina of goldfish caused the fish to rotate in the opposite direction to that of the spinning pattern during an optomotor response (OMR) measurement. Muscimol, a GABAA receptor agonist, modified OMR in a concentration-dependent manner. The GABAB receptor agonist baclofen and GABAC receptor agonist CACA did not affect OMR. The observed modifications in OMR included decreased anterograde rotation (0.01~0.03 µM), coexistence of retrograde rotation and decreased anterograde rotation (0.1~30 µM) and only retrograde rotation (100 µM~1 mM). In contrast, the GABAA receptor antagonist bicuculline blocked muscimolinduced retrograde rotation. Based on these results, we inferred that the coding inducing retrograde movement of the goldfish retina is essentially associated with the GABAA receptor-related visual pathway. Furthermore, from our novel approach using observations of goldfish behavior the induced discrete snapshot duration was approximately 573 ms when the fish were under the influence of muscimol. PMID:20054494

  4. Time-dependent retrograde amnesic effects of muscimol on conditioned taste aversion extinction

    PubMed Central

    DiSorbo, Anthony; Wilson, Gina N.; Bacik, Stephanie; Hoxha, Zana; Biada, Jaclyn M.; Mickley, G. Andrew

    2009-01-01

    We explored how stimulation of GABAA receptors at different times during conditioned taste aversion (CTA) acquisition or extinction influenced extinction. In Experiment 1, rats acquired a CTA to 0.3% saccharin-flavored water (SAC) when it followed an injection of lithium chloride (LiCl; 81.0 mg/kg, i.p.). Following conditioning, rats received extinction training in which the GABAA agonist muscimol (1.0 mg/kg, i.p.), or control (saline) injections, were administered either before or after each extinction trial. Muscimol hindered extinction when administered after extinction trials. Muscimol’s inhibitory effects may have impeded extinction learning by disrupting synaptic mechanisms required to consolidate information experienced during extinction training. In Experiment 2, we studied the effects of muscimol on CTA acquisition and subsequent extinction. Rats received muscimol (1.0 mg/kg, i.p.) either before or after CTA conditioning trials. Following CTA acquisition, all rats were given CTA extinction training without muscimol administration. All groups developed CTA, but the group that received muscimol before CTA conditioning trials extinguished rapidly in comparison to other treatment groups. Differences between muscimol’s effects on CTA conditioning and CTA extinction indicate that fear conditioning and extinction involve, to some degree, different neuronal mechanisms. PMID:19171164

  5. Infusions of muscimol into the lateral septum do not reduce rats' defensive behaviors toward a cat odor stimulus.

    PubMed

    Chee, San-San A; Patel, Ronak; Menard, Janet L

    2015-01-01

    The lateral septum (LS) is implicated in behavioral defense. We tested whether bilateral infusions of the GABAA receptor agonist muscimol into the LS suppress rats' defensive responses to cat odor. Rats received intra-LS infusions of either saline or muscimol (40 ng/rat) and were exposed to either a piece of a cat collar that had been previously worn by a cat or to a control (cat odor free) collar. Rats exposed to the cat odor collar displayed more head-out postures, while intra-LS application of muscimol reduced the number of head-out postures. However, this reduction was also present in rats exposed to a control (cat odor free) collar. This latter finding suggests that despite its involvement in other defensive behaviors (e.g., open arm avoidance in the elevated plus maze), the LS does not selectively regulate rats' receptor defensive responding to the olfactory cues present in our cat odor stimulus.

  6. Fighting in the home cage: Agonistic Encounters and Effects on Neurobiological Markers within the Social Decision-Making Network of House Mice (Mus musculus)

    PubMed Central

    Greenberg, Gian D.; Howerton, Chris L.; Trainor, Brian C.

    2014-01-01

    Inbred strains of mice, such as C57Bl/6, have become preferred animal models for neurobehavioral studies. A main goal in creating inbred lines is to reduce the effects of individual genetic variation on observed phenotypes. Most studies use only males, and there is increasing evidence that agonistic interactions within the home cage may produce systematic variability in behavior and brain function. Previous studies have demonstrated that the outcomes of aggressive interactions have powerful effects on the brain and behavior, but less is known about whether aggressive interactions within the home cage have similar effects. We assessed group-housed laboratory mice C57Bl/6 for competitive ability and then tested the extent high competitive ability (CA) or low CA was related to gene and protein expression within related pathways. We focused on a broad social behavior network, including the nucleus accumbens (NAc) and bed nucleus of the stria terminalis (BNST). High CA mice had significantly more corticotropin releasing hormone receptor 2 (CRHR2) and estrogen receptor alpha (ESR1) mRNA in the BNST. Our data suggest a simple test of CA could yield valuable information that could be used to reduce error variance and increase power in neurobiological studies using mice. PMID:24602985

  7. [Effects of muscimol and diazepam: a comparative study on behavioral inhibiton induced by novelty, punishment, and nonreward (author's transl)].

    PubMed

    Thiébot, M H; Jobert, A; Soubrié, P

    1979-03-14

    Diazepam and muscimol, a direct GABA agonist, were compared on behavioral inhibition induced in rats by (1) novelty, (2) punishment, and (3) nonreward. (1) Muscimol (0.03--0.25 mg . kg-1 i.p. 30 min before testing, or i.v. immediately before testing) failed to enhance food intake consistently in a nonfamiliar situation and (0.125--0.5 mg . kg-1 i.p. or i.v.) to increase the ingestion of an unknown food (chocolate); (2) muscimol (0.125--0.5 mg . kg-1 i.p. or 0.25 i.v. 10 min before testing) was ineffective in reducing the inhibition of lever presses for food elicited by the delivery of an electric shock at every eighth press; (3) muscimol (0.125--0.5 mg . kg-1 i.p.) failed to attenuate the inhibitory effects on responding induced by the suppression of the reinforcement during extinction. Contrastingly, diazepam (2 mg . kg-1 i.p. 30 min before testing) was found to reduce each type of behavioral inhibition. These data lend no support to the hypotheses of GABA control of behavioral inhibition and of GABA involvement in the action of benzodiazepines on inhibition induced by novelty, punishment, or nonreward. PMID:108725

  8. Temporary inhibition of dorsal or ventral hippocampus by muscimol: distinct effects on measures of innate anxiety on the elevated plus maze, but similar disruption of contextual fear conditioning.

    PubMed

    Zhang, Wei-Ning; Bast, Tobias; Xu, Yan; Feldon, Joram

    2014-04-01

    Studies in rats, involving hippocampal lesions and hippocampal drug infusions, have implicated the hippocampus in the modulation of anxiety-related behaviors and conditioned fear. The ventral hippocampus is considered to be more important for anxiety- and fear-related behaviors than the dorsal hippocampus. In the present study, we compared the role of dorsal and ventral hippocampus in innate anxiety and classical fear conditioning in Wistar rats, examining the effects of temporary pharmacological inhibition by the GABA-A agonist muscimol (0.5 ug/0.5 ul/side) in the elevated plus maze and on fear conditioning to a tone and the conditioning context. In the elevated plus maze, dorsal and ventral hippocampal muscimol caused distinct behavioral changes. The effects of ventral hippocampal muscimol were consistent with suppression of locomotion, possibly accompanied by anxiolytic effects, whereas the pattern of changes caused by dorsal hippocampal muscimol was consistent with anxiogenic effects. In contrast, dorsal and ventral hippocampal muscimol caused similar effects in the fear conditioning experiments, disrupting contextual, but not tone, fear conditioning.

  9. Alteration of behavior in mice by muscimol is associated with regional electroencephalogram synchronization.

    PubMed

    Vyazovskiy, V V; Tobler, I; Winsky-Sommerer, R

    2007-07-13

    We tested the hypothesis that the effects of GABAergic agonists on behavior and the electroencephalogram (EEG) result from an increased regional synchronization in cortical circuits. The relationship between regional EEG topography, EEG synchronization and alteration of behavior was investigated by administering male C57BL/6 mice (n=7) a high, 3 mg/kg i.p. dose of muscimol, a selective GABA(A) agonist. Parietal and frontal cortical EEG, electromyogram, infrared and running wheel activity were recorded for 3 h before and 9 h after injection. Muscimol consistently elicited biphasic behavioral changes. Initially, it induced a catalepsy-like state lasting 96.0+/-12.4 min. This state was followed by a hyperactivity period of 49.7+/-5.4 min, during which the mice engaged in vigorous wheel running. During catalepsy, the EEG exhibited high amplitude waves which showed a consistent phase relationship between the frontal and parietal derivation. Moreover, the typical regional differences between the EEG spectra of the two derivations were abolished, and a redistribution of EEG power toward lower frequencies (<3 Hz) occurred in both derivations. In contrast, during hyperactivity the parietal EEG was dominated by theta-activity (7-9 Hz), which is typical for running behavior, while high amplitude slow waves, resembling the normal non-rapid eye movement sleep EEG pattern, predominated in the frontal EEG. The data indicate that the GABAergic system is involved in the regulation of cortical synchronization of neuronal activity and suggest a link between regional EEG synchronization and behavioral states. PMID:17570598

  10. AT1 receptor blockade in the central nucleus of the amygdala attenuates the effects of muscimol on sodium and water intake.

    PubMed

    Hu, B; Qiao, H; Sun, B; Jia, R; Fan, Y; Wang, N; Lu, B; Yan, J Q

    2015-10-29

    The blockade of the central nucleus of the amygdala (CeA) with the GABAA receptor agonist muscimol significantly reduces hypertonic NaCl and water intake by sodium-depleted rats. In the present study we investigated the effects of previous injection of losartan, an angiotensin II type-1 (AT1) receptor antagonist, into the CeA on 0.3M NaCl and water intake reduced by muscimol bilaterally injected into the same areas in rats submitted to water deprivation-partial rehydration (WD-PR) and in rats treated with the diuretic furosemide (FURO). Male Sprague-Dawley rats with stainless steel cannulas bilaterally implanted into the CeA were used. Bilateral injections of muscimol (0.2 nmol/0.5 μl, n=8 rats/group) into the CeA in WD-PR-treated rats reduced 0.3M NaCl intake and water intake, and pre-treatment of the CeA with losartan (50 μg/0.5 μl) reversed the inhibitory effect of muscimol. The negative effect of muscimol on sodium and water intake could also be blocked by pretreatment with losartan microinjected into the CeA in rats given FURO (n=8 rats/group). However, bilateral injections of losartan (50 μg/0.5 μl) alone into the CeA did not affect the NaCl or water intake. These results suggest that the deactivation of CeA facilitatory mechanisms by muscimol injection into the CeA is promoted by endogenous angiotensin II acting on AT1 receptors in the CeA, which prevents rats from ingesting large amounts of hypertonic NaCl and water.

  11. Muscimol inactivation caudal to the interstitial nucleus of Cajal induces hemi-seesaw nystagmus.

    PubMed

    Das, Vallabh E; Leigh, R John; Swann, Michelle; Thurtell, Matthew J

    2010-09-01

    Hemi-seesaw nystagmus (hemi-SSN) is a jerk-waveform nystagmus with conjugate torsional and disjunctive vertical components. Halmagyi et al. in Brain 117(Pt 4):789-803 (1994), reported hemi-SSN in patients with unilateral lesions in the vicinity of the Interstitial Nucleus of Cajal (INC) and suggested that an imbalance in projections from the vestibular nuclei to the INC was the source of the nystagmus. However, this hypothesis was called into question by Helmchen et al. in Exp Brain Res 119(4):436-452 (1998), who inactivated INC in monkeys with muscimol (a GABA(A) agonist) and induced failure of vertical gaze-holding (neural integrator) function but not hemi-SSN. We injected 0.1-0.2 microl of 2% muscimol into the supraoculomotor area, 1-2 mm dorso-lateral to the right oculomotor nucleus and caudal to the right INC. A total of seven injections in two juvenile rhesus monkeys were performed. Hemi-SSN was noted within 5-10 min after injection for six of the injections. Around the time the hemi-SSN began, a small skew deviation also developed. However, there was no limitation of horizontal or vertical eye movements, suggesting that the nearby oculomotor nucleus was not initially compromised. Limitations in eye movement range developed about (1/2)-1 h following the injections. Clinical signs that were observed after the animal was released to his cage included a moderate to marked head tilt toward the left (contralesional) side, consistent with an ocular tilt reaction. We conclude that hemi-SSN can be caused by lesions just caudal to the INC, whereas lesions of the INC itself cause down-beat nystagmus and vertical gaze-holding failure, as demonstrated by Helmchen et al. Combined deficits may be encountered with lesions that involve several midbrain structures.

  12. Y Chromosome Evolution in the Subgenus Mus (Genus Mus)

    PubMed Central

    Tucker, P. K.; Lee, B. K.; Eicher, E. M.

    1989-01-01

    A 305 base pair DNA sequence isolated from the Y chromosome of the inbred mouse strain C57BL/10 was used to investigate the pattern and tempo of evolution of Y chromosome DNA sequences for five species in the subgenus Mus, including Mus spretus, Mus hortulanus, Mus abbotti, Mus musculus and Mus domesticus. Variation in hybridization patterns between species was characterized by differences in fragment lengths of both intensely and faintly hybridizing fragments, whereas variation in hybridization patterns within species was characterized primarily by differences in fragment lengths of faintly hybridizing fragments. Phylogenetic analyses were conducted based on fragment size variation within and among species. Phylogenetic relationships inferred from these analyses partly agree with the phylogenetic relationships obtained from biochemical and mitochondrial DNA data. We conclude that a set of DNA sequences common to the Y chromosomes of a closely related group of species in the subgenus Mus has evolved rapidly as reflected by sequence divergence and sequence amplification. PMID:2543607

  13. NMDA-receptor-dependent, muscimol-sensitive role of the entorhinal cortex in post-training memory processing.

    PubMed

    Ferreira, M.B.C.; Wolfman, C.; Walz, R.; Da Silva, R.C.; Zanatta, M.S.; Medina, J.H.; Izquierdo, I.

    1992-08-01

    The bilateral infusion into the entorhinal cortex of the NMDA receptor antagonist, AP5 (5.0µg) or of the GABA(A) agonist, muscimol (0.03µg) 90min after training but not 30min before training, 0min after training or 10min before testing, hindered retention test performance 24h after inhibitory avoidance in rats. Glutamate (5.0µg) or picrotoxin (0.08µg) infused 90min after training had no effect. In animals trained with a low level footshock a second training session, 120min after the first, was needed in order to obtain a good retention test performance. This was taken to reflect summation of the consecutive memory traces left by the two training sessions. In these animals, the infusion of AP5 or muscimol into the entorhinal cortex between the two training sessions impeded their summation. The present results suggest that the entorhinal cortex plays a late role in memory processing, that this role does not need a hyperactivation of the entorhinal cortex, and that it is important for the interaction between consecutive memory traces.

  14. (/sup 3/H)muscimol binding sites increased in autopsied brains of chronic schizophrenics

    SciTech Connect

    Hanada, S.; Mita, T.; Nishino, N.; Tanaka, C.

    1987-01-19

    (/sup 3/H)muscimol binding and glutamic acid decarboxylase (GAD) activity in the prefrontal cortex and caudate nucleus of autopsied brains from 19 chronic schizophrenics and 17 control subjects were investigated. In the schizophrenics, saturation analysis with varying concentrations of (/sup 3/H)muscimol revealed an increase in the number GABA/sub A/ receptors, but there was no significant difference in the affinity. In addition, the enhancement of (/sup 3/H)muscimol binding by diazepam was significantly greater in schizophrenics than in controls. GAD activity did not differ between controls and schizophrenics. The possibility that GABAergic mechanisms might play a role in case of chronic schizophrenia should be given further attention.

  15. Effects of strongly anisosmotic and NaCl deficient solutions on muscimol- and glutamate evoked whole-cell currents in freshly dissociated hippocampal neurons.

    PubMed

    Vreugdenhil, M; Somjen, G G; Wadman, W J

    1995-01-23

    Sudden exposure of dissociated hippocampal neurons to strongly hypo- or hyperosmotic solutions suppresses voltage gated Na+, K+ and Ca2+ currents. We investigated whether ligand gated ion currents were similarly shut down by exposure to anisosmotic solutions. The effect of hypo-osmotic, NaCl deficient (mannitol-substituted), or hyper-osmotic test solutions delivered from a flow pipette was tested on voltage gated Ca2+ currents and on currents and conductance changes evoked by brief administration of either the GABAA-agonist muscimol or glutamate. Hyper-osmotic solution caused cells to shrink, but cell membrane capacitance did not change. Muscimol-induced conductance increases were depressed by hypo-osmotic and by NaCl deficient solutions and often by hyper-osmotic solution. Voltage gated Ca2+ currents were depressed by anisosmotic, but not by NaCl deficient isosmotic solution. NMDA- and non-NMDA evoked conductance increases were depressed by hyperosmotic solution; hypo-osmotic and NaCl deficient solutions were not tested on glutamate induced currents. Ligand gated currents are suppressed by anisosmotic solutions more slowly than are voltage gated channels. The changes caused by anisosmotic and NaCl deficient solutions were much greater then expected from calculated electrochemical effects and are probably the result of change in receptor controlled channels. PMID:7536614

  16. Theoretical and experimental NMR studies on muscimol from fly agaric mushroom (Amanita muscaria)

    NASA Astrophysics Data System (ADS)

    Kupka, Teobald; Wieczorek, Piotr P.

    2016-01-01

    In this article we report results of combined theoretical and experimental NMR studies on muscimol, the bioactive alkaloid from fly agaric mushroom (Amanita muscaria). The assignment of 1H and 13C NMR spectra of muscimol in DMSO-d6 was supported by additional two-dimensional heteronuclear correlated spectra (2D NMR) and gauge independent atomic orbital (GIAO) NMR calculations using density functional theory (DFT). The effect of solvent in theoretical calculations was included via polarized continuum model (PCM) and the hybrid three-parameter B3LYP density functional in combination with 6-311++G(3df,2pd) basis set enabled calculation of reliable structures of non-ionized (neutral) molecule and its NH and zwitterionic forms in the gas phase, chloroform, DMSO and water. GIAO NMR calculations, using equilibrium and rovibrationally averaged geometry, at B3LYP/6-31G* and B3LYP/aug-cc-pVTZ-J levels of theory provided muscimol nuclear magnetic shieldings. The theoretical proton and carbon chemical shifts were critically compared with experimental NMR spectra measured in DMSO. Our results provide useful information on its structure in solution. We believe that such data could improve the understanding of basic features of muscimol at atomistic level and provide another tool in studies related to GABA analogs.

  17. Multivariate optimization of the hollow fibre liquid phase microextraction of muscimol in human urine samples.

    PubMed

    Ncube, Somandla; Poliwoda, Anna; Tutu, Hlanganani; Wieczorek, Piotr; Chimuka, Luke

    2016-10-15

    A liquid phase microextraction based on hollow fibre followed by liquid chromatographic determination was developed for the extraction and quantitation of the hallucinogenic muscimol from urine samples. Method applicability on polar hallucinogens was also tested on two alkaloids, a psychedelic hallucinogen, tryptamine and a polar amino acid, tryptophan which exists in its charged state in the entire pH range. A multivariate design of experiments was used in which a half fractional factorial approach was applied to screen six factors (donor phase pH, acceptor phase HCl concentration, carrier composition, stirring rate, extraction time and salt content) for their extent of vitality in carrier mediated liquid microextractions. Four factors were deemed essential for the effective extraction of each analyte. The vital factors were further optimized for the extraction of single-spiked analyte solutions using a central composite design. When the simultaneous extraction of analytes was performed under universal factor conditions biased towards maximizing the enrichment of muscimol, a good composite desirability value of 0.687 was obtained. The method was finally applied on spiked urine samples with acceptable enrichments of 4.1, 19.7 and 24.1 obtained for muscimol, tryptophan and tryptamine respectively. Matrix-based calibration curves were used to address matrix effects. The r(2) values of the matrix-based linear regression prediction models ranged from 0.9933 to 0.9986. The linearity of the regression line of the matrix-based calibration curves for each analyte was directly linked to the analyte enrichment repeatability which ranged from an RSD value of 8.3-13.1%. Limits of detection for the developed method were 5.12, 3.10 and 0.21ngmL(-1) for muscimol, tryptophan and tryptamine respectively. The developed method has proven to offer a viable alternative for the quantitation of muscimol in human urine samples.

  18. Muscimol prevents long-lasting potentiation of dorsal horn field potentials in rats with chronic constriction injury exhibiting decreased levels of the GABA transporter GAT-1.

    PubMed

    Miletic, Gordana; Draganic, Pero; Pankratz, Matthew T; Miletic, Vjekoslav

    2003-09-01

    The inhibitory activity of gamma-aminobutyric acid (GABA) is considered critical in setting the conditions for synaptic plasticity, and many studies support an important role of GABA in the suppression of nociceptive transmission in the dorsal horn. Consequently, any injury-induced modification of the GABA action has the potential to critically modify spinal synaptic plasticity. We have previously reported that chronic constriction injury of the sciatic nerve was accompanied by long-lasting potentiation of superficial spinal dorsal horn field potentials following high-frequency tetanus. In this study we examined whether the GABA-A receptor agonist muscimol would modify post-tetanic responses in rats with chronic constriction injury. In animals exhibiting maximal thermal hyperalgesia as one sign of neuropathic pain 7 days after loose ligation of the sciatic nerve, spinal application of muscimol (5, 10 or 20 microg) before the high-frequency (50 Hz) tetanus produced a long-lasting depression (rather than potentiation) of spinal dorsal horn field potentials. In separate but related Western immunoblot experiments, we also established that the chronic constriction injury was accompanied by significant decreases in the content of the GABA transporter GAT-1. These data demonstrated that GABA-A receptor agonists may effectively influence the expression of long-lasting synaptic plasticity in the spinal dorsal horn, and that an injury-induced loss in GABA transporter content may have contributed to a depletion of GABA from its terminals within the spinal dorsal horn. These data lent further support to the notion that the loss of GABA inhibition may have important consequences for the development of neuropathic pain. PMID:14499453

  19. Fungal hallucinogens psilocin, ibotenic acid, and muscimol: analytical methods and biologic activities.

    PubMed

    Stebelska, Katarzyna

    2013-08-01

    Psychoactive drugs of fungal origin, psilocin, ibotenic acid, and muscimol among them have been proposed for recreational use and popularized since the 1960s, XX century. Despite their well-documented neurotoxicity, they reached reputation of being safe and nonaddictive. Scientific efforts to find any medical application for these hallucinogens in psychiatry, psychotherapy, and even for religious rituals support are highly controversial. Even if they show any healing potential, their usage in psychotherapy is in some cases inadequate and may additionally harm seriously suffering patients. Hallucinogens are thought to reduce cognitive functions. However, in case of indolealkylamines, such as psilocin, some recent findings suggest their ability to improve perception and mental skills, what would motivate the consumption of "magic mushrooms." The present article offers an opportunity to find out what are the main symptoms of intoxication with mushrooms containing psilocybin/psilocin, muscimol, and ibotenic acid. The progress in analytical methods for detection of them in fungal material, food, and body fluids is reviewed. Findings on the mechanisms of their biologic activity are summarized. Additionally, therapeutic potential of these fungal psychoactive compounds and health risk associated with their abuse are discussed. PMID:23851905

  20. Fungal hallucinogens psilocin, ibotenic acid, and muscimol: analytical methods and biologic activities.

    PubMed

    Stebelska, Katarzyna

    2013-08-01

    Psychoactive drugs of fungal origin, psilocin, ibotenic acid, and muscimol among them have been proposed for recreational use and popularized since the 1960s, XX century. Despite their well-documented neurotoxicity, they reached reputation of being safe and nonaddictive. Scientific efforts to find any medical application for these hallucinogens in psychiatry, psychotherapy, and even for religious rituals support are highly controversial. Even if they show any healing potential, their usage in psychotherapy is in some cases inadequate and may additionally harm seriously suffering patients. Hallucinogens are thought to reduce cognitive functions. However, in case of indolealkylamines, such as psilocin, some recent findings suggest their ability to improve perception and mental skills, what would motivate the consumption of "magic mushrooms." The present article offers an opportunity to find out what are the main symptoms of intoxication with mushrooms containing psilocybin/psilocin, muscimol, and ibotenic acid. The progress in analytical methods for detection of them in fungal material, food, and body fluids is reviewed. Findings on the mechanisms of their biologic activity are summarized. Additionally, therapeutic potential of these fungal psychoactive compounds and health risk associated with their abuse are discussed.

  1. The medial prefrontal cortex plays an important role in the excitation of A10 dopaminergic neurons following intravenous muscimol administration.

    PubMed

    Lokwan, S J; Overton, P G; Berry, M S; Clark, D

    2000-01-01

    Intravenous muscimol administration increases the activity of dopaminergic neurons of the A10 cell group, located in the ventral tegmental area. Evidence suggests that this increase in activity is produced by disinhibition following the inhibition of GABAergic ("non-dopaminergic") cells in the ventral tegmental area. We hypothesized that the activation of A10 cells by muscimol is likely to be at least partly caused by the action of excitatory afferents. To verify this, A10 cells were isolated from ipsilateral afferent sources which utilise excitatory amino acids (which play an important role in the activity of these neurons), using hemisections at the level of the subthalamic nucleus (or just anterior to the subthalamic nucleus), electrolytic lesions of the pedunculopontine tegmental nucleus, or a combination of both. Following hemisections, and hemisections combined with lesions of the pedunculopontine tegmental nucleus, muscimol inhibited rather than excited A10 dopaminergic neurons. The pedunculopontine tegmental nucleus itself appeared to make little intrinsic contribution to muscimol-induced excitation, although the results suggested that part of the excitation which originates in the forebrain may be conducted to A10 cells via the pedunculopontine tegmental nucleus. The source of the effective forebrain excitation was investigated using electrolytic lesions of documented sources of excitatory amino acidergic afferents to the ventral tegmental area: the medial prefrontal cortex, certain nuclei of the amygdalar complex and the lateral habenular nucleus. In the medial prefrontal cortex-lesioned group, muscimol again produced inhibition, an effect qualitatively and quantitatively similar to that in the hemisected groups. Habenular lesions blocked muscimol-induced excitation without producing inhibition, whilst amygdalar lesions produced no significant change in the effects of muscimol. The results suggest that under normal circumstances, an active excitation

  2. Elicitation of feeding, drinking, and gnawing following microinjections of muscimol into the median raphe nucleus of rats.

    PubMed

    Klitenick, M A; Wirtshafter, D

    1989-05-01

    Previous studies have demonstrated that injections of muscimol into the median raphe nucleus (MR) result in large increases in locomotor activity and food intake. The current experiment extends these results by showing that intra-MR muscimol injections in nondeprived rats also elicit nonprandial drinking and gnawing of wooden blocks. These findings indicate that stimulation of GABA receptors within the MR is able to energize a wide range of oral behaviors and is compatible with the view that the MR may be part of a "nonspecific" behavioral activation system. PMID:2730501

  3. Effects of gamma-aminobutyric acid agonist and antagonist drugs on local cerebral glucose utilization

    SciTech Connect

    Palacios, J.M.; Kuhar, M.J.; Rapoport, S.I.; London, E.D.

    1982-07-01

    The (/sup 14/C)2-deoxy-D-glucose method of Sokoloff et al. was used to study local cerebral glucose utilization (LCGU) in rats treated with gamma-aminobutyric acid (GABA) agonist (muscimol and 4,5,6,7-tetrahydroisoxazolo(5,4-C)pyridin-3-ol, THIP) and antagonist (bicuculline) drugs. It was of interest to determine if the pattern of LCGU responses to GABA agonists and antagonists administered systemically in vivo would reflect the known distributions of markers for central GABAergic synapses. The patterns of LCGU responses to muscimol and THIP generally were similar. Most brain regions showed dose-dependent decreases in LCGU; others showed no effects; but the red nucleus showed an increase. The GABA antagonist bicuculline produced convulsions and variable LCGU responses, depending on the time of administration. Bicuculline also partially antagonized the depressant effects of muscimol of LCGU. The magnitudes and distribution of in vivo cerebral metabolic responses to specific GABA agonists were not correlated simply with markers for GABAergic synapses. This lack of correlation indicates that additional factors, such as neural circuitry, regulate the LCGU responses to GABAergic drugs.

  4. GC/MS determination of ibotenic acid and muscimol in the urine of patients intoxicated with Amanita pantherina.

    PubMed

    Stříbrný, Jan; Sokol, Miloš; Merová, Barbora; Ondra, Peter

    2012-07-01

    Ibotenic acid and muscimol are substances which mostly participate in psychotropic properties of Amanita pantherina and Amanita muscaria. They are rapidly absorbed from the gastrointestinal tract and readily excreted in urine. The poisoning with A. pantherina is in the majority of cases accidental because it can be easily mistaken for the edible species (Amanita rubescens, Amanita spissa and Macrolepiota procera). Intoxication with A. muscaria is mostly intentional for recreational purposes. Prognosis of the poisoning is generally good; lethal cases are rare. Mushroom poisoning is often proved by microscopic examination of spores in the stomach or intestinal content. Authors of this article introduce an instrumental method of proving A. pantherina or A. muscaria poisoning. The article describes the isolation of ibotenic acid and muscimol from urine, the derivatization step and the determination of these compounds by gas chromatography/mass spectrometry. Isolation of these alkaloids from urine was performed on a strong cation exchanger (Dowex® 50W X8), and the elution and derivatization of the alkaloids were made in one step with ethyl chloroformate in aqueous solution of sodium hydroxide with the addition of ethanol and pyridine. Cycloserine was used as internal standard. By this method, concentrations of ibotenic acid and muscimol in the urine of four persons intoxicated with A. pantherina were determined. In this study, mass spectra of derivatized ibotenic acid and muscimol are shown, and validation of the method is described. PMID:21751026

  5. Reversible inactivations of the cerebellum with muscimol prevent the acquisition and extinction of conditioned nictitating membrane responses in the rabbit.

    PubMed

    Hardiman, M J; Ramnani, N; Yeo, C H

    1996-07-01

    Lesions of the cerebellum severely impair the classically conditioned nictitating membrane response (NMR) in rabbits. Thus, the cerebellum is essential for the production of conditioned responses (CRs), either because it is actively involved in NMR conditioning or because damage to it causes motor or other general deficits. To distinguish between these alternatives, the cerebellum may be inactivated during training. Inactivation of the cerebellum during acquisition training might result in the absence of CRs on initial trials of subsequent training without the neuronal blockade. The blockade may have prevented learning but it may have produced other deficits that require time or further training to overcome. This problem can be addressed by inactivating the cerebellum during extinction training. If inactivation during extinction training results in the immediate production of CRs when training is resumed without the blockade, then it may be concluded that extinction learning was prevented by the blockade-the presence of CRs argues against any deficits not associated with learning. We used muscimol to inactivate the cerebellum and test its involvement in acquisition and extinction of NMR conditioning in the same subjects. We injected muscimol close to the interpositus nucleus of the cerebellum 1 h before each of four daily training sessions of delay conditioning. Almost no CRs were produced in these training sessions-there was little or no acquisition of NMR conditioning during cerebellar inactivation. The subjects were then trained for four daily sessions without injections of muscimol. There were no CRs on initial trials of the first session of retraining, but all subjects produced CRs by the end of this session. The subjects then received four daily sessions of extinction training with muscimol inactivation of the nuclei-no CRs were produced. Extinction training then continued for four daily sessions without muscimol inactivation. On the first of these sessions

  6. Distinct activities of GABA agonists at synaptic- and extrasynaptic-type GABAA receptors.

    PubMed

    Mortensen, Martin; Ebert, Bjarke; Wafford, Keith; Smart, Trevor G

    2010-04-15

    The activation characteristics of synaptic and extrasynaptic GABA(A) receptors are important for shaping the profile of phasic and tonic inhibition in the central nervous system, which will critically impact on the activity of neuronal networks. Here, we study in isolation the activity of three agonists, GABA, muscimol and 4,5,6,7-tetrahydoisoxazolo[5,4-c]pyridin-3(2H)-one (THIP), to further understand the activation profiles of alpha 1 beta 3 gamma 2, alpha 4 beta 3 gamma 2 and alpha 4 beta 3 delta receptors that typify synaptic- and extrasynaptic-type receptors expressed in the hippocampus and thalamus. The agonists display an order of potency that is invariant between the three receptors, which is reliant mostly on the agonist dissociation constant. At delta subunit-containing extrasynaptic-type GABA(A) receptors, both THIP and muscimol additionally exhibited, to different degrees, superagonist behaviour. By comparing whole-cell and single channel currents induced by the agonists, we provide a molecular explanation for their different activation profiles. For THIP at high concentrations, the unusual superagonist behaviour on alpha 4 beta 3 delta receptors is a consequence of its ability to increase the duration of longer channel openings and their frequency, resulting in longer burst durations. By contrast, for muscimol, moderate superagonist behaviour was caused by reduced desensitisation of the extrasynaptic-type receptors. The ability to specifically increase the efficacy of receptor activation, by selected exogenous agonists over that obtained with the natural transmitter, may prove to be of therapeutic benefit under circumstances when synaptic inhibition is compromised or dysfunctional.

  7. Presence of a low molecular weight endogenous inhibitor on 3H-muscimol binding in synaptic membranes

    NASA Astrophysics Data System (ADS)

    Yoneda, Yukio; Kuriyama, Kinya

    1980-06-01

    The specific binding of 3H-muscimol to synaptic membrane preparations obtained from the rat brain has been thought to reflect the association of γ-aminobutyric acid (GABA), a potential candidate as an inhibitory neurotransmitter in the mammalian central nervous system (CNS), with its synaptic receptors1,2. Treatment of synaptic membranes with Triton X-100 significantly increases the specific binding of 3H-muscimol2. Several reports also indicate the presence of endogenous substances, such as GABA3, acidic protein4 and phosphatidylethanolamine5, which inhibit Na-independent binding of 3H-GABA in the synaptic membranous fractions from the rat brain. We report here that in the supernatant obtained from Triton-treated synaptic membranes there exists a new type of endogenous inhibitor of 3H-muscimol binding which is apparently different from the inhibitory substances described previously3-5. The new inhibitor has a low molecular weight (MW) and probably originated from neurones rather than glial cells. We have termed this endogenous inhibitor the GABA receptor binding inhibitory factor (GRIF).

  8. Molecular diagnosis of a laboratory mouse papillomavirus (MusPV).

    PubMed

    Joh, Joongho; Jenson, A Bennett; Proctor, Mary; Ingle, Arvind; Silva, Kathleen A; Potter, Christopher S; Sundberg, John P; Ghim, Shin-je

    2012-12-01

    MusPV, a novel papillomavirus (PV) that naturally infects laboratory mice, was isolated and characterized from a colony of NMRI-Foxn1(nu)/Foxn1(nu) (nude) mice in India. Because MusPV may have been missed during routine pathogen screening of mice in colonies worldwide, a variety of detection methods are described to detect MusPV. The clinical and histologic lesions of productive MusPV infections fit PV-associated features, including papillomas, koilocytes within the stratum granulosum of the hyperplastic/acanthotic papillomatous epithelium, and the presence of intranuclear virus particles in koilocytotic cells visualized by electron microscopy. Antiserum against disrupted PV virions, isolated from another species (canine), identified conserved viral antigens in productively infected cells by immunohistochemistry. A rolling circle technique was used to amplify viral circular DNAs followed by endonuclease restriction enzyme digestion to determine the correct size of PV DNA. Consensus PV degenerative primers, My09/11, commonly used to detect many different types of PVs by polymerase chain reaction (PCR), particularly mucosotropic HPVs, also identified MusPV and all rodent PVs tested. Since there was one nucleotide mismatch between the My09/11 primer set and the MusPV template, a new primer set, MusPV-My09/11, was designed to specifically detect MusPV in latent infections and spontaneous MusPV-induced papillomas. Southern blot analysis verified the presence of full size PV DNA in infected tissues. Virus-like particles (VLPs), generated from MusPV L1 genes, provided a substrate for serological testing of naturally and experimentally infected mice. In summary, a series of diagnostic assays were developed and validated to detect MusPV infection in skin tumors and serological response in laboratory mice. PMID:22796029

  9. GABAergic Agonists Modulate the Glutamate Release from Frontal Cortex Synaptosomes of Rats with Experimental Autoimmune Encephalomyelitis.

    PubMed

    Fernández Hurst, Nicolás; Chanaday, Natalí L; Roth, German A

    2015-01-01

    Experimental autoimmune encephalomyelitis (EAE) is an inflammatory demyelinating disease that mimics many of the clinical and pathological features of multiple sclerosis. We have previously described a significant diminution in the GABAergic regulation of glutamate release from synaptosomes of EAE rats isolated during the acute stage of the disease. In order to explore the possible metabolic pathways responsible for this alteration, in this work we evaluate the direct effect of different GABAergic agonists on the glutamate release and concomitant synapsin I phosphorylation in synaptosomes from the frontal cortex of control and EAE animals. The results show that GABA as well as the GABA receptor agonists Muscimol (GABAA agonist) and Baclofen (GABAB agonist) caused a decrease in glutamate release in control rats paralleled by a similar reduction in synapsin I phosphorylation. Meanwhile synaptosomes from EAE animals are responsive only to Baclofen with respect to nontreated EAE synaptosomes, since glutamate release from the synaptosomes treated with Muscimol was similar to that observed in EAE rat synaptosomes which was already reduced as consequence of the disease. In the case of the benzodiazepines Diazepam and Clonazepam (GABAA allosteric agonists), both of them induced a reduction in glutamate release in synaptosomes from the CFA rats, effect that was only observed in synaptosomes of EAE rats treated with Clonazepam. In all cases both benzodiazepines showed a higher effect on synapsin I phosphorylation than in glutamate release. These results indicate that the extent of GABAergic modulation of presynaptic terminals depends on the type of agonist employed and this regulation is altered in the frontal cortex during the acute phase of EAE with respect to control animals. PMID:26631092

  10. Determination of mushroom toxins ibotenic acid, muscimol and muscarine by capillary electrophoresis coupled with electrospray tandem mass spectrometry.

    PubMed

    Ginterová, Pavlína; Sokolová, Barbora; Ondra, Peter; Znaleziona, Joanna; Petr, Jan; Ševčík, Juraj; Maier, Vítězslav

    2014-07-01

    The CE-ESI-MS/MS method for the identification, separation and determination of mushroom toxins, namely ibotenic acid, muscimol and muscarine, was developed. It proved to be sensitive and thus useful for the real sample analysis with omitting the labor and time consuming pretreatment step. The CE-ESI-MS/MS method was applied on the spiked human urine. The analytical characteristics of the proposed method, such as limits of detection, linearity and repeatability of the peak area and the migration time, were evaluated. The RSD of the migration time and peak area were from 0.93% to 1.60% and from 2.96% to 3.42%, respectively. The obtained LOD values were at the nanomolar concentration level, therefore the developed method is sufficient for the determination and quantification of studied toxins in human urine after mushroom intoxication. PMID:24840440

  11. Determination of mushroom toxins ibotenic acid, muscimol and muscarine by capillary electrophoresis coupled with electrospray tandem mass spectrometry.

    PubMed

    Ginterová, Pavlína; Sokolová, Barbora; Ondra, Peter; Znaleziona, Joanna; Petr, Jan; Ševčík, Juraj; Maier, Vítězslav

    2014-07-01

    The CE-ESI-MS/MS method for the identification, separation and determination of mushroom toxins, namely ibotenic acid, muscimol and muscarine, was developed. It proved to be sensitive and thus useful for the real sample analysis with omitting the labor and time consuming pretreatment step. The CE-ESI-MS/MS method was applied on the spiked human urine. The analytical characteristics of the proposed method, such as limits of detection, linearity and repeatability of the peak area and the migration time, were evaluated. The RSD of the migration time and peak area were from 0.93% to 1.60% and from 2.96% to 3.42%, respectively. The obtained LOD values were at the nanomolar concentration level, therefore the developed method is sufficient for the determination and quantification of studied toxins in human urine after mushroom intoxication.

  12. Two alternatively spliced transcripts generated from OsMUS81, a rice homolog of yeast MUS81, are up-regulated by DNA-damaging treatments.

    PubMed

    Mimida, Naozumi; Kitamoto, Hiroko; Osakabe, Keishi; Nakashima, Marina; Ito, Yuji; Heyer, Wolf-Dietrich; Toki, Seiichi; Ichikawa, Hiroaki

    2007-04-01

    OsMUS81, a rice homolog of the yeast MUS81 endonuclease gene, produced two alternative transcripts, OsMUS81alpha and OsMUS81beta. OsMus81alpha contained a Helix-hairpin-Helix (HhH) motif at the N- and C-termini, and a conserved XPF-like motif in the center, while the OsMus81beta isoform lacked the second HhH motif by alternative splicing of a cryptic intron generating a truncated protein. The two transcripts were induced after DNA-damaging treatments such as high intensity light, UV-C and gamma-radiation. The yeast two-hybrid assay detected a strong interaction between OsMus81 and OsRad54 recombinational repair proteins. These findings suggest that OsMus81 functions in maintaining genome integrity through homologous recombination. PMID:17327258

  13. Crystal structure of the Mus81-Eme1 complex.

    PubMed

    Chang, Jeong Ho; Kim, Jeong Joo; Choi, Jung Min; Lee, Jung Hoon; Cho, Yunje

    2008-04-15

    The Mus81-Eme1 complex is a structure-specific endonuclease that plays an important role in rescuing stalled replication forks and resolving the meiotic recombination intermediates in eukaryotes. We have determined the crystal structure of the Mus81-Eme1 complex. Both Mus81 and Eme1 consist of a central nuclease domain, two repeats of the helix-hairpin-helix (HhH) motif at their C-terminal region, and a linker helix. While each domain structure resembles archaeal XPF homologs, the overall structure is significantly different from those due to the structure of a linker helix. We show that a flexible intradomain linker that formed with 36 residues in the nuclease domain of Eme1 is essential for the recognition of DNA. We identified several basic residues lining the outer surface of the active site cleft of Mus81 that are involved in the interaction with a flexible arm of a nicked Holliday junction (HJ). These interactions might contribute to the optimal positioning of the opposite junction across the nick into the catalytic site, which provided the basis for the "nick and counternick" mechanism of Mus81-Eme1 and for the nicked HJ to be the favored in vitro substrate of this enzyme. PMID:18413719

  14. Rat behavior in two models of anxiety and brain [3H]muscimol binding: pharmacological, correlation, and multifactor analysis.

    PubMed

    Sienkiewicz-Jarosz, Helena; Szyndler, Janusz; Członkowska, Agnieszka I; Siemiatkowski, Marek; Maciejak, Piotr; Wisłowska, Aleksandra; Zienowicz, Małgorzata; Lehner, Małgorzata; Turzyńska, Danuta; Bidziński, Andrzej; Płaźnik, Adam

    2003-10-17

    The contribution of GABAergic mechanisms to rat emotional behavior in two animal models of anxiety (open field test of neophobia and aversively conditioned freezing reaction), was confirmed by pharmacological analysis, using anxiolytic (midazolam) and anxiogenic (picrotoxin) compounds. Both substances are known to modulate GABA(A) receptors' activity in a positive or negative manner, respectively. It seemed, therefore, worthwhile to check whether the behavioral parameters measured in these animal models of anxiety correlate with [3H]muscimol binding (a highly selective GABA(A) receptor ligand) in different brain structures of nai;ve rats, with a view to establish the role of genetically determined expression of local GABA(A) receptors in the organization of rat emotional and motor behavior. Correlation analysis revealed no links between individually determined expression of GABA(A) receptors (quantitative receptor autoradiography) in the brain structures, and the emotional behavior of nai;ve, drug-free animals, in both tests. Factor analysis confirmed that animal behavior in both tests was under control of different central processes. Moreover, none of the behavioral and ligand binding parameters loaded on the same factor, confirming the negative results of the correlation study. The present results indicate that the origin of emotions is a complex phenomenon, probably involving the interaction between GABA-ergic innervation of many brain structures. PMID:14529801

  15. Immunologic Control of Mus musculus Papillomavirus Type 1

    PubMed Central

    Peng, Shiwen; Chang, Yung-Nien; Hung, Chien-Fu; Roden, Richard B. S.

    2015-01-01

    Persistent papillomas developed in ~10% of out-bred immune-competent SKH-1 mice following MusPV1 challenge of their tail, and in a similar fraction the papillomas were transient, suggesting potential as a model. However, papillomas only occurred in BALB/c or C57BL/6 mice depleted of T cells with anti-CD3 antibody, and they completely regressed within 8 weeks after depletion was stopped. Neither CD4+ nor CD8+ T cell depletion alone in BALB/c or C57BL/6 mice was sufficient to permit visible papilloma formation. However, low levels of MusPV1 were sporadically detected by either genomic DNA-specific PCR analysis of local skin swabs or in situ hybridization of the challenge site with an E6/E7 probe. After switching to CD3+ T cell depletion, papillomas appeared upon 14/15 of mice that had been CD4+ T cell depleted throughout the challenge phase, 1/15 of CD8+ T cell depleted mice, and none in mice without any prior T cell depletion. Both control animals and those depleted with CD8-specific antibody generated MusPV1 L1 capsid-specific antibodies, but not those depleted with CD4-specific antibody prior to T cell depletion with CD3 antibody. Thus, normal BALB/c or C57BL/6 mice eliminate the challenge dose, whereas infection is suppressed but not completely cleared if their CD4 or CD8 T cells are depleted, and recrudescence of MusPV1 is much greater in the former following treatment with CD3 antibody, possibly reflecting their failure to generate capsid antibody. Systemic vaccination of C57BL/6 mice with DNA vectors expressing MusPV1 E6 or E7 fused to calreticulin elicits potent CD8 T cell responses and these immunodominant CD8 T cell epitopes were mapped. Adoptive transfer of a MusPV1 E6-specific CD8+ T cell line controlled established MusPV1 infection and papilloma in RAG1-knockout mice. These findings suggest the potential of immunotherapy for HPV-related disease and the importance of host immunogenetics in the outcome of infection. PMID:26495972

  16. Tracing the eastward dispersal of the house mouse, Mus musculus.

    PubMed

    Suzuki, Hitoshi; Yakimenko, Lyudmila V; Usuda, Daiki; Frisman, Liubov V

    2015-01-01

    Here we describe recent advances in our understanding of the natural history of the house mouse, Mus musculus, with a focus on the genetic characteristics of the home territories and how this relates to prehistoric eastward movements from the predicted source areas. Recent studies of mitochondrial and nuclear gene sequences provide insight into the ancient divergence of the three subspecies groups, M. m. castaneus (CAS), M. m. domesticus (DOM), and M. m. musculus (MUS), with inferred natural habits (homelands) in central (Iran, Afghanistan, Pakistan, and India), western (western Iran), and northern (central Asia) areas, respectively. Our mitochondrial DNA and nuclear gene analyses indicate that only one local lineage of CAS extended its range via historical rapid expansion at two different times to Southeast Asia and East Asia, including Japan and southern Sakhalin. This is suggestive of a rapid range expansion of CAS out of its homeland, perhaps associated with the spread of agricultural practices in Asia. The subspecies group MUS now occurs in a large portion of northern Eurasia from eastern Europe in the West to the Japanese Islands in the East, including Uzbekistan, Kazakhstan, southern Siberia, northern China, and Korea, showing divergent patterns in terms of Mus musculus genetics, particularly in relation to nuclear gene sequences, allozymes (e.g., hemoglobin), morphological characteristics, and cytogenetic C-banding patterns. In this review article, we explain the complex spatial patterns of MUS. We postulate that two historical dispersal events took place, from two different source areas, and tentatively assign the taxon names "musculus" and "wagneri" to the two populations, which are associated with distinct genetic modules.

  17. MUS-2, a novel variant of the chromosome-encoded β-lactamase MUS-1, from Myroides odoratimimus

    PubMed Central

    Al-Bayssari, C.; Gupta, S. Kumar; Dabboussi, F.; Hamze, M.; Rolain, J.-M.

    2015-01-01

    The aim of the present study was to investigate the molecular mechanism of carbapenem resistance of three imipenem-resistant isolates of Myroides odoratimimus recovered from two livestock farms of cows and pigeons by rectal swab in Lebanon in January 2014. Investigation of imipenem resistance of these isolates using the modified Hodge test, the EDTA test, the modified CarbaNP test and the matrix-assisted laser desorption/ionization time-of-flight mass spectrometry Ultraflex assay showed a carbapenemase activity due to the presence of a chromosome-encoded β-lactamase MUS, verified by PCR. However amplification and sequencing of this chromosomal gene showed a novel variant of it designated MUS-2 by the curators of the Lahey database of β-lactamases (http://www.lahey.org/Studies/webt.asp). Cloning of the blaMUS-2 was performed, followed by protein expression in Escherichia coli TOP 10. Pulsed-field gel electrophoresis clearly showed that the three isolates belonged to the same clone. This study reports a novel variant of the chromosome-encoded blaMUS-1 associated with carbapenem resistance in Myroides odoratimimus and shows that animals may represent a reservoir of bacteria harbouring several variants of resistance genes. PMID:26257915

  18. The DNA repair endonuclease Mus81 facilitates fast DNA replication in the absence of exogenous damage

    PubMed Central

    Fu, Haiqing; Martin, Melvenia M.; Regairaz, Marie; Huang, Liang; You, Yang; Lin, Chi-Mei; Ryan, Michael; Kim, RyangGuk; Shimura, Tsutomu; Pommier, Yves; Aladjem, Mirit I.

    2015-01-01

    The Mus81 endonuclease resolves recombination intermediates and mediates cellular responses to exogenous replicative stress. Here, we show that Mus81 also regulates the rate of DNA replication during normal growth by promoting replication fork progression while reducing the frequency of replication initiation events. In the absence of Mus81 endonuclease activity, DNA synthesis is slowed and replication initiation events are more frequent. In addition, Mus81 deficient cells fail to recover from exposure to low doses of replication inhibitors and cell viability is dependent on the XPF endonuclease. Despite an increase in replication initiation frequency, cells lacking Mus81 use the same pool of replication origins as Mus81-expressing cells. Therefore, decelerated DNA replication in Mus81 deficient cells does not initiate from cryptic or latent origins not used during normal growth. These results indicate that Mus81 plays a key role in determining the rate of DNA replication without activating a novel group of replication origins. PMID:25879486

  19. The DNA repair endonuclease Mus81 facilitates fast DNA replication in the absence of exogenous damage.

    PubMed

    Fu, Haiqing; Martin, Melvenia M; Regairaz, Marie; Huang, Liang; You, Yang; Lin, Chi-Mei; Ryan, Michael; Kim, RyangGuk; Shimura, Tsutomu; Pommier, Yves; Aladjem, Mirit I

    2015-01-01

    The Mus81 endonuclease resolves recombination intermediates and mediates cellular responses to exogenous replicative stress. Here, we show that Mus81 also regulates the rate of DNA replication during normal growth by promoting replication fork progression while reducing the frequency of replication initiation events. In the absence of Mus81 endonuclease activity, DNA synthesis is slowed and replication initiation events are more frequent. In addition, Mus81-deficient cells fail to recover from exposure to low doses of replication inhibitors and cell viability is dependent on the XPF endonuclease. Despite an increase in replication initiation frequency, cells lacking Mus81 use the same pool of replication origins as Mus81-expressing cells. Therefore, decelerated DNA replication in Mus81-deficient cells does not initiate from cryptic or latent origins not used during normal growth. These results indicate that Mus81 plays a key role in determining the rate of DNA replication without activating a novel group of replication origins. PMID:25879486

  20. Intracavity frequency doubling of {mu}s alexandrite laser pulses

    SciTech Connect

    Brinkmann, R.; Schoof, K.

    1994-12-31

    Intracavity second harmonic generation (SHG) with a three mirror folded cavity configuration was investigated with a flashlamp pumped, Q-switched Alexandrite laser. The authors therefore used different nonlinear optical crystals to convert the fundamental 750 nm radiation into the near UV spectral ,range (3 75 nm). The laser pulses were stretched into the {mu}s time domain by an electronic feedback system regulating the losses of the resonator. They investigated the conversion efficiency for different pulse lengths as well as the effect of pulse-lengthening due to the nonlinearity of the intracavity losses introduced by the optical crystal used. Working with BBO-crystals, they were able to achieve a second harmonic output of 25 mJ per pulse at 375 mn with a temporal rectangular pulse of 1 {mu}s in length and a stable nearly gaussian shaped beam profile.

  1. Mys retrotransposons in Peromyscus leucopus and transgenic Mus musculus.

    PubMed

    Pine, D S; Bourekas, E C; Potter, S S

    1988-04-25

    The mys family of retrotransposons exhibits an interesting phylogenetic distribution with 500-1000 copies per haploid genome in the white-footed mouse Peromyscus leucopus and no copies detectable in the house mouse Mus musculus, even though most other repeated sequences are shared by these two species. Comparison of the DNA sequences from the 3' ends of five mys elements show that insertion occurs just upstream of a well-conserved 11 bp target sequence. Transcription patterns of the elements in brain, liver, heart, kidneys and gonads in Peromyscus leucopus are analyzed. Transcripts are found in all tissues examined, but they are remarkably heterogeneous in size. When four cloned elements are introduced into transgenic Mus musculus, however, discrete patterns of expression are revealed. Furthermore, a study of the structure of the concatemers of mys elements in the transgenic mice demonstrates that recircularization of injected linear molecules is an important event in concatemer generation.

  2. The enhancement of diazepam and muscimol binding by pentobarbital and (+)-etomidate: size of the molecular arrangement estimated by electron irradiation inactivation of rat cortex.

    PubMed

    Maksay, G; Nielsen, M; Simonyi, M

    1986-09-25

    Synaptosomal membranes were prepared from frozen rat cortices irradiated by 10 MeV electrons and the enhancement of [3H]diazepam and [3H]muscimol binding by pentobarbital (PB) and (+)-etomidate was studied. The target sizes of the corresponding parts of the receptor complex were estimated from the decrease in the enhancement as a function of irradiation dose. Different radiation inactivation constants suggest different regulatory units for the enhancement by PB and (+)-etomidate. Target sizes for PB and (+)-etomidate enhancement of [3H]diazepam binding were 127 +/- 14 and 360 + 124 kDa, respectively.

  3. Characterization of the mus308 gene in Drosophila melanogaster

    SciTech Connect

    Leonhardt, E.A.; Henderson, D.S.; Rinehart, J.E.; Boyd, J.B. )

    1993-01-01

    Among the available mutagen-sensitive mutations in Drosophila, those at the mus3O8 locus are unique in conferring hypersensitivity to DNA cross-linking agents but not to monofunctional agents. Those mutations are also associated with an elevated frequency of chromosomal aberrations, altered DNA metabolism and the modification of a deoxyribonuclease. This spectrum of phenotypes is shared with selected mammalian mutations including Fanconi anemia in humans. In anticipation of the molecular characterization of the mus3O8 gene, it has been localized cytogenetically to 87C9-87D1,2 on the right arm of chromosome three. Nine new mutant alleles of the gene have been generated by X-ray mutagenesis and one was recovered following hybrid dysgenesis. Characterization of these new alleles has uncovered additional phenotypes of mutations at this locus. Homozygous mus3O8 flies that have survived moderate mutagen treatment exhibit an altered wing position that is correlated with reduced flight ability and an altered mitochondrial morphology. In addition, observations of elevated embryo mortality are potentially explained by an aberrant distribution of nuclear material in early embryos which is similar to that seen in the mutant giant nuclei.

  4. Characterization of the Mus308 Gene in Drosophila Melanogaster

    PubMed Central

    Leonhardt, E. A.; Henderson, D. S.; Rinehart, J. E.; Boyd, J. B.

    1993-01-01

    Among the available mutagen-sensitive mutations in Drosophila, those at the mus308 locus are unique in conferring hypersensitivity to DNA cross-linking agents but not to monofunctional agents. Those mutations are also associated with an elevated frequency of chromosomal aberrations, altered DNA metabolism and the modification of a deoxyribonuclease. This spectrum of phenotypes is shared with selected mammalian mutations including Fanconi anemia in humans. In anticipation of the molecular characterization of the mus308 gene, it has been localized cytogenetically to 87C9-87D1,2 on the right arm of chromosome three. Nine new mutant alleles of the gene have been generated by X-ray mutagenesis and one was recovered following hybrid dysgenesis. Characterization of these new alleles has uncovered additional phenotypes of mutations at this locus. Homozygous mus308 flies that have survived moderate mutagen treatment exhibit an altered wing position that is correlated with reduced flight ability and an altered mitochondrial morphology. In addition, observations of elevated embryo mortality are potentially explained by an aberrant distribution of nuclear material in early embryos which is similar to that seen in the mutant giant nuclei. PMID:8417992

  5. Cepheid Masses: FUSE Observations of S Mus B

    NASA Astrophysics Data System (ADS)

    Evans, N. R.; Massa, D.; Fullerton, A. W.; Sonneborn, G.; Iping, R.

    2004-05-01

    Measurement of Cepheid masses has been a goal both in order to understand these primary distance indicators and also as a benchmark for stellar evolution calculations of high mass stars. The approach is to use ultraviolet spectroscopy (IUE, HST GHRS, and HST STIS) to measure the orbital velocity amplitude of the hot companion of a binary Cepheid. This amplitude plus the Cepheid orbital velocity amplitude from the ground provides the mass ratio between the Cepheid and the companion. The mass of the companion is inferred from an ultraviolet spectral type and hence the mass of the Cepheid is determined. S Mus B is the hottest Cepheid companion known. As a benefit, the large ultraviolet flux made it the only Cepheid companion for which the velocity amplitude could be measured with the echelle mode of the HST GHRS. Unfortunately, the high temperature of S Mus B is difficult to constrain at wavelengths longer than 1200 A because of the degeneracy between temperature and reddening. Thus the companion has the most accurate velocity amplitude of any Cepheid binary, but a relatively inaccurate mass. We have now obtained a FUSE spectrum, and have identified two regions which are temperature sensitive but relatively unaffected by H2 absorption (940 A and Ly Beta wings). By comparing S Mus B with other FUSE spectra, we have determined a temperature of 17,000 K. The resultant Cepheid mass is 6.0 +/- 0.4 solar masses. Financial assistance was provided by Chandra X-ray Center NASA Contract NAS8-39073 for NRE and FUSE grant NAG5-11946.

  6. GABAA receptor partial agonists and antagonists: structure, binding mode, and pharmacology.

    PubMed

    Krall, Jacob; Balle, Thomas; Krogsgaard-Larsen, Niels; Sørensen, Troels E; Krogsgaard-Larsen, Povl; Kristiansen, Uffe; Frølund, Bente

    2015-01-01

    A high degree of structural heterogeneity of the GABAA receptors (GABAARs) has been revealed and is reflected in multiple receptor subtypes. The subunit composition of GABAAR subtypes is believed to determine their localization relative to the synapses and adapt their functional properties to the local temporal pattern of GABA impact, enabling phasic or tonic inhibition. Specific GABAAR antagonists are essential tools for physiological and pharmacological elucidation of the different type of GABAAR inhibition. However, distinct selectivity among the receptor subtypes (populations) has been shown for only a few orthosteric ligands. Still, these examples show that it is indeed possible to obtain orthosteric subtype selectivity and they serve as models for further development in the orthosteric GABAAR ligand area. This review presents the very few existing structural classes of orthosteric GABAAR antagonists and describes the development of potent antagonists from partial agonists originally derived from the potent GABAAR agonist muscimol. In this process, several heterocyclic aromatic systems have been used in combination with structural models in order to map the orthosteric binding site and to reveal structural details to be used for obtaining potency and subtype selectivity. The challenges connected to functional characterization of orthosteric GABAAR partial agonists and antagonists, especially with regard to GABAAR stoichiometry and alternative binding sites are discussed. GABAAR antagonists have been essential in defining the tonic current but both remaining issues concerning the GABAARs involved and the therapeutic possibilities of modulating tonic inhibition underline the need for GABAAR antagonists with improved selectivity.

  7. The Mass of the Classical Cepheid S Mus

    NASA Astrophysics Data System (ADS)

    Remage Evans, Nancy

    A measured mass of a classical Cepheid provides a unique test of evolutionary calculations in evolved stars because it is combined with a precisely known luminosity. The quantitative understanding of Cepheids reinforces the key role they play in determining extragalactic distances. IUE, HST, and Voyager observations have now made possible observational determination of masses for several Cepheids in binary systems. A FUSE spectrum of the hot companion of the Cepheid S Mus A is the key to a significantly improved accuracy for the mass, which is particularly important because S Mus A is the Cepheid with the largest measured mass. A FUSE spectrum is necessary because this wavelength range is particularly sensitive to temperature at the spectral type of the companion (B3 V), and the high resolution of FUSE is required to correct for the H_2 absorption accurately. The spectral type or temperature (and the mass inferred from it) will be combined with the orbital velocity amplitude of the companion from HST GHRS echelle spectra, and the orbital velocity amplitude of the Cepheid from the ground-based orbit to determine the mass of the Cepheid. By including the FUSE data, the uncertainty in the mass of the Cepheid will be reduced from the current value of 12 percent to 7 percent. This will make it the most accurate Cepheid mass currently available and provide the strongest constraint on evolutionary calculations.

  8. A natural history of "agonist".

    PubMed

    Russo, Ruth

    2002-01-01

    This paper constructs a brief history of the biochemical term agonist by exploring the multiple meanings of the root agôn in ancient Greek literature and describing how agonist first appeared in the scientific literature of the 20th century in the context of neurophysiologists' debates about the existence and properties of cellular receptors. While the narrow scientific definition of agonist may appear colorless and dead when compared with the web of allusions spun by the ancient Greek agôn, the scientific power and creativity of agonist actually resides precisely in its exact, restricted meaning for biomedical researchers.

  9. [Retrospective evaluation of brucellosis cases inhabiting in Mus province].

    PubMed

    Sit, Dede; Kadiroğlu, Ali Kemal; Kayabaşi, Hasan; Hoşoğlu, Salih

    2006-07-01

    The aim of this study was to evaluate the brucellosis patients inhabiting in Mus province, in Eastern Anatolia of Turkey, retrospectively. The mean age of the patients (n: 87) was 38.1 +/- 12.4 years, and 45% of them were female. The transmission route was the consumption of unpasteurized fresh cheese (in 85%), and unboiled milk (in 45%). The most common symptoms were recorded as chills (89%), fever (87%), and arthralgia (81%). Splenomegaly (71%) and hepatomegaly (63%) were the predominant physical examination signs. Diagnosis was made based on the clinical features and positive Rose-Bengal test result (93%), however, blood cultures could not be performed due to insufficient laboratory equipment. In 92% of the patients at least one complication has been detected indicating delayed admission to the hospital, while the most common complications were sacroileitis (79%) and spondylitis (44%). Streptomycin+doxycyclin, streptomycin+doxycyclin+ ciprofloxacin, and streptomycin+doxycyclin+ rifampicin combination therapies were used in 62%, 24% and 14% of the patients, respectively, for six weeks, resulting with complete cure. PMID:17001861

  10. Genomic resources for wild populations of the house mouse, Mus musculus and its close relative Mus spretus

    PubMed Central

    Harr, Bettina; Karakoc, Emre; Neme, Rafik; Teschke, Meike; Pfeifle, Christine; Pezer, Željka; Babiker, Hiba; Linnenbrink, Miriam; Montero, Inka; Scavetta, Rick; Abai, Mohammad Reza; Molins, Marta Puente; Schlegel, Mathias; Ulrich, Rainer G.; Altmüller, Janine; Franitza, Marek; Büntge, Anna; Künzel, Sven; Tautz, Diethard

    2016-01-01

    Wild populations of the house mouse (Mus musculus) represent the raw genetic material for the classical inbred strains in biomedical research and are a major model system for evolutionary biology. We provide whole genome sequencing data of individuals representing natural populations of M. m. domesticus (24 individuals from 3 populations), M. m. helgolandicus (3 individuals), M. m. musculus (22 individuals from 3 populations) and M. spretus (8 individuals from one population). We use a single pipeline to map and call variants for these individuals and also include 10 additional individuals of M. m. castaneus for which genomic data are publically available. In addition, RNAseq data were obtained from 10 tissues of up to eight adult individuals from each of the three M. m. domesticus populations for which genomic data were collected. Data and analyses are presented via tracks viewable in the UCSC or IGV genome browsers. We also provide information on available outbred stocks and instructions on how to keep them in the laboratory. PMID:27622383

  11. Genomic resources for wild populations of the house mouse, Mus musculus and its close relative Mus spretus.

    PubMed

    Harr, Bettina; Karakoc, Emre; Neme, Rafik; Teschke, Meike; Pfeifle, Christine; Pezer, Željka; Babiker, Hiba; Linnenbrink, Miriam; Montero, Inka; Scavetta, Rick; Abai, Mohammad Reza; Molins, Marta Puente; Schlegel, Mathias; Ulrich, Rainer G; Altmüller, Janine; Franitza, Marek; Büntge, Anna; Künzel, Sven; Tautz, Diethard

    2016-01-01

    Wild populations of the house mouse (Mus musculus) represent the raw genetic material for the classical inbred strains in biomedical research and are a major model system for evolutionary biology. We provide whole genome sequencing data of individuals representing natural populations of M. m. domesticus (24 individuals from 3 populations), M. m. helgolandicus (3 individuals), M. m. musculus (22 individuals from 3 populations) and M. spretus (8 individuals from one population). We use a single pipeline to map and call variants for these individuals and also include 10 additional individuals of M. m. castaneus for which genomic data are publically available. In addition, RNAseq data were obtained from 10 tissues of up to eight adult individuals from each of the three M. m. domesticus populations for which genomic data were collected. Data and analyses are presented via tracks viewable in the UCSC or IGV genome browsers. We also provide information on available outbred stocks and instructions on how to keep them in the laboratory. PMID:27622383

  12. Genomic resources for wild populations of the house mouse, Mus musculus and its close relative Mus spretus.

    PubMed

    Harr, Bettina; Karakoc, Emre; Neme, Rafik; Teschke, Meike; Pfeifle, Christine; Pezer, Željka; Babiker, Hiba; Linnenbrink, Miriam; Montero, Inka; Scavetta, Rick; Abai, Mohammad Reza; Molins, Marta Puente; Schlegel, Mathias; Ulrich, Rainer G; Altmüller, Janine; Franitza, Marek; Büntge, Anna; Künzel, Sven; Tautz, Diethard

    2016-01-01

    Wild populations of the house mouse (Mus musculus) represent the raw genetic material for the classical inbred strains in biomedical research and are a major model system for evolutionary biology. We provide whole genome sequencing data of individuals representing natural populations of M. m. domesticus (24 individuals from 3 populations), M. m. helgolandicus (3 individuals), M. m. musculus (22 individuals from 3 populations) and M. spretus (8 individuals from one population). We use a single pipeline to map and call variants for these individuals and also include 10 additional individuals of M. m. castaneus for which genomic data are publically available. In addition, RNAseq data were obtained from 10 tissues of up to eight adult individuals from each of the three M. m. domesticus populations for which genomic data were collected. Data and analyses are presented via tracks viewable in the UCSC or IGV genome browsers. We also provide information on available outbred stocks and instructions on how to keep them in the laboratory.

  13. Molecular mass spectrometric identification of superoxide dismutase in the liver of mice Mus musculus and Mus spretus using a metallomics analytical approach.

    PubMed

    González-Fernández, M; García-Barrera, T; Gómez-Ariza, J L

    2011-11-01

    This paper reports the identification and quantification of superoxide dismutase in the liver of Mus musculus and Mus spretus mice using a metallomics analytical approach. The approach consisted of using orthogonal chromatographic systems coupled to ICP-MS and UV detectors. Size-exclusion fractionation of the cytosolic extracts was followed by anion-exchange chromatographic separation of Cu- and Zn-containing species. After purification then tryptic digestion, Cu- and Zn-containing superoxide dismutase was identified by nESI-QqTOF. The MS-MS spectra of doubly charged peptides, with the Mascot searching engine, were used to obtain the sequence of the protein.

  14. Intrathecal administration of a gap junction decoupler, an inhibitor of Na(+)-K(+)-2Cl(-) cotransporter 1, or a GABA(A) receptor agonist attenuates mechanical pain hypersensitivity induced by REM sleep deprivation in the rat.

    PubMed

    Wei, Hong; Hao, Bin; Huang, Jin-Lu; Ma, Ai-Niu; Li, Xin-Yan; Wang, Yong-Xiang; Pertovaara, Antti

    2010-12-01

    We studied the hypothesis that some of the spinal mechanisms that are involved in neuropathic hypersensitivity play a role in hypersensitivity induced by REM sleep deprivation (REMSD). Rats with a chronic intrathecal (i.t.) catheter had REMSD of 48h duration that induced hypersensitivity to mechanical stimulation. After REMSD, the animals were treated i.t. with carbenoxolone (a gap junction decoupler), bumetanide (a blocker of Na(+)-K(+)-2Cl(-) cotransporter 1 or NKCC1), muscimol (a GABA(A) receptor agonist), or pretreated intraperitoneally with minocycline (an inhibitor of microglia activation). Previously, all these treatments attenuated neuropathic hypersensitivity. Following REMSD, carbenoxolone, bumetanide and muscimol had a strong antihypersensitivity effect, whereas pretreatment with minocycline failed to prevent development of hypersensitivity. The results suggest that among spinal pain facilitatory mechanisms that are common to REMSD and neuropathy are NKCC1 blocker- and gap junction decoupler-reversible mechanisms. Moreover, there is a net pain inhibitory effect by spinal administration of an exogenous GABA(A) receptor agonist following REMSD as shown earlier in neuropathy. In contrast, activation of spinal microglia may not be as important for the development of hypersensitivity induced by REMSD as following nerve injury.

  15. Mus308 Processes Oxygen and Nitrogen Ethylation DNA Damage in Germ Cells of Drosophila

    PubMed Central

    Díaz-Valdés, Nancy; Comendador, Miguel A.; Sierra, L. María

    2010-01-01

    The D. melanogaster mus308 gene, highly conserved among higher eukaryotes, is implicated in the repair of cross-links and of O-ethylpyrimidine DNA damage, working in a DNA damage tolerance mechanism. However, despite its relevance, its possible role on the processing of different DNA ethylation damages is not clear. To obtain data on mutation frequency and on mutation spectra in mus308 deficient (mus308−) conditions, the ethylating agent diethyl sulfate (DES) was analysed in postmeiotic male germ cells. These data were compared with those corresponding to mus308 efficient conditions. Our results indicate that Mus308 is necessary for the processing of oxygen and N-ethylation damage, for the survival of fertilized eggs depending on the level of induced DNA damage, and for an influence of the DNA damage neighbouring sequence. These results support the role of mus308 in a tolerance mechanism linked to a translesion synthesis pathway and also to the alternative end-joinig system. PMID:20936147

  16. Model of anaesthetic induction by unilateral intracerebral microinjection of GABAergic agonists.

    PubMed

    Devor, Marshall; Zalkind, Vladimir; Fishman, Yelena; Minert, Anne

    2016-03-01

    General anaesthetic agents induce loss of consciousness coupled with suppression of movement, analgesia and amnesia. Although these diverse functions are mediated by neural structures located in wide-ranging parts of the neuraxis, anaesthesia can be induced rapidly and reversibly by bilateral microinjection of minute quantities of γ-aminobutyric acid (GABA)A -R agonists at a small, focal locus in the mesopontine tegmentum (MPTA). State switching under these circumstances is presumably executed by dedicated neural pathways and does not require widespread distribution of the anaesthetic agent itself, the classical assumption regarding anaesthetic induction. Here it was asked whether these pathways serve each hemisphere independently, or whether there is bilateral redundancy such that the MPTA on each side is capable of anaesthetizing the entire brain. Either of two GABAA -R ligands were microinjected unilaterally into the MPTA in awake rats, the barbiturate modulator pentobarbital and the direct receptor agonist muscimol. Both agents, microinjected on either side, induced clinical anaesthesia, including bilateral atonia, bilateral analgesia and bilateral changes in cortical activity. The latter was monitored using c-fos expression and electroencephalography. This action, however, was not simply a consequence of suppressing spike activity in MPTA neurons, as unilateral (or bilateral) microinjection of the local anaesthetic lidocaine at the same locus failed to induce anaesthesia. A model of the state-switching circuitry that accounts for the bilateral action of unilateral microinjection and also for the observation that inactivation with lidocaine is not equivalent to inhibition with GABAA -R agonists was proposed. This is a step in defining the overall switching circuitry that underlies anaesthesia. PMID:26804488

  17. Mph1 and Mus81-Mms4 prevent aberrant processing of mitotic recombination intermediates

    PubMed Central

    Mazón, Gerard; Symington, Lorraine S

    2013-01-01

    SUMMARY Homology-dependent repair of double-strand breaks (DSBs) from non-sister templates has the potential to generate loss of heterozygosity or deleterious genome rearrangements. Here we show the Saccharomyces cerevisiae Mph1 helicase prevents crossovers between ectopic sequences by removing substrates for Mus81-Mms4 or Rad1-Rad10 cleavage. A role for Yen1 is only apparent in the absence of Mus81. Cells lacking Mph1 and the three nucleases are highly defective in the repair of a single DSB, suggesting the recombination intermediates that accumulate cannot be processed by the Sgs1-Top3-Rmi1 complex (STR). Consistent with this hypothesis, ectopic joint molecules accumulate transiently in the mph1Δ mutant and persistently when Mus81 is eliminated. Furthermore, the ectopic JMs formed in the absence of Mus81 are connected by a single HJ explaining why STR is unable to process them. We suggest that Mph1 and Mus81-Mms4 recognize a common early strand exchange intermediate and direct repair to non-crossover or crossover outcomes, respectively. PMID:24119400

  18. Evidence for the participation of peripheral α5 subunit-containing GABAA receptors in GABAA agonists-induced nociception in rats.

    PubMed

    Bravo-Hernández, Mariana; Feria-Morales, Luis Alberto; Torres-López, Jorge Elías; Cervantes-Durán, Claudia; Delgado-Lezama, Rodolfo; Granados-Soto, Vinicio; Rocha-González, Héctor Isaac

    2014-07-01

    The activation of GABAA receptor by γ-amino butyric acid (GABA) in primary afferent fibers produces depolarization. In normal conditions this depolarization causes a reduction in the release of neurotransmitters. Therefore, this depolarization remains inhibitory. However, previous studies have suggested that in inflammatory pain, GABA shifts its signaling from inhibition to excitation by an increased GABA-induced depolarization. The contribution of peripheral α5 subunit-containing GABAA receptors to the inflammatory pain is unknown. The purpose of this study was to investigate the possible pronociceptive role of peripheral α5 subunit-containing GABAA receptors in the formalin test. Formalin (0.5%) injection into the dorsum of the right hind paw produced flinching behavior in rats. Ipsilateral local peripheral pre-treatment (-10min) with exogenous GABA (0.003-0.03µg/paw) or common GABAA receptor agonists muscimol (0.003-0.03µg/paw), diazepam (0.017-0.056µg/paw) or phenobarbital (1-100µg/paw) significantly increased 0.5% formalin-induced nociceptive behavior. The pronociceptive effects of GABA (0.03µg/paw), muscimol (0.03µg/paw), diazepam (0.056µg/paw) and phenobarbital (100µg/paw) were prevented by either the GABAA receptor antagonist bicuculline (0.01-0.1µg/paw) or selective α5 subunit-containing GABAA receptor inverse agonist L-655,708 (0.017-0.17µg/paw). The α5 subunit-containing GABAA receptor protein was expressed in dorsal root ganglion (DRG) and dorsal spinal cord of naïve rats. The formalin injection did not modify α5 subunit-containing GABAA receptor expression. Overall, these results suggest that peripheral α5 subunit-containing GABAA receptors play a pronociceptive role in the rat formalin test. PMID:24726872

  19. Fission yeast Mus81.Eme1 Holliday junction resolvase is required for meiotic crossing over but not for gene conversion.

    PubMed Central

    Smith, Gerald R; Boddy, Michael N; Shanahan, Paul; Russell, Paul

    2003-01-01

    Most models of homologous recombination invoke cleavage of Holliday junctions to explain crossing over. The Mus81.Eme1 endonuclease from fission yeast and humans cleaves Holliday junctions and other branched DNA structures, leaving its physiological substrate uncertain. We report here that Schizosaccharomyces pombe mus81 mutants have normal or elevated frequencies of gene conversion but 20- to 100-fold reduced frequencies of crossing over. Thus, gene conversion and crossing over can be genetically separated, and Mus81 is required for crossing over, supporting the hypothesis that the fission yeast Mus81.Eme1 protein complex resolves Holliday junctions in meiotic cells. PMID:14704204

  20. X-RAY DETECTION OF THE CLUSTER CONTAINING THE CEPHEID S MUS

    SciTech Connect

    Evans, Nancy Remage; Pillitteri, Ignazio; Wolk, Scott; Karovska, Margarita; DePasquale, Joseph; Tingle, Evan; Guinan, Edward; Engle, Scott; Bond, Howard E.; Schaefer, Gail H.

    2014-04-20

    The galactic Cepheid S Muscae has recently been added to the important list of Cepheids linked to open clusters, in this case the sparse young cluster ASCC 69. Low-mass members of a young cluster are expected to have rapid rotation and X-ray activity, making X-ray emission an excellent way to discriminate them from old field stars. We have made an XMM-Newton observation centered on S Mus and identified a population of X-ray sources whose near-IR Two Micron All Sky Survey counterparts lie at locations in the J, (J – K) color-magnitude diagram consistent with cluster membership at the distance of S Mus. Their median energy and X-ray luminosity are consistent with young cluster members as distinct from field stars. These strengthen the association of S Mus with the young cluster, making it a potential Leavitt law (period-luminosity relation) calibrator.

  1. Agonist-trafficking and hallucinogens.

    PubMed

    González-Maeso, Javier; Sealfon, Stuart C

    2009-01-01

    Seven transmembrane domain receptors, also termed G protein-coupled receptors (GPCRs), represent the most common molecular target for therapeutic drugs. The generally accepted pharmacological model for GPCR activation is the ternary complex model, in which GPCRs exist in a dynamic equilibrium between the active and inactive conformational states. However, the demonstration that different agonists sometimes elicit a different relative activation of two signaling pathways downstream of the same receptor has led to a revision of the ternary complex model. According to this agonist- trafficking model, agonists stabilize distinct activated receptor conformations that preferentially activate specific signaling pathways. Hallucinogenic drugs and non-hallucinogenic drugs represent an attractive experimental system with which to study agonist-trafficking of receptor signaling. Thus many of the behavioral responses induced by hallucinogenic drugs, such as lysergic acid diethylamide (LSD), psilocybin or mescaline, depend on activation of serotonin 5-HT(2A) receptors (5-HT2ARs). In contrast, this neuropsychological state in humans is not induced by closely related chemicals, such as lisuride or ergotamine, despite their similar in vitro activity at the 5-HT2AR. In this review, we summarize the current knowledge, as well as unresolved questions, regarding agonist-trafficking and the mechanism of action of hallucinogenic drugs.

  2. Affinities and densities of high-affinity (/sup 3/H)muscimol (GABA-A) binding sites and of central benzodiazepine receptors are unchanged in autopsied brain tissue from cirrhotic patients with hepatic encephalopathy

    SciTech Connect

    Butterworth, R.F.; Lavoie, J.; Giguere, J.F.; Pomier-Layrargues, G.

    1988-09-01

    The integrity of GABA-A receptors and of central benzodiazepine receptors was evaluated in membrane preparations from prefrontal cortex and caudate nuclei obtained at autopsy from nine cirrhotic patients who died in hepatic coma and an equal number of age-matched control subjects. Histopathological studies revealed Alzheimer Type II astrocytosis in all cases in the cirrhotic group; controls were free from neurological, psychiatric or hepatic diseases. Binding to GABA-A receptors was studied using (/sup 3/H)muscimol as radioligand. The integrity of central benzodiazepine receptors was evaluated using (/sup 3/H)flunitrazepam and (/sup 3/H)Ro15-1788. Data from saturation binding assays was analyzed by Scatchard plot. No modifications of either affinities (Kd) or densities (Bmax) of (/sup 3/H)muscimol of central benzodiazepine binding sites were observed. These findings do not support recent suggestions that alterations of either high-affinity GABA or benzodiazepine receptors play a significant role in the pathogenesis of hepatic encephalopathy.

  3. Genome Sequences of Murine Pneumotropic Virus (Polyomaviridae) Detected in Wild House Mice (Mus musculus)

    PubMed Central

    Ben Salem, Nicole; Moens, Ugo

    2016-01-01

    Using generic PCR, we identified a variant of murine pneumotropic virus (MptV) (family Polyomaviridae) in 3 wild house mice (Mus musculus). The fully amplified and sequenced genomes display considerable differences from the MptV genomes published previously and enlighten us on the natural diversity of rodent polyomaviruses. PMID:26798094

  4. Drosophila FANCM Helicase Prevents Spontaneous Mitotic Crossovers Generated by the MUS81 and SLX1 Nucleases

    PubMed Central

    Kuo, H. Kenny; McMahan, Susan; Rota, Christopher M.; Kohl, Kathryn P.; Sekelsky, Jeff

    2014-01-01

    Several helicases function during repair of double-strand breaks and handling of blocked or stalled replication forks to promote pathways that prevent formation of crossovers. Among these are the Bloom syndrome helicase BLM and the Fanconi anemia group M (FANCM) helicase. To better understand functions of these helicases, we compared phenotypes of Drosophila melanogaster Blm and Fancm mutants. As previously reported for BLM, FANCM has roles in responding to several types of DNA damage in preventing mitotic and meiotic crossovers and in promoting the synthesis-dependent strand annealing pathway for repair of a double-strand gap. In most assays, the phenotype of Fancm mutants is less severe than that of Blm mutants, and the phenotype of Blm Fancm double mutants is more severe than either single mutant, indicating both overlapping and unique functions. It is thought that mitotic crossovers arise when structure-selective nucleases cleave DNA intermediates that would normally be unwound or disassembled by these helicases. When BLM is absent, three nucleases believed to function as Holliday junction resolvases—MUS81-MMS4, MUS312-SLX1, and GEN—become essential. In contrast, no single resolvase is essential in mutants lacking FANCM, although simultaneous loss of GEN and either of the others is lethal in Fancm mutants. Since Fancm mutants can tolerate loss of a single resolvase, we were able to show that spontaneous mitotic crossovers that occur when FANCM is missing are dependent on MUS312 and either MUS81 or SLX1. PMID:25205745

  5. Wee1 controls genomic stability during replication by regulating the Mus81-Eme1 endonuclease

    PubMed Central

    Domínguez-Kelly, Raquel; Koundrioukoff, Stephane; Tanenbaum, Marvin E.; Smits, Veronique A.J.; Medema, René H.; Debatisse, Michelle

    2011-01-01

    Correct replication of the genome and protection of its integrity are essential for cell survival. In a high-throughput screen studying H2AX phosphorylation, we identified Wee1 as a regulator of genomic stability. Wee1 down-regulation not only induced H2AX phosphorylation but also triggered a general deoxyribonucleic acid (DNA) damage response (DDR) and caused a block in DNA replication, resulting in accumulation of cells in S phase. Wee1-deficient cells showed a decrease in replication fork speed, demonstrating the involvement of Wee1 in DNA replication. Inhibiting Wee1 in cells treated with short treatment of hydroxyurea enhanced the DDR, which suggests that Wee1 specifically protects the stability of stalled replication forks. Notably, the DDR induced by depletion of Wee1 critically depends on the Mus81-Eme1 endonuclease, and we found that codepletion of Mus81 and Wee1 abrogated the S phase delay. Importantly, Wee1 and Mus81 interact in vivo, suggesting direct regulation. Altogether, these results demonstrate a novel role of Wee1 in controlling Mus81 and DNA replication in human cells. PMID:21859861

  6. MAXI/GSC detected a high state on an RS CVn star GT Mus

    NASA Astrophysics Data System (ADS)

    Sasaki, R.; Nakamura, Y.; Tsuboi, Y.; Nakahira, S.; Negoro, H.; Ueno, S.; Tomida, H.; Nakahira, S.; Ishikawa, M.; Nakagawa, Y. E.; Sugawara, Y.; Mihara, T.; Sugizaki, M.; Serino, M.; Iwakiri, W.; Shidatsu, M.; Sugimoto, J.; Takagi, T.; Matsuoka, M.; Kawai, N.; Isobe, N.; Sugita, S.; Yoshii, T.; Tachibana, Y.; Ono, Y.; Fujiwara, T.; Yoshida, A.; Sakamoto, T.; Kawakubo, Y.; Kitaoka, Y.; Tsunemi, H.; Shomura, R.; Nakajima, M.; Tanaka, K.; Masumitsu, T.; Kawase, T.; Ueda, Y.; Kawamuro, T.; Hori, T.; Tanimoto, A.; Yamauchi, M.; Furuya, K.; Yamaoka, K.

    2016-07-01

    At 2016-07-16 19:18 UT , the MAXI/GSC nova alert system triggered on a bright source at a position consistent with that of an RS CVn star GT Mus. The flux increased from 2016-07-16 13:08:30 UT to 2016-07-16 19:18 UT (the trigger time).

  7. A Comparative Analysis of Gene Expression Profiles during Skin Regeneration in Mus and Acomys.

    PubMed

    Brant, Jason Orr; Lopez, Maria-Cecilia; Baker, Henry V; Barbazuk, W Brad; Maden, Malcolm

    2015-01-01

    The African spiny mouse (Acomys spp.) can heal full thickness excisional skin wounds in a scar-free manner with regeneration of all dermal components including hair and associated structures. Comparing Acomys scar-free healing from Mus scarring identifies gene expression differences that discriminate these processes. We have performed an extensive comparison of gene expression profiles in response to 8mm full-thickness excisional wounds at days 3, 5, 7 and 14 post-wounding between Acomys and Mus to characterize differences in wound healing, and identify mechanisms involved in scar-free healing. We also identify similarities with scar-free healing observed in fetal wounds. While wounding in Mus elicits a strong inflammatory response, wounding in Acomys produces a moderated immune response and little to no increase in expression for most cytokines and chemokines assayed. We also identified differences in the ECM profiles of the Acomys wounds, which appear to have a collagen profile more similar to fetal wounds, with larger increases in expression of collagen types III and V. In contrast, Mus wounds have very high levels of collagen XII. This data suggests that an overall lack of induction of cytokines and chemokines, coupled with an ECM profile more similar to fetal wounds, may underlie scar-free wound healing in Acomys skin. These data identify candidate genes for further testing in order to elucidate the causal mechanisms of scar-free healing. PMID:26606282

  8. Genome Sequences of Murine Pneumotropic Virus (Polyomaviridae) Detected in Wild House Mice (Mus musculus).

    PubMed

    Ben Salem, Nicole; Moens, Ugo; Ehlers, Bernhard

    2016-01-01

    Using generic PCR, we identified a variant of murine pneumotropic virus (MptV) (family Polyomaviridae) in 3 wild house mice (Mus musculus). The fully amplified and sequenced genomes display considerable differences from the MptV genomes published previously and enlighten us on the natural diversity of rodent polyomaviruses. PMID:26798094

  9. Crystal structures of the structure-selective nuclease Mus81-Eme1 bound to flap DNA substrates

    PubMed Central

    Gwon, Gwang Hyeon; Jo, Aera; Baek, Kyuwon; Jin, Kyeong Sik; Fu, Yaoyao; Lee, Jong-Bong; Kim, YoungChang; Cho, Yunje

    2014-01-01

    The Mus81-Eme1 complex is a structure-selective endonuclease with a critical role in the resolution of recombination intermediates during DNA repair after interstrand cross-links, replication fork collapse, or double-strand breaks. To explain the molecular basis of 3′ flap substrate recognition and cleavage mechanism by Mus81-Eme1, we determined crystal structures of human Mus81-Eme1 bound to various flap DNA substrates. Mus81-Eme1 undergoes gross substrate-induced conformational changes that reveal two key features: (i) a hydrophobic wedge of Mus81 that separates pre- and post-nick duplex DNA and (ii) a “5′ end binding pocket” that hosts the 5′ nicked end of post-nick DNA. These features are crucial for comprehensive protein-DNA interaction, sharp bending of the 3′ flap DNA substrate, and incision strand placement at the active site. While Mus81-Eme1 unexpectedly shares several common features with members of the 5′ flap nuclease family, the combined structural, biochemical, and biophysical analyses explain why Mus81-Eme1 preferentially cleaves 3′ flap DNA substrates with 5′ nicked ends. PMID:24733841

  10. Novel diazabicycloalkane delta opioid agonists.

    PubMed

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

    2015-09-01

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

  11. Phylogeographic origin of Hokkaido house mice (Mus musculus) as indicated by genetic markers with maternal, paternal and biparental inheritance.

    PubMed

    Terashima, M; Furusawa, S; Hanzawa, N; Tsuchiya, K; Suyanto, A; Moriwaki, K; Yonekawa, H; Suzuki, H

    2006-02-01

    We examined intraspecies genetic variation in house mice (Mus musculus molossinus) from the northern third of the Japanese Islands, in order to obtain evidence of the history of mouse colonization that might have shaped the current genetic diversity. We extended the previous sampling of mitochondrial cytochrome b sequence and added information from the Y-linked Sry gene and ribosomal RNA gene surveys. We distinguish mitochondrial haplotypes characteristic of the North Asian musculus subspecies group (involving M. m. musculus and M. m. molossinus) as 'MUS', and that of the Southeast Asian castaneus subspecies group as 'CAS' (although the mice resemble MUS morphologically). There was a clear geographic partition of MUS and CAS types into southern and northern Hokkaido, respectively. Conversely, on Tohoku, the MUS and CAS types were interspersed without clear geographic subdivision. In contrast to the mtDNA data, all Hokkaido and Tohoku mice examined were found to possess a unique type for the Y-linked Sry gene, specific to Korea and Japan. Restriction site analysis of nuclear rDNA probe showed a consistent distribution of MUS and CAS types, as major and minor components, respectively, in the Hokkaido and Tohoku mice. These data support the previous notion that the Hokkaido and Tohoku mice experienced genetic hybridization between primary residents of CAS origin and MUS newcomers arriving via a southern route. The invasion of the MUS type could correspond with the evidence for arrival of prehistoric peoples. There are, however, alternative interpretations, including genetic admixture between MUS arriving by a southern route and CAS from a northern route.

  12. Evolution of the Iga Heavy Chain Gene in the Genus Mus

    PubMed Central

    Osborne, B. A.; Golde, T. E.; Schwartz, R. L.; Rudikoff, S.

    1988-01-01

    To examine questions of immunoglobulin gene evolution, the IgA α heavy chain gene from Mus pahari, an evolutionarily distant relative to Mus musculus domesticus, was cloned and sequenced. The sequence, when compared to the IgA gene of BALB/c or human, demonstrated that the IgA gene is evolving in a mosaic fashion with the hinge region accumulating mutations most rapidly and the third domain at a considerably lower frequency. In spite of this pronounced accumulation of mutations, the hinge region appears to maintain the conformation of a random coil. A marked propensity to accumulate replacement over silent site changes in the coding regions was noted, as was a definite codon bias. The possibility that these two phenomena are interrelated is discussed. PMID:2842228

  13. Corrected placement of Mus-Rattus fossil calibration forces precision in the molecular tree of rodents.

    PubMed

    Kimura, Yuri; Hawkins, Melissa T R; McDonough, Molly M; Jacobs, Louis L; Flynn, Lawrence J

    2015-09-28

    Time calibration derived from the fossil record is essential for molecular phylogenetic and evolutionary studies. Fossil mice and rats, discovered in the Siwalik Group of Pakistan, have served as one of the best-known fossil calibration points in molecular phylogenic studies. Although these fossils have been widely used as the 12 Ma date for the Mus/Rattus split or a more basal split, conclusive paleontological evidence for the nodal assignments has been absent. This study analyzes newly recognized characters that demonstrate lineage separation in the fossil record of Siwalik murines and examines the most reasonable nodal placement of the diverging lineages in a molecular phylogenetic tree by ancestral state reconstruction. Our specimen-based approach strongly indicates that Siwalik murines of the Karnimata clade are fossil members of the Arvicanthini-Otomyini-Millardini clade, which excludes Rattus and its relatives. Combining the new interpretation with the widely accepted hypothesis that the Progonomys clade includes Mus, the lineage separation event in the Siwalik fossil record represents the Mus/Arvicanthis split. Our test analysis on Bayesian age estimates shows that this new calibration point provides more accurate estimates of murine divergence than previous applications. Thus, we define this fossil calibration point and refine two other fossil-based points for molecular dating.

  14. The HPV16 and MusPV1 papillomaviruses initially interact with distinct host components on the basement membrane.

    PubMed

    Day, Patricia M; Thompson, Cynthia D; Lowy, Douglas R; Schiller, John T

    2015-07-01

    To understand and compare the mechanisms of murine and human PV infection, we examined pseudovirion binding and infection of the newly described MusPV1 using the murine cervicovaginal challenge model. These analyses revealed primary tissue interactions distinct from those previously described for HPV16. Unlike HPV16, MusPV1 bound basement membrane (BM) in an HSPG-independent manner. Nevertheless, subsequent HSPG interactions were critical. L2 antibodies or low doses of VLP antibodies, sufficient to prevent infection, did not lead to disassociation of the MusPV1 pseudovirions from the BM, in contrast to previous findings with HPV16. Similarly, furin inhibition did not lead to loss of MusPV1 from the BM. Therefore, phylogenetically distant PV types differ in their initial interactions with host attachment factors, but initiate their lifecycle on the acellular BM. Despite these differences, these distantly related PV types displayed similar intracellular trafficking patterns and susceptibilities to biochemical inhibition of infection.

  15. Potential of MuS1 Transgenic Tobacco for Phytoremediation of the Urban Soils Contaminated with Cadmium

    NASA Astrophysics Data System (ADS)

    Kim, K. H.; Kim, Y. N.; Kim, S. H.

    2010-05-01

    Urban soils are prone to contamination by trace elements such as Cd, Cu, Pb and Zn. Phytoremediation is one of the attractive remediation methods for soils contaminated with trace elements due to its non-destructive and environmentally-friendly characteristic. Scientists have tried to find hyper-accumulator plants in nature or to develop transgenic plant through genetic engineering. This study was carried out to identify a potential of MuS1 transgenic tobacco for phytoremediation of the urban soils contaminated with Cd. MuS1 is known as a multiple stress related gene with several lines. The previous study using RT-PCR showed that the expression of MuS1 gene in tobacco plant induced tolerance to Cd stress. For this study, MuS1 transgenic tobacco and wild-type tobacco (control) were cultivated in a hydroponic system treated with Cd (0, 50, 100 and 200μM Cd) for 3 weeks. At harvest, both tobacco and nutrient solution were collected and were analyzed for Cd. Effect of Cd treatment on morphological change of the tobacco leaves was also observed by variable-pressure scanning electron microscopy (VP-SEM). The tolerance of MuS1 transgenic tobacco to Cd stress was better than that of wild-type tobacco at all Cd levels. Especially, wild-type tobacco showed chlorosis and withering with 200μM Cd treatment, whereas MuS1 transgenic tobacco gradually recovered from Cd damage. Wild-type tobacco accumulated more Cd (4.65mg per plant) than MuS1 transgenic tobacco (2.37mg per plant) with 200μM Cd treatment. Cd translocation rate from root to leaves was 81.8 % for wild-type tobacco compared to 37.1 % for MuS1 transgenic tobacco. Result of VP-SEM showed that the number of trichome in the leaves for wild-type tobacco increased in comparison with that for untreated samples after 3 weeks, while that for MuS1 transgenic tobacco was not changed by Cd treatment. Results showed that the mechanism of the recovery of the MuS1 tobacco plant was not by high level of Cd uptake and accumulation

  16. 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

  17. Cleavage of stalled forks by fission yeast Mus81/Eme1 in absence of DNA replication checkpoint.

    PubMed

    Froget, Benoît; Blaisonneau, Joël; Lambert, Sarah; Baldacci, Giuseppe

    2008-02-01

    During replication arrest, the DNA replication checkpoint plays a crucial role in the stabilization of the replisome at stalled forks, thus preventing the collapse of active forks and the formation of aberrant DNA structures. How this checkpoint acts to preserve the integrity of replication structures at stalled fork is poorly understood. In Schizosaccharomyces pombe, the DNA replication checkpoint kinase Cds1 negatively regulates the structure-specific endonuclease Mus81/Eme1 to preserve genomic integrity when replication is perturbed. Here, we report that, in response to hydroxyurea (HU) treatment, the replication checkpoint prevents S-phase-specific DNA breakage resulting from Mus81 nuclease activity. However, loss of Mus81 regulation by Cds1 is not sufficient to produce HU-induced DNA breaks. Our results suggest that unscheduled cleavage of stalled forks by Mus81 is permitted when the replisome is not stabilized by the replication checkpoint. We also show that HU-induced DNA breaks are partially dependent on the Rqh1 helicase, the fission yeast homologue of BLM, but are independent of its helicase activity. This suggests that efficient cleavage of stalled forks by Mus81 requires Rqh1. Finally, we identified an interplay between Mus81 activity at stalled forks and the Chk1-dependent DNA damage checkpoint during S-phase when replication forks have collapsed.

  18. Beta-agonists and animal welfare

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

  19. Effect of bromadiolone on haematology, liver and kidney in Mus musculus.

    PubMed

    Revathi, K; Yogananda, M

    2006-01-01

    Bromadiolone, a second generation anticoagulant rodenticide was tested on Mus musculus to evaluate its effects on blood, liver and kidney at varied time intervals of 6, 12, 24 and 48 hrs. Groups of six animals each were selected for experiment. Animals were administered with bromadiolone in the form of bait at 6, 12, 24 and 48 hrs time intervals. Control animals were maintained for each time interval. After each time interval the experiment and the control animals were sacrificed and the effect of bromadiolone on blood, liver and kidney were studied. PMID:16850891

  20. Laboratory trials of three anticoagulant rodenticides for use against the Indian field mouse, Mus booduga Gray.

    PubMed Central

    Balasubramanyam, M.; Christopher, M. J.; Purushotham, K. R.

    1984-01-01

    The efficacy of three anticoagulant rodenticides for use against the Indian field mouse, Mus booduga, was evaluated in the laboratory. The poisons, namely warfarin, bromadiolone and brodifacoum, were all found to be toxic enough at the concentrations normally used against other commensal and field rodents. With brodifacoum (0.001 25%), bromadiolone (0.005%) and warfarin (0.025%), 83% of the animals died respectively after 1, 1 and 6 days' feeding. It is suggested that brodifacoum and bromadiolone might be more economical than warfarin for use in practical rodent control. PMID:6512257

  1. Identification of lymphocytic choriomeningitis mammarenavirus in house mouse (Mus musculus, Rodentia) in French Guiana.

    PubMed

    Lavergne, Anne; de Thoisy, Benoît; Tirera, Sourakhata; Donato, Damien; Bouchier, Christiane; Catzeflis, François; Lacoste, Vincent

    2016-01-01

    Thirty-seven house mice (Mus musculus, Rodentia) caught in different localities in French Guiana were screened to investigate the presence of lymphocytic choriomeningitis mammarenavirus (LCMV). Two animals trapped in an urban area were found positive, hosting a new strain of LCMV, that we tentatively named LCMV "Comou". The complete sequence was determined using a metagenomic approach. Phylogenetic analyses revealed that this strain is related to genetic lineage I composed of strains inducing severe disease in humans. These results emphasize the need for active surveillance in humans as well as in house mouse populations, which is a rather common rodent in French Guianese cities and settlements.

  2. Are ribosomal DNA clusters rearrangement hotspots? A case study in the genus Mus (Rodentia, Muridae)

    PubMed Central

    2011-01-01

    Background Recent advances in comparative genomics have considerably improved our knowledge of the evolution of mammalian karyotype architecture. One of the breakthroughs was the preferential localization of evolutionary breakpoints in regions enriched in repetitive sequences (segmental duplications, telomeres and centromeres). In this context, we investigated the contribution of ribosomal genes to genome reshuffling since they are generally located in pericentromeric or subtelomeric regions, and form repeat clusters on different chromosomes. The target model was the genus Mus which exhibits a high rate of karyotypic change, a large fraction of which involves centromeres. Results The chromosomal distribution of rDNA clusters was determined by in situ hybridization of mouse probes in 19 species. Using a molecular-based reference tree, the phylogenetic distribution of clusters within the genus was reconstructed, and the temporal association between rDNA clusters, breakpoints and centromeres was tested by maximum likelihood analyses. Our results highlighted the following features of rDNA cluster dynamics in the genus Mus: i) rDNA clusters showed extensive diversity in number between species and an almost exclusive pericentromeric location, ii) a strong association between rDNA sites and centromeres was retrieved which may be related to their shared constraint of concerted evolution, iii) 24% of the observed breakpoints mapped near an rDNA cluster, and iv) a substantial rate of rDNA cluster change (insertion, deletion) also occurred in the absence of chromosomal rearrangements. Conclusions This study on the dynamics of rDNA clusters within the genus Mus has revealed a strong evolutionary relationship between rDNA clusters and centromeres. Both of these genomic structures coincide with breakpoints in the genus Mus, suggesting that the accumulation of a large number of repeats in the centromeric region may contribute to the high level of chromosome repatterning observed

  3. [Adrenergic beta-agonist intoxication].

    PubMed

    Carrola, Paulo; Devesa, Nuno; Silva, José Manuel; Ramos, Fernando; Alexandrino, Mário B; Moura, José J

    2003-01-01

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

  4. β2-agonist therapy in lung disease.

    PubMed

    Cazzola, Mario; Page, Clive P; Rogliani, Paola; Matera, M Gabriella

    2013-04-01

    β2-Agonists are effective bronchodilators due primarily to their ability to relax airway smooth muscle (ASM). They exert their effects via their binding to the active site of β2-adrenoceptors on ASM, which triggers a signaling cascade that results in a number of events, all of which contribute to relaxation of ASM. There are some differences between β2-agonists. Traditional inhaled short-acting β2-agonists albuterol, fenoterol, and terbutaline provide rapid as-needed symptom relief and short-term prophylactic protection against bronchoconstriction induced by exercise or other stimuli. The twice-daily β2-agonists formoterol and salmeterol represent important advances. Their effective bronchodilating properties and long-term improvement in lung function offer considerable clinical benefits to patients. More recently, a newer β2-agonist (indacaterol) with a longer pharmacodynamic half-life has been discovered, with the hopes of achieving once-daily dosing. In general, β2-agonists have an acceptable safety profile, although there is still controversy as to whether long-acting β2-agonists may increase the risk of asthma mortality. In any case, they can induce adverse effects, such as increased heart rate, palpitations, transient decrease in PaO2, and tremor. Desensitization of β2-adrenoceptors that occurs during the first few days of regular use of β2-agonist treatment may account for the commonly observed resolution of the majority of these adverse events after the first few doses. Nevertheless, it can also induce tolerance to bronchoprotective effects of β2-agonists and has the potential to reduce bronchodilator sensitivity to them. Some novel once-daily β2-agonists (olodaterol, vilanterol, abediterol) are under development, mainly in combination with an inhaled corticosteroid or a long-acting antimuscarinic agent. PMID:23348973

  5. Mus308 Mutants of Drosophila Exhibit Hypersensitivity to DNA Cross-Linking Agents and Are Defective in a Deoxyribonuclease

    PubMed Central

    Boyd, J. B.; Sakaguchi, K.; Harris, P. V.

    1990-01-01

    Mutagen-sensitive strains that identify 16 different Drosophila genes have been screened for alterations in DNA metabolic enzymes. A characteristic defect in an acid-active deoxyribonuclease was observed in strains carrying the six available mutant alleles of the mus308 gene. Since that enzyme is detected at normal levels in a mutant strain that is deficient in the previously identified enzymes DNase 1 and DNase 2, it represents a new Drosophila nuclease that is designated Nuclease 3. The mus308 mutants were originally distinguished from all other mutagen-sensitive mutants of Drosophila because they exhibit hypersensitivity to the DNA cross-linking agent nitrogen mustard without expressing a concurrent sensitivity to the monofunctional agent methyl methanesulfonate. Further observations of hypersensitivity to the mutagens trimethylpsoralen, diepoxybutane and cis-platinum now establish a more general sensitivity of these mutants to agents capable of generating DNA cross-links. In spite of the hypersensitivity of the mus308 mutants to DNA cross-linking agents, the initial incision step of DNA cross-link repair is normal in mus308 cells as assayed by the alkaline elution procedure. The Drosophila mus308 mutants show promise of providing a useful model for analogous defects in other organisms including man. PMID:2397884

  6. Mate choice in Mus musculus is relative and dependent on the estrous state.

    PubMed

    Zinck, Léa; Lima, Susana Q

    2013-01-01

    Mate choice is a critical behavioral decision process with profound impact on evolution. However, the mechanistic basis of mate choice is poorly understood. In this study we focused on assortative mate choice, which is known to contribute to the reproductive isolation of the two European subspecies of house mouse, Mus musculus musculus and Mus musculus domesticus. To understand the decision process, we developed both full mating and limited-contact paradigms and tested musculus females' preference for musculus versus domesticus males, mimicking the natural musculus/domesticus contact zone. As hypothesized, when allowed to mate we found that sexually receptive musculus females exhibited a robust preference to mate with musculus males. In contrast, when non-receptive, females did not exhibit a preference and rather alternated between males in response to male mount attempts. Moreover in a no-choice condition, females mated readily with males from both subspecies. Finally, when no physical contact was allowed, and therefore male's behavior could not influence female's behavior, female's preference for its own subspecies was maintained independently of the estrous state. Together, our results suggest that the assortative preference is relative and based on a comparison of the options available rather than on an absolute preference. The results of the limited-contact experiments highlight the interplay between female's internal state and the nature of the interaction with prospective mates in the full mating conditions. With these experiments we believe we established an assortative mate preference assay that is appropriate for the investigation of its underlying substrates.

  7. Mate Choice in Mus musculus Is Relative and Dependent on the Estrous State

    PubMed Central

    Zinck, Léa; Lima, Susana Q.

    2013-01-01

    Mate choice is a critical behavioral decision process with profound impact on evolution. However, the mechanistic basis of mate choice is poorly understood. In this study we focused on assortative mate choice, which is known to contribute to the reproductive isolation of the two European subspecies of house mouse, Mus musculus musculus and Mus musculus domesticus. To understand the decision process, we developed both full mating and limited-contact paradigms and tested musculus females' preference for musculus versus domesticus males, mimicking the natural musculus/domesticus contact zone. As hypothesized, when allowed to mate we found that sexually receptive musculus females exhibited a robust preference to mate with musculus males. In contrast, when non-receptive, females did not exhibit a preference and rather alternated between males in response to male mount attempts. Moreover in a no-choice condition, females mated readily with males from both subspecies. Finally, when no physical contact was allowed, and therefore male's behavior could not influence female's behavior, female's preference for its own subspecies was maintained independently of the estrous state. Together, our results suggest that the assortative preference is relative and based on a comparison of the options available rather than on an absolute preference. The results of the limited-contact experiments highlight the interplay between female's internal state and the nature of the interaction with prospective mates in the full mating conditions. With these experiments we believe we established an assortative mate preference assay that is appropriate for the investigation of its underlying substrates. PMID:23762466

  8. Bitter avoidance in guinea pigs (Cavia porcellus) and mice (Mus musculus and Peromyscus leucopus).

    PubMed

    Field, Kristin L; Beauchamp, Gary K; Kimball, Bruce A; Mennella, Julie A; Bachmanov, Alexander A

    2010-11-01

    Rejection of bitter substances is common in many species and may function to protect an animal from ingestion of bitter-tasting toxins. Since many plants are bitter, it has been proposed that high tolerance for bitterness would be adaptive for herbivores. Earlier studies conducted on herbivorous guinea pigs (Cavia porcellus) have been used to support this proposal. We tested guinea pigs with bitter plant secondary metabolites (salicin, caffeine, quinine hydrochloride) and bitter protein hydrolysates (two types of hydrolyzed casein, hydrolyzed soy) in a series of two-choice preference tests. For comparison, we tested two nonherbivorous mouse species (Mus musculus and Peromyscus leucopus). Guinea pigs did show weaker avoidance of quinine hydrochloride than did the mice, confirming predictions generated from earlier work. However, guinea pigs had similar responses to caffeine as did Peromyscus. Both of these species showed weaker avoidance responses than Mus to 10 mM caffeine. For salicin, guinea pigs were the only species to avoid it at 10 mM and their preference scores at this concentration were significantly lower than for the two mice species. Guinea pigs avoided all of the protein hydrolysates more strongly than the other species. Responses to the protein hydrolysates did not reflect the patterns observed with the simple bitter compounds, suggesting that other properties of these complex stimuli may be responsible for guinea pig avoidance of them. Our results suggest caution in accepting, without further empirical support, the premise that guinea pigs (and herbivores in general) have a generalized reduced bitter sensitivity. PMID:21090891

  9. The level of major urinary proteins is socially regulated in wild Mus musculus musculus.

    PubMed

    Janotova, Katerina; Stopka, Pavel

    2011-06-01

    Major urinary proteins (MUPs) are highly polymorphic proteins that have been shown to perform several important functions in the chemical communication of the house mouse, Mus musculus. Production of these proteins in C57Bl/6 females is cyclic, reaching the maximum just before the beginning of estrus. Social environment is an important factor that increases MUP production in both sexes. We examined responsiveness of MUP production to social stimuli in wild mice, Mus musculus musculus. The direction of change of MUP production in males depended on the sex of the stimulus animal. Males up-regulated MUP production when caged with a female, but down-regulated MUP production when caged with a male. Down-regulation was more pronounced in males that were defeated in a male-male encounter. Females responded to a male's presence with a decrease in MUP production. We conclude that social modulation of MUP production is specific and, in coordination with other mechanisms, facilitates adjustment of the animal's odor profile to different social contexts. Our results also suggest that in males, MUPs may play an important role in advertizing the male's quality to females. Furthermore, we highlight the importance of analyzing data corrected with creatinine, which show MUP production on the (post)translational level as well as raw data (non-corrected with creatinine), which represent actual concentrations of MUPs in the urine. PMID:21594616

  10. Bitter avoidance in guinea pigs (Cavia porcellus) and mice (Mus musculus and Peromyscus leucopus).

    PubMed

    Field, Kristin L; Beauchamp, Gary K; Kimball, Bruce A; Mennella, Julie A; Bachmanov, Alexander A

    2010-11-01

    Rejection of bitter substances is common in many species and may function to protect an animal from ingestion of bitter-tasting toxins. Since many plants are bitter, it has been proposed that high tolerance for bitterness would be adaptive for herbivores. Earlier studies conducted on herbivorous guinea pigs (Cavia porcellus) have been used to support this proposal. We tested guinea pigs with bitter plant secondary metabolites (salicin, caffeine, quinine hydrochloride) and bitter protein hydrolysates (two types of hydrolyzed casein, hydrolyzed soy) in a series of two-choice preference tests. For comparison, we tested two nonherbivorous mouse species (Mus musculus and Peromyscus leucopus). Guinea pigs did show weaker avoidance of quinine hydrochloride than did the mice, confirming predictions generated from earlier work. However, guinea pigs had similar responses to caffeine as did Peromyscus. Both of these species showed weaker avoidance responses than Mus to 10 mM caffeine. For salicin, guinea pigs were the only species to avoid it at 10 mM and their preference scores at this concentration were significantly lower than for the two mice species. Guinea pigs avoided all of the protein hydrolysates more strongly than the other species. Responses to the protein hydrolysates did not reflect the patterns observed with the simple bitter compounds, suggesting that other properties of these complex stimuli may be responsible for guinea pig avoidance of them. Our results suggest caution in accepting, without further empirical support, the premise that guinea pigs (and herbivores in general) have a generalized reduced bitter sensitivity.

  11. Mus cervicolor Murine Leukemia Virus Isolate M813 Belongs to a Unique Receptor Interference Group

    PubMed Central

    Prassolov, Vladimir; Hein, Sibyll; Ziegler, Marion; Ivanov, Dmitry; Münk, Carsten; Löhler, Jürgen; Stocking, Carol

    2001-01-01

    Murine leukemia virus (MuLV) M813 was originally isolated from the Southeast Asian rodent Mus cervicolor. As with the ecotropic MuLVs derived from Mus musculus, its host range is limited to rodent cells. Earlier studies have mapped its receptor to chromosome 2, but it has not been established whether M813 shares a common receptor with any other MuLVs. In this study, we have performed interference assays with M813 and viruses from four interference groups of MuLV. The infection efficiency of M813 was not compromised in cells expressing any one of the other MuLVs, demonstrating that M813 must use a distinct receptor for cell entry. The entire M813 env coding region was molecularly cloned. Sequence analysis revealed high similarity with other MuLVs but with a unique receptor-binding domain. Substitution of M813 env sequences in Moloney MuLV resulted in a replication-competent virus with a host range and interference profile similar to those of the biological clone M813. M813 thus defines a novel receptor interference group of type C MuLVs. PMID:11312319

  12. Mus cervicolor murine leukemia virus isolate M813 belongs to a unique receptor interference group.

    PubMed

    Prassolov, V; Hein, S; Ziegler, M; Ivanov, D; Münk, C; Löhler, J; Stocking, C

    2001-05-01

    Murine leukemia virus (MuLV) M813 was originally isolated from the Southeast Asian rodent Mus cervicolor. As with the ecotropic MuLVs derived from Mus musculus, its host range is limited to rodent cells. Earlier studies have mapped its receptor to chromosome 2, but it has not been established whether M813 shares a common receptor with any other MuLVs. In this study, we have performed interference assays with M813 and viruses from four interference groups of MuLV. The infection efficiency of M813 was not compromised in cells expressing any one of the other MuLVs, demonstrating that M813 must use a distinct receptor for cell entry. The entire M813 env coding region was molecularly cloned. Sequence analysis revealed high similarity with other MuLVs but with a unique receptor-binding domain. Substitution of M813 env sequences in Moloney MuLV resulted in a replication-competent virus with a host range and interference profile similar to those of the biological clone M813. M813 thus defines a novel receptor interference group of type C MuLVs.

  13. Structural and functional relationships of the XPF/MUS81 family of proteins.

    PubMed

    Ciccia, Alberto; McDonald, Neil; West, Stephen C

    2008-01-01

    Proteins belonging to the XPF/MUS81 family play important roles in the repair of DNA lesions caused by UV-light or DNA cross-linking agents. Most eukaryotes have four family members that assemble into two distinct heterodimeric complexes, XPF-ERCC1 and MUS81-EME1. Each complex contains one catalytic and one noncatalytic subunit and exhibits endonuclease activity with a variety of 3'-flap or fork DNA structures. The catalytic subunits share a characteristic core containing an excision repair cross complementation group 4 (ERCC4) nuclease domain and a tandem helix-hairpin-helix (HhH)(2) domain. Diverged domains are present in the noncatalytic subunits and may be required for substrate targeting. Vertebrates possess two additional family members, FANCM and Fanconi anemia-associated protein 24 kDa (FAAP24), which possess inactive nuclease domains. Instead, FANCM contains a functional Superfamily 2 (SF2) helicase domain that is required for DNA translocation. Determining how these enzymes recognize specific DNA substrates and promote key repair reactions is an important challenge for the future. PMID:18518821

  14. BEHAVIORAL AND MEMORY CHANGES IN Mus musculus COINFECTED BY Toxocara canis AND Toxoplasma gondii

    PubMed Central

    Corrêa, Flávia Motta; Chieffi, Pedro Paulo; Lescano, Susana A. Zevallos; dos Santos, Sergio Vieira

    2014-01-01

    Several researchers have stated that parasites can alter the behavior of their hosts, in order to increase the transmission rate, principally when prey-predator relationships are a reliable way of infection transmission. The aim of this study was to verify the occurrence of changes in anxiety and short-term memory patterns in experimentally infected Mus musculus by Toxocara canis and/or Toxoplasma gondii. Forty male Mus musculus (Balb/c) eight-week-old were divided into four groups of 10 mice each. One group was infected with 300 eggs of Toxocara canis; a second group was submitted to infection with 10 cysts of Toxoplasma gondii; a third group was concomitantly infected with both parasites with the same inoculums and the last group was maintained without infection. The anxiety levels were evaluated using an elevated plus maze and an actometer; the short-term memory was determined by a two-way active avoidance equipment. The determination of anxiety levels were conducted 40 and 70 days after infection and the short-term memory was evaluated 140 days after infection. Mice chronically infected by Toxoplasma gondii showed impaired learning and short-term memory, but no significant differences were found in mice infected by Toxocara canis or concomitantly infected by Toxocara canis and Toxoplasma gondii when compared to non infected mice. PMID:25076438

  15. Characterization of the RHEPP 1 {mu}s magnetic pulse compression module

    SciTech Connect

    Harjes, C.; Adcock, J.; Martinez, L.; Van DeValde, D.; Wavrik, R.; Laderach, G.; Pena, G.

    1993-08-01

    The technology for pulsed power based high average power accelerators is being developed in the RHEPP (Repetitive High Energy Pulsed Power) project. This technology base uses magnetic pulse compression to generate repetitive, high peak power pulses. The 1 {mu}s pulse compressor accepts 3400 V rms, 120 Hz input power from a 600-kW alternator and delivers unipolar {approximately}1 {mu}s rise time, 260 kV pulses to the RHEPP pulse forming line at a rate of 120 pps. The compressor consists of 5 stages of pulse compression with a 15 to 260 kV step up transformer between stages 2 and 3. Magnetic switches are used throughout the compressor because such switches seem to offer the potential of meeting the lifetime requirements of high average power systems. Thermal and electrical data has been acquired to characterize the compressor during several long duration runs (some over 1 million shots). A description of the compressor and its components along with data and a discussion of the compressors performance are presented.

  16. The LSH/DDM1 Homolog MUS-30 Is Required for Genome Stability, but Not for DNA Methylation in Neurospora crassa

    PubMed Central

    Basenko, Evelina Y.; Kamei, Masayuki; Ji, Lexiang; Schmitz, Robert J.; Lewis, Zachary A.

    2016-01-01

    LSH/DDM1 enzymes are required for DNA methylation in higher eukaryotes and have poorly defined roles in genome maintenance in yeast, plants, and animals. The filamentous fungus Neurospora crassa is a tractable system that encodes a single LSH/DDM1 homolog (NCU06306). We report that the Neurospora LSH/DDM1 enzyme is encoded by mutagen sensitive-30 (mus-30), a locus identified in a genetic screen over 25 years ago. We show that MUS-30-deficient cells have normal DNA methylation, but are hypersensitive to DNA damaging agents. MUS-30 is a nuclear protein, consistent with its predicted role as a chromatin remodeling enzyme, and levels of MUS-30 are increased following DNA damage. MUS-30 co-purifies with Neurospora WDR76, a homolog of yeast Changed Mutation Rate-1 and mammalian WD40 repeat domain 76. Deletion of wdr76 rescued DNA damage-hypersensitivity of Δmus-30 strains, demonstrating that the MUS-30-WDR76 interaction is functionally important. DNA damage-sensitivity of Δmus-30 is partially suppressed by deletion of methyl adenine glycosylase-1, a component of the base excision repair machinery (BER); however, the rate of BER is not affected in Δmus-30 strains. We found that MUS-30-deficient cells are not defective for DSB repair, and we observed a negative genetic interaction between Δmus-30 and Δmei-3, the Neurospora RAD51 homolog required for homologous recombination. Together, our findings suggest that MUS-30, an LSH/DDM1 homolog, is required to prevent DNA damage arising from toxic base excision repair intermediates. Overall, our study provides important new information about the functions of the LSH/DDM1 family of enzymes. PMID:26771905

  17. The evolution of beta2-agonists.

    PubMed

    Sears, M R

    2001-08-01

    Beta-agonists have been widely used in the treatment of asthma for many years Although concerns have been expressed over their safety based largely upon epidemics of increased mortality in asthmatics associated with high doses of isoprenaline in the 1960s and fenoterol in the 1970s and 1980s, the specific beta2-agonists are vital drugs in asthma management. The short-acting beta2-agonists have an important prophylactic role in the prevention of exercise-induced bronchoconstriction, and are essential in the emergency treatment of severe asthma. However, little if any benefit seems to be derived from regular use of short-acting beta2-agonists and regular or frequent use can increase the severity of the condition. The development of beta2-agonists with long-acting properties, such as salmeterol and formoterol, has provided advantages over short-acting beta-agonists, such as prolonged bronchodilation, reduced day- and night-time symptoms and improved quality of sleep, and has reduced the requirement for short-acting beta2-agonists as relief medication. Both drugs are well tolerated and, when added to inhaled corticosteroids, produce greater mprovement in lung function than increased steroid dose alone. Because of its rapid onset of action, formoterol also has the potential to be used for as-needed bronchodilator therapy in asthma.

  18. SLX4-SLX1 Protein-independent Down-regulation of MUS81-EME1 Protein by HIV-1 Viral Protein R (Vpr).

    PubMed

    Zhou, Xiaohong; DeLucia, Maria; Ahn, Jinwoo

    2016-08-12

    Evolutionarily conserved structure-selective endonuclease MUS81 forms a complex with EME1 and further associates with another endonuclease SLX4-SLX1 to form a four-subunit complex of MUS81-EME1-SLX4-SLX1, coordinating distinctive biochemical activities of both endonucleases in DNA repair. Viral protein R (Vpr), a highly conserved accessory protein in primate lentiviruses, was previously reported to bind SLX4 to mediate down-regulation of MUS81. However, the detailed mechanism underlying MUS81 down-regulation is unclear. Here, we report that HIV-1 Vpr down-regulates both MUS81 and its cofactor EME1 by hijacking the host CRL4-DCAF1 E3 ubiquitin ligase. Multiple Vpr variants, from HIV-1 and SIV, down-regulate both MUS81 and EME1. Furthermore, a C-terminally truncated Vpr mutant and point mutants R80A and Q65R, all of which lack G2 arrest activity, are able to down-regulate MUS81-EME1, suggesting that Vpr-induced G2 arrest is not correlated with MUS81-EME1 down-regulation. We also show that neither the interaction of MUS81-EME1 with Vpr nor their down-regulation is dependent on SLX4-SLX1. Together, these data provide new insight on a conserved function of Vpr in a host endonuclease down-regulation.

  19. SLX4-SLX1 Protein-independent Down-regulation of MUS81-EME1 Protein by HIV-1 Viral Protein R (Vpr).

    PubMed

    Zhou, Xiaohong; DeLucia, Maria; Ahn, Jinwoo

    2016-08-12

    Evolutionarily conserved structure-selective endonuclease MUS81 forms a complex with EME1 and further associates with another endonuclease SLX4-SLX1 to form a four-subunit complex of MUS81-EME1-SLX4-SLX1, coordinating distinctive biochemical activities of both endonucleases in DNA repair. Viral protein R (Vpr), a highly conserved accessory protein in primate lentiviruses, was previously reported to bind SLX4 to mediate down-regulation of MUS81. However, the detailed mechanism underlying MUS81 down-regulation is unclear. Here, we report that HIV-1 Vpr down-regulates both MUS81 and its cofactor EME1 by hijacking the host CRL4-DCAF1 E3 ubiquitin ligase. Multiple Vpr variants, from HIV-1 and SIV, down-regulate both MUS81 and EME1. Furthermore, a C-terminally truncated Vpr mutant and point mutants R80A and Q65R, all of which lack G2 arrest activity, are able to down-regulate MUS81-EME1, suggesting that Vpr-induced G2 arrest is not correlated with MUS81-EME1 down-regulation. We also show that neither the interaction of MUS81-EME1 with Vpr nor their down-regulation is dependent on SLX4-SLX1. Together, these data provide new insight on a conserved function of Vpr in a host endonuclease down-regulation. PMID:27354282

  20. Aspirin metabolites are GPR35 agonists.

    PubMed

    Deng, Huayun; Fang, Ye

    2012-07-01

    Aspirin is widely used as an anti-inflammatory, anti-platelet, anti-pyretic, and cancer-preventive agent; however, the molecular mode of action is unlikely due entirely to the inhibition of cyclooxygenases. Here, we report the agonist activity of several aspirin metabolites at GPR35, a poorly characterized orphan G protein-coupled receptor. 2,3,5-Trihydroxybenzoic acid, an aspirin catabolite, was found to be the most potent GPR35 agonist among aspirin metabolites. Salicyluric acid, the main metabolite of aspirin, was also active. These results suggest that the GPR35 agonist activity of certain aspirin metabolites may contribute to the clinical features of aspirin. PMID:22526472

  1. Monoterpenoid agonists of TRPV3

    PubMed Central

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

    2007-01-01

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

  2. [Safety of beta-agonists in asthma].

    PubMed

    Oscanoa, Teodoro J

    2014-01-01

    Beta 2 agonist bronchodilators (β2A) are very important part in the pharmacotherapy of bronchial asthma, a disease that progresses in the world in an epidemic way. The β2A are prescribed to millions of people around the world, therefore the safety aspects is of public interest. Short-Acting β2 Agonists (SABAs), such as albuterol inhaler, according to current evidence, confirming its safety when used as a quick-relief or rescue medication. The long-acting β2 agonists (LABAs) The long-acting bronchodilators β2A (Long acting β2 Agonists or LABAs) are used associated with inhaled corticosteroids as controller drugs for asthma exacerbationsaccess, for safety reasons LABAs are not recommended for use as monotherapy.

  3. Dopamine receptor partial agonists and addiction.

    PubMed

    Moreira, Fabricio A; Dalley, Jeffrey W

    2015-04-01

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

  4. PPAR Agonists and Cardiovascular Disease in Diabetes.

    PubMed

    Calkin, Anna C; Thomas, Merlin C

    2008-01-01

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

  5. PPAR Agonists and Cardiovascular Disease in Diabetes

    PubMed Central

    Calkin, Anna C.; Thomas, Merlin C.

    2008-01-01

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

  6. Sibling effects on the behavior of infant mouse litters (Mus domesticus).

    PubMed

    Laviola, G; Alleva, E

    1995-03-01

    We investigated whether the number of same- or other-sex littermates had a graded effect on the occurrence of early solitary play and social play by mouse (Mus domesticus) family units. Sixty litters, reduced at birth to 5 different sex ratios (6 males, 5 males and 1 female, 3 males and 3 females, 1 male and 5 females, and 6 females) were scored in 15-min sessions on postnatal Days 18 and 21. An increasing trend with age was found for run, pounce, popcorn, self-groom, and explore episodes. Type of family unit influenced the occurrence of specific social interactions: One male-5 female and 6 female litters showed more social play than similar male litters. Litters with a balanced sex ratio showed higher exploration than isosexual litters. The results extend previous reports of both social and solitary play in developing laboratory mice and, in contrast with rat data, indicate a marked female primacy in playful social behavior.

  7. Did the house mouse (Mus musculus L.) shape the evolutionary trajectory of wheat (Triticum aestivum L.)?

    PubMed Central

    Morris, C F; Fuerst, E P; Beecher, B S; Mclean, D J; James, C P; Geng, H W

    2013-01-01

    Wheat (Triticum aestivum L.) is one of the most successful domesticated plant species in the world. The majority of wheat carries mutations in the Puroindoline genes that result in a hard kernel phenotype. An evolutionary explanation, or selective advantage, for the spread and persistence of these hard kernel mutations has yet to be established. Here, we demonstrate that the house mouse (Mus musculus L.) exerts a pronounced feeding preference for soft over hard kernels. When allele frequencies ranged from 0.5 to 0.009, mouse predation increased the hard allele frequency as much as 10-fold. Studies involving a single hard kernel mixed with ∼1000 soft kernels failed to recover the mutant kernel. Nevertheless, the study clearly demonstrates that the house mouse could have played a role in the evolution of wheat, and therefore the cultural trajectory of humankind. PMID:24223281

  8. Sexual selection and the rodent baculum: an intraspecific study in the house mouse (Mus musculus domesticus).

    PubMed

    Ramm, Steven A; Khoo, Lin; Stockley, Paula

    2010-01-01

    The rapid divergence of genitalia is a pervasive trend in animal evolution, thought to be due to the action of sexual selection. To test predictions from the sexual selection hypothesis, we here report data on the allometry, variation, plasticity and condition dependence of baculum morphology in the house mouse (Mus musculus domesticus). We find that that baculum size: (a) exhibits no consistent pattern of allometric scaling (baculum size being in most cases unrelated to body size), (b) exhibits low to moderate levels of phenotypic variation, (c) does not exhibit phenotypic plasticity in response to differences in perceived levels of sexual competition and (d) exhibits limited evidence of condition dependence. These patterns provide only limited evidence in support of the sexual selection hypothesis, and no consistent support for any particular sexual selection mechanism; however, more direct measures of how genital morphology influences male fertilization success are required.

  9. Bitter avoidance in Guinea Pigs (Cavia porcellus) and Mice (Mus musculus and Peromyscus leucopus)

    PubMed Central

    Field, Kristin L.; Beauchamp, Gary K.; Kimball, Bruce A.; Mennella, Julie A.; Bachmanov, Alexander A.

    2010-01-01

    Rejection of bitter substances is common in many species and may function to protect an animal from ingestion of bitter-tasting toxins. Since many plants are bitter, it has been proposed that high tolerance for bitterness would be adaptive for herbivores. Earlier studies conducted on herbivorous guinea pigs (Cavia porcellus) have been used to support this proposal. We tested guinea pigs with bitter plant secondary metabolites (salicin, caffeine, quinine hydrochloride) and bitter protein hydrolysates (two types of hydrolyzed casein, hydrolyzed soy) in a series of two-choice preference tests. For comparison, we tested two non-herbivorous mouse species (Mus musculus and Peromyscus leucopus). Guinea pigs did show weaker avoidance of QHCl than did the mice, confirming predictions generated from earlier work. However, guinea pigs had similar responses to caffeine as did Peromyscus. Both of these species showed weaker avoidance responses than Mus to 10 mM caffeine. For salicin, guinea pigs were the only species to avoid it at 10 mM and their preference scores at this concentration were significantly lower than for the two mice species. Guinea pigs avoided all of the protein hydrolysates more strongly than the other species. Responses to the protein hydrolysates did not reflect the patterns observed with the simple bitter compounds, suggesting that other properties of these complex stimuli may be responsible for guinea pig avoidance of them. Our results suggest caution in accepting, without further empirical support, the premise that guinea pigs (and herbivores in general) have a generalized reduced bitter sensitivity. PMID:21090891

  10. Mitochondrial DNA Variation and the Evolution of Robertsonian Chromosomal Races of House Mice, Mus Domesticus

    PubMed Central

    Nachman, M. W.; Boyer, S. N.; Searle, J. B.; Aquadro, C. F.

    1994-01-01

    The house mouse, Mus domesticus, includes many distinct Robertsonian (Rb) chromosomal races with diploid numbers from 2n = 22 to 2n = 38. Although these races are highly differentiated karyotypically, they are otherwise indistinguishable from standard karyotype (i.e., 2n = 40) mice, and consequently their evolutionary histories are not well understood. We have examined mitochondrial DNA (mtDNA) sequence variation from the control region and the ND3 gene region among 56 M. domesticus from Western Europe, including 15 Rb populations and 13 standard karyotype populations, and two individuals of the sister species, Mus musculus. mtDNA exhibited an average sequence divergence of 0.84% within M. domesticus and 3.4% between M. domesticus and M. musculus. The transition/transversion bias for the regions sequenced is 5.7:1, and the overall rate of sequence evolution is approximately 10% divergence per million years. The amount of mtDNA variation was as great among different Rb races as among different populations of standard karyotype mice, suggesting that different Rb races do not derive from a single recent maternal lineage. Phylogenetic analysis of the mtDNA sequences resulted in a parsimony tree which contained six major clades. Each of these clades contained both Rb and standard karyotype mice, consistent with the hypothesis that Rb races have arisen independently multiple times. Discordance between phylogeny and geography was attributable to ancestral polymorphism as a consequence of the recent colonization of Western Europe by mice. Two major mtDNA lineages were geographically localized and contained both Rb and standard karyotype mice. The age of these lineages suggests that mice have moved into Europe only within the last 10,000 years and that Rb populations in different geographic regions arose during this time. PMID:8005418

  11. Alterations in Chromosomal Synapses and DNA Repair in Apoptotic Spermatocytes of Mus m. Domesticus

    PubMed Central

    Ayarza, E.; González, M.; López, F.; Fernández-Donoso, R.; Page, J.; Berrios, S.

    2016-01-01

    We investigated whether apoptotic spermatocytes from the mouse Mus m. domesticus presented alterations in chromosomal synapses and DNA repair. To enrich for apoptotic spermatocytes, the scrotum’s temperature was raised by partially exposing animals for 15 min to a 42ºC water bath. Spermatocytes in initial apoptosis were identified in situ by detecting activated caspase-9. SYCP1 and SYCP3 were markers for evaluating synapses or the structure of synaptonemal complexes and Rad51 and γH2AX for detecting DNA repair and chromatin remodeling. Apoptotic spermatocytes were concentrated in spermatogenic cycle stages III-IV (50.3%), XI-XII (44.1%) and IX-X (4.2%). Among apoptotic spermatocytes, 48% were in middle pachytene, 44% in metaphase and 6% in diplotene. Moreover, apoptotic spermatocytes showed several structural anomalies in autosomal bivalents, including splitting of chromosomal axes and partial asynapses between homologous chromosomes. γH2AX and Rad51 were atypically distributed during pachytene and as late as diplotene and associated with asynaptic chromatin, single chromosome axes or discontinuous chromosome axes. Among apoptotic spermatocytes at pachytene, 70% showed changes in the structure of synapses, 67% showed changes in γH2AX and Rad51 distribution and 50% shared alterations in both synapses and DNA repair. Our results showed that apoptotic spermatocytes from Mus m. domesticus contain a high frequency of alterations in chromosomal synapses and in the recruitment and distribution of DNA repair proteins. Together, these observations suggest that these alterations may have been detected by meiotic checkpoints triggering apoptosis. PMID:27349323

  12. Alterations in chromosomal synapses and DNA repair in apoptotic spermatocytes of Mus m. domesticus.

    PubMed

    Ayarza, E; González, M; López, F; Fernández-Donoso, R; Page, J; Berrios, S

    2016-01-01

    We investigated whether apoptotic spermatocytes from the mouse Mus m. domesticus presented alterations in chromosomal synapses and DNA repair. To enrich for apoptotic spermatocytes, the scrotum's temperature was raised by partially exposing animals for 15 min to a 42ºC water bath. Spermatocytes in initial apoptosis were identified in situ by detecting activated Caspase-9.  SYCP1 and SYCP3 were markers for evaluating synapses or the structure of synaptonemal complexes and Rad51 and γH2AX for detecting DNA repair and chromatin remodeling. Apoptotic spermatocytes were concentrated in spermatogenic cycle stages III-IV (50.3%), XI-XII (44.1%) and IX-X (4.2%). Among apoptotic spermatocytes, 48% were in middle pachytene, 44% in metaphase and 6% in diplotene. Moreover, apoptotic spermatocytes showed several structural anomalies in autosomal bivalents, including splitting of chromosomal axes and partial asynapses between homologous chromosomes. gH2AX and Rad51 were atypically distributed during pachytene and as late as diplotene and associated with asynaptic chromatin, single chromosome axes or discontinuous chromosome axes. Among apoptotic spermatocytes at pachytene, 70% showed changes in the structure of synapses, 67% showed changes in gH2AX and Rad51 distribution and 50% shared alterations in both synapses and DNA repair. Our results showed that apoptotic spermatocytes from Mus m. domesticus contain a high frequency of alterations in chromosomal synapses and in the recruitment and distribution of DNA repair proteins. Together, these observations suggest that these alterations may have been detected by meiotic checkpoints triggering apoptosis. PMID:27349323

  13. Low Diversity of T Haplotypes in the Eastern Form of the House Mouse, Mus Musculus L

    PubMed Central

    Ruvinsky, A.; Polyakov, A.; Agulnik, A.; Tichy, H.; Figueroa, F.; Klein, J.

    1991-01-01

    In previous studies, 13 different recessive embryonic lethal genes have been associated with t haplotypes in the wild mice of the species Mus domesticus. In this communication we have analyzed five populations of Mus musculus for the presence and identity of t haplotypes. The populations occupy geographically distant regions in the Soviet Union: Altai Mountains, western and eastern Siberia, Azerbaijan and Turkmenistan. No t haplotypes were found in mice from eastern Siberia. In the remaining four populations, t haplotypes occurred with frequencies ranging from 0.07 to 0.21. All the t haplotypes extracted from these populations and analyzed by the genetic complementation test were shown to carry the same lethal gene tcl-w73. In one population (that of western Siberia), another lethal gene (tcl-w5) was found to be present on the same chromosome as tcl-w73. This situation is in striking contrast to that found in the populations of the western form of the house mouse, M. domesticus. In the latter species, tcl-w73 has not been found at all and the different populations are characterized by the presence of several different lethal genes. The low diversity of t haplotypes in M. musculus is consistent with lower genetic variability of other traits and indicates a different origin and speciation mode compared to M. domesticus. Serological typing for H-2 antigenic determinants suggests that most, if not all, of the newly described t haplotypes might have arisen by recombination of t(w73) from M. musculus with t haplotypes from M. domesticus either in the hybrid zone between the two species or in regions where the two species mixed accidentally. PMID:2016041

  14. Synthetic Lethality of Drosophila in the Absence of the MUS81 Endonuclease and the DmBlm Helicase Is Associated With Elevated Apoptosis

    PubMed Central

    Trowbridge, Kirsten; McKim, Kim; Brill, Steven J.; Sekelsky, Jeff

    2007-01-01

    Mus81-Mms4 (Mus81-Eme1 in some species) is a heterodimeric DNA structure-specific endonuclease that has been implicated in meiotic recombination and processing of damaged replication forks in fungi. We generated and characterized mutations in Drosophila melanogaster mus81 and mms4. Unlike the case in fungi, we did not find any role for MUS81-MMS4 in meiotic crossing over. A possible role for this endonuclease in repairing double-strand breaks that arise during DNA replication is suggested by the finding that mus81 and mms4 mutants are hypersensitive to camptothecin; however, these mutants are not hypersensitive to other agents that generate lesions that slow or block DNA replication. In fungi, mus81, mms4, and eme1 mutations are synthetically lethal with mutations in genes encoding RecQ helicase homologs. Similarly, we found that mutations in Drosophila mus81 and mms4 are synthetically lethal with null mutations in mus309, which encodes the ortholog of the Bloom Syndrome helicase. Synthetic lethality is associated with high levels of apoptosis in proliferating tissues. Lethality and elevated apoptosis were partially suppressed by a mutation in spn-A, which encodes the ortholog of the strand invasion protein Rad51. These findings provide insights into the causes of synthetic lethality. PMID:17603121

  15. The HPV16 and MusPV1 papillomaviruses initially interact with distinct host components on the basement membrane

    PubMed Central

    Day, Patricia M.; Thompson, Cynthia D.; Lowy, Douglas R.; Schiller, John T.

    2015-01-01

    To understand and compare the mechanisms of murine and human PV infection, we examined pseudovirion binding and infection of the newly described MusPV1 using the murine cervicovaginal challenge model. These analyses revealed primary tissue interactions distinct from those previously described for HPV16. Unlike HPV16, MusPV1 bound basement membrane (BM) in an HSPG-independent manner. Nevertheless, subsequent HSPG interactions were critical. L2 antibodies or low doses of VLP antibodies, sufficient to prevent infection, did not lead to disassociation of the MusPV1 pseudovirions from the BM, in contrast to previous findings with HPV16. Similarly, furin inhibition did not lead to loss of MusPV1 from the BM. Therefore, phylogenetically distant PV types that differ in their initial interactions with host attachment factors, but initiate their lifecycle on the acellular BM. Despite these differences, these distantly related PV types displayed similar intracellular trafficking patterns and susceptibilities to biochemical inhibition of infection. PMID:25771496

  16. Participative Decision Making in IGE/MUS-E Schools. Technical Report No. 356 (Parts 1 and 2).

    ERIC Educational Resources Information Center

    Nerlinger, Constance M.

    The purpose of this study was to examine the relationships of the Instructional Improvement Committee's (IIC) involvement in decision making, the representation of teachers on the IIC, and the effectiveness of the Instruction and Research (I&R) Unit in Individually Guided Education/Multiunit Elementary (IGE/MUS-E) schools. The theoretical base for…

  17. Effect of GABAergic ligands on the anxiolytic-like activity of DOI (a 5-HT(2A/2C) agonist) in the four-plate test in mice.

    PubMed

    Massé, Fabienne; Hascoët, Martine; Bourin, Michel

    2007-01-01

    5-HTergic and GABAergic systems are involved in neurobiology of anxiety. Precedent studies have demonstrated that SSRIs possessed an anxiolytic-like effect in the four-plate test (FPT) at doses that did not modify spontaneous locomotor activity. This effect seems to be mediated through the activation of 5-HT(2A) postsynaptic receptors. The purpose of the present study was to examine the implication of GABA system in the anxiolytic-like activity of DOI in the FPT. To achieve this, the co-administration of DOI (5-HT(2A/2C) receptor agonists) with GABA(A) and GABA(B) receptor ligands was evaluated in the FPT. Alprazolam, diazepam and muscimol (for higher dose) potentiated the anxiolytic-like effect of DOI. Bicuculline, picrotoxin and baclofen inhibited the anxiolytic-like effect of DOI. Flumazenil and CGP 35348 had no effect on the anxiolytic-like activity of DOI. These results suggest that the GABA system seems to be strongly implicated in the anxiolytic-like activity of DOI in the FPT.

  18. Synthesis of GABAA Receptor Agonists and Evaluation of their α-Subunit Selectivity and Orientation in the GABA Binding Site

    PubMed Central

    Jansen, Michaela; Rabe, Holger; Strehle, Axelle; Dieler, Sandra; Debus, Fabian; Dannhardt, Gerd; Akabas, Myles H.; Lüddens, Hartmut

    2008-01-01

    Drugs used to treat various disorders target GABAA receptors. To develop α subunit selective compounds, we synthesized 5-(4-piperidyl)-3-isoxazolol (4-PIOL) derivatives. The 3-isoxazolol moiety was substituted by 1,3,5-oxadiazol-2-one, 1,3,5-oxadiazol-2-thione, and substituted 1,2,4-triazol-3-ol heterocycles with modifications to the basic piperidine substituent as well as substituents without basic nitrogen. Compounds were screened by [3H]muscimol binding and in patch-clamp experiments with heterologously expressed GABAA αiβ3γ2 receptors (i = 1–6). The effects of 5-aminomethyl-3H-[1,3,4]oxadiazol-2-one 5d were comparable to GABA for all α subunit isoforms. 5-piperidin-4-yl-3H-[1,3,4]oxadiazol-2-one 5a and 5-piperidin-4-yl-3H- [1,3,4]oxadiazol-2-thione 6a were weak agonists at α3–, α3–, and α5–containing receptors. When coapplied with GABA they were antagonistic inα2–, α4–, and α6–containing receptors and potentiated α3-containing receptors. 6a protected GABA binding site cysteine-substitution mutants α1F64C and α1S68C from reacting with methanethiosulfonate-ethylsulfonate. 6a specifically covalently modified the α1R66C thiol, in the GABA binding site, through its oxadiazolethione sulfur. These results demonstrate the feasibility of synthesizing α subtype selective GABA mimetic drugs. PMID:18651727

  19. beta2-Agonists at the Olympic Games.

    PubMed

    Fitch, Kenneth D

    2006-01-01

    The different approaches that the International Olympic Committee (IOC) had adopted to beta2-agonists and the implications for athletes are reviewed by a former Olympic team physician who later became a member of the Medical Commission of the IOC (IOC-MC). Steadily increasing knowledge of the effects of inhaled beta2-agonists on health, is concerned with the fact that oral beta2-agonists may be anabolic, and rapid increased use of inhaled beta2-agonists by elite athletes has contributed to the changes to the IOC rules. Since 2001, the necessity for athletes to meet IOC criteria (i.e., that they have asthma and/or exercise-induced asthma [EIA]) has resulted in improved management of athletes. The prevalence of beta2-agonist use by athletes mirrors the known prevalence of asthma symptoms in each country, although athletes in endurance events have the highest prevalence. The age-of-onset of asthma/EIA in elite winter athletes may be atypical. Of the 193 athletes at the 2006 Winter Olympics who met th IOC's criteria, only 32.1% had childhood asthma and 48.7% of athletes reported onset at age 20 yr or older. These findings lead to speculation that years of intense endurance training may be a causative factor in bronchial hyperreactivity. The distinction between oral (prohibited in sports) and inhaled salbutamol is possible, but athletes must be warned that excessive use of inhaled salbutamol can lead to urinary concentrations similar to those observed after oral administration. This article provides justification that athletes should provide evidence of asthma or EIA before being permitted to use inhaled beta2-agonists. PMID:17085798

  20. Drosophila mus301/spindle-C Encodes a Helicase With an Essential Role in Double-Strand DNA Break Repair and Meiotic Progression

    PubMed Central

    McCaffrey, Ruth; St Johnston, Daniel; González-Reyes, Acaimo

    2006-01-01

    mus301 was identified independently in two genetic screens, one for mutants hypersensitive to chemical mutagens and another for maternal mutants with eggshell defects. mus301 is required for the proper specification of the oocyte and for progression through meiosis in the Drosophila ovary. We have cloned mus301 and show that it is a member of the Mus308 subfamily of ATP-dependent helicases and the closest homolog of human and mouse HEL308. Functional analyses demonstrate that Mus301 is involved in chromosome segregation in meiosis and in the repair of double-strand-DNA breaks in both meiotic and mitotic cells. Most of the oogenesis defects of mus301 mutants are suppressed by mutants in the checkpoint kinase Mei41 and in MeiW68, the Spo11 homolog that is thought to generate the dsDNA breaks that initiate recombination, indicating that these phenotypes are caused by activation of the DNA damage checkpoint in response to unrepaired Mei-W68-induced dsDNA breaks. However, neither mei-W68 nor mei-41 rescue the defects in oocyte specification of mus301 mutants, suggesting that this helicase has another function in oocyte selection that is independent from its role in meiotic recombination. PMID:16888338

  1. Environmental temperature affects the dynamics of ingestion in the nectivorous ant Camponotus mus.

    PubMed

    Falibene, Agustina; Josens, Roxana

    2014-12-01

    Environmental temperature influences physiology and behavior in animals in general and is particularly determinant in ectotherms. Not least because temperature defines metabolism and body temperature, muscle activity in insects also strongly depends on this factor. Here, we analyzed how environmental temperature influences the dynamics of ingestion due to its effect on the sucking pump muscles in the nectivorous ants Camponotus mus. Feeding behavior and sucking pump activity during sucrose solution ingestion were first recorded in a natural environment in an urban setting throughout the day and in different seasons. Then, controlled temperature experiments were performed in the laboratory. In both situations, feeding time decreased and pumping frequency increased with temperature. However, different pumping frequencies under a same temperature were also observed in different seasons. Besides, in the laboratory, the volume of solution ingested increased with temperature. Consequently, intake rate increased when temperature rose. This change was exclusively promoted by a variation in the pumping frequency while volume taken in per pump contraction was not affected by temperature. In summary, environmental temperature modified the dynamics of ingestion and feeding behavior by directly affecting pumping frequency.

  2. Antimutagenic effects of aqueous fraction of Myristica fragrans (Houtt.) leaves on Salmonella typhimurium and Mus musculus.

    PubMed

    Akinboro, Akeem; Bin Mohamed, Kamaruzaman; Asmawi, Mohd Zaini; Yekeen, Taofeek A

    2014-01-01

    Natural plant extracts offer a promising hope in the prevention/treatment of cancer arising from genetic mutations. This study evaluated in vitro and in vivo mutagenic and antimutagenic effects of aqueous fraction of Myristica fragrans (AFMF) leaves on TA100 strain of Salmonella typhimurium and Mus musculus (Male Swiss albino mice), respectively. The antioxidant activity of AFMF against 2,2-diphenyl-1-picrylhydrazyl (DPPH), total phenolic and flavonoid contents were determined, followed by its phytochemical elucidation using the Ultra Performance Liquid Chromatography technique (UPLC). The mutagenicity of AFMF at 4, 20, 50, 100, 200, 500, and 1000 µg/well was <2.0 in S. typhimurium and the induced micronucleated polychromatic and normochromatic erythrocytes at 500, 1000, 2000, and 4000 mg/kg were not significantly different from the negative control (p≥0.05). The mutagenic activity of benzo[a]pyrene and cyclophosphamide was significantly suppressed above 50.0% throughout the tested concentrations. Fifty percent of the free radicals from DPPH were scavenged by AFMF at 0.11 mg/ml. Total phenolic and flavonoid contents of AFMF were 51.0 mg GAE/g and 27 mg QE/g, respectively. Rutin was elucidated by the UPLC technique, and thereby suspected to be the phytochemical responsible for the observed antimutagenic activity. Thus far, AFMF seems to contain a promising chemotherapeutic agent for the prevention of genetic damage that is crucial for cancer development.

  3. Insights into mammalian biology from the wild house mouse Mus musculus.

    PubMed

    Phifer-Rixey, Megan; Nachman, Michael W

    2015-01-01

    The house mouse, Mus musculus, was established in the early 1900s as one of the first genetic model organisms owing to its short generation time, comparatively large litters, ease of husbandry, and visible phenotypic variants. For these reasons and because they are mammals, house mice are well suited to serve as models for human phenotypes and disease. House mice in the wild consist of at least three distinct subspecies and harbor extensive genetic and phenotypic variation both within and between these subspecies. Wild mice have been used to study a wide range of biological processes, including immunity, cancer, male sterility, adaptive evolution, and non-Mendelian inheritance. Despite the extensive variation that exists among wild mice, classical laboratory strains are derived from a limited set of founders and thus contain only a small subset of this variation. Continued efforts to study wild house mice and to create new inbred strains from wild populations have the potential to strengthen house mice as a model system.

  4. Discovery of a 10 {mu}s isomeric state in {sub 63}{sup 139}Eu

    SciTech Connect

    Cullen, D. M.; Mason, P. J. R; Kishada, A. M.; Procter, M. G.; Rigby, S. V.; Varley, B. J.; Scholey, C.; Eeckhaudt, S.; Grahn, T.; Greenlees, P. T.; Jakobsson, U.; Jones, P. M.; Julin, R.; Juutinen, S.; Ketelhut, S.; Leino, M.; Leppaenen, A.-P.; Maentyniemi, K.; Nieminen, P.; Nyman, M.

    2011-01-15

    Recoil-isomer tagging with the {sup 54}Fe+{sup 92}Mo reaction was used to establish a 10(2)-{mu}s isomeric state in {sup 139}Eu. Prompt versus delayed {gamma}-ray coincidence data have revealed the presence of a prompt rotational band built upon the isomer. The alignment properties of the states in this band show that the isomer is based upon a proton g{sub 7/2} configuration. The decay of the isomer takes place through a single 26-keV E1 transition. The {gamma}-ray transition strength for this decay is consistent with those established in the neighboring isomeric gamma-soft nuclei. In these nuclei, isomers are expected to form as a consequence of differences in nuclear shapes or configurations, and the natural hindrance associated with configuration-changing E1 transitions. The isomeric nature of the state in {sup 139}Eu is reasoned to be because of difference in shape of the proton g{sub 7/2} state and the proton h{sub 11/2} ground state to which it decays.

  5. Systematic biochemical characterization of the SAM domains in Eph receptor family from Mus Musculus.

    PubMed

    Wang, Yue; Li, Qingxia; Zheng, Yunhua; Li, Gang; Liu, Wei

    2016-05-13

    The Eph receptor family is the largest subfamily of receptor tyrosine kinases and well-known for their pivotal roles in axon guidance, synaptogenesis, artery/venous differentiation and tumorigenesis, etc. Activation of the Eph receptor needs multimerization of the receptors. The intracellular C-terminal SAM domain of Eph receptor was reported to mediate self-association of Eph receptors via the homo SAM-SAM interaction. In this study, we systematically expressed and purified the SAM domain proteins of all fourteen Eph receptors of Mus musculus in Escherichia coli. The FPLC (fast protein liquid chromatography) results showed the recombinant SAM domains were highly homogeneous. Using CD (circular dichroism) spectrometry, we found that the secondary structure of all the SAM domains was typically alpha helical folded and remarkably similar. The thermo-stability tests showed that they were quite stable in solution. SEC-MALS (size exclusion chromatography coupled with multiple angle light scattering) results illustrated 200 μM Eph SAM domains behaved as good monomers in the size-exclusion chromatography. More importantly, DLS (dynamic light scattering) results revealed the overwhelming majority of SAM domains was not multimerized in solution either at 200 μM or 2000 μM protein concentration, which indicating the SAM domain alone was not sufficient to mediate the polymerization of Eph receptor. In summary, our studies provided the systematic biochemical characterizations of the Eph receptor SAM domains and implied their roles in Eph receptor mediated signaling pathways. PMID:27086853

  6. Susceptibility of Peromyscus leucopus and Mus musculus to infection with Baylisascaris procyonis.

    PubMed

    Sheppard, C H; Kazacos, K R

    1997-12-01

    In this study, we compared the susceptibility of Peromyscus leucopus (white-footed mouse), a common natural intermediate host, and Mus musculus, a commonly used experimental model, to infection with larvae of the raccoon ascarid, Baylisascaris procyonis. Three groups of 10 mice of each species were given 50, 250, or 500 infective B. procyonis eggs by gavage. The mice were observed daily for clinical signs of central nervous system (CNS) disease and at necropsy the distribution of larvae in 10 body regions and organs was determined and compared. Clinical CNS disease developed in 57% of P. leucopus and 93% of M. musculus. The average clinical incubation period was significantly longer in P. leucopus (20.6 days postinfection [PI]) than in M. musculus (10.7 days PI), and clinical disease progressed slower in P. leucopus. Significantly fewer larvae were recovered from P. leucopus than from M. musculus. Most larvae were recovered from the anterior carcass and viscera of P. leucopus and from the carcass, head, and brain of M. musculus. CNS invasion was dose dependent in M. musculus but not in P. leucopus. Few or no grossly visible larval granulomas were present in P. leucopus but were abundant in M. musculus. We concluded that P. leucopus was less susceptible than M. musculus to B. procyonis infection, based on a decreased intensity of infection, longer clinical incubation period or lack of clinical disease, slower progression of disease, different larval distribution, and lower tissue reactivity to larvae.

  7. MusA: Using Indoor Positioning and Navigation to Enhance Cultural Experiences in a Museum

    PubMed Central

    Rubino, Irene; Xhembulla, Jetmir; Martina, Andrea; Bottino, Andrea; Malnati, Giovanni

    2013-01-01

    In recent years there has been a growing interest in the use of multimedia mobile guides in museum environments. Mobile devices have the capabilities to detect the user context and to provide pieces of information suitable to help visitors discover and follow the logical and emotional connections that develop during the visit. In this scenario, location based services (LBS) currently represent an asset, and the choice of the technology to determine users' position, combined with the definition of methods that can effectively convey information, become key issues in the design process. In this work, we present Museum Assistant (MusA), a general framework for the development of multimedia interactive guides for mobile devices. Its main feature is a vision-based indoor positioning system that allows the provision of several LBS, from way-finding to the contextualized communication of cultural contents, aimed at providing a meaningful exploration of exhibits according to visitors' personal interest and curiosity. Starting from the thorough description of the system architecture, the article presents the implementation of two mobile guides, developed to respectively address adults and children, and discusses the evaluation of the user experience and the visitors' appreciation of these applications. PMID:24351645

  8. Electrical signals during nectar sucking in the carpenter ant Camponotus mus.

    PubMed

    Josens, Roxana; Falibene, Agustina; Gontijo, Alberto de Figueiredo

    2006-01-01

    Ants of the same size can vary their intake rate of a given sucrose solution depending on the colony's needs for carbohydrates. As this capacity has not yet been described for another insect, the question of how they can do that was the focus of our work. When viscosity and ant-morphometry remain constant, changes in intake rate can only be attributed to the sucking forces. The aim of this study was to analyze the nectar sucking activity in the ant Camponotus mus. Feeding behavior seems to be under motivational control; therefore, we developed a non-invasive experimental device. We recorded the electrical signal generated during nectar feeding by offering ants sucrose solutions of different concentrations (from 10%w/w to 70%w/w). The signal frequency was between 2 and 12 peaks/s. We could distinguish two different patterns of electrical signal during feeding depending on the solution concentration. Only the more concentrated solutions reached frequencies higher than 7 peaks/s and the signal performance was quite irregular. For the other concentrations (10%, 30% and 50%), signal frequencies were lower than 6 peaks/s and the signal pattern was sinusoidal, regular and decreased with intake in all cases. We discuss the possible implications of these two signal patterns.

  9. Karyomegaly and intranuclear inclusions in the renal tubules of sentinel ICR mice (mus musculus).

    PubMed

    Baze, Wallace B; Steinbach, Thomas J; Fleetwood, Michelle L; Blanchard, Terrell W; Barnhart, Kirstin F; McArthur, Mark J

    2006-10-01

    Among 585 sentinel ICR mice (Mus musculus), 8 (7 female, 1 male) had unusual microscopic lesions in the kidney. Light microscopy revealed occasional tubular epithelial cells with large, karyomegalic nuclei that contained intranuclear inclusions and marginated chromatin. These cells were randomly present in the cortex and medulla but were more prominent near the corticomedullary junc tion. Rare pyknotic cells and mild interstitial infiltrates of lymphocytes and plasma cells were associated with occasional foci of abnormal cells. Electron microscopy performed on 2 (1 female, 1 male) of the mice demonstrated intranuclear inclusions composed of abundant flocculent, electron-lucent material. No viral particles or other pathogens were identified. General health monitoring that included serology, microbiology, parasitology, necropsy, and histopathology was negative for pathogens. Polymerase chain reaction-based testing for polyomavirus and immunohistochemistry for adenovirus were performed on 5 of the 7 female mice; all were negative for both viruses. In light of microscopy findings and the lack of evidence for an infectious agent, the tubular lesions were considered degenerative changes, possibly due to a toxic insult. The cause and significance of the findings in these mice can not be explained fully.

  10. Insights into mammalian biology from the wild house mouse Mus musculus

    PubMed Central

    Phifer-Rixey, Megan; Nachman, Michael W

    2015-01-01

    The house mouse, Mus musculus, was established in the early 1900s as one of the first genetic model organisms owing to its short generation time, comparatively large litters, ease of husbandry, and visible phenotypic variants. For these reasons and because they are mammals, house mice are well suited to serve as models for human phenotypes and disease. House mice in the wild consist of at least three distinct subspecies and harbor extensive genetic and phenotypic variation both within and between these subspecies. Wild mice have been used to study a wide range of biological processes, including immunity, cancer, male sterility, adaptive evolution, and non-Mendelian inheritance. Despite the extensive variation that exists among wild mice, classical laboratory strains are derived from a limited set of founders and thus contain only a small subset of this variation. Continued efforts to study wild house mice and to create new inbred strains from wild populations have the potential to strengthen house mice as a model system. DOI: http://dx.doi.org/10.7554/eLife.05959.001 PMID:25875302

  11. Ecological basis for fertility control in the house mouse (Mus domesticus) using immunocontraceptive vaccines.

    PubMed

    Singleton, G R; Farroway, L N; Chambers, L K; Lawson, M A; Smith, A L; Hinds, L A

    2002-01-01

    Laboratory studies confirm the potential for fertility control in the house mouse Mus domesticus using mouse cytomegalovirus (MCMV) as a vector for an immunocontraceptive vaccine. This article presents an overview of key results from research in Australia on enclosed and field populations of mice and the associated epidemiology of MCMV. The virus is geographically widespread in Australia. It also persists in low population densities of mice, although if population densities are low for at least a year, transmission of the virus is sporadic until a population threshold of approximately 40 mice ha(-1) is reached. The serological prevalence of MCMV was high early in the breeding season of four field populations. Enclosure studies confirm that MCMV has minimal impact on the survival and breeding performance of mice and that it can be transmitted to most adults within 10-12 weeks. Other enclosure studies indicate that about two-thirds of females would need to be sterilized to provide effective control of the rate of growth of mouse populations. If this level is not maintained for 20-25 weeks after the commencement of breeding, the mouse population can compensate through increased recruitment per breeding female. The findings from this series of descriptive and manipulative population studies of mice support the contention that MCMV would be a good carrier for an immunocontraceptive vaccine required to sustain female sterility levels at or above 65%.

  12. Spermatogenic structure and fertility of Mus musculus after exposure of mangosteen (Garcinia mangostana L) pericarp extract

    NASA Astrophysics Data System (ADS)

    Hayati, Alfiah; Agustin, Melia Eka; Rokhimaningrum, Farida Ayu; Adro'i, Hasan; Darmanto, Win

    2016-03-01

    This study aimed to determine the effect of mangosteen (Garcinia mangostana L.) pericarp extract on spermatogenics number, seminiferous tubules sized, profile protein of epididymal and testicular sperm, and fertility of mice (Mus musculus). Fourty two male mice strain BALB/C was divided equally into 7 groups. The control group was given 0.05 ml of 0.05% CMC solution. Three group were given mangosteen pericarp extract at various doses (75, 100 and 150 mg/kg body weight, respectively) for 7 days, while the other three groups were given the same extract dose for 35 days. Parameters evaluated on histological of spermatogonia, spermatocytes, round spermatids, seminiferous tubule diameter, and thickness of germinal epithelium, analysis of testicular and epidydimal protein profile with SDS-Page, and than fertility test on female mice. The results showed that mangosteen pericarp extract at 75 and 100 mg/kg dose for 7 days had no effect on spermatogenics number and seminiferous tubule sizes, but the treatment dose of 150 mg/kg for 7 days and all treatment (doses of 75, 100, and 150 mg/kg) for 35 days led to significant decrease on the number of spermatogenics and seminiferous tubule sizes; effect on protein profiles testicular and epididymal sperm; and lower fertilization.

  13. Trials of the anticoagulant rodenticides bromadiolone and difenacoum against the house mouse (Mus musculus L.).

    PubMed

    Rowe, F P; Plant, C J; Bradfield, A

    1981-10-01

    Laboratory and field trials were conducted to determine the efficacy of the anticoagulant rodenticide bromadiolone against the house mouse (Mus musculus). In laboratory feeding tests, family groups of warfarin-resistant mice maintained in pens and conditioned to feeding on plain foods were offered pinhead oatmeal bait containing bromadiolone at 0.005%. Overall mortality in replicated 21-day poison treatments was 55/58 or 94.8%. Six field trials were carried out, using the same poison bait, against mice infesting farm buildings. Treatment success, estimated from the results of census baitings conducted before and after treatment, ranged between 60.4% and 100%, mean 92.4%. In equivalent field trials using difenacoum, another newly developed anticoagulant rodenticide, the control achieved ranged between 70.2% and 100%, mean 96.0%. Five field trials, three involving bromadiolone and two difenacoum, were not completely successful and the surviving mice were removed for laboratory examination. In 21-day toxicity tests, each animal was fed the poison bait offered to it earlier in the field. Bromadiolone and difenacoum gave kills of 12/21 (57.1%) and 9/11 (81.8%) respectively. The possible emergence of mouse populations resistant to these anticoagulants is considered. PMID:7288171

  14. Pen and field trials of flupropadine against the house mouse (Mus musculus L.).

    PubMed

    Rowe, F P; Bradfield, A; Swinney, T

    1985-10-01

    Laboratory and field trials were conducted to determine the efficacy of the candidate rodenticide flupropadine against the house mouse (Mus musculus L.). In laboratory feeding tests, family groups of wild mice maintained in pens and conditioned to feeding on plain foods were offered flupropadine at either 0.10%, 0.15%, 0.18% or 0.20% in pinhead oatmeal bait. Overall mortalities in replicated 21-day treatments were 66/71 (93.0%), 71/79 (89.9%), 72/76 (94.7%) and 69/75 (92.0%) respectively. In 17 field trials carried out against mice infesting farm buildings, flupropadine was used at 0.10%, 0.15% and 0.18% in oatmeal bait. Mean treatment success, estimated from live-capture and mortality data, was 88.6%, 96.2% and 96.6% respectively. Flupropadine was found to be as near effective against mice as calciferol/warfarin and the second-generation anticoagulant rodenticides difenacoum, bromadiolone and brodifacoum. In further comparison with the anticoagulants, treatment with flupropadine bait achieved markedly quicker control. PMID:4067302

  15. Electrical signals during nectar sucking in the carpenter ant Camponotus mus.

    PubMed

    Josens, Roxana; Falibene, Agustina; Gontijo, Alberto de Figueiredo

    2006-01-01

    Ants of the same size can vary their intake rate of a given sucrose solution depending on the colony's needs for carbohydrates. As this capacity has not yet been described for another insect, the question of how they can do that was the focus of our work. When viscosity and ant-morphometry remain constant, changes in intake rate can only be attributed to the sucking forces. The aim of this study was to analyze the nectar sucking activity in the ant Camponotus mus. Feeding behavior seems to be under motivational control; therefore, we developed a non-invasive experimental device. We recorded the electrical signal generated during nectar feeding by offering ants sucrose solutions of different concentrations (from 10%w/w to 70%w/w). The signal frequency was between 2 and 12 peaks/s. We could distinguish two different patterns of electrical signal during feeding depending on the solution concentration. Only the more concentrated solutions reached frequencies higher than 7 peaks/s and the signal performance was quite irregular. For the other concentrations (10%, 30% and 50%), signal frequencies were lower than 6 peaks/s and the signal pattern was sinusoidal, regular and decreased with intake in all cases. We discuss the possible implications of these two signal patterns. PMID:17069844

  16. 20 {mu}s isomeric state in doubly odd {sub 61}{sup 134}Pm

    SciTech Connect

    Cullen, D. M.; Mason, P. J. R; Rigby, S. V.; Kishada, A. M.; Varley, B. J.; Scholey, C.; Eeckhaudt, S.; Grahn, T.; Greenlees, P. T.; Jakobsson, U.; Jones, P. M.; Julin, R.; Juutinen, S.; Ketelhut, S.; Leino, M.; Leppaenen, A.-P.; Maentyniemi, K.; Nieminen, P.; Nyman, M.; Pakarinen, J.

    2009-08-15

    Recoil-isomer tagging at the Accelerator Laboratory of the University of Jyvaeskylae has been used to establish the isomeric nature of a known (7{sup -}) excited state in the doubly odd nucleus {sup 134}Pm. The isomeric state was determined to have a half-life of 20(1) {mu}s and was populated from the decay of a {pi}h{sub 11/2} x {nu}h{sub 11/2} band using the {sup 92}Mo({sup 54}Fe,2{alpha}3pn) reaction at 305 and 315 MeV. The isomer decays by a 71-keV transition that provides an intermediate step in linking the established {sup 134}Pm high-spin level scheme to the lower-spin states observed from the {beta} decay of {sup 134}Sm. Electron-conversion analysis for the 71-keV {gamma}-ray transition reveals that it is of E1 character and its small reduced-transition probability suggests that {sup 134}Pm may have a nuclear shape more rigid than that of the neighboring nuclei.

  17. XY females do better than the XX in the African pygmy mouse, Mus minutoides.

    PubMed

    Saunders, Paul A; Perez, Julie; Rahmoun, Massilva; Ronce, Ophélie; Crochet, Pierre-André; Veyrunes, Frédéric

    2014-07-01

    All therian mammals have a similar XY/XX sex-determination system except for a dozen species. The African pygmy mouse, Mus minutoides, harbors an unconventional system in which all males are XY, and there are three types of females: the usual XX but also XX* and X*Y ones (the asterisk designates a sex-reversal mutation on the X chromosome). The long-term evolution of such a system is a paradox, because X*Y females are expected to face high reproductive costs (e.g., meiotic disruption and loss of unviable YY embryos), which should prevent invasion and maintenance of a sex-reversal mutation. Hence, mechanisms for compensating for the costs could have evolved in M. minutoides. Data gathered from our laboratory colony revealed that X*Y females do compensate and even show enhanced reproductive performance in comparison to the XX and XX*; they produce significantly more offspring due to (i) a higher probability of breeding, (ii) an earlier first litter, and (iii) a larger litter size, linked to (iv) a greater ovulation rate. These findings confirm that rare conditions are needed for an atypical sex-determination mechanism to evolve in mammals, and provide valuable insight into understanding modifications of systems with highly heteromorphic sex chromosomes.

  18. Trials of the anticoagulant rodenticides bromadiolone and difenacoum against the house mouse (Mus musculus L.).

    PubMed Central

    Rowe, F. P.; Plant, C. J.; Bradfield, A.

    1981-01-01

    Laboratory and field trials were conducted to determine the efficacy of the anticoagulant rodenticide bromadiolone against the house mouse (Mus musculus). In laboratory feeding tests, family groups of warfarin-resistant mice maintained in pens and conditioned to feeding on plain foods were offered pinhead oatmeal bait containing bromadiolone at 0.005%. Overall mortality in replicated 21-day poison treatments was 55/58 or 94.8%. Six field trials were carried out, using the same poison bait, against mice infesting farm buildings. Treatment success, estimated from the results of census baitings conducted before and after treatment, ranged between 60.4% and 100%, mean 92.4%. In equivalent field trials using difenacoum, another newly developed anticoagulant rodenticide, the control achieved ranged between 70.2% and 100%, mean 96.0%. Five field trials, three involving bromadiolone and two difenacoum, were not completely successful and the surviving mice were removed for laboratory examination. In 21-day toxicity tests, each animal was fed the poison bait offered to it earlier in the field. Bromadiolone and difenacoum gave kills of 12/21 (57.1%) and 9/11 (81.8%) respectively. The possible emergence of mouse populations resistant to these anticoagulants is considered. PMID:7288171

  19. Pen and field trials of flupropadine against the house mouse (Mus musculus L.).

    PubMed Central

    Rowe, F. P.; Bradfield, A.; Swinney, T.

    1985-01-01

    Laboratory and field trials were conducted to determine the efficacy of the candidate rodenticide flupropadine against the house mouse (Mus musculus L.). In laboratory feeding tests, family groups of wild mice maintained in pens and conditioned to feeding on plain foods were offered flupropadine at either 0.10%, 0.15%, 0.18% or 0.20% in pinhead oatmeal bait. Overall mortalities in replicated 21-day treatments were 66/71 (93.0%), 71/79 (89.9%), 72/76 (94.7%) and 69/75 (92.0%) respectively. In 17 field trials carried out against mice infesting farm buildings, flupropadine was used at 0.10%, 0.15% and 0.18% in oatmeal bait. Mean treatment success, estimated from live-capture and mortality data, was 88.6%, 96.2% and 96.6% respectively. Flupropadine was found to be as near effective against mice as calciferol/warfarin and the second-generation anticoagulant rodenticides difenacoum, bromadiolone and brodifacoum. In further comparison with the anticoagulants, treatment with flupropadine bait achieved markedly quicker control. PMID:4067302

  20. Nectar foraging behaviour is affected by ant body size in Camponotus mus.

    PubMed

    Medan, Violeta; Josens, Roxana B

    2005-08-01

    The nectivorous ant Camponotus mus shows a broad size variation within the worker caste. Large ants can ingest faster and larger loads than small ones. Differences in physiological abilities in fluid ingestion due to the insect size could be related to differences in decision-making according to ant size during nectar foraging. Sucrose solutions of different levels of sugar concentration (30% or 60%w/w), viscosity (high or low) or flow rate (ad libitum or 1microl/min) were offered in combination to analyse the behavioural responses to each of these properties separately. Differences were found depending on ant body size and the property compared. A regulated flow produced smaller crop loads for medium and large ants compared to the same solution given ad libitum. All foragers remained longer times feeding at the regulated flow source but larger ants often made longer interruptions. When sugar concentration was constant but viscosity was high, only large ants increased feeding time. Constant viscosity with different sugar concentration determined longer feeding time and bigger loads for the most concentrated solution for small but not for large ants. Small ants reached similar crop loads in a variety of conditions while large ants did not. These differences could be evidence of a possible specialization for nectar foraging based on ant body size.

  1. Antimutagenic effects of aqueous fraction of Myristica fragrans (Houtt.) leaves on Salmonella typhimurium and Mus musculus.

    PubMed

    Akinboro, Akeem; Bin Mohamed, Kamaruzaman; Asmawi, Mohd Zaini; Yekeen, Taofeek A

    2014-01-01

    Natural plant extracts offer a promising hope in the prevention/treatment of cancer arising from genetic mutations. This study evaluated in vitro and in vivo mutagenic and antimutagenic effects of aqueous fraction of Myristica fragrans (AFMF) leaves on TA100 strain of Salmonella typhimurium and Mus musculus (Male Swiss albino mice), respectively. The antioxidant activity of AFMF against 2,2-diphenyl-1-picrylhydrazyl (DPPH), total phenolic and flavonoid contents were determined, followed by its phytochemical elucidation using the Ultra Performance Liquid Chromatography technique (UPLC). The mutagenicity of AFMF at 4, 20, 50, 100, 200, 500, and 1000 µg/well was <2.0 in S. typhimurium and the induced micronucleated polychromatic and normochromatic erythrocytes at 500, 1000, 2000, and 4000 mg/kg were not significantly different from the negative control (p≥0.05). The mutagenic activity of benzo[a]pyrene and cyclophosphamide was significantly suppressed above 50.0% throughout the tested concentrations. Fifty percent of the free radicals from DPPH were scavenged by AFMF at 0.11 mg/ml. Total phenolic and flavonoid contents of AFMF were 51.0 mg GAE/g and 27 mg QE/g, respectively. Rutin was elucidated by the UPLC technique, and thereby suspected to be the phytochemical responsible for the observed antimutagenic activity. Thus far, AFMF seems to contain a promising chemotherapeutic agent for the prevention of genetic damage that is crucial for cancer development. PMID:25520963

  2. Identification of Selective ERRγ Inverse Agonists.

    PubMed

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

    2016-01-12

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

  3. Multiple tyrosine metabolites are GPR35 agonists

    PubMed Central

    Deng, Huayun; Hu, Haibei; Fang, Ye

    2012-01-01

    Both kynurenic acid and 2-acyl lysophosphatidic acid have been postulated to be the endogenous agonists of GPR35. However, controversy remains whether alternative endogenous agonists exist. The molecular targets accounted for many nongenomic actions of thyroid hormones are mostly unknown. Here we report the agonist activity of multiple tyrosine metabolites at the GPR35. Tyrosine metabolism intermediates that contain carboxylic acid and/or catechol functional groups were first selected. Whole cell dynamic mass redistribution (DMR) assays enabled by label-free optical biosensor were then used to characterize their agonist activity in native HT-29. Molecular assays including β-arrestin translocation, ERK phosphorylation and receptor internalization confirmed that GPR35 functions as a receptor for 5,6-dihydroxyindole-2-carboxylic acid, 3,3′,5′-triiodothyronine, 3,3′,5-triiodothyronine, gentisate, rosmarinate, and 3-nitrotyrosine. These results suggest that multiple tyrosine metabolites are alternative endogenous ligands of GPR35, and GPR35 may represent a druggable target for treating certain diseases associated with abnormality of tyrosine metabolism. PMID:22523636

  4. Hold your horSSEs: controlling structure-selective endonucleases MUS81 and Yen1/GEN1

    PubMed Central

    Blanco, Miguel G.; Matos, Joao

    2015-01-01

    Repair of DNA lesions through homologous recombination promotes the establishment of stable chromosomal interactions. Multiple helicases, topoisomerases and structure-selective endonucleases (SSEs) act upon recombining joint molecules (JMs) to disengage chromosomal connections and safeguard chromosome segregation. Recent studies on two conserved SSEs – MUS81 and Yen1/GEN1– uncovered multiple layers of regulation that operate to carefully tailor JM-processing according to specific cellular needs. Temporal restriction of SSE function imposes a hierarchy in pathway usage that ensures efficient JM-processing while minimizing reciprocal exchanges between the recombining DNAs. Whereas a conserved strategy of fine-tuning SSE functions exists in different model systems, the precise molecular mechanisms to implement it appear to be significantly different. Here, we summarize the current knowledge on the cellular switches that are in place to control MUS81 and Yen1/GEN1 functions. PMID:26284109

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

    SciTech Connect

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

    2010-09-27

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

  6. 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.

  7. Phylogeography of Chinese house mice (Mus musculus musculus/castaneus): distribution, routes of colonization and geographic regions of hybridization.

    PubMed

    Jing, Meidong; Yu, Hon-Tsen; Bi, Xiaoxin; Lai, Yung-Chih; Jiang, Wei; Huang, Ling

    2014-09-01

    House mice (Mus musculus) are human commensals and have served as a primary model in biomedical, ecological and evolutionary research. Although there is detailed knowledge of the biogeography of house mice in Europe, little is known of the history of house mice in China, despite the fact that China encompasses an enormous portion of their range. In the present study, 535 house mice caught from 29 localities in China were studied by sequencing the mitochondrial D-loop and genotyping 10 nuclear microsatellite markers distributed on 10 chromosomes. Phylogenetic analyses revealed two evolutionary lineages corresponding to Mus musculus castaneus and Mus musculus musculus in the south and north, respectively, with the Yangtze River approximately representing the boundary. More detailed analyses combining published sequence data from mice sampled in neighbouring countries revealed the migration routes of the two subspecies into China: M. m. castaneus appeared to have migrated through a southern route (Yunnan and Guangxi), whereas M. m. musculus entered China from Kazakhstan through the north-west border (Xinjiang). Bayesian analysis of mitochondrial sequences indicated rapid population expansions in both subspecies, approximately 4650-9300 and 7150-14 300 years ago for M. m. castaneus and M. m. musculus, respectively. Interestingly, the migration routes of Chinese house mice coincide with the colonization routes of modern humans into China, and the expansion times of house mice are consistent with the development of agriculture in southern and northern China, respectively. Finally, our study confirmed the existence of a hybrid zone between M. m. castaneus and M. m. musculus in China. Further study of this hybrid zone will provide a useful counterpart to the well-studied hybrid zone between M. m. musculus and Mus musculus domesticus in central Europe.

  8. Evolutionary and dispersal history of Eurasian house mice Mus musculus clarified by more extensive geographic sampling of mitochondrial DNA

    PubMed Central

    Suzuki, H; Nunome, M; Kinoshita, G; Aplin, K P; Vogel, P; Kryukov, A P; Jin, M-L; Han, S-H; Maryanto, I; Tsuchiya, K; Ikeda, H; Shiroishi, T; Yonekawa, H; Moriwaki, K

    2013-01-01

    We examined the sequence variation of mitochondrial DNA control region and cytochrome b gene of the house mouse (Mus musculus sensu lato) drawn from ca. 200 localities, with 286 new samples drawn primarily from previously unsampled portions of their Eurasian distribution and with the objective of further clarifying evolutionary episodes of this species before and after the onset of human-mediated long-distance dispersals. Phylogenetic analysis of the expanded data detected five equally distinct clades, with geographic ranges of northern Eurasia (musculus, MUS), India and Southeast Asia (castaneus, CAS), Nepal (unspecified, NEP), western Europe (domesticus, DOM) and Yemen (gentilulus). Our results confirm previous suggestions of Southwestern Asia as the likely place of origin of M. musculus and the region of Iran, Afghanistan, Pakistan, and northern India, specifically as the ancestral homeland of CAS. The divergence of the subspecies lineages and of internal sublineage differentiation within CAS were estimated to be 0.37–0.47 and 0.14–0.23 million years ago (mya), respectively, assuming a split of M. musculus and Mus spretus at 1.7 mya. Of the four CAS sublineages detected, only one extends to eastern parts of India, Southeast Asia, Indonesia, Philippines, South China, Northeast China, Primorye, Sakhalin and Japan, implying a dramatic range expansion of CAS out of its homeland during an evolutionary short time, perhaps associated with the spread of agricultural practices. Multiple and non-coincident eastward dispersal events of MUS sublineages to distant geographic areas, such as northern China, Russia and Korea, are inferred, with the possibility of several different routes. PMID:23820581

  9. Structural and functional analyses of an archaeal XPF/Rad1/Mus81 nuclease: asymmetric DNA binding and cleavage mechanisms.

    PubMed

    Nishino, Tatsuya; Komori, Kayoko; Ishino, Yoshizumi; Morikawa, Kosuke

    2005-08-01

    XPF/Rad1/Mus81/Hef proteins recognize and cleave branched DNA structures. XPF and Rad1 proteins cleave the 5' side of nucleotide excision repair bubble, while Mus81 and Hef cleave similar sites of the nicked Holliday junction, fork, or flap structure. These proteins all function as dimers and consist of catalytic and helix-hairpin-helix DNA binding (HhH) domains. We have determined the crystal structure of the HhH domain of Pyrococcus furiosus Hef nuclease (HefHhH), which revealed the distinct mode of protein dimerization. Our structural and biochemical analyses also showed that each of the catalytic and HhH domains binds to distinct regions within the fork-structured DNA: each HhH domain from two separate subunits asymmetrically binds to the arm region, while the catalytic domain binds near the junction center. Upon binding to DNA, Hef nuclease disrupts base pairs near the cleavage site. It is most likely that this bipartite binding mode is conserved in the XPF/Rad1/Mus81 nuclease family. PMID:16084390

  10. MicroRNA Expression Profiling in CCl4-Induced Liver Fibrosis of Mus musculus

    PubMed Central

    Hyun, Jeongeun; Park, Jungwook; Wang, Sihyung; Kim, Jieun; Lee, Hyun-Hee; Seo, Young-Su; Jung, Youngmi

    2016-01-01

    Liver fibrosis is a major pathological feature of chronic liver diseases, including liver cancer. MicroRNAs (miRNAs), small noncoding RNAs, regulate gene expression posttranscriptionally and play important roles in various kinds of diseases; however, miRNA-associated hepatic fibrogenesis and its acting mechanisms are poorly investigated. Therefore, we performed an miRNA microarray in the fibrotic livers of Mus musculus treated with carbon-tetrachloride (CCl4) and analyzed the biological functions engaged by the target genes of differentially-expressed miRNAs through gene ontology (GO) and in-depth pathway enrichment analysis. Herein, we found that four miRNAs were upregulated and four miRNAs were downregulated more than two-fold in CCl4-treated livers compared to a control liver. Eight miRNAs were predicted to target a total of 4079 genes. GO analysis revealed that those target genes were located in various cellular compartments, including cytoplasm, nucleolus and cell surface, and they were involved in protein-protein or protein-DNA bindings, which influence the signal transductions and gene transcription. Furthermore, pathway enrichment analysis demonstrated that the 72 subspecialized signaling pathways were associated with CCl4-induced liver fibrosis and were mostly classified into metabolic function-related pathways. These results suggest that CCl4 induces liver fibrosis by disrupting the metabolic pathways. In conclusion, we presented several miRNAs and their biological processes that might be important in the progression of liver fibrosis; these findings help increase the understanding of liver fibrogenesis and provide novel ideas for further studies of the role of miRNAs in liver fibrosis. PMID:27322257

  11. Stimulus probability effects on temporal bisection performance of mice (Mus musculus).

    PubMed

    Akdoğan, Başak; Balcı, Fuat

    2016-01-01

    In the temporal bisection task, participants classify experienced stimulus durations as short or long based on their temporal similarity to previously learned reference durations. Temporal decision making in this task should be influenced by the experienced probabilities of the reference durations for adaptiveness. In this study, we tested the temporal bisection performance of mice (Mus musculus) under different short and long reference duration probability conditions implemented across two experimental phases. In Phase 1, the proportion of reference durations (compared to probe durations) was 0.5, whereas in Phase 2 it was increased to 0.8 to further examine the adjustment of choice behavior with more frequent reference duration presentations (under higher reinforcement rate). Our findings suggest that mice developed adaptive biases in their choice behaviors. These adjustments in choice behavior were nearly optimal as the mice maximized their gain to a great extent which required them to monitor stimulus probabilities as well as the level of variability in their temporal judgments. We further found that short but not long categorization response times were sensitive to stimulus probability manipulations, which in turn suggests an asymmetry between short and long categorizations. Finally, we investigated the latent decision processes underlying the bias manifested in subjects' choice behavior within the diffusion model framework. Our results revealed that probabilistic information influenced the starting point and the rate of evidence accumulation process. Overall, the stimulus probability effects on choice behavior were modulated by the reinforcement rate. Our findings illustrate that mice can adapt their temporal behaviors with respect to the probabilistic contingencies in the environment.

  12. Thermoregulatory responses of two mouse Mus musculus strains selectively bred for high and low food intake.

    PubMed

    Selman, C; Korhonen, T K; Bünger, L; Hill, W G; Speakman, J R

    2001-11-01

    We examined the thermoregulatory responses of male and female mice Mus musculus that had been divergently selected on voluntary food intake, corrected for body mass, to produce a high-intake and a low-intake strain. Resting metabolic rate was determined by indirect calorimetry (at 30 degrees C, 25 degrees C, 15 degrees C and 5 degrees C). Body temperature responses were measured in a separate group of mice in a parallel protocol. High-intake mice had significantly elevated body masses compared to low-intake mice in both sexes. Lower critical temperature in both strains appeared to be around 28 degrees C. At 30 degrees C there was a significant strain effect on resting metabolic rate, with high strain mice having greater metabolism than low strain mice. Sex and body mass were not significant main effects on resting metabolic rate and there were no significant interactions. Body temperature measured at 30 degrees C, 25 degrees C, 15 degrees C and 5 degrees C differed significantly between sexes (females higher) and there was a significant sexxbody mass interaction effect, but there was no difference between strains. Thermal conductance was significantly related to strain and sex, mice from the high strain and males having greater thermal conductances than mice from the low strain and females. Artificial selection has resulted in high-intake mice having greater body masses and greater thermal conductances, which together account for up to 45% of the elevated daily energy demands that underpin the increase in food intake. The greater levels of food intake were also associated with higher resting metabolic rates at 30 degrees C.

  13. Neuroprotective Actions of Clinoptilolite and Ethylenediaminetetraacetic Acid Against Lead-induced Toxicity in Mice Mus musculus

    PubMed Central

    Basha, Mahaboob P.; Begum, Shabana; Mir, Bilal Ahmed

    2013-01-01

    Objectives: Oxidative stress is considered as a possible molecular mechanism involved in lead (Pb2+) neurotoxicity. Very few studies have been investigated on the occurrence of oxidative stress in developing animals due to Pb2+ exposure. Considering the vulnerability of the developing brain to Pb2+, this study was carried out to investigate the effects of Pb2+ exposure in brain regions especially on antioxidant enzyme activities along with ameliorative effects of ethylenediaminetetraacetic acid (EDTA) and clinoptilolite. Methods: Three-week old developing Swiss mice Mus musculus were intraperitoneally administered with Pb2+ acetate in water (w/v) (100 mg/kg body weight/day) for 21 days and control group was given distilled water. Further Pb2+-toxicated mice were made into two subgroups and separately supplemented with EDTA and clinoptilolite (100 mg/kg body weight) for 2 weeks. Results: In Pb2+-exposed mice, in addition to increased lipid peroxidation, the activity levels of catalase, superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione (GSH) found to decrease in all regions of brain indicating, existence of severe oxidative stress due to decreased antioxidant function. Treatment of Pb2+-exposed mice with EDTA and clinoptilolite lowered the lipid peroxidation (LPO) levels revealing their antioxidant potential to prevent oxidative stress. Similarly their administration led to recover the level of catalase, SOD, and GPx enzymes affected during Pb2+ toxicity in different regions of brain. Conclusions: The protection of brain tissue against Pb2+-induced toxicity by clinoptilolite and EDTA in the present experiment might be due to their ability to react faster with peroxyl radicals there by reducing the severity of biochemical variable indicative of oxidative damage. Thus, the results of present study indicate the neuroprotective potential of clinoptilolite and EDTA against Pb2+ toxicity. PMID:24403728

  14. Morphometric characteristics of the small and large intestines of Mus musculus during postnatal development.

    PubMed

    Wołczuk, K; Wilczyńska, B; Jaroszewska, M; Kobak, J

    2011-11-01

    The objective of this study was to investigate the size of the small and large intestine in postnatal development of Mus musculus mice. The gut was obtained from 2-, 4-, 6-, and 12-week-old animals. The morphometric analysis was performed at microscopic level. Measurements and calculations included dimensions of villi (height, diameter) and their number per 1 mm(2) surface area in the proximal, middle, and distal section of the small intestine, as well as the length and surface area (external and internal) of the small and large intestines. To find the allometric relationship between the size of the small and large intestines and body mass, reduced major axis regression was applied. The length and surface area of both intestinal segments gradually increased with age. The increase in the internal surface area of the small intestine was the result of lengthening of the intestine and increasing diameter of the villi in its proximal and middle sections. No increase in villus height during the studied period was detected. A marked increase in the size of the intestinal segments was observed between the 2(nd) and 4(th) weeks of life, when the length doubled and the surface area tripled in size. Allometric analysis revealed that the increase in length and internal surface area of the small and large intestines was more rapid than the body mass increase during the weaning period, while it was not different from isometry after the weaning. In conclusion, the greatest changes in the structure and size of the small and large intestines of mice occurred in the weaning period. During this period these two segments of intestine grew faster than the rest of the body and reached adult proportions.

  15. Identification of ejaculated proteins in the house mouse (Mus domesticus) via isotopic labeling

    PubMed Central

    2011-01-01

    Background Seminal fluid plays an important role in successful fertilization, but knowledge of the full suite of proteins transferred from males to females during copulation is incomplete. The list of ejaculated proteins remains particularly scant in one of the best-studied mammalian systems, the house mouse (Mus domesticus), where artificial ejaculation techniques have proven inadequate. Here we investigate an alternative method for identifying ejaculated proteins, by isotopically labeling females with 15N and then mating them to unlabeled, vasectomized males. Proteins were then isolated from mated females and identified using mass spectrometry. In addition to gaining insights into possible functions and fates of ejaculated proteins, our study serves as proof of concept that isotopic labeling is a powerful means to study reproductive proteins. Results We identified 69 male-derived proteins from the female reproductive tract following copulation. More than a third of all spectra detected mapped to just seven genes known to be structurally important in the formation of the copulatory plug, a hard coagulum that forms shortly after mating. Seminal fluid is significantly enriched for proteins that function in protection from oxidative stress and endopeptidase inhibition. Females, on the other hand, produce endopeptidases in response to mating. The 69 ejaculated proteins evolve significantly more rapidly than other proteins that we previously identified directly from dissection of the male reproductive tract. Conclusion Our study attempts to comprehensively identify the proteins transferred from males to females during mating, expanding the application of isotopic labeling to mammalian reproductive genomics. This technique opens the way to the targeted monitoring of the fate of ejaculated proteins as they incubate in the female reproductive tract. PMID:21663664

  16. Temporal behaviour profiles of Mus musculus in nature are affected by population activity.

    PubMed

    Robbers, Yuri; Koster, Eva A S; Krijbolder, Doortje I; Ruijs, Amanda; van Berloo, Sander; Meijer, Johanna H

    2015-02-01

    Animals have circadian clocks that govern their activity pattern, resulting in 24h rhythms in physiology and behaviour. Under laboratory conditions, light is the major external signal that affects temporal patterns in behaviour, and Mus musculus is strictly nocturnal in its behaviour. In the present study we questioned whether under natural conditions, environmental factors other than light affect the temporal profile of mice. In order to test this, we investigated the activity patterns of free-ranging M. musculus in a natural habitat, using sensors and a camera integrated into a recording unit that the mice could freely enter and leave. Our data show that mice have seasonal fluctuations in activity duration (6.7±0.82 h in summer, 11.3±1.80 h in winter). Furthermore, although primarily nocturnal, wild mice also exhibit daytime activity from spring until late autumn. A multivariate analysis revealed that the major factor correlating with increased daytime activity was population activity, defined as the number of visits to the recording site. Day length had a small but significant effect. Further analysis revealed that the relative population activity (compared to the past couple of days) is a better predictor of daytime activity than absolute population activity. Light intensity and temperature did not have a significant effect on daytime activity. The amount of variance explained by external factors is 51.9%, leaving surprisingly little unexplained variance that might be attributed to the internal clock. Our data further indicate that mice determine population activity by comparing a given night with the preceding 2-7 nights, a time frame suggesting a role for olfactory cues. We conclude that relative population activity is a major factor controlling the temporal activity patterns of M. musculus in an unrestricted natural population.

  17. Biochemical and structural characterization of MUPP1-PDZ4 domain from Mus musculus.

    PubMed

    Zhu, Haili; Liu, Zexu; Huang, Yuxin; Zhang, Chao; Li, Gang; Liu, Wei

    2015-03-01

    Specific protein-protein interactions are important for biological signal transduction. The postsynaptic density-95, disc-large, and zonulin-1 (PDZ) domain is one of the most abundant protein interaction modules. Multi-PDZ-domain protein 1 (MUPP1), as a scaffold protein, contains 13 PDZ domains and plays an important role in cytoskeletal organization, cell polarity, and cell proliferation. The study on PDZ domain of MUPP1 helps to understand the mechanisms and functions of MUPP1. In the present study, the fourth PDZ domain of MUPP1 (MUPP1-PDZ4) from Mus musculus was cloned, expressed, purified, and characterized. The MUPP1-PDZ4 domain was subcloned into a pET-vector and expressed in Escherichia coli. Affinity chromatography and size-exclusion chromatography were used to purify the protein. MUPP1-PDZ4 protein was a monomer with a molar mass of 16.4 kDa in solution and had a melting point of 60.3°C. Using the sitting-drop vapor-diffusion method, MUPP1-PDZ4 protein crystals were obtained in a solution (pH 7.0) containing 2% (v/v) polyethylene glycol 400, 0.1 M imidazole, and 24% (w/v) polyethylene glycol monoethyl ether 5000. Finally, the crystal was diffracted with 1.6 Å resolution. The crystal structure showed that MUPP1-PDZ4 domain contained three α-helices and six β-strands in the core. The GLGI motif, L562/A564 on the β-strand B, and H605/V608/L612 on the α-helix B formed a PDZ binding pocket which could bind to the C-terminal of the binding partners. This biochemical and structural information will provide insights into how PDZ binds to its target peptide and the theoretical foundation for the function of MUPP1. PMID:25662616

  18. The involvement of proline-rich protein Mus musculus predicted gene 4736 in ocular surface functions

    PubMed Central

    Qi, Xia; Ren, Sheng-Wei; Zhang, Feng; Wang, Yi-Qiang

    2016-01-01

    AIM To research the two homologous predicted proline-rich protein genes, Mus musculus predicted gene 4736 (MP4) and proline-rich protein BstNI subfamily 1 (Prb1) which were significantly upregulated in cultured corneal organs when encountering fungal pathogen preparations. This study was to confirm the expression and potential functions of these two genes in ocular surface. METHODS A Pseudomonas aeruginosa keratitis model was established in Balb/c mice. One day post infection, mRNA level of MP4 was measured using real-time polymerase chain reaction (PCR), and MP4 protein detected by immunohistochemistry (IHC) or Western blot using a customized polyclonal anti-MP4 antibody preparation. Lacrimal glands from normal mice were also subjected to IHC staining for MP4. An online bioinformatics program, BioGPS, was utilized to screen public data to determine other potential locations of MP4. RESULTS One day after keratitis induction, MP4 was upregulated in the corneas at both mRNA level as measured using real-time PCR and protein levels as measured using Western blot and IHC. BioGPS analysis of public data suggested that the MP4 gene was most abundantly expressed in the lacrimal glands, and IHC revealed that normal murine lacrimal glands were positive for MP4 staining. CONCLUSION MP4 and Prb1 are closely related with the physiology and pathological processes of the ocular surface. Considering the significance of ocular surface abnormalities like dry eye, we propose that MP4 and Prb1 contribute to homeostasis of ocular surface, and deserve more extensive functional and disease correlation studies. PMID:27588265

  19. Stimulus probability effects on temporal bisection performance of mice (Mus musculus).

    PubMed

    Akdoğan, Başak; Balcı, Fuat

    2016-01-01

    In the temporal bisection task, participants classify experienced stimulus durations as short or long based on their temporal similarity to previously learned reference durations. Temporal decision making in this task should be influenced by the experienced probabilities of the reference durations for adaptiveness. In this study, we tested the temporal bisection performance of mice (Mus musculus) under different short and long reference duration probability conditions implemented across two experimental phases. In Phase 1, the proportion of reference durations (compared to probe durations) was 0.5, whereas in Phase 2 it was increased to 0.8 to further examine the adjustment of choice behavior with more frequent reference duration presentations (under higher reinforcement rate). Our findings suggest that mice developed adaptive biases in their choice behaviors. These adjustments in choice behavior were nearly optimal as the mice maximized their gain to a great extent which required them to monitor stimulus probabilities as well as the level of variability in their temporal judgments. We further found that short but not long categorization response times were sensitive to stimulus probability manipulations, which in turn suggests an asymmetry between short and long categorizations. Finally, we investigated the latent decision processes underlying the bias manifested in subjects' choice behavior within the diffusion model framework. Our results revealed that probabilistic information influenced the starting point and the rate of evidence accumulation process. Overall, the stimulus probability effects on choice behavior were modulated by the reinforcement rate. Our findings illustrate that mice can adapt their temporal behaviors with respect to the probabilistic contingencies in the environment. PMID:26242608

  20. Food preferences and mound-building behaviour of the mound-building mice Mus spicilegus

    NASA Astrophysics Data System (ADS)

    Hölzl, Michaela; Krištofík, Ján; Darolová, Alžbeta; Hoi, Herbert

    2011-10-01

    Optimal foraging strategies and food choice are influenced by various factors, e.g. availability, size and caloric content of the food type and predation risk. However, food choice criteria may change when food is not eaten immediately but has to be carried to a storage site for later use. For example, handling time in terms of harvesting and transport time should be optimized, particularly when the risk of predation is high. Thus, it is not clear whether food selected by hoarding animals reflects their food preference due to intrinsic features of the food type, e.g. size, caloric or lipid content, or whether the food type selected is a compromise that also considers the handling time required for harvesting and transport. We investigate this question in relation to food hoarding behaviour in mound-building mice. In autumn, mound-building mice Mus spicilegus collect seeds and other plant material and cover it with soil. Such above-ground storage is quite unusual for rodents. Here, we investigated whether there is a relationship between the seed species preferred as building materials and those preferred for food. We conducted a seed preference test using three most collected weed species for mound building. Controlling factors like food availability or predation risk, mice prefer Setaria spp. as food, although Amaranthus spp. and Chenopodium spp. were preferentially harvested and stored. By including the availability of the three species, our experimental results were confirmed, namely, a clear preference for Setaria spp. Also, handling time and seed size revealed to influence plant choice.

  1. X-ray structure of a soluble Rieske-type ferredoxin from Mus musculus

    SciTech Connect

    Levin, Elena J.; Elsen, Nathaniel L.; Seder, Kory D.; McCoy, Jason G.; Fox, Brian G; Phillips, Jr., George N.

    2009-03-11

    The 2.07 {angstrom} resolution X-ray crystal structure of a soluble Rieske-type ferredoxin from Mus musculus encoded by the gene Mm.266515 is reported. Although they are present as covalent domains in eukaryotic membrane oxidase complexes, soluble Rieske-type ferredoxins have not previously been observed in eukaryotes. The overall structure of the mouse Rieske-type ferredoxin is typical of this class of iron-sulfur proteins and consists of a larger partial {beta}-barrel domain and a smaller domain containing Cys57, His59, Cys80 and His83 that binds the [2Fe-2S] cluster. The S atoms of the cluster are hydrogen-bonded by six backbone amide N atoms in a pattern typical of membrane-bound high-potential eukaryotic respiratory Rieske ferredoxins. However, phylogenetic analysis suggested that the mouse Rieske-type ferredoxin was more closely related to bacterial Rieske-type ferredoxins. Correspondingly, the structure revealed an extended loop most similar to that seen in Rieske-type ferredoxin subunits of bacterial aromatic dioxygenases, including the positioning of an aromatic side chain (Tyr85) between this loop and the [2Fe-2S] cluster. The mouse Rieske-type ferredoxin was shown to be capable of accepting electrons from both eukaryotic and prokaryotic oxidoreductases, although it was unable to serve as an electron donor for a bacterial monooxygenase complex. The human homolog of mouse Rieske-type ferredoxin was also cloned and purified. It behaved identically to mouse Rieske-type ferredoxin in all biochemical characterizations but did not crystallize. Based on its high sequence identity, the structure of the human homolog is likely to be modeled well by the mouse Rieske-type ferredoxin structure.

  2. Recent advances in the discovery of alpha1-adrenoceptor agonists.

    PubMed

    Bishop, Michael J

    2007-01-01

    The alpha(1) adrenoceptors are three of nine well-characterized receptors that are activated by epinephrine and norepinephrine. Agonists acting at the alpha(1) adrenoceptors produce numerous physiological effects, and are used therapeutically for several indications. Many known alpha(1) adrenoceptor agonists are alpha(1A) selective, but the discovery of highly selective alpha(1B) and alpha(1D) adrenoceptor agonists has proven to be an extremely difficult goal to achieve. This review will focus on recent advances in the discovery, development and clinical utility of subtype-specific alpha(1) agonists as well as contributions to our understanding of agonist-receptor interactions.

  3. Increased agonist affinity at the mu-opioid receptor induced by prolonged agonist exposure

    PubMed Central

    Birdsong, William T.; Arttamangkul, Seksiri; Clark, Mary J.; Cheng, Kejun; Rice, Kenner C.; Traynor, John R.; Williams, John T.

    2013-01-01

    Prolonged exposure to high-efficacy agonists results in desensitization of the mu opioid receptor (MOR). Desensitized receptors are thought to be unable to couple to G-proteins, preventing downstream signaling, however the changes to the receptor itself are not well characterized. In the current study, confocal imaging was used to determine whether desensitizing conditions cause a change in agonist-receptor interactions. Using rapid solution exchange, the binding kinetics of fluorescently labeled opioid agonist, dermorphin Alexa594 (derm A594), to MORs was measured in live cells. The affinity of derm A594 binding increased following prolonged treatment of cells with multiple agonists that are known to cause receptor desensitization. In contrast, binding of a fluorescent antagonist, naltrexamine Alexa 594, was unaffected by similar agonist pre-treatment. The increased affinity of derm A594 for the receptor was long-lived and partially reversed after a 45 min wash. Treatment of the cells with pertussis toxin did not alter the increase in affinity of the derm A594 for MOR. Likewise the affinity of derm A594 for MORs expressed in mouse embryonic fibroblasts derived from arrestin 1 and 2 knockout animals increased following treatment of the cells with the desensitization protocol. Thus, opioid receptors were “imprinted” with a memory of prior agonist exposure that was independent of G-protein activation or arrestin binding that altered subsequent agonist-receptor interactions. The increased affinity suggests that acute desensitization results in a long lasting but reversible conformational change in the receptor. PMID:23447620

  4. Agonistic and reproductive interactions in Betta splendens.

    PubMed

    Bronstein, P M

    1984-12-01

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

  5. Signal Use by Octopuses in Agonistic Interactions.

    PubMed

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

    2016-02-01

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

  6. Signal Use by Octopuses in Agonistic Interactions.

    PubMed

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

    2016-02-01

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

  7. X-ray structure of a soluble Rieske-type ferredoxin from Mus musculus

    SciTech Connect

    Levin, Elena J.; Elsen, Nathaniel L.; Seder, Kory D.; McCoy, Jason G.; Fox, Brian G.; Phillips Jr, George N.

    2008-09-01

    The X-ray crystal structure of a soluble Rieske ferredoxin from M. musculus was solved at 2.07 Å resolution, revealing an iron–sulfur cluster-binding domain with similar architecture to the Rieske-type domains of bacterial aromatic dioxygenases. The ferredoxin was also shown to be capable of accepting electrons from both eukaryotic and prokaryotic oxidoreductases. The 2.07 Å resolution X-ray crystal structure of a soluble Rieske-type ferredoxin from Mus musculus encoded by the gene Mm.266515 is reported. Although they are present as covalent domains in eukaryotic membrane oxidase complexes, soluble Rieske-type ferredoxins have not previously been observed in eukaryotes. The overall structure of the mouse Rieske-type ferredoxin is typical of this class of iron–sulfur proteins and consists of a larger partial β-barrel domain and a smaller domain containing Cys57, His59, Cys80 and His83 that binds the [2Fe–2S] cluster. The S atoms of the cluster are hydrogen-bonded by six backbone amide N atoms in a pattern typical of membrane-bound high-potential eukaryotic respiratory Rieske ferredoxins. However, phylogenetic analysis suggested that the mouse Rieske-type ferredoxin was more closely related to bacterial Rieske-type ferredoxins. Correspondingly, the structure revealed an extended loop most similar to that seen in Rieske-type ferredoxin subunits of bacterial aromatic dioxygenases, including the positioning of an aromatic side chain (Tyr85) between this loop and the [2Fe–2S] cluster. The mouse Rieske-type ferredoxin was shown to be capable of accepting electrons from both eukaryotic and prokaryotic oxidoreductases, although it was unable to serve as an electron donor for a bacterial monooxygenase complex. The human homolog of mouse Rieske-type ferredoxin was also cloned and purified. It behaved identically to mouse Rieske-type ferredoxin in all biochemical characterizations but did not crystallize. Based on its high sequence identity, the structure of the

  8. Acute behavioral responses to light and darkness in nocturnal Mus musculus and diurnal Arvicanthis niloticus.

    PubMed

    Shuboni, D D; Cramm, S; Yan, L; Nunez, A A; Smale, Laura

    2012-08-01

    The term masking refers to immediate responses to stimuli that override the influence of the circadian timekeeping system on behavior and physiology. Masking by light and darkness plays an important role in shaping an organism's daily pattern of activity. Nocturnal animals generally become more active in response to darkness (positive masking) and less active in response to light (negative masking), and diurnal animals generally have opposite patterns of response. These responses can vary as a function of light intensity as well as time of day. Few studies have directly compared masking in diurnal and nocturnal species, and none have compared rhythms in masking behavior of diurnal and nocturnal species. Here, we assessed masking in nocturnal mice (Mus musculus) and diurnal grass rats (Arvicanthis niloticus). In the first experiment, animals were housed in a 12:12 light-dark (LD) cycle, with dark or light pulses presented at 6 Zeitgeber times (ZTs; with ZT0 = lights on). Light pulses during the dark phase produced negative masking in nocturnal mice but only at ZT14, whereas light pulses resulted in positive masking in diurnal grass rats across the dark phase. In both species, dark pulses had no effect on behavior. In the 2nd experiment, animals were kept in constant darkness or constant light and were presented with light or dark pulses, respectively, at 6 circadian times (CTs). CT0 corresponded to ZT0 of the preceding LD cycle. Rhythms in masking responses to light differed between species; responses were evident at all CTs in grass rats but only at CT14 in mice. Responses to darkness were observed only in mice, in which there was a significant increase in activity at CT 22. In the 3rd experiment, animals were kept on a 3.5:3.5-h LD cycle. Surprisingly, masking was evident only in grass rats. In mice, levels of activity during the light and dark phases of the 7-h cycle did not differ, even though the same animals had responded to discrete photic stimuli in the

  9. Srs2 and Mus81–Mms4 Prevent Accumulation of Toxic Inter-Homolog Recombination Intermediates

    PubMed Central

    Keyamura, Kenji; Arai, Kota

    2016-01-01

    Homologous recombination is an evolutionally conserved mechanism that promotes genome stability through the faithful repair of double-strand breaks and single-strand gaps in DNA, and the recovery of stalled or collapsed replication forks. Saccharomyces cerevisiae ATP-dependent DNA helicase Srs2 (a member of the highly conserved UvrD family of helicases) has multiple roles in regulating homologous recombination. A mutation (srs2K41A) resulting in a helicase-dead mutant of Srs2 was found to be lethal in diploid, but not in haploid, cells. In diploid cells, Srs2K41A caused the accumulation of inter-homolog joint molecule intermediates, increased the levels of spontaneous Rad52 foci, and induced gross chromosomal rearrangements. Srs2K41A lethality and accumulation of joint molecules were suppressed by inactivating Rad51 or deleting the Rad51-interaction domain of Srs2, whereas phosphorylation and sumoylation of Srs2 and its interaction with sumoylated proliferating cell nuclear antigen (PCNA) were not required for lethality. The structure-specific complex of crossover junction endonucleases Mus81 and Mms4 was also required for viability of diploid, but not haploid, SRS2 deletion mutants (srs2Δ), and diploid srs2Δ mus81Δ mutants accumulated joint molecule intermediates. Our data suggest that Srs2 and Mus81–Mms4 have critical roles in preventing the formation of (or in resolving) toxic inter-homolog joint molecules, which could otherwise interfere with chromosome segregation and lead to genetic instability. PMID:27390022

  10. New data on occurrence of Demodex flagellurus (Acari, Demodecidae) - rarely recorded parasite from the house mouse Mus musculus (Rodentia, Muridae).

    PubMed

    Izdebska, Joanna N; Rolbiecki, Leszek

    2015-01-01

    Demodex flagellurus Bukva, 1985 is one of two known demodecid mites of the house mouse Mus musculus Linnaeus, 1758, in which it is observed in genital area. Skin fragments of 30 house mice from various regions of Poland (residential buildings in Gdynia and Gdańsk, rural region in Wielkopolska-Kujawska Lowland) were examined. The mites were noted in 25.0% of the mice, with mean intensity of 48.0 and intensity range of 2-103. D. flagellurus demonstrated the differentiated occurrence in host populations. PMID:25911036

  11. 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

  12. 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.

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

    PubMed Central

    2015-01-01

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

  14. Serum biochemical analysis to indicate pathogenic risk on mouse Mus musculus exposure to source of drinking water.

    PubMed

    Yun, Shi Feng; Tian, Xiao Yun; Cheng, Shu Pei; Zhang, Yan; Li, Ai Min; Zhang, Li Bo; Zhang, Xu Xiang; Chen, Li; Wu, Bing; Guo, Lian Qin; Shi, Yun Zhong

    2011-07-01

    The 18 biochemical parameters of serum were measured to analyze the pathogenic risks of the Yangtze River Source of Drinking Water in Nanjing area (YZR-SDW-NJ) on mouse Mus musculus for protection of human health in this research. The male mice Mus musculus were sampled and fed with YZR-SDW-NJ for 90 days then the eighteen serum biochemical levels were measured with Automatic Biochemical Analysis/RerLi 600. And the parameter data were treated by One-Way ANOVA statistic approach. The results showed that five parameter levels for the sample group mice were different from those for the control group significantly (0.01 < P or 0.05 < P). Four 4 of the 5 altered parameter levels were decreased including glutamate pyruvate transaminase 38% lower, glutamine-oxaloacetic transaminase 24% lower, triglyceride 76% lower and cystatin C 73% lower, only creatinine level was 26% higher than that in the control group. The data suggest that YZR-SDW-NJ had toxicity on the mouse and the organic pollutants in YZR-SDW-NJ might lead to liver, kidney, cardiovascular and metabolic pathogenic risks on the human beings. The results might be cited as evidence to control pollutants in the source water for the protection of NJ people's health.

  15. PRDM9 Drives Evolutionary Erosion of Hotspots in Mus musculus through Haplotype-Specific Initiation of Meiotic Recombination

    PubMed Central

    Baker, Christopher L.; Kajita, Shimpei; Walker, Michael; Saxl, Ruth L.; Raghupathy, Narayanan; Choi, Kwangbom; Petkov, Petko M.; Paigen, Kenneth

    2015-01-01

    Meiotic recombination generates new genetic variation and assures the proper segregation of chromosomes in gametes. PRDM9, a zinc finger protein with histone methyltransferase activity, initiates meiotic recombination by binding DNA at recombination hotspots and directing the position of DNA double-strand breaks (DSB). The DSB repair mechanism suggests that hotspots should eventually self-destruct, yet genome-wide recombination levels remain constant, a conundrum known as the hotspot paradox. To test if PRDM9 drives this evolutionary erosion, we measured activity of the Prdm9 Cst allele in two Mus musculus subspecies, M.m. castaneus, in which Prdm9Cst arose, and M.m. domesticus, into which Prdm9Cst was introduced experimentally. Comparing these two strains, we find that haplotype differences at hotspots lead to qualitative and quantitative changes in PRDM9 binding and activity. Using Mus spretus as an outlier, we found most variants affecting PRDM9Cst binding arose and were fixed in M.m. castaneus, suppressing hotspot activity. Furthermore, M.m. castaneus×M.m. domesticus F1 hybrids exhibit novel hotspots, with large haplotype biases in both PRDM9 binding and chromatin modification. These novel hotspots represent sites of historic evolutionary erosion that become activated in hybrids due to crosstalk between one parent's Prdm9 allele and the opposite parent's chromosome. Together these data support a model where haplotype-specific PRDM9 binding directs biased gene conversion at hotspots, ultimately leading to hotspot erosion. PMID:25568937

  16. Multiple paternity in wild house mice (Mus musculus musculus): effects on offspring genetic diversity and body mass

    PubMed Central

    Thonhauser, Kerstin E; Thoß, Michaela; Musolf, Kerstin; Klaus, Teresa; Penn, Dustin J

    2014-01-01

    Multiple mating is common in many species, but it is unclear whether multiple paternity enhances offspring genetic diversity or fitness. We conducted a survey on wild house mice (Mus musculus musculus), and we found that in 73 pregnant females, 29% of litters had multiple sires, which is remarkably similar to the 23–26% found in feral populations of Mus musculus domesticus in the USA and Australia, respectively. The question is: How has selection maintained multiple mating in these subspecies since the evolutionary divergence, ca. 2800–6000 years ago? We found no evidence that multiple paternity enhanced females’ litter size, contrary to the fertility assurance or genetic benefits hypotheses. Multiple paternity was associated with reduced mean and variance in offspring body mass, which suggests that females allocate fewer resources or that there is increased intrauterine conflict in multiple-versus single-sired litters. We found increased allelic diversity (though not heterozygosity) in multiple-sired litters, as predicted by the genetic diversity hypothesis. Finally, we found that the dams’ heterozygosity was correlated with the mean heterozygosity of their offspring in single-and multiple-sired litters, suggesting that outbred, heterozygous females were more likely to avoid inbreeding than inbred, homozygous females. Future studies are needed to examine how increased genetic diversity of litters and smaller mean (and variance) offspring body mass associated with multiple paternity affect offspring fitness. PMID:24558575

  17. [Relationship between characteristics of sexual behavior and male sperm competitive ability in taxa of superspecies complex Mus musculus sensu lato].

    PubMed

    Ambaryan, A B; Maltzev, A N; Kotenkova, E V

    2015-01-01

    Some physiological parameters that determine quality of male sperm (its concentration, spermatozoa morphology) and testicle size vary in integrity, i.e. the bigger are testicles the higher is sperm quality. Therefore, the estimate of testicles relative mass is often used as a characteristic of sperm competitive ability when comparing phylogenetically close mammal species. In house mice belonging to the superspecies complex Mus musculus s.l., testicles relative mass is greater in exoanthropic species than in synanthropic ones. It is shown in our study that this pattern is apparent also at the intraspecies level since testicles mass index, sperm concentration, and percentage of morphologically normal spermatozoa in subspecies Mus musculus wagneri, which is facultatively synanthropic, are higher compared with synanthropic subspecies M m. musculus. An analysis of sexual behavior of the three forms (namely, exoanthropic species M. spicilegus and two subspecies mentioned above) indicates that in M. spicilegus both sexual behavior efficiency and ejaculation rate during coupling were higher as compared with other two subspecies. Based on the analysis of life pattern, reproduction systems, and group spatial-ethological structure, the hypotheses are formulated that explain the maintenance of selection directed to increase of sperm competitive ability in exoanthropic house mice species.

  18. PRDM9 drives evolutionary erosion of hotspots in Mus musculus through haplotype-specific initiation of meiotic recombination.

    PubMed

    Baker, Christopher L; Kajita, Shimpei; Walker, Michael; Saxl, Ruth L; Raghupathy, Narayanan; Choi, Kwangbom; Petkov, Petko M; Paigen, Kenneth

    2015-01-01

    Meiotic recombination generates new genetic variation and assures the proper segregation of chromosomes in gametes. PRDM9, a zinc finger protein with histone methyltransferase activity, initiates meiotic recombination by binding DNA at recombination hotspots and directing the position of DNA double-strand breaks (DSB). The DSB repair mechanism suggests that hotspots should eventually self-destruct, yet genome-wide recombination levels remain constant, a conundrum known as the hotspot paradox. To test if PRDM9 drives this evolutionary erosion, we measured activity of the Prdm9Cst allele in two Mus musculus subspecies, M.m. castaneus, in which Prdm9Cst arose, and M.m. domesticus, into which Prdm9Cst was introduced experimentally. Comparing these two strains, we find that haplotype differences at hotspots lead to qualitative and quantitative changes in PRDM9 binding and activity. Using Mus spretus as an outlier, we found most variants affecting PRDM9Cst binding arose and were fixed in M.m. castaneus, suppressing hotspot activity. Furthermore, M.m. castaneus×M.m. domesticus F1 hybrids exhibit novel hotspots, with large haplotype biases in both PRDM9 binding and chromatin modification. These novel hotspots represent sites of historic evolutionary erosion that become activated in hybrids due to crosstalk between one parent's Prdm9 allele and the opposite parent's chromosome. Together these data support a model where haplotype-specific PRDM9 binding directs biased gene conversion at hotspots, ultimately leading to hotspot erosion. PMID:25568937

  19. Small Molecule Bax Agonists for Cancer Therapy

    PubMed Central

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

    2014-01-01

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

  20. A pharmacological assessment of agonists and modulators at α4β2γ2 and α4β2δ GABAA receptors: The challenge in comparing apples with oranges.

    PubMed

    Ahring, Philip K; Bang, Line H; Jensen, Marianne L; Strøbæk, Dorte; Hartiadi, Leonny Y; Chebib, Mary; Absalom, Nathan

    2016-09-01

    Extrasynaptically located γ-aminobutyric acid (GABA) receptors type A are often characterized by the presence of a δ subunit in the receptor complex. δ-Containing receptors respond to low ambient concentrations of GABA, or respond to spillover of GABA from the synapse, and give rise to tonic inhibitory currents. In certain brain regions, e.g. thalamocortical neurons, tonic inhibition is estimated to represent the majority of total GABA-mediated inhibition, which has raised substantial interest in extrasynaptic receptors as potential drug targets. Thalamocortical neurons typically express α4β2/3δ receptors, however, these have proven difficult to study in recombinant in vitro expression systems due to the inherently low current levels elicited in response to GABA. In this study, we sought to characterize a range of agonists and positive allosteric modulators at α4β2δ and α4β2γ2 receptors. All tested agonists (GABA, THIP, muscimol, and taurine) displayed between 8 and 22 fold increase in potency at the α4β2δ receptor. In contrast, modulatory potencies of steroids (allopregnanolone, THDOC and alfaxalone), anesthetics (etomidate, pentobarbital) and Delta-Selective agents 1 and 2 (DS1 and DS2) were similar at α4β2δ and α4β2γ2 receptors. When evaluating modulatory efficacies, the neurosteroids and anesthetics displayed highest efficacy at α4β2γ2 receptors whereas DS1 and in particular DS2 had highest efficacy at α4β2δ receptors. Overall, several key messages emerged: (i) none of the tested compounds displayed significant selectivity and a great need for identifying new δ-selective compounds remains; (ii) α4β2δ and α4β2γ2 receptors have such divergent intrinsic activation properties that valid comparisons of modulator efficacies are at best challenging. PMID:27178730

  1. 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…

  2. GLP-1 agonist treatment: implications for diabetic retinopathy screening.

    PubMed

    Varadhan, Lakshminarayanan; Humphreys, Tracy; Hariman, Christian; Walker, Adrian B; Varughese, George I

    2011-12-01

    Rapid improvement in glycaemic control induced by GLP-1 agonist therapy could be yet another illustration of transient or permanent progression of diabetic retinopathy, similar to documented examples such as pregnancy and continuous subcutaneous insulin infusion. Specific guidelines would be needed to monitor this paradoxical phenomenon during treatment with GLP-1 agonists. PMID:21906831

  3. 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...

  4. Interactions between cannabinoid receptor agonists and mu opioid receptor agonists in rhesus monkeys discriminating fentanyl.

    PubMed

    Maguire, David R; France, Charles P

    2016-08-01

    Cannabinoid receptor agonists such as delta-9-tetrahydrocannabinol (Δ(9)-THC) enhance some (antinociceptive) but not other (positive reinforcing) effects of mu opioid receptor agonists, suggesting that cannabinoids might be combined with opioids to treat pain without increasing, and possibly decreasing, abuse. The degree to which cannabinoids enhance antinociceptive effects of opioids varies across drugs insofar as Δ(9)-THC and the synthetic cannabinoid receptor agonist CP55940 increase the potency of some mu opioid receptor agonists (e.g., fentanyl) more than others (e.g., nalbuphine). It is not known whether interactions between cannabinoids and opioids vary similarly for other (abuse-related) effects. This study examined whether Δ(9)-THC and CP55940 differentially impact the discriminative stimulus effects of fentanyl and nalbuphine in monkeys (n=4) discriminating 0.01mg/kg of fentanyl (s.c.) from saline. Fentanyl (0.00178-0.0178mg/kg) and nalbuphine (0.01-0.32mg/kg) dose-dependently increased drug-lever responding. Neither Δ(9)-THC (0.032-1.0mg/kg) nor CP55940 (0.0032-0.032mg/kg) enhanced the discriminative stimulus effects of fentanyl or nalbuphine; however, doses of Δ(9)-THC and CP55940 that shifted the nalbuphine dose-effect curve markedly to the right and/or down were less effective or ineffective in shifting the fentanyl dose-effect curve. The mu opioid receptor antagonist naltrexone (0.032mg/kg) attenuated the discriminative stimulus effects of fentanyl and nalbuphine similarly. These data indicate that the discriminative stimulus effects of nalbuphine are more sensitive to attenuation by cannabinoids than those of fentanyl. That the discriminative stimulus effects of some opioids are more susceptible to modification by drugs from other classes has implications for developing maximally effective therapeutic drug mixtures with reduced abuse liability. PMID:27184925

  5. Changes in the protein metabolism in liver and kidney of Mus booduga gray after oral BHC feeding

    SciTech Connect

    Philip, G.H.; Reddy, P.M.; Ramamurthi, R.

    1988-12-01

    Recent years have seen phenomenal increases in the use of pesticides to control various types of pests to increase food supply. Among them the organochlorine (OC) group of insecticides are widely used in India because of their cheapness and long persistency. The technical grade Benzenehexachloride is a mixture of several stereo isomers and it has low acute toxicity but high chronic toxicity to animals mainly due to the accumulation and slow degradation of ..beta..-isomer in animal tissues. Since the derrangement in tissue protein degradation is reflected by changes in protein composition, later may be considered in assessing the protein metabolic perturberations during toxic stress. So, the present work is aimed to study the effect of BHC on the protein metabolism in the mice, Mus booduga.

  6. Two deeply divergent mitochondrial clades in the wild mouse Mus macedonicus reveal multiple glacial refuges south of Caucasus.

    PubMed

    Orth, A; Auffray, J-C; Bonhomme, F

    2002-11-01

    A survey of 77 individuals covering the range of Mus macedonicus from Georgia in the East to Greece and Bulgaria in the West and Israel in the South has shown the existence of two deeply divergent mitochondrial clades. The southern clade was until now undetected and characterises mice from Israel. Nuclear genes also show some amount of regional differentiation tending to separate the southern M. macedonicus from the northern ones. These results point towards the fact that the eastern Mediterranean short-tailed mouse, which was seen as a fairly homogeneous monotypic species, has in fact a more complex phylogeographic history than has been suspected, and that it warrants the existence of two subspecies. The reasons for this non-uniformity probably ought to be looked for in the history of faunal movements linked to glacial periods, underlining the possible existence of at least two refugia south of the Caucasus.

  7. Pen and field trials of a new anticoagulant rodenticide flocoumafen against the house mouse (Mus musculus L.).

    PubMed

    Rowe, F P; Bradfield, A; Swinney, T

    1985-12-01

    The efficacy of flocoumafen, a novel anticoagulant rodenticide, was evaluated in feeding tests on confined and free-living populations of house mice (Mus musculus L.). In four pen trials, family groups of laboratory-reared wild mice were conditioned to feeding on plain foods and then offered flocoumafen at 0.005% in pinhead oatmeal bait. All 68 mice, comprising juvenile and adult animals, died within 10 days. Ten field trials were carried out, using the same formulated poison bait, against mice infesting farm buildings. Mean treatment success, estimated from live-capture and mortality data, ranged between 87.1 and 100%. The performance of flocoumafen is compared with that of difenacoum, bromadiolone and brodifacoum used at the same concentration in oatmeal bait. Flocoumafen gave an equally effective but quicker kill of mice. It is concluded that flocoumafen is a promising new rodenticide for the control of M. musculus. PMID:3841547

  8. Retrovirus Packaging Cells Expressing the Mus dunni Endogenous Virus Envelope Facilitate Transduction of CHO and Primary Hematopoietic Cells

    PubMed Central

    Wolgamot, Greg; Rasko, John E. J.; Miller, A. Dusty

    1998-01-01

    Mus dunni endogenous virus (MDEV) infects a wide variety of cell types from many different species. To take advantage of this broad host range, we have constructed packaging cells (PD223) that produce virions bearing the MDEV envelope. PD223 cells are able to package Moloney murine leukemia virus-based vectors at a titer of 4 × 105 infectious units per ml in the absence of contaminating replication-competent retrovirus. Vectors packaged by PD223 cells are able to transduce CHO cells, which are resistant to transduction by many retroviruses, at ≥25-fold higher efficiency than vectors having other pseudotypes. A vector packaged by PD223 was found to be among the most efficient for transducing primary baboon and human CD34+ cells. PMID:9811768

  9. Pen and field trials of a new anticoagulant rodenticide flocoumafen against the house mouse (Mus musculus L.).

    PubMed Central

    Rowe, F. P.; Bradfield, A.; Swinney, T.

    1985-01-01

    The efficacy of flocoumafen, a novel anticoagulant rodenticide, was evaluated in feeding tests on confined and free-living populations of house mice (Mus musculus L.). In four pen trials, family groups of laboratory-reared wild mice were conditioned to feeding on plain foods and then offered flocoumafen at 0.005% in pinhead oatmeal bait. All 68 mice, comprising juvenile and adult animals, died within 10 days. Ten field trials were carried out, using the same formulated poison bait, against mice infesting farm buildings. Mean treatment success, estimated from live-capture and mortality data, ranged between 87.1 and 100%. The performance of flocoumafen is compared with that of difenacoum, bromadiolone and brodifacoum used at the same concentration in oatmeal bait. Flocoumafen gave an equally effective but quicker kill of mice. It is concluded that flocoumafen is a promising new rodenticide for the control of M. musculus. PMID:3841547

  10. The cardiovascular effects of peroxisome proliferator-activated receptor agonists.

    PubMed

    Friedland, Sayuri N; Leong, Aaron; Filion, Kristian B; Genest, Jacques; Lega, Iliana C; Mottillo, Salvatore; Poirier, Paul; Reoch, Jennifer; Eisenberg, Mark J

    2012-02-01

    Although peroxisome proliferator-activated receptor agonists are prescribed to improve cardiovascular risk factors, their cardiovascular safety is controversial. We therefore reviewed the literature to identify landmark randomized controlled trials evaluating the effect of peroxisome proliferator-activated receptor gamma agonists (pioglitazone and rosiglitazone), alpha agonists (fenofibrate and gemfibrozil), and pan agonists (bezafibrate, muraglitazar, ragaglitazar, tesaglitazar, and aleglitazar) on cardiovascular outcomes. Pioglitazone may modestly reduce cardiovascular events but also may increase the risk of bladder cancer. Rosiglitazone increases the risk of myocardial infarction and has been withdrawn in European and restricted in the United States. Fibrates improve cardiovascular outcomes only in select subgroups: fenofibrate in diabetic patients with metabolic syndrome, gemfibrozil in patients with dyslipidemia, and bezafibrate in patients with diabetes or metabolic syndrome. The cardiovascular safety of the new pan agonist aleglitazar, currently in phase II trials, remains to be determined. The heterogenous effects of peroxisome proliferator-activated receptor agonists to date highlight the importance of postmarketing surveillance. The critical question of why peroxisome proliferator-activated receptor agonists seem to improve cardiovascular risk factors without significantly improving cardiovascular outcomes requires further investigation. PMID:22269613

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

    PubMed

    Pégorier, J-P

    2005-04-01

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

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

    PubMed

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

    1981-01-01

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

  13. Characterization of Mus musculus Papillomavirus 1 Infection In Situ Reveals an Unusual Pattern of Late Gene Expression and Capsid Protein Localization

    PubMed Central

    Handisurya, Alessandra; Day, Patricia M.; Thompson, Cynthia D.; Buck, Christopher B.; Pang, Yuk-Ying S.; Lowy, Douglas R.

    2013-01-01

    Full-length genomic DNA of the recently identified laboratory mouse papillomavirus 1 (MusPV1) was synthesized in vitro and was used to establish and characterize a mouse model of papillomavirus pathobiology. MusPV1 DNA, whether naked or encapsidated by MusPV1 or human papillomavirus 16 (HPV 16) capsids, efficiently induced the outgrowth of papillomas as early as 3 weeks after application to abraded skin on the muzzles and tails of athymic NCr nude mice. High concentrations of virions were extracted from homogenized papillomatous tissues and were serially passaged for >10 generations. Neutralization by L1 antisera confirmed that infectious transmission was capsid mediated. Unexpectedly, the skin of the murine back was much less susceptible to virion-induced papillomas than the muzzle or tail. Although reporter pseudovirions readily transduced the skin of the back, infection with native MusPV1 resulted in less viral genome amplification and gene expression on the back, including reduced expression of the L1 protein and very low expression of the L2 protein, results that imply skin region-specific control of postentry aspects of the viral life cycle. Unexpectedly, L1 protein on the back was predominantly cytoplasmic, while on the tail the abundant L1 was cytoplasmic in the lower epithelial layers and nuclear in the upper layers. Nuclear localization of L1 occurred only in cells that coexpressed the minor capsid protein, L2. The pattern of L1 protein staining in the infected epithelium suggests that L1 expression occurs earlier in the MusPV1 life cycle than in the life cycle of high-risk HPV and that virion assembly is regulated by a previously undescribed mechanism. PMID:24067981

  14. [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.

  15. [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.

  16. [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. PMID:25437461

  17. [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. PMID:25326839

  18. PPAR dual agonists: are they opening Pandora's Box?

    PubMed

    Balakumar, Pitchai; Rose, Madhankumar; Ganti, Subrahmanya S; Krishan, Pawan; Singh, Manjeet

    2007-08-01

    Cardiovascular disorders are the major cause of mortality in patients of diabetes mellitus. Peroxisome proliferator activated receptors (PPARs) are ligand-activated transcription factors of nuclear hormone receptor superfamily comprising of three subtypes such as PPARalpha, PPARgamma and PPARdelta/beta. Activation of PPARalpha reduces triglycerides and involves in regulation of energy homeostasis. Activation of PPARgamma causes insulin sensitization and enhances glucose metabolism, whereas activation of PPARdelta enhances fatty acid metabolism. Current therapeutic strategies available for the treatment of diabetes do not inhibit the associated secondary cardiovascular complications. Hence, the development of multimodal drugs which can reduce hyperglycemia and concomitantly inhibit the progression of secondary cardiovascular complications may offer valuable therapeutic option. Several basic and clinical studies have exemplified the beneficial effects of PPARalpha and PPARgamma ligands in preventing the cardiovascular risks. The PPARalpha/gamma dual agonists are developed to increase insulin sensitivity and simultaneously prevent diabetic cardiovascular complications. Such compounds are under clinical trials and proposed for treatment of Type II diabetes with secondary cardiovascular complications. However, PPARalpha/gamma dual agonists such as muraglitazar, tesaglitazar and ragaglitazar have been noted to produce several cardiovascular risks and carcinogenicity, which raised number of questions about the clinical applications of dual agonists in diabetes and its associated complications. The ongoing basic studies have elucidated the cardio protective role of PPARdelta. Therefore, further studies are on the track to develop PPARalpha/delta and PPAR gamma/delta dual agonists and PPARalpha/gamma/delta pan agonists for the treatment of diabetic cardiovascular complications. The present review critically analyzes the protective and detrimental effect of PPAR agonists in

  19. Identification of M-CSF agonists and antagonists

    SciTech Connect

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

    2000-02-15

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

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

    PubMed

    Ortega, V E

    2014-07-01

    Beta2 (β2) adrenergic receptor agonists (beta agonists) are a commonly prescribed treatment for asthma despite the small increase in risk for life-threatening adverse responses associated with long-acting beta agonist (LABA). The concern for life-threatening adverse effects associated with LABA and the inter-individual variability of therapeutic responsiveness to LABA-containing combination therapies provide the rationale for pharmacogenetic studies of beta agonists. These studies primarily evaluated genes within the β2-adrenergic receptor and related pathways; however, recent genome-wide studies have identified novel loci for beta agonist response. Recent studies have identified a role for rare genetic variants in determining beta agonist response and, potentially, the risk for rare, adverse responses to LABA. Before genomics research can be applied to the development of genetic profiles for personalized medicine, it will be necessary to continue adapting to the analysis of an increasing volume of genetic data in larger cohorts with a combination of analytical methods and in vitro studies.

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

    PubMed

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

    2010-07-01

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

  2. Perception of specific trigeminal chemosensory agonists

    PubMed Central

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

    2011-01-01

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

  3. 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

  4. Tissue-Specific Contributions of Paternally Expressed Gene 3 in Lactation and Maternal Care of Mus musculus

    PubMed Central

    Frey, Wesley D.; Kim, Joomyeong

    2015-01-01

    Paternally Expressed Gene 3 (Peg3) is an imprinted gene that controls milk letdown and maternal-caring behaviors. In this study, a conditional knockout allele has been developed in Mus musculus to further characterize these known functions of Peg3 in a tissue-specific manner. The mutant line was first crossed with a germline Cre. The progeny of this cross displayed growth retardation phenotypes. This is consistent with those seen in the previous mutant lines of Peg3, confirming the usefulness of the new mutant allele. The mutant line was subsequently crossed individually with MMTV- and Nkx2.1-Cre lines to test Peg3’s roles in the mammary gland and hypothalamus, respectively. According to the results, the milk letdown process was impaired in the nursing females with the Peg3 mutation in the mammary gland, but not in the hypothalamus. This suggests that Peg3’s roles in the milk letdown process are more critical in the mammary gland than in the hypothalamus. In contrast, one of the maternal-caring behaviors, nest-building, was interrupted in the females with the mutation in both MMTV- and Nkx2.1-driven lines. Overall, this is the first study to introduce a conditional knockout allele of Peg3 and to further dissect its contribution to mammalian reproduction in a tissue-specific manner. PMID:26640945

  5. The nuclease FAN1 is involved in DNA crosslink repair in Arabidopsis thaliana independently of the nuclease MUS81

    PubMed Central

    Herrmann, Natalie J.; Knoll, Alexander; Puchta, Holger

    2015-01-01

    Fanconi anemia is a severe genetic disorder. Mutations in one of several genes lead to defects in DNA crosslink (CL) repair in human cells. An essential step in CL repair is the activation of the pathway by the monoubiquitination of the heterodimer FANCD2/FANCI, which recruits the nuclease FAN1 to the CL site. Surprisingly, FAN1 function is not conserved between different eukaryotes. No FAN1 homolog is present in Drosophila and Saccharomyces cerevisiae. The FAN1 homolog in Schizosaccharomyces pombe is involved in CL repair; a homolog is present in Xenopus but is not involved in CL repair. Here we show that a FAN1 homolog is present in plants and it is involved in CL repair in Arabidopsis thaliana. Both the virus-type replication-repair nuclease and the ubiquitin-binding ubiquitin-binding zinc finger domains are essential for this function. FAN1 likely acts upstream of two sub-pathways of CL repair. These pathways are defined by the Bloom syndrome homolog RECQ4A and the ATPase RAD5A, which is involved in error-free post-replicative repair. Mutations in both FAN1 and the endonuclease MUS81 resulted in greater sensitivity against CLs than in the respective single mutants. These results indicate that the two nucleases define two independent pathways of CL repair in plants. PMID:25779053

  6. The Myriapoda and Onychophora collection (MY) of the Muséum national d'Histoire naturelle (MNHN, Paris).

    PubMed

    Bras, Gwenaël Le; Geoffroy, Jean-Jacques; Albenga, Laurent; Mauriès, Jean-Paul

    2015-01-01

    The Myriapoda and Onychophora collection dataset inventories the occurrence records of the collection of myriapods and onychophorans in the Muséum national d'Histoire naturelle, Paris. The dataset currently consists of 202 lots of onychophorans, representing all of those present, and almost ten thousand (9 795) lots of myriapods, representing 33 to 40% of the MNHN Myriapoda collection. This collection, which is of key historic importance, represents the results of two centuries of myriapod and onychophoran studies. The sources of the collection are worldwide, with a high representation for metropolitan France for the myriapods. None of the occurrences are yet georeferenced. Access to the dataset via the data portals of the MNHN and the GBIF has been made possible through the e-ReColNat project (ANR-11-INBS-0004). The Myriapoda and Onychophora collection of MNHN is actively expanding, hence both the collection and dataset are in continuous growth. The dataset can be accessed through the portals of GBIF at http://www.gbif.org/dataset/3287044c-8c48-4ad6-81d4-4908071bc8db and the MNHN at http://science.mnhn.fr/institution/mnhn/collection/my/item/search/form. PMID:26448704

  7. Characterization of the 32 {mu}s isomer in {sup 189}Pb as a shears-mode bandhead

    SciTech Connect

    Dracoulis, G. D.; Lane, G. J.; Kibedi, T.; Nieminen, P.

    2009-03-15

    Internal conversion coefficients have been measured for transitions following the decay of the 32 {mu}s isomer in the neutron-deficient isotope {sup 189}Pb. The main branch at 337 keV to the 25/2{sup +} excited state is shown to be of E3 multipolarity with a strength of about 24 W.u. This, together with multipolarity assignments to other branches, leads to a spin and parity assignment of K{sup {pi}}=31/2{sup -} for the 2435-keV state. This also defines that state as the isomer, rather than the lifetime being due to feeding from a higher lying 33/2{sup +} isomeric state as had been proposed previously. The isomer is suggested to arise from the partially aligned coupling of the 11{sup -} two-proton configuration with the i{sub 13/2} neutron hole. The low-lying nature of the 31/2{sup -} multiplet member is attributed to the change in quasiparticle character of the i{sub 13/2} neutron configuration as the neutron shell is depleted.

  8. On the saliva proteome of the Eastern European house mouse (Mus musculus musculus) focusing on sexual signalling and immunity

    PubMed Central

    Stopka, Pavel; Kuntová, Barbora; Klempt, Petr; Havrdová, Leona; Černá, Martina; Stopková, Romana

    2016-01-01

    Chemical communication is mediated by sex-biased signals abundantly present in the urine, saliva and tears. Because most studies concentrated on the urinary signals, we aimed to determine the saliva proteome in wild Mus musculus musculus, to extend the knowledge on potential roles of saliva in chemical communication. We performed the gel-free quantitative LC-MS/MS analyses of saliva and identified 633 proteins with 134 (21%) of them being sexually dimorphic. They include proteins that protect and transport volatile organic compounds in their beta barrel including LCN lipocalins, major urinary proteins (MUPs), and odorant binding proteins (OBPs). To our surprise, the saliva proteome contains one MUP that is female biased (MUP8) and the two protein pheromones MUP20 (or ‘Darcin’) and ESP1 in individuals of both sex. Thus, contrary to previous assumptions, our findings reveal that these proteins cannot function as male-unique signals. Our study also demonstrates that many olfactory proteins (e.g. LCNs, and OBPs) are not expressed by submandibular glands but are produced elsewhere–in nasal and lacrimal tissues, and potentially also in other oro-facial glands. We have also detected abundant proteins that are involved in wound healing, immune and non-immune responses to pathogens, thus corroborating that saliva has important protective roles. PMID:27577013

  9. Discrimination of Ultrasonic Vocalizations by CBA/CaJ Mice (Mus musculus) Is Related to Spectrotemporal Dissimilarity of Vocalizations

    PubMed Central

    Neilans, Erikson G.; Holfoth, David P.; Radziwon, Kelly E.; Portfors, Christine V.; Dent, Micheal L.

    2014-01-01

    The function of ultrasonic vocalizations (USVs) produced by mice (Mus musculus) is a topic of broad interest to many researchers. These USVs differ widely in spectrotemporal characteristics, suggesting different categories of vocalizations, although this has never been behaviorally demonstrated. Although electrophysiological studies indicate that neurons can discriminate among vocalizations at the level of the auditory midbrain, perceptual acuity for vocalizations has yet to be determined. Here, we trained CBA/CaJ mice using operant conditioning to discriminate between different vocalizations and between a spectrotemporally modified vocalization and its original version. Mice were able to discriminate between vocalization types and between manipulated vocalizations, with performance negatively correlating with spectrotemporal similarity. That is, discrimination performance was higher for dissimilar vocalizations and much lower for similar vocalizations. The behavioral data match previous neurophysiological results in the inferior colliculus (IC), using the same stimuli. These findings suggest that the different vocalizations could carry different meanings for the mice. Furthermore, the finding that behavioral discrimination matched neural discrimination in the IC suggests that the IC plays an important role in the perceptual discrimination of vocalizations. PMID:24416405

  10. Track recognition in 4 [mu]s by a systolic trigger processor using a parallel Hough transform

    SciTech Connect

    Klefenz, F.; Noffz, K.H.; Conen, W.; Zoz, R.; Kugel, A. . Lehrstuhl fuer Informatik V); Maenner, R. . Lehrstuhl fuer Informatik V Univ. Heidelberg . Interdisziplinaeres Zentrum fuer Wissenschaftliches Rechnen)

    1993-08-01

    A parallel Hough transform processor has been developed that identifies circular particle tracks in a 2D projection of the OPAL jet chamber. The high-speed requirements imposed by the 8 bunch crossing mode of LEP could be fulfilled by computing the starting angle and the radius of curvature for each well defined track in less than 4 [mu]s. The system consists of a Hough transform processor that determines well defined tracks, and a Euler processor that counts their number by applying the Euler relation to the thresholded result of the Hough transform. A prototype of a systolic processor has been built that handles one sector of the jet chamber. It consists of 35 [times] 32 processing elements that were loaded into 21 programmable gate arrays (XILINX). This processor runs at a clock rate of 40 MHz. It has been tested offline with about 1,000 original OPAL events. No deviations from the off-line simulation have been found. A trigger efficiency of 93% has been obtained. The prototype together with the associated drift time measurement unit has been installed at the OPAL detector at LEP and 100k events have been sampled to evaluate the system under detector conditions.

  11. On the saliva proteome of the Eastern European house mouse (Mus musculus musculus) focusing on sexual signalling and immunity.

    PubMed

    Stopka, Pavel; Kuntová, Barbora; Klempt, Petr; Havrdová, Leona; Černá, Martina; Stopková, Romana

    2016-01-01

    Chemical communication is mediated by sex-biased signals abundantly present in the urine, saliva and tears. Because most studies concentrated on the urinary signals, we aimed to determine the saliva proteome in wild Mus musculus musculus, to extend the knowledge on potential roles of saliva in chemical communication. We performed the gel-free quantitative LC-MS/MS analyses of saliva and identified 633 proteins with 134 (21%) of them being sexually dimorphic. They include proteins that protect and transport volatile organic compounds in their beta barrel including LCN lipocalins, major urinary proteins (MUPs), and odorant binding proteins (OBPs). To our surprise, the saliva proteome contains one MUP that is female biased (MUP8) and the two protein pheromones MUP20 (or 'Darcin') and ESP1 in individuals of both sex. Thus, contrary to previous assumptions, our findings reveal that these proteins cannot function as male-unique signals. Our study also demonstrates that many olfactory proteins (e.g. LCNs, and OBPs) are not expressed by submandibular glands but are produced elsewhere-in nasal and lacrimal tissues, and potentially also in other oro-facial glands. We have also detected abundant proteins that are involved in wound healing, immune and non-immune responses to pathogens, thus corroborating that saliva has important protective roles. PMID:27577013

  12. Trials of the anticoagulant rodenticide WBA 8119 against confined colonies of warfarin-resistant house mice (Mus musculus L.).

    PubMed Central

    Roew, F. P.; Bradfield, A.

    1976-01-01

    The efficacy of the newly developed anticoagulant rodenticide WBA 8119 was evaluated against the house mouse (Mus musculus L.) using individual and family groups of warfarin-resistant animals. WBA 8119 at 0-002%, 0-005% and 0-01% in pinhead oatmeal bait gave complete kills of mice in 'no-choice' feeding tests carried out in cages and small pens. In replicated 21-day treatments on families of mice confined in larger pens conditioned to feeding on plain foods, the overall mortalities obtained using the three formulated poison baits were 71/72, 62/63 and 57/57 respectively. The results of the WBA 8119 toxicity tests are considered in relation to previous findings on other anticoagulant rodenticides, particularly difenacoum. In equivalents tests, WBA 8119 performed better than difenacoum. The data thus suport the laboratory findings that WBA 8119 is the most active anticoagulant so far tested for the control of warfarin-resistant house mice. PMID:1069821

  13. Trials of the anticoagulants rodenticide WBA 8119 against confined colonies of warfarin-resistant house mice (Mus musculus L.).

    PubMed

    Rowe, F P; Bradfield, A

    1976-12-01

    The efficacy of the newly developed anticoagulant rodenticide WBA 8119 was evaluated against the house mouse (Mus musculus L.) using individual and family groups of warfarin-resistant animals. WBA 8119 at 0-002%, 0-005% and 0-01% in pinhead oatmeal bait gave complete kills of mice in 'no-choice' feeding tests carried out in cages and small pens. In replicated 21-day treatments on families of mice confined in larger pens and conditioned to feeding on plain foods, the overall mortalities obtained using the three formulated poison baits were 71/72, 62/63 and 57/57 respectively. The results of the WBA 8119 toxicity tests are considered in relation to previous findings on other anticoagulant rodenticides, particularly difenacoum. In equivalent tests, WBA 8119 performed better than difenacoum. The data thus support the laboratory findings that WBA 8119 is the most active anticoagulant so far tested for the control of warfarin-resistant house mice. PMID:1069822

  14. The Myriapoda and Onychophora collection (MY) of the Muséum national d'Histoire naturelle (MNHN, Paris).

    PubMed

    Bras, Gwenaël Le; Geoffroy, Jean-Jacques; Albenga, Laurent; Mauriès, Jean-Paul

    2015-01-01

    The Myriapoda and Onychophora collection dataset inventories the occurrence records of the collection of myriapods and onychophorans in the Muséum national d'Histoire naturelle, Paris. The dataset currently consists of 202 lots of onychophorans, representing all of those present, and almost ten thousand (9 795) lots of myriapods, representing 33 to 40% of the MNHN Myriapoda collection. This collection, which is of key historic importance, represents the results of two centuries of myriapod and onychophoran studies. The sources of the collection are worldwide, with a high representation for metropolitan France for the myriapods. None of the occurrences are yet georeferenced. Access to the dataset via the data portals of the MNHN and the GBIF has been made possible through the e-ReColNat project (ANR-11-INBS-0004). The Myriapoda and Onychophora collection of MNHN is actively expanding, hence both the collection and dataset are in continuous growth. The dataset can be accessed through the portals of GBIF at http://www.gbif.org/dataset/3287044c-8c48-4ad6-81d4-4908071bc8db and the MNHN at http://science.mnhn.fr/institution/mnhn/collection/my/item/search/form.

  15. The Myriapoda and Onychophora collection (MY) of the Muséum national d’Histoire naturelle (MNHN, Paris)

    PubMed Central

    Bras, Gwenaël Le; Geoffroy, Jean-Jacques; Albenga, Laurent; Mauriès, Jean-Paul

    2015-01-01

    Abstract The Myriapoda and Onychophora collection dataset inventories the occurrence records of the collection of myriapods and onychophorans in the Muséum national d’Histoire naturelle, Paris. The dataset currently consists of 202 lots of onychophorans, representing all of those present, and almost ten thousand (9 795) lots of myriapods, representing 33 to 40% of the MNHN Myriapoda collection. This collection, which is of key historic importance, represents the results of two centuries of myriapod and onychophoran studies. The sources of the collection are worldwide, with a high representation for metropolitan France for the myriapods. None of the occurrences are yet georeferenced. Access to the dataset via the data portals of the MNHN and the GBIF has been made possible through the e-ReColNat project (ANR-11-INBS-0004). The Myriapoda and Onychophora collection of MNHN is actively expanding, hence both the collection and dataset are in continuous growth. The dataset can be accessed through the portals of GBIF at http://www.gbif.org/dataset/3287044c-8c48-4ad6-81d4-4908071bc8db and the MNHN at http://science.mnhn.fr/institution/mnhn/collection/my/item/search/form. PMID:26448704

  16. Tissue-Specific Contributions of Paternally Expressed Gene 3 in Lactation and Maternal Care of Mus musculus.

    PubMed

    Frey, Wesley D; Kim, Joomyeong

    2015-01-01

    Paternally Expressed Gene 3 (Peg3) is an imprinted gene that controls milk letdown and maternal-caring behaviors. In this study, a conditional knockout allele has been developed in Mus musculus to further characterize these known functions of Peg3 in a tissue-specific manner. The mutant line was first crossed with a germline Cre. The progeny of this cross displayed growth retardation phenotypes. This is consistent with those seen in the previous mutant lines of Peg3, confirming the usefulness of the new mutant allele. The mutant line was subsequently crossed individually with MMTV- and Nkx2.1-Cre lines to test Peg3's roles in the mammary gland and hypothalamus, respectively. According to the results, the milk letdown process was impaired in the nursing females with the Peg3 mutation in the mammary gland, but not in the hypothalamus. This suggests that Peg3's roles in the milk letdown process are more critical in the mammary gland than in the hypothalamus. In contrast, one of the maternal-caring behaviors, nest-building, was interrupted in the females with the mutation in both MMTV- and Nkx2.1-driven lines. Overall, this is the first study to introduce a conditional knockout allele of Peg3 and to further dissect its contribution to mammalian reproduction in a tissue-specific manner. PMID:26640945

  17. High-spin level scheme and decay of the 67-{mu}s isomer in {sup 142}Pm

    SciTech Connect

    Liu, M.L.; Zhang, Y.H.; Zhou, X.H.; Guo, Y.X.; Lei, X.G.; Liu, Z.; He, J.J.; Wen, S.X.; Wu, X.G.; Yuan, G.J.

    2004-07-01

    An in-beam {gamma}-ray spectroscopy experiment for {sup 142}Pm has been performed via the {sup 128}Te({sup 19}F,5n) reaction at beam energies of 75 MeV through 95 MeV. Excitation functions and {gamma}-{gamma} coincidences have been measured. Detailed analysis of {gamma}-{gamma} coincidence relationships leads to a revised high-spin level scheme for {sup 142}Pm. The {pi}h{sub 11/2}x{nu}h{sub 11/2}{sup -1} multiplet in this nucleus has been identified and the discussion is based on a systematic of corresponding states in neighboring odd-odd nuclei. The previously known 67-{mu}s isomer and associated decay {gamma} rays have been placed into the new level scheme. This long-lived isomer is proposed to be a four-hole state with predominantly the ({pi}g{sub 7/2}{sup -1}d{sub 5/2}{sup -2}x{nu}h{sub 11/2}{sup -1}){sub 13{sup -}} configuration.

  18. Sodium-Dependent myo-Inositol Transporter 1 Is a Cellular Receptor for Mus cervicolor M813 Murine Leukemia Virus

    PubMed Central

    Hein, Sibyll; Prassolov, Vladimir; Zhang, Yuanming; Ivanov, Dmitry; Löhler, Jürgen; Ross, Susan R.; Stocking, Carol

    2003-01-01

    Retrovirus infection is initiated by binding of the surface (SU) portion of the viral envelope glycoprotein (Env) to specific receptors on cells. This binding triggers conformational changes in the transmembrane portion of Env, leading to membrane fusion and cell entry, and is thus a major determinant of retrovirus tissue and species tropism. The M813 murine leukemia virus (MuLV) is a highly fusogenic gammaretrovirus, isolated from Mus cervicolor, whose host range is limited to mouse cells. To delineate the molecular mechanisms of its restricted host range and its high fusogenic potential, we initiated studies to characterize the cell surface protein that mediates M813 infection. Screening of the T31 mouse-hamster radiation hybrid panel for M813 infectivity localized the receptor gene to the distal end of mouse chromosome 16. Expression of one of the likely candidate genes (slc5a3) within this region in human cells conferred susceptibility to both M813 infection and M813-induced fusogenicity. slc5a3 encodes sodium myo-inositol transporter 1 (SMIT1), thus adding another sodium-dependent transporter to the growing list of proteins used by MuLVs for cell entry. Characterization of SMIT1 orthologues in different species identified several amino acid variations within two extracellular loops that may restrict susceptibility to M813 infection. PMID:12719585

  19. Sodium-dependent myo-inositol transporter 1 is a cellular receptor for Mus cervicolor M813 murine leukemia virus.

    PubMed

    Hein, Sibyll; Prassolov, Vladimir; Zhang, Yuanming; Ivanov, Dmitry; Löhler, Jürgen; Ross, Susan R; Stocking, Carol

    2003-05-01

    Retrovirus infection is initiated by binding of the surface (SU) portion of the viral envelope glycoprotein (Env) to specific receptors on cells. This binding triggers conformational changes in the transmembrane portion of Env, leading to membrane fusion and cell entry, and is thus a major determinant of retrovirus tissue and species tropism. The M813 murine leukemia virus (MuLV) is a highly fusogenic gammaretrovirus, isolated from Mus cervicolor, whose host range is limited to mouse cells. To delineate the molecular mechanisms of its restricted host range and its high fusogenic potential, we initiated studies to characterize the cell surface protein that mediates M813 infection. Screening of the T31 mouse-hamster radiation hybrid panel for M813 infectivity localized the receptor gene to the distal end of mouse chromosome 16. Expression of one of the likely candidate genes (slc5a3) within this region in human cells conferred susceptibility to both M813 infection and M813-induced fusogenicity. slc5a3 encodes sodium myo-inositol transporter 1 (SMIT1), thus adding another sodium-dependent transporter to the growing list of proteins used by MuLVs for cell entry. Characterization of SMIT1 orthologues in different species identified several amino acid variations within two extracellular loops that may restrict susceptibility to M813 infection.

  20. Whole body cholesterol, fat, and fatty acid concentrations of mice (Mus domesticus) used as a food source.

    PubMed

    Crissey, S D; Slifka, K A; Lintzenich, B A

    1999-06-01

    The concentrations of dry matter, cholesterol, saturated fat, monounsaturated fat, and 29 fatty acids were measured in four size categories of whole mice (Mus domesticus) that are commonly fed to zoo animals. Dry matter increased with age/size of mice, whereas cholesterol decreased with age/size. Significant differences in fatty acid content were found among mice categories with capric, lauric, and myristic acids. Mice categories had similar levels of palmitic, palmitoleic, heptadecenoic, stearic, oleic, linoleic, gamma linolenic, alpha linolenic, eicosenoic, eicosadienoic, arachidonic, docosahexaenoic, and lignoceric acids. Analyzed lipid content of mice exceeded domestic carnivorous animal requirements for linoleic and arachidonic acids. The fatty acid levels in mice were high, falling between published values in beef and fish. Generally, mice contained higher levels of polyunsaturated fatty acids, including the omega-3 fatty acids, and lower levels of saturated fatty acids than beef. Although fatty acid levels met or exceeded some dietary requirements for carnivores and omnivores, a possibility of excessive levels exists that could lead to eye and tissue abnormalities. Furthermore, as the intake of dietary polyunsaturated fatty acids increases, the dietary requirement for vitamin E increases. Thus, it is important that lipid profiles of feeder mice be known and considered when examining captive animal diets.

  1. Risk assessment for release of genetically modified organisms: a virus to reduce the fertility of introduced wild mice, Mus domesticus.

    PubMed

    Williams, C K

    2002-01-01

    Risk assessment is a key task in developing genetically modified organisms (GMOs) intended for release into the environment. A risk assessment protocol is described, focusing on genetically modified biological control agents intended to reduce fertility in mammalian pests. The protocol is being applied to development of an immunocontraceptive murine cytomegalovirus vaccine intended to reduce the frequency and extent of costly troublesome plagues of introduced house mice, Mus domesticus, in southern Australia. Success of the agent, including regulatory approval for release to target populations, will depend on demonstrated biosafety, on the biophysical consequences of releasing the agent, and on public perceptions of the consequences and ongoing risks. The proposed risk assessment protocol addresses biosafety and the biophysical and social risks. It elicits perceptions of interaction and risk from the project scientists and from representatives of interested or affected sectors of society. The perceptions are documented for examination interactively in subsequent socially inclusive formal risk assessments. Representatives of the relevant social sectors participate with the scientists, iteratively if needed, in a workshop to assess the risks of releasing the particular GMO into the environment, using a formal inductive procedure, GENHAZ, designed specifically for assessment and management of the risks of GMOs. Use of this protocol is intended to precede and complement risk assessment and risk management procedures specified by gene technology legislation and regulations.

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

    PubMed Central

    2012-01-01

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

  3. Dihydrocodeine/Agonists for Alcohol Dependents

    PubMed Central

    Ulmer, Albrecht; Müller, Markus; Frietsch, Bernhard

    2012-01-01

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

  4. Molecular cloning of Drosophila mus308, a gene involved in DNA cross-link repair with homology to prokaryotic DNA polymerase I genes.

    PubMed Central

    Harris, P V; Mazina, O M; Leonhardt, E A; Case, R B; Boyd, J B; Burtis, K C

    1996-01-01

    Mutations in the Drosophila mus308 gene confer specific hypersensitivity to DNA-cross-linking agents as a consequence of defects in DNA repair. The mus308 gene is shown here to encode a 229-kDa protein in which the amino-terminal domain contains the seven conserved motifs characteristic of DNA and RNA helicases and the carboxy-terminal domain shares over 55% sequence similarity with the polymerase domains of prokaryotic DNA polymerase I-like enzymes. This is the first reported member of this family of DNA polymerases in a eukaryotic organism, as well as the first example of a single polypeptide with homology to both DNA polymerase and helicase motifs. Identification of a closely related gene in the genome of Caenorhabditis elegans suggests that this novel polypeptide may play an evolutionarily conserved role in the repair of DNA damage in eukaryotic organisms. PMID:8816490

  5. Mutagen sensitivity of Drosophila melanogaster. VII Alkylation mutagenesis of mature and immature oocytes of the excision-deficient mus (2) 201/sup D1/ mutant

    SciTech Connect

    Badaruddin, A.S.; Dusenbery, R.L.; Smith, P.D.

    1984-01-01

    The mus (2) 201/sup D1/ strain has normal meiotic processes but is absolutely defective in excision repair ability following alkylation treatment. The authors examined what effect total excision deficiency has on induced mutagenesis in these stages of oogenesis. Excision-proficient cn/sup 35/ females and excision-deficient cn/sup 35/ mus (2) 201/sup D1/ females were exposed to MMS in phosphate buffer, and subsequently mated to Basc males for five broods. From their data they conclude: first, even at this low exposure to MMS, the mus (2) 201/sup D1/ females exhibit high infertility in broods 3 through 5, indicative of extensive cell killing in the excision-deficient genotype; second, for the excision-proficient cn/sup 35/ strain, the frequency of induced mutagenesis in brood 1 is approximately threefold that observed in brood 2; third, by comparing the induced frequencies for broods 1 and 2 between two strains, the data demonstrate a very substantial increase in mutagenesis in the excision-deficient strain over that observed for the control strain. The data clearly demonstrate the extensive contribution that the excision repair process makes during oogenesis and early embryogenesis in protecting the female and zygotic genomes from mutational consequences arising fron DNA damage.

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

    PubMed Central

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

    2013-01-01

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

  7. Modification of opiate agonist binding by pertussis toxin

    SciTech Connect

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

    1986-03-05

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

  8. Sound production during agonistic behavior of male Drosophila melanogaster

    PubMed Central

    Jonsson, Thorin; Kravitz, Edward A

    2011-01-01

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

  9. Radiation therapy generates platelet-activating factor agonists

    PubMed Central

    Sahu, Ravi P.; Harrison, Kathleen A.; Weyerbacher, Jonathan; Murphy, Robert C.; Konger, Raymond L.; Garrett, Joy Elizabeth; Chin-Sinex, Helen Jan; Johnston, Michael Edward; Dynlacht, Joseph R.; Mendonca, Marc; McMullen, Kevin; Li, Gengxin; Spandau, Dan F.; Travers, Jeffrey B.

    2016-01-01

    Pro-oxidative stressors can suppress host immunity due to their ability to generate oxidized lipid agonists of the platelet-activating factor-receptor (PAF-R). As radiation therapy also induces reactive oxygen species, the present studies were designed to define whether ionizing radiation could generate PAF-R agonists and if these lipids could subvert host immunity. We demonstrate that radiation exposure of multiple tumor cell lines in-vitro, tumors in-vivo, and human subjects undergoing radiation therapy for skin tumors all generate PAF-R agonists. Structural characterization of radiation-induced PAF-R agonistic activity revealed PAF and multiple oxidized glycerophosphocholines that are produced non-enzymatically. In a murine melanoma tumor model, irradiation of one tumor augmented the growth of the other (non-treated) tumor in a PAF-R-dependent process blocked by a cyclooxygenase-2 inhibitor. These results indicate a novel pathway by which PAF-R agonists produced as a byproduct of radiation therapy could result in tumor treatment failure, and offer important insights into potential therapeutic strategies that could improve the overall antitumor effectiveness of radiation therapy regimens. PMID:26959112

  10. Radiation therapy generates platelet-activating factor agonists.

    PubMed

    Sahu, Ravi P; Harrison, Kathleen A; Weyerbacher, Jonathan; Murphy, Robert C; Konger, Raymond L; Garrett, Joy Elizabeth; Chin-Sinex, Helen Jan; Johnston, Michael Edward; Dynlacht, Joseph R; Mendonca, Marc; McMullen, Kevin; Li, Gengxin; Spandau, Dan F; Travers, Jeffrey B

    2016-04-12

    Pro-oxidative stressors can suppress host immunity due to their ability to generate oxidized lipid agonists of the platelet-activating factor-receptor (PAF-R). As radiation therapy also induces reactive oxygen species, the present studies were designed to define whether ionizing radiation could generate PAF-R agonists and if these lipids could subvert host immunity. We demonstrate that radiation exposure of multiple tumor cell lines in-vitro, tumors in-vivo, and human subjects undergoing radiation therapy for skin tumors all generate PAF-R agonists. Structural characterization of radiation-induced PAF-R agonistic activity revealed PAF and multiple oxidized glycerophosphocholines that are produced non-enzymatically. In a murine melanoma tumor model, irradiation of one tumor augmented the growth of the other (non-treated) tumor in a PAF-R-dependent process blocked by a cyclooxygenase-2 inhibitor. These results indicate a novel pathway by which PAF-R agonists produced as a byproduct of radiation therapy could result in tumor treatment failure, and offer important insights into potential therapeutic strategies that could improve the overall antitumor effectiveness of radiation therapy regimens. PMID:26959112

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

    PubMed Central

    Grove, A; Lipworth, B J

    1995-01-01

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

  12. Current issues with beta2-adrenoceptor agonists: historical background.

    PubMed

    Tattersfield, Anne E

    2006-01-01

    The discovery that dessicated adrenal glands had beneficial effects in asthma arose in 1900 following a vogue for studying organotherapy at the end of the 19th century. The adrenal hormone adrenaline was found to have sympathomimetic properties and was isolated and synthesized in 1901. The first nonselective beta-agonist, isoproterenol, was isolated in 1940, followed by the development of selective beta2-agonists in the 1960s and the introduction of the long-acting beta2-agonists in the 1990s. The introduction of beta2-selectivity reduced adverse effects, as did developments in inhaler technology that allowed subjects to inhale much smaller doses of drug selectively to the airways. The beta2-agonists are some of the more important drugs to have been developed in the 20th century. Excessive doses can cause problems, and attempts to maximize the benefit from beta2-agonists and to reduce adverse effects has led to considerable epidemiological, clinical, and mechanistic research over the last 50 yr.

  13. Genome Patterns of Selection and Introgression of Haplotypes in Natural Populations of the House Mouse (Mus musculus)

    PubMed Central

    Staubach, Fabian; Lorenc, Anna; Messer, Philipp W.; Tang, Kun; Petrov, Dmitri A.; Tautz, Diethard

    2012-01-01

    General parameters of selection, such as the frequency and strength of positive selection in natural populations or the role of introgression, are still insufficiently understood. The house mouse (Mus musculus) is a particularly well-suited model system to approach such questions, since it has a defined history of splits into subspecies and populations and since extensive genome information is available. We have used high-density single-nucleotide polymorphism (SNP) typing arrays to assess genomic patterns of positive selection and introgression of alleles in two natural populations of each of the subspecies M. m. domesticus and M. m. musculus. Applying different statistical procedures, we find a large number of regions subject to apparent selective sweeps, indicating frequent positive selection on rare alleles or novel mutations. Genes in the regions include well-studied imprinted loci (e.g. Plagl1/Zac1), homologues of human genes involved in adaptations (e.g. alpha-amylase genes) or in genetic diseases (e.g. Huntingtin and Parkin). Haplotype matching between the two subspecies reveals a large number of haplotypes that show patterns of introgression from specific populations of the respective other subspecies, with at least 10% of the genome being affected by partial or full introgression. Using neutral simulations for comparison, we find that the size and the fraction of introgressed haplotypes are not compatible with a pure migration or incomplete lineage sorting model. Hence, it appears that introgressed haplotypes can rise in frequency due to positive selection and thus can contribute to the adaptive genomic landscape of natural populations. Our data support the notion that natural genomes are subject to complex adaptive processes, including the introgression of haplotypes from other differentiated populations or species at a larger scale than previously assumed for animals. This implies that some of the admixture found in inbred strains of mice may also have

  14. Toxicological evaluation of essential oil from the leaves of Croton tetradenius (Euphorbiaceae) on Aedes aegypti and Mus musculus.

    PubMed

    Carvalho, Karine da Silva; E Silva, Sandra Lúcia da Cunha; de Souza, Ivone Antonia; Gualberto, Simone Andrade; da Cruz, Rômulo Carlos Dantas; Dos Santos, Frances Regiane; de Carvalho, Mário Geraldo

    2016-09-01

    For control of Aedes aegypti, the main vector of dengue, botanical insecticides can be a viable alternative. Herein, we evaluated the chemical composition and insecticidal activity of the essential oils of the leaves of Croton tetradenius on Ae. aegypti larvae and adults. We also evaluated the acute toxicity in Mus musculus. The essential oil chemical analysis was performed using chromatography coupled with mass spectrometry and flame ionization detection. Female mice were used for assessing toxicity according to the Organization for Economic Cooperation and Development's Test Guideline 423/2001. Doses administered to mice orally and intraperitoneally were 5, 50, 300, and 2000 mg kg(-1). There was a greater toxic effect on larvae (LC50 = 0.152 mg mL(-1) and LC90 = 0.297 mg mL(-1)) and on adults (LC50 = 1.842 mg mL(-1) and LC90 = 3.156 mg mL(-1)) of Ae. aegypti after 24 h of exposure, when compared to other periods of exposure. Chemical analysis revealed 26 components, with camphor (25.49 %) as the major component. The acute toxicity via the intraperitoneal route identified an LD50 = 200 mg kg(-1) and by the oral route an LD50 = 500 mg kg(-1). Thus, the essential oil of C. tetradenius presents insecticidal potential for Ae. aegypti and has high safety threshold at the concentrations evaluated in this study. PMID:27169864

  15. Polymorphism in hybrid male sterility in wild-derived Mus musculus musculus strains on proximal chromosome 17.

    PubMed

    Vyskocilová, Martina; Prazanová, Gabriela; Piálek, Jaroslav

    2009-02-01

    The hybrid sterility-1 (Hst1) locus at Chr 17 causes male sterility in crosses between the house mouse subspecies Mus musculus domesticus (Mmd) and M. m. musculus (Mmm). This locus has been defined by its polymorphic variants in two laboratory strains (Mmd genome) when mated to PWD/Ph mice (Mmm genome): C57BL/10 (carrying the sterile allele) and C3H (fertile allele). The occurrence of sterile and/or fertile (wild Mmm x C57BL)F1 males is evidence that polymorphism for this trait also exists in natural populations of Mmm; however, the nature of this polymorphism remains unclear. Therefore, we derived two wild-origin Mmm strains, STUS and STUF, that produce sterile and fertile males, respectively, in crosses with C57BL mice. To determine the genetic basis underlying male fertility, the (STUS x STUF)F1 females were mated to C57BL/10 J males. About one-third of resulting hybrid males (33.8%) had a significantly smaller epididymis and testes than parental animals and lacked spermatozoa due to meiotic arrest. A further one-fifth of males (20.3%) also had anomalous reproductive traits but produced some spermatozoa. The remaining fertile males (45.9%) displayed no deviation from values found in parental individuals. QTL analysis of the progeny revealed strong associations of male fitness components with the proximal end of Chr 17, and a significant effect of the central section of Chr X on testes mass. The data suggest that genetic incompatibilities associated with male sterility have evolved independently at the proximal end of Chr 17 and are polymorphic within both Mmd and Mmm genomes.

  16. Toxicological evaluation of essential oil from the leaves of Croton tetradenius (Euphorbiaceae) on Aedes aegypti and Mus musculus.

    PubMed

    Carvalho, Karine da Silva; E Silva, Sandra Lúcia da Cunha; de Souza, Ivone Antonia; Gualberto, Simone Andrade; da Cruz, Rômulo Carlos Dantas; Dos Santos, Frances Regiane; de Carvalho, Mário Geraldo

    2016-09-01

    For control of Aedes aegypti, the main vector of dengue, botanical insecticides can be a viable alternative. Herein, we evaluated the chemical composition and insecticidal activity of the essential oils of the leaves of Croton tetradenius on Ae. aegypti larvae and adults. We also evaluated the acute toxicity in Mus musculus. The essential oil chemical analysis was performed using chromatography coupled with mass spectrometry and flame ionization detection. Female mice were used for assessing toxicity according to the Organization for Economic Cooperation and Development's Test Guideline 423/2001. Doses administered to mice orally and intraperitoneally were 5, 50, 300, and 2000 mg kg(-1). There was a greater toxic effect on larvae (LC50 = 0.152 mg mL(-1) and LC90 = 0.297 mg mL(-1)) and on adults (LC50 = 1.842 mg mL(-1) and LC90 = 3.156 mg mL(-1)) of Ae. aegypti after 24 h of exposure, when compared to other periods of exposure. Chemical analysis revealed 26 components, with camphor (25.49 %) as the major component. The acute toxicity via the intraperitoneal route identified an LD50 = 200 mg kg(-1) and by the oral route an LD50 = 500 mg kg(-1). Thus, the essential oil of C. tetradenius presents insecticidal potential for Ae. aegypti and has high safety threshold at the concentrations evaluated in this study.

  17. l-5-hydroxytryptophan resets the circadian locomotor activity rhythm of the nocturnal Indian pygmy field mouse, Mus terricolor

    NASA Astrophysics Data System (ADS)

    Basu, Priyoneel; Singaravel, Muniyandi; Haldar, Chandana

    2012-03-01

    We report that l-5-hydroxytryptophan (5-HTP), a serotonin precursor, resets the overt circadian rhythm in the Indian pygmy field mouse, Mus terricolor, in a phase- and dose-dependent manner. We used wheel running to assess phase shifts in the free-running locomotor activity rhythm. Following entrainment to a 12:12 h light-dark cycle, 5-HTP (100 mg/kg in saline) was intraperitoneally administered in complete darkness at circadian time (CT)s 0, 3, 6, 9, 12, 15, 18, and 21, and the ensuing phase shifts in the locomotor activity rhythm were calculated. The results show that 5-HTP differentially shifts the phase of the rhythm, causing phase advances from CT 0 to CT 12 and phase delays from CT 12 to CT 21. Maximum advance phase shift was at CT 6 (1.18 ± 0.37 h) and maximum delay was at CT 18 (-2.36 ± 0.56 h). No extended dead zone is apparent. Vehicle (saline) at any CT did not evoke a significant phase shift. Investigations with different doses (10, 50, 100, and 200 mg/kg) of 5-HTP revealed that the phase resetting effect is dose-dependent. The shape of the phase-response curve (PRC) has a strong similarity to PRCs obtained using some serotonergic agents. There was no significant increase in wheel-running activity after 5-HTP injection, ruling out behavioral arousal-dependent shifts. This suggests that this phase resetting does not completely depend on feedback of the overt rhythmic behavior on the circadian clock. A mechanistic explanation of these shifts is currently lacking.

  18. New Metacentric Populations and Phylogenetic Hypotheses Involving Whole-Arm Reciprocal Translocation in Mus musculus domesticus from Sicily, Southern Italy.

    PubMed

    Castiglia, Riccardo; Capanna, Ernesto; Bezerra, Alexandra M R; Bizzoco, Domenico; Zambigli, Emanuela; Solano, Emanuela

    2015-01-01

    The house mouse Mus musculus domesticus is characterized by more than 100 metacentric populations, due to the occurrence of Robertsonian (Rb) fusions, together with the standard all-telocentric karyotype (2n = 40). We examined G-banded karyotypes of 18 mice from 10 localities in Sicily and describe 3 new metacentric populations: 'Ragusa Ibla' (IRAG), 2n = 33-36, Rb(2.4), Rb(5.6), Rb(9.16), Rb(13.17); 'Piana degli Albanesi' (IPIA), 2n = 23, Rb(1.18), Rb(2.15), Rb(3.5), Rb(4.12), Rb(6.11), Rb(7.8), Rb(9.16), Rb(10.14), Rb(13.17); 'Trapani' (ITRA), 2n = 22, Rb(1.18), Rb(2.15), Rb(3.7), Rb(4.12), Rb(5.9), Rb(6.11), Rb(8.16), Rb(10.14), Rb(13.17). Three mice belonged to the previously reported 'Castelbuono' race (ICAS), 2n = 24, which is very similar to the nearby 'Palermo' (IPAL) race, 2n = 26. Three Rb fusions not yet observed in wild mouse populations were identified: Rb(3.5), Rb(3.7) and Rb(5.9). Rb fusions shared among 4 races (IPIA, IRAG, ICAS, and IPAL) allowed us to describe their potential phylogenetic relationships. We obtained 2 alternative phylogenetic trees. The differences between them are mainly due to various modes of formation of IPIA and ITRA. In the first hypothesis, the specific Rb fusions occurred independently. In the second, those of IRAG originated from those of IPIA via whole-arm reciprocal translocations.

  19. Acute effects of light on the brain and behavior of diurnal Arvicanthis niloticus and nocturnal Mus musculus.

    PubMed

    Shuboni, Dorela D; Cramm, Shannon L; Yan, Lily; Ramanathan, Chidambaram; Cavanaugh, Breyanna L; Nunez, Antonio A; Smale, Laura

    2015-01-01

    Photic cues influence daily patterns of activity via two complementary mechanisms: (1) entraining the internal circadian clock and (2) directly increasing or decreasing activity, a phenomenon referred to as "masking". The direction of this masking response is dependent on the temporal niche an organism occupies, as nocturnal animals often decrease activity when exposed to light, while the opposite response is more likely to be seen in diurnal animals. Little is known about the neural mechanisms underlying these differences. Here, we examined the masking effects of light on behavior and the activation of several brain regions by that light, in diurnal Arvicanthis niloticus (Nile grass rats) and nocturnal Mus musculus (mice). Each species displayed the expected behavioral response to a 1h pulse of light presented 2h after lights-off, with the diurnal grass rats and nocturnal mice increasing and decreasing their activity, respectively. In grass rats light induced an increase in cFOS in all retinorecipient areas examined, which included the suprachiasmatic nucleus (SCN), the ventral subparaventricular zone (vSPZ), intergeniculate leaflet (IGL), lateral habenula (LH), olivary pretectal nucleus (OPT) and the dorsal lateral geniculate (DLG). In mice, light led to an increase in cFOS in one of these regions (SCN), no change in others (vSPZ, IGL and LH) and a decrease in two (OPT and DLG). In addition, light increased cFOS expression in three arousal-related brain regions (the lateral hypothalamus, dorsal raphe, and locus coeruleus) and in one sleep-promoting region (the ventrolateral preoptic area) in grass rats. In mice, light had no effect on cFOS in these four regions. Taken together, these results highlight several brain regions whose responses to light suggest that they may play a role in masking, and that the possibility that they contribute to species-specific patterns of behavioral responses to light should be explored in future.

  20. Evolution of messenger RNA structure and regulation in the genus Mus: the androgen-inducible RP2 mRNAs.

    PubMed

    Chaudhuri, A; Barbour, K W; Berger, F G

    1991-09-01

    The RP2 gene is one of several genes that are regulated by androgens in the mouse kidney. Previous studies have demonstrated that androgen inducibility of RP2 transcription varies among species within the genus Mus, indicating extensive evolutionary modification of the participating regulatory elements. Thus, while a five-fold induction of transcription occurs in M. domesticus, none is detectable in M. hortulanus or M. caroli. In the present paper, we have sequenced cDNAs representing the RP2 mRNAs of M. caroli and M. saxicola and have compared them with each other and with M. domesticus. Several findings from the sequence comparisons indicate that the encoded 41-kD polypeptide is physiologically functional. First, divergence within noncoding regions of the mRNAs exceeds that within coding regions. Second, the 357-codon open reading frame has been maintained among the species, with approximately 90% of the amino acid replacements being conservative. Finally, substitution rates at synonymous sites within the coding regions are from twofold to threefold greater than those at nonsynonymous sites. The genetic elements responsible for variations in RP2 inducibility among species were studied by cis/trans analyses of mice heterozygous for RP2 alleles, using a primer extension assay to measure expression of species-specific mRNAs. The results show that the absence of transcriptional induction in M. hortulanus is due to a cis-acting genetic element, while that in M. caroli is due to a trans-acting element. Thus, the androgen-resistant RP2 phenotypes of these two species derive from distinct genetic events.

  1. Confounding of the Comparative Safety of Prenatal Opioid Agonist Therapy

    PubMed Central

    Brogly, Susan B; Hahn, Kristen A; Diaz, Sonia Hernandez; Werler, Martha

    2016-01-01

    Prenatal opioid agonist therapy with methadone or buprenorphine prevents maternal illicit opioid use and withdrawal and improves pregnancy outcomes compared to heroin use alone. Historically, methadone has been the first-line opioid agonist therapy for pregnant opioid dependent women; in recent years buprenorphine has become first-line treatment for some opioid dependent pregnant women. While there is some evidence of better outcomes in neonates exposed to buprenorphine vs. methadone, the effect of confounding from differences in women who use buprenorphine and methadone has not been carefully examined in most studies. This review explores mechanisms by which confounding can arise in measuring associations between prenatal buprenorphine vs. methadone exposure on neonatal outcomes using a graphical approach, directed acyclic graphs. The goal of this paper is to facilitate better understanding of the factors influencing neonatal abstinence syndrome and accurate assessment of the comparative safety of opioid agonist therapies on the neonate. PMID:27547489

  2. Adenosine receptor agonists for promotion of dermal wound healing

    PubMed Central

    Valls, María D.; Cronstein, Bruce N.; Montesinos, M. Carmen

    2009-01-01

    Wound healing is a dynamic and complex process that involves a well coordinated, highly regulated series of events including inflammation, tissue formation, revascularization and tissue remodeling. However, this orderly sequence is impaired in certain pathophysiological conditions such as diabetes mellitus, venous insufficiency, chronic glucocorticoid use, aging and malnutrition. Together with proper wound care, promotion of the healing process is the primary objective in the management of chronic poorly healing wounds. Recent studies have demonstrated that A2A adenosine receptor agonists promote wound healing in normal and diabetic animals and one such agonist, Sonedenoson, is currently being evaluated as a prospective new therapy of diabetic foot ulcers. We will review the mechanisms by which adenosine receptor activation affects the function of the cells and tissues that participate in wound healing, emphasizing the potential beneficial impact of adenosine receptor agonists in diabetic impaired healing. PMID:19041853

  3. Design, evaluation, and comparison of ghrelin receptor agonists and inverse agonists as suitable radiotracers for PET imaging.

    PubMed

    Chollet, Constance; Bergmann, Ralf; Pietzsch, Jens; Beck-Sickinger, Annette G

    2012-04-18

    Ghrelin agonist and inverse agonist radiotracers, suitable for positron emission tomography (PET), were developed to study the behavior of ghrelin receptor ligands in vivo and for further design of druggable peptides. The target peptides were synthesized on solid support and conjugated to the bifunctional chelator 1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid (NODAGA), which is known to form a stable complex with Ga(3+). Complexation with (68)Ga could be achieved under mild conditions and led to radiotracers with high radiochemical purity and specific activity. The biological activity of the radiotracers was evaluated in vitro by an inositol phosphate turnover assay. Pharmacokinetic profile and metabolic stability of the (68)Ga-NODAGA-radiotracers were investigated by small animal PET in rodent. Ghrelin derived agonists presented very high kidney accumulation, negligible tissue distribution, fast blood clearance, and poor stability in blood. Contrarily, the inverse agonist radiotracer exhibited very high stability in blood, large diffusion in tissues, reasonable kidney and liver metabolism, and slow blood clearance. This pharmacokinetic profile makes the ghrelin inverse agonist motif KwFwLL-CONH(2) suitable for further development of radiotracers and a promising lead to design peptide-based therapeutics against obesity. PMID:22372770

  4. Agonist treatment in opioid use: advances and controversy.

    PubMed

    Viswanath, Biju; Chand, Prabhat; Benegal, Vivek; Murthy, Pratima

    2012-06-01

    Opioid dependence is a chronic relapsing condition which requires comprehensive care; pharmacological agents form the mainstay of its long term treatment. The two most popular approaches are the harm reduction method using agonists and the complete abstinence method using antagonists. Currently, particularly from the harm minimization perspective and the low feasibility of an abstinence based approach, there is an increasing trend toward agonist treatment. The use of buprenorphine has gained popularity in view of its safety profile and the availability of the buprenorphine-naloxone combination has made it popular as a take-home treatment. This review outlines the pharmacological advances and controversies in this area. PMID:22813654

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

    PubMed Central

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

    2013-01-01

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

  6. Beta2-agonist extraction procedures for chromatographic analysis.

    PubMed

    dos Ramos, F J

    2000-06-01

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

  7. The emerging therapeutic roles of κ-opioid agonists.

    PubMed

    Jones, Mark R; Kaye, Alan D; Kaye, Aaron J; Urman, Richard D

    2016-01-01

    The current practice of μ-opioid receptor agonists such as morphine as the primary means of acute and chronic pain relief has several dangerous consequences that limit their effectiveness, including respiratory depression, gastrointestinal motility inhibition, addiction, tolerance, and abuse. Several other opioid receptors, notably the μ-opioid (KOP) receptor, have long been known to play a role in pain relief. Recent discoveries and advancements in laboratory techniques have allowed significant developments of KOP agonists as potential novel therapies for pain relief and other pathological processes. These drugs exhibit none of the classic opioid adverse effects and have displayed pronounced analgesia in several different scenarios. New formulations since 2014 have unveiled increased oral bioavailability, exceptional peripheral versus central selectivity, and a positive safety profile. Continued refinements of established μ-opioid agonist formulations have virtually eliminated the centrally mediated side effects of dysphoria and sedation that limited the applicability of previous KOP agonists. Further research is required to better elucidate the potential of these compounds in pain management, as well as in the mediation or modulation of other complex pathophysiological processes as therapeutic agents. PMID:27194194

  8. Systemic cancer immunotherapy with Toll-like receptor 7 agonists

    PubMed Central

    Hotz, Christian; Bourquin, Carole

    2012-01-01

    Toll-like receptor (TLR) 7 agonists represent a promising strategy for the immunotherapy of cancer. We have recently investigated the influence of TLR tolerance on the efficacy of systemic tumor treatment with TLR7 ligands. We propose that considering the kinetics of receptor sensitivity highly improves the outcome of cancer immunotherapy. PMID:22720251

  9. Synthesis and immunostimulatory activity of substituted TLR7 agonists.

    PubMed

    Akinbobuyi, Babatope; Wang, Lei; Upchurch, Katherine C; Byrd, Matthew R; Chang, Charles A; Quintana, Jeremy M; Petersen, Rachel E; Seifert, Zacharie J; Boquin, José R; Oh, SangKon; Kane, Robert R

    2016-09-01

    Fifteen new substituted adenines were synthesized as potential TLR7 agonists. These compounds, along with 9 previously reported compounds, were analyzed for TLR7 activity and for the selective stimulation of B cell proliferation. Several functionalized derivatives exhibit significant activity, suggesting their potential for use as vaccine adjuvants. PMID:27476423

  10. The emerging therapeutic roles of κ-opioid agonists.

    PubMed

    Jones, Mark R; Kaye, Alan D; Kaye, Aaron J; Urman, Richard D

    2016-01-01

    The current practice of μ-opioid receptor agonists such as morphine as the primary means of acute and chronic pain relief has several dangerous consequences that limit their effectiveness, including respiratory depression, gastrointestinal motility inhibition, addiction, tolerance, and abuse. Several other opioid receptors, notably the μ-opioid (KOP) receptor, have long been known to play a role in pain relief. Recent discoveries and advancements in laboratory techniques have allowed significant developments of KOP agonists as potential novel therapies for pain relief and other pathological processes. These drugs exhibit none of the classic opioid adverse effects and have displayed pronounced analgesia in several different scenarios. New formulations since 2014 have unveiled increased oral bioavailability, exceptional peripheral versus central selectivity, and a positive safety profile. Continued refinements of established μ-opioid agonist formulations have virtually eliminated the centrally mediated side effects of dysphoria and sedation that limited the applicability of previous KOP agonists. Further research is required to better elucidate the potential of these compounds in pain management, as well as in the mediation or modulation of other complex pathophysiological processes as therapeutic agents.

  11. Synthesis and immunostimulatory activity of substituted TLR7 agonists.

    PubMed

    Akinbobuyi, Babatope; Wang, Lei; Upchurch, Katherine C; Byrd, Matthew R; Chang, Charles A; Quintana, Jeremy M; Petersen, Rachel E; Seifert, Zacharie J; Boquin, José R; Oh, SangKon; Kane, Robert R

    2016-09-01

    Fifteen new substituted adenines were synthesized as potential TLR7 agonists. These compounds, along with 9 previously reported compounds, were analyzed for TLR7 activity and for the selective stimulation of B cell proliferation. Several functionalized derivatives exhibit significant activity, suggesting their potential for use as vaccine adjuvants.

  12. Evolution of the post-nova GQ MUS (Nova MUSCAE 1983). II. Stellar atmospheres, coronal lines, and turnoff.

    NASA Astrophysics Data System (ADS)

    Morisset, C.; Pequignot, D.

    1996-09-01

    Photoionization models for the shell ejected by Nova Muscae 1983 are obtained for the period 1984-1992, considering post-nova atmosphere continua computed by MacDonald & Vennes (1991). A fit to their grid of models is proposed in an appendix. All features of the model shell obtained by Morisset & Pequignot assuming a blackbody primary source are preserved. However the effective temperature T_*_ derived for the source is about 15% lower. Reliable collision strengths for coronal lines are needed before the late evolution of the post-nova can be accurately determined. An extensive exploration of possible photoionization-model solutions indicates that (1) a suitable effective collision strength {OMEGA}_X_ for [Fe X] 637.5nm at 2x10^4^K is 3 to 5 times the pioneering result of Blaha (1969) and less than one half recent elaborate values, which are therefore strongly suspected to be overestimated, (2) the collision strength for [S VIII] 991.1 is moderately larger than according to Blaha, (3) the decline of the bolometric luminosity L_*_ amounts to a factor ~2 at the time of soft X-ray detection by ROSAT (day 3330), which may therefore nearly coincide with nuclear burning turnoff and maximum T_*_, and (4) depending on the collision strength {OMEGA}_XI_ for [Fe XI] 789.2nm, the maximum T_*_ is either of the order of 5x10^5^K ({OMEGA}_XI_ close to Blaha's result) or smaller than 4x10^5^K (large {OMEGA}_XI_). A way out of the conflict between theoretical and astrophysical determinations of {OMEGA}_X_ may be managed in the framework of present models if {OMEGA}_XI_ happens to be very large. Source parameters derived from nova shell models are relatively insensitive to details of stellar atmosphere models and may help to enhance the value of soft X-ray observations. Properties of GQ Mus disclosed by photoionization model analysis are shown to constitute a challenge to current understanding of novae and post-novae.

  13. Activation of endplate nicotinic acetylcholine receptors by agonists.

    PubMed

    Auerbach, Anthony

    2015-10-15

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

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

    PubMed

    Craft, R M; Bernal, S A

    2001-08-01

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

  15. GABA-induced inactivation of dorsal midline thalamic subregions has distinct effects on emotional behaviors.

    PubMed

    Barson, Jessica R; Leibowitz, Sarah F

    2015-11-16

    The paraventricular nucleus of the thalamus (PVT) is a key node integrating information about emotion and relaying output to other limbic structures influencing motor behavior. With recent studies showing the anterior (aPVT) and posterior (pPVT) subregions of this nucleus to have different anatomical connections and functions in ingestive behavior, the present study investigated whether they also make different contributions to emotional behaviors. Rats were microinjected in the aPVT or pPVT with saline vehicle or the GABAB+GABAA agonists, baclofen+muscimol (bac+mus; 0.3+0.03nmol), to inhibit neural activity and were then tested between-subject for differences in emotional behavior. In a novel activity chamber, bac+mus significantly reduced locomotor activity, with this change somewhat larger after injection in the pPVT than the aPVT. In a familiar activity chamber, bac+mus again reduced locomotor activity but induced similar changes after injection in the aPVT and pPVT. In an elevated plus maze, bac+mus significantly decreased open arm time and entries, although this was observed only after injection in the pPVT. Thus, while both PVT subregions are necessary for general locomotor activity, the pPVT appears to have a greater function in both novelty-induced activity and anxiety-like behavior, indicating that this subregion makes a greater contribution than the aPVT to reactions to stressful stimuli.

  16. Synthesis and structure-activity relationships of novel indazolyl glucocorticoid receptor partial agonists.

    PubMed

    Gilmore, John L; Sheppeck, James E; Wang, Jim; Dhar, T G Murali; Cavallaro, Cullen; Doweyko, Arthur M; Mckay, Lorraine; Cunningham, Mark D; Habte, Sium F; Nadler, Steven G; Dodd, John H; Somerville, John E; Barrish, Joel C

    2013-10-01

    SAR was used to further develop an indazole class of non-steroidal glucocorticoid receptor agonists aided by a GR LBD (ligand-binding domain)-agonist co-crystal structure described in the accompanying paper. Progress towards discovering a dissociated GR agonist guided by human in vitro assays biased the optimization of this compound series towards partial agonists that possessed excellent selectivity against other nuclear hormone receptors. PMID:23916594

  17. E mu/S mu transposition into Myc is sometimes a precursor for T(12;15) translocation in mouse B cells.

    PubMed

    Kovalchuk, Alexander L; Kim, Joong Su; Janz, Siegfried

    2003-05-01

    Misguided immunoglobulin (Ig) class switch recombination (CSR) has been implicated in the origin of Myc-activating chromosomal translocations, T(12;15), in BALB/c mouse plasmacytomas (PCTs). CSR has also been involved in the progression of T(12;15); for example, the approximation of Myc to the 3'-C alpha enhancer. This study provides evidence for an additional mechanism by which aberrant CSR may facilitate T(12;15): transposition of Ig heavy-chain (IgH) sequences to Myc. Five IgH transposons containing the intronic heavy-chain enhancer, E mu, and a truncated switch mu region, S mu, were found in the first intron of Myc in lymph node cells of IL-6 transgenic BALB/c mice. In two cases E mu/S mu transposition primed Myc to get involved in apparent trans-chromosomal CSR to C gamma 1, presumably leading to T(12;15). Translocations preceded by E mu/S mu transposition can sometimes be distinguished from de novo translocations by molecular fingerprints in translocation breakpoint regions (Ig switch region [S] inversions and unusual gene orders in composite S regions). The presence of such fingerprints in some PCTs suggests that the tumors sometimes evolve from transposition-bearing precursors. We propose that E mu/S mu transposition to Myc may facilitate plasmacytomagenesis by sensitizing Myc to undergo T(12;15) translocation. T(12;15), in turn, juxtaposes Myc to the 3'-C alpha enhancer, which appears to be required for deregulating Myc in a manner that is conducive to PCT development.

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

    SciTech Connect

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

    2009-03-27

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

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

    PubMed

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

    2006-02-14

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

  20. 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

  1. Cell type and gene-specific activity of the retinoid inverse agonist AGN 193109: divergent effects from agonist at retinoic acid receptor gamma in human keratinocytes.

    PubMed

    Thacher, S M; Nagpal, S; Klein, E S; Arefieg, T; Krasinski, G; DiSepio, D; Agarwal, C; Johnson, A; Eckert, R L; Chandraratna, R A

    1999-04-01

    Retinoids are important regulators of epithelial differentiation. AGN 193109 is a high-affinity antagonist and inverse agonist for the nuclear retinoic acid receptors (RARs). Paradoxically, both AGN 193109 and retinoid agonists inhibit the expression of the differentiation marker MRP-8 in normal human keratinocytes (NHKs). TTNPB, an RAR agonist, and AGN 193109 mutually antagonize MRP-8 inhibition at both mRNA and protein levels. We find that this antagonism, which is greatest at an AGN 193109:TTNPB ratio of about 10:1, is absent when either compound is in significant excess. The potent RARalpha-specific agonist, AGN 193836, has no effect on MRP-8 regulation. These data indicate that inverse agonists and agonists suppress MRP-8 in NHKs through RARgamma using distinct and mutually inhibitory mechanisms. The activity of AGN 193109 on MRP-8 is cell type specific. In differentiating ECE16-1 cervical cells, TTNPB inhibits while AGN 193109 induces MRP-8 mRNA levels. The effect of AGN 193109 on genes inhibited by retinoid agonists in NHKs is also selective; expression of the differentiation markers transglutaminase 1 and keratin 6 is not down-regulated by AGN 193109 whereas stromelysin-1 expression is suppressed. These results show a complex gene and cell context-specific interplay between agonist and inverse agonist for the regulation of gene expression.

  2. Novel Arenavirus Sequences in Hylomyscus sp. and Mus (Nannomys) setulosus from Côte d'Ivoire: Implications for Evolution of Arenaviruses in Africa

    PubMed Central

    Kouassi, Stéphane K.; Fichet-Calvet, Elisabeth; Becker-Ziaja, Beate; Rieger, Toni; Ölschläger, Stephan; Dosso, Hernri; Denys, Christiane; ter Meulen, Jan; Akoua-Koffi, Chantal; Günther, Stephan

    2011-01-01

    This study aimed to identify new arenaviruses and gather insights in the evolution of arenaviruses in Africa. During 2003 through 2005, 1,228 small mammals representing 14 different genera were trapped in 9 villages in south, east, and middle west of Côte d'Ivoire. Specimens were screened by pan-Old World arenavirus RT-PCRs targeting S and L RNA segments as well as immunofluorescence assay. Sequences of two novel tentative species of the family Arenaviridae, Menekre and Gbagroube virus, were detected in Hylomyscus sp. and Mus (Nannomys) setulosus, respectively. Arenavirus infection of Mus (Nannomys) setulosus was also demonstrated by serological testing. Lassa virus was not found, although 60% of the captured animals were Mastomys natalensis. Complete S RNA and partial L RNA sequences of the novel viruses were recovered from the rodent specimens and subjected to phylogenetic analysis. Gbagroube virus is a closely related sister taxon of Lassa virus, while Menekre virus clusters with the Ippy/Mobala/Mopeia virus complex. Reconstruction of possible virus–host co-phylogeny scenarios suggests that, within the African continent, signatures of co-evolution might have been obliterated by multiple host-switching events. PMID:21695269

  3. Recombination between homologous chromosomes induced by unrepaired UV-generated DNA damage requires Mus81p and is suppressed by Mms2p.

    PubMed

    Yin, Yi; Petes, Thomas D

    2015-03-01

    DNA lesions caused by UV radiation are highly recombinogenic. In wild-type cells, the recombinogenic effect of UV partially reflects the processing of UV-induced pyrimidine dimers into DNA gaps or breaks by the enzymes of the nucleotide excision repair (NER) pathway. In this study, we show that unprocessed pyrimidine dimers also potently induce recombination between homologs. In NER-deficient rad14 diploid strains, we demonstrate that unexcised pyrimidine dimers stimulate crossovers, noncrossovers, and break-induced replication events. The same dose of UV is about six-fold more recombinogenic in a repair-deficient strain than in a repair-proficient strain. We also examined the roles of several genes involved in the processing of UV-induced damage in NER-deficient cells. We found that the resolvase Mus81p is required for most of the UV-induced inter-homolog recombination events. This requirement likely reflects the Mus81p-associated cleavage of dimer-blocked replication forks. The error-free post-replication repair pathway mediated by Mms2p suppresses dimer-induced recombination between homologs, possibly by channeling replication-blocking lesions into recombination between sister chromatids.

  4. OT1_gsacco_1: Characterizing the evolved, planet-forming disks orbiting the "old" classical T Tauri systems V4046 Sgr and MP Mus

    NASA Astrophysics Data System (ADS)

    Sacco, G.

    2010-07-01

    V4046 Sgr and MP Mus are the second and the third closest known classical (actively accreting) T Tauri systems, respectively (the intensively studied TW Hya being the closest). We have recently established that, like TW Hya, both systems are orbited by dusty, molecular disks. Given their proximity (d<100 pc), ages (~10 Myr), and masses (0.7-1.2 solar masses), these three systems represent readily-studied analogs of the young sun during the crucial, late phases of the star formation process, when the circumstellar disk still retains a significant gaseous component and giant planets likely are forming or have recently formed. Furthermore, the close binary V4046 Sgr affords an unusual opportunity to investigate planet formation within circumbinary disks. We propose to observe the V4046 Sgr and MP Mus disks using Herschel's PACS and SPIRE spectrometers with the complementary aims of (1) measuring the detailed spectral energy distribution of the continuum dust emission between 55 and 670 micron and (2) detecting the brightest atomic emission lines. These data, together with the comprehensive suite of X-ray, mid-infrared and radio observations we are already collecting for these two systems, will allow us to fully characterize the physical properties of both the dust and the gas components of their circumstellar disks and to investigate the effects of high energy emission from the central star on the evolution of the circumstellar, planet-forming environment.

  5. Detailed ordering of markers localizing to the Xq26-Xqter region of the human X chromosome by the use of an interspecific Mus spretus mouse cross

    SciTech Connect

    Avner, P.; Amar, L.; Arnaud, D.; Hanauer, A.; Cambrou, J.

    1987-03-01

    Five probes localizing to the Xq26-Xqter region of the human X chromosome have been genetically mapped on the mouse X chromosome using an interspecific cross involving Mus spretus to a contiguous region lying proximally to the Tabby (Ta) locus. Pedigree and recombinational analysis establish the marker order as being Hprt-FIX-c11-G6PD-St14-1. The size of this contiguous region is such that the X-linked muscular dystrophy (mdx) mouse mutation probably maps within this segment. This in turn suggests that it is highly improbable that the mouse mdx locus represents a model for Duchenne muscular dystrophy (DMD). It is, however, compatible with the idea that this mutation may correspond in man to Emery Dreifuss muscular dystrophy. The high frequency of restriction fragment length polymorphisms found in this interspecific system for all the human cross-reacting probes examined up until now, using only a limited number of restriction enzymes, suggests that the Mus spretus mapping system may be of great potential value for establishing the linkage relationships existing in man when conserved chromosomal regions are concerned and human/mouse cross-reacting probes are available or can be obtained.

  6. Agonist-antagonist combinations in opioid dependence: a translational approach

    PubMed Central

    Mannelli, P.

    2011-01-01

    Summary The potential therapeutic benefits of co-administering opiate agonist and antagonist agents remain largely to be investigated. This paper focuses on the mechanisms of very low doses of naltrexone that help modulate the effects of methadone withdrawal and review pharmacological properties of the buprenorphine/naltrexone combination that support its clinical investigation. The bench-to-bedside development of the very low dose naltrexone treatment can serve as a translational paradigm to investigate and treat drug addiction. Further research on putative mechanisms elicited by the use of opioid agonist-antagonist combinations may lead to effective pharmacological alternatives to the gold standard methadone treatment, also useful for the management of the abuse of non opioid drugs and alcohol. PMID:22448305

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

    PubMed Central

    2013-01-01

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

  8. Orvinols with mixed kappa/mu opioid receptor agonist activity.

    PubMed

    Greedy, Benjamin M; Bradbury, Faye; Thomas, Mark P; Grivas, Konstantinos; Cami-Kobeci, Gerta; Archambeau, Ashley; Bosse, Kelly; Clark, Mary J; Aceto, Mario; Lewis, John W; Traynor, John R; Husbands, Stephen M

    2013-04-25

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

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

    PubMed

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

    2009-02-01

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

  10. Ligand Binding Ensembles Determine Graded Agonist Efficacies at a G Protein-coupled Receptor.

    PubMed

    Bock, Andreas; Bermudez, Marcel; Krebs, Fabian; Matera, Carlo; Chirinda, Brian; Sydow, Dominique; Dallanoce, Clelia; Holzgrabe, Ulrike; De Amici, Marco; Lohse, Martin J; Wolber, Gerhard; Mohr, Klaus

    2016-07-29

    G protein-coupled receptors constitute the largest family of membrane receptors and modulate almost every physiological process in humans. Binding of agonists to G protein-coupled receptors induces a shift from inactive to active receptor conformations. Biophysical studies of the dynamic equilibrium of receptors suggest that a portion of receptors can remain in inactive states even in the presence of saturating concentrations of agonist and G protein mimetic. However, the molecular details of agonist-bound inactive receptors are poorly understood. Here we use the model of bitopic orthosteric/allosteric (i.e. dualsteric) agonists for muscarinic M2 receptors to demonstrate the existence and function of such inactive agonist·receptor complexes on a molecular level. Using all-atom molecular dynamics simulations, dynophores (i.e. a combination of static three-dimensional pharmacophores and molecular dynamics-based conformational sampling), ligand design, and receptor mutagenesis, we show that inactive agonist·receptor complexes can result from agonist binding to the allosteric vestibule alone, whereas the dualsteric binding mode produces active receptors. Each agonist forms a distinct ligand binding ensemble, and different agonist efficacies depend on the fraction of purely allosteric (i.e. inactive) versus dualsteric (i.e. active) binding modes. We propose that this concept may explain why agonist·receptor complexes can be inactive and that adopting multiple binding modes may be generalized also to small agonists where binding modes will be only subtly different and confined to only one binding site.

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

    PubMed Central

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

    2012-01-01

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

  12. Ligand Binding Ensembles Determine Graded Agonist Efficacies at a G Protein-coupled Receptor.

    PubMed

    Bock, Andreas; Bermudez, Marcel; Krebs, Fabian; Matera, Carlo; Chirinda, Brian; Sydow, Dominique; Dallanoce, Clelia; Holzgrabe, Ulrike; De Amici, Marco; Lohse, Martin J; Wolber, Gerhard; Mohr, Klaus

    2016-07-29

    G protein-coupled receptors constitute the largest family of membrane receptors and modulate almost every physiological process in humans. Binding of agonists to G protein-coupled receptors induces a shift from inactive to active receptor conformations. Biophysical studies of the dynamic equilibrium of receptors suggest that a portion of receptors can remain in inactive states even in the presence of saturating concentrations of agonist and G protein mimetic. However, the molecular details of agonist-bound inactive receptors are poorly understood. Here we use the model of bitopic orthosteric/allosteric (i.e. dualsteric) agonists for muscarinic M2 receptors to demonstrate the existence and function of such inactive agonist·receptor complexes on a molecular level. Using all-atom molecular dynamics simulations, dynophores (i.e. a combination of static three-dimensional pharmacophores and molecular dynamics-based conformational sampling), ligand design, and receptor mutagenesis, we show that inactive agonist·receptor complexes can result from agonist binding to the allosteric vestibule alone, whereas the dualsteric binding mode produces active receptors. Each agonist forms a distinct ligand binding ensemble, and different agonist efficacies depend on the fraction of purely allosteric (i.e. inactive) versus dualsteric (i.e. active) binding modes. We propose that this concept may explain why agonist·receptor complexes can be inactive and that adopting multiple binding modes may be generalized also to small agonists where binding modes will be only subtly different and confined to only one binding site. PMID:27298318

  13. 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

  14. Octopaminergic agonists for the cockroach neuronal octopamine receptor

    PubMed Central

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

    2003-01-01

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

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

    PubMed

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

    2008-04-01

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

  16. Synthesis of fluorinated agonist of sphingosine-1-phosphate receptor 1.

    PubMed

    Aliouane, Lucie; Chao, Sovy; Brizuela, Leyre; Pfund, Emmanuel; Cuvillier, Olivier; Jean, Ludovic; Renard, Pierre-Yves; Lequeux, Thierry

    2014-09-01

    The bioactive metabolite sphingosine-1-phosphate (S1P), a product of sphingosine kinases (SphKs), mediates diverse biological processes such as cell differentiation, proliferation, survival and angiogenesis. A fluorinated analogue of S1P receptor agonist has been synthesized by utilizing a ring opening reaction of oxacycles by a lithiated difluoromethylphosphonate anion as the key reaction. In vitro activity of this S1P analogue is also reported.

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

    PubMed

    Lee, Mei Yan; Diamond, Scott L

    2015-02-01

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

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

    PubMed

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

    2010-12-01

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

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

    PubMed

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

    2010-12-01

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

  20. Antipsychotic Induced Symptomatic Hyperprolactinemia: Are Dopamine Agonists Safe?

    PubMed Central

    Lertxundi, Unax; Domingo-Echaburu, Saioa; Peral, Javier; García, Montserrat

    2011-01-01

    Published literature shows that dopamine agonists can reverse antipsychotic-induced hyperprolactinemia without worsening psychotic symptoms in the majority of schizophrenic patients. However, psychiatrists have been reluctant to use drugs with dopaminergic properties for fear of exacerbating psychiatric symptoms. There are reported cases of psychosis worsening published for both cabergoline and bromocriptine. Cabergoline has proven to be more effective and safe when used to treat hyperprolactinemia, but whether cabergoline is also safer than bromocriptine in antipsychotic induced hyperprolactinemia remains unproven.

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

    PubMed

    Lee, Mei Yan; Diamond, Scott L

    2015-02-01

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

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

    SciTech Connect

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

    2010-09-17

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

  3. 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

  4. Gonadotropin-releasing hormone agonist-induced pituitary apoplexy

    PubMed Central

    Keane, Fergus; Navin, Patrick; Brett, Francesca; Dennedy, Michael C

    2016-01-01

    Summary Pituitary apoplexy represents an uncommon endocrine emergency with potentially life-threatening consequences. Drug-induced pituitary apoplexy is a rare but important consideration when evaluating patients with this presentation. We describe an unusual case of a patient with a known pituitary macroadenoma presenting with acute-onset third nerve palsy and headache secondary to tumour enlargement and apoplexy. This followed gonadotropin-releasing hormone (GNRH) agonist therapy used to treat metastatic prostate carcinoma. Following acute management, the patient underwent transphenoidal debulking of his pituitary gland with resolution of his third nerve palsy. Subsequent retrospective data interpretation revealed that this had been a secretory gonadotropinoma and GNRH agonist therapy resulted in raised gonadotropins and testosterone. Hence, further management of his prostate carcinoma required GNRH antagonist therapy and external beam radiotherapy. This case demonstrates an uncommon complication of GNRH agonist therapy in the setting of a pituitary macroadenoma. It also highlights the importance of careful, serial data interpretation in patients with pituitary adenomas. Finally, this case presents a unique insight into the challenges of managing a hormonal-dependent prostate cancer in a patient with a secretory pituitary tumour. Learning points While non-functioning gonadotropinomas represent the most common form of pituitary macroadenoma, functioning gonadotropinomas are exceedingly rare. Acute tumour enlargement, with potential pituitary apoplexy, is a rare but important adverse effect arising from GNRH agonist therapy in the presence of both functioning and non-functioning pituitary gonadotropinomas. GNRH antagonist therapy represents an alternative treatment option for patients with hormonal therapy-requiring prostate cancer, who also have diagnosed with a pituitary gonadotropinoma. PMID:27284452

  5. Increased flow precedes remote arteriolar dilations for some microapplied agonists.

    PubMed

    Frame, M D

    2000-04-01

    This study asks which occurs first in time for remote responses: a dilation or a remote change in flow. Arteriolar diameter (approximately 20 microm) and fluorescently labeled red blood cell (RBC) velocity were measured in the cremaster muscle of anesthetized (pentobarbital sodium, 70 mg/kg) hamsters (n = 51). Arterioles were locally stimulated for 60 s with micropipette-applied 10 microg/ml LM-609 (alpha(v)beta(3)-integrin agonist), 10(-3) M adenosine, or 10(-3) M 3-morpholinosydnonimine (SIN-1, nitric oxide donor) as remote response agonists or with 10(-3) M papaverine, which dilates only locally. Observations were made at a remote site 1,200 microm upstream. With LM-609 or adenosine, the RBC velocity increased first (within 5 s), and the remote dilation followed 5-7 s later. N-nitro-L-arginine (100 microM) blocked the LM-609 (100%) and adenosine (60%) remote dilations. SIN-1 induced a concurrent remote dilation and decrease in RBC velocity (approximately 10 s), suggesting the primary signal was to dilate. Papaverine had no remote effects. This study suggests that, although remote responses to some agonists are induced by primary signals to dilate, additionally, network changes in flow can stimulate extensive remote changes in diameter.

  6. Suppression of atherosclerosis by synthetic REV-ERB agonist

    SciTech Connect

    Sitaula, Sadichha; Billon, Cyrielle; Kamenecka, Theodore M.; Solt, Laura A.; Burris, Thomas P.

    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 compared 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.

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

    PubMed

    Pertwee, Roger G

    2009-02-01

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

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

    PubMed

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

    2014-05-01

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

  9. Structure of the agonist-bound neurotensin receptor.

    PubMed

    White, Jim F; Noinaj, Nicholas; Shibata, Yoko; Love, James; Kloss, Brian; Xu, Feng; Gvozdenovic-Jeremic, Jelena; Shah, Priyanka; Shiloach, Joseph; Tate, Christopher G; Grisshammer, Reinhard

    2012-10-25

    Neurotensin (NTS) is a 13-amino-acid peptide that functions as both a neurotransmitter and a hormone through the activation of the neurotensin receptor NTSR1, a G-protein-coupled receptor (GPCR). In the brain, NTS modulates the activity of dopaminergic systems, opioid-independent analgesia, and the inhibition of food intake; in the gut, NTS regulates a range of digestive processes. Here we present the structure at 2.8 Å resolution of Rattus norvegicus NTSR1 in an active-like state, bound to NTS(8-13), the carboxy-terminal portion of NTS responsible for agonist-induced activation of the receptor. The peptide agonist binds to NTSR1 in an extended conformation nearly perpendicular to the membrane plane, with the C terminus oriented towards the receptor core. Our findings provide, to our knowledge, the first insight into the binding mode of a peptide agonist to a GPCR and may support the development of non-peptide ligands that could be useful in the treatment of neurological disorders, cancer and obesity.

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

    PubMed

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

    2014-05-01

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

  11. Meclizine is an agonist ligand for mouse constitutive androstane receptor (CAR) and an inverse agonist for human CAR.

    PubMed

    Huang, Wendong; Zhang, Jun; Wei, Ping; Schrader, William T; Moore, David D

    2004-10-01

    The constitutive androstane receptor (CAR, NR1I3) is a key regulator of xenobiotic and endobiotic metabolism. The ligand-binding domains of murine (m) and human (h) CAR are divergent relative to other nuclear hormone receptors, resulting in species-specific differences in xenobiotic responses. Here we identify the widely used antiemetic meclizine (Antivert; Bonine) as both an agonist ligand for mCAR and an inverse agonist for hCAR. Meclizine increases mCAR transactivation in a dose-dependent manner. Like the mCAR agonist 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene, meclizine stimulates binding of steroid receptor coactivator 1 to the murine receptor in vitro. Meclizine administration to mice increases expression of CAR target genes in a CAR-dependent manner. In contrast, meclizine suppresses hCAR transactivation and inhibits the phenobarbital-induced expression of the CAR target genes, cytochrome p450 monooxygenase (CYP)2B10, CYP3A11, and CYP1A2, in primary hepatocytes derived from mice expressing hCAR, but not mCAR. The inhibitory effect of meclizine also suppresses acetaminophen-induced liver toxicity in humanized CAR mice. These results demonstrate that a single compound can induce opposite xenobiotic responses via orthologous receptors in rodents and humans. PMID:15272053

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

    PubMed

    Maguire, David R; France, Charles P

    2016-02-01

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

  13. Different serotonin receptor agonists have distinct effects on sound-evoked responses in inferior colliculus.

    PubMed

    Hurley, Laura M

    2006-11-01

    The neuromodulator serotonin has a complex set of effects on the auditory responses of neurons within the inferior colliculus (IC), a midbrain auditory nucleus that integrates a wide range of inputs from auditory and nonauditory sources. To determine whether activation of different types of serotonin receptors is a source of the variability in serotonergic effects, four selective agonists of serotonin receptors in the serotonin (5-HT) 1 and 5-HT2 families were iontophoretically applied to IC neurons, which were monitored for changes in their responses to auditory stimuli. Different agonists had different effects on neural responses. The 5-HT1A agonist had mixed facilitatory and depressive effects, whereas 5-HT1B and 5-HT2C agonists were both largely facilitatory. Different agonists changed threshold and frequency tuning in ways that reflected their effects on spike count. When pairs of agonists were applied sequentially to the same neurons, selective agonists sometimes affected neurons in ways that were similar to serotonin, but not to other selective agonists tested. Different agonists also differentially affected groups of neurons classified by the shapes of their frequency-tuning curves, with serotonin and the 5-HT1 receptors affecting proportionally more non-V-type neurons relative to the other agonists tested. In all, evidence suggests that the diversity of serotonin receptor subtypes in the IC is likely to account for at least some of the variability of the effects of serotonin and that receptor subtypes fulfill specialized roles in auditory processing. PMID:16870843

  14. Temporal differentiation in two strains of small rodents: a wood mouse (Apodemus sylvaticus) and an albino mouse (Mus musculus OF1).

    PubMed

    Lejeune, H; Huynen, M C.; Ferrara, A

    2000-12-01

    Wood mice (Apodemus sylvaticus) and OF1 albino mice (Mus musculus) were compared over durations ranging from 0.5 to 7 s, using the differential reinforcement of response duration schedule (DRRD) and a 'platform' response, i.e. staying on a small platform for a specified criterion duration to be reinforced. Species-related differences were found for mean response durations, efficiency and the number of trials needed to reach a preset performance criterion. Coefficients of variation of response durations did not differ. Overall, OF1 mice needed more trials than wood mice to reach a temporal criterion. However, over 3-7 s, data from both strains almost fitted the behavioral assumptions of Scalar Timing theory. Performance of mongolian gerbils (Meriones unguiculatus) trained in a similar setting was shown for visual comparison.

  15. [The role of hybrid zones in speciation: a case study on chromosome races of the house mouse Mus domesticus and common shrew Sorex araneus].

    PubMed

    Lavrenchenko, L A; Bulatova, N Sh

    2015-01-01

    Although diverse complexes of chromosome races are of rather rare occurrence in mammals, that does not reduce its importance to insignificant phenomenon not worthy of studying as some unique case without direct analogy. Moreover, these complexes present virtually ideal models for estimation of the impact of hybridization on the process of microevolution. The chromosome races are characterized by almost zero level of genetic differentiation and well-defined distinctions, usually induced by chromosome rearrangements only. The presented review shows the valuable contribution of the studies on Sorex araneus and Mus domesticus chromosome Robertsonian systems into our understanding of varied impacts of hybridization on the speciation process. Particularly, it promotes better understanding of such evolutionary phenomena as "reinforcement" of reproductive isolation in secondary contact zones between divergent populations, speciation without geographic separation ("divergence with gene flow"), and "zonal raciation". PMID:26353396

  16. Biochemical comparison of major histocompatibility complex molecules from different subspecies of Mus musculus: evidence for trans-specific evolution of alleles.

    PubMed

    Arden, B; Klein, J

    1982-04-01

    H-2 haplotypes were extracted from wild mice of three subspecies, Mus musculus domesticus, M. m. molossinus, and M. m. castaneus, that are known to have been separated from one another for some 1 to 2 million years. Serologically indistinguishable molecules controlled by some of the polymorphic H-2 loci were compared by tryptic peptide mapping, and the maps were found to be identical. In addition, a number of instances of biochemically indistinguishable H-2 molecules were found among wild mice and inbred strains of the M. m. domesticus subspecies. These findings suggest that some of the H-2 alleles have not altered for greater than 1 million years. To reconcile this apparent stability of H-2 genes with their extraordinary polymorphism (some 100 alleles at each of the polymorphic H-2 loci), it is proposed that the H-2 alleles evolve as if they were separate loci.

  17. Defining Nicotinic Agonist Binding Surfaces through Photoaffinity Labeling†

    PubMed Central

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

    2016-01-01

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

  18. Two New Species of Demodex (Acari: Demodecidae) with a Redescription of Demodex musculi and Data on Parasitism in Mus musculus (Rodentia: Muridae).

    PubMed

    Izdebska, Joanna N; Rolbiecki, Leszek

    2015-07-01

    This article describes two new skin mite species found on the house mouse Mus musculus L., 1758. Demodex marculus sp. nov. is a very small demodecid mite (adult stages, on average, 99 µm in length) found in mouse skin in the abdomen, back, limbs, and anal area. It is characterized by relatively large bossing hammer-shaped supracoxal spines, embedded in the trapezoidal gnathosoma. Demodex fusiformis sp. nov., in turn, is a little larger (adult stages on average 111 µm in length), with a small oval gnathosoma equipped with fine, knob-like supracoxal spines. It was found in the skin of abdomen, back, and limbs. Moreover, Demodex musculi (Oudemans, 1897) was redescribed, which is small demodecid mite (adult stages on average 142 µm in length) and characterized by relatively large morphological variation and considerable sexual dimorphism. The characteristic feature of this species is the strongly elongated and rectangular gnathosoma equipped with very large wedge-shaped supracoxal spines. D. musculi was found in the skin of various, haired regions of the mice body (head, neck, abdomen, back, limbs, genital-anal region, and tail). Moreover, one more demodecid mite was found in the skin of the examined mice, it was Demodex flagellurus Bukva, 1985, which was found only in the genital area. Overall infection of Mus musculus L. by all species of Demodex was with the prevalence of 100%, mean intensity of 24.0, and range of intensity of 1-109. Despite high infection levels, no symptoms of parasitosis were observed in the hosts. PMID:26335466

  19. A phylogeographic survey of the pygmy mouse Mus minutoides in South Africa: taxonomic and karyotypic inference from cytochrome b sequences of museum specimens.

    PubMed

    Chevret, Pascale; Robinson, Terence J; Perez, Julie; Veyrunes, Frédéric; Britton-Davidian, Janice

    2014-01-01

    The African pygmy mice (Mus, subgenus Nannomys) are a group of small-sized rodents that occur widely throughout sub-Saharan Africa. Chromosomal diversity within this group is extensive and numerous studies have shown the karyotype to be a useful taxonomic marker. This is pertinent to Mus minutoides populations in South Africa where two different cytotypes (2n = 34, 2n = 18) and a modification of the sex determination system (due to the presence of a Y chromosome in some females) have been recorded. This chromosomal diversity is mirrored by mitochondrial DNA sequences that unambiguously discriminate among the various pygmy mouse species and, importantly, the different M. minutoides cytotypes. However, the geographic delimitation and taxonomy of pygmy mice populations in South Africa is poorly understood. To address this, tissue samples of M. minutoides were taken and analysed from specimens housed in six South African museum collections. Partial cytochrome b sequences (400 pb) were successfully amplified from 44% of the 154 samples processed. Two species were identified: M. indutus and M. minutoides. The sequences of the M. indutus samples provided two unexpected features: i) nuclear copies of the cytochrome b gene were detected in many specimens, and ii) the range of this species was found to extend considerably further south than is presently understood. The phylogenetic analysis of the M. minutoides samples revealed two well-supported clades: a Southern clade which included the two chromosomal groups previously identified in South Africa, and an Eastern clade that extended from Eastern Africa into South Africa. Congruent molecular phylogenetic and chromosomal datasets permitted the tentative chromosomal assignments of museum specimens within the different clades as well as the correction of misidentified museum specimens.

  20. Genetic mapping of Cmv1 in the region of mouse chromosome 6 encoding the NK gene complex-associated loci Ly49 and musNKR-P1

    SciTech Connect

    Scalzo, A.A.; Lyons, P.A.; Fitzgerald, N.A.

    1995-06-10

    The Cmv1 resistance gene controls splenic replication of murine cytomegalovirus (MCMV) and confers natural killer (NK) cell-mediated resistance to otherwise lethal infection. The Cmv1 phenotypes of 13 inbred mouse strains have been assessed, and it was found that the Cmv1{sup r} resistance phenotype was restricted to the C57BL/6J and Ma/MyJ strains. We have further analyzed the linkage of Cmv1 to the NK gene complex (NKC) mapping to distal mouse chromosome 6 in 99 (BALB/c x C57BL/6J)F{sub 1} x BALB/c backcross mice using cloned gene probes and microsatellite markers from this region. No recombinants were observed between Cmv1 and the NKC-associated Ly49 and musNKR-P1 multigene families, nor the Kap locus, nor with 7 microsatellite markers, indicating that Cmv1 is closely linked (<1 cM) to all of these markers. Analysis of the genotype of the MCMV-susceptible BXD8 RI strain around the NKC region revealed that it had C57BL/6J alleles at microsatellite markers immediately proximal and distal to Cmv1. This suggests that the Cmv1{sup s} phenotype of this strain is due to a germ-line mutation. Thus, the close linkage of Cmv1 to the Ly49 and musNK-R-P1 multigene families suggests that it may represent an NK cell recognition structure encoded in the NKC region. 37 refs., 3 figs., 1 tab.

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

    PubMed

    Mahon, Eugene J

    2015-07-01

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

  2. Narrow SAR in odorant sensing Orco receptor agonists.

    PubMed

    Romaine, Ian M; Taylor, Robert W; Saidu, Samsudeen P; Kim, Kwangho; Sulikowski, Gary A; Zwiebel, Laurence J; Waterson, Alex G

    2014-06-15

    The systematic exploration of a series of triazole-based agonists of the cation channel insect odorant receptor is reported. The structure-activity relationships of independent sections of the molecules are examined. Very small changes to the compound structure were found to exert a large impact on compound activity. Optimal substitutions were combined using a 'mix-and-match' strategy to produce best-in-class compounds that are capable of potently agonizing odorant receptor activity and may form the basis for the identification of a new mode of insect behavior modification. PMID:24813736

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

    NASA Technical Reports Server (NTRS)

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

    1987-01-01

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

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

    PubMed

    Mahon, Eugene J

    2015-07-01

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

  5. Induction of depersonalization by the serotonin agonist meta-chlorophenylpiperazine.

    PubMed

    Simeon, D; Hollander, E; Stein, D J; DeCaria, C; Cohen, L J; Saoud, J B; Islam, N; Hwang, M

    1995-09-29

    Sixty-seven subjects, including normal volunteers and patients with obsessive-compulsive disorder, social phobia, and borderline personality disorder, received ratings of depersonalization after double-blind, placebo-controlled challenges with the partial serotonin agonist meta-chlorophenylpiperazine (m-CPP). Challenge with m-CPP induced depersonalization significantly more than did placebo. Subjects who became depersonalized did not differ in age, sex, or diagnosis from those who did not experience depersonalization. There was a significant correlation between the induction of depersonalization and increase in panic, but not nervousness, anxiety, sadness, depression, or drowsiness. This report suggests that serotonergic dysregulation may in part underlie depersonalization.

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

    PubMed

    Wang, Si; Bovee, Toine F H

    2016-01-01

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

  7. Discovery of a potent and selective GPR120 agonist.

    PubMed

    Shimpukade, Bharat; Hudson, Brian D; Hovgaard, Christine Kiel; Milligan, Graeme; Ulven, Trond

    2012-05-10

    GPR120 is a receptor of unsaturated long-chain fatty acids reported to mediate GLP-1 secretion, insulin sensitization, anti-inflammatory, and anti-obesity effects and is therefore emerging as a new potential target for treatment of type 2 diabetes and metabolic diseases. Further investigation is however hindered by the lack of suitable receptor modulators. Screening of FFA1 ligands provided a lead with moderate activity on GPR120 and moderate selectivity over FFA1. Optimization led to the discovery of the first potent and selective GPR120 agonist.

  8. Contamination with retinoic acid receptor agonists in two rivers in the Kinki region of Japan.

    PubMed

    Inoue, Daisuke; Nakama, Koki; Sawada, Kazuko; Watanabe, Taro; Takagi, Mai; Sei, Kazunari; Yang, Min; Hirotsuji, Junji; Hu, Jianying; Nishikawa, Jun-ichi; Nakanishi, Tsuyoshi; Ike, Michihiko

    2010-04-01

    This study was conducted to investigate the agonistic activity against human retinoic acid receptor (RAR) alpha in the Lake Biwa-Yodo River and the Ina River in the Kinki region of Japan. To accomplish this, a yeast two-hybrid assay was used to elucidate the spatial and temporal variations and potential sources of RARalpha agonist contamination in the river basins. RARalpha agonistic activity was commonly detected in the surface water samples collected along two rivers at different periods, with maximum all-trans retinoic acid (atRA) equivalents of 47.6 ng-atRA/L and 23.5 ng-atRA/L being observed in Lake Biwa-Yodo River and Ina River, respectively. The results indicated that RARalpha agonists are always present and widespread in the rivers. Comparative investigation of RARalpha and estrogen receptor alpha agonistic activities at 20 stations along each river revealed that the spatial variation pattern of RARalpha agonist contamination was entirely different from that of the estrogenic compound contamination. This suggests that the effluent from municipal wastewater treatment plants, a primary source of estrogenic compounds, seemed not to be the cause of RARalpha agonist contamination in the rivers. Fractionation using high performance liquid chromatography (HPLC) directed by the bioassay found two bioactive fractions from river water samples, suggesting the presence of at least two RARalpha agonists in the rivers. Although a trial conducted to identify RARalpha agonists in the major bioactive fraction was not completed as part of this study, comparison of retention times in HPLC analysis and quantification with liquid chromatography-mass spectrometry analysis revealed that the major causative contaminants responsible for the RARalpha agonistic activity were not RAs (natural RAR ligands) and 4-oxo-RAs, while 4-oxo-RAs were identified as the major RAR agonists in sewage in Beijing, China. These findings suggest that there are unknown RARalpha agonists with high

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

    SciTech Connect

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

    2010-09-27

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

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

    PubMed

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

    2009-06-01

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

  11. Discovery of potent and selective nonsteroidal indazolyl amide glucocorticoid receptor agonists.

    PubMed

    Sheppeck, James E; Gilmore, John L; Xiao, Hai-Yun; Dhar, T G Murali; Nirschl, David; Doweyko, Arthur M; Sack, Jack S; Corbett, Martin J; Malley, Mary F; Gougoutas, Jack Z; Mckay, Lorraine; Cunningham, Mark D; Habte, Sium F; Dodd, John H; Nadler, Steven G; Somerville, John E; Barrish, Joel C

    2013-10-01

    Modification of a phenolic lead structure based on lessons learned from increasing the potency of steroidal glucocorticoid agonists lead to the discovery of exceptionally potent, nonsteroidal, indazole GR agonists. SAR was developed to achieve good selectivity against other nuclear hormone receptors with the ultimate goal of achieving a dissociated GR agonist as measured by human in vitro assays. The specific interactions by which this class of compounds inhibits GR was elucidated by solving an X-ray co-crystal structure. PMID:23953070

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

    PubMed Central

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

    2015-01-01

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

  13. Effects of LAAM and methadone utilization in an opiate agonist treatment program.

    PubMed

    Valdivia, J F; Khattak, S

    2000-01-01

    The development and approval of levo-alpha-acetylmethadol (LAAM) as a pharmacotherapeutic agent in opioid agonist therapy provided an alternative to methadone. Clinicians recognized the potential benefits that LAAM, a synthetic mu agonist with pharmacological properties which differ from those of methadone,could have in the treatment management of addicts in opioid agonist therapy. We report our experience utilizing LAAM from 1995 to 1999 at the Hines VA opioid agonist therapy clinic. The addition of LAAM to the clinic's treatment armamentarium has resulted in management options that have improved the areas of patient recruitment, patient retention, patient traffic, take-home medication, detoxification, and treatment outcomes.

  14. Trial Watch: Immunostimulation with Toll-like receptor agonists in cancer therapy

    PubMed Central

    Iribarren, Kristina; Bloy, Norma; Buqué, Aitziber; Cremer, Isabelle; Eggermont, Alexander; Fridman, Wolf Hervé; Fucikova, Jitka; Galon, Jérôme; Špíšek, Radek; Zitvogel, Laurence; Kroemer, Guido; Galluzzi, Lorenzo

    2016-01-01

    ABSTRACT Accumulating preclinical evidence indicates that Toll-like receptor (TLR) agonists efficiently boost tumor-targeting immune responses (re)initiated by most, if not all, paradigms of anticancer immunotherapy. Moreover, TLR agonists have been successfully employed to ameliorate the efficacy of various chemotherapeutics and targeted anticancer agents, at least in rodent tumor models. So far, only three TLR agonists have been approved by regulatory agencies for use in cancer patients. Moreover, over the past decade, the interest of scientists and clinicians in these immunostimulatory agents has been fluctuating. Here, we summarize recent advances in the preclinical and clinical development of TLR agonists for cancer therapy. PMID:27141345

  15. Dopamine agonist-induced substance addiction: the next piece of the puzzle.

    PubMed

    Evans, Andrew

    2011-02-01

    Traditional antiparkinson treatment strategies strive to balance the antiparkinson effects of dopaminergic drugs with the avoidance of motor response complications. Dopamine agonists have an established role in delaying the emergence of motor response complications or reducing motor "off" periods. The recent recognition of a range of "behavioural addictions" that are linked to dopamine agonist use has highlighted the role of dopamine in brain reward function and addiction disorders in general. Dopamine agonists have now even been linked occasionally to new substance addictions. The challenge now for the Parkinsonologist is to also balance the net benefits of using dopamine agonists for their motor effects with avoiding the harm from behavioural compulsions. PMID:20980151

  16. Analysis of agonist dissociation constants as assessed by functional antagonism in guinea pig left atria

    SciTech Connect

    Molenaar, P.; Malta, E.

    1986-04-01

    In electrically driven guinea pig left atria, positive inotropic responses to (-)-isoprenaline and the selective beta 1-adrenoceptor agonist RO363 were obtained in the absence and in the presence of the functional antagonists adenosine, carbachol, gallopamil, nifedipine, and Ro 03-7894. Each of the functional antagonists reduced the maximum response to both agonists and produced nonparallel rightward shifts in the cumulative concentration effect curves. For both agonists, dissociation constants (KA) were calculated using the equation described by Furchgott (1966) for irreversible antagonism. For RO363, which is a partial agonist with high agonist activity, the equations outlined for functional interaction by Mackay (1981) were also employed to calculate KA values. The KA values obtained by each method were compared with the dissociation constants (KD) for the two agonists determined from their ability to displace the radioligand (-)-(/sup 125/I)iodocyanopindolol from beta 1-adrenoceptors in guinea pig left atrial membrane preparations. The estimates of KA varied substantially from KD values. The KD values were taken as more accurate estimates of the true values for the dissociation constants because a high degree of correlation exists between pKD and pD2 values for a number of other beta-adrenoceptor agonists that behave as partial agonists and between pKD and pKB values for a number of beta-adrenoceptor antagonists. Thus, it appears that there are serious limitations in the current theory for using functional antagonism as a means of obtaining agonist dissociation constants.

  17. Structural complexes of the agonist, inverse agonist and antagonist bound C5a receptor: insights into pharmacology and signaling.

    PubMed

    Rana, Soumendra; Sahoo, Amita Rani; Majhi, Bharat Kumar

    2016-04-26

    The C5a receptor (C5aR) is a pharmacologically important G-protein coupled receptor (GPCR) that interacts with (h)C5a, by recruiting both the "orthosteric" sites (site1 at the N-terminus and site2 at the ECS, extra cellular surface) on C5aR in a two site-binding model. However, the complex pharmacological landscape and the distinguishing chemistry operating either at the "orthosteric" site1 or at the functionally important "orthosteric" site2 of C5aR are still not clear, which greatly limits the understanding of C5aR pharmacology. One of the major bottlenecks is the lack of an experimental structure or a refined model structure of C5aR with appropriately defined active sites. The study attempts to understand the pharmacology at the "orthosteric" site2 of C5aR rationally by generating a highly refined full-blown model structure of C5aR through advanced molecular modeling techniques, and further subjecting it to automated docking and molecular dynamics (MD) studies in the POPC bilayer. The first series of structural complexes of C5aR respectively bound to a linear native peptide agonist ((h)C5a-CT), a small molecule inverse agonist (NDT) and a cyclic peptide antagonist (PMX53) are reported, apparently establishing the unique pharmacological landscape of the "orthosteric" site2, which also illustrates an energetically distinct but coherent competitive chemistry ("cation-π" vs. "π-π" interactions) involved in distinguishing the established ligands known for targeting the "orthosteric" site2 of C5aR. Over a total of 1 μs molecular dynamics (MD) simulation in the POPC bilayer, it is evidenced that while the agonist prefers a "cation-π" interaction, the inverse agonist prefers a "cogwheel/L-shaped" interaction in contrast to the "edge-to-face/T-shaped" type π-π interactions demonstrated by the antagonist by engaging the F275(7.28) of the C5aR. In the absence of a NMR or crystallographically guided model structure of C5aR, the computational model complexes not only

  18. The house mouse (Mus musculus L.) exerts strong differential grain consumption preferences among hard red and white spring wheat (Triticum aestivum L.) varieties in a single-elimination tournament design

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Wheat (Triticum aestivum) plays a central role in the health and nutrition of humans. Yet, little is known about possible flavor differences among different varieties. We have developed a model system using the house mouse (Mus musculus) to determine feeding preferences as a prelude to extending res...

  19. Serotonergic agonists stimulate inositol lipid metabolism in rabbit platelets

    SciTech Connect

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

    1985-10-28

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

  20. Long-Acting Beta Agonists Enhance Allergic Airway Disease

    PubMed Central

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

    2015-01-01

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

  1. Agonistic induction of PPARγ reverses cigarette smoke–induced emphysema

    PubMed Central

    Shan, Ming; You, Ran; Yuan, Xiaoyi; Frazier, Michael V.; Porter, Paul; Seryshev, Alexander; Hong, Jeong-Soo; Song, Li-zhen; Zhang, Yiqun; Hilsenbeck, Susan; Whitehead, Lawrence; Zarinkamar, Nazanin; Perusich, Sarah; Corry, David B.; Kheradmand, Farrah

    2014-01-01

    The development of emphysema in humans and mice exposed to cigarette smoke is promoted by activation of an adaptive immune response. Lung myeloid dendritic cells (mDCs) derived from cigarette smokers activate autoreactive Th1 and Th17 cells. mDC-dependent activation of T cell subsets requires expression of the SPP1 gene, which encodes osteopontin (OPN), a pleiotropic cytokine implicated in autoimmune responses. The upstream molecular events that promote SPP1 expression and activate mDCs in response to smoke remain unknown. Here, we show that peroxisome proliferator–activated receptor γ (PPARG/Pparg) expression was downregulated in mDCs of smokers with emphysema and mice exposed to chronic smoke. Conditional knockout of PPARγ in APCs using Cd11c-Cre Ppargflox/flox mice led to spontaneous lung inflammation and emphysema that resembled the phenotype of smoke-exposed mice. The inflammatory phenotype of Cd11c-Cre Ppargflox/flox mice required OPN, suggesting an antiinflammatory mechanism in which PPARγ negatively regulates Spp1 expression in the lung. A 2-month treatment with a PPARγ agonist reversed emphysema in WT mice despite continual smoke exposure. Furthermore, endogenous PPARγ agonists were reduced in the plasma of smokers with emphysema. These findings reveal a proinflammatory pathway, in which reduced PPARγ activity promotes emphysema, and suggest that targeting this pathway in smokers could prevent and reverse emphysema. PMID:24569375

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

    PubMed

    Hsu, Wei-Hsuan; Pan, Tzu-Ming

    2014-07-25

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

  3. Nicotinic acetylcholine receptor agonist attenuates ILC2-dependent airway hyperreactivity

    PubMed Central

    Galle-Treger, Lauriane; Suzuki, Yuzo; Patel, Nisheel; Sankaranarayanan, Ishwarya; Aron, Jennifer L.; Maazi, Hadi; Chen, Lin; Akbari, Omid

    2016-01-01

    Allergic asthma is a complex and chronic inflammatory disorder that is associated with airway hyperreactivity (AHR) and driven by Th2 cytokine secretion. Type 2 innate lymphoid cells (ILC2s) produce large amounts of Th2 cytokines and contribute to the development of AHR. Here, we show that ILC2s express the α7-nicotinic acetylcholine receptor (α7nAChR), which is thought to have an anti-inflammatory role in several inflammatory diseases. We show that engagement of a specific agonist with α7nAChR on ILC2s reduces ILC2 effector function and represses ILC2-dependent AHR, while decreasing expression of ILC2 key transcription factor GATA-3 and critical inflammatory modulator NF-κB, and reducing phosphorylation of upstream kinase IKKα/β. Additionally, the specific α7nAChR agonist reduces cytokine production and AHR in a humanized ILC2 mouse model. Collectively, our data suggest that α7nAChR expressed by ILC2s is a potential therapeutic target for the treatment of ILC2-mediated asthma. PMID:27752043

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

    PubMed

    Hsu, Wei-Hsuan; Pan, Tzu-Ming

    2014-07-25

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

  5. Mood disorders, circadian rhythms, melatonin and melatonin agonists.

    PubMed

    Quera Salva, M A; Hartley, S

    2012-01-01

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

  6. Pindolol--the pharmacology of a partial agonist.

    PubMed Central

    Clark, B J; Menninger, K; Bertholet, A

    1982-01-01

    1 Pindolol is a non-selective beta-adrenoceptor blocking agent; its affinity to adrenoceptors in guinea pig atria (beta 1) is not significantly different from that in guinea pig trachea (beta 1 + beta 2) and canine vascular smooth muscle (beta 2). 2 Pindolol displays a striking diversity of agonist activities in isolated tissues. Stimulant effects correspond to 40--50% of the maximum effects of isoprenaline in isolated kitten atria and guinea pig trachea and to only 10% in guinea pig atria. Effects in canine isolated mesenteric vessels are those of a full agonist, maximum responses equaling those of isoprenaline. These findings suggest that the stimulant effects of pindolol are exerted principally on beta 2-adrenoceptors. 3 Cardiac stimulation produced by pindolol in the dog is sufficient to compensate for the cardiac depression resulting from blockade of beta-adrenoceptors in the heart. Reductions in cardiac output and compensatory increases in total peripheral resistance do not occur or are much smaller than those produced by beta-adrenoceptor blocking agents lacking sympathomimetic activity. 4 Pindolol-induced relaxation of bronchial smooth muscle prevents or minimizes the bronchoconstrictor effects of injected spasmogens in the cat. 5 Pindolol has marked vasodilator activity, small doses reducing femoral and mesenteric vascular resistance by approximately 30%. Doses comparable to those used in hypertensive patients lower blood pressure by 20 mmHg in non-anaesthetized dogs. PMID:7049208

  7. Pharmacology and toxicology of Cannabis derivatives and endocannabinoid agonists.

    PubMed

    Gerra, Gilberto; Zaimovic, Amir; Gerra, Maria L; Ciccocioppo, Roberto; Cippitelli, Andrea; Serpelloni, Giovanni; Somaini, Lorenzo

    2010-01-01

    For centuries Cannabis sativa and cannabis extracts have been used in natural medicine. Delta(9)-tetrahydrocannabinol (THC) is the main active ingredient of Cannabis. THC seems to be responsible for most of the pharmacological and therapeutic actions of cannabis. In a few countries THC extracts (i.e. Sativex) or THC derivatives such as nabilone, and dronabinol are used in the clinic for the treatment of several pathological conditions like chemotherapy-induced nausea and vomiting, multiple sclerosis and glaucoma. On the other hand the severe side effects and the high abuse liability of these agents represent a serious limitation in their medical use. In addition, diversion in the use of these active ingredients for recreational purpose is a concern. Over recent years, alternative approaches using synthetic cannabinoid receptor agonists or agents acting as activators of the endocannabinoid systems are under scrutiny with the hope to develop more effective and safer clinical applications. Likely, in the near future few of these new molecules will be available for clinical use. The present article review recent study and patents with focus on the cannabinoid system as a target for the treatment of central nervous system disorders with emphasis on agonists. PMID:19832688

  8. Pharmacology and toxicology of Cannabis derivatives and endocannabinoid agonists.

    PubMed

    Gerra, Gilberto; Zaimovic, Amir; Gerra, Maria L; Ciccocioppo, Roberto; Cippitelli, Andrea; Serpelloni, Giovanni; Somaini, Lorenzo

    2010-01-01

    For centuries Cannabis sativa and cannabis extracts have been used in natural medicine. Delta(9)-tetrahydrocannabinol (THC) is the main active ingredient of Cannabis. THC seems to be responsible for most of the pharmacological and therapeutic actions of cannabis. In a few countries THC extracts (i.e. Sativex) or THC derivatives such as nabilone, and dronabinol are used in the clinic for the treatment of several pathological conditions like chemotherapy-induced nausea and vomiting, multiple sclerosis and glaucoma. On the other hand the severe side effects and the high abuse liability of these agents represent a serious limitation in their medical use. In addition, diversion in the use of these active ingredients for recreational purpose is a concern. Over recent years, alternative approaches using synthetic cannabinoid receptor agonists or agents acting as activators of the endocannabinoid systems are under scrutiny with the hope to develop more effective and safer clinical applications. Likely, in the near future few of these new molecules will be available for clinical use. The present article review recent study and patents with focus on the cannabinoid system as a target for the treatment of central nervous system disorders with emphasis on agonists.

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

    PubMed Central

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

    2015-01-01

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

  10. How does agonistic behaviour differ in albino and pigmented fish?

    PubMed Central

    Horký, Pavel; Wackermannová, Marie

    2016-01-01

    In addition to hypopigmentation of the skin and red iris colouration, albino animals also display distinct physiological and behavioural alterations. However, information on the social interactions of albino animals is rare and has mostly been limited to specially bred strains of albino rodents and animals from unique environments in caves. Differentiating between the effects of albinism and domestication on behaviour in rodents can be difficult, and social behaviour in cave fish changes according to species-specific adaptations to conditions of permanent darkness. The agonistic behaviours of albino offspring of pigmented parents have yet to be described. In this study, we observed agonistic behaviour in albino and pigmented juvenile Silurus glanis catfish. We found that the total number of aggressive interactions was lower in albinos than in pigmented catfish. The distance between conspecifics was also analysed, and albinos showed a tendency towards greater separation from their same-coloured conspecifics compared with pigmented catfish. These results demonstrate that albinism can be associated with lower aggressiveness and with reduced shoaling behaviour preference, as demonstrated by a tendency towards greater separation of albinos from conspecifics. PMID:27114883

  11. Modulation of PPAR subtype selectivity. Part 2: Transforming PPARα/γ dual agonist into α selective PPAR agonist through bioisosteric modification.

    PubMed

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

    2011-01-15

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

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed Central

    Velázquez-Martínez, D N; López Cabrera, M; Sánchez, H; Ramírez, J I; Hong, E

    1999-01-01

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

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

    PubMed Central

    Maguire, David R.

    2014-01-01

    Cannabinoid receptor agonists, such as Δ9-tetrahydrocannabinol (Δ9-THC), enhance the antinociceptive effects of μ-opioid receptor agonists, which suggests that combining cannabinoids with opioids would improve pain treatment. Combinations with lower efficacy agonists might be preferred and could avoid adverse effects associated with large doses; however, it is unclear whether interactions between opioids and cannabinoids vary across drugs with different efficacy. The antinociceptive effects of μ-opioid receptor agonists alone and in combination with cannabinoid receptor agonists were studied in rhesus monkeys (n = 4) using a warm water tail withdrawal procedure. Etorphine, fentanyl, morphine, buprenorphine, nalbuphine, Δ9-THC, and CP 55,940 (2-[(1R,2R,5R)-5-hydroxy-2-(3-hydroxypropyl) cyclohexyl]-5-(2-methyloctan-2-yl)phenol) each increased tail withdrawal latency. Pretreatment with doses of Δ9-THC (1.0 mg/kg) or CP 55,940 (0.032 mg/kg) that were ineffective alone shifted the fentanyl dose-effect curve leftward 20.6- and 52.9-fold, respectively, and the etorphine dose-effect curve leftward 12.4- and 19.6-fold, respectively. Δ9-THC and CP 55,940 shifted the morphine dose-effect curve leftward only 3.4- and 7.9-fold, respectively, and the buprenorphine curve only 5.4- and 4.1-fold, respectively. Neither Δ9-THC nor CP 55,940 significantly altered the effects of nalbuphine. Cannabinoid receptor agonists increase the antinociceptive potency of higher efficacy opioid receptor agonists more than lower efficacy agonists; however, because much smaller doses of each drug can be administered in combinations while achieving adequate pain relief and that other (e.g., abuse-related) effects of opioids do not appear to be enhanced by cannabinoids, these results provide additional support for combining opioids with cannabinoids to treat pain. PMID:25194020

  15. Yawning and locomotor behavior induced by dopamine receptor agonists in mice and rats.

    PubMed

    Li, Su-Min; Collins, Gregory T; Paul, Noel M; Grundt, Peter; Newman, Amy H; Xu, Ming; Grandy, David K; Woods, James H; Katz, Jonathan L

    2010-05-01

    Dopaminergic (DA) agonist-induced yawning in rats seems to be mediated by DA D3 receptors, and low doses of several DA agonists decrease locomotor activity, an effect attributed to presynaptic D2 receptors. Effects of several DA agonists on yawning and locomotor activity were examined in rats and mice. Yawning was reliably produced in rats, and by the cholinergic agonist, physostigmine, in both the species. However, DA agonists were ineffective in producing yawning in Swiss-Webster or DA D2R and DA D3R knockout or wild-type mice. The drugs significantly decreased locomotor activity in rats at one or two low doses, with activity returning to control levels at higher doses. In mice, the drugs decreased locomotion across a 1000-10 000-fold range of doses, with activity at control levels (U-91356A) or above control levels [(+/-)-7-hydroxy-2-dipropylaminotetralin HBr, quinpirole] at the highest doses. Low doses of agonists decreased locomotion in all mice except the DA D2R knockout mice, but were not antagonized by DA D2R or D3R antagonists (L-741 626, BP 897, or PG01037). Yawning does not provide a selective in-vivo indicator of DA D3R agonist activity in mice. Decreases in mouse locomotor activity by the DA agonists seem to be mediated by D2 DA receptors.

  16. Prolonging Survival of Corneal Transplantation by Selective Sphingosine-1-Phosphate Receptor 1 Agonist

    PubMed Central

    Gao, Min; Liu, Yong; Xiao, Yang; Han, Gencheng; Jia, Liang; Wang, Liqiang; Lei, Tian; Huang, Yifei

    2014-01-01

    Corneal transplantation is the most used therapy for eye disorders. Although the cornea is somewhat an immune privileged organ, immune rejection is still the major problem that reduces the success rate. Therefore, effective chemical drugs that regulate immunoreactions are needed to improve the outcome of corneal transplantations. Here, a sphingosine-1-phosphate receptor 1 (S1P1) selective agonist was systematically evaluated in mouse allogeneic corneal transplantation and compared with the commonly used immunosuppressive agents. Compared with CsA and the non-selective sphingosine 1-phosphate (S1P) receptor agonist FTY720, the S1P1 selective agonist can prolong the survival corneal transplantation for more than 30 days with a low immune response. More importantly, the optimal dose of the S1P1 selective agonist was much less than non-selective S1P receptor agonist FTY720, which would reduce the dose-dependent toxicity in drug application. Then we analyzed the mechanisms of the selected S1P1 selective agonist on the immunosuppression. The results shown that the S1P1 selective agonist could regulate the distribution of the immune cells with less CD4+ T cells and enhanced Treg cells in the allograft, moreover the expression of anti-inflammatory cytokines TGF-β1 and IL-10 unregulated which can reduce the immunoreactions. These findings suggest that S1P1 selective agonist may be a more appropriate immunosuppressive compound to effectively prolong mouse allogeneic corneal grafts survival. PMID:25216235

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

    PubMed

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

    2008-08-01

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

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed Central

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

    2012-01-01

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

  20. Proopiomelanocortin Deficiency Treated with a Melanocortin-4 Receptor Agonist.

    PubMed

    Kühnen, Peter; Clément, Karine; Wiegand, Susanna; Blankenstein, Oliver; Gottesdiener, Keith; Martini, Lea L; Mai, Knut; Blume-Peytavi, Ulrike; Grüters, Annette; Krude, Heiko

    2016-07-21

    Patients with rare defects in the gene encoding proopiomelanocortin (POMC) have extreme early-onset obesity, hyperphagia, hypopigmentation, and hypocortisolism, resulting from the lack of the proopiomelanocortin-derived peptides melanocyte-stimulating hormone and corticotropin. In such patients, adrenal insufficiency must be treated with hydrocortisone early in life. No effective pharmacologic treatments have been available for the hyperphagia and obesity that characterize the condition. In this investigator-initiated, open-label study, two patients with proopiomelanocortin deficiency were treated with setmelanotide, a new melanocortin-4 receptor agonist. The patients had a sustainable reduction in hunger and substantial weight loss (51.0 kg after 42 weeks in Patient 1 and 20.5 kg after 12 weeks in Patient 2). PMID:27468060

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

    PubMed

    Soldevila, Berta; Puig-Domingo, Manel

    2014-01-01

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

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

    PubMed

    Soldevila, Berta; Puig-Domingo, Manel

    2014-09-01

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

  3. Locomotion induced by ventral tegmental microinjections of a nicotinic agonist.

    PubMed

    Museo, E; Wise, R A

    1990-03-01

    Bilateral microinjections of the nicotinic agonist cytisine (0.1, 1 or 10 nanomoles per side) into the ventral tegmental area increased locomotor activity. This increase in locomotion was antagonized by mecamylamine (2 mg/kg, IP), a nicotinic antagonist that readily crosses the blood-brain barrier, and by pimozide (0.3 mg/kg, IP), a central dopaminergic antagonist. Hexamethonium (2 mg/kg, IP), a nicotinic antagonist that, unlike mecamylamine, does not cross the blood-brain barrier, had no effect; this suggests that mecamylamine's attenuation of cytisine-induced locomotor activity resulted from a blockade of central and not peripheral nicotinic receptors. The data support the notion that nicotinic and dopaminergic substrates interact at the level of the VTA to produce increases in locomotor activity.

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

    PubMed

    Crane, James; McGowan, Barbara

    2016-03-01

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

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

    PubMed Central

    Crane, James; McGowan, Barbara

    2015-01-01

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

  6. Effects of dopamine agonists on hypothalamic defensive attack in cats.

    PubMed

    Maeda, H; Sato, T; Maki, S

    1985-07-01

    The effects of methamphetamine (MAT) and apomorphine (APO), dopamine agonists, were studied in 16 cats to evaluate their effects on threshold for defensive attack behavior elicited by electrical stimulation of the ventromedial hypothalamic nucleus (VMH). Directed attack and hissing were selected from elementary responses as constituting a defensive attack. Hissing threshold was measured in two situations, one with human provocation and the other without provocation. MAT administered systemically lowered the thresholds for all three types of responses in a dose-related manner (0.5, 1.0, and 3.0 mg/kg). The effects of 1.0 mg/kg of APO were almost identical to those observed with 0.5 or 1.0 mg/kg of MAT. These results suggest that MAT-induced aggressive behavior may be mediated by a dopamine-induced increase in the excitability of the VMH. PMID:4059404

  7. Antiinfective applications of toll-like receptor 9 agonists.

    PubMed

    Krieg, Arthur M

    2007-07-01

    The innate immune system detects pathogens by the presence of highly conserved pathogen-expressed molecules, which trigger host immune defenses. Toll-like receptor (TLR) 9 detects unmethylated CpG dinucleotides in bacterial or viral DNA, and can be stimulated for therapeutic applications with synthetic oligodeoxynucleotides containing immune stimulatory "CpG motifs." TLR9 activation induces both innate and adaptive immunity. The TLR9-induced innate immune activation can be applied in the prevention or treatment of infectious diseases, and the adaptive immune-enhancing effects can be harnessed for improving vaccines. This article highlights the current understanding of the mechanism of action of CpG oligodeoxynucleotides, and provides an overview of the preclinical data and early human clinical trial results, applying these TLR9 agonists in the field of infectious diseases. PMID:17607015

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

    PubMed Central

    Frank, Guido K. W.

    2014-01-01

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

  9. Asimadoline, a κ-Opioid Agonist, and Visceral Sensation

    PubMed Central

    Camilleri, Michael

    2009-01-01

    SUMMARY Asimadoline is a potent κ-opioid receptor agonist with a diaryl acetamide structure. It has high affinity for the κ receptor, with IC50 of 5.6 nM (guinea pig) and 1.2 nM (human recombinant), and high selectively with κ: μ: δ binding ratios of 1:501:498 in human recombinant receptors. It acts as a complete agonist in in vitro assay. Asimadoline reduced sensation in response to colonic distension at subnoxious pressures in healthy volunteers and in IBS patients without alteration of colonic compliance. Asimadoline reduced satiation and enhanced the postprandial gastric volume (in female volunteers). However, there were no significant effects on gastrointestinal transit, colonic compliance, fasting or postprandial colonic tone. In a clinical trial in 40 patients with functional dyspepsia (Rome II), asimadoline did not significantly alter satiation or symptoms over 8 weeks. However, asimadoline, 0.5 mg, significantly decreased satiation in patients with higher postprandial fullness scores, and daily postprandial fullness severity (over 8 weeks); the asimadoline 1.0 mg group was borderline significant. In a clinical trial in patients with IBS, average pain 2 hours post-on-demand treatment with asimadoline was not significantly reduced. Post-hoc analyses suggest asimadoline was effective in mixed IBS. In a 12-week study in 596 patients, chronic treatment with asimadoline, 0.5 mg and 1.0 mg, was associated with adequate relief of pain and discomfort, improvement in pain score and number of pain free days in patients with IBS-D. The 1.0 mg dose was also efficacious in IBS-alternating. There were also weeks with significant reduction in bowel frequency and urgency. Asimadoline has been well tolerated in human trials to date. PMID:18715494

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

    PubMed Central

    Carey, Elizabeth J.; Lindor, Keith D.

    2015-01-01

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

  11. Theory of partial agonist activity of steroid hormones

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2011-07-01

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

  13. Agonist-specific behaviour of the intracellular Ca2+ response in rat hepatocytes.

    PubMed Central

    Chatton, J Y; Cao, Y; Stucki, J W

    1997-01-01

    A variety of agonists stimulate in hepatocytes a response that takes the shape of repetitive cytosolic free Ca2+ transients called Ca2+ oscillations. The shape of spikes and the pattern of oscillations in a given cell differ depending on the agonist of the phosphoinositide pathway that is applied. In this study, the response of individual rat hepatocytes to maximal stimulation by arginine vasopressin (AVP), phenylephrine and ADP was investigated by fluorescence microscopy and flash photolysis. Hepatocytes loaded with Ca2+-sensitive probes were stimulated with a first agonist to evoke a maximal response, and then a second agonist was added. When phenylephrine or ADP was used as the first agonist, AVP applied subsequently could elicit an additional response, which did not happen when AVP was first applied and phenylephrine or ADP was applied later. Cells microinjected with caged myo-inositol 1,4,5-trisphosphate (IP3) were challenged with the different agonists and, when a maximal response was obtained, photorelease of IP3 was triggered. Cells maximally stimulated with AVP did not respond to IP3 photorelease, whereas those stimulated with phenylephrine or ADP responded with a fast Ca2+ spike above the elevated steady-state level, which was followed by an undershoot. In contrast, with all three agonists, IP3 photorelease triggered at the top of an oscillatory Ca2+ transient was able to mobilize additional Ca2+. These experiments indicate that the differential response of cells to agonists is found not only during Ca2+ oscillations but also during maximal agonist stimulation and that potency and efficacy differences exist among agonists. PMID:9371717

  14. Dissociated sterol-based liver X receptor agonists as therapeutics for chronic inflammatory diseases.

    PubMed

    Yu, Shan; Li, Sijia; Henke, Adam; Muse, Evan D; Cheng, Bo; Welzel, Gustav; Chatterjee, Arnab K; Wang, Danling; Roland, Jason; Glass, Christopher K; Tremblay, Matthew

    2016-07-01

    Liver X receptor (LXR), a nuclear hormone receptor, is an essential regulator of immune responses. Activation of LXR-mediated transcription by synthetic agonists, such as T0901317 and GW3965, attenuates progression of inflammatory disease in animal models. However, the adverse effects of these conventional LXR agonists in elevating liver lipids have impeded exploitation of this intriguing mechanism for chronic therapy. Here, we explore the ability of a series of sterol-based LXR agonists to alleviate inflammatory conditions in mice without hepatotoxicity. We show that oral treatment with sterol-based LXR agonists in mice significantly reduces dextran sulfate sodium colitis-induced body weight loss, which is accompanied by reduced expression of inflammatory markers in the large intestine. The anti-inflammatory property of these agonists is recapitulated in vitro in mouse lamina propria mononuclear cells, human colonic epithelial cells, and human peripheral blood mononuclear cells. In addition, treatment with LXR agonists dramatically suppresses inflammatory cytokine expression in a model of traumatic brain injury. Importantly, in both disease models, the sterol-based agonists do not affect the liver, and the conventional agonist T0901317 results in significant liver lipid accumulation and injury. Overall, these results provide evidence for the development of sterol-based LXR agonists as novel therapeutics for chronic inflammatory diseases.-Yu, S., Li, S., Henke, A., Muse, E. D., Cheng, B., Welzel, G., Chatterjee, A. K., Wang, D., Roland, J., Glass, C. K., Tremblay, M. Dissociated sterol-based liver X receptor agonists as therapeutics for chronic inflammatory diseases. PMID:27025962

  15. Allosteric coupling from G protein to the agonist-binding pocket in GPCRs.

    PubMed

    DeVree, Brian T; Mahoney, Jacob P; Vélez-Ruiz, Gisselle A; Rasmussen, Soren G F; Kuszak, Adam J; Edwald, Elin; Fung, Juan-Jose; Manglik, Aashish; Masureel, Matthieu; Du, Yang; Matt, Rachel A; Pardon, Els; Steyaert, Jan; Kobilka, Brian K; Sunahara, Roger K

    2016-07-01

    G-protein-coupled receptors (GPCRs) remain the primary conduit by which cells detect environmental stimuli and communicate with each other. Upon activation by extracellular agonists, these seven-transmembrane-domain-containing receptors interact with heterotrimeric G proteins to regulate downstream second messenger and/or protein kinase cascades. Crystallographic evidence from a prototypic GPCR, the β2-adrenergic receptor (β2AR), in complex with its cognate G protein, Gs, has provided a model for how agonist binding promotes conformational changes that propagate through the GPCR and into the nucleotide-binding pocket of the G protein α-subunit to catalyse GDP release, the key step required for GTP binding and activation of G proteins. The structure also offers hints about how G-protein binding may, in turn, allosterically influence ligand binding. Here we provide functional evidence that G-protein coupling to the β2AR stabilizes a ‘closed’ receptor conformation characterized by restricted access to and egress from the hormone-binding site. Surprisingly, the effects of G protein on the hormone-binding site can be observed in the absence of a bound agonist, where G-protein coupling driven by basal receptor activity impedes the association of agonists, partial agonists, antagonists and inverse agonists. The ability of bound ligands to dissociate from the receptor is also hindered, providing a structural explanation for the G-protein-mediated enhancement of agonist affinity, which has been observed for many GPCR–G-protein pairs. Our data also indicate that, in contrast to agonist binding alone, coupling of a G protein in the absence of an agonist stabilizes large structural changes in a GPCR. The effects of nucleotide-free G protein on ligand-binding kinetics are shared by other members of the superfamily of GPCRs, suggesting that a common mechanism may underlie G-protein-mediated enhancement of agonist affinity. PMID:27362234

  16. A new species of the genus Demodex Owen, 1843 (Acari: Demodecidae) from the ear canals of the house mouse Mus musculus L. (Rodentia: Muridae).

    PubMed

    Izdebska, Joanna N; Rolbiecki, Leszek

    2015-06-01

    A new species Demodex conicus n. sp. is described based on adult and juvenile stages from the ear canals of the house mouse Mus musculus L. in Poland. The new species is most similar to D. auricularis Izdebska, Rolbiecki & Fryderyk, 2014 from the ear canals of the wood mouse Apodemus sylvaticus (L.), but differs in the following features: the gnathosoma is triangular, the supracoxal spines (setae elc.p) are conical, the spines on the terminal segment of palp are four, the striation on opisthosoma is fine but dense, the vulva is located at a distance of c.17 µm from posterior level of legs IV, and the male genital opening is located at the level of legs I. The differences also relate to body size and proportions, female D. conicus n. sp. being, on average slightly larger, and male significantly larger than D. auricularis. Males of the new species also have longer and more massive opisthosoma than males of D. auricularis. Demodex conicus n. sp. was found in 17.5% of the mice studied from different locations in Poland. PMID:25962464

  17. A new genus and species of demodecid mites from the tongue of a house mouse Mus musculus: description of adult and immature stages with data on parasitism.

    PubMed

    Izdebska, J N; Rolbiecki, L

    2016-06-01

    The study of the parasitofauna of the house mouse Mus musculus (Rodentia: Muridae) Linnaeus is particularly important owing to its multiple relationships with humans - as a cosmopolitan, synanthropic rodent, bred for pets, food for other animals or laboratory animal. This article proposes and describes a new genus and species of the parasitic mite based on adult and immature stages from the house mouse. Glossicodex musculi gen. n., sp. n. is a medium-sized demodecid mite (adult stages on average 199 µm in length) found in mouse tissue of the tongue. It is characterized by two large, hooked claws on each tarsus of the legs; the legs are relatively massive, consisting of large, non-overlapping segments. The palps consist of three slender, clearly separated, relatively narrow segments, wherein their coxal segments are also quite narrow and spaced. Also, segments of the palps of larva and nymphs are clearly isolated, and on the terminal segment, trident claws that resemble legs' claws can be found. On the ventral side, in immature stages, triangular scuta, topped with sclerotized spur, can be also observed. Glossicodex musculi was noted in 10.8% of mice with a mean infection intensity of 2.2 parasites per host.

  18. Expression of alpha-synuclein during eye development of mice (Mus musculus), chick (Gallus gallus domisticus) and fish (Ctenopharyngodon idella) in a comparison study.

    PubMed

    Seleem, Amin A

    2015-08-01

    Synucleins are small proteins associated with neurodegenerative diseases, alpha-synuclein is a Parkinson's disease-linked protein of ubiquitous expression in the central nervous system. This study aimed at the localization of alpha-synuclein during eye development of mice (Mus musculus), chick (Gallus gallus domisticus) and fish (Ctenopharyngodon idella) by immunohistochemical staining in a comparison study. The results showed that alpha-synuclein expression increased gradually with the development of ciliary body, iris, retina and cornea of mice at E17, P1, P3, P7 and chick at E5, E10, E15 with unequal appearance of alpha-synuclein expression. Also, it was not detected in iridocorneal angle during eye development of mice and chick. Alpha-synuclein expression during fish eye development at P10, P15, P20 was not detected either in the ciliray body or Iris regions and it was pronounced with sharp signals in the highly specialized tissue of the iridocorneal angle at P20. Also, the expression was gradually increased from P15 to P20 in fish retina and cornea. The pattern of expression and distribution of alpha-synuclein during the development of ciliary body and iris of mice, chick and fish has not been previously characterized, The data concluded that alpha-synuclein has important cellular function during eye development of studied animals.

  19. The genus Aphidura (Hemiptera, Aphididae) in the collection of the Muséum national d’Histoire naturelle of Paris, with six new species

    PubMed Central

    Nieto Nafría, Juan-Manuel; Mier Durante, Milagros-Pilar; Remaudière, Georges

    2013-01-01

    Abstract Specimens were studied of 65 samples of the genus Aphidura (Aphididae, Aphidinae, Macrosiphini) from the collection of the Muséum national d’Histoire naturelle (Paris). The possible synonymies of three pairs of species are discussed. New aphid host plant relationships are reported for Aphidura bozhkoae, Aphidura delmasi, Aphidura ornata, Aphidura pannonica and Aphidura picta; this last species is recorded for first time from Afghanistan. The record of Aphidura pujoli from Pakistan is refuted. The fundatrices, oviparous females and males of Aphidura delmasi are described. Six new species are established: Aphidura gallica sp. n. and Aphidura amphorosiphon sp. n. from specimens caught on species of Silene (Caryophyllaceae) from France and Iran, respectively, Aphidura pakistanensis sp. n., Aphidura graeca sp. n. and Aphidura urmiensis sp. n. from specimens caught on species of Dianthus, Gypsophila and Spergula (Caryophyllaceae) from Pakistan, Greece and Iran, respectively, and Aphidura iranensis sp. n. from specimens caught on Prunus sp. from Iran. Modifications are made to the keys by Blackman and Eastop to aphids living on Dianthus, Gypsophyla, Silene, Spergula and Prinsepia and Prunus (Rosaceae). An identification key to apterous viviparous females of species of Aphidura is also provided. PMID:23950674

  20. Structures of PHR domains from Mus musculus Phr1 (Mycbp2) explain the loss-of-function mutation (Gly1092-->Glu) of the C. elegans ortholog RPM-1.

    PubMed

    Sampathkumar, Parthasarathy; Ozyurt, Sinem A; Miller, Stacy A; Bain, Kevin T; Rutter, Marc E; Gheyi, Tarun; Abrams, Benjamin; Wang, Yingchun; Atwell, Shane; Luz, John G; Thompson, Devon A; Wasserman, Stephen R; Emtage, J Spencer; Park, Eun Chan; Rongo, Christopher; Jin, Yishi; Klemke, Richard L; Sauder, J Michael; Burley, Stephen K

    2010-04-01

    PHR [PAM (protein associated with Myc)-HIW (Highwire)-RPM-1 (regulator of presynaptic morphology 1)] proteins are conserved, large multi-domain E3 ubiquitin ligases with modular architecture. PHR proteins presynaptically control synaptic growth and axon guidance and postsynaptically regulate endocytosis of glutamate receptors. Dysfunction of neuronal ubiquitin-mediated proteasomal degradation is implicated in various neurodegenerative diseases. PHR proteins are characterized by the presence of two PHR domains near the N-terminus, which are essential for proper localization and function. Structures of both the first and second PHR domains of Mus musculus (mouse) Phr1 (MYC binding protein 2, Mycbp2) have been determined, revealing a novel beta sandwich fold composed of 11 antiparallel beta-strands. Conserved loops decorate the apical side of the first PHR domain (MmPHR1), yielding a distinct conserved surface feature. The surface of the second PHR domain (MmPHR2), in contrast, lacks significant conservation. Importantly, the structure of MmPHR1 provides insights into a loss-of-function mutation, Gly1092-->Glu, observed in the Caenorhabditis elegans ortholog RPM-1. PMID:20156452

  1. Grain, pellet and wax block bait take by the house mouse (Mus musculus) and non-target species: implications for mouse eradications on coral cay islands.

    PubMed

    Cruz, Jennyffer; Leung, Luke K-P; Lisle, Allan; Rivera, Dario F; Staples, Linton; Smith, Michelle

    2008-09-01

    Introduced rodents have been eradicated from large numbers of offshore islands using toxic baits; however, toxic baits have been linked with negative impacts on non-target species. The present study assessed the bait take of target (house mouse, Mus musculus) and non-target (buff banded rail, Rallus philippensis) animals on Northwest and Heron Islands in the Great Barrier Reef. Three non-toxic bait formulations (wax block, pellet and grain) were tested and each was applied at 1 kg ha(-1) in six treatment grids. The tracks of animals visiting the baits were identified using 30 tracking stations per treatment grid. A tracking station consisted of a track-board placed in the centre of a sand-pad. Mean bait take differed significantly between the formulations: birds took more grain bait than wax block bait; mice took more wax block than grain bait. Both mice and birds were equally selective of pellet bait. Thus, the findings indicate that wax blocks are the most suitable formulation for future baiting programs to eradicate mice on these and other islands.

  2. Short-term early exposure to pups alters infanticide in adulthood in male but not in female wild house mice (Mus domesticus).

    PubMed

    McCarthy, M M

    1990-06-01

    Male and female wild house mice (Mus domesticus) were allowed to remain in the cage of their parents until 30-35 days of age. When a second litter was delivered, the first litter was exposed to the younger pups for 2-10 days. In adulthood the male and female mice that had been exposed to pups as juveniles and an additional group that had cohabitated with their parents for the same length of time but were not exposed to pups were tested for infanticidal behavior. The frequency of infanticide by the adult female mice was not significantly different (55% vs. 70%, respectively). In contrast, the adult males that were exposed to pups as juveniles were significantly less likely to kill young in adulthood when compared with males that were not similarly exposed (35% vs. 80%, respectively). These data further demonstrate the strong influence of experience on the expression of infanticide by male mice and its relative unimportance to the expression of female infanticide. PMID:2364665

  3. Evidence of evolutionary up-regulation of the single active X chromosome in mammals based on Clc4 expression levels in Mus spretus and Mus musculus

    PubMed Central

    Adler, David A.; Rugarli, Elena I.; Lingenfelter, Patricia A.; Tsuchiya, Karen; Poslinski, Diane; Liggitt, H. Denny; Chapman, Verne M.; Elliott, Rosemary W.; Ballabio, Andrea; Disteche, Christine M.

    1997-01-01

    Previous studies have shown that the chloride channel gene Clc4 is X-linked and subject to X inactivation in Mus spretus, but that the same gene is autosomal in laboratory strains of mice. This exception to the conservation of linkage of the X chromosome in one of two interfertile mouse species was exploited to compare expression of Clc4 from the X chromosome to that from the autosome. Clc4 was found to be highly expressed in brain tissues of both mouse species. Quantitative analyses of species-specific expression of Clc4 in brain tissues from mice resulting from M. spretus × laboratory strain crosses, demonstrate that each autosomal locus has half the level of Clc4 expression as compared with the single active X-linked locus. In contrast expression of another chloride channel gene, Clc3, which is autosomal in both mouse species is equal between alleles in F1 animals. There is no evidence of imprinting of the Clc4 autosomal locus. These results are consistent with Ohno’s hypothesis of an evolutionary requirement for a higher expression of genes on the single active X chromosome to maintain balance with autosomal gene expression [Ohno, S. (1967) Sex Chromosomes and Sex-Linked Genes (Springer, Berlin)]. PMID:9256467

  4. The Mus cervicolor MuLV isolate M813 is highly fusogenic and induces a T-cell lymphoma associated with large multinucleated cells.

    PubMed

    Prassolov, V; Ivanov, D; Hein, S; Rutter, G; Münk, C; Löhler, J; Stocking, C

    2001-11-10

    M813 is a type-C murine leukemia virus (MuLV) isolated from the Asian rodent Mus cervicolor. We have recently demonstrated that M813 defines a distinct MuLV receptor interference group. Here we show that M813 rapidly induces fusion of MuLV-expressing fibroblasts from "without," with syncytia being observed within 1 h after exposure to virus. Infection of fibroblasts with MuLV from all tested receptor-interference groups imparts susceptibility to M813-induced fusion, provided the cells also express the M813 receptor. Syncytium induction is also observed in vivo; mice infected with M813 develop a peripheral T-cell lymphoma, which is associated with large multinucleated cells of macrophage origin. A recombinant Moloney MuLV/M813 chimeric virus demonstrated that syncytium induction is a function of the Env SU protein. We postulate that the highly fusogenic property of M813 is attributable to either its unique receptor usage or sequences in the proline-rich domain of the Env protein.

  5. Peroral Echinococcus multilocularis egg inoculation in Myodes glareolus, Mesocricetus auratus and Mus musculus (CD-1 IGS and C57BL/6j).

    PubMed

    Woolsey, Ian David; Jensen, Per Moestrup; Deplazes, Peter; Kapel, Christian Moliin Outzen

    2016-08-01

    Echinococcus multilocularis transmission predominantly occurs in Europe between the red fox (Vulpes vulpes) and various species of rodent intermediate hosts. We infected 3 species of rodent, Myodes glareolus (n = 47), Mesocricetus auratus (n = 11) and outbred Mus musculus (CD-1 IGS) (n = 9) with an E. multilocularis egg suspension that contained 100 eggs with viable oncospheres and performed post mortem examination 6, 8 (M. glareolus) and 10 weeks post inoculation (wpi). C57BL/6j mice (n = 4) were used as positive controls as they have been shown to exhibit macroscopic liver lesions 4 wpi. To the best of our knowledge, this is the first study to experimentally assess susceptibility in the ostensibly competent host M. glareolus. Lesions were only detected in 2 of 47 M. glareolus (4.3%) at 8 and 10 wpi and although both contained protoscolices (1675 at 8 wpi and 88 at 12 wpi) the low percentage of infected animals brings into question their role as transmitters of the parasite. Significant differences were observed between inbred and outbred mice with E. multilocularis infection in the former demonstrating increased establishment (p ≤ 0.0001) and growth (p ≤ 0.0001). No lesions were found in all 11 M. auratus. PMID:27330986

  6. Expression of a soluble form of iodotyrosine deiodinase for active site characterization by engineering the native membrane protein from Mus musculus

    SciTech Connect

    Buss, Jennifer M.; McTamney, Patrick M.; Rokita, Steven E.

    2012-06-27

    Reductive deiodination is critical for thyroid function and represents an unusual exception to the more common oxidative and hydrolytic mechanisms of dehalogenation in mammals. Studies on the reductive processes have been limited by a lack of convenient methods for heterologous expression of the appropriate proteins in large scale. The enzyme responsible for iodide salvage in the thyroid, iodotyrosine deodinase, is now readily generated after engineering its gene from Mus musculus. High expression of a truncated derivative lacking the membrane domain at its N-terminal was observed in Sf9 cells, whereas expression in Pichia pastoris remained low despite codon optimization. Ultimately, the desired expression in Escherichia coli was achieved after replacing the two conserved Cys residues of the deiodinase with Ala and fusing the resulting protein to thioredoxin. This final construct provided abundant enzyme for crystallography and mutagenesis. Utility of the E. coli system was demonstrated by examining a set of active site residues critical for binding to the zwitterionic portion of substrate.

  7. Mimicking corticosterone's daily rhythm with specific receptor agonists: effects on food, water, and sodium intake.

    PubMed

    Devenport, L; Stith, R

    1992-06-01

    The endogenous pattern of type I and II corticosteroid receptor stimulation was systematically assembled from specific agonists in order to detect any unique receptor interactions in the control of ingestive behavior. The type II agonists dexamethasone (0, 5, or 25 micrograms/kg) or RU28362 (0, 5, or 25 micrograms/kg) were injected daily in the final hour of the light phase of the illumination cycle of adrenalectomized rats. This was carried out in the presence or absence of continuous aldosterone (type I agonist) infusion. Additional comparisons were made with sham-operated groups and animals receiving type II agonists by continuous infusion. Type II agonists increased the intake of 2% saline and the proportion of food taken at night, but had negligible effects on total food intake. Type II agonists did not interact with the type I agonist. Type II effects were greatly potentiated by continuous infusion, though administered at the same doses as acute injection. When the effects of type II receptor stimulation emerged, they always consisted of an exacerbation of the adrenalectomy syndrome, not a return to normal quantities or patterns. In contrast, type I receptor stimulation restored both the quantities and unique day-night patterns of saline, water, and food intake to values matching intact animals. The findings suggest that the behavioral significance of corticosterone's nocturnal peak of type II stimulation is small, and that its most important function may lie in the metabolic processes it instigates during its steady rise in the light phase.

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

    PubMed Central

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

    2008-01-01

    Background Use of gonadotropin-releasing hormone (GnRH) agonists has become popular for virtually all stages of prostate cancer. We hypothesized that some men receive these agents after only a limited work-up for their cancer. Such cases may be missed by tumor registries, leading to underestimates of the total extent of GnRH agonist use. Methods We used linked Surveillance, Epidemiology and End-Results (SEER)-Medicare data from 1993 through 2001 to identify GnRH agonist use in men with either a diagnosis of prostate cancer registered in SEER, or with a diagnosis of prostate cancer based only on Medicare claims (from the 5% control sample of Medicare beneficiaries residing in SEER areas without a registered diagnosis of cancer). The proportion of incident GnRH agonist users without a registry diagnosis of prostate cancer was calculated. Factors associated with lack of a registry diagnosis were examined in multivariable analyses. Results Of incident GnRH agonist users, 8.9% had no diagnosis of prostate cancer registered in SEER. In a multivariable logistic regression model, lack of a registry diagnosis of prostate cancer in GnRH agonist users was significantly more likely with increasing comorbidity, whereas it was less likely in men who had undergone either inpatient admission or procedures such as radical prostatectomy, prostate biopsy, or transurethral resection of the prostate. Conclusion Reliance solely on tumor registry data may underestimate the rate of GnRH agonist use in men with prostate cancer. PMID:18620606

  9. Use of gonadotrophin-releasing hormone agonists in controlled ovarian hyperstimulation for in vitro fertilization.

    PubMed

    Muasher, S J

    1992-01-01

    The aim of ovarian hyperstimulation for in vitro fertilization (IVF) is the recruitment of multiple fertilizable healthy oocytes. Transfer of multiple embryos yields a better success rate than single-embryo transfers. Moreover, cryopreservation of excess pre-embryos allows patients an added opportunity to achieve a pregnancy without undergoing a repeat stimulated cycle. In the last 4 years, gonadotrophin-releasing hormone (Gn-RH) agonists have been used widely as adjuncts to gonadotrophins for ovarian hyperstimulation. Advantages of Gn-RH agonist use include prevention of a premature luteinising hormone (LH) surge, suppression of endogenous basal LH levels and recruitment of a larger cohort of follicles. Gn-RH agonists can be used in a long (suppression) or a short (stimulatory, flare-up) protocol. In our clinic, the use of Gn-RH agonist suppression (starting in the mid-luteal phase) prior to ovarian hyperstimulation was demonstrated to be extremely beneficial in intermediate and high responder patients but not in low responders (defined endocrinologically as patients with a basal follicle-stimulating hormone [FSH]: LH ratio of 1:1 and a basal LH:FSH ratio of greater than or equal to 1.5, respectively). We have not been able to demonstrate any beneficial effects from the use of Gn-RH agonist suppression in low responder patients (defined endocrinologically as patients with a basal FSH greater than or equal to 15 mIU/ml). In such low responder patients, the use of a 'flare-up' Gn-RH agonist protocol (Gn-RH agonist starting on day 2 of the cycle, followed by gonadotrophins on day 4 of the cycle), taking advantage of the initial agonistic stimulatory effect of Gn-RH agonists on endogenous FSH and LH secretion, has provided significant improvements in stimulation characteristics and better pregnancy results. It should be emphasised that comparisons of results cannot be attempted due to the selective use of each protocol in different patient populations.

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

    SciTech Connect

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

    2013-04-26

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

  11. Utility of gonadotropin-releasing hormone agonists in programs of ovarian hyperstimulation with intrauterine insemination.

    PubMed

    Gagliardi, C L

    1993-09-01

    The GnRH agonists have practical and theoretic advantages for adjunctive use in ovulation induction. The IVF cycles demonstrate a decrease in the cancellation rate, an increase in the ease of scheduling, and an increase in the number of oocytes obtained per retrieval when GnRH agonists are employed. Other advantages, such as an improvement in the fertilization and cleavage rate, an increased length of the luteal phase, and an increased pregnancy rate, are suggested but not universally accepted. The utility of adding GnRH agonists to human menopausal gonadotropin-intrauterine insemination cycles is similarly in dispute. Although controlled ovarian hyperstimulation with both human menopausal gonadotropins alone and in conjunction with GnRH agonists have produced pregnancies when coupled with intrauterine insemination, it was demonstrated that there was a significantly greater pregnancy rate per cycle with the use of a GnRH agonist in a recalcitrant infertile population. Others did not substantiate this improvement in pregnancy rate per cycle in their patient population of regularly ovulating women undergoing their first controlled ovarian stimulation cycle either with or without GnRH agonist therapy. This suggests that women with ovulatory dysfunction, and particularly women who previously have not responded to therapy with human menopausal gonadotropin therapy, will reap the most benefits from the addition of a GnRH agonist to their ovulation induction regimen. The addition of a GnRH agonist to controlled ovarian hyperstimulation is a highly effective method of inducing pregnancy in a recalcitrant infertile population. Patients who did not conceive with human menopausal gonadotropins-intrauterine insemination may conceive with GnRH agonist-human menopausal gonadotropins-intrauterine insemination therapy.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8403617

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

    PubMed

    Jaeger, Daniel T L; Diamond, Scott L

    2013-05-01

    Understanding the response of cells to multiple stimuli is vital for predicting donor specific responses and better understanding the signaling pathways involved. This is of particular importance in platelets because exposure of phosphatidylserine (PS) occurs upon costimulation but not with a single agonist. Here, we describe a multiplexed pairwise agonist scanning-flow cytometry (PAS-FC) method of measuring platelet inside-out responses to all pairs of six platelet agonists (convulxin, SFLLRN, AYPGKF, ADP, U46619, and PGE(2)) used at their EC(50) concentrations. These agonists allowed exploration of platelet signaling downstream of GPVI, PAR-1, PAR-4, P2Y(1), P2Y(12), TP, and IP receptors. The three-color flow cytometry method simultaneously measured integrin α(IIb)β(3) activation with PAC-1 antibody, P-selectin exposure (via α granule release) with anti-P-selectin, and PS exposure with annexin V. These responses were consistent across a healthy male donor pool. In duplicate measurements with each donor, 4 of the 10 donors had a sufficiently unique 45-parameter (15 pairs × 3 colors) phenotype to self-cluster (P < 0.001). This method has the potential for efficiently scanning for patient specific responses across a broad agonist-receptor space.

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

    PubMed

    Jaeger, Daniel T L; Diamond, Scott L

    2013-05-01

    Understanding the response of cells to multiple stimuli is vital for predicting donor specific responses and better understanding the signaling pathways involved. This is of particular importance in platelets because exposure of phosphatidylserine (PS) occurs upon costimulation but not with a single agonist. Here, we describe a multiplexed pairwise agonist scanning-flow cytometry (PAS-FC) method of measuring platelet inside-out responses to all pairs of six platelet agonists (convulxin, SFLLRN, AYPGKF, ADP, U46619, and PGE(2)) used at their EC(50) concentrations. These agonists allowed exploration of platelet signaling downstream of GPVI, PAR-1, PAR-4, P2Y(1), P2Y(12), TP, and IP receptors. The three-color flow cytometry method simultaneously measured integrin α(IIb)β(3) activation with PAC-1 antibody, P-selectin exposure (via α granule release) with anti-P-selectin, and PS exposure with annexin V. These responses were consistent across a healthy male donor pool. In duplicate measurements with each donor, 4 of the 10 donors had a sufficiently unique 45-parameter (15 pairs × 3 colors) phenotype to self-cluster (P < 0.001). This method has the potential for efficiently scanning for patient specific responses across a broad agonist-receptor space. PMID:23662898

  14. Agonist/antagonist modulation in a series of 2-aryl benzimidazole H4 receptor ligands.

    PubMed

    Savall, Brad M; Edwards, James P; Venable, Jennifer D; Buzard, Daniel J; Thurmond, Robin; Hack, Michael; McGovern, Patricia

    2010-06-01

    The present work details the transformation of a series of human histamine H(4) agonists into potent functional antagonists. Replacement of the aminopyrrolidine diamine functionality with a 5,6-fused pyrrolopiperidine ring system led to an antagonist. The dissection of this fused diamine led to the eventual replacement with heterocycles. The incorporation of histamine as the terminal amine led to a very potent and selective histamine H(4) agonist; whereas incorporation of the constrained histamine analog, spinacamine, modulated the functional activity to give a partial agonist. In two separate series, we demonstrate that constraining the terminal amino portion modulated the spectrum of functional activity of histamine H(4) ligands.

  15. 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

  16. Synthesis and characterization of photoactivatable peptide agonists of the human thrombin receptor.

    PubMed

    Bischoff, R; Cordier, Y; Rasmussen, U B; Schlesinger, Y; Gachet, C; Jaquinod, M; Tripet, B; Chong, P C; Pavirani, A

    1994-08-01

    Chemical synthesis and biochemical analysis of modified agonist peptides of the human thrombin receptor derived from the sequence SFLLRNP containing photoactivatable azido groups and biotin for sensitive detection is described. Substitution of leucine in position three with p-azidophenylalanine and extension of the C-terminus with a KGGK spacer containing biotin covalently linked to the side chain of the C-terminal lysine residue resulted in an active receptor agonist as determined by intracellular Ca2+ mobilization in human erythroleukemia (HEL) cells. In contrast, substitution of phenylalanine in position two with p-azidophenylalanine reduced agonist activity significantly. PMID:8050586

  17. PPARα agonist, fenofibrate, ameliorates age-related renal injury.

    PubMed

    Kim, Eun Nim; Lim, Ji Hee; Kim, Min Young; Kim, Hyung Wook; Park, Cheol Whee; Chang, Yoon Sik; Choi, Bum Soon

    2016-08-01

    The kidney ages quickly compared with other organs. Expression of senescence markers reflects changes in the energy metabolism in the kidney. Two important issues in aging are mitochondrial dysfunction and oxidative stress. Peroxisome proliferator-activated receptor α (PPARα) is a member of the ligand-activated nuclear receptor superfamily. PPARα plays a major role as a transcription factor that regulates the expression of genes involved in various processes. In this study, 18-month-old male C57BL/6 mice were divided into two groups, the control group (n=7) and the fenofibrate-treated group (n=7) was fed the normal chow plus fenofibrate for 6months. The PPARα agonist, fenofibrate, improved renal function, proteinuria, histological change (glomerulosclerosis and tubular interstitial fibrosis), inflammation, and apoptosis in aging mice. This protective effect against age-related renal injury occurred through the activation of AMPK and SIRT1 signaling. The activation of AMPK and SIRT1 allowed for the concurrent deacetylation and phosphorylation of their target molecules and decreased the kidney's susceptibility to age-related changes. Activation of the AMPK-FOXO3a and AMPK-PGC-1α signaling pathways ameliorated oxidative stress and mitochondrial dysfunction. Our results suggest that activation of PPARα and AMPK-SIRT1 signaling may have protective effects against age-related renal injury. Pharmacological targeting of PPARα and AMPK-SIRT1 signaling molecules may prevent or attenuate age-related pathological changes in the kidney. PMID:27130813

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

    PubMed

    Blank, David; Yang, Weikang

    2014-03-01

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

  19. Therapeutic applications of TRAIL receptor agonists in cancer and beyond

    PubMed Central

    Amarante-Mendes, Gustavo P.; Griffith, Thomas S.

    2016-01-01

    TRAIL/Apo-2L is a member of the TNF superfamily first described as an apoptosis-inducing cytokine in 1995. Similar to TNF and Fas ligand, TRAIL induces apoptosis in caspase-dependent manner following TRAIL death receptor trimerization. Because tumor cells were shown to be particularly sensitive to this cytokine while normal cells/tissues proved to be resistant along with being able to synthesize and release TRAIL, it was rapidly appreciated that TRAIL likely served as one of our major physiologic weapons against cancer. In line with this, a number of research laboratories and pharmaceutical companies have attempted to exploit the ability of TRAIL to kill cancer cells by developing recombinant forms of TRAIL or TRAIL receptor agonists (e.g., receptor-specific mAb) for therapeutic purposes. In this review article we will describe the biochemical pathways used by TRAIL to induce different cell death programs. We will also summarize the clinical trials related to this pathway and discuss possible novel uses of TRAIL-related therapies. In recent years, the physiological importance of TRAIL has expanded beyond being a tumoricidal molecule to one critical for a number of clinical settings — ranging from infectious disease and autoimmunity to cardiovascular anomalies. We will also highlight some of these conditions where modulation of the TRAIL/TRAIL receptor system may be targeted in the future. PMID:26343199

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

    PubMed Central

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

    2012-01-01

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

  1. Therapeutic applications of TRAIL receptor agonists in cancer and beyond.

    PubMed

    Amarante-Mendes, Gustavo P; Griffith, Thomas S

    2015-11-01

    TRAIL/Apo-2L is a member of the TNF superfamily first described as an apoptosis-inducing cytokine in 1995. Similar to TNF and Fas ligand, TRAIL induces apoptosis in caspase-dependent manner following TRAIL death receptor trimerization. Because tumor cells were shown to be particularly sensitive to this cytokine while normal cells/tissues proved to be resistant along with being able to synthesize and release TRAIL, it was rapidly appreciated that TRAIL likely served as one of our major physiologic weapons against cancer. In line with this, a number of research laboratories and pharmaceutical companies have attempted to exploit the ability of TRAIL to kill cancer cells by developing recombinant forms of TRAIL or TRAIL receptor agonists (e.g., receptor-specific mAb) for therapeutic purposes. In this review article we will describe the biochemical pathways used by TRAIL to induce different cell death programs. We will also summarize the clinical trials related to this pathway and discuss possible novel uses of TRAIL-related therapies. In recent years, the physiological importance of TRAIL has expanded beyond being a tumoricidal molecule to one critical for a number of clinical settings - ranging from infectious disease and autoimmunity to cardiovascular anomalies. We will also highlight some of these conditions where modulation of the TRAIL/TRAIL receptor system may be targeted in the future.

  2. Neurotensin agonist attenuates nicotine potentiation to cocaine sensitization.

    PubMed

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

    2014-03-01

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

  3. Lipid metabolome-wide effects of the PPARgamma agonist rosiglitazone.

    PubMed

    Watkins, Steven M; Reifsnyder, Peter R; Pan, Huei-ju; German, J Bruce; Leiter, Edward H

    2002-11-01

    Successful therapy for chronic diseases must normalize a targeted aspect of metabolism without disrupting the regulation of other metabolic pathways essential for maintaining health. Use of a limited number of single molecule surrogates for disease, or biomarkers, to monitor the efficacy of a therapy may fail to predict undesirable side effects. In this study, a comprehensive metabolomic assessment of lipid metabolites was employed to determine the specific effects of the peroxisome proliferator-activated receptor gamma (PPARgamma) agonist rosiglitazone on structural lipid metabolism in a new mouse model of Type 2 diabetes. Dietary supplementation with rosiglitazone (200 mg/kg diet) suppressed Type 2 diabetes in obese (NZO x NON)F1 male mice, but chronic treatment markedly exacerbated hepatic steatosis. The metabolomic data revealed that rosiglitazone i) induced hypolipidemia (by dysregulating liver-plasma lipid exchange), ii) induced de novo fatty acid synthesis, iii) decreased the biosynthesis of lipids within the peroxisome, iv) substantially altered free fatty acid and cardiolipin metabolism in heart, and v) elicited an unusual accumulation of polyunsaturated fatty acids within adipose tissue. These observations suggest that the phenotypes induced by rosiglitazone are mediated by multiple tissue-specific metabolic variables. Because many of the effects of rosiglitazone on tissue metabolism were reflected in the plasma lipid metabolome, metabolomics has excellent potential for developing clinical assessments of metabolic response to drug therapy. PMID:12401879

  4. Agonist Derived Molecular Probes for A2A Adenosine Receptors

    PubMed Central

    Jacobson, Kenneth A.; Pannell, Lewis K.; Ji, Xiao-duo; Jarvis, Michael F.; Williams, Michael; Hutchison, Alan J.; Barrington, William W.; Stiles, Gary L.

    2011-01-01

    The adenosine agonist 2-(4-(2-carboxyethyl)phenylethylamino)-5′-N-ethylcarboxamidoadenosine (CGS21680) was recently reported to be selective for the A2A adenosine receptor subtype, which mediates its hypotensive action. To investigate structurelactivity relationships at a distal site, CGS21680 was derivatized using a functionalized congener approach. The carboxylic group of CGS21680 has been esterified to form a methyl ester, which was then treated with ethylenediamine to produce an amine congener. The amine congener was an intermediate for acylation reactions, in which the reactive acyl species contained a reported group, or the precursor for such. For radioiodination, derivatives of p-hydroxyphenylpropionic, 2-thiophenylacetic, and p-aminophenylacetic acids were prepared. The latter derivative (PAPA-APEC) was iodinated electrophilically using [125I]iodide resulting in a radioligand which was used for studies of competition of binding to striatal A, adenosine receptors in bovine brain. A biotin conjugate and an aryl sulfonate were at least 350-fold selective for A, receptors. For spectroscopic detection, a derivative of the stable free radical tetramethyl-1-piperidinyloxy (TEMPO) was prepared. For irreversible inhibition of receptors, meta- and para-phenylenediisothiocyanate groups were incorporated in the analogs. We have demonstrated that binding at A2A receptors is relatively insensitive to distal structural changes at the 2-position, and we report high affinity molecular probes for receptor characterization by radioactive, spectroscopic and affinity labelling methodology. PMID:2561548

  5. Agonists and Antagonists of TGF-β Family Ligands.

    PubMed

    Chang, Chenbei

    2016-08-01

    The discovery of the transforming growth factor β (TGF-β) family ligands and the realization that their bioactivities need to be tightly controlled temporally and spatially led to intensive research that has identified a multitude of extracellular modulators of TGF-β family ligands, uncovered their functions in developmental and pathophysiological processes, defined the mechanisms of their activities, and explored potential modulator-based therapeutic applications in treating human diseases. These studies revealed a diverse repertoire of extracellular and membrane-associated molecules that are capable of modulating TGF-β family signals via control of ligand availability, processing, ligand-receptor interaction, and receptor activation. These molecules include not only soluble ligand-binding proteins that were conventionally considered as agonists and antagonists of TGF-β family of growth factors, but also extracellular matrix (ECM) proteins and proteoglycans that can serve as "sink" and control storage and release of both the TGF-β family ligands and their regulators. This extensive network of soluble and ECM modulators helps to ensure dynamic and cell-specific control of TGF-β family signals. This article reviews our knowledge of extracellular modulation of TGF-β growth factors by diverse proteins and their molecular mechanisms to regulate TGF-β family signaling.

  6. Minireview: Challenges and opportunities in development of PPAR agonists.

    PubMed

    Wright, Matthew B; Bortolini, Michele; Tadayyon, Moh; Bopst, Martin

    2014-11-01

    The clinical impact of the fibrate and thiazolidinedione drugs on dyslipidemia and diabetes is driven mainly through activation of two transcription factors, peroxisome proliferator-activated receptors (PPAR)-α and PPAR-γ. However, substantial differences exist in the therapeutic and side-effect profiles of specific drugs. This has been attributed primarily to the complexity of drug-target complexes that involve many coregulatory proteins in the context of specific target gene promoters. Recent data have revealed that some PPAR ligands interact with other non-PPAR targets. Here we review concepts used to develop new agents that preferentially modulate transcriptional complex assembly, target more than one PPAR receptor simultaneously, or act as partial agonists. We highlight newly described on-target mechanisms of PPAR regulation including phosphorylation and nongenomic regulation. We briefly describe the recently discovered non-PPAR protein targets of thiazolidinediones, mitoNEET, and mTOT. Finally, we summarize the contributions of on- and off-target actions to select therapeutic and side effects of PPAR ligands including insulin sensitivity, cardiovascular actions, inflammation, and carcinogenicity. PMID:25148456

  7. 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

  8. The long-acting β2-adrenoceptor agonist, indacaterol, enhances glucocorticoid receptor-mediated transcription in human airway epithelial cells in a gene- and agonist-dependent manner

    PubMed Central

    Joshi, T; Johnson, M; Newton, R; Giembycz, M A

    2015-01-01

    Background and Purpose Inhaled glucocorticoid (ICS)/long-acting β2-adrenoceptor agonist (LABA) combination therapy is a recommended treatment option for patients with moderate/severe asthma in whom adequate control cannot be achieved by an ICS alone. Previously, we discovered that LABAs can augment dexamethasone-inducible gene expression and proposed that this effect may explain how these two drugs interact to deliver superior clinical benefit. Herein, we extended that observation by analysing, pharmacodynamically, the effect of the LABA, indacaterol, on glucocorticoid receptor (GR)-mediated gene transcription induced by seven ligands with intrinsic activity values that span the spectrum of full agonism to antagonism. Experimental Approach BEAS-2B human airway epithelial cells stably transfected with a 2× glucocorticoid response element luciferase reporter were used to model gene transcription together with an analysis of several glucocorticoid-inducible genes. Key Results Indacaterol augmented glucocorticoid-induced reporter activation in a manner that was positively related to the intrinsic activity of the GR agonist. This effect was demonstrated by an increase in response maxima without a change in GR agonist affinity or efficacy. Indacaterol also enhanced glucocorticoid-inducible gene expression. However, the magnitude of this effect was dependent on both the GR agonist and the gene of interest. Conclusions and Implications These data suggest that indacaterol activates a molecular rheostat, which increases the transcriptional competency of GR in an agonist- and gene-dependent manner without apparently changing the relationship between fractional GR occupancy and response. These findings provide a platform to rationally design ICS/LABA combination therapy that is based on the generation of agonist-dependent gene expression profiles in target and off-target tissues. PMID:25598440

  9. Effects of sub-lethal heroin administration on thyroid stimulating hormone (TSH), thyroid hormones (T3, T4) and thyroid gland of Mus norvegicus.

    PubMed

    Bhoir, Kaminidevi K; Suryawanshi, S A; Pandey, A K

    2009-11-01

    Serum TSH level of control Mus norvegicus fluctuated between 498.20 +/- 21.92 and 506.80 +/- 22.35 ng ml(-1), thyroxine (T4) between 68.17 +/- 3.46 and 69.03 +/- 4.12 microg dl(-1) and triiodothyronine (T3) between 4.76 +/- 0.52 and 5.00 +/- 0.66 microg dl(-1). Sub-lethal heroin administration induced a significant decline in the levels of all the three hormones at 24 hr and 15 days post-administration. Decline in the levels of these hormones registered the lowest values (p<0.001) by day 30 of the treatment. Thyroid gland of control rat consisted of spherical, round follicles lined with low cuboidal and columnar epithelial cells and lumina filled with eosinophilic colloid. Ultrastructurally, the thyroid follicular cells showed the presence of round nuclei, polymorphic mitochondria, Golgi complex as well as lysosomes located on the apical side of the nucleus and cytoplasm with different sizes of lipid droplets and smooth along with rough endoplasmic reticulum. Basal lamina of the follicular cells was often in association with the endothelium of the capillaries. Sub-lethal heroin administration for 30 days elicited degenerative changes in the follicular epithelial cells as evident by the vacuolization of cytoplasm, pycnotic nuclei and reduced colloidal content. Ultrastructurally, the thyroid follicular cells showed indented nuclei with heavy deposition of chromatin material on the inner membrane of nucleus and dilated rough endoplasmic reticulum. Along with RBC infiltration, vesiculated mitochondria owing to the loss of cristae were also seen. Diffused electron-dense material was seen at the periphery of the cell body. Heroin treatment caused cellular necrosis as revealed by the fragmentation of cytoplasmic materials in follicular epithelial cells of the gland.

  10. Successful eradication of the European rabbit (Oryctolagus cuniculus) and house mouse (Mus musculus) from the island of Selvagem Grande (Macaronesian archipelago), in the Eastern Atlantic.

    PubMed

    Olivera, Paulo; Menezes, Dilia; Trout, Roger; Buckle, Alan; Geraldes, Pedro; Jesus, José

    2010-03-01

    The Portuguese island of Selvagem Grande (Great Salvage) in Macaronesia is an important seabird breeding station in the eastern Atlantic. Significant populations of Cory's shearwater Calonectris diomedea (Scopoli, 1769), Bulwer's petrel Bulweria bulweria (Jardine & Selby, 1828) and little shearwater Puffinus assimilis baroli (Bonaparte, 1857) are present, and white-faced storm-petrel Pelagodroma marina (Latham, 1790) and Madeiran storm-petrel Oceanodroma castro (Harcourt, 1851) populations are of global significance. Selvagem Grande also provides diverse habitats for an extensive flora, including 11 endemic species. The 270-ha island was also inhabited by two alien invasive mammals: the European rabbit Oryctolagus cuniculus (Linnaeus, 1758) and the house mouse Mus musculus (Linnaeus, 1758). Both are known to have had adverse impacts on breeding seabirds and island vegetation. In 2002, the Natural Park of Madeira conducted a program using brodifacoum bait formulations aimed at rabbit and mouse eradication. Approximately 17 000 individual baiting points were established on a 12.5 × 12.5 m grid. Baits were also applied by hand "seeding" on steep slopes and cliffs where bait stations could not be placed. Rabbits were removed after a month. However, mice persisted for considerably longer and strategic bait applications against them continued for a further six months. Subsequent assessments by trapping, bait takes and systematic observation of signs over three years, has confirmed the removal of both alien invasive species. This paper presents information on these operations, on measures adopted to mitigate adverse impacts of the eradication program on important vertebrate non-target species, including Berthelot's pipit Anthus berthelotii Bolle, 1862 and a species of gecko Tarentola bischoffi Joger, 1984 and on the initial response of the island's ecosystem to the eradication of rabbits and mice. PMID:21392324

  11. Of mice and the 'Age of Discovery': the complex history of colonization of the Azorean archipelago by the house mouse (Mus musculus) as revealed by mitochondrial DNA variation.

    PubMed

    Gabriel, S I; Mathias, M L; Searle, J B

    2015-01-01

    Humans have introduced many species onto remote oceanic islands. The house mouse (Mus musculus) is a human commensal and has consequently been transported to oceanic islands around the globe as an accidental stowaway. The history of these introductions can tell us not only about the mice themselves but also about the people that transported them. Following a phylogeographic approach, we used mitochondrial D-loop sequence variation (within an 849- to 864-bp fragment) to study house mouse colonization of the Azores. A total of 239 sequences were obtained from all nine islands, and interpretation was helped by previously published Iberian sequences and 66 newly generated Spanish sequences. A Bayesian analysis revealed presence in the Azores of most of the D-loop clades previously described in the domesticus subspecies of the house mouse, suggesting a complex colonization history of the archipelago as a whole from multiple geographical origins, but much less heterogeneity (often single colonization?) within islands. The expected historical link with mainland Portugal was reflected in the pattern of D-loop variation of some of the islands but not all. A more unexpected association with a distant North European source area was also detected in three islands, possibly reflecting human contact with the Azores prior to the 15th century discovery by Portuguese mariners. Widening the scope to colonization of the Macaronesian islands as a whole, human linkages between the Azores, Madeira, the Canaries, Portugal and Spain were revealed through the sharing of mouse sequences between these areas. From these and other data, we suggest mouse studies may help resolve historical uncertainties relating to the 'Age of Discovery'.

  12. A Comparison of mucosal surface area and villous histology in small intestines of the Brazilian free-tailed bat (Tadarida brasiliensis) and the mouse (Mus musculus).

    PubMed

    Zhang, Zhi-Qiang; Brun, Antonio; Price, Edwin R; Cruz-Neto, Ariovaldo P; Karasov, William H; Caviedes-Vidal, Enrique

    2015-01-01

    Studies on birds have led to the hypothesis that increased intestinal absorption between enterocytes (paracellular) evolved as a compensation for smaller intestinal size in fliers, which was perhaps selected to minimize the mass of digesta carried. This hypothesis predicts that bats will also exhibit relatively reduced intestinal size and high paracellular absorption, compared with nonflying mammals. Published studies on three bat species indicate relatively high paracellular absorption. One mechanism for increasing paracellular absorption per cm2 small intestine (SI) is increased number of tight junctions (TJs) across which paracellular absorption occurs. To our knowledge, we provide the first comparative analysis of enterocyte size and number in flying and nonflying mammals. Intestines of insectivorous bats Tadarida brasiliensis were compared with Mus musculus using hematoxylin and eosin staining method. Bats had shorter and narrower SIs than mice, and after correction for body size difference by normalizing to mass3/4, the bats had 40% less nominal surface area than the mouse, as predicted. Villous enhancement of surface area was 90% greater in the bat than in the mouse, mainly because of longer villi and a greater density of villi in bat intestines. Bat and mouse were similar in enterocyte diameter. Bats exceeded mice by 54.4% in villous area per cm length SI and by 95% in number of enterocytes per cm2 of the nominal surface area of the SI. Therefore, an increased density of TJs per cm2 SI may be a mechanistic explanation that helps to understand the high paracellular absorption observed in bats compared to nonflying mammals.

  13. Divergence patterns of genic copy number variation in natural populations of the house mouse (Mus musculus domesticus) reveal three conserved genes with major population-specific expansions

    PubMed Central

    Pezer, Željka; Harr, Bettina; Teschke, Meike; Babiker, Hiba; Tautz, Diethard

    2015-01-01

    Copy number variation represents a major source of genetic divergence, yet the evolutionary dynamics of genic copy number variation in natural populations during differentiation and adaptation remain unclear. We applied a read depth approach to genome resequencing data to detect copy number variants (CNVs) ≥1 kb in wild-caught mice belonging to four populations of Mus musculus domesticus. We complemented the bioinformatics analyses with experimental validation using droplet digital PCR. The specific focus of our analysis is CNVs that include complete genes, as these CNVs could be expected to contribute most directly to evolutionary divergence. In total, 1863 transcription units appear to be completely encompassed within CNVs in at least one individual when compared to the reference assembly. Further, 179 of these CNVs show population-specific copy number differences, and 325 are subject to complete deletion in multiple individuals. Among the most copy-number variable genes are three highly conserved genes that encode the splicing factor CWC22, the spindle protein SFI1, and the Holliday junction recognition protein HJURP. These genes exhibit population-specific expansion patterns that suggest involvement in local adaptations. We found that genes that overlap with large segmental duplications are generally more copy-number variable. These genes encode proteins that are relevant for environmental and behavioral interactions, such as vomeronasal and olfactory receptors, as well as major urinary proteins and several proteins of unknown function. The overall analysis shows that genic CNVs contribute more to population differentiation in mice than in humans and may promote and speed up population divergence. PMID:26149421

  14. Magnesium ions and opioid agonist activity in streptozotocin-induced hyperalgesia.

    PubMed

    Bujalska, Magdalena; Malinowska, Ewelina; Makulska-Nowak, Helena; Gumułka, Stanisław Witold

    2008-01-01

    Streptozotocin-induced hyperglycemia accompanied by a chronic decrease in the nociceptive threshold is considered a useful model of experimental hyperalgesia. We examined (1) the effect of the opioid receptor agonists and (2) the effect of the magnesium ions (Mg(2+)) on the antinociceptive action of opioid agonists in a diabetic neuropathic pain model. When administered alone, opioid agonists like morphine (5 mg/kg i.p.) and fentanyl (0.0625 mg/kg i.p.), as well as the partial agonist buprenorphine (0.075 mg/kg) had only little effect on streptozotocin-induced hyperalgesia. However, pretreatment with Mg(2+) at a dose of 40 mg magnesium sulfate/kg i.p. markedly enhanced the analgesic activity of all three investigated opioids. Practical aspects of co-administration of magnesium and opioids in diabetic neuropathy are discussed. PMID:18701828

  15. Increasing Potential Access to Opioid Agonist Treatment in U.S. Treatment Shortage Areas

    PubMed Central

    Dick, Andrew W.; Pacula, Rosalie Liccardo; Gordon, Adam J.; Sorbero, Mark; Burns, Rachel M.; Leslie, Douglas L.; Stein, Bradley D.

    2015-01-01

    Opioid use disorders are a significant public health problem, affecting over 2 million individuals in the US. Although opioid agonist treatment, predominantly offered in licensed methadone clinics, is both effective and cost-effective, many individuals do not receive it. Buprenorphine, approved in 2002 for prescription by waivered physicians, could improve opioid agonist treatment access for individuals unable or unwilling to receive methadone. We examine the extent to which the geographic distribution of waivered physicians has enhanced potential opioid agonist treatment access, particularly in non-metropolitan areas with fewer methadone clinics. We found that while the approximately 90% of counties classified as methadone clinic shortage areas remained constant, buprenorphine shortage areas fell from 99% of counties in 2002 to 51% in 2011, lowering the US population percentage residing in opioid treatment shortage counties to approximately 10%. The increase in buprenorphine-waivered physicians has dramatically increased potential access to opioid agonist treatment, especially in non-metropolitan counties. PMID:26056209

  16. Agonist binding to the NMDA receptor drives movement of its cytoplasmic domain without ion flow

    PubMed Central

    Dore, Kim; Aow, Jonathan; Malinow, Roberto

    2015-01-01

    The NMDA receptor (R) plays important roles in brain physiology and pathology as an ion channel. Here we examine the ion flow-independent coupling of agonist to the NMDAR cytoplasmic domain (cd). We measure FRET between fluorescently tagged cytoplasmic domains of GluN1 subunits of NMDARs expressed in neurons. Different neuronal compartments display varying levels of FRET, consistent with different NMDARcd conformations. Agonist binding drives a rapid and transient ion flow-independent reduction in FRET between GluN1 subunits within individual NMDARs. Intracellular infusion of an antibody targeting the GluN1 cytoplasmic domain blocks agonist-driven FRET changes in the absence of ion flow, supporting agonist-driven movement of the NMDARcd. These studies indicate that extracellular ligand binding to the NMDAR can transmit conformational information into the cell in the absence of ion flow. PMID:26553997

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

    PubMed

    Lin, Hsiang-Ru

    2015-01-01

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

  18. Potent agonists of a hematopoietic stem cell cytokine receptor, c-Mpl.

    PubMed

    Tarasova, Anna; Haylock, David N; Meagher, Laurence; Be, Cheang Ly; White, Jacinta; Nilsson, Susan K; Andrade, Jessica; Cartledge, Kellie; Winkler, David A

    2013-05-01

    Several growth factors feature prominently in the control of hematopoiesis. Thrombopoietin, a class I hematopoietic cytokine, plays critical roles in regulating hematopoietic stem cell numbers and also stimulates the production and differentiation of megakaryocytes, the bone marrow cells that ultimately produce platelets. Thrombopoietin interacts with the c-Mpl cell-surface receptor. Recently, several peptide and small-molecule agonists and antagonists of c-Mpl have been reported. We conducted a bioinformatics and molecular modeling study aimed at understanding the agonist activities of peptides that bind to c-Mpl, and developed new potent peptide agonists with low nanomolar activity. These agonists also show very high activity in human CD34(+) primary cell cultures, and doubled the mean blood platelet counts when injected into mice.

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

    PubMed

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

    2011-03-01

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

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

    PubMed Central

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

    2011-01-01

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

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

    PubMed Central

    Karner, Charlotta; Cates, Christopher J

    2014-01-01

    Background Long-acting bronchodilators comprising long-acting beta2-agonists and the anticholinergic agent tiotropium are commonly used for managing persistent symptoms of chronic obstructive pulmonary disease. Combining these treatments, which have different mechanisms of action, may be more effective than the individual components. However, the benefits and risks of combining tiotropium and long-acting beta2-agonists for the treatment of chronic obstructive pulmonary (COPD) disease are unclear. Objectives To assess the relative effects of treatment with tiotropium in addition to long-acting beta2-agonist compared to tiotropium or long-acting beta2-agonist alone in patients with chronic obstructive pulmonary disease. Search methods We searched the Cochrane Airways Group Specialised Register of trials and clinicaltrials.gov up to January 2012. Selection criteria We included parallel group, randomised controlled trials of three months or longer comparing treatment with tiotropium in addition to long-acting beta2-agonist against tiotropium or long-acting beta2-agonist alone for patients with chronic obstructive pulmonary disease. Data collection and analysis Two review authors independently assessed trials for inclusion and then extracted data on trial quality and the outcome results. We contacted study authors for additional information. We collected information on adverse effects from the trials. Main results Five trials were included in this review, mostly recruiting participants with moderate or severe chronic obstructive pulmonary disease. All of them compared tiotropium in addition to long-acting beta2-agonist to tiotropium alone, but only one trial additionally compared a combination of the two types of bronchodilator with long-acting beta2-agonist (formoterol) alone. Two studies used the long-acting beta2-agonist indacaterol, two used formoterol and one used salmeterol. Compared to tiotropium alone (3263 patients), treatment with tiotropium plus long

  2. Competitive molecular docking approach for predicting estrogen receptor subtype α agonists and antagonists

    PubMed Central

    2014-01-01

    Background Endocrine disrupting chemicals (EDCs) are exogenous compounds that interfere with the endocrine system of vertebrates, often through direct or indirect interactions with nuclear receptor proteins. Estrogen receptors (ERs) are particularly important protein targets and many EDCs are ER binders, capable of altering normal homeostatic transcription and signaling pathways. An estrogenic xenobiotic can bind ER as either an agonist or antagonist to increase or inhibit transcription, respectively. The receptor conformations in the complexes of ER bound with agonists and antagonists are different and dependent on interactions with co-regulator proteins that vary across tissue type. Assessment of chemical endocrine disruption potential depends not only on binding affinity to ERs, but also on changes that may alter the receptor conformation and its ability to subsequently bind DNA response elements and initiate transcription. Using both agonist and antagonist conformations of the ERα, we developed an in silico approach that can be used to differentiate agonist versus antagonist status of potential binders. Methods The approach combined separate molecular docking models for ER agonist and antagonist conformations. The ability of this approach to differentiate agonists and antagonists was first evaluated using true agonists and antagonists extracted from the crystal structures available in the protein data bank (PDB), and then further validated using a larger set of ligands from the literature. The usefulness of the approach was demonstrated with enrichment analysis in data sets with a large number of decoy ligands. Results The performance of individual agonist and antagonist docking models was found comparable to similar models in the literature. When combined in a competitive docking approach, they provided the ability to discriminate agonists from antagonists with good accuracy, as well as the ability to efficiently select true agonists and antagonists from

  3. Agonist-sensitive calcium pool in the pancreatic acinar cell. II. Characterization of reloading

    SciTech Connect

    Muallem, S.; Schoeffield, M.S.; Fimmel, C.J.; Pandol, S.J.

    1988-08-01

    45Ca2+ fluxes and free cytosolic Ca2+ measurements in guinea pig pancreatic acini indicated that after agonist stimulation and the release of Ca2+ from the agonist-sensitive pool at least part of the Ca2+ is extruded from the cell, resulting in 45Ca2+ efflux. In the continued presence of agonist, the pool remains permeable to Ca2+ but partially refills with Ca2+. This reloading is dependent on the concentration of extracellular Ca2+. In the absence of extracellular Ca2+, the pool is completely depleted of Ca2+. However, with increasing concentrations of CaCl2 in the incubation solution (from 0.5 to 2.0 mM) there is increasing repletion of the pool with Ca2+ during agonist stimulation. With termination of agonist stimulation, the Ca2+ permeability of the agonist-sensitive pool is rapidly reduced to that measured in the unstimulated cell. As a result, the Ca2+ incorporated into the pool during the stimulation period is rapidly trapped within the pool and exchanges poorly with medium Ca2+. Subsequently, the pool completely refills with Ca2+. The rate of Ca2+ reloading at the termination of agonist stimulation is slower than the conversion of the pool to the impermeable state. In incubation media containing 1.3 mM CaCl2, the half-time for reloading at the termination of stimulation is 5 min. These observations demonstrate the characteristics of Ca2+ reloading of the agonist-sensitive pool both during stimulation and at the termination of stimulation.

  4. 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.

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

    SciTech Connect

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

    2008-01-01

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

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

    SciTech Connect

    Thompson, Scott K.; Washburn, David G.; Frazee, James S.; Madauss, Kevin P.; Hoang, Tram H.; Lapinski, Leahann; Grygielko, Eugene T.; Glace, Lindsay E.; Trizna, Walter; Williams, Shawn P.; Duraiswami, Chaya; Bray, Jeffrey D.; Laping, Nicholas J.

    2010-09-03

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

  7. Identification of Hydroxybenzoic Acids as Selective Lactate Receptor (GPR81) Agonists with Antilipolytic Effects.

    PubMed

    Dvorak, Curt A; Liu, Changlu; Shelton, Jonathan; Kuei, Chester; Sutton, Steven W; Lovenberg, Timothy W; Carruthers, Nicholas I

    2012-08-01

    Following the characterization of the lactate receptor (GPR81), a focused screening effort afforded 3-hydroxybenzoic acid 1 as a weak agonist of both GPR81 and GPR109a (niacin receptor). An examination of structurally similar arylhydroxy acids led to the identification of 3-chloro-5-hydroxybenzoic acid 2, a selective GPR81 agonist that exhibited favorable in vivo effects on lipolysis in a mouse model of obesity.

  8. Identification of Hydroxybenzoic Acids as Selective Lactate Receptor (GPR81) Agonists with Antilipolytic Effects

    PubMed Central

    2012-01-01

    Following the characterization of the lactate receptor (GPR81), a focused screening effort afforded 3-hydroxybenzoic acid 1 as a weak agonist of both GPR81 and GPR109a (niacin receptor). An examination of structurally similar arylhydroxy acids led to the identification of 3-chloro-5-hydroxybenzoic acid 2, a selective GPR81 agonist that exhibited favorable in vivo effects on lipolysis in a mouse model of obesity. PMID:24900524

  9. Identification of benzoxazole analogs as novel, S1P(3) sparing S1P(1) agonists.

    PubMed

    Deng, Guanghui; Meng, Qinghua; Liu, Qian; Xu, Xuesong; Xu, Qiongfeng; Ren, Feng; Guo, Taylor B; Lu, Hongtao; Xiang, Jia-Ning; Elliott, John D; Lin, Xichen

    2012-06-15

    A novel series of benzoxazole-derived S1P(1) agonists were designed based on scaffold hopping molecular design strategy combined with computational approaches. Extensive SAR studies led to the discovery of compound 17d as a selective S1P(1) agonist (over S1P(3)) with high CNS penetration and favorable DMPK properties. 17d also demonstrated in vivo pharmacological efficacy to reduce blood lymphocyte in mice after oral administration.

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

    PubMed

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

    2005-10-15

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

  11. Topography of dyskinesias and torticollis evoked by inhibition of substantia nigra pars reticulata.

    PubMed

    Dybdal, David; Forcelli, Patrick A; Dubach, Mark; Oppedisano, Michael; Holmes, Angela; Malkova, Ludise; Gale, Karen

    2013-04-01

    GABAergic neurons of the substantia nigra pars reticulata (SNpr) and globus pallidus pars interna (GPi) constitute the output pathways of the basal ganglia. In monkeys, choreiform limb dyskinesias have been described after inhibition of the GPi, but not the SNpr. Given the anatomical and functional similarities between these structures, we hypothesized that choreiform dyskinesias could be evoked by inhibition of an appropriate region within the SNpr. The GABAA receptor agonist, muscimol, was infused into various sites within the SNpr and the adjacent STN of freely moving macaques. The effect of the GABAA antagonist, bicuculline (BIC), was also examined. Muscimol (MUS) in SNpr evoked the following: (1) choreiform dyskinesias of the contralateral arm and/or leg from central and lateral sites; (2) contralaterally directed torticollis from central and posterior sites; and (3) contraversive quadrupedal rotation from anterior and lateral sites. MUS infusions into the adjacent SN pars compacta or STN were without effect, ruling out a contribution of drug spread to adjacent structures. BIC in SNpr induced ipsiversive postures without choreiform dyskinesia or torticollis, whereas in the STN, it evoked ballistic movements. This is the first report of choreiform dyskinesia evoked by inhibition of the SNpr. This highly site-specific effect was obtained from a restricted region within the SNpr distinct from that responsible for inducing torticollis. These results suggest that overactivity of different SNpr outputs mediates choreiform dyskinesia and torticollis. These abnormalities are symptoms of dystonia, Huntington's disease, and iatrogenic dyskinesias, suggesting that these conditions may result, in part, from a loss of function in SNpr efferent projections.

  12. 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

  13. Scaffold-Based Pan-Agonist Design for the PPARα, PPARβ and PPARγ Receptors

    PubMed Central

    Xu, Wei-Ren; Wang, Run-Ling; Wang, Jing-Fang

    2012-01-01

    As important members of nuclear receptor superfamily, Peroxisome proliferator-activated receptors (PPAR) play essential roles in regulating cellular differentiation, development, metabolism, and tumorigenesis of higher organisms. The PPAR receptors have 3 identified subtypes: PPARα, PPARβ and PPARγ, all of which have been treated as attractive targets for developing drugs to treat type 2 diabetes. Due to the undesirable side-effects, many PPAR agonists including PPARα/γ and PPARβ/γ dual agonists are stopped by US FDA in the clinical trials. An alternative strategy is to design novel pan-agonist that can simultaneously activate PPARα, PPARβ and PPARγ. Under such an idea, in the current study we adopted the core hopping algorithm and glide docking procedure to generate 7 novel compounds based on a typical PPAR pan-agonist LY465608. It was observed by the docking procedures and molecular dynamics simulations that the compounds generated by the core hopping and glide docking not only possessed the similar functions as the original LY465608 compound to activate PPARα, PPARβ and PPARγ receptors, but also had more favorable conformation for binding to the PPAR receptors. The additional absorption, distribution, metabolism and excretion (ADME) predictions showed that the 7 compounds (especially Cpd#1) hold high potential to be novel lead compounds for the PPAR pan-agonist. Our findings can provide a new strategy or useful insights for designing the effective pan-agonists against the type 2 diabetes. PMID:23119024

  14. Scaffold-based pan-agonist design for the PPARα, PPARβ and PPARγ receptors.

    PubMed

    Zhang, Li-Song; Wang, Shu-Qing; Xu, Wei-Ren; Wang, Run-Ling; Wang, Jing-Fang

    2012-01-01

    As important members of nuclear receptor superfamily, Peroxisome proliferator-activated receptors (PPAR) play essential roles in regulating cellular differentiation, development, metabolism, and tumorigenesis of higher organisms. The PPAR receptors have 3 identified subtypes: PPARα, PPARβ and PPARγ, all of which have been treated as attractive targets for developing drugs to treat type 2 diabetes. Due to the undesirable side-effects, many PPAR agonists including PPARα/γ and PPARβ/γ dual agonists are stopped by US FDA in the clinical trials. An alternative strategy is to design novel pan-agonist that can simultaneously activate PPARα, PPARβ and PPARγ. Under such an idea, in the current study we adopted the core hopping algorithm and glide docking procedure to generate 7 novel compounds based on a typical PPAR pan-agonist LY465608. It was observed by the docking procedures and molecular dynamics simulations that the compounds generated by the core hopping and glide docking not only possessed the similar functions as the original LY465608 compound to activate PPARα, PPARβ and PPARγ receptors, but also had more favorable conformation for binding to the PPAR receptors. The additional absorption, distribution, metabolism and excretion (ADME) predictions showed that the 7 compounds (especially Cpd#1) hold high potential to be novel lead compounds for the PPAR pan-agonist. Our findings can provide a new strategy or useful insights for designing the effective pan-agonists against the type 2 diabetes. PMID:23119024

  15. How neighborhood disorder increases blood pressure in youth: agonistic striving and subordination

    PubMed Central

    Elder, Gavin J.; Smyth, Joshua M.

    2012-01-01

    Growing evidence links perceptions of neighborhood disorder to adverse health outcomes but little is known about psychological processes that may mediate this association. We tested the hypothesis that two psychological mechanisms—agonistic striving and subordination—mediate the link between perceived neighborhood disorder and hypertension risk in youth. Perceived neighborhood disorder, agonistic striving, subordination experiences, negative affect, obesity, and ambulatory blood pressure during daily activities (48 h) were assessed in a multiethnic sample of 167 low- to middle-income urban adolescents. Path analyses revealed that agonistic striving, subordination, and obesity each independently mediated the association between neighborhood disorder and blood pressure; these variables accounted for 73 % of the shared variance, 42 % of which was explained by agonistic striving. The direct relationship between perceived neighborhood disorder and blood pressure was no longer significant in the presence of these mediators. Negative affect was associated with neighborhood disorder and subordination, but not blood pressure. Agonistic striving proved to be a significant and substantial mediator of the association between perceived neighborhood disorder, blood pressure, and future hypertension risk. New research should seek to clarify the processes by which stressful neighborhoods induce persistent agonistic motives and perceptions of subordination in adolescents. PMID:23229689

  16. 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.

  17. GLP-1 receptor agonists or DPP-4 inhibitors: how to guide the clinician?

    PubMed

    Scheen, André J

    2013-12-01

    Pharmacological treatment of type 2 diabetes has been enriched during recent years, with the launch of incretin therapies targeting glucagon-like peptide-1 (GLP-1). Such medications comprise either GLP-1 receptor agonists, with short (one or two daily injections: exenatide, liraglutide, lixisenatide) or long duration (one injection once weekly: extended-released exenatide, albiglutide, dulaglutide, taspoglutide); or oral compounds inhibiting dipeptidyl peptidase-4 (DPP-4), the enzyme that inactives GLP-1, also called gliptins (sitagliptin, vildagliptin, saxagliptin, linagliptin, alogliptin). Although both pharmacological approaches target GLP-1, important differences exist concerning the mode of administration (subcutaneous injection versus oral ingestion), the efficacy (better with GLP-1 agonists), the effects on body weight and systolic blood pressure (diminution with agonists versus neutrality with gliptins), the tolerance profile (nausea and possibly vomiting with agonists) and the cost (higher with GLP-1 receptor agonists). Both agents may exert favourable cardiovascular effects. Gliptins may represent a valuable alternative to a sulfonylurea or a glitazone after failure of monotherapy with metformin while GLP-1 receptor agonists may be considered as a good alternative to insulin (especially in obese patients) after failure of a dual oral therapy. However, this scheme is probably too restrictive and modalities of using incretins are numerous, in almost all stages of type 2 diabetes. Physicians may guide the pharmacological choice based on clinical characteristics, therapeutic goals and patient's preference.

  18. β-Adrenoreceptor agonists in the management of pain associated with renal colic: a systematic review

    PubMed Central

    Johnson, Graham David; Fakis, Apostolos; Surtees, Jane; Lennon, Robert Iain

    2016-01-01

    Objectives To determine whether β-adrenoreceptor agonists are effective analgesics for patients with renal colic through a systematic review of the literature. Setting Adult emergency departments or acute assessment units. Participants Human participants with proven or suspected renal colic. Interventions β-adrenoreceptor agonists. Outcome measures Primary: level of pain at 30 min following administration of the β-agonist. Secondary: level of pain at various time points following β-agonist administration; length of hospital stay; analgesic requirement; stone presence, size and position; degree of hydronephrosis. Results 256 records were screened and 4 identified for full-text review. No articles met the inclusion criteria. Conclusions and implications There is no evidence to support or refute the proposed use of β-agonists for analgesia in patients with renal colic. Given the biological plausibility and existing literature base, clinical trials investigating the use of β-adrenoreceptor agonists in the acute setting for treatment of the pain associated with renal colic are recommended. Trial registration number CRD42015016266. PMID:27324714

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

    PubMed

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

    2002-01-01

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

  20. Identification of metals from osteoblastic ST-2 cell supernatants as novel OGR1 agonists.

    PubMed

    Abe-Ohya, Rie; Ishikawa, Tomio; Shiozawa, Hideyuki; Suda, Koji; Nara, Futoshi

    2015-01-01

    Ovarian cancer G-protein-coupled receptor 1 (OGR1) is a G-protein-coupled receptor (GPCR), which has previously been identified as a receptor for protons. It has been reported in this and previous studies that OGR1 expression was markedly up-regulated during osteoclast differentiation. We predicted the possibility of other molecules activating OGR1 in neutral pH, and that osteoblasts might release OGR1 agonistic molecules and activate OGR1 expressed in osteoclasts such as RANKL. We screened for cell supernatants and organ extracts and discovered OGR1 agonistic activity in ST-2 osteoblastic cell supernatants and pancreatic tissues. Finally, we partially purified and identified essential metals, Fe, Zn, Co, Ni and Mn, as novel OGR1 agonists. These OGR1 agonistic metals induce intracellular Gq-coupled inositol phosphate signals in OGR1-expressing cells and primary osteoclasts through OGR1. We also confirmed that these OGR1 agonistic metals activated OGR1 through the same residues which act with protons. Here, we demonstrate that metals, Fe, Zn, Co, Ni and Mn are the novel OGR1 agonists, which can singly activate OGR1 in neutral pH.

  1. Functional assays to define agonists and antagonists of the sigma-2 receptor

    PubMed Central

    Zeng, Chenbo; Rothfuss, Justin M.; Zhang, Jun; Vangveravong, Suwanna; Chu, Wenhua; Li, Shihong; Tu, Zhude; Xu, Jinbin; Mach, Robert H.

    2014-01-01

    The sigma-2 receptor has been identified as a biomarker in proliferating tumors. Up to date there is no well-established functional assay for defining sigma-2 agonists and antagonists. Many sigma-2 ligands with diverse structures have been shown to induce cell death in a variety of cancer cells by triggering caspase-dependent and independent apoptosis. Therefore, in the current study, we used the cell viability assay and the caspase-3 activity assay to determine sigma-2 agonists and antagonists. Three classes of sigma-2 ligands developed in our laboratory were evaluated for their potency to induce cell death in two tumor cell lines, mouse breast cancer cell line EMT-6 and human melanoma cell line MDA-MB-435. The data showed that the EC50 values of the sigma-2 ligands using the cell viability assay ranged from 11.4 μM to >200 μM, which were comparable with the EC50 values obtained using the caspase-3 assay. Based on the cytotoxicity of a sigma-2 ligand relative to that of siramesine, a commonly accepted sigma-2 agonist, we have categorized our sigma-2 ligands into agonists, partial agonists, and antagonists. The establishment of functional assays for defining sigma-2 agonists and antagonists will facilitate functional characterization of sigma-2 receptor ligands and sigma-2 receptors. PMID:24333652

  2. Do inhaled beta(2)-agonists have an ergogenic potential in non-asthmatic competitive athletes?

    PubMed

    Kindermann, Wilfried

    2007-01-01

    The prevalence of asthma is higher in elite athletes than in the general population. The risk of developing asthmatic symptoms is the highest in endurance athletes and swimmers. Asthma seems particularly widespread in winter-sport athletes such as cross-country skiers. Asthmatic athletes commonly use inhaled beta(2)-agonists to prevent and treat asthmatic symptoms. However, beta(2)-agonists are prohibited according to the Prohibited List of the World Anti-Doping Agency. An exception can be made only for the substances formoterol, salbutamol, salmeterol and terbutaline by inhalation, as long as a therapeutic use exemption has been applied for and granted. In this context, the question arises of whether beta(2)-agonists have ergogenic benefits justifying the prohibition of these substances. In 17 of 19 randomised placebo-controlled trials in non-asthmatic competitive athletes, performance-enhancing effects of the inhaled beta(2)-agonists formoterol, salbutamol, salmeterol and terbutaline could not be proved. This is particularly true for endurance performance, anaerobic power and strength performance. In three of four studies, even supratherapeutic doses of salbutamol (800-1200 microg) had no ergogenic effect. In contrast to inhaled beta(2)-agonists, oral administration of salbutamol seems to be able to improve the muscle strength and the endurance performance. There appears to be no justification to prohibit inhaled beta(2)-agonists from the point of view of the ergogenic effects. PMID:17241101

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

    PubMed

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

    2002-01-01

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

  4. Alpha/sub 1/ receptor coupling events initiated by methoxy-substituted tolazoline partial agonists

    SciTech Connect

    Wick, P.; Keung, A.; Deth, R.

    1986-03-01

    A series of mono- and dimethyoxy substituted tolazoline derivatives, known to be partial agonists at the alpha/sub 1/ receptor, were compared with the ..cap alpha../sub 1/ selective full agonist phenylephrine (PE) on isolated strips of rabbit aorta Agonist activity was evaluated in contraction, /sup 45/Ca influx, /sup 45/Ca efflux, and /sup 32/P-Phospholipid labelling studies. Maximum contractile responses for the 2-, 3-, and 3, 5- methoxy substituted tolazoline derivatives (10/sup -5/M) were 53.8, 67.6 and 99.7% of the PE (10/sup -5/M) response respectively. These same partial agonists caused a stimulation of /sup 45/Ca influx to the extent of 64, 86, and 95% of the PE response respectively. In /sup 45/Ca efflux studies, (a measure of the intracellular Ca/sup +2/ release) the tolazolines caused: 30%, 63%, and 78% of the PE stimulated level. /sup 32/P-Phosphatidic acid (PA) labelling was measured as an index of PI turnover after ..cap alpha../sub 1/ receptor stimulation. Compared to PE, the 2-, 3-, and 3,5- methoxy substituted tolazoline derivatives caused 22, 46, and 72% PA labelling. The above values are all in reasonable accord with the rank order or agonist activity shown in maximum contractile responses. The results of this investigation suggest that partial agonists stimulate ..cap alpha.. receptor coupling events at a level which is quantitatively comparable to their potencies in causing contraction of arterial smooth muscle.

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

    PubMed

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

    2013-01-01

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

  6. Selective Retinoic Acid Receptor γ Agonists Promote Repair of Injured Skeletal Muscle in Mouse

    PubMed Central

    Di Rocco, Agnese; Uchibe, Kenta; Larmour, Colleen; Berger, Rebecca; Liu, Min; Barton, Elisabeth R.; Iwamoto, Masahiro

    2016-01-01

    Retinoic acid signaling regulates several biological events, including myogenesis. We previously found that retinoic acid receptor γ (RARγ) agonist blocks heterotopic ossification, a pathological bone formation that mostly occurs in the skeletal muscle. Interestingly, RARγ agonist also weakened deterioration of muscle architecture adjacent to the heterotopic ossification lesion, suggesting that RARγ agonist may oppose skeletal muscle damage. To test this hypothesis, we generated a critical defect in the tibialis anterior muscle of 7-week-old mice with a cautery, treated them with RARγ agonist or vehicle corn oil, and examined the effects of RARγ agonist on muscle repair. The muscle defects were partially repaired with newly regenerating muscle cells, but also filled with adipose and fibrous scar tissue in both RARγ-treated and control groups. The fibrous or adipose area was smaller in RARγ agonist–treated mice than in the control. In addition, muscle repair was remarkably delayed in RARγ-null mice in both critical defect and cardiotoxin injury models. Furthermore, we found a rapid increase in retinoid signaling in lacerated muscle, as monitored by retinoid signaling reporter mice. Together, our results indicate that endogenous RARγ signaling is involved in muscle repair and that selective RARγ agonists may be beneficial to promote repair in various types of muscle injuries. PMID:26205250

  7. Identification of Ecdysone Hormone Receptor Agonists as a Therapeutic Approach for Treating Filarial Infections

    PubMed Central

    Mhashilkar, Amruta S.; Vankayala, Sai L.; Liu, Canhui; Kearns, Fiona; Mehrotra, Priyanka; Tzertzinis, George; Palli, Subba R.; Woodcock, H. Lee; Unnasch, Thomas R.

    2016-01-01

    Background A homologue of the ecdysone receptor has previously been identified in human filarial parasites. As the ecdysone receptor is not found in vertebrates, it and the regulatory pathways it controls represent attractive potential chemotherapeutic targets. Methodology/ Principal Findings Administration of 20-hydroxyecdysone to gerbils infected with B. malayi infective larvae disrupted their development to adult stage parasites. A stable mammalian cell line was created incorporating the B. malayi ecdysone receptor ligand-binding domain, its heterodimer partner and a secreted luciferase reporter in HEK293 cells. This was employed to screen a series of ecdysone agonist, identifying seven agonists active at sub-micromolar concentrations. A B. malayi ecdysone receptor ligand-binding domain was developed and used to study the ligand-receptor interactions of these agonists. An excellent correlation between the virtual screening results and the screening assay was observed. Based on both of these approaches, steroidal ecdysone agonists and the diacylhydrazine family of compounds were identified as a fruitful source of potential receptor agonists. In further confirmation of the modeling and screening results, Ponasterone A and Muristerone A, two compounds predicted to be strong ecdysone agonists stimulated expulsion of microfilaria and immature stages from adult parasites. Conclusions The studies validate the potential of the B. malayi ecdysone receptor as a drug target and provide a means to rapidly evaluate compounds for development of a new class of drugs against the human filarial parasites. PMID:27300294

  8. Metabolic mapping of A3 adenosine receptor agonist MRS5980.

    PubMed

    Fang, Zhong-Ze; Tosh, Dilip K; Tanaka, Naoki; Wang, Haina; Krausz, Kristopher W; O'Connor, Robert; Jacobson, Kenneth A; Gonzalez, Frank J

    2015-09-15

    (1S,2R,3S,4R,5S)-4-(2-((5-Chlorothiophen-2-yl)ethynyl)-6-(methylamino)-9H-purin-9-yl)-2,3-dihydroxy-N-methylbicyclo[3.1.0]hexane-1-carboxamide (MRS5980) is an A3AR selective agonist containing multiple receptor affinity- and selectivity-enhancing modifications and a therapeutic candidate drug for many inflammatory diseases. Metabolism-related poor pharmacokinetic behavior and toxicities are a major reason for drug R&D failure. Metabolomics with UPLC-MS was employed to profile the metabolism of MRS5980 and MRS5980-induced disruption of endogenous compounds. Recombinant drug-metabolizing enzymes screening experiment were used to determine the enzymes involved in MRS5980 metabolism. Analysis of lipid metabolism-related genes was performed to investigate the reason for MRS5980-induced lipid metabolic disorders. Unsupervised principal components analysis separated the control and MRS5980 treatment groups in feces, urine, and liver samples, but not in bile and serum. The major ions mainly contributing to the separation of feces and urine were oxidized MRS5980, glutathione (GSH) conjugates and cysteine conjugate (degradation product of the GSH conjugates) of MRS5980. The major ions contributing to the group separation of liver samples were phosphatidylcholines. In vitro incubation experiments showed the involvement of CYP3A enzymes in the oxidative metabolism of MRS5980 and direct GSH reactivity of MRS5980. The electrophilic attack by MRS5980 is a minor pathway and did not alter GSH levels in liver or liver histology, and thus may be of minor clinical consequence. Gene expression analysis further showed decreased expression of PC biosynthetic genes choline kinase a and b, which further accelerated conversion of lysophosphatidylcholine to phosphatidylcholines through increasing the expression of lysophosphatidylcholine acyltransferase 3. These data will be useful to guide rational design of drugs targeting A3AR, considering efficacy, metabolic elimination, and

  9. Cardiovascular Effects of Glucagon-Like Peptide-1 Receptor Agonists

    PubMed Central

    Kang, Yu Mi

    2016-01-01

    Glucagon-like peptide-1 (GLP-1) is a member of the proglucagon incretin family, and GLP-1 receptor agonists (RAs) have been introduced as a new class of antidiabetic medications in the past decade. The benefits of GLP-1 RAs are derived from their pleiotropic effects, which include glucose-dependent insulin secretion, suppressed glucagon secretion, and reduced appetite. Moreover, GLP-1 RAs also exert beneficial roles on multiple organ systems in which the GLP-1 receptors exist, including the cardiovascular system. Cardiovascular effects of GLP-1 RAs have been of great interest since the burden from cardiovascular diseases (CVD) has been unbearably increasing in a diabetic population worldwide, despite strict glycemic control and advanced therapeutic techniques to treat CVD. Preclinical studies have already demonstrated the beneficial effects of GLP-1 on myocardium and vascular endothelium, and many clinical studies evaluating changes in surrogate markers of CVD have suggested potential benefits from the use of GLP-1 RAs. Data from numerous clinical trials primarily evaluating the antihyperglycemic effects of multiple GLP-1 RAs have also revealed that changes in most CVD risk markers reported as secondary outcomes have been in favor of GLP-1 RAs treatment. However, to date, there is only one randomized clinical trial of GLP-1 RAs (the ELIXA study) evaluating major cardiovascular events as their primary outcomes, and in this study, a neutral cardiovascular effect of lixisenatide was observed in high-risk diabetic subjects. Therefore, the results of ongoing CVD outcome trials with the use of GLP-1 RAs should be awaited to elucidate the translation of benefits previously seen in CVD risk marker studies into large clinical trials with primary cardiovascular outcomes. PMID:27118277

  10. Metabolic mapping of A3 adenosine receptor agonist MRS5980

    PubMed Central

    Fang, Zhong-Ze; Tosh, Dilip K.; Tanaka, Naoki; Wang, Haina; Krausz, Kristopher W.; O'Connor, Robert; Jacobson, Kenneth A.; Gonzalez, Frank J.

    2015-01-01

    (1S,2R,3S,4R,5S)-4-(2-((5-Chlorothiophen-2-yl)ethynyl)-6-(methylamino)-9H-purin-9-yl)-2,3-dihydroxy-N-methylbicyclo[3.1.0]hexane-1-carboxamide (MRS5980) is an A3AR selective agonist containing multiple receptor affinity- and selectivity-enhancing modifications and a therapeutic candidate drug for many inflammatory diseases. Metabolism-related poor pharmacokinetic behavior and toxicities are a major reason of drug R&D failure. Metabolomics with UPLC-MS was employed to profile the metabolism of MRS5980 and MRS5980-induced disruption of endogenous compounds. Recombinant drug-metabolizing enzymes screening experiment were used to determine the enzymes involved in MRS5980 metabolism. Analysis of lipid metabolism-related genes was performed to investigate the reason for MRS5980-induced lipid metabolic disorders. Unsupervised principal components analysis separated the control and MRS5980 treatment group in feces, urine, and liver samples, but not in bile and serum. The major ions mainly contributing to the separation for feces and urine were oxidized MRS5980, glutathione (GSH) conjugates and cysteine conjugate (degradation product of the GSH conjugates) of MRS5980. The major ions contributing to the group separation of liver samples were phosphatidylcholines. In vitro incubation experiments showed the major involvement of CYP3A enzymes in the oxidative metabolism of MRS5980 and direct GSH reactivity of MRS5980. The electrophilic attack by MRS5980 is a minor pathway and did not alter GSH levels in liver or liver histology, and thus may be of minor clinical consequence. Gene expression analysis further showed decreased expression of PC biosynthetic genes choline kinase a and b, which further accelerated conversion of lysophosphatidylcholine to phosphatidylcholines through increasing the expression of lysophosphatidylcholine acyltransferase 3. These data will be useful to guide rational design of drugs targeting A3AR, considering efficacy, metabolic elimination, and

  11. Radiolabelled D2 agonists as prolactinoma imaging agents

    SciTech Connect

    Otto, C.A.

    1989-08-01

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

  12. GABAA agonist reduces visual awareness: a masking-EEG experiment.

    PubMed

    van Loon, Anouk M; Scholte, H Steven; van Gaal, Simon; van der Hoort, Björn J J; Lamme, Victor A F

    2012-04-01

    Consciousness can be manipulated in many ways. Here, we seek to understand whether two such ways, visual masking and pharmacological intervention, share a common pathway in manipulating visual consciousness. We recorded EEG from human participants who performed a backward-masking task in which they had to detect a masked figure form its background (masking strength was varied across trials). In a within-subject design, participants received dextromethorphan (a N-methyl-d-aspartate receptor antagonist), lorazepam (LZP; a GABA(A) receptor agonist), scopolamine (a muscarine receptor antagonist), or placebo. The behavioral results show that detection rate decreased with increasing masking strength and that of all the drugs, only LZP induced a further decrease in detection rate. Figure-related ERP signals showed three neural events of interest: (1) an early posterior occipital and temporal generator (94-121 msec) that was not influenced by any pharmacological manipulation nor by masking, (2) a later bilateral perioccipital generator (156-211 msec) that was reduced by masking as well as LZP (but not by any other drugs), and (3) a late bilateral occipital temporal generator (293-387 msec) that was mainly affected by masking. Crucially, only the intermediate neural event correlated with detection performance. In combination with previous findings, these results suggest that LZP and masking both reduce visual awareness by means of modulating late activity in the visual cortex but leave early activation intact. These findings provide the first evidence for a common mechanism for these two distinct ways of manipulating consciousness. PMID:22264199

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

    PubMed

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

    2015-01-22

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

  14. Agonist-bound structure of the human P2Y12 receptor

    PubMed Central

    Zhang, Jin; Zhang, Kaihua; Gao, Zhan-Guo; Paoletta, Silvia; Zhang, Dandan; Han, Gye Won; Li, Tingting; Ma, Limin; Zhang, Wenru; Müller, Christa E.; Yang, Huaiyu; Jiang, Hualiang; Cherezov, Vadim; Katritch, Vsevolod; Jacobson, Kenneth A.; Stevens, Raymond C.; Wu, Beili; Zhao, Qiang

    2014-01-01

    The P2Y12 receptor (P2Y12R), one of eight members of the P2YR family expressed in humans, has been identified as one of the most prominent clinical drug targets for inhibition of platelet aggregation. Consequently, extensive mutagenesis and modeling studies of the P2Y12R have revealed many aspects of agonist/antagonist binding1-4. However, the details of agonist and antagonist recognition and function at the P2Y12R remain poorly understood at the molecular level. Here, we report the structures of the human P2Y12R in complex with a full agonist 2-methylthio-adenosine-5′-diphosphate (2MeSADP, a close analogue of endogenous agonist ADP) at 2.5 Å resolution, and the corresponding ATP derivative 2-methylthio-adenosine-5′-triphosphate (2MeSATP) at 3.1 Å resolution. Analysis of these structures, together with the structure of the P2Y12R with antagonist ethyl 6-(4-((benzylsulfonyl)carbamoyl)piperidin-1-yl)-5-cyano-2-methylnicotinate (AZD1283)5, reveals dramatic conformational changes between nucleotide and non-nucleotide ligand complexes in the extracellular regions, providing the first insight into a different ligand binding landscape in the δ-group of class A G protein-coupled receptors (GPCRs). Agonist and non-nucleotide antagonist adopt different orientations in the P2Y12R, with only partially overlapped binding pockets. The agonist-bound P2Y12R structure answers long-standing ambiguities surrounding P2Y12R-agonist recognition, and reveals interactions with several residues that had not been reported to be involved in agonist binding. As a first example of a GPCR where agonist access to the binding pocket requires large scale rearrangements in the highly malleable extracellular region, the structural studies therefore will provide invaluable insight into the pharmacology and mechanisms of action of agonists and different classes of antagonists for the P2Y12R and potentially for other closely related P2YRs. PMID:24784220

  15. Dopamine agonists, anti-progestins, anti-androgens, long-term-release GnRH agonists and anti-estrogens in canine reproduction: a review.

    PubMed

    Gobello, C

    2006-10-01

    Over the last 10 years, new drugs have been applied to canine reproduction, widening the spectrum of therapeutic possibilities for diseases that were previously surgically treated, and facilitating better control of the estrous cycle and fertility. Some are not approved for use in dogs; their use is experimental and further clinical trials are necessary. Dopamine agonists such as cabergoline, bromocriptine or metergoline are ergoderivative alkaloids that exert an anti-prolactinergic effect via stimulation of D2 pituitary receptors or inhibition of central serotoninergic ones. Their main indication is suppression of lactation. Anti-prolactinergic compounds have also been successfully used for pregnancy termination and shortening of interestrous intervals. Anti-progestins, (e.g. mifepristone and aglepristone) are synthetic steroids that bind with high affinity to progesterone (P4) receptors, preventing P4 from exerting its biological effects. Anti-progestins have been indicated in P4-dependent conditions, such as pregnancy termination, induction of parturition and the medical treatment of pyometra. Several groups of drugs have been described to have anti-androgenic properties through different mechanisms of action: progestins, receptor binding anti-androgens (e.g. flutamide), competitive enzyme inhibitors (e.g. finasteride), aromatase inhibitors, and GnRH agonists. Their main application is medical treatment of benign prostatic hyperplasia. Long-term release formulations of GnRH agonists (e.g. leuprolide or deslorelin acetate) postponed puberty and reversibly suppressed reproductive function in male and female dogs for periods exceeding 1 year. Anti-estrogens (e.g. clomiphene and tamoxifen citrate) are synthetic non-steroidal type I anti-estrogenic compounds that competitively block estrogen receptors with a combined antagonist-agonistic effect. In dogs, their action is more agonistic than antagonistic. PMID:16542717

  16. Water and sodium balances and metabolic physiology of house mice (Mus domesticus) and short-tailed mice (Leggadina lakedownensis) under laboratory conditions.

    PubMed

    Moro, D; Bradshaw, S D

    1999-12-01

    A laboratory study investigated the metabolic physiology, and response to variable periods of water and sodium supply, of two arid-zone rodents, the house mouse (Mus domesticus) and the Lakeland Downs short-tailed mouse (Leggadina lakedownensis) under controlled conditions. Fractional water fluxes for M. domesticus (24 +/- 0.8%) were significantly higher than those of L. lakedownensis (17 +/- 0.7%) when provided with food ad libitum. In addition, the amount of water produced by M. domesticus and by L. lakedownensis from metabolic processes (1.3 +/- 0.4 ml.day-1 and 1.2 +/- 0.4 ml.day-1, respectively) was insufficient to provide them with their minimum water requirement (1.4 +/- 0.2 ml.day-1 and 2.0 +/- 0.3 ml.day-1, respectively). For both species of rodent, evaporative water loss was lowest at 25 degrees C, but remained significantly higher in M. domesticus (1.1 +/- 0.1 mg H2O.g-0.122.h-1) than in L. lakedownensis (0.6 +/- 0.1 mg H2O.g-0.122.h-1). When deprived of drinking water, mice of both species initially lost body mass, but regained it within 18 days following an increase in the amount of seed consumed. Both species were capable of drinking water of variable saline concentrations up to 1 mol.l-1, and compensated for the increased sodium in the water by excreting more urine to remove the sodium. Basal metabolic rate was significantly higher in M. domesticus (3.3 +/- 0.2 mg O2.g-0.75.h-1) than in L. lakedownensis (2.5 +/- 0.1 mg O2.g-0.75.h-1). The study provides good evidence that water flux differences between M. domesticus and L. lakedownensis in the field are due to a requirement for more water in M. domesticus to mect their physiological and metabolic demands. Sodium fluxes were lower than those observed in free-ranging mice, whose relatively high sodium fluxes may reflect sodium associated with available food.

  17. A short pulse (7 {mu}s FWHM) and high repetition rate (dc-5kHz) cantilever piezovalve for pulsed atomic and molecular beams

    SciTech Connect

    Irimia, Daniel; Dobrikov, Dimitar; Kortekaas, Rob; Voet, Han; Janssen, Maurice H. M.; Ende, Daan A. van den; Groen, Wilhelm A.

    2009-11-15

    In this paper we report on the design and operation of a novel piezovalve for the production of short pulsed atomic or molecular beams. The high speed valve operates on the principle of a cantilever piezo. The only moving part, besides the cantilever piezo itself, is a very small O-ring that forms the vacuum seal. The valve can operate continuous (dc) and in pulsed mode with the same drive electronics. Pulsed operation has been tested at repetition frequencies up to 5 kHz. The static deflection of the cantilever, as mounted in the valve body, was measured as a function of driving field strength with a confocal microscope. The deflection and high speed dynamical response of the cantilever can be easily changed and optimized for a particular nozzle diameter or repetition rate by a simple adjustment of the free cantilever length. Pulsed molecular beams with a full width at half maximum pulse width as low as 7 {mu}s have been measured at a position 10 cm downstream of the nozzle exit. This represents a gas pulse with a length of only 10 mm making it well matched to for instance experiments using laser beams. Such a short pulse with 6 bar backing pressure behind a 150 {mu}m nozzle releases about 10{sup 16} particles/pulse and the beam brightness was estimated to be 4x10{sup 22} particles/(s str). The short pulses of the cantilever piezovalve result in a much reduced gas load in the vacuum system. We demonstrate operation of the pulsed valve with skimmer in a single vacuum chamber pumped by a 520 l/s turbomolecular pump maintaining a pressure of 5x10{sup -6} Torr, which is an excellent vacuum to have the strong and cold skimmed molecular beam interact with laser beams only 10 cm downstream of the nozzle to do velocity map slice imaging with a microchannel-plate imaging detector in a single chamber. The piezovalve produces cold and narrow ({Delta}v/v=2%-3%) velocity distributions of molecules seeded in helium or neon at modest backing pressures of only 6 bar. The low gas

  18. Analysis of the biological response of mouse liver (Mus musculus) exposed to As2O3 based on integrated -omics approaches.

    PubMed

    García-Sevillano, M A; García-Barrera, T; Navarro, F; Gómez-Ariza, J L

    2013-12-01

    Organic and inorganic mass spectrometries were used to investigate the biochemical response of mice (Mus musculus) to inorganic arsenic exposure using liver as the target organ. The toxicological effects of trivalent inorganic arsenic after oral administration (3 mg kg(-1) body weight and per day) were investigated over a period of 7 days using metallomics, metabonomics and redox proteomics approaches. Size-exclusion chromatography (SEC) with ICP-MS detection was combined with anion exchange chromatography (AEC) to characterize the biological response of the exposed mice. On the other hand, direct infusion mass spectrometry (DI-ESI-QTOF-MS) of polar and lipophilic extracts using positive and negative modes of acquisition (ESI+/ESI-) provided information about time-dependent changes in endogenous metabolites identified by Partial Least Square-Discriminant Analysis (PLS-DA). Finally, the study has been complemented with the evaluation of up/down-regulation of enzymes related to oxidative stress such as superoxide dismutase (SOD), glutathione reductase (GR), catalase (CAT) and peroxidases in connection with metal toxicity issues. The results show that the inorganic arsenic methylation in the liver may reach the saturation point upon chronic exposure to the element. On the other hand, SEC-ICP-MS coupling provided information about metal containing-proteins and metabolites related to arsenic exposure (metallomics) which has been correlated with the changes in the global metabolism (metabonomics), also considering their consequences on the redox status of protein and protein expression (redox proteomics). Our study shows that arsenic causes biochemical pathway alterations, such as energy metabolism (e.g. glycolysis, Krebs cycle), amino acid metabolism, choline metabolism and degradation of membrane phospholipids (apoptosis). This work illustrates the high reliability of the integrated use of organic mass spectrometry for the metabonomic study of biochemical effects

  19. Selective α4β2 nicotinic acetylcholine receptor agonists target epigenetic mechanisms in cortical GABAergic neurons.

    PubMed

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

    2011-06-01

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

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

    PubMed Central

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

    2013-01-01

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

  1. 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.

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

    SciTech Connect

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

    1987-05-19

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

  3. β2-Adrenoceptor agonists as novel, safe and potentially effective therapies for Amyotrophic lateral sclerosis (ALS).

    PubMed

    Bartus, Raymond T; Bétourné, Alexandre; Basile, Anthony; Peterson, Bethany L; Glass, Jonathan; Boulis, Nicholas M

    2016-01-01

    Amyotrophic lateral sclerosis (ALS) is a chronic and progressive neuromuscular disease for which no cure exists and better treatment options are desperately needed. We hypothesize that currently approved β2-adrenoceptor agonists may effectively treat the symptoms and possibly slow the progression of ALS. Although β2-agonists are primarily used to treat asthma, pharmacologic data from animal models of neuromuscular diseases suggest that these agents may have pharmacologic effects of benefit in treating ALS. These include inhibiting protein degradation, stimulating protein synthesis, inducing neurotrophic factor synthesis and release, positively modulating microglial and systemic immune function, maintaining the structural and functional integrity of motor endplates, and improving energy metabolism. Moreover, stimulation of β2-adrenoceptors can activate a range of downstream signaling events in many different cell types that could account for the diverse array of effects of these agents. The evidence supporting the possible therapeutic benefits of β2-agonists is briefly reviewed, followed by a more detailed review of clinical trials testing the efficacy of β-agonists in a variety of human neuromuscular maladies. The weight of evidence of the potential benefits from treating these diseases supports the hypothesis that β2-agonists may be efficacious in ALS. Finally, ways to monitor and manage the side effects that may arise with chronic administration of β2-agonists are evaluated. In sum, effective, safe and orally-active β2-agonists may provide a novel and convenient means to reduce the symptoms of ALS and possibly delay disease progression, affording a unique opportunity to repurpose these approved drugs for treating ALS, and rapidly transforming the management of this serious, unmet medical need. PMID:26459114

  4. 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. PMID:25036611

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

    PubMed

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

    2011-12-01

    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. PMID:21968142

  6. β2-Adrenergic agonists attenuate organic dust-induced lung inflammation.

    PubMed

    Romberger, Debra J; Heires, Art J; Nordgren, Tara M; Poole, Jill A; Toews, Myron L; West, William W; Wyatt, Todd A

    2016-07-01

    Agricultural dust exposure results in significant lung inflammation, and individuals working in concentrated animal feeding operations (CAFOs) are at risk for chronic airway inflammatory diseases. Exposure of bronchial epithelial cells to aqueous extracts of hog CAFO dusts (HDE) leads to inflammatory cytokine production that is driven by protein kinase C (PKC) activation. cAMP-dependent protein kinase (PKA)-activating agents can inhibit PKC activation in epithelial cells, leading to reduced inflammatory cytokine production following HDE exposure. β2-Adrenergic receptor agonists (β2-agonists) activate PKA, and we hypothesized that β2-agonists would beneficially impact HDE-induced adverse airway inflammatory consequences. Bronchial epithelial cells were cultured with the short-acting β2-agonist salbutamol or the long-acting β2-agonist salmeterol prior to stimulation with HDE. β2-Agonist treatment significantly increased PKA activation and significantly decreased HDE-stimulated IL-6 and IL-8 production in a concentration- and time-dependent manner. Salbutamol treatment significantly reduced HDE-induced intracellular adhesion molecule-1 expression and neutrophil adhesion to epithelial cells. Using an established intranasal inhalation exposure model, we found that salbutamol pretreatment reduced airway neutrophil influx and IL-6, TNF-α, CXCL1, and CXCL2 release in bronchoalveolar lavage fluid following a one-time exposure to HDE. Likewise, when mice were pretreated daily with salbutamol prior to HDE exposure for 3 wk, HDE-induced neutrophil influx and inflammatory mediator production were also reduced. The severity of HDE-induced lung pathology in mice repetitively exposed to HDE for 3 wk was also decreased with daily salbutamol pretreatment. Together, these results support the need for future clinical investigations to evaluate the utility of β2-agonist therapies in the treatment of airway inflammation associated with CAFO dust exposure. PMID:27190062

  7. CAR and PXR agonists stimulate hepatic bile acid and bilirubin detoxification and elimination pathways in mice.

    PubMed

    Wagner, Martin; Halilbasic, Emina; Marschall, Hanns-Ulrich; Zollner, Gernot; Fickert, Peter; Langner, Cord; Zatloukal, Kurt; Denk, Helmut; Trauner, Michael

    2005-08-01

    Induction of hepatic phase I/II detoxification enzymes and alternative excretory pumps may limit hepatocellular accumulation of toxic biliary compounds in cholestasis. Because the nuclear xenobiotic receptors constitutive androstane receptor (CAR) and pregnane X receptor (PXR) regulate involved enzymes and transporters, we aimed to induce adaptive alternative pathways with different CAR and PXR agonists in vivo. Mice were treated with the CAR agonists phenobarbital and 1,4-bis-[2-(3,5-dichlorpyridyloxy)]benzene, as well as the PXR agonists atorvastatin and pregnenolone-16alpha-carbonitrile. Hepatic bile acid and bilirubin-metabolizing/detoxifying enzymes (Cyp2b10, Cyp3a11, Ugt1a1, Sult2a1), their regulatory nuclear receptors (CAR, PXR, farnesoid X receptor), and bile acid/organic anion and lipid transporters (Ntcp, Oatp1,2,4, Bsep, Mrp2-4, Mdr2, Abcg5/8, Asbt) in the liver and kidney were analyzed via reverse-transcriptase polymerase chain reaction and Western blotting. Potential functional relevance was tested in common bile duct ligation (CBDL). CAR agonists induced Mrp2-4 and Oatp2; PXR agonists induced only Mrp3 and Oatp2. Both PXR and CAR agonists profoundly stimulated bile acid-hydroxylating/detoxifying enzymes Cyp3a11 and Cyp2b10. In addition, CAR agonists upregulated bile acid-sulfating Sult2a1 and bilirubin-glucuronidating Ugt1a1. These changes were accompanied by reduced serum levels of bilirubin and bile acids in healthy and CBDL mice and by increased levels of polyhydroxylated bile acids in serum and urine of cholestatic mice. Atorvastatin significantly increased Oatp2, Mdr2, and Asbt, while other transporters and enzymes were moderately affected. In conclusion, administration of specific CAR or PXR ligands results in coordinated stimulation of major hepatic bile acid/bilirubin metabolizing and detoxifying enzymes and hepatic key alternative efflux systems, effects that are predicted to counteract cholestasis. PMID:15986414

  8. Preclinical pharmacology of mGlu2/3 receptor agonists: novel agents for schizophrenia?

    PubMed

    DD, Darryle D Schoepp; Marek, Gerard J

    2002-04-01

    Agonists for mGlu2/3 receptors decrease the evoked release of glutamate at certain (ie. forebrain / limbic) glutamatergic synapses, indicating that the functional role of mGlu2 and/or mGlu3 receptors is to suppress glutamate excitations. This offers a mechanism for dampening glutamate excitation under pathological states resulting from excessive glutamate release. Based, in part, on the psychotomimetic actions of phencyclidine (PCP)- like drugs, excessive or pathological glutamate release has been implicated in a number of clinical conditions including psychosis. With this in mind, the pharmacology of multiple mGlu2/3 receptor agonists have been investigated in PCP treated rats. Agonists for mGlu2/3 receptors such as LY354740 and LY379268 have been shown to block certain behavioral responses to PCP in rats. The effects of mGlu2/3 agonists on PCP-induced behaviors are blocked by a low doses of a selective mGlu2/3 receptor antagonist, indicating that these actions are mediated via mGlu2/3 receptors. In addition, mGlu2/3 agonists potently suppress glutamate release in rat prefrontal cortex, as reflected by excitatory post-synaptic potentials (EPSPs) induced by serotonin (5-HT) acting on 5HT(2A) receptors. These actions of LY354740 and LY379268 are also blocked by a selective mGlu2/3 antagonist. Atypical antipsychotic drugs such as clozapine also suppress 5-HT-induced EPSPs in this brain region, thus suggesting a common pathway for the actions of atypical antipsychotic drugs and mGlu2/3 receptor agonists. As glutamatergic dysfunction has been implicated in psychotic states and possibly in the etiology of schizophrenia, clinical studies with mGlu2/3 agonists may be warranted to further explore the validity of the glutamatergic hypothesis of schizophrenia. PMID:12769628

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

    PubMed

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

    2016-02-15

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

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

    PubMed

    McKay, N J; Daniels, D

    2013-10-01

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

  11. Glucagon-like peptide-1 receptor agonists suppress water intake independent of effects on food intake.

    PubMed

    McKay, Naomi J; Kanoski, Scott E; Hayes, Matthew R; Daniels, Derek

    2011-12-01

    Glucagon-like peptide-1 (GLP-1) is produced by and released from the small intestine following ingestion of nutrients. GLP-1 receptor (GLP-1R) agonists applied peripherally or centrally decrease food intake and increase glucose-stimulated insulin secretion. These effects make the GLP-1 system an attractive target for the treatment of type 2 diabetes mellitus and obesity. In addition to these more frequently studied effects of GLP-1R stimulation, previous reports indicate that GLP-1R agonists suppress water intake. The present experiments were designed to provide greater temporal resolution and site specificity for the effect of GLP-1 and the long-acting GLP-1R agonists, exendin-4 and liraglutide, on unstimulated water intake when food was and was not available. All three GLP-1R ligands suppressed water intake after peripheral intraperitoneal administration, both in the presence of and the absence of food; however, the magnitude and time frame of water intake suppression varied by drug. GLP-1 had an immediate, but transient, hypodipsic effect when administered peripherally, whereas the water intake suppression by IP exendin-4 and liraglutide was much more persistent. Additionally, intracerebroventricular administration of GLP-1R agonists suppressed water intake when food was absent, but the suppression of intake showed modest differences depending on whether the drug was administered to the lateral or fourth ventricle. To the best of our knowledge, this is the first demonstration of GLP-1 receptor agonists affecting unstimulated, overnight intake in the absence of food, the first test for antidipsogenic effects of hindbrain application of GLP-1 receptor agonists, and the first test of a central effect (forebrain or hindbrain) of liraglutide on water intake. Overall, these results show that GLP-1R agonists have a hypodipsic effect that is independent of GLP-1R-mediated effects on food intake, and this occurs, in part, through central nervous system GLP-1R activation.

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

    PubMed Central

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

    2014-01-01

    Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that act as ligand-activated transcription factors. Although prescribed for dyslipidemia and type-II diabetes, PPAR agonists also possess anti-addictive characteristics. PPAR agonists decrease ethanol consumption and reduce withdrawal severity and susceptibility to stress-induced relapse in rodents. However, the cellular and molecular mechanisms facilitating these properties have yet to be investigated. We tested three PPAR agonists in a continuous access two-bottle choice (2BC) drinking paradigm and found that tesaglitazar (PPARα/γ; 1.5 mg/kg) and fenofibrate (PPARα; 150 mg/kg) decreased ethanol consumption in male C57BL/6J mice while bezafibrate (PPARα/γ/β; 75 mg/kg) did not. We hypothesized that changes in brain gene expression following fenofibrate and tesaglitazar treatment lead to reduced ethanol drinking. We studied unbiased genomic profiles in areas of the brain known to be important for ethanol dependence, the prefrontal cortex (PFC) and amygdala, and also profiled gene expression in liver. Genomic profiles from the non-effective bezafibrate treatment were used to filter out genes not associated with ethanol consumption. Because PPAR agonists are anti-inflammatory, they would be expected to target microglia and astrocytes. Surprisingly, PPAR agonists produced a strong neuronal signature in mouse brain, and fenofibrate and tesaglitazar (but not bezafibrate) targeted a subset of GABAergic interneurons in the amygdala. Weighted gene co-expression network analysis (WGCNA) revealed co-expression of treatment-significant genes. Functional annotation of these gene networks suggested that PPAR agonists might act via neuropeptide and dopaminergic signaling pathways in the amygdala. Our results reveal gene targets through which PPAR agonists can affect alcohol consumption behavior. PMID:25036611

  13. GABAergic influences on ORX receptor-dependent abnormal motor behaviors and neurodegenerative events in fish

    SciTech Connect

    Facciolo, Rosa Maria; Crudo, Michele; Giusi, Giuseppina; Canonaco, Marcello

    2010-02-15

    At date the major neuroreceptors i.e. gamma-aminobutyric acid{sub A} (GABA{sub A}R) and orexin (ORXR) systems are beginning to be linked to homeostasis, neuroendocrine and emotional states. In this study, intraperitoneal treatment of the marine teleost Thalassoma pavo with the highly selective GABA{sub A}R agonist (muscimol, MUS; 0,1 mug/g body weight) and/or its antagonist bicuculline (BIC; 1 mug/g body weight) have corroborated a GABA{sub A}ergic role on motor behaviors. In particular, MUS induced moderate (p < 0.05) and great (p < 0.01) increases of swimming towards food sources and resting states after 24 (1 dose) and 96 (4 doses) h treatment sessions, respectively, when compared to controls. Conversely, BIC caused a very strong (p < 0.001) reduction of the former behavior and in some cases convulsive swimming. From the correlation of BIC-dependent behavioral changes to neuronal morphological and ORXR transcriptional variations, it appeared that the disinhibitory action of GABA{sub A}R was very likely responsible for very strong and strong ORXR mRNA reductions in cerebellum valvula and torus longitudinalis, respectively. Moreover these effects were linked to evident ultra-structural changes such as shrunken cell membranes and loss of cytoplasmic architecture. In contrast, MUS supplied a very low, if any, argyrophilic reaction in hypothalamic and mesencephalic regions plus a scarce level of ultra-structural damages. Interestingly, combined administrations of MUS + BIC were not related to consistent damages, aside mild neuronal alterations in motor-related areas such as optic tectum. Overall it is tempting to suggest, for the first time, a neuroprotective role of GABA{sub A}R inhibitory actions against the overexcitatory ORXR-dependent neurodegeneration and consequently abnormal swimming events in fish.

  14. Modulation of acetylcholine release from rat striatal slices by the GABA/benzodiazepine receptor complex

    SciTech Connect

    Supavilai, P.; Karobath, M.

    1985-02-04

    GABA, THIP and muscimol enhance spontaneous and inhibit electrically induced release of tritium labelled compounds from rat striatal slices which have been pre-labelled with /sup 3/H-choline. Baclofen is inactive in this model. Muscimol can inhibit electrically induced release of tritiated material by approximately 75% with half maximal effects at 2 ..mu..M. The response to muscimol can be blocked by the GABA antagonists bicuculline methobromide, picrotoxin, anisatin, R 5135 and CPTBO (cyclopentylbicyclophosphate). Drugs which act on the benzodiazepine receptor (BR) require the presence of muscimol to be effective and they modulate the effects of muscimol in a bidirectional manner. Thus BR agonists enhance and inverse BR agonists attenuate the inhibitory effects of muscimol on electrically induced release. Ro15-1788, a BR antagonist, does not modulate the inhibitory effects of muscimol but antagonizes the actions of clonazepam, a BR agonist, and of DMCM, an inverse BR agonist. These results demonstrate that a GABA/benzodiazepine receptor complex can modulate acetylcholine release from rat striatal slices in vitro. 24 references, 3 figures, 5 table.

  15. Successful Treatment of Chronic Hepatitis C with Triple Therapy in an Opioid Agonist Treatment Program

    PubMed Central

    Litwin, Alain H.; Soloway, Irene J.; Cockerham-Colas, Lauren; Reynoso, Sheila; Heo, Moonseong; Tenore, Christopher; Roose, Robert J.

    2015-01-01

    Background People who inject drugs (PWID) constitute 10 million people globally with hepatitis C virus, including many opioid agonist treatment patients. Little data exist describing clinical outcomes for patients receiving HCV treatment with direct-acting antiviral agents (DAAs) in opioid agonist treatment settings. Methods In this retrospective observational study, we describe clinical outcomes for 50 genotype-1 patients receiving HCV treatment with triple therapy: telaprevir (n = 42) or boceprevir (n = 8) in combination with pegylated interferon and ribavirin on-site in an opioid agonist treatment program. Results Overall, 70% achieved an end of treatment response (ETR) and 62% achieved a sustained virological response (SVR). These treatment outcomes are nearly equivalent to previously published HCV outcomes shown in registration trials, despite high percentages of recent drug use prior to treatment (52%), ongoing drug use during treatment (45%) and psychiatric comorbidity (86%). Only 12% (n=6) discontinued antiviral treatment early for non-virological reasons. Four patients received a blood transfusion, and one discontinued telaprevir due to severe rash. Conclusions These data demonstrate that on-site HCV treatment with direct-acting antiviral agents is effective in opioid agonist treatment patients including patients who are actively using drugs. Future interferon-free regimens will likely be even more effective. Opioid agonist treatment programs represent an opportunity to safely and effectively treat chronic hepatitis C, and PWID should have unrestricted access to DAAs. PMID:26341685

  16. Effects of an LH-RH agonist on reproductive responses and endocrinological parameters in landais ganders.

    PubMed

    Sellier, N; Do Thi, D X; Rousselot-Pailley, D; Péczely, P; de Reviers, M; Guémené, D

    1995-10-15

    Semen quantitative (sperm production) and qualitative parameters (percentage of live and normal spermatozoa, sperm motility, egg fertility and hatchability), as well as hormonal parameters (LH and testosterone plasma concentrations) were compared for landais ganders, which were treated or not, with an LH-RH agonist prior to being sexually active. Treatment with the LH-RH agonist at this physiological stage delayed the onset of sperm production in some of the treated males. Although, comparable data were obtained during the first half of the reproductive period, treatment with the LH-RH agonist maintained sperm output at higher levels during its second half. Although the percentage of normal and live spermatozoa, sperm motility and true hatchability did not differ, the LH-RH agonist treatment had a positive effect on gosling production because of the higher fertility of the treated birds during the second part of the reproductive period. Treatment induced a large short-term decrease in testosterone levels followed by a rebound, leading to higher levels during the second half of the reproductive period. We conclude that treatment of ganders with an LH-RH agonist partially prevented the naturally occurring decline in sperm production and induced an increase in the rate of fertility rates during the second half of the productive period.

  17. GLP-1 Receptor Agonists: Nonglycemic Clinical Effects in Weight Loss and Beyond

    PubMed Central

    Ryan, Donna; Acosta, Andres

    2015-01-01

    Obective Glucagon-like peptide-1 (GLP-1) receptor agonists are indicated for treatment of type 2 diabetes since they mimic the actions of native GLP-1 on pancreatic islet cells, stimulating insulin release, while inhibiting glucagon release, in a glucose-dependent manner. The observation of weight loss has led to exploration of their potential as antiobesity agents, with liraglutide 3.0 mg day−1 approved for weight management in the US on December 23, 2014, and in the EU on March 23, 2015. This review examines the potential nonglycemic effects of GLP-1 receptor agonists. Methods A literature search was conducted to identify preclinical and clinical evidence on nonglycemic effects of GLP-1 receptor agonists. Results GLP-1 receptors are distributed widely in a number of tissues in humans, and their effects are not limited to the well-recognized effects on glycemia. Nonglycemic effects include weight loss, which is perhaps the most widely recognized nonglycemic effect. In addition, effects on the cardiovascular, neurologic, and renal systems and on taste perception may occur independently of weight loss. Conclusions GLP-1 receptor agonists may provide other nonglycemic clinical effects besides weight loss. Understanding these effects is important for prescribers in using GLP-1 receptor agonists for diabetic patients, but also if approved for chronic weight management. PMID:25959380

  18. Identification of dual PPARα/γ agonists and their effects on lipid metabolism.

    PubMed

    Gao, Quanqing; Hanh, Jacky; Váradi, Linda; Cairns, Rose; Sjöström, Helena; Liao, Vivian W Y; Wood, Peta; Balaban, Seher; Ong, Jennifer Ai; Lin, Hsuan-Yu Jennifer; Lai, Felcia; Hoy, Andrew J; Grewal, Thomas; Groundwater, Paul W; Hibbs, David E

    2015-12-15

    The three peroxisome proliferator-activated receptor (PPAR) isoforms; PPARα, PPARγ and PPARδ, play central roles in lipid metabolism and glucose homeostasis. Dual PPARα/γ agonists, which stimulate both PPARα and PPARγ isoforms to similar extents, are gaining popularity as it is believed that they are able to ameliorate the unwanted side effects of selective PPARα and PPARγ agonists; and may also be used to treat dyslipidemia and type 2 diabetes mellitus simultaneously. In this study, virtual screening of natural product libraries, using both structure-based and ligand-based drug discovery approaches, identified ten potential dual PPARα/γ agonist lead compounds (9-13 and 16-20). In vitro assays confirmed these compounds to show no statistically significant toxicity to cells, with the exception of compound 12 which inhibited cell growth to 74.5%±3.5 and 54.1%±3.7 at 50μM and 100μM, respectively. In support of their potential as dual PPARα/γ agonists, all ten compounds upregulated the expression of cholesterol transporters ABCA1 and ABCG1 in THP-1 macrophages, with indoline derivative 16 producing the greatest elevation (2.3-fold; 3.3-fold, respectively). Furthermore, comparable to the activity of established PPARα and PPARγ agonists, compound 16 stimulated triacylglycerol accumulation during 3T3-L1 adipocyte differentiation as well as fatty acid β-oxidation in HuH7 hepatocytes. PMID:26616289

  19. 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.

  20. Use of clinically available PPAR agonists for heart failure; do the risks outweigh the potential benefits?

    PubMed

    Sarma, Satyam

    2012-06-01

    PPAR agonists represent a heterogeneous group of compounds that have been used in the treatment of cardiovascular and metabolic diseases for over thirty years. While the primary indications for PPAR agonist therapy focus on hyperlipidemia and diabetes, there is a growing body of pre-clinical data that suggests they may be beneficial in the treatment of heart failure; a disease marked by abnormal myocardial metabolism, fibrosis and insulin insensitivity. PPAR agonist treatment in numerous animal models of systolic heart failure have demonstrated improvement in cardiac function with decreased fibrosis, improved contractility and endothelial function. However, considerable controversy exists on the cardiac safety profile of PPAR agonists, particularly concern for inducing lipotoxicty and precipitating or worsening heart failure. In addition during pre-clinical testing, many compounds have been associated with increased death and adverse cardiovascular outcomes casting a pall over their future use for treating disorders of myocardial function. This article will review cardiac pathways involved in PPAR activation and their potential regulation of maladaptive pathways involved in heart failure and highlight molecular mechanisms that may contribute to adverse events and raise safety concerns. Specific attention will be focused on PPAR alpha and gamma, subtypes for which commercially available PPAR agonists are currently available.

  1. PPAR-γ Agonists and Their Effects on IGF-I Receptor Signaling: Implications for Cancer

    PubMed Central

    Belfiore, A.; Genua, M.; Malaguarnera, R.

    2009-01-01

    It is now well established that the development and progression of a variety of human malignancies are associated with dysregulated activity of the insulin-like growth factor (IGF) system. In this regard, promising drugs have been developed to target the IGF-I receptor or its ligands. These therapies are limited by the development of insulin resistance and compensatory hyperinsulinemia, which in turn, may stimulate cancer growth. Novel therapeutic approaches are, therefore, required. Synthetic PPAR-γ agonists, such as thiazolidinediones (TZDs), are drugs universally used as antidiabetic agents in patients with type 2 diabetes. In addition of acting as insulin sensitizers, PPAR-γ agonists mediate in vitro and in vivo pleiotropic anticancer effects. At least some of these effects appear to be linked with the downregulation of the IGF system, which is induced by the cross-talk of PPAR-γ agonists with multiple components of the IGF system signaling. As hyperinsulinemia is an emerging cancer risk factor, the insulin lowering action of PPAR-γ agonists may be expected to be also beneficial to reduce cancer development and/or progression. In light of these evidences, TZDs or other PPAR-γ agonists may be exploited in those tumors “addicted” to the IGF signaling and/or in tumors occurring in hyperinsulinemic patients. PMID:19609453

  2. 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

  3. 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.

  4. 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.

  5. Neuroprotection by a selective estrogen receptor beta agonist in a mouse model of global ischemia.

    PubMed

    Carswell, H V O; Macrae, I M; Gallagher, L; Harrop, E; Horsburgh, K J

    2004-10-01

    The present study employs selective estrogen receptor (ER) agonists to determine whether 17beta-estradiol-induced neuroprotection in global ischemia is receptor mediated and, if so, which subtype of receptor (ERalpha or ERbeta) is predominantly responsible. Halothane-anesthetized female C57Bl/6J mice were ovariectomized, and osmotic minipumps containing ERbeta agonist diarylpropiolnitrile (DPN) (8 mg.kg(-1).day(-1), n = 12) or vehicle (50% DMSO in 0.9% saline) (n = 9) or ERalpha agonist propyl pyrazole triol (PPT) (2 mg.kg(-1).day(-1), n = 13) or vehicle (50% DMSO in 0.9% saline) (n = 10) were implanted subcutaneously. One week later transient global ischemia was induced by bilateral carotid artery occlusion under halothane anesthesia, and the mice were perfusion fixed 72 h later. ERbeta agonist DPN significantly reduced ischemic damage by 70% in the caudate nucleus and 55% in the CA1 region compared with vehicle controls (P < 0.05, Mann-Whitney U-statistic). In contrast, pretreatment with the ERalpha agonist PPT had no effect on the extent of neuronal damage compared with controls. The data indicate a significant estrogen receptor-mediated neuroprotection in a global cerebral ischemia model involving ERbeta.

  6. Computational Prediction and Biochemical Analyses of New Inverse Agonists for the CB1 Receptor.

    PubMed

    Scott, Caitlin E; Ahn, Kwang H; Graf, Steven T; Goddard, William A; Kendall, Debra A; Abrol, Ravinder

    2016-01-25

    Human cannabinoid type 1 (CB1) G-protein coupled receptor is a potential therapeutic target for obesity. The previously predicted and experimentally validated ensemble of ligand-free conformations of CB1 [Scott, C. E. et al. Protein Sci. 2013 , 22 , 101 - 113 ; Ahn, K. H. et al. Proteins 2013 , 81 , 1304 - 1317] are used here to predict the binding sites for known CB1-selective inverse agonists including rimonabant and its seven known derivatives. This binding pocket, which differs significantly from previously published models, is used to identify 16 novel compounds expected to be CB1 inverse agonists by exploiting potential new interactions. We show experimentally that two of these compounds exhibit inverse agonist properties including inhibition of basal and agonist-induced G-protein coupling activity, as well as an enhanced level of CB1 cell surface localization. This demonstrates the utility of using the predicted binding sites for an ensemble of CB1 receptor structures for designing new CB1 inverse agonists.

  7. Alcohol Screening among Opioid Agonist Patients in a Primary Care Clinic and an Opioid Treatment Program

    PubMed Central

    Klimas, Jan; Muench, John; Wiest, Katharina; Croff, Raina; Rieckmann, Traci; McCarty, Dennis

    2016-01-01

    Problem alcohol use is associated with adverse health and economic outcomes, especially among people in opioid agonist treatment. Screening, brief intervention and referral to treatment (SBIRT) are effective in reducing alcohol use; however, issues involved in SBIRT implementation among opioid agonist patients are unknown. To assess identification and treatment of alcohol use disorders, we reviewed clinical records of opioid agonist patients screened for an alcohol use disorder in a primary care clinic (n =208) and in an opioid treatment program (n = 204) over a two year period. In the primary care clinic, 193 (93%) buprenorphine patients completed an annual alcohol screening and six (3%) had elevated AUDIT scores. Among the patients treated in the opioid treatment program, an alcohol abuse or dependence diagnosis was recorded for 54 (27%) methadone patients. Practitioner focus groups were completed in the primary care (n = 4 physicians) and the opioid treatment program (n = 11 counsellors) to assess experience with and attitudes towards screening opioid agonist patients for alcohol use disorders. Focus groups suggested organizational, structural, provider, patient and community variables hindered or fostered alcohol screening. Alcohol screening is feasible among opioid agonist patients. Effective implementation, however, requires physician training and systematic changes in workflow. PMID:25715074

  8. Identification of adiponectin receptor agonist utilizing a fluorescence polarization based high throughput assay.

    PubMed

    Sun, Yiyi; Zang, Zhihe; Zhong, Ling; Wu, Min; Su, Qing; Gao, Xiurong; Zan, Wang; Lin, Dong; Zhao, Yan; Zhang, Zhonglin

    2013-01-01

    Adiponectin, the adipose-derived hormone, plays an important role in the suppression of metabolic disorders that can result in type 2 diabetes, obesity, and atherosclerosis. It has been shown that up-regulation of adiponectin or adiponectin receptor has a number of therapeutic benefits. Given that it is hard to convert the full size adiponectin protein into a viable drug, adiponectin receptor agonists could be designed or identified using high-throughput screening. Here, we report on the development of a two-step screening process to identify adiponectin agonists. First step, we developed a high throughput screening assay based on fluorescence polarization to identify adiponectin ligands. The fluorescence polarization assay reported here could be adapted to screening against larger small molecular compound libraries. A natural product library containing 10,000 compounds was screened and 9 hits were selected for validation. These compounds have been taken for the second-step in vitro tests to confirm their agonistic activity. The most active adiponectin receptor 1 agonists are matairesinol, arctiin, (-)-arctigenin and gramine. The most active adiponectin receptor 2 agonists are parthenolide, taxifoliol, deoxyschizandrin, and syringin. These compounds may be useful drug candidates for hypoadiponectin related diseases. PMID:23691032

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

    SciTech Connect

    Remmers, A.E.; Medzihradsky, F. )

    1991-03-15

    In synaptosomal membranes from rat brain cortex, the {mu} selective agonist ({sup 3}H)dihydromorphine in the absence of sodium, and the nonselective antagonist ({sup 3}H)naltrexone in the presence of sodium, bound to two populations of opioid receptor sites with K{sub d} values of 0.69 and 8.7 nM for dihydromorphine, and 0.34 and 5.5 nM for naltrexone. The addition of 5 {mu}M guanosine 5{prime}-({gamma}-thio)triphosphate (GTP({gamma}S)) strongly reduced high-affinity agonist but not antagonist binding. Exposure of the membranes to high pH reduced the number of GTP({gamma}-{sup 35}S) binding sites by 90% and low K{sub m}, opioid-sensitive GTPase activity by 95%. In these membranes, high-affinity agonist binding was abolished and modulation of residual binding by GTP({gamma}S) was diminished. Alkali treatment of the glioma cell membranes prior to fusion inhibited most of the low K{sub m} GTPase activity and prevented the reconstitution of agonist binding. The results show that high-affinity opioid agonist binding reflects the ligand-occupied receptor - guanine nucleotide binding protein complex.

  10. Pharmacological Profiles of Alpha 2 Adrenergic Receptor Agonists Identified Using Genetically Altered Mice and Isobolographic Analysis

    PubMed Central

    Fairbanks, Carolyn A.; Stone, Laura S.; Wilcox, George L.

    2009-01-01

    Endogenous, descending noradrenergic fibers convey powerful analgesic control over spinal afferent circuitry mediating the rostrad transmission of pain signals. These fibers target alpha 2 adrenergic receptors (α2ARs) on both primary afferent terminals and secondary neurons, and their activation mediates substantial inhibitory control over this transmission, rivaling that of opioid receptors which share similar a similar pattern of distribution. The terminals of primary afferent nociceptive neurons and secondary spinal dorsal horn neurons express α2AAR and α2CAR subtypes, respectively. Spinal delivery of these agents serves to reduce their side effects, which are mediated largely at supraspinal sites, by concentrating the drugs at the spinal level. Targeting these spinal α2ARs with one of five selective therapeutic agonists, clonidine, dexmedetomidine, brimonidine, ST91 and moxonidine, produces significant antinociception that can work in concert with opioid agonists to yield synergistic antinociception. Application of several genetically altered mouse lines had facilitated identification of the primary receptor subtypes that likely mediate the antinociceptive effects of these agents. This review provides first an anatomical description of the localization of the three subtypes in the central nervous system, second a detailed account of the pharmacological history of each of these six primary agonists, and finally a comprehensive report of the specific interactions of other GPCR agonists with each of the six principal α2AR agonists featured. PMID:19393691

  11. Agonists-induced platelet activation varies considerably in healthy male individuals: studies by flow cytometry.

    PubMed

    Panzer, Simon; Höcker, Lisa; Koren, Daniela

    2006-02-01

    Flow cytometric evaluation of platelet function extends our understanding of platelets' role in various clinical conditions associated with either bleeding disorders, thrombosis, or monitoring of antiplatelet therapy. The use of suboptimal concentrations of various agonists may allow assessing the "activatability" of platelets. We determined platelet responsiveness to thrombin-receptor-activating peptide-6, arachidonic acid, adenosine 5c-diphosphate (ADP), epinephrine, collagen, and ristocetin at suboptimal concentrations by determination of P-selectin expression and binding of PAC-1 in 26 healthy male individuals. The response varied considerably from one individual to the next. However, within individuals, responses to all agonists except collagen correlated strongly (p<0.05), suggesting a global variability of platelet responses. Moreover, P-selectin expression and PAC-1 binding were strongly correlated (p<0.05). Interestingly, with epinephrine, PAC-1 positive events outnumbered P-selectin positive events, while this was not seen with the other agonists. Thus, epinephrine may specifically affect the conformational switch mechanism and receptor clustering. Our data indicate that the in vitro response to suboptimal concentrations of agonists varies, but individuals with selective platelet defects may still be identified based on data obtained with the various agonists. PMID:16283308

  12. Functional selectivity of dopamine D1 receptor agonists in regulating the fate of internalized receptors *

    PubMed Central

    Ryman-Rasmussen, Jessica P.; Griffith, Adam; Oloff, Scott; Vaidehi, Nagarajan; Brown, Justin T.; Goddard, William A.; Mailman, Richard B.

    2007-01-01

    Recently, we demonstrated that D1 agonists can cause functionally selective effects when the endpoints of receptor internalization and adenylate cyclase activation are compared. The present study was designed to probe the phenomenon of functional selectivity at the D1 receptor further by testing the hypothesis that structurally dissimilar agonists with efficacies at these endpoints that equal or exceed those of dopamine would differ in ability to influence receptor fate after internalization, a functional endpoint largely unexplored for the D1 receptor. We selected two novel agonists of therapeutic interest that meet these criteria (the isochroman A-77636, and the isoquinoline dinapsoline), and compared the fates of the D1 receptor after internalization in response to these two compounds with that of dopamine. We found that dopamine caused the receptor to be rapidly recycled to the cell surface within 1 h of removal. Conversely, A-77636 caused the receptor to be retained intracellularly up to 48 h after agonist removal. Most surprisingly, the D1 receptor recovered to the cell surface 48 h after removal of dinapsoline. Taken together, these data indicate that these agonists target the D1 receptor to different intracellular trafficking pathways, demonstrating that the phenomenon of functional selectivity at the D1 receptor is operative for cellular events that are temporally downstream of immediate receptor activation. We hypothesize that these differential effects result from interactions of the synthetic ligands with aspects of the D1 receptor that are distal from the ligand binding domain. PMID:17067639

  13. Agonist mediated conformational changes of solubilized calf forebrain muscarinic acetylcholine receptors.

    PubMed

    Vanderheyden, P; Andre, C; de Backer, J P; Vauquelin, G

    1984-10-01

    Muscarinic receptors in calf forebrain membranes can be identified by the specific binding of the radiolabelled antagonist [3H]dexetimide. These receptors (2.8 pM/mg protein) comprise two non-interconvertible subpopulations with respectively high and low agonist affinity but with the same antagonist affinity. For all the agonists tested the low affinity sites represent 85 +/- 5% of the total receptor population. 0.5% Digitonin solubilized extracts contain 0.8 pM muscarinic receptor/mg protein. In contrast with the membranes, these extracts contain only sites with low agonist affinity. The alkylating reagent N-ethylmaleimide causes an increase of the acetylcholine affinity for the low affinity sites in membranes as well as for the solubilized sites. This effect is time dependent until a maximal 3-fold increase in affinity is attained. The rate of N-ethylmaleimide action is enhanced by the concomitant presence of agonists. In contrast, N-ethylmaleimide does not affect antagonist binding. This suggests that agonists mediate a conformational change of both the membrane bound low affinity muscarinic sites and of the solubilized sites, resulting in their increased susceptibility towards NEM alkylation. PMID:6487351

  14. Effect of different beta-adrenergic agonists on the intestinal absorption of galactose and phenylalanine.

    PubMed

    Díez-Sampedro, A; Pérez, M; Cobo, M T; Martínez, J A; Barber, A

    1998-08-01

    Nutrient transport across the mammalian small intestine is regulated by several factors, including intrinsic and extrinsic neural pathways, paracrine modulators, circulating hormones and luminal agents. Because beta-adrenoceptors seem to regulate gastrointestinal functions such as bicarbonate and acid secretion, intestinal motility and gastrointestinal mucosal blood flow, we have investigated the effects of different beta-adrenergic agonists on nutrient absorption by the rat jejunum in-vitro. When intestinal everted sacs were used the beta2-agonist salbutamol had no effect either on galactose uptake by the tissue or mucosal-to-serosal flux whereas mixed beta1- and beta2-agonists (isoproterenol and orciprenaline) and beta3-agonists (BRL 35135, Trecadrine, ICI 198157 and ZD 7114) inhibited galactose uptake and transfer of D-galactose from the mucosal-to-serosal media across the intestinal wall (although the inhibiting effects of isoproterenol and Trecadrine were not statistically significant). In intestinal everted rings both Trecadrine and BRL 35135 clearly reduced galactose uptake, the effect being a result of inhibition of the phlorizin-sensitive component. Total uptake of phenylalanine by the intestinal rings was also reduced by those beta3-adrenergic agonists. These results suggest that beta1- and beta3-adrenergic receptors could be involved in the regulation of intestinal active transport of sugars and amino acids. PMID:9751456

  15. 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

  16. 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.

  17. Diamine Derivatives as Novel Small-Molecule, Potent, and Subtype-Selective Somatostatin SST3 Receptor Agonists

    PubMed Central

    2014-01-01

    A novel class of small-molecule, highly potent, and subtype-selective somatostatin SST3 agonists was discovered through modification of a SST3 antagonist. As an example, (1R,2S)-9 demonstrated not only potent in vitro SST3 agonist activity but also in vivo SST3 agonist activity in a mouse oral glucose tolerance test (OGTT). These agonists may be useful reagents for studying the physiological roles of the SST3 receptor and may potentially be useful as therapeutic agents. PMID:24944745

  18. Incorporation of Phosphonate into Benzonaphthyridine Toll-like Receptor 7 Agonists for Adsorption to Aluminum Hydroxide.

    PubMed

    Cortez, Alex; Li, Yongkai; Miller, Andrew T; Zhang, Xiaoyue; Yue, Kathy; Maginnis, Jillian; Hampton, Janice; Hall, De Shon; Shapiro, Michael; Nayak, Bishnu; D'Oro, Ugo; Li, Chun; Skibinski, David; Mbow, M Lamine; Singh, Manmohan; O'Hagan, Derek T; Cooke, Michael P; Valiante, Nicholas M; Wu, Tom Y-H

    2016-06-23

    Small molecule Toll-like receptor 7 (TLR7) agonists have been used as vaccine adjuvants by enhancing innate immune activation to afford better adaptive response. Localized TLR7 agonists without systemic exposure can afford good adjuvanticity, suggesting peripheral innate activation (non-antigen-specific) is not required for immune priming. To enhance colocalization of antigen and adjuvant, benzonaphthyridine (BZN) TLR7 agonists are chemically modified with phosphonates to allow adsorption onto aluminum hydroxide (alum), a formulation commonly used in vaccines for antigen stabilization and injection site deposition. The adsorption process is facilitated by enhancing aqueous solubility of BZN analogs to avoid physical mixture of two insoluble particulates. These BZN-phosphonates are highly adsorbed onto alum, which significantly reduced systemic exposure and increased local retention post injection. This report demonstrates a novel approach in vaccine adjuvant design using phosphonate modification to afford adsorption of small molecule immune potentiator (SMIP) onto alum, thereby enhancing co-delivery with antigen. PMID:27270029

  19. Label-Free Cell Phenotypic Identification of D-Luciferin as an Agonist for GPR35.

    PubMed

    Hu, Heidi; Deng, Huayun; Fang, Ye

    2016-01-01

    D-Luciferin (also known as beetle or firefly luciferin) is one of the most widely used bioluminescent reporters for monitoring in vitro or in vivo luciferase activity. The identification of several natural phenols and thieno[3,2-b]thiophene-2-carboxylic acid derivatives as agonists for GPR35, an orphan G protein-coupled receptor, had motivated us to examine the pharmacological activity of D-Luciferin, given that it also contains phenol and carboxylic acid moieties. Here, we describe label-free cell phenotypic assays that ascertain D-Luciferin as a partial agonist for GPR35. The agonistic activity of D-Luciferin at the GPR35 shall evoke careful interpretation of biological data when D-Luciferin or its analogues are used as probes. PMID:27424891

  20. Nicotinamide is an endogenous agonist for a C. elegans TRPV OSM-9 and OCR-4 channel

    PubMed Central

    Upadhyay, Awani; Pisupati, Aditya; Jegla, Timothy; Crook, Matt; Mickolajczyk, Keith J.; Shorey, Matthew; Rohan, Laura E.; Billings, Katherine A.; Rolls, Melissa M.; Hancock, William O.; Hanna-Rose, Wendy

    2016-01-01

    TRPV ion channels are directly activated by sensory stimuli and participate in thermo-, mechano- and chemo-sensation. They are also hypothesized to respond to endogenous agonists that would modulate sensory responses. Here, we show that the nicotinamide (NAM) form of vitamin B3 is an agonist of a Caenorhabditis elegans TRPV channel. Using heterologous expression in Xenopus oocytes, we demonstrate that NAM is a soluble agonist for a channel consisting of the well-studied OSM-9 TRPV subunit and relatively uncharacterized OCR-4 TRPV subunit as well as the orthologous Drosophila Nan-Iav TRPV channel, and we examine stoichiometry of subunit assembly. Finally, we show that behaviours mediated by these C. elegans and Drosophila channels are responsive to NAM, suggesting conservation of activity of this soluble endogenous metabolite on TRPV activity. Our results in combination with the role of NAM in NAD+ metabolism suggest an intriguing link between metabolic regulation and TRPV channel activity. PMID:27731314

  1. PPARγ AGONISTS AS THERAPEUTICS FOR THE TREATMENT OF ALZHEIMER’S DISEASE

    PubMed Central

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

    2008-01-01

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

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

    SciTech Connect

    Luci, Sebastian; Geissler, Stefanie; Koenig, Bettina; Koch, Alexander; Stangl, Gabriele I.; Hirche, Frank; Eder, Klaus . E-mail: klaus.eder@landw.uni-halle.de

    2006-11-24

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

  3. 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.

  4. Quantitative Measure of Receptor Agonist and Modulator Equi-Response and Equi-Occupancy Selectivity

    PubMed Central

    Zhang, Rumin; Kavana, Michael

    2016-01-01

    G protein-coupled receptors (GPCRs) are an important class of drug targets. Quantitative analysis by global curve fitting of properly designed dose-dependent GPCR agonism and allosterism data permits the determination of all affinity and efficacy parameters based on a general operational model. We report here a quantitative and panoramic measure of receptor agonist and modulator equi-response and equi-occupancy selectivity calculated from these parameters. The selectivity values help to differentiate not only one agonist or modulator from another, but on-target from off-target receptor or functional pathway as well. Furthermore, in conjunction with target site free drug concentrations and endogenous agonist tones, the allosterism parameters and selectivity values may be used to predict in vivo efficacy and safety margins. PMID:27116909

  5. 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. PMID:27132867

  6. Bifunctional epitope-agonist ligands of the bradykinin B(2) receptor.

    PubMed

    Gera, Lajos; Roy, Caroline; Marceau, François

    2013-03-01

    Two bradykinin (BK) B(2) receptor agonists N-terminally extended with the myc epitope were synthesized and evaluated: myc-KPG-BK and myc-KGP-B-9972. The latter was modeled on the inactivation-resistant agonist B-9972 (D-Arg(0), Hyp(3), Igl(5), Oic(7), Igl(8)-BK) and is also resistant to endosomal inactivation. Despite a large loss of affinity relative to the parent peptide, the tagged analogs are conventional agonists in the umbilical vein contractility assay and compete for [(3)H]BK binding at the rabbit B(2) receptor. Endocytosed myc-KGP-B-9972 most effectively carried AlexaFluor-488-conjugated anti-myc monoclonal antibodies into intact cells expressing the B(2) receptor. Results support the prospects of functionally-active cargoes entering cells in a pharmacologically controlled manner.

  7. 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.

  8. Thrombin receptor agonist Peptide immobilized in microspheres stimulates reparative processes in rats with gastric ulcer.

    PubMed

    Rusanova, A V; Makarova, A M; Strukova, S M; Markvicheva, E A; Gorbachyova, L R; Stashevskaya, K S; Vasil'eva, T V; Sidorova, E I; Bespalova, Zh D; Grandfils, Ch

    2006-07-01

    The effect of synthetic thrombin receptor (PAR1) agonist peptide encapsulated in microspheres made of lactic and glycolic acid copolymer on tissue reparation was studied in rats with acetate-induced ulcer. PAR1 agonist peptide was immobilized in biodegraded lactic and glycolic acid microspheres by double emulgation, the kinetics of peptide release was analyzed, and the dynamics of ulcer healing was studied in experimental (administration of microspheres with the peptide into the stomach) and two control groups (administration of saline or spheres without peptide). Thrombin receptor agonist peptide gradually released from lactic and glycolic acid microspheres into the stomach shortened the inflammation phase and shifted the proliferation phase to the earlier period, thus accelerating healing of experimental ulcers in rats. PMID:17369897

  9. Competitive Agonists and Antagonists of Steroid Nuclear Receptors: Evolution of the Concept or Its Reversal.

    PubMed

    Smirnova, O V

    2015-10-01

    The mechanisms displaying pure and mixed steroid agonist/antagonist activity as well as principles underlying in vivo action of selective steroid receptor modulators dependent on tissue or cell type including interaction with various types of nuclear receptors are analyzed in this work. Mechanisms of in vitro action for mixed agonist/antagonist steroids are discussed depending on: specific features of their interaction with receptor hormone-binding pocket; steroid-dependent allosteric modulation of interaction between hormone-receptor complex and hormone response DNA elements; features of interacting hormone-receptor complex with protein transcriptional coregulators; level and tissue-specific composition of transcriptional coregulators. A novel understanding regarding context-selective modulators replacing the concept of steroid agonists and antagonists is discussed.

  10. Estrogen receptor agonists alleviate cardiac and renal oxidative injury in rats with renovascular hypertension.

    PubMed

    Özdemir Kumral, Zarife Nigâr; Kolgazi, Meltem; Üstünova, Savaş; Kasımay Çakır, Özgür; Çevik, Özge Dağdeviren; Şener, Göksel; Yeğen, Berrak Ç

    2016-01-01

    Although endogenous estrogen is known to offer cardiac and vascular protection, the involvement of estrogen receptors in mediating the protective effect of estrogen on hypertension-induced cardiovascular and renal injury is not fully explained. We aimed to investigate the effects of estrogen receptor (ER) agonists on oxidative injury, cardiovascular and renal functions of rats with renovascular hypertension (RVH). Female Sprague-Dawley rats were randomly divided as control and RVH groups, and RVH groups had either ovariectomy (OVX) or sham-OVX. Sham-OVX-RVH and OVX-RVH groups received either ERβ agonist diarylpropiolnitrile (1 mg/kg/day) or ERα agonist propyl pyrazole triol (1 mg/kg/day) for 6 weeks starting at the third week following the surgery. At the end of the 9(th) week, systolic blood pressures were recorded, cardiac functions were determined, and the contraction/relaxation responses of aortic rings were obtained. Serum creatinine levels, tissue malondialdehyde, glutathione, superoxide dismutase, catalase levels, and myeloperoxidase activity in heart and kidney samples were analyzed, and Na(+), K(+)-ATPase activity was measured in kidney samples. In both sham-OVX and OVX rats, both agonists reduced blood pressure and reversed the impaired contractile performance of the heart, while ERβ agonist improved renal functions in both the OVX and non-OVX rats. Both agonists reduced neutrophil infiltration, lipid peroxidation, and elevated antioxidant levels in the heart, but a more ERβ-mediated protective effect was observed in the kidney. Our data suggest that activation of ERβ might play a role in preserving the function of the stenotic kidney and delaying the progression of renal injury, while both receptors mediate similar cardioprotective effects. PMID:27399230

  11. Early postnatal stress alters place conditioning to both mu- and kappa-opioid agonists.

    PubMed

    Michaels, Clifford C; Holtzman, Stephen G

    2008-04-01

    Clinical literature has established a link between early childhood incidents of neglect and trauma and adult problems with substance abuse. In rats, such early life stress has been modeled using a maternal separation (MS) paradigm in which rat pups were removed from their mothers for a few hours daily during the first two postnatal weeks. In this study, we used the MS model to investigate the effects of early postnatal stress on place conditioning to both mu- and kappa-opioid agonists in male and female Long-Evans rats. Offspring of both rearing conditions [MS or nonhandled (NH)] were conditioned using a biased procedure to saline, the mu-opioid agonist morphine (3.0, 5.6, and 10 mg/kg s.c.), or the kappa-opioid agonist spiradoline (0.3, 1.0, and 3.0 mg/kg) for 3 days, followed by a drug-free place-conditioning test 24 h later. Saline was administered in the morning, 30 min before confinement in one compartment, whereas morphine or spiradoline was administered in a similar manner 6 h later in the opposite compartment. MS offspring spent significantly more time in the morphine-paired compartment than NH offspring, indicating a greater place preference for the mu-opioid agonist. In the case of spiradoline, NH offspring spent significantly less time in the spiradoline-paired compartment, indicating a greater aversion to the kappa-opioid agonist in these animals than in MS offspring. These findings indicate that early postnatal stress can significantly alter the rewarding or aversive value of mu- and kappa-opioid agonists when measured using place conditioning. PMID:18203949

  12. Diabetogenic effect of a series of tricyclic delta opioid agonists structurally related to cyproheptadine.

    PubMed

    Codd, Ellen E; Baker, Judith; Brandt, Michael R; Bryant, Stewart; Cai, Chaozhong; Carson, John R; Chevalier, Kristen M; Colburn, Raymond W; Coogan, Timothy P; Dax, Scott L; Decorte, Bart; Kemmerer, Michael; Legrand, Edmund K; Lenhard, James M; Leone, Angelique M; Lin, Ling; Mabus, John R; McDonnell, Mark E; McMillian, Michael K; McNally, James J; Stone, Dennis J; Wang, Charles Y; Zhang, Sui-Po; Flores, Christopher M

    2010-10-01

    The unexpected observation of a hyperglycemic effect of some tricycle-based delta opioid receptor (DOR) agonists led to a series of studies to better understand the finding. Single administration of two novel tricyclic DOR agonists dose dependently elevated rat plasma glucose levels; 4-week toxicology studies confirmed the hyperglycemic finding and further revealed pancreatic β-cell hypertrophy, including vacuole formation, as well as bone dysplasia and Harderian gland degeneration with regeneration. Similar diabetogenic effects were observed in dog. A review of the literature on the antiserotonergic and antihistaminergic drug cyproheptadine (CPH) and its metabolites revealed shared structural features as well as similar hyperglycemic effects to the present series of DOR agonists. To further evaluate these effects, we established an assay measuring insulin levels in the rat pancreatic β-cell-derived RINm5F cell line, extensively used to study CPH and its metabolites. Like CPH, the initial DOR agonists studied reduced RINm5F cell insulin levels in a concentration-dependent manner. Importantly, compound DOR potency did not correlate with the insulin-reducing potency. Furthermore, the RINm5F cell insulin results correlated with the diabetogenic effect of the compounds in a 5-day mouse study. The RINm5F cell insulin assay enabled the identification of aryl-aryl-amine DOR agonists that lacked an insulin-reducing effect and did not elevate blood glucose in repeated dosing studies conducted over a suprapharmacologic dose range. Thus, not only did the RINm5F cell assay open a path for the further discovery of DOR agonists lacking diabetogenic potential but also it established a reliable, economical, and high-throughput screen for such potential, regardless of chemotype or target pharmacology. The present findings also suggest a mechanistic link between the toxicity observed here and that underlying Wolcott-Rallison Syndrome.

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

    PubMed Central

    Riese, David J.

    2010-01-01

    Introduction Receptor tyrosine kinases (RTKs) are validated targets for oncology drug discovery and several RTK antagonists have been approved for the treatment of human malignancies. Nonetheless, the discovery and development of RTK antagonists has lagged behind the discovery and development of agents that target G-protein coupled receptors. In part, this is because it has been difficult to discover analogs of naturally-occurring RTK agonists that function as antagonists. Areas covered Here we describe ligands of ErbB receptors that function as partial agonists for these receptors, thereby enabling these ligands to antagonize the activity of full agonists for these receptors. We provide insights into the mechanisms by which these ligands function as antagonists. We discuss how information concerning these mechanisms can be translated into screens for novel small molecule- and antibody-based antagonists of ErbB receptors and how such antagonists hold great potential as targeted cancer chemotherapeutics. Expert opinion While there have been a number of important key findings into this field, the identification of the structural basis of ligand functional specificity is still of the greatest importance. While it is true that, with some notable exceptions, peptide hormones and growth factors have not proven to be good platforms for oncology drug discovery; addressing the fundamental issues of antagonistic partial agonists for receptor tyrosine kinases has the potential to steer oncology drug discovery in new directions. Mechanism based approaches are now emerging to enable the discovery of RTK partial agonists that may antagonize both agonist-dependent and –independent RTK signaling and may hold tremendous promise as targeted cancer chemotherapeutics. PMID:21532939

  14. PPARγ Agonists Promote Oligodendrocyte Differentiation of Neural Stem Cells by Modulating Stemness and Differentiation Genes

    PubMed Central

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

    2012-01-01

    Neural stem cells (NSCs) are a small population of resident cells that can grow, migrate and differentiate into neuro-glial cells in the central nervous system (CNS). Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor transcription factor that regulates cell growth and differentiation. In this study we analyzed the influence of PPARγ agonists on neural stem cell growth and differentiation in culture. We found that in vitro culture of mouse NSCs in neurobasal medium with B27 in the presence of epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) induced their growth and expansion as neurospheres. Addition of all-trans retinoic acid (ATRA) and PPARγ agonist ciglitazone or 15-Deoxy-Δ12,14-Prostaglandin J2 (15d-PGJ2) resulted in a dose-dependent inhibition of cell viability and proliferation of NSCs in culture. Interestingly, NSCs cultured with PPARγ agonists, but not ATRA, showed significant increase in oligodendrocyte precursor-specific O4 and NG2 reactivity with a reduction in NSC marker nestin, in 3–7 days. In vitro treatment with PPARγ agonists and ATRA also induced modest increase in the expression of neuronal β-III tubulin and astrocyte-specific GFAP in NSCs in 3–7 days. Further analyses showed that PPARγ agonists and ATRA induced significant alterations in the expression of many stemness and differentiation genes associated with neuro-glial differentiation in NSCs. These findings highlight the influence of PPARγ agonists in promoting neuro-glial differentiation of NSCs and its significance in the treatment of neurodegenerative diseases. PMID:23185633

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

    PubMed Central

    Chakraborty, Sandipan; Biswas, P. K.

    2014-01-01

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