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1

Dissociation of peripheral T cell responses from thymocyte negative selection by weak agonists supports a spare receptor model of T cell activation  

PubMed Central

We have focused on stability of the peptide-MHC complex as a determining factor of ligand potency for thymocytes and peripheral CD4+ T cell responses. MHC variant peptides that have low affinities and fast dissociation rates are different in that they stimulate proliferation and cytolysis of mature T cells (classifying the variant peptides as weak agonists) but do not induce thymocyte negative selection. The MHC variant weak agonists require significant receptor reserve, because decreasing the level of T cell receptor on mature T cells blocks the proliferative response. These results demonstrate that peripheral T cells are more sensitive to MHC variant ligands by virtue of increased T cell receptor expression; in addition, the data support a T cell model of the spare receptor theory.

McNeil, Lisa K.; Evavold, Brian D.

2002-01-01

2

Dissociation of peripheral T cell responses from thymocyte negative selection by weak agonists supports a spare receptor model of T cell activation.  

PubMed

We have focused on stability of the peptide-MHC complex as a determining factor of ligand potency for thymocytes and peripheral CD4+ T cell responses. MHC variant peptides that have low affinities and fast dissociation rates are different in that they stimulate proliferation and cytolysis of mature T cells (classifying the variant peptides as weak agonists) but do not induce thymocyte negative selection. The MHC variant weak agonists require significant receptor reserve, because decreasing the level of T cell receptor on mature T cells blocks the proliferative response. These results demonstrate that peripheral T cells are more sensitive to MHC variant ligands by virtue of increased T cell receptor expression; in addition, the data support a T cell model of the spare receptor theory. PMID:11904393

McNeil, Lisa K; Evavold, Brian D

2002-03-19

3

?-Galactosylceramide Analogs with Weak Agonist Activity for Human iNKT Cells Define New Candidate Anti-Inflammatory Agents  

Microsoft Academic Search

CD1d-restricted natural killer T cells with invariant T cell receptor ? chains (iNKT cells) are a unique lymphocyte subset that responds to recognition of specific lipid and glycolipid antigens. They are conserved between mice and humans and exert various immunoregulatory functions through their rapid secretion of a variety of cytokines and secondary activation of dendritic cells, B cells and NK

Gabriel Bricard; Manjunatha M. Venkataswamy; Karl O. A. Yu; Jin S. Im; Rachel M. Ndonye; Amy R. Howell; Natacha Veerapen; Petr A. Illarionov; Gurdyal S. Besra; Qian Li; Young-Tae Chang; Steven A. Porcelli

2010-01-01

4

Aluminum is a weak agonist for the calcium-sensing receptor  

Microsoft Academic Search

Aluminum is a weak agonist for the calcium-sensing receptor.BackgroundAluminum (Al3+) has diverse biological effects mediated through activation of a putative extracellular cation-sensing receptor. A recently identified calcium-sensing receptor (CaSR), which has been identified in target tissues for Al3+, may transduce some of the biological effects of Al3+.MethodsTo test this possibility, we transfected human embryonic kidney 293 (HEK 293) cells with

Robert F. Spurney; Min Pi; Patrick Flannery; L. Darryl Quarles

1999-01-01

5

Agonist-activated ion channels  

PubMed Central

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

Colquhoun, David

2006-01-01

6

TCR reserve: a novel principle of CD4 T cell activation by weak ligands.  

PubMed

Some ligand-receptor systems have a receptor reserve where a maximal response can be achieved by occupation of a fraction of available receptors. An implication of a receptor reserve is the expansion of the number of ligands for response. To determine whether T cells follow receptor reserve, we have characterized the effect of reducing TCR levels on CD4 T cell responses elicited by altered peptide ligands that vary in potency. Agonist peptide is unaffected by a 90% reduction in TCR level while proliferation to weak agonists is significantly inhibited when TCR expression is reduced by 40%. Thymocyte-negative selection similarly demonstrates a differential requirement of TCR for response to agonist, weak agonist, and partial agonist. Therefore, our data demonstrate receptor reserve as a novel principle of T cell activation in which excess TCRs expand the antigenic repertoire to include less potent ligands. PMID:12538680

McNeil, Lisa K; Evavold, Brian D

2003-02-01

7

Agonistic and antagonistic activities of chemokines.  

PubMed

Since the discovery of interleukin-8, about 50 chemokines have been identified and characterized. Originally, they were considered as inducible mediators of inflammation, but in recent years, several chemokines were identified that are expressed constitutively and function in physiological traffic and homing of leukocyte-lymphocytes in particular. All chemokines act via seven-transmembrane domain, G protein-coupled receptors. Eighteen such receptors have been identified so far. Studies on structure-activity relationships indicate that chemokines have two main sites of interaction with their receptors, the flexible NH2-terminal region and the conformationally rigid loop that follows the second cysteine. Chemokines are thought to dock onto receptors by means of the loop region, and this contact is believed to facilitate the binding of the NH2-terminal region that results in receptor activation. These studies have also highlighted the importance of the NH2-terminal region for agonistic and antagonistic activity. Recently, we have shown that some naturally occurring chemokines can function as receptor antagonists. These observations suggest a new mechanism for the regulation of leukocyte recruitment during inflammatory and immune reactions, which are based on the combination of agonistic and antagonistic effects. PMID:11404371

Loetscher, P; Clark-Lewis, I

2001-06-01

8

Enhanced gastrointestinal motility with orally active ghrelin receptor agonists.  

PubMed

The orexigenic peptide ghrelin has been shown to have prokinetic activity in the gastrointestinal (GI) system of several species, including humans. In this series of experiments, we have evaluated the prokinetic activity of novel, small-molecule ghrelin receptor (GhrR) agonists after parenteral and peroral dosing in mice and rats. Gastric emptying, small intestinal transport, and fecal output were determined after intraperitoneal and intracerebroventricular dosing of GhrR agonists, using ghrelin as a positive control. These same parameters were evaluated after oral gavage dosing of the synthetic agonists. Regardless of dose route, GhrR agonist treatment increased gastric emptying, small intestinal transit, and fecal output. However, fecal output was only increased by GhrR agonist treatment if mice were able to feed during the stimulatory period. Thus, GhrR agonists can stimulate upper GI motility, and the orexigenic action of the compounds can indirectly contribute to prokinetic activity along the entire GI tract. The orexigenic and prokinetic effects of either ghrelin or small-molecule GhrR agonists were selective for the GhrR because they were absent when evaluated in GhrR knockout mice. We next evaluated the efficacy of the synthetic GhrR agonists dosed in a model of opiate-induced bowel dysfunction induced by a single injection of morphine. Oral dosing of a GhrR agonist normalized GI motility in opiate-induced dysmotility. These data demonstrate the potential utility of GhrR agonists for treating gastrointestinal hypomotility disorders. PMID:19252061

Charoenthongtrakul, Soratree; Giuliana, Derek; Longo, Kenneth A; Govek, Elizabeth K; Nolan, Anna; Gagne, Samantha; Morgan, Kristen; Hixon, Jeffrey; Flynn, Neil; Murphy, Brian J; Hernández, Andres S; Li, Jun; Tino, Joseph A; Gordon, David A; DiStefano, Peter S; Geddes, Brad J

2009-02-27

9

Dehydroepiandrosterone Derivatives as Potent Antiandrogens with Marginal Agonist Activity.  

National Technical Information Service (NTIS)

We hypothesized that dehydroepiandrosterone (DHEA) metabolites or their synthetic derivatives are able to bind to the androgen receptor with low, if any, agonist activity and thus function as better antiandrogens than currently available ones. We previous...

H. Miyamoto

2010-01-01

10

[Weak magnetic fields and cognitive activity].  

PubMed

The influence of natural level of uniform magnetic field (to 200 microT) on Wistar rat cognition was studied in this work. It was found that influence of disturbed Earth magnetic field has caused a long depression of explorative activity only in the presence of information loading. Such depression was removed only after short external stimulation. After this stimulation rats were able to learn by themselves and it took them twice less time than in the control (nootropic effect). It is suggested that a weak magnetic field disturbances may be considered as a negative psychogenic factor which distorts normal conditions for cognitive activity. PMID:8962888

Nikol'skaia, K A; Shtemler, A V; Savonenko, A V; Osipov, A I; Nikol'ski?, S V

11

Which agonist properties are important for the activation of 5-HT3A receptors?  

PubMed

Purpose: Why do anesthetics not activate excitatory ligand-gated ion channels such as 5-HT3 receptors in contrast to inhibitory ligand-gated ion channels? This study examines the actions of structural closely-related 5-HT derivatives and 5-HT constituent parts on 5-HT3A receptors with the aim of finding simpler if not minimal agonists and thus determining requirements for successful agonist action. Experimental approach: Responses to 5-HT derivatives of human 5-HT3A receptors stably expressed in HEK 293 cells have been examined with the patch-clamp technique in the outside-out configuration combined with a fast solution exchange system. Results: Phenol, pyrrole and alkyl amines, constituents of 5-HT, even at high concentrations, cannot activate 5-HT3A receptors but they can inhibit them. To date, tyramines are the smallest known agonists. However, an aromatic ring is not required for activation as acetylcholine is also an agonist of similar strength. Conclusion: Simultaneous interactions of adequate strength at two separate subsites within the 5-HT binding domain appear to be essential for successful agonist function. Anesthetics either fail to achieve this or the activation they produce is so weak that it is masked by a comparatively very strong inhibition. PMID:23792067

Meiboom, M F; Barann, M; Witten, S; Groeneveld, K; Urban, B W

2013-06-18

12

Weakness  

MedlinePLUS

Lack of strength; Muscle weakness ... weak, but there is no real loss of strength. For example, you may feel weak if you ... flu . Objective means there is a loss of strength that can be noted during a physical exam.

13

Optimisation of the Anti-Trypanosoma brucei Activity of the Opioid Agonist U50488  

PubMed Central

Screening of the Sigma–Aldrich Library of Pharmacologically Active Compounds (LOPAC) against cultured Trypanosoma brucei, the causative agent of African sleeping sickness, resulted in the identification of a number of compounds with selective antiproliferative activity over mammalian cells. These included (+)-(1R,2R)-U50488, a weak opioid agonist with an EC50 value of 59 nm as determined in our T. brucei in vitro assay reported previously. This paper describes the modification of key structural elements of U50488 to investigate structure–activity relationships (SAR) and to optimise the antiproliferative activity and pharmacokinetic properties of this compound.

Smith, Victoria C; Cleghorn, Laura A T; Woodland, Andrew; Spinks, Daniel; Hallyburton, Irene; Collie, Iain T; Yi Mok, N; Norval, Suzanne; Brenk, Ruth; Fairlamb, Alan H; Frearson, Julie A; Read, Kevin D; Gilbert, Ian H; Wyatt, Paul G

2011-01-01

14

Optimisation of the anti-Trypanosoma brucei activity of the opioid agonist U50488.  

PubMed

Screening of the Sigma-Aldrich Library of Pharmacologically Active Compounds (LOPAC) against cultured Trypanosoma brucei, the causative agent of African sleeping sickness, resulted in the identification of a number of compounds with selective antiproliferative activity over mammalian cells. These included (+)-(1R,2R)-U50488, a weak opioid agonist with an EC(50) value of 59 nM as determined in our T. brucei in vitro assay reported previously. This paper describes the modification of key structural elements of U50488 to investigate structure-activity relationships (SAR) and to optimise the antiproliferative activity and pharmacokinetic properties of this compound. PMID:21834094

Smith, Victoria C; Cleghorn, Laura A T; Woodland, Andrew; Spinks, Daniel; Hallyburton, Irene; Collie, Iain T; Mok, N Yi; Norval, Suzanne; Brenk, Ruth; Fairlamb, Alan H; Frearson, Julie A; Read, Kevin D; Gilbert, Ian H; Wyatt, Paul G

2011-08-10

15

Agonist-antagonist muscle activation during drop jumps.  

PubMed

Abstract Pre-programmed and stretch-induced muscle activities of agonist muscles can play important roles during stretch-shortening cycle exercises. It is still not clear how the antagonist muscles function when the drop and rebound intensities are varied during drop jump (DJ) exercises. The purpose of the present study was to examine the regulation of agonist-antagonist muscle activation during DJ with different drop and rebound heights. The subjects performed DJs with two drop heights (0.2 and 0.4 m) and three different efforts (maximal rebound height, 50% effort of maximal rebound height and landing without rebound). Ankle and knee joint angles, and vertical ground reaction force together with an electromyogram of the lower leg muscles (medial gastrocnemius [MG], soleus [SOL] and tibialis anterior [TA]) were measured simultaneously during DJ. Our results clearly showed that the pre-activation of the antagonist TA was increased with increasing rebound height. Our results further showed that the coactivations of agonist and antagonist muscles during the post-impact 30-ms phase were increased with increasing rebound height. These results suggested that not only the pre-programmed agonist MG muscle activation, but also the pre-programmed antagonist TA activation and the coactivation of the post-impact 30-ms phase may play important roles in the control of rebound height. PMID:24050466

Arai, Aya; Ishikawa, Masaki; Ito, Akira

2013-01-29

16

PPAR agonists modulate human osteoclast formation and activity in vitro  

Microsoft Academic Search

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear steroid hormone superfamily and exist in three isoforms: PPAR?, ? and ?, each with specific functions. In this study, we have investigated the expression of PPARs by human osteoclast precursors and osteoclasts generated in vitro. In addition, the effects of fibrates and isoform-specific PPAR agonists on osteoclast formation and resorption in

B. Y. Chan; A. Gartland; P. J. M. Wilson; K. A. Buckley; J. P. Dillon; W. D. Fraser; J. A. Gallagher

2007-01-01

17

Synthesis and biological properties of 2-methylene-19-nor-25-dehydro-1alpha-hydroxyvitamin D(3)-26,23-lactones--weak agonists.  

PubMed

In a continuing effort to explore the 2-methylene-1alpha-hydroxy-19-norvitamin D(3) class of pharmacologically important vitamin D compounds, two novel 2-methylene-19-nor-25-dehydro-1alpha-hydroxyvitamin D(3)-26,23-lactones, GC-3 and HLV, were synthesized and biologically tested. Based on reports of similarly structured molecules, it was hypothesized that these compounds might act as antagonists, at least in vitro. The pathway designed to synthesize these compounds was based on two key steps: first, the Lythgoe-type Wittig-Horner coupling of Windaus-Grundmann-type ketone 18, with phosphine oxide 15, followed, later in the synthesis, by the Zn-mediated Reformatsky-type allylation of aldehyde 20 with methylbromomethylacrylate 8. Our biological data show that neither compound has antagonistic activity but acts as weak agonists in vitro and in vivo. PMID:18722130

Chiellini, Grazia; Grzywacz, Pawel; Plum, Lori A; Barycki, Rafal; Clagett-Dame, Margaret; DeLuca, Hector F

2008-08-07

18

Partial Agonists Activate PPARgamma Using a Helix 12 Independent Mechanism  

SciTech Connect

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

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

2009-05-28

19

Co-activation: its association with weakness and specific neurological pathology  

PubMed Central

Background Net agonist muscle strength is in part determined by the degree of antagonist co-activation. The level of co-activation might vary in different neurological disorders causing weakness or might vary with agonist strength. Aim This study investigated whether antagonist co-activation changed a) with the degree of muscle weakness and b) with the nature of the neurological lesion causing weakness. Methods Measures of isometric quadriceps and hamstrings strength were obtained. Antagonist (hamstring) co-activation during knee extension was calculated as a ratio of hamstrings over quadriceps activity both during an isometric and during a functional sit to stand (STS) task (using kinematics) in groups of patients with extrapyramidal (n = 15), upper motor neuron (UMN) (n = 12), lower motor neuron (LMN) with (n = 18) or without (n = 12) sensory loss, primary muscle or neuromuscular junction disorder (n = 17) and in healthy matched controls (n = 32). Independent t-tests or Mann Witney U tests were used to compare between the groups. Correlations between variables were also investigated. Results In healthy subjects mean (SD) co-activation of hamstrings during isometric knee extension was 11.8 (6.2)% and during STS was 20.5 (12.9)%. In patients, co-activation ranged from 7 to 17% during isometric knee extension and 15 to 25% during STS. Only the extrapyramidal group had lower co-activation levels than healthy matched controls (p < 0.05). Agonist isometric muscle strength and co-activation correlated only in muscle disease (r = -0.6, p < 0.05) and during STS in UMN disorders (r = -0.7, p < 0.5). Conclusion It is concluded that antagonist co-activation does not systematically vary with the site of neurological pathology when compared to healthy matched controls or, in most patient groups, with strength. The lower co-activation levels found in the extrapyramidal group require confirmation and further investigation. Co-activation may be relevant to individuals with muscle weakness. Within patient serial studies in the presence of changing muscle strength may help to understand these relationships more clearly.

Busse, Monica E; Wiles, Charles M; van Deursen, Robert WM

2006-01-01

20

Activity patterns, behavioural repertoires, and agonistic interactions of crayfish: A non-manipulative field study  

Microsoft Academic Search

Summary Agonistic behaviour of crayfish has been studied extensively in laboratory settings where pairs or groups of individuals are allowed to interact within an experimental arena. Crayfish agonistic behaviour within its natural context, however, has received little attention to date. The present, non-manipulative field study explored activity patterns, behavioural repertoires, and agonistic encounters of rusty crayfish (Orconectes rusticus) during the

Karen M. Davis; Robert Huber

2007-01-01

21

Neuromodulation of the agonistic behavior in two species of weakly electric fish that display different types of aggression.  

PubMed

Agonistic behavior has shaped sociality across evolution. Though extremely diverse in types of displays and timing, agonistic encounters always follow the same conserved phases (evaluation, contest and post-resolution) and depend on homologous neural circuits modulated by the same neuroendocrine mediators across vertebrates. Among neuromodulators, serotonin (5-HT) is the main inhibitor of aggression, and arginine vasotocin (AVT) underlies sexual, individual and social context differences in behavior across vertebrate taxa. We aim to demonstrate that a distinct spatio-temporal pattern of activation of the social behavior network characterizes each type of aggression by exploring its modulation by both the 5-HT and AVT systems. We analyze the neuromodulation of aggression between the intermale reproduction-related aggression displayed by the gregarious Brachyhypopomus gauderio and the non-breeding intrasexual and intersexual territorial aggression displayed by the solitary Gymnotus omarorum. Differences in the telencephalic activity of 5-HT between species were paralleled by a differential serotonergic modulation through 1A receptors that inhibited aggression in the territorial aggression of G. omarorum but not in the reproduction-related aggression of B. gauderio. AVT injection increased the motivation towards aggression in the territorial aggression of G. omarorum but not in the reproduction-related aggression of B. gauderio, whereas the electric submission and dominance observed in G. omarorum and B. gauderio, respectively, were both AVT-dependent in a distinctive way. The advantages of our model species allowed us to identify precise target areas and mechanisms of the neuromodulation of two types of aggression that may represent more general and conserved strategies of the control of social behavior among vertebrates. PMID:23761466

Silva, Ana C; Perrone, Rossana; Zubizarreta, Lucía; Batista, Gervasio; Stoddard, Philip K

2013-07-01

22

Cold suppresses agonist-induced activation of TRPV1.  

PubMed

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

Chung, M-K; Wang, S

2011-06-10

23

FXR agonist activity of conformationally constrained analogs of GW 4064  

SciTech Connect

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.

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

2010-09-27

24

A Novel Strategy for Designing the Selective PPAR Agonist by the “Sum of Activity” Model  

Microsoft Academic Search

Peroxisome proliferator-activated receptors ?, ?, and ? are a collection of ligand-activated transcription factors crucial in lipid and glucose homeostasis. The involvement of these receptors in lipid metabolism makes them perfect therapeutic target for treating obesity and stroke. In this study, ‘sum of activity’ model was employed to design multi-target agonists. We used a new strategy to design agonists that

Hung-Jin Huang; Kuei-Jen Lee; Hsin Wei Yu; Hsin-Yi Chen; Fuu-Jen Tsai; Calvin Yu-Chian Chen

2010-01-01

25

Computational structure-activity relationship analysis of small-molecule agonists for human formyl peptide receptors.  

PubMed

N-formyl peptide receptors (FPRs) are important in host defense. Because of the potential for FPRs as therapeutic targets, recent efforts have focused on identification of non-peptide agonists for two FPR subtypes, FPR1 and FPR2. Given that a number of specific small-molecule agonists have recently been identified, we hypothesized that computational structure-activity relationship (SAR) analysis of these molecules could provide new information regarding molecular features required for activity. We used a training set of 71 compounds, including 10 FPR1-specific agonists, 36 FPR2-specific agonists, and 25 non-active analogs. A sequence of (1) one-way analysis of variance selection, (2) cluster analysis, (3) linear discriminant analysis, and (4) classification tree analysis led to the derivation of SAR rules with high (95.8%) accuracy for correct classification of compounds. These SAR rules revealed key features distinguishing FPR1 versus FPR2 agonists. To verify predictive ability, we evaluated a test set of 17 additional FPR agonists, and found that the majority of these agonists (>94%) were classified correctly as agonists. This study represents the first successful application of classification tree methodology based on atom pairs to SAR analysis of FPR agonists. Importantly, these SAR rules represent a relatively simple classification approach for virtual screening of FPR1/FPR2 agonists. PMID:20870313

Khlebnikov, Andrei I; Schepetkin, Igor A; Quinn, Mark T

2010-09-15

26

Computational Structure-activity Relationship Analysis of Small-Molecule Agonists for Human Formyl Peptide Receptors  

PubMed Central

N-formyl peptide receptors (FPR) are important in host defense. Because of the potential for FPRs as therapeutic targets, recent efforts have focused on identification of non-peptide agonists for two FPR subtypes, FPR1 and FPR2. Given that a number of specific small molecule agonists have recently been identified, we hypothesized that computational structure-activity relationship (SAR) analysis of these molecules could provide new information regarding molecular features required for activity. We used a training set of 71 compounds, including 10 FPR1-specific agonists, 36 FPR2-specific agonists, and 25 non-active analogs. A sequence of (1) one-way analysis of variance selection, (2) cluster analysis, (3) linear discriminant analysis, and (4) classification tree analysis led to the derivation of SAR rules with high (95.8%) accuracy for correct classification of compounds. These SAR rules revealed key features distinguishing FPR1 versus FPR2 agonists. To verify predictive ability, we evaluated a test set of 17 additional FPR agonists, and found that the majority of these agonists (>94%) were classified correctly as agonists. This study represents the first successful application of classification tree methodology based on atom pairs to SAR analysis of FPR agonists. Importantly, these SAR rules represent a relatively simple classification approach for virtual screening of FPR1/FPR2 agonists.

Khlebnikov, Andrei I.; Schepetkin, Igor A; Quinn, Mark T.

2010-01-01

27

Protective effects of a peroxisome proliferator-activated receptor-?\\/? agonist in experimental autoimmune encephalomyelitis  

Microsoft Academic Search

Agonists of the peroxisome proliferator-activated receptor gamma (PPAR?) exert anti-inflammatory and anti-proliferative effects which led to testing of these drugs in experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis. In contrast, the effect of PPARdelta (PPAR?) agonists in EAE is not yet known. We show that oral administration of the selective PPAR? agonist GW0742 reduced clinical symptoms in C57BL\\/6

Paul E. Polak; Sergey Kalinin; Cinzia Dello Russo; Vitaliy Gavrilyuk; Anthony Sharp; Jeffrey M. Peters; Jill Richardson; Tim M. Willson; Guy Weinberg; Douglas L. Feinstein

2005-01-01

28

The dopamine agonist cabergoline provides neuroprotection by activation of the glutathione system and scavenging free radicals  

Microsoft Academic Search

Free radicals are involved in the pathogenesis and\\/or progression of Parkinson's disease (PD). Several ergot derivative dopamine (DA) agonists have been reported to scavenge free radicals in vitro and to show a neuroprotective effect in vivo. We investigated the in vitro free radical scavenging and antioxidant activities of cabergoline, a long-acting ergot DA agonist, as well as its ability to

Michiyo Yoshioka; Ken-ichi Tanaka; Ikuko Miyazaki; Naoko Fujita; Youichirou Higashi; Masato Asanuma; Norio Ogawa

2002-01-01

29

Agonist activation of ?7 nicotinic acetylcholine receptors via an allosteric transmembrane site  

PubMed Central

Conventional nicotinic acetylcholine receptor (nAChR) agonists, such as acetylcholine, act at an extracellular “orthosteric” binding site located at the interface between two adjacent subunits. Here, we present evidence of potent activation of ?7 nAChRs via an allosteric transmembrane site. Previous studies have identified a series of nAChR-positive allosteric modulators (PAMs) that lack agonist activity but are able to potentiate responses to orthosteric agonists, such as acetylcholine. It has been shown, for example, that TQS acts as a conventional ?7 nAChR PAM. In contrast, we have found that a compound with close chemical similarity to TQS (4BP-TQS) is a potent allosteric agonist of ?7 nAChRs. Whereas the ?7 nAChR antagonist metyllycaconitine acts competitively with conventional nicotinic agonists, metyllycaconitine is a noncompetitive antagonist of 4BP-TQS. Mutation of an amino acid (M253L), located in a transmembrane cavity that has been proposed as being the binding site for PAMs, completely blocks agonist activation by 4BP-TQS. In contrast, this mutation had no significant effect on agonist activation by acetylcholine. Conversely, mutation of an amino acid located within the known orthosteric binding site (W148F) has a profound effect on agonist potency of acetylcholine (resulting in a shift of ?200-fold in the acetylcholine dose-response curve), but had little effect on the agonist dose-response curve for 4BP-TQS. Computer docking studies with an ?7 homology model provides evidence that both TQS and 4BP-TQS bind within an intrasubunit transmembrane cavity. Taken together, these findings provide evidence that agonist activation of nAChRs can occur via an allosteric transmembrane site.

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

2011-01-01

30

Design, synthesis, and evaluation of potent, structurally novel peroxisome proliferator-activated receptor (PPAR) ?-selective agonists  

Microsoft Academic Search

A series of 3-(4-alkoxyphenyl)propanoic acid derivatives was prepared as candidate peroxisome proliferator-activated receptor (PPAR) ?-selective agonists, based on our previously discovered potent human PPAR?\\/? dual agonist TIPP-401 as a lead compound. Structure–activity relationship studies clearly indicated the importance of the chain length of the alkoxy group at the 4-position, and the n-butoxy compound exhibited the most potent PPAR? transactivation activity

Jun-ichi Kasuga; Izumi Nakagome; Atsushi Aoyama; Kumiko Sako; Michiyasu Ishizawa; Michitaka Ogura; Makoto Makishima; Shuichi Hirono; Yuichi Hashimoto; Hiroyuki Miyachi

2007-01-01

31

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

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. PMID:10319995

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

32

Discovery and structure-activity relationship studies of indole derivatives as liver X receptor (LXR) agonists.  

PubMed

A structurally novel liver X receptor (LXR) agonist (1) was identified from internal compound collection utilizing the combination of structure-based virtual screening and high-throughput gene profiling. Compound 1 increased ABCA1 gene expression by eightfold and SREBP1c by threefold in differentiated THP-1 macrophage cell lines. Confirmation of its agonistic activity against LXR was obtained in the co-factor recruitment and reporter transactivation assays. Structure-activity relationship studies on compound 1 are described. PMID:17416521

Bakir, Farid; Kher, Sunil; Pannala, Madhavi; Wilson, Norma; Nguyen, Trang; Sircar, Ila; Takedomi, Kei; Fukushima, Chiaki; Zapf, James; Xu, Kui; Zhang, Shao-Hui; Liu, Juping; Morera, Lisa; Schneider, Lisa; Sakurai, Naoki; Jack, Rick; Cheng, Jie-Fei

2007-03-27

33

Weakly sheared active suspensions: Hydrodynamics, stability, and rheology  

NASA Astrophysics Data System (ADS)

We present a kinetic model for flowing active suspensions and analyze the behavior of a suspension subjected to a weak steady shear. Asymptotic solutions are sought in Deborah number expansions. At the leading order, we explore the steady states and perform their stability analysis. We predict the rheology of active systems including an activity thickening or thinning behavior of the apparent viscosity and a negative apparent viscosity depending on the particle type, flow alignment, and the anchoring conditions, which can be tested on bacterial suspensions. We find remarkable dualities that show that flow-aligning rodlike contractile (extensile) particles are dynamically and rheologically equivalent to flow-aligning discoid extensile (contractile) particles for both tangential and homeotropic anchoring conditions. Another key prediction of this work is the role of the concentration of active suspensions in controlling the rheological behavior: The apparent viscosity may decrease with the increase of the concentration.

Cui, Zhenlu

2011-03-01

34

Physicochemical characterization and biological activity of synthetic TLR4 agonist formulations.  

PubMed

Immunostimulatory molecules such as monophosphoryl lipid A (MPL), a Toll-like receptor 4 (TLR4) agonist, can be formulated to enhance vaccine adjuvant effects and to promote a Th1-type immune response. This study compares the in vitro and in vivo potency of aqueous and emulsion formulations containing a synthetic MPL analogue. In addition, formulation structure and association of the synthetic TLR-4 agonist and antigen with the formulation are characterized using dynamic light scattering, zeta potential measurement, HPLC, and SDS-PAGE. The biological and biophysical effects of formulating the agonist with different oil and surfactant components from animal, plant, and synthetic sources are examined. These findings have important implications for the formulation of TLR4 agonists as well as the influence of formulation component substitution on adjuvant activity. The results indicate that (1) the agonist is associated with the oil droplets in emulsion formulations, (2) the emulsion formulations containing synthetic TLR4 agonist induce higher IgG2a/IgG1 antibody ratios than aqueous formulations or an emulsion formulation without the agonist, and (3) appropriate plant-derived components can be substituted for animal-derived components in oil-in-water emulsions without loss of biological activity. PMID:19748238

Anderson, Ryan C; Fox, Christopher B; Dutill, Timothy S; Shaverdian, Narek; Evers, Tara L; Poshusta, Garrett R; Chesko, James; Coler, Rhea N; Friede, Martin; Reed, Steven G; Vedvick, Thomas S

2009-08-20

35

Did Weak-line Quasars Just Begin an Active Phase?  

NASA Astrophysics Data System (ADS)

Active Galactic Nuclei (AGN) are often defined by their prominent emission lines, and rare instances of AGN lacking strong emission features are often explained by the presence of a relativistically boosted radio jet (i.e., as for BL Lac objects). However, the SDSS has discovered a population of 80 high-redshift (z>2.2) radio-quiet quasars with weak emission lines (WLQs) not predicted by the standard orientation based model. Inclusive AGN selection approaches are now also revealing lower-redshift radio-quiet AGN lacking strong emission lines (around 100 objects to date), which are potential analogs to WLQs. Here, we describe our sample of low-redshift WLQ candidates, and we present follow-up multiwavelength observations for 26 objects. Our conclusion is WLQs likely have intrinsically weak broad emission line regions. Finally, we compare WLQs to accreting stellar mass black holes to explore the possibility that WLQs are in a short-lived evolutionary stage where quasar activity has only recently begun. Studying extreme examples of AGN like WLQs may lead to new insight into the formation of broad emission line regions in AGN. Support for this work was provided by a Netherlands Organization for Scientific Research (NWO) Vidi Fellowship.

Plotkin, Richard M.; Anderson, S. F.; Brandt, W. N.; Diamond-Stanic, A. M.; Fan, X.; MacLeod, C. L.; Markoff, S.; Schneider, D. P.; Shemmer, O.

2011-01-01

36

Dopamine Agonist Increases Risk Taking but Blunts Reward-Related Brain Activity  

Microsoft Academic Search

The use of D2\\/D3 dopaminergic agonists in Parkinson's disease (PD) may lead to pathological gambling. In a placebo-controlled double-blind study in healthy volunteers, we observed riskier choices in a lottery task after administration of the D3 receptor-preferring agonist pramipexole thus mimicking risk-taking behavior in PD. Moreover, we demonstrate decreased activation in the rostral basal ganglia and midbrain, key structures of

Jordi Riba; Ulrike M. Krämer; Marcus Heldmann; Sylvia Richter; Thomas F. Münte; Bernhard Baune

2008-01-01

37

Organization and activation of sexual and agonistic behavior in the leopard gecko, Eublepharis macularius.  

PubMed

Gonadal sex is determined by the temperature experienced during incubation in the leopard gecko (Eublepharis macularius). Furthermore, both factors, incubation temperature and gonadal sex, influence adult sexual and agonistic behavior in this species. Yet it is unclear whether such differences in behavior are irreversibly organized during development or are mediated by differences in hormone levels in adulthood. To address this question, we gonadectomized adult females and males generated from a female-biased (30 degrees C) and a male-biased (32.5 degrees C) incubation temperature and treated them with equivalent levels of various sex steroids. We found that 17beta-estradiol (E(2)) activated sexual receptivity in females but not males, suggesting an organized sex difference in behavioral sensitivity to E(2). There were also organized and activated sex differences in attractivity to stimulus males. Although females were more attractive than males when treated with E(2), both sexes were equally unattractive when treated with dihydrotestosterone (DHT) or testosterone (T). Likewise, sex differences in aggressive and submissive behavior were organized and activated. Attacks on stimulus males were activated by T in males but not in females. In contrast, hormones did not influence flight behavior in males but did affect female submissiveness. Overall, males also evoked more attacks by stimulus males than did females. Nevertheless, females and males treated with androgens evoked more attacks than animals of the same sex that were treated with cholesterol or E(2). Incubation temperature had some weak effects on certain behaviors and no effect on others. This suggests that temperature effects in gonadally intact geckos may be due primarily to differences in circulating levels of hormones in adulthood. We conclude that gonadal sex has both organizational and activational effects on various behaviors in the leopard gecko. PMID:10773745

Rhen, T; Crews, D

2000-04-01

38

Influence of agonist intrinsic activity on the desensitisation of ?2-adrenoceptor-mediated responses in mast cells  

PubMed Central

The aim of the present study was to determine whether the intrinsic activity of an agonist influences the extent of desensitisation of ?2-adrenoceptor-mediated responses in human lung mast cells. The effects of a wide range of ?-adrenoceptor agonists (10?10–10?5 M) on the IgE-mediated release of histamine from mast cells were determined. The intrinsic activity of agonists was established by comparing the maximal inhibitory response (Emax) of an agonist relative to the maximal response obtained with the full agonist, isoprenaline. The intrinsic activity order for the inhibition of histamine release was isoprenaline (1.0)>formoterol (0.94)>fenoterol (0.89)>terbutaline (0.84)>salbutamol (0.69)>clenbuterol (0.65)>salmeterol (0.30)>dobutamine (0.20). There was a significant (P<0.05) positive correlation (r=0.81) between the extent to which ?-adrenoceptor agonists inhibited histamine release and the degree to which the agonists caused elevations in cAMP in mast cells. Further studies investigated the effects of long-term (24 h) incubation of mast cells with ?-adrenoceptor agonists on the subsequent ability of isoprenaline to inhibit histamine release. At concentrations of agonists selected to occupy a large percentage (88%) of ?2-adrenoceptors, there was a significant (P<0.05) correlation (r=0.73) between the relative intrinsic activity of agonists as inhibitors of histamine release and the extent of functional desensitisation induced by the agonists. At lower receptor occupancies, however, there was no correlation between the relative intrinsic activity of agonists and the extent of agonist-induced desensitisation. These data indicate that, under experimental conditions where high receptor occupancies prevail, agonist intrinsic activity influences the extent of desensitisation of ?2-adrenoceptor-mediated responses in mast cells.

Scola, Anne-Marie; Chong, Lee K; Chess-Williams, Russell; Peachell, Peter T

2004-01-01

39

Activation of PLC-delta1 by Gi/o-coupled receptor agonists.  

PubMed

The mechanism of phospholipase (PLC)-delta activation by G protein-coupled receptor agonists was examined in rabbit gastric smooth muscle. Ca(2+) stimulated an eightfold increase in PLC-delta1 activity in permeabilized muscle cells. Treatment of dispersed or cultured muscle cells with three G(i/o)-coupled receptor agonists (somatostatin, delta-opioid agonist [D-Pen(2),D-Pen(5)]enkephalin, and A(1) agonist cyclopentyl adenosine) caused delayed increase in phosphoinositide (PI) hydrolysis (8- to 10-fold) that was strongly inhibited by overexpression of dominant-negative PLC-delta1(E341R/D343R; 65-76%) or constitutively active RhoA(G14V). The response coincided with capacitative Ca(2+) influx and was not observed in the absence of extracellular Ca(2+), but was partly inhibited by nifedipine (16-30%) and strongly inhibited by SKF-96365, a blocker of store-operated Ca(2+) channels. Treatment of the cells with a G(q/13)-coupled receptor agonist, CCK-8, caused only transient, PLC-beta1-mediated PI hydrolysis. Unlike G(i/o)-coupled receptor agonists, CCK-8 activated RhoA and stimulated RhoA:PLC-delta1 association. Inhibition of RhoA activity with C3 exoenzyme or by overexpression of dominant-negative RhoA(T19N) or Galpha(13) minigene unmasked a delayed increase in PI hydrolysis that was strongly inhibited by coexpression of PLC-delta1(E341R/D343R) or by SKF-96365. Agonist-independent capacitative Ca(2+) influx induced by thapsigargin stimulated PI hydrolysis (8-fold), which was partly inhibited by nifedipine ( approximately 25%) and strongly inhibited by SKF-96365 ( approximately 75%) and in cells expressing PLC-delta1(E341R/D343R). Agonist-independent Ca(2+) release or Ca(2+) influx via voltage-gated Ca(2+) channels stimulated only moderate PI hydrolysis (2- to 3-fold), which was abolished by PLC-delta1 antibody or nifedipine. We conclude that PLC-delta1 is activated by G(i/o)-coupled receptor agonists that do not activate RhoA. The activation is preferentially mediated by Ca(2+) influx via store-operated Ca(2+) channels. PMID:15525688

Murthy, Karnam S; Zhou, Huiping; Huang, Jiean; Pentyala, Srinivas N

2004-12-01

40

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

PubMed

Previous studies have established that pro-oxidative stressors suppress host immunity because of their ability to generate oxidized lipids with platelet-activating factor receptor (PAF-R) agonist activity. Although exposure to the pro-oxidative stressor cigarette smoke (CS) is known to exert immunomodulatory effects, little is known regarding the role of PAF in these events. The current studies sought to determine the role of PAF-R signaling in CS-mediated immunomodulatory effects. We demonstrate that CS exposure induces the generation of a transient PAF-R agonistic activity in the blood of mice. CS exposure inhibits contact hypersensitivity in a PAF-R-dependent manner as PAF-R-deficient mice were resistant to these effects. Blocking PAF-R agonist production either by systemic antioxidants or treatment with serum PAF-acetyl hydrolase enzyme blocked both the CS-mediated generation of PAF-R agonists and PAF-R-dependent inhibition of contact hypersensitivity (CHS) reactions, indicating a role for oxidized glycerophosphocholines with PAF-R agonistic activity in this process. In addition, cyclooxygenase-2 inhibition did not block PAF-R agonist production but prevented CS-induced inhibition of CHS. This suggests that cyclooxygenase-2 acts downstream of the PAF-R in mediating CS-induced systemic immunosuppression. Moreover, CS exposure induced a significant increase in the expression of the regulatory T cell reporter gene in Foxp3(EGFP) mice but not in Foxp3(EGFP) mice on a PAF-R-deficient background. Finally, regulatory T cell depletion via anti-CD25 Abs blocked CS-mediated inhibition of CHS, indicating the potential involvement of regulatory T cells in CS-mediated systemic immunosuppression. These studies provide the first evidence, to our knowledge, that the pro-oxidative stressor CS can modulate cutaneous immunity via the generation of PAF-R agonists produced through lipid oxidation. PMID:23355733

Sahu, Ravi P; Petrache, Irina; Van Demark, Mary J; Rashid, Badri M; Ocana, Jesus A; Tang, Yuxuan; Yi, Qiaofang; Turner, Matthew J; Konger, Raymond L; Travers, Jeffrey B

2013-01-25

41

Platelet-activating Factor Receptor Agonists Mediate Xeroderma Pigmentosum A Photosensitivity*  

PubMed Central

To date, oxidized glycerophosphocholines (Ox-GPCs) with platelet-activating factor (PAF) activity produced non-enzymatically have not been definitively demonstrated to mediate any known disease processes. Here we provide evidence that these Ox-GPCs play a pivotal role in the photosensitivity associated with the deficiency of the DNA repair protein xeroderma pigmentosum type A (XPA). It should be noted that XPA-deficient cells are known to have decreased antioxidant defenses. These studies demonstrate that treatment of human XPA-deficient fibroblasts with the pro-oxidative stressor ultraviolet B (UVB) radiation resulted in increased reactive oxygen species and PAF receptor (PAF-R) agonistic activity in comparison with gene-corrected cells. The UVB irradiation-generated PAF-R agonists were inhibited by antioxidants. UVB irradiation of XPA-deficient (Xpa?/?) mice also resulted in increased PAF-R agonistic activity and skin inflammation in comparison with control mice. The increased UVB irradiation-mediated skin inflammation and TNF-? production in Xpa?/? mice were blocked by systemic antioxidants and by PAF-R antagonists. Structural characterization of PAF-R-stimulating activity in UVB-irradiated XPA-deficient fibroblasts using mass spectrometry revealed increased levels of sn-2 short-chain Ox-GPCs along with native PAF. These studies support a critical role for PAF-R agonistic Ox-GPCs in the pathophysiology of XPA photosensitivity.

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

2012-01-01

42

Indole alkoloids from Nauclea officinalis with weak antimalarial activity.  

PubMed

Five indole alkaloids (naucleofficines A-E) were isolated from the stems (with bark) of Nauclea officinalis: (E)-2-(1-beta-d-glucopyranosyloxybut-2-en-2-yl)-3-(hydroxymethyl)-6,7-dihydro-indolo[2,3-a]quinolizin-4(12H)-one (1), (E)-1-propenyl-12-beta-d-glucopyranosyloxy-2,7,8-trihydro-indolo[2,3-a]pyran[3,4-g]quinolizin-4,5(13H)-dione (2), (E)-2-(1-hydroxybut-2-en-2-yl)-11-beta-d-glucopyranosyloxy-6,7-dihydro-indolo[2,3-a]quinolizin-4(12H)-one (3), (E)-1-propenyl-4-hydroxy-2,4a,7,8,13b,14,14a-hepthydro-(4alpha,4abeta,13balpha,14abeta)indolo[2,3-a]pyran[3,4-g]quinolizin-5(13H)-one (4) and 1-(1-hydroxyethyl)-10-hydroxy-7,8-dihydro-indolo[2,3-a]pirydine[3,4-g]quinolizin-5(13H)-one (10-hydroxyangustoline) (5), together with two known compounds, naucleidinal (6) and angustoline (7). All of the structures of the seven compounds above were elucidated by spectroscopic methods including use of 1D- and 2D-NMR spectroscopic analyses. Compounds 2 and 3 are rare examples of monoterpene indole alkaloids with a glucopyranosyloxy group attached to position C-12. In vitro activity screening of the above seven compounds showed weak to moderate inhibitory activity against Plasmodium falciparum. PMID:18328515

Sun, Jingyong; Lou, Hongxiang; Dai, Shengjun; Xu, Hui; Zhao, Feng; Liu, Ke

2008-03-06

43

Expression of bax in lung cancer cell apoptosis induced by peroxisome proliferator-activated receptor-? agonists  

Microsoft Academic Search

Objective  To discuss the relationship between Bax expression level and lung cancer cell apoptosis induced by peroxisome proliferator-activated\\u000a receptor-? (PPAR-?) agonists.\\u000a \\u000a \\u000a \\u000a Methods  RT-PCR and Western blot analysis were used to detect PPAR-? expression in the lung cancer cells, and TUNEL was used to detect\\u000a apoptosis induced by PPAR-? agonists, while in situ hybridization and immunohistochemistry were used to monitor the changes\\u000a of

Zhang Min; Zou Ping; Bai Ming; Jin Yang; Guo Rong; Tao Xiaolan; He Wei

2002-01-01

44

Chemical communication in scarab beetles: reciprocal behavioral agonist-antagonist activities of chiral pheromones.  

PubMed Central

A novel mechanism of reciprocal behavioral agonist-antagonist activities of enantiomeric pheromones plays a pivotal role in overcoming the signal-to-noise problem derived from the use of a single-constituent pheromone system in scarab beetles. Female Anomala osakana produce (S, Z)-5-(+)-(1-decenyl)oxacyclopentan-2-one, which is highly attractive to males; the response is completely inhibited even by 5% of its antipode. These two enantiomers have reverse roles in the Popillia japonica sex pheromone system. Chiral GC-electroantennographic detector experiments suggest that A. osakana and P. japonica have both R and S receptors that are responsible for behavioral agonist and antagonist responses.

Leal, W S

1996-01-01

45

Peroxisome Proliferator-Activated Receptor Agonists: Do They Increase Cardiovascular Risk?  

PubMed Central

Cardiovascular disease is a major cause of morbidity and mortality among people with type 2 diabetes mellitus. The peroxisome proliferator-activated receptor (PPAR) agonists have a significant role on glucose and fat metabolism. Thiazolidinediones (TZDs) are predominantly PPAR? agonists, and their primary benefit appears to be the prevention of diabetic complications by improving glycemic control and lipid profile. Recently, the cardiovascular safety of rosiglitazone was brought to center stage following meta analyses and the interim analysis of the RECORD trial. Current evidence points to rosiglitazone having a greater risk of myocardial ischemic events than placebo, metformin, or sulfonylureas. This review article discusses the mechanism of action of PPAR agonists and correlates it with clinical and laboratory outcomes in the published literature. In addition, this review article attempts to discuss some of the molecular mechanisms regarding the association between TZDs therapy and the nontraditional cardiovascular risks.

Aljada, Ahmad; Shah, Kshitij Ashwin; Mousa, Shaker A.

2009-01-01

46

Novel benzodifuran analogs as potent 5-HT2A receptor agonists with ocular hypotensive activity.  

PubMed

A series of 8-substituted benzodifuran analogs was prepared and evaluated for 5-HT(2A) receptor binding and activation. Several compounds containing ether and ester functionality were found to be potent agonists. Topical ocular administration of 5, 18, and 25 effectively reduced intra-ocular pressure in the hypertensive cynomolgus monkey eye in the range of 25-37%. PMID:17419053

Feng, Zixia; Mohapatra, Suchismita; Klimko, Peter G; Hellberg, Mark R; May, Jesse A; Kelly, Curtis; Williams, Gary; McLaughlin, Marsha A; Sharif, Najam A

2007-03-25

47

Structure-activity relationships of xanthocillin derivatives as thrombopoietin receptor agonist.  

PubMed

Xanthocillin derivatives, which show thrombopoietin receptor agonist activity, were synthesized through our developed method. Bioassay data suggest the importance of alkene geometry, the presence of substituents at the benzene ring that support hydrophobic character, and the moderate size of the molecule. One of the two isonitrile group of the natural product appears to be dispensable. PMID:17256473

Yamaguchi, Takahiro; Miyake, Yumi; Miyamura, Atsushi; Ishiwata, Norihisa; Tatsuta, Kuniaki

2006-11-01

48

Peroxisome Proliferator-Activated Receptor Gamma Agonists in Kidney Disease – Future Promise, Present Fears  

Microsoft Academic Search

The peroxisome proliferator-activated receptor superfamily (PPARs) comprises a class of nuclear receptors with significant effects in regulating multiple cellular pathways. Much research and clinical interest has surrounded the PPAR-? isoform because of its key role in the transcriptional regulation of metabolic pathways and the efficacy of thiazolidinediones, the most clinically used PPAR-? agonist, in the management of type 2 diabetes

Zhiguo Mao; Albert C. M. Ong

2009-01-01

49

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

PubMed Central

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

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

2006-01-01

50

Ah receptor agonist activity in frequently consumed food items  

Microsoft Academic Search

The aryl hydrocarbon receptor (AhR) receives much attention for its role in the toxicity of dioxins and dioxin-like polychlorinated biphenyls. However, many other compounds have also been reported to bind and activate AhR, of which natural food components are of special interest from a human health perspective. Using the dioxin receptor–chemical-activated luciferase gene expression (DR CALUX®) bioassay, extracts from many

W. J. De Waard; J. M. M. J. G. Aarts; A. A. C. M. Peijnenburg; T. M. C. M. De Kok; F.-J. Van Schooten; L. A. P. Hoogenboom

2008-01-01

51

Structural requirement for the agonist activity of the TLR2 ligand Pam2Cys  

Microsoft Academic Search

Synthetic lipopeptides have demonstrated great potential as a vaccine strategy for eliciting cellular and humoral immunity.\\u000a One of the most potent lipid moieties used is S-[2,3-bis(palmitoyloxy)propyl]cysteine (Pam2Cys). Pam2Cys binds to and activates dendritic cells by engagement of Toll like\\u000a receptor 2 (TLR 2). In this study, we have investigated the structural requirement of the agonist activity of Pam2Cys by varying

Weiguang Zeng; Emily Eriksson; Brendon Chua; Lara Grollo; David C. Jackson

2010-01-01

52

Agonist-independent inactivation and agonist-induced desensitization of the G protein-activated K + channel (GIRK) in Xenopus oocytes  

Microsoft Academic Search

The G-protein-activated K+ channels of the GIRK (Kir 3) family are activated by G?? subunits of heterotrimeric Gi\\/Go proteins. Atrial GIRK currents evoked by acetylcholine (ACh)1 via muscarinic m2 receptors (m2R) display prominent desensitization. We studied desensitization of basal and ACh-evoked whole-cell\\u000a GIRK currents in Xenopus oocytes. In the absence of receptor and\\/or agonist, the basal GIRK activity showed inactivation

Dmitry Vorobiov; G. Levin; Ilana Lotan; N. Dascal

1998-01-01

53

Peroxisomal Proliferator-Activated Receptor  Agonists Induce Partial Reversion of Epithelial-Mesenchymal Transition in Anaplastic Thyroid Cancer Cells  

Microsoft Academic Search

Anaplastic thyroid cancer (ATC) is an extremely aggressive tumor characterized by marked epithelial mesenchymal tran- sition, which leads, almost invariably, to death. Peroxisomal proliferator-activated receptor (PPAR)- agonists have re- centlyemergedaspotentialantineoplasticdrugs.Toestablish whether ATC could be a target of PPAR agonists, we first examined PPAR protein expression in a panel of six ATC cell lines and then studied the biologic effects of

Aurora Aiello; Giuseppe Pandini; Francesco Frasca; Enrico Conte; Antonella Murabito; Antonella Sacco; Marco Genua; Riccardo Vigneri; Antonino Belfiore

2006-01-01

54

Differential activation of catalase expression and activity by PPAR agonists: Implications for astrocyte protection in anti-glioma therapy?  

PubMed Central

Glioma survival is dismal, in part, due to an imbalance in antioxidant expression and activity. Peroxisome proliferator-activated receptor (PPAR) agonists have antineoplastic properties which present new redox-dependent targets for glioma anticancer therapies. Herein, we demonstrate that treatment of primary cultures of normal rat astrocytes with PPAR agonists increased the expression of catalase mRNA protein, and enzymatic activity. In contrast, these same agonists had no effect on catalase expression and activity in malignant rat glioma cells. The increase in steady-state catalase mRNA observed in normal rat astrocytes was due, in part, to de novo mRNA synthesis as opposed to increased catalase mRNA stability. Moreover, pioglitazone-mediated induction of catalase activity in normal rat astrocytes was completely blocked by transfection with a PPAR?-dominant negative plasmid. These data suggest that defects in PPAR-mediated signaling and gene expression may represent a block to normal catalase expression and induction in malignant glioma. The ability of PPAR agonists to differentially increase catalase expression and activity in normal astrocytes but not glioma cells suggests that these compounds might represent novel adjuvant therapeutic agents for the treatment of gliomas.

Khoo, Nicholas K.H.; Hebbar, Sachin; Zhao, Weiling; Moore, Steven A.; Domann, Frederick E.; Robbins, Mike E.

2013-01-01

55

Differential activation of catalase expression and activity by PPAR agonists: Implications for astrocyte protection in anti-glioma therapy.  

PubMed

Glioma survival is dismal, in part, due to an imbalance in antioxidant expression and activity. Peroxisome proliferator-activated receptor (PPAR) agonists have antineoplastic properties which present new redox-dependent targets for glioma anticancer therapies. Herein, we demonstrate that treatment of primary cultures of normal rat astrocytes with PPAR agonists increased the expression of catalase mRNA protein, and enzymatic activity. In contrast, these same agonists had no effect on catalase expression and activity in malignant rat glioma cells. The increase in steady-state catalase mRNA observed in normal rat astrocytes was due, in part, to de novo mRNA synthesis as opposed to increased catalase mRNA stability. Moreover, pioglitazone-mediated induction of catalase activity in normal rat astrocytes was completely blocked by transfection with a PPAR?-dominant negative plasmid. These data suggest that defects in PPAR-mediated signaling and gene expression may represent a block to normal catalase expression and induction in malignant glioma. The ability of PPAR agonists to differentially increase catalase expression and activity in normal astrocytes but not glioma cells suggests that these compounds might represent novel adjuvant therapeutic agents for the treatment of gliomas. PMID:24024139

Khoo, Nicholas K H; Hebbar, Sachin; Zhao, Weiling; Moore, Steven A; Domann, Frederick E; Robbins, Mike E

2013-01-26

56

Balaglitazone: a second generation peroxisome proliferator-activated receptor (PPAR) gamma (?) agonist.  

PubMed

Balaglitazone (DRF-2593) is a novel partial agonist of PPAR-gamma (?), which is developed by Dr. Reddy's laboratories India. Balaglitazone is a second generation peroxisome proliferator-activated receptor (PPAR) gamma agonist with only partial agonistic properties. Balaglitazone is currently being evaluated in phase III clinical trial in United States and Europe. Selective PPAR-? modulators bind in distinct manners to the ligand-binding pocket of PPAR-?, leading to alternative receptor conformations, differential cofactor recruitment/displacement, differential gene expression, and ultimately differential biological responses. Based on this concept, new and improved novel antidiabetic agents are in current development. Clinical studies conducted with 409 subjects of randomized, double blind, parallel-group placebo and active comparator-controlled subject groups to determine the efficacy and safety of Balaglitazone. The study showed that the trial met its primary endpoint. Balaglitazone treated groups shown significantly reduce of HbA1c (%), FSG (mmol/L), postprandial glucose as comparison to pioglitazone. Phase III clinical studies data clearly shows that Balaglitazone provides robust glycemic control as an add-on to insulin therapy. Balaglitazone 10 mg and 20 mg show the similar magnitudes of the effects which comparable to the effects seen in the pioglitazone 45 mg group. The incidence of fluid retention and fat accumulation fewer than those observed with pioglitazone 45 mg. Hence, Balaglitazone is prominent candidate of new glitazone which requires fewer doses as comparison pioglitazone and shows better safety profile less incidence of special adverse effect like heart failure, peripheral oedema, and myocardial infarction. Unlike other marketed PPAR gamma agonists, Balaglitazone shows less fluid retention, less heart enlargement and no reduction of bone formation than full PPAR gamma agonists in preclinical studies. In present review, we have tried to cover classification PPARs various ligands, chemistry, physical properties, commercial synthesis, current patent status, polymorphic information, receptor interaction, pharmacophore rational, mechanism, adverse effect and clinical status of Balaglitazone, giving emphasis on medicinal chemistry aspect. PMID:22372600

Agrawal, R; Jain, P; Dikshit, S N

2012-02-01

57

Design and synthesis of benzoxazole containing indole analogs as peroxisome proliferator-activated receptor-?/? dual agonists.  

PubMed

A series of benzoxazole or benzothiazole containing indole analogs, 6-alkoxyindole-2-carboxylic acids and 5-alkoxy-3-indolylacetic acids, were synthesized as novel candidates of PPAR?/? dual agonists and their ligand activities for PPAR subtypes (?, ?, and ?) were investigated. In transient transactivation assay, several compounds activated PPAR? and ? with little activity of PPAR?. Putative binding mode of the compounds 1a and 2a in the active site of PPAR? was similar with that of rosiglitazone and the molecular modeling provides molecular insight to the observed activity. PMID:21482466

Gim, Hyo Jin; Cheon, Ye-Jin; Ryu, Jae-Ha; Jeon, Raok

2011-03-24

58

Agonist-induced activation of rat mesenteric resistance vessels: comparison between noradrenaline and vasopressin  

SciTech Connect

The effects of noradrenaline (NA, 10(-5) M) and (arginine8)vasopressin (AVP, 10(-7) M) on tension in Ca2+-free medium and on membrane potential, and the inhibition of NA- and AVP-induced contractions by isradipine, have been compared in mesenteric resistance vessels (MRVs) from Wistar-Kyoto (WKY) rats. The release of intracellular Ca2+ by AVP contributed significantly less to its tension development than does that by NA. Nonetheless, the concentration-response curves for inhibition by isradipine of NA- and AVP-induced tonic tension were nearly identical. Similarly, these two agonists produced the same degree of membrane depolarization. In addition, both agonists were able to stimulate large contractions in vessels previously depolarized by 80 mM K+. AVP also stimulated /sup 45/Ca influx into rat cultured aortic smooth muscle cells. In contrast to the stimulation of /sup 45/Ca influx by KCl depolarization, the agonist-stimulated /sup 45/Ca influx was insensitive to inhibition by organic Ca2+ antagonists. It is concluded that Ca2+ entry through receptor-operated Ca2+-permeable channels (ROCs) may contribute to agonist-induced activation of rat aortic and MRV smooth muscle.

Cauvin, C.; Weir, S.W.; Wallnoefer, A.R.; Rueegg, U.P.

1988-01-01

59

Agonist-independent GPCR activity regulates anterior-posterior targeting of olfactory sensory neurons.  

PubMed

G-protein-coupled receptors (GPCRs) are known to possess two different conformations, active and inactive, and they spontaneously alternate between the two in the absence of ligands. Here, we analyzed the agonist-independent GPCR activity for its possible role in receptor-instructed axonal projection. We generated transgenic mice expressing activity mutants of the ?2-adrenergic receptor, a well-characterized GPCR with the highest homology to odorant receptors (ORs). We found that mutants with altered agonist-independent activity changed the transcription levels of axon-targeting molecules--e.g., Neuropilin-1 and Plexin-A1--but not of glomerular segregation molecules--e.g., Kirrel2 and Kirrel3--thus causing shifts in glomerular locations along the anterior-posterior (A-P) axis. Knockout and in vitro experiments demonstrated that Gs, but not Golf, is responsible for mediating the agonist-independent GPCR activity. We conclude that the equilibrium of conformational transitions set by each OR is the major determinant of expression levels of A-P-targeting molecules. PMID:24034253

Nakashima, Ai; Takeuchi, Haruki; Imai, Takeshi; Saito, Harumi; Kiyonari, Hiroshi; Abe, Takaya; Chen, Min; Weinstein, Lee S; Yu, C Ron; Storm, Daniel R; Nishizumi, Hirofumi; Sakano, Hitoshi

2013-09-12

60

Activation of carbonic anhydrase by beta-adrenergic agonists and inhibition by beta-adrenergic blockers.  

PubMed

Knowing the in vitro and in vivo gastric secretory effects of beta-adrenergic agonists and antagonists, as well as the role of carbonic anhydrase in the gastric HCl production, we investigated the effect of some beta-adrenoceptor agonists (isoprenaline and orciprenaline) and antagonists (propranolol, timolol, atenolol, pindolol, acebutolol, metoprolol, exoxprenolol) on the purified, human red blood cell and gastric mucosa carbonic anhydrase. All the drugs were added to enzymatic preparations in a concentration range of 10(-7)-10(-3) M, the enzymatic activity being determined according to Maren's micro-method. Dose-response relationships were plotted for each drug. The activating effect of the beta-adrenergic agonists isoprenaline and orciprenaline on all the three species of carbonic anhydrase was dose-dependent, maximum effect being reached at 10(-3) M, when a highly significant (p less than 0.001) enzymatic activation was achieved. Beta-adrenergic blocking drugs decreased significantly the activity of carbonic anhydrase, thus, the activity of purified enzyme decreased with propranolol depending on the dose from 2140 +/- 68 to 1060 +/- 82 I.U. (p less than 0.001), that of red blood cell enzyme from 3340 +/- 280 to 1050 +/- 180 I.U. (p less than 0.001) and that of gastric mucosa enzyme from 2.1 +/- 0.2 to 1.1 +/- 0.1 E.U./mg bioptic sample. They also antagonized dose-dependently the activating effect of beta-adrenergic agonists on the enzyme. The results suggest that carbonic anhydrase might be one of the sites of beta-adrenoceptors, further studies using specific radioligands being necessary to elucidate whether these effects represent the interaction of these drugs with their specific receptor or if they are unspecific pharmacologic effects. PMID:2864736

Pu?cas, I; Reznicek, A; Moldovan, A; Pu?ca?, C; Sturzu, L

61

Orally Active Adenosine A1 Receptor Agonists with Antinociceptive Effects in Mice  

PubMed Central

Adenosine A1 receptor (A1AR) agonists have antinociceptive effects in multiple preclinical models of acute and chronic pain. Although numerous A1AR agonists have been developed, clinical applications of these agents have been hampered by their cardiovascular side effects. Herein we report a series of novel A1AR agonists, some of which are structurally related to adenosine 5?-monophosphate (5?-AMP), a naturally occurring nucleotide that itself activates A1AR. These novel compounds potently activate A1AR in several orthogonal in vitro assays and are subtype selective for A1AR over A2AAR, A2BAR, and A3AR. Among them, UNC32A (3a) is orally active and has dose-dependent antinociceptive effects in wild-type mice. The antinociceptive effects of 3a were completely abolished in A1AR knockout mice, revealing a strict dependence on A1AR for activity. The apparent lack of cardiovascular side effects when administered orally and high affinity (Ki of 36 nM for the human A1AR) make this compound potentially suitable as a therapeutic.

Korboukh, Ilia; Hull-Ryde, Emily A.; Rittiner, Joseph E.; Randhawa, Amarjit S.; Coleman, Jennifer; Fitzpatrick, Brendan J.; Setola, Vincent; Janzen, William P.; Frye, Stephen V.; Zylka, Mark J.; Jin, Jian

2012-01-01

62

Pharmacological profile of AS1670542, a novel orally-active human thrombopoietin receptor agonist.  

PubMed

Eltrombopag, an orally-active small molecule thrombopoietin (TPO) receptor agonist, was used for the first time in 2008 to treat patients with chronic idiopathic thrombocytopenic purpura. Here, we investigated the pharmacological effect of a new orally-active small molecule TPO receptor agonist which may be effective in treating these patients. 50% effective concentration values for cell proliferation with AS1670542 or eltrombopag were 1.9 and 13nM, respectively, while those for megakaryocyte colony formation from human cord blood CD34(+) cells with AS1670542 or eltrombopag were 260 and 950nM, respectively. On Day 14 after the start of administration, AS1670542 significantly increased the number of human platelets in non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice with transplanted human hematopoietic stem cells at 0.3 (P<0.05); in contrast, while administration of eltrombopag also increased the numbers of these platelets at 30mg/kg/day (P=0.058), no statistical significance was noted in the increase. Here, we identified AS1670542, a novel orally-active TPO receptor agonist which mimics the biological activity of TPO and may demonstrate greater in vitro and in vivo pharmacologically efficacy than eltrombopag. PMID:20950606

Abe, Masaki; Suzuki, Ken-Ichi; Sakata, Chinatsu; Sugasawa, Keizo; Hirayama, Fukushi; Koga, Yuji; Kawasaki, Tomihisa; Naganuma, Shin; Itoh, Hiroyuki

2010-10-13

63

Structure-activity relationships in toll-like receptor 2-agonists leading to simplified monoacyl lipopeptides.  

PubMed

Toll-like receptor 2-agonistic lipopeptides typified by S-[2,3-bis(palmitoyloxy)-(2RS)-propyl]-R-cysteinyl-S-serine (PAM(2)CS) compounds are potential vaccine adjuvants. In continuation of previously reported structure-activity relationships on this chemotype, we have determined that at least one acyl group of optimal length (C(16)) and an appropriately oriented ester carbonyl group is essential for TLR2-agonistic activity. The spacing between one of the palmitoyl ester carbonyl and the thioether is crucial to allow for an important H-bond, which observed in the crystal structure of the lipopeptide:TLR2 complex; consequently, activity is lost in homologated compounds. Penicillamine-derived analogues are also inactive, likely due to unfavorable steric interactions with the carbonyl of Ser 12 in TLR2. The thioether in this chemotype can be replaced with a selenoether. Importantly, the thioglycerol motif can be dispensed with altogether and can be replaced with a thioethanol bridge. These results have led to a structurally simpler, synthetically more accessible, and water-soluble analogue possessing strong TLR2-agonistic activities in human blood. PMID:22007676

Agnihotri, Geetanjali; Crall, Breanna M; Lewis, Tyler C; Day, Timothy P; Balakrishna, Rajalakshmi; Warshakoon, Hemamali J; Malladi, Subbalakshmi S; David, Sunil A

2011-11-04

64

Isoflavone agonists of IRF-3 dependent signaling have antiviral activity against RNA viruses.  

PubMed

There is a growing need for novel antiviral therapies that are broad spectrum, effective, and not subject to resistance due to viral mutations. Using high-throughput screening methods, including computational docking studies and an interferon-stimulated gene 54 (ISG54)-luciferase reporter assay, we identified a class of isoflavone compounds that act as specific agonists of innate immune signaling pathways and cause activation of the interferon regulatory factor (IRF-3) transcription factor. The isoflavone compounds activated the ISG54 promoter, mediated nuclear translocation of IRF-3, and displayed highly potent activity against hepatitis C virus (HCV) and influenza virus. Additionally, these agonists efficiently activated IRF-3 in the presence of the HCV protease NS3-4A, which is known to blunt the host immune response. Furthermore, genomic studies showed that discrete innate immune pathways centered on IRF signaling were regulated following agonist treatment without causing global changes in host gene expression. Following treatment, the expression of only 64 cellular genes was significantly induced. This report provides the first evidence that innate immune pathways dependent on IRF-3 can be successfully targeted by small-molecule drugs for the development of novel broad-spectrum antiviral compounds. PMID:22532686

Bedard, Kristin M; Wang, Myra L; Proll, Sean C; Loo, Yueh-Ming; Katze, Michael G; Gale, Michael; Iadonato, Shawn P

2012-04-24

65

Structure-Activity Relationships in Toll-like Receptor 2-Agonists Leading to Simplified Monoacyl Lipopeptides  

PubMed Central

Toll-like receptor 2-agonistic lipopeptides typified by S-[2,3-bis(palmitoyloxy)-(2RS)-propyl]-R-cysteinyl-S-serine (PAM2CS) compounds are potential vaccine adjuvants. In continuation of previously reported structure-activity relationships on this chemotype, we have determined that at least one acyl group of optimal length (C16) and an appropriately orientated ester carbonyl group is essential for TLR2-agonistic activity. The spacing between one of the palmitoyl ester carbonyl and the thioether is crucial to allow for an important H-bond, which observed in the crystal structure of the lipopeptide:TLR2 complex; consequently, activity is lost in homologated compounds. Penicillamine-derived analogues are also inactive, likely due to unfavorable steric interactions with the carbonyl of Ser 12 in TLR2. The thioether in this chemotype can be replaced with a selenoether. Importantly, the thioglycerol motif can be dispensed with altogether, and can be replaced with a thioethanol bridge. These results have led to a structurally simpler, synthetically more accessible, and water-soluble analogue possessing strong TLR2-agonistic activities in human blood.

Agnihotri, Geetanjali; Crall, Breanna M.; Lewis, Tyler C.; Day, Timothy P.; Balakrishna, Rajalakshmi; Warshakoon, Hemamali J.; Malladi, Subbalakshmi S.; David, Sunil A.

2011-01-01

66

Liver X Receptor and Peroxisome Proliferator-Activated Receptor Agonist from Cornus alternifolia  

PubMed Central

Background Peroxisome proliferator-activated receptors (PPARs) belong to the nuclear receptors superfamily and are transcription factors activated by specific ligands. Liver X receptors (LXR) belong to the nuclear hormone receptors and have been shown to play an important role in cholesterol homeostasis. From the previous screening of several medicinal plants for potential partial PPAR? agonists, the extracts of Cornus alternifolia were found to exhibit promising bioactivity. In this paper, we report the isolation and structural elucidation of four new compounds and their potential as ligands for PPAR. Methods The new compounds were extracted from the leaves of Cornus alternifolia and fractionated by high-performance liquid chromatography. Their structures were elucidated on the basis of spectroscopic evidence and analysis of their hydrolysis products. Results Three new iridoid glycosides including an iridolactone, alternosides A-C (1–3), a new megastigmane glycoside, cornalternoside (4) and 10 known compounds, were obtained from the leaves of Cornus alternifolia. Kaempferol-3-O-?-glucopyranoside (5) exhibited potent agonistic activities for PPAR?, PPAR? and LXR with EC50 values of 0.62, 3.0 and 1.8 ? M, respectively. Conclusions We isolated four new and ten known compounds from Cornus alternifolia, and one known compound showed agonistic activities for PPAR?, PPAR? and LXR. General significance Compound 1 is the first example of a naturally occurring iridoid glycoside containing a ?-glucopyranoside moiety at C-6.

He, Yang-Qing; Ma, Guo-Yi; Peng, Jiang-nan; Ma, Zhan-Ying; Hamann, Mark T.

2012-01-01

67

Lanthanide labeling of a potent protease activated receptor-2 agonist for time-resolved fluorescence analysis  

PubMed Central

Protease activated receptor-2 (PAR2) is one of four G-protein coupled receptors (GPCRs) that can be activated by exogenous or endogenous proteases, which cleave the extracellular amino-terminus to expose a tethered ligand and subsequent G-protein signaling. Alternatively, PAR2 can be activated by peptide or peptidomimetic ligands derived from the sequence of the natural tethered ligand. Screening of novel ligands that directly bind to PAR2 to agonize or antagonize the receptor has been hindered by the lack of a sensitive, high-throughput, affinity binding assay. In this report we describe the synthesis and use of a modified PAR2 peptidomimetic agonist, 2-furoyl-LIGRLO-(diethylenetriaminepentaacetic acid)-NH2 (2-f-LIGRLO-dtpa), designed for lanthanide-based time resolved fluorescence screening. We first demonstrate that 2-f-LIGRLO-dtpa is a potent and specific PAR2 agonist across a full spectrum of in vitro assays. We then show that 2-f-LIGRLO-dtpa can be utilized in an affinity binding assay to evaluate the ligand-receptor interactions between known high potency peptidomimetic agonists (2-furoyl-LIGRLO-NH2, 2-f-LIGRLO; 2-aminothiazol-4-yl-LIGRL-NH2, 2-at-LIGRL and; 6-aminonicotinyl-LIGRL-NH2, 6-an-LIGRL) and PAR2. A separate N-terminal peptidomimetic modification (3-indoleacetyl-LIGRL-NH2, 3-ia-LIGRL) that does not activate PAR2 signaling was used as a negative control. All three peptidomimetic agonists demonstrated sigmoidal competitive binding curves, with the more potent agonists (2-f-LIGRLO and 2-at-LIGRL) displaying increased competition. In contrast, the control peptide (3-ia-LIGRL) displayed limited competition for PAR2 binding. In summary, we have developed a Europium-containing PAR2 agonist that can be used in a highly sensitive affinity binding assay to screen novel PAR2 ligands in a high-throughput format. This ligand can serve as a critical tool in the screening and development of PAR2 ligands.

Hoffman, Justin; Flynn, Andrea N.; Tillu, Dipti V.; Zhang, Zhenyu; Patek, Renata; Price, Theodore J.; Vagner, Josef; Boitano, Scott

2012-01-01

68

The discovery of novel isoflavone pan peroxisome proliferator-activated receptor agonists.  

PubMed

Twenty three dual PPAR? and ? molecules of natural product origin, previously reported by our group, were further investigated for pan PPAR transactivation against PPAR?. The in vitro cell toxicity profile, as well as, in silico study of the most active molecules within this new class of pan PPAR agonists are also described. 3',5' Dimethoxy-7 hydroxyisoflavone 6, ?-baptigenin 7, 4' fluoro-7 hydroxyisoflavone 8, and 3' methoxy-7 hydroxyisoflavone 9 were identified as the most potent molecules studied within the set compared to the commercially available pan PPAR agonist, bezafibrate 1. These novel active molecules may thus be useful as future leads in PPAR-related disorders, including type II diabetes mellitus and metabolic syndrome. PMID:23265844

Matin, Azadeh; Doddareddy, Munikumar Reddy; Gavande, Navnath; Nammi, Srinivas; Groundwater, Paul W; Roubin, Rebecca H; Hibbs, David E

2012-12-03

69

Dopamine receptor agonistic and antagonistic effects of 3PPP enantiomers  

Microsoft Academic Search

The pharmacological profile of the enantiomers of the proposed selective dopamine (DA) autoreceptor agonist 3-PPP [3-(3-hydroxyphenyl)-N-n-propylpiperidine] has been studied. In vitro both enantiomers showed weak DA agonistic activity, and (-)-3-PPP some DA antagonistic effect on DA-stimulated adenylate cyclase activity. Both enantiomers in low doses had a similar profile in vivo: Inhibition of locomotor activity of mice and rats, induction of

J. Arnt; K. P. Bøgesø; A. V. Christensen; J. Hyttel; J.-J. Larsen; O. Svendsen

1983-01-01

70

Different neural mechanisms underlie dizocilpine maleate- and dopamine agonist-induced locomotor activity  

Microsoft Academic Search

This study evaluated and compared the role of mesoaccumbens dopamine and the ventral pallidal region in the locomotor stimulatory action of the non-competitive N-methyl-d-aspartate antagonist dizocilpine maleate and dopamine agonists. Intra-accumbens injections of both amphetamine (1, 5 and 25nmol) and dizocilpine maleate (1, 5, 25 and 50nmol) induced a dose-dependent increase in locomotor activity. The N-methyl-d-aspartate antagonist was somewhat less

A Mele; D. N Thomas; A Pert

1997-01-01

71

Antioxidative, Antinitrative, and Vasculoprotective Effects of a Peroxisome Proliferator-Activated Receptor  Agonist in Hypercholesterolemia  

Microsoft Academic Search

Background—Peroxisome proliferator-activated receptor (PPAR) signaling pathways have been reported to exert anti-inflammatory effects and attenuate atherosclerosis formation. However, the mechanisms responsible for their anti-inflammatory and antiatherosclerotic effects remain largely unknown. The present study tested the hypothesis that a PPAR agonist may exert significant endothelial protection by antioxidative and antinitrative effects. Methods and Results—Male New Zealand White rabbits were randomized to

Ling Tao; Hui-Rong Liu; Erhe Gao; Zhi-Ping Teng; Bernard L. Lopez; Theodore A. Christopher; Xin-Liang Ma; Ines Batinic-Haberle; Robert N. Willette; Eliot H. Ohlstein; Tian-Li Yue

2003-01-01

72

Peroxisome Proliferator-Activated Receptor-? Agonist Rosiglitazone Prevents Albuminuria but Not Glomerulosclerosis in Experimental Diabetes  

Microsoft Academic Search

Backgrounds\\/Aims:Renal inflammation and nephrin downregulation contribute to albuminuria in diabetes. We studied, in streptozotocin-induced diabetic rats, the effect of rosiglitazone (RSG), a peroxisome proliferator-activated receptor-? agonist, on renal macrophage infiltration, MCP1, and nephrin expression in relation to albuminuria. Methods: We investigated control and diabetic rats treated or untreated with RSG. Animals were sacrificed at 1, 3, and 9 months. Renal

Giorgia Setti; Anthea Hayward; Cecile Dessapt; Francesca Barone; Robin Buckingham; Kathryn White; Rudolf Bilous; Kawachi Hiroshi; Gabriella Gruden; GianCarlo Viberti; Luigi Gnudi

2010-01-01

73

Design, synthesis and structure–activity relationships of azole acids as novel, potent dual PPAR ?\\/? agonists  

Microsoft Academic Search

The design, synthesis and structure–activity relationships of a novel series of N-phenyl-substituted pyrrole, 1,2-pyrazole and 1,2,3-triazole acid analogs as PPAR ligands are outlined. The triazole acid analogs 3f and 4f were identified as potent dual PPAR?\\/? agonists both in binding and functional assays in vitro. The 3-oxybenzyl triazole acetic acid analog 3f showed excellent glucose and triglyceride lowering in diabetic

Hao Zhang; Denis E. Ryono; Pratik Devasthale; Wei Wang; Kevin O’Malley; Dennis Farrelly; Liqun Gu; Thomas Harrity; Michael Cap; Cuixia Chu; Kenneth Locke; Litao Zhang; Jonathan Lippy; Lori Kunselman; Nathan Morgan; Neil Flynn; Lisa Moore; Vinayak Hosagrahara; Lisa Zhang; Pathanjali Kadiyala; Carrie Xu; Arthur M. Doweyko; Aneka Bell; Chiehying Chang; Jodi Muckelbauer; Robert Zahler; Narayanan Hariharan; Peter T. W. Cheng

2009-01-01

74

Ultraviolet B radiation generated platelet-activating factor receptor agonist formation involves EGF-R-mediated reactive oxygen species.  

PubMed

Recent studies have implicated the lipid mediator platelet-activating factor (PAF) in UVB-mediated systemic immunosuppression known to be a major cause for skin cancers. Previously, our group has demonstrated that UVB irradiation triggers the production of PAF and oxidized glycerophosphocholines that act as PAF-receptor (PAF-R) agonists. The present studies explored the mechanisms by which UVB generates PAF-R agonists. UVB irradiation of human epidermal KB cells resulted in both increased levels of reactive oxygen species (ROS) and PAF-R agonistic activity. Pretreatment of KB cells with antioxidants vitamin C and N-acetylcysteine or the pharmacological inhibitor PD168393 specific for the epidermal growth factor receptor all inhibited UVB-induced ROS as well as PAF-R agonists, yet had no effect on fMLP-mediated PAF-R agonist production. In addition, in vivo production of PAF-R agonists from UVB-irradiated mouse skin was blocked by both systemic vitamin C administration and topical PD168393 application. Moreover, both vitamin C and PD168393 abolished UVB-mediated but not the PAF-R agonist 1-hexadecyl-2-N-methylcarbamoyl glycerophosphocholine-mediated immunosuppression as measured by the inhibition of delayed type contact hypersensitivity to the chemical dinitrofluorobenzene. These studies suggest that UVB-induced systemic immunosuppression is due to epidermal growth factor receptor-mediated ROS which results in PAF-R agonist formation. PMID:19234179

Yao, Yongxue; Wolverton, Jay E; Zhang, Qiwei; Marathe, Gopal K; Al-Hassani, Mohammed; Konger, Raymond L; Travers, Jeffrey B

2009-03-01

75

The interaction of respiration and visual feedback on the control of force and neural activation of the agonist muscle  

PubMed Central

The purpose of this study was to compare force variability and the neural activation of the agonist muscle during constant isometric contractions at different force levels when the amplitude of respiration and visual feedback were varied. Twenty young adults (20–32 years, 10 men and 10 women) were instructed to accurately match a target force at 15 and 50% of their maximal voluntary contraction (MVC) with abduction of the index finger while controlling their respiration at different amplitudes (85, 100 and 125% normal) in the presence and absence of visual feedback. Each trial lasted 22 s and visual feedback was removed from 8–12 to 16–20 s. Each subject performed 3 trials with each respiratory condition at each force level. Force variability was quantified as the standard deviation of the detrended force data. The neural activation of the first dorsal interosseus (FDI) was measured with bipolar surface electrodes placed distal to the innervation zone. Relative to normal respiration, force variability increased significantly only during high-amplitude respiration (~63%). The increase in force variability from normal- to high-amplitude respiration was strongly associated with amplified force oscillations from 0–3 Hz (R2 ranged from .68 – .84; p < .001). Furthermore, the increase in force variability was exacerbated in the presence of visual feedback at 50% MVC (vision vs. no-vision: .97 vs. .87 N) and was strongly associated with amplified force oscillations from 0–1 Hz (R2 = .82) and weakly associated with greater power from 12–30 Hz (R2 = .24) in the EMG of the agonist muscle. Our findings demonstrate that high-amplitude respiration and visual feedback of force interact and amplify force variability in young adults during moderate levels of effort.

Baweja, Harsimran S.; Patel, Bhavini K.; Neto, Osmar P.; Christou, Evangelos A.

2011-01-01

76

Direct Assessment of Cumulative Aryl Hydrocarbon Receptor Agonist Activity in Sera from Experimentally Exposed Mice and Environmentally Exposed Humans  

PubMed Central

Background Aryl hydrocarbon receptor (AhR) ligands adversely affect many biological processes. However, assessment of the significance of human exposures is hampered by an incomplete understanding of how complex mixtures affect AhR activation/inactivation. Objectives These studies used biological readouts to provide a broader context for estimating human risk than that obtained with serum extraction and gas chromatography/mass spectroscopy (GC/MS)-based assays alone. Methods AhR agonist activity was quantified in sera from dioxin-treated mice, commercial human sources, and polychlorinated biphenyl (PCB)–exposed Faroe Islanders using an AhR-driven reporter cell line. To validate relationships between serum AhR agonist levels and biological outcomes, AhR agonist activity in mouse sera correlated with toxic end points. AhR agonist activity in unmanipulated (“neat”) human sera was compared with these biologically relevant doses and with GC/MS-assayed PCB levels. Results Mouse serum AhR agonist activity correlated with injected dioxin dose, thymic atrophy, and heptomegaly, validating the use of neat serum to assess AhR agonist activity. AhR agonist activity in sera from Faroe Islanders varied widely, was associated with the frequency of recent pilot whale dinners, but did not correlate with levels of PCBs quantified by GC/MS. Surprisingly, significant “baseline” AhR activity was found in commercial human sera. Conclusions An AhR reporter assay revealed cumulative levels of AhR activation potential in neat serum, whereas extraction may preclude detection of important non-dioxin-like biological activity. Significant levels of AhR agonist activity in commercial sera and in Faroe Islander sera, compared with that from experimentally exposed mice, suggest human exposures that are biologically relevant in both populations.

Schlezinger, Jennifer J.; Bernard, Pamela L.; Haas, Amelia; Grandjean, Philippe; Weihe, Pal; Sherr, David H.

2010-01-01

77

Design, Synthesis, and Functional Activity of Labeled CD1d Glycolipid Agonists  

PubMed Central

Invariant natural killer T cells (iNKT cells) are restricted by CD1d molecules and activated upon CD1d-mediated presentation of glycolipids to T cell receptors (TCRs) located on the surface of the cell. Because the cytokine response profile is governed by the structure of the glycolipid, we sought a method for labeling various glycolipids to study their in vivo behavior. The prototypical CD1d agonist, ?-galactosyl ceramide (?-GalCer) 1, instigates a powerful immune response and the generation of a wide range of cytokines when it is presented to iNKT cell TCRs by CD1d molecules. Analysis of crystal structures of the TCR??-GalCer–CD1d ternary complex identified the ?-methylene unit in the fatty acid side chain, and more specifically the pro-S hydrogen at this position, as a site for incorporating a label. We postulated that modifying the glycolipid in this way would exert a minimal impact on the TCR–glycolipid–CD1d ternary complex, allowing the labeled molecule to function as a good mimic for the CD1d agonist under investigation. To test this hypothesis, the synthesis of a biotinylated version of the CD1d agonist threitol ceramide (ThrCer) was targeted. Both diastereoisomers, epimeric at the label tethering site, were prepared, and functional experiments confirmed the importance of substituting the pro-S, and not the pro-R, hydrogen with the label for optimal activity. Significantly, functional experiments revealed that biotinylated ThrCer (S)-10 displayed behavior comparable to that of ThrCer 5 itself and also confirmed that the biotin residue is available for streptavidin and antibiotin antibody recognition. A second CD1d agonist, namely ?-GalCer C20:2 4, was modified in a similar way, this time with a fluorescent label. The labeled ?-GalCer C20:2 analogue (11) again displayed functional behavior comparable to that of its unlabeled substrate, supporting the notion that the ?-methylene unit in the fatty acid amide chain should be a suitable site for attaching a label to a range of CD1d agonists. The flexibility of the synthetic strategy, and late-stage incorporation of the label, opens up the possibility of using this labeling approach to study the in vivo behavior of a wide range of CD1d agonists.

2013-01-01

78

[Activity of motorcycle taxi driver: risks and weaknesses self referred].  

PubMed

Descriptive research, with qualitative approach, that aimed to identify occupational hazards and weaknesses self-reported by motorcycle drivers. Data were collected in the first half of 2010 through interviews with twelve motorcycle drivers, invited to participate and work on two central points of a municipality in the state of Rio Grande do Sul, Brazil. Data were analyzed using thematic analysis, from which emerged five categories. According to subjects' perception, accidents and assaults represent the greatest risks of the profession. It can be inferred that the actions of health education and disease prevention should be governmental and no governmental strategies that would assign value to the health and safety of these workers. PMID:22664603

da Silva, Mariéli Brum; de Oliveira, Michele Braga; Fontana, Rosane Teresinha

79

AGONISTIC ENCOUNTERS AND BRAIN ACTIVATION IN DOMINANT AND SUBORDINATE MALE GREATER LONG-TAILED HAMSTERS  

PubMed Central

During an agonistic encounter test, dominant male greater long-tailed hamsters (Tscheskia triton) initiated attacks sooner and displayed higher levels of aggression and flank marking behavior than their subordinate counterparts. Accordingly, subordinate males exhibited more defensive behavior than dominant ones. Specific patterns of neuronal activation, measured by Fos-immunoreactive staining (Fos-ir), were found in the hamster brain following agonistic interactions. Increased Fos-ir was observed in the bed nucleus of the stria terminalis (BST), ventromedial hypothalamus (VMH), and medial (MeA) and anterior cortical (ACo) nuclei of the amygdala (AMYG) in both dominant and subordinate males. In contrast, dominant males had significantly higher Fos-ir densities in the medial preoptic area (MPOA) than subordinate males, whereas subordinate males expressed higher densities of Fos-ir in the anterior hypothalamus (AH) and central nucleus of the amygdala (CeA). Additionally, Fos-ir levels in the MPOA were significantly correlated with aggression and Fos-ir levels in the AH and CeA were correlated with defensive behavior. Together, our data indicate distinct patterns of neuronal activation associated with agonistic encounters in a behavior-specific manner in male greater long-tailed hamsters.

Pan, Yongliang; Xu, Linxi; Young, Kimberly A.; Wang, Zuoxin; Zhang, Zhibin

2010-01-01

80

Peroxisome proliferator-activated receptor alpha agonists as therapy for autoimmune disease.  

PubMed

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily. PPAR gamma ligands, which include the naturally occurring PG metabolite 15-deoxy-Delta(12,14)-PGJ(2) (15d-PGJ(2)), as well as thiazolidinediones, have been shown to have anti-inflammatory activity. The PPAR alpha agonists, gemfibrozil, ciprofibrate, and fenofibrate, have an excellent track history as oral agents used to treat hypertriglyceridemia. In the present study, we demonstrate that these PPAR alpha agonists can increase the production of the Th2 cytokine, IL-4, and suppress proliferation by TCR transgenic T cells specific for the myelin basic protein Ac1-11, as well as reduce NO production by microglia. Oral administration of gemfibrozil and fenofibrate inhibited clinical signs of experimental autoimmune encephalomyelitis. More importantly, gemfibrozil was shown to shift the cytokine secretion of human T cell lines by inhibiting IFN-gamma and promoting IL-4 secretion. These results suggest that PPAR alpha agonists such as gemfibrozil and fenofibrate, may be attractive candidates for use in human inflammatory conditions such as multiple sclerosis. PMID:15100326

Lovett-Racke, Amy E; Hussain, Rehana Z; Northrop, Sara; Choy, Judy; Rocchini, Anne; Matthes, Lela; Chavis, Janet A; Diab, Asim; Drew, Paul D; Racke, Michael K

2004-05-01

81

De Novo Peptide Design with C3a Receptor Agonist and Antagonist Activities: Theoretical Predictions and Experimental Validation†  

PubMed Central

Targeting the complement component 3a receptor (C3aR) with selective agonists or antagonists is believed to be a viable therapeutic option for several diseases such as stroke, heart attack, reper-fusion injuries, and rheumatoid arthritis. We designed a number of agonists, partial agonists, and antagonists of C3aR using our two-stage de novo protein design framework. Of the peptides tested using a degranulation assay in C3aR-transfected rat basophilic leukemia cells, two were prominent agonists (EC50 values of 25.3 and 66.2 nM) and two others were partial agonists (IC50 values of 15.4 and 26.1 nM). Further testing of these lead compounds in a calcium flux assay in U937 cells yielded similar results, although with reduced potencies compared to transfected cells. The partial agonists also displayed full antagonist activity when tested in a C3aR inhibition assay. In addition, the electrostatic potential profile was shown to potentially discriminate between full agonists and partial agonists.

Bellows-Peterson, Meghan L.; Fung, Ho Ki; Floudas, Christodoulos A.; Kieslich, Chris A.; Zhang, Li; Morikis, Dimitrios; Wareham, Kathryn J.; Monk, Peter N.; Hawksworth, Owen A.; Woodruff, Trent

2012-01-01

82

Corticosteroids and ?2-agonists upregulate mitogen-activated protein kinase phosphatase 1: in vitro mechanisms  

PubMed Central

BACKGROUND AND PURPOSE Airway remodelling is a consequence of long-term inflammation and MAPKs are key signalling molecules that drive pro-inflammatory pathways. The endogenous MAPK deactivator – MAPK phosphatase 1 (MKP-1) – is a critical negative regulator of the myriad pro-inflammatory pathways activated by MAPKs in the airway. EXPERIMENTAL APPROACH Herein we investigated the molecular mechanisms responsible for the upregulation of MKP-1 in airway smooth muscle (ASM) by the corticosteroid dexamethasone and the ?2-agonist formoterol, added alone and in combination. KEY RESULTS MKP-1 is a corticosteroid-inducible gene whose expression is enhanced by long-acting ?2-agonists in an additive manner. Formoterol induced MKP-1 expression via the ?2-adrenoceptor and we provide the first direct evidence (utilizing overexpression of PKI?, a highly selective PKA inhibitor) to show that PKA mediates ?2-agonist-induced MKP-1 upregulation. Dexamethasone activated MKP-1 transcription in ASM cells via a cis-acting corticosteroid-responsive region located between ?1380 and ?1266 bp of the MKP-1 promoter. While the 3?-untranslated region of MKP-1 contains adenylate + uridylate elements responsible for regulation at the post-transcriptional level, actinomycin D chase experiments revealed that there was no increase in MKP-1 mRNA stability in the presence of dexamethasone, formoterol, alone or in combination. Rather, there was an additive effect of the asthma therapeutics on MKP-1 transcription. CONCLUSIONS AND IMPLICATIONS Taken together, these studies allow us a greater understanding of the molecular basis of MKP-1 regulation by corticosteroids and ?2-agonists and this new knowledge may lead to elucidation of optimized corticosteroid-sparing therapies in the future.

Manetsch, M; Ramsay, EE; King, EM; Seidel, P; Che, W; Ge, Q; Hibbs, DE; Newton, R; Ammit, AJ

2012-01-01

83

Protective effects of peroxisome proliferator-activated receptor agonists on human podocytes: proposed mechanisms of action  

PubMed Central

BACKGROUND AND PURPOSE Peroxisome proliferator-activated receptor (PPAR) agonists exert anti-albuminuric effects. However, the nephroprotective effects of these drugs remain to be fully understood. We have investigated whether gemfibrozil, GW0742 and pioglitazone protect human podocytes against nutrient deprivation (ND)-induced cell death and the role of mitochondrial biogenesis as a cytoprotective process. EXPERIMENTAL APPROACH Immortalized human podocytes were pre-treated with the PPAR agonists and exposed to ND (5 h) under normoxia, hypoxia or in the presence of pyruvate. Cell death was measured at the end of the ND and of the recovery phase (24 h). Mitochondrial mass, cytochrome c oxidase (COX) subunits 1 and 4 were measured as markers of mitochondrial cell content, while membrane potential as an index of mitochondrial function. PGC-1?, NRF1 and Tfam expression was studied, as crucial regulators of mitochondrial biogenesis. KEY RESULTS Cell pre-treatment with gemfibrozil, GW0742, or pioglitazone significantly decreased the ND-induced cell loss, necrosis and apoptosis. These effects were attenuated by hypoxia and potentiated by pyruvate. Pre-treatment with these drugs significantly increased mitochondrial cell content, while it did not affect mitochondrial function. In all these experiments pioglitazone exerted significantly larger effects than gemfibrozil or GW0742. CONCLUSIONS AND IMPLICATIONS Gemfibrozil, GW0742 and pioglitazone may exert direct protective effects on human podocytes. Mitochondrial biogenesis is a cell response to the PPAR agonists related to their cytoprotective activity. These results provide a mechanistic support to the clinical evidence indicating PPAR agonists as disease-modifying agents for glomerular diseases.

Miglio, Gianluca; Rosa, Arianna Carolina; Rattazzi, Lorenza; Grange, Cristina; Camussi, Giovanni; Fantozzi, Roberto

2012-01-01

84

Thrombin generation by activated factor VII on platelet activated by different agonists. Extending the cell-based model of hemostasis  

PubMed Central

Background Platelet activation is crucial in normal hemostasis. Using a clotting system free of external tissue factor, we investigated whether activated Factor VII in combination with platelet agonists increased thrombin generation (TG) in vitro. Methods and results TG was quantified by time parameters: lag time (LT) and time to peak (TTP), and by amount of TG: peak of TG (PTG) and area under thrombin formation curve after 35 minutes (AUC?35min) in plasma from 29 healthy volunteers using the calibrated automated thrombography (CAT) technique. TG parameters were measured at basal conditions and after platelet stimulation by sodium arachidonate (AA), ADP, and collagen (Col). In addition, the effects of recombinant activated FVII (rFVIIa) alone or combined with the other platelet agonists on TG parameters were investigated. We found that LT and TTP were significantly decreased (p < 0.05) and PTG and AUC?35min were significantly increased (p < 0.05) in platelet rich plasma activated with AA, ADP, Col, and rFVIIa compared to non-activated platelet rich plasma from normal subjects (p = 0.01). Furthermore platelet rich plasma activated by the combined effects of rFVIIa plus AA, ADP or Col had significantly reduced LT and TTP and increased AUC?35min (but not PTG) when compared to platelet rich plasma activated with agonists in the absence of rFVIIa. Conclusion Platelets activated by AA, ADP, Col or rFVIIa triggered TG. This effect was increased by combining rFVIIa with other agonists. Our intrinsic coagulation system produced a burst in TG independent of external tissue factor activity an apparent hemostatic effect with little thrombotic capacity. Thus we suggest a modification in the cell-based model of hemostasis.

Altman, Raul; Scazziota, Alejandra Silvia; Herrera, Maria de Lourdes; Gonzalez, Claudio

2006-01-01

85

Indol-1-yl acetic acids as peroxisome proliferator-activated receptor agonists: design, synthesis, structural biology, and molecular docking studies.  

PubMed

A series of novel indole-based PPAR agonists is described leading to discovery of 10k, a highly potent PPAR pan-agonist. The structural biology and molecular docking studies revealed that the distances between the acidic group and the linker, when a ligand was complexed with PPARgamma protein, were important for the potent activity. The hydrophobic tail part of 10k makes intensive hydrophobic interaction with the PPARgamma protein resulting in potent activity. PMID:16451087

Mahindroo, Neeraj; Wang, Chiung-Chiu; Liao, Chun-Chen; Huang, Chien-Fu; Lu, I-Lin; Lien, Tzu-Wen; Peng, Yi-Huei; Huang, Wei-Jan; Lin, Ying-Ting; Hsu, Ming-Chen; Lin, Chia-Hui; Tsai, Chia-Hua; Hsu, John T-A; Chen, Xin; Lyu, Ping-Chiang; Chao, Yu-Sheng; Wu, Su-Ying; Hsieh, Hsing-Pang

2006-02-01

86

BAY36-7620: a potent non-competitive mGlu1 receptor antagonist with inverse agonist activity  

Microsoft Academic Search

L-glutamate (Glu) activates at least eight different G protein-coupled receptors, the metabotropic glutamate (mGlu) receptors, which mostly act as regulators of synaptic transmission. These receptors consist of two domains: an extracellular one where agonists bind, and a transmembrane heptahelix region involved in G-protein activation. Although new mGlu receptor agonists and antagonists have been described, few are selective for a single

Stolle Andreas; Voerste Arnd; Brabet Isabelle; Mauler Frank; Joly C cile é; Antonicek Horst; Bockaert Jo; Pin Jean-Philippe

87

Intracellular activation of vasopressin V2 receptor mutants in nephrogenic diabetes insipidus by nonpeptide agonists  

PubMed Central

Binding of the peptide hormone vasopressin to its type-2 receptor (V2R) in kidney triggers a cAMP-mediated translocation of Aquaporin-2 water channels to the apical membrane, resulting in water reabsorption and thereby preventing dehydration. Mutations in the V2R gene lead to Nephrogenic Diabetes Insipidus (NDI), a disorder in which this process is disturbed, because the encoded, often intrinsically functional mutant V2 receptors are misfolded and retained in the endoplasmic reticulum (ER). Since plasma membrane expression is thought to be essential for V2R activation, cell permeable V2R antagonists have been used to induce maturation and rescue cell surface expression of V2R mutants, after which they need to be displaced by vasopressin for activation. Here, however, we show that 3 novel nonpeptide V2R agonists, but not vasopressin, activate NDI-causing V2R mutants at their intracellular location, without changing their maturation and at a sufficient level to induce the translocation of aquaporin-2 to the apical membrane. Moreover, in contrast to plasma membrane V2R, degradation of intracellular V2R mutants is not increased by their activation. Our data reveal that G protein-coupled receptors (GPCRs) normally active at the plasma membrane can be activated intracellularly and that intracellular activation does not induce their degradation; the data also indicate that nonpeptide agonists constitute highly promising therapeutics for diseases caused by misfolded GPCRs in general, and NDI in particular.

Robben, Joris H.; Kortenoeven, Marleen L. A.; Sze, Mozes; Yae, Chris; Milligan, Graeme; Oorschot, Viola M.; Klumperman, Judith; Knoers, Nine V. A. M.; Deen, Peter M. T.

2009-01-01

88

Marked behavioral activation from inhibitory stimulation of locus coeruleus alpha1-adrenoceptors by a full agonist.  

PubMed

alpha(1)-Adrenoceptors are concentrated in the locus coeruleus (LC) where they appear to regulate various active behaviors but have been difficult to stimulate effectively. The present study examined the behavioral, pharmacological and neural effects of possible stimulation of these receptors with 6-fluoronorepinephrine (6FNE), the only known selective alpha-agonist that has full efficacy at all brain alpha-receptors. Infusion of this compound in the mouse LC was found to produce extreme activation of diverse motivated behaviors of exploration, wheel-running and operant approach responding in different environments consistent with a global behavioral function of the dorsal noradrenergic system. Infusion of selective antagonists of alpha(1)- (terazosin) or alpha(2)- (atipamezole) receptors or of either the partial alpha(1)-agonist, phenylephrine, or full alpha(2)-agonist, dexmedetomidine, indicated that the behavioral effects of 6FNE were due largely due to activation of LC alpha(1)-receptors consistent with the known greater density of alpha(1)- than alpha(2)-adrenoreceptors in the mouse nucleus. Immunohistochemistry of fos in tyrosine hydroxylase-positive LC neurons following IV ventricular infusions indicated that 6FNE markedly depressed whereas terazosin strongly enhanced the apparent functional activity of the nucleus. The changes in fos expression following 6FNE and terazosin were significantly greater than those following dexmedetomidine and atipamezole. It is hypothesized that the alpha(1)-receptors of the mouse LC are strongly activated by 6FNE and serve to potently inhibit its tonic or stress-induced activity which in turn disinhibits prepotent motivated behaviors. PMID:19632210

Stone, Eric A; Lin, Yan; Sarfraz, Yasmeen; Quartermain, David

2009-07-24

89

Direct agonist activity of tricyclic antidepressants at distinct opioid receptor subtypes.  

PubMed

Tricyclic antidepressants (TCAs) have been reported to interact with the opioid system, but their pharmacological activity at opioid receptors has not yet been elucidated. In the present study, we investigated the actions of amoxapine, amitriptyline, nortriptyline, desipramine, and imipramine at distinct cloned and native opioid receptors. In Chinese hamster ovary (CHO) cells expressing delta-opioid receptors (CHO/DOR), TCAs displaced [3H]naltrindole binding and stimulated guanosine 5'-O-(3-[(35)S]thio)triphosphate ([(35)S]GTPgammaS) binding at micromolar concentrations with amoxapine displaying the highest potency and efficacy. Amoxapine and amitriptyline inhibited cyclic AMP formation and induced the phosphorylation of signaling molecules along the extracellular signal-regulated kinase 1/2 (ERK1/2) and phosphatidylinositol-3 kinase pathways. Amoxapine also activated delta-opioid receptors in rat dorsal striatum and nucleus accumbens and human frontal cortex. In CHO cells expressing kappa-opioid receptors (CHO/KOR), TCAs, but not amoxapine, exhibited higher receptor affinity and more potent stimulation of [(35)S]GTPgammaS binding than in CHO/DOR and effectively inhibited cyclic AMP accumulation. Amitriptyline regulated ERK1/2 phosphorylation and activity in CHO/KOR and C6 glioma cells endogenously expressing kappa-opioid receptors, and this effect was attenuated by the kappa-opioid antagonist nor-binaltorphimine. In rat nucleus accumbens, amitriptyline slightly inhibited adenylyl cyclase activity and counteracted the inhibitory effect of the full kappa agonist trans-(-)-3,4dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide (U50,488). At the cloned mu-opioid receptor, TCAs showed low affinity and no significant agonist activity. These results show that TCAs differentially regulate opioid receptors with a preferential agonist activity on either delta or kappa subtypes and suggest that this property may contribute to their therapeutic and/or side effects. PMID:19828880

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

2009-10-14

90

Insights into the Structural Basis of Endogenous Agonist Activation of Family B G Protein-Coupled Receptors  

PubMed Central

Agonist drugs targeting the glucagon-like peptide-1 (GLP1) receptor represent important additions to the clinical management of patients with diabetes mellitus. In the current report, we have explored whether the recently described concept of a receptor-active endogenous agonist sequence within the amino terminus of the secretin receptor may also be applicable to the GLP1 receptor. If so, this could provide a lead for the development of additional small molecule agonists targeting this and other important family members. Indeed, the region of the GLP1 receptor analogous to that containing the active WDN within the secretin receptor was found to possess full agonist activity at the GLP1 receptor. The minimal fragment within this region that had full agonist activity was NRTFD. Despite having no primary sequence identity with the WDN, it was also active at the secretin receptor, where it had similar potency and efficacy to WDN, suggesting common structural features. Molecular modeling demonstrated that an intradomain salt bridge between the side chains of arginine and aspartate could yield similarities in structure with cyclic WDN. This directly supports the relevance of the endogenous agonist concept to the GLP1 receptor and provides new insights into the rational development and refinement of new types of drugs activating this important receptor.

Dong, Maoqing; Gao, Fan; Pinon, Delia I.; Miller, Laurence J.

2008-01-01

91

Non-conventional synchronization of weakly coupled active oscillators  

NASA Astrophysics Data System (ADS)

We present a new type of self-sustained vibrations in the fundamental physical model covering a broad area of applications from wave generation in radiophysics and nonlinear optics to the heart muscle contraction and eyesight disorder in biophysics. Such a diversity of applications is due to the universal physical phenomenon of synchronization. Previous studies of this phenomenon, originating from Huygens famous observation, are based mainly on the model of two weakly coupled Van der Pol oscillators and usually deal with their synchronization in the regimes close to nonlinear normal modes (NNMs). In this work, we show for the first time that, in the important case of threshold excitation, an alternative synchronization mechanism can develop when the conventional synchronization becomes impossible. We identify this mechanism as an appearance of dynamic attractor with the complete periodic energy exchange between the oscillators, which is the dissipative analogue of highly intensive beats in a conservative system. This type of motion is therefore opposite to the NNM-type synchronization with no energy exchange by definition. The analytical description of these vibrations employs the concept of Limiting Phase Trajectories (LPTs) introduced by one of the authors earlier for conservative systems. Finally, within the LPT approach, we describe the transition from the complete energy exchange between the oscillators to the energy localization mostly on one of the two oscillators. The localized mode is an attractor in the range of model parameters wherein the LPT as well as the in-phase and out-of-phase NNMs become unstable.

Manevitch, L. I.; Kovaleva, M. A.; Pilipchuk, V. N.

2013-03-01

92

In vitro study on the agonistic and antagonistic activities of bisphenol-S and other bisphenol-A congeners and derivatives via nuclear receptors.  

PubMed

Bisphenols are a group of chemicals structurally similar to bisphenol-A (BPA) in current use as the primary raw material in the production of polycarbonate and epoxy resins. Some bisphenols are intended to replace BPA in several industrial applications. This is the case of bisphenol-S (BPS), which has an excellent stability at high temperature and resistance to sunlight. Studies on the endocrine properties of BPS have focused on its interaction with human estrogen receptor alpha (hER?), but information on its interaction with other nuclear receptors is scarce. The aim of this study was to investigate interactions of BPS, BPF, BPA and its halogenated derivatives, tetrachlorobisphenol A (TCBPA), and tetrabromobisphenol A (TBBPA), with human estrogen receptors (hER? and hER?), androgen receptor (hAR), and pregnane X receptor (hPXR), using a panel of in vitro bioassays based on competitive binding to nuclear receptors (NRs), reporter gene expression, and cell proliferation assessment. BPS, BPF, and BPA efficiently activated both ERs, while TCBPA behaved as weak hER? agonist. Unlike BPF and BPA, BPS was more active in the hER? versus hER? assay. BPF and BPA were full hAR antagonists (BPA>BPF), whereas BPA and BPS were weak hAR agonists. Only BPA, TCBPA, and TBBPA, were hPXR agonists (TCBPA>TBBPA>BPA). These findings provide evidence that BPA congeners and derivatives disrupt multiple NRs and may therefore interfere with the endocrine system. Hence, further research is needed to evaluate the potential endocrine-disrupting activity of putative BPA substitutes. PMID:23714657

Molina-Molina, José-Manuel; Amaya, Esperanza; Grimaldi, Marina; Sáenz, José-María; Real, Macarena; Fernández, Mariana F; Balaguer, Patrick; Olea, Nicolás

2013-05-25

93

Airway peroxidases catalyze nitration of the {beta}2-agonist salbutamol and decrease its pharmacological activity.  

PubMed

?(2)-agonists are the most effective bronchodilators for the rapid relief of asthma symptoms, but for unclear reasons, their effectiveness may be decreased during severe exacerbations. Because peroxidase activity and nitrogen oxides are increased in the asthmatic airway, we examined whether salbutamol, a clinically important ?(2)-agonist, is subject to potentially inactivating nitration. When salbutamol was exposed to myeloperoxidase, eosinophil peroxidase or lactoperoxidase in the presence of hydrogen peroxide (H(2)O(2)) and nitrite (NO(2)(-)), both absorption spectroscopy and mass spectrometry indicated formation of a new metabolite with features expected for the nitrated drug. The new metabolites showed an absorption maximum at 410 nm and pK(a) of 6.6 of the phenolic hydroxyl group. In addition to nitrosalbutamol (m/z 285.14), a salbutamol-derived nitrophenol, formed by elimination of the formaldehyde group, was detected (m/z 255.13) by mass spectrometry. It is noteworthy that the latter metabolite was detected in exhaled breath condensates of asthma patients receiving salbutamol but not in unexposed control subjects, indicating the potential for ?(2)-agonist nitration to occur in the inflamed airway in vivo. Salbutamol nitration was inhibited in vitro by ascorbate, thiocyanate, and the pharmacological agents methimazole and dapsone. The efficacy of inhibition depended on the nitrating system, with the lactoperoxidase/H(2)O(2)/NO(2)(-) being the most affected. Functionally, nitrated salbutamol showed decreased affinity for ?(2)-adrenergic receptors and impaired cAMP synthesis in airway smooth muscle cells compared with the native drug. These results suggest that under inflammatory conditions associated with asthma, phenolic ?(2)-agonists may be subject to peroxidase-catalyzed nitration that could potentially diminish their therapeutic efficacy. PMID:20974700

Reszka, Krzysztof J; Sallans, Larry; Macha, Stephen; Brown, Kari; McGraw, Dennis W; Kovacic, Melinda Butsch; Britigan, Bradley E

2010-10-25

94

DMCM, a benzodiazepine site inverse agonist, improves active avoidance and motivation in the rat.  

PubMed

There are several modulatory sites at GABA(A) receptors, which mediate the actions of many drugs, among them benzodiazepine. Three kinds of allosteric modulators act through the benzodiazepine binding site: positive (agonist), neutral (antagonist), and negative (inverse agonist). The goal of the present study was to examine the influence of the inverse agonist methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) acting on ? GABA(A) receptor and compare its dose-response effects on memory and depression-like behavior. We independently studied the effects of DMCM (0.05-1.0 mg/kg) on retention versus acquisition of active avoidance and depression-like behavior in the forced swim test. Throughout the study, drugs were given intraperitoneally, 30 min before testing. ANOVA has showed that treatment with DMCM significantly affected retrieval of avoidance response (p<0.05), exerted promnesic effects in inverted U-shape manner. Dunnett's test indicated that the DMCM avoidance-facilitatory dose was 0.1mg/kg. At the dose facilitating retrieval of avoidance memory, DMCM significantly (p<0.05, comparison of regression coefficients by Student's t-test) and progressively increased acquisition rate during 5 days training, compared to the saline group. In forced swim test, ANOVA indicated statistically significant effects of DMCM (p<0.05). Dunnett's analysis showed that DMCM significantly decreased immobility time at the dose of 0.1mg/kg, exerted acute antidepressant-like effects. Our results experimentally support the findings that under certain circumstances, nonselective benzodiazepine site inverse agonists, produce memory-enhancing and antidepressant-like effects. The molecular and neuronal substrates linking the actions of specific GABA-benzodiazepine receptor complex subunits remains to be further elucidated. PMID:22878232

Samardži?, Janko; Strac, Dubravka Švob; Obradovi?, Miljana; Opri?, Dejan; Obradovi?, Dragan I

2012-08-01

95

Positive allosteric modulators differentially affect full versus partial agonist activation of the glycine receptor.  

PubMed

Taurine acts as a partial agonist at the glycine receptor (GlyR) in some brain regions such as the hippocampus, striatum, and nucleus accumbens. Ethanol, volatile anesthetics, and inhaled drugs of abuse are all known positive allosteric modulators of GlyRs, but their effects on taurine-activated GlyRs remain poorly understood, especially their effects on the high concentrations of taurine likely to be found after synaptic release. Two-electrode voltage-clamp electrophysiology in Xenopus laevis oocytes was used to compare the enhancing effects of ethanol, anesthetics, and inhalants on human homomeric ?1-GlyR activated by saturating concentrations of glycine versus taurine. Allosteric modulators had negligible effects on glycine-activated GlyR while potentiating taurine-activated currents. In addition, inhaled anesthetics markedly enhanced desensitization rates of taurine- but not glycine-activated receptors. Our findings suggest that ethanol, volatile anesthetics, and inhalants differentially affect the time courses of synaptic events at GlyR, depending on whether the receptor is activated by a full or partial agonist. PMID:22473615

Kirson, Dean; Todorovic, Jelena; Mihic, S John

2012-04-03

96

Cholinergic and glutamatergic agonists induce gamma frequency activity in dorsal subcoeruleus nucleus neurons  

PubMed Central

The dorsal subcoeruleus nucleus (SubCD) is involved in generating two signs of rapid eye movement (REM) sleep: muscle atonia and ponto-geniculo-occipital (PGO) waves. We tested the hypothesis that single cell and/or population responses of SubCD neurons are capable of generating gamma frequency activity in response to intracellular stimulation or receptor agonist activation. Whole cell patch clamp recordings (immersion chamber) and population responses (interface chamber) were conducted on 9- to 20-day-old rat brain stem slices. All SubCD neurons (n = 103) fired at gamma frequency when subjected to depolarizing steps. Two statistically distinct populations of neurons were observed, which were distinguished by their high (>80 Hz, n = 24) versus low (35–80 Hz, n = 16) initial firing frequencies. Both cell types exhibited subthreshold oscillations in the gamma range (n = 43), which may underlie the gamma band firing properties of these neurons. The subthreshold oscillations were blocked by the sodium channel blockers tetrodotoxin (TTX, n = 21) extracellularly and N-(2,6-dimethylphenylcarbamoylmethyl)triethylammonium bromide (QX-314) intracellularly (n = 5), indicating they were sodium channel dependent. Gamma frequency subthreshold oscillations were observed in response to the nonspecific cholinergic receptor agonist carbachol (CAR, n = 11, d = 1.08) and the glutamate receptor agonists N-methyl-d-aspartic acid (NMDA, n = 12, d = 1.09) and kainic acid (KA, n = 13, d = 0.96), indicating that cholinergic and glutamatergic inputs may be involved in the activation of these subthreshold currents. Gamma band activity also was observed in population responses following application of CAR (n = 4, P < 0.05), NMDA (n = 4, P < 0.05) and KA (n = 4, P < 0.05). Voltage-sensitive, sodium channel-dependent gamma band activity appears to be a part of the intrinsic membrane properties of SubCD neurons.

Simon, Christen; Kezunovic, Nebojsa; Williams, D. Keith; Urbano, Francisco J.

2011-01-01

97

A Weakly Turbulent Flame with High Activation Energy.  

National Technical Information Service (NTIS)

A previously outlined approach to turbulent flame theory is extended to premixed combustibles with high activation energy. Emphasis is placed primarily on turbulence whose integral scale is large compared with the thickness of the laminar flame. Only the ...

F. A. Williams

1973-01-01

98

Structure-activity relationships in nucleotide oligomerization domain 1 (Nod1) agonistic ?-glutamyldiaminopimelic acid derivatives.  

PubMed

N-acyl-?-glutamyldiaminopimelic acid is a prototype ligand for Nod1. We report a detailed SAR of C(12)-?-D-Glu-DAP. Analogues with glutaric or ?-aminobutyric acid replacing the glutamic acid show greatly attenuated Nod1-agonistic activity. Substitution of the meso-diaminopimelic (DAP) acid component with monoaminopimelic acid, L- or D-lysine, or cadaverine also results in reduced activity. The free amine on DAP is crucial. However, the N-acyl group on the D-glutamyl residue can be substituted with N-alkyl groups with full preservation of activity. The free carboxylates on the DAP and Glu components can also be esterified, resulting in more lipophilic but active analogues. Transcriptomal profiling showed a dominant up-regulation of IL-19, IL-20, IL-22, and IL-24, which may explain the pronounced Th2-polarizing activity of these compounds and also implicate cell signaling mediated by TREM-1. These results may explain the hitherto unknown mechanism of synergy between Nod1 and TLR agonists and are likely to be useful in designing vaccine adjuvants. PMID:21299227

Agnihotri, Geetanjali; Ukani, Rehman; Malladi, Subbalakshmi S; Warshakoon, Hemamali J; Balakrishna, Rajalakshmi; Wang, Xinkun; David, Sunil A

2011-02-07

99

Effects of the muscarinic agonist pilocarpine on vigilance states and locomotor activity in ring doves.  

PubMed

Cholinergic systems play a significant role in regulating a variety of behavioral functions in mammals and birds. The aim of this work is to study the effects of the muscarinic agonist pilocarpine on behavioral states by visual inspection and electroencephalographic recording; also, locomotor activity was continuously recorded by infrared interruption system in ring doves. The current results in birds demonstrated that the muscarinic agonist pilocarpine (1 and 3mg/kg, i.p.) primarily induced theta activity in addition to promote passive waking, while diminished active waking, the EEG slow wave rhythm and REM sleep in ring doves. The locomotor activity recorded continuously in ring doves diminished after pilocarpine treatment, which was in good agreement with the observed reduction of active waking derived of the EEG study. Altogether, the current results are similar to the effects of pilocarpine previously reported in mammals. In conclusion, hippocampal theta rhythm in birds suggests that this rhythm is an ancestral property of hippocampal function and similar cholinergic mechanisms regulate vigilance states and theta generation in mammals and birds. PMID:22138442

Tejada, S; Nicolau, M C; Gamundí, A; Esteban, S

2011-11-25

100

A 7-phenyl substituted triazolopyridazine has inverse agonist activity at the benzodiazepine receptor site.  

PubMed Central

To investigate further the structural requirements for benzodiazepine (BZD) receptor ligands, we synthesized SR 95195, [7-phenyl-3-methyl-1,2,4-triazolo-(4,3-b) pyridazine], a positional isomer of the 6-phenyl-triazolo-pyridazines, which were the first non-BZD derivatives to exhibit high affinity for the BZD receptor and BZD-like activity in vivo. In vitro, SR 95195 displaced specifically bound [3H]-flunitrazepam from rat cerebellar and hippocampal membranes with respective IC50 values of 4 and 8 microM. In vivo, SR 95195 lacked BZD-like activity. At high doses SR 95195 induced clonic seizures in mice (threshold convulsant dose: 150 mg kg-1; CD50: 160 mg kg-1 i.p.) which were antagonized by Ro 15-1788. At non-convulsant doses (25 mg kg-1 i.p. and 100 mg kg-1 i.p.) SR 95195 significantly decreased punished responding in an operant conflict procedure in the rat, suggesting SR 95195 has intrinsic anxiogenic activity. SR 95195, in mice, reversed the anticonvulsant and myorelaxant actions of diazepam 3 mg kg-1, orally (respective ED50 values: 45 mg kg-1 i.p. and 44 mg kg-1 i.p.). In an operant-conflict test in rats, SR 95195 at non-anxiogenic doses, antagonized the disinhibitory action of diazepam 4 mg kg-1, i.p. (ED50: 8.6 mg kg-1, i.p.), but not that of pentobarbitone 15 mg kg-1, i.p. It is concluded that SR 95195 has the pharmacological profile of an inverse BZD agonist and that displacing the phenyl from the 6- to the 7-position in the triazolopyridazine series causes a shift from agonist to inverse agonist type activity at the BZD receptor site.

Biziere, K.; Bourguignon, J. J.; Chambon, J. P.; Heaulme, M.; Perio, A.; Tebib, S.; Wermuth, C. G.

1987-01-01

101

Weak Internal Controls Make Some Navy Activities Vulnerable to Fraud, Waste, and Abuse.  

National Technical Information Service (NTIS)

Weaknesses in internal controls at the Naval Sea Systems Command, including two shipyards, and two other activities that provide services to the command make them vulnerable to fraudulent acts as well as nonintentional misuse of Federal funds. GAO believe...

1981-01-01

102

Identity of Endogenous NMDAR Glycine Site Agonist in Amygdala Is Determined by Synaptic Activity Level  

PubMed Central

Mechanisms of NMDA receptor-dependent synaptic plasticity contribute to the acquisition and retention of conditioned fear memory. However, synaptic rules which may determine the extent of NMDA receptor activation in the amygdala, a key structure implicated in fear learning, remain unknown. Here we show that the identity of the NMDAR glycine site agonist at synapses in the lateral nucleus of the amygdala may depend on the level of synaptic activation. Tonic activation of NMDARs at synapses in the amygdala under low-activity conditions is supported by ambient D-serine, whereas glycine may be released from astrocytes in response to afferent impulses. The release of glycine may decode the increases in afferent activity levels into enhanced NMDAR-mediated synaptic events, serving an essential function in the induction of NMDAR-dependent long-term potentiation in fear conditioning pathways.

Li, Yan; Sacchi, Silvia; Pollegioni, Loredano; Basu, Alo C.; Coyle, Joseph T.; Bolshakov, Vadim Y.

2013-01-01

103

Cellular signaling by an agonist-activated receptor/Gs alpha fusion protein.  

PubMed Central

The consequences of agonist-dependent activation of guanine nucleotide-binding protein (G protein)-coupled receptors vary from cell to cell, depending on a complex network of regulations between components of the signaling cascade. Specific interactions between receptors, G proteins, and effectors are difficult to analyze in intact cells. Engineering of receptor-transducer fusion proteins might be an effective strategy to target cellular effectors more efficiently and specifically. As a model, we evaluated the ability of a fusion protein of beta 2-adrenergic receptor bound to the alpha subunit of adenylyl cyclase-stimulatory G protein (Gs alpha) to restore the defective activation of adenylyl cyclase in S49 cyc- cells that lack endogenous Gs alpha. The coupling between the two partners of the fusion protein was functional, and the agonist-dependent activation of the effector was more potent and more productive in transfected than in wild-type S49 cells. The covalent link between receptor and Gs alpha could thus convey an advantage over freely interacting components. Such receptor-G alpha fusion proteins may help to elucidate the complex interactions between members of signaling pathways and may also constitute a useful tool for studying the effects of single effector activation. Images

Bertin, B; Freissmuth, M; Jockers, R; Strosberg, A D; Marullo, S

1994-01-01

104

Peroxisome proliferator-activated receptor ? agonists inhibit the proliferation and invasion of human colon cancer cells  

PubMed Central

Background and aims Data regarding the effect of peroxisome proliferator?activated receptor ? (PPAR??) ligands on the invasive ability of colon cancer cells are currently limited. This study was designed to examine the effects of PPAR?? agonists on the proliferation and invasion of two colon cancer cells to identify the role of PPAR?? in colon cancer growth and metastasis. Methods SW480 and LS174T cells were treated with PPAR?? ligands, pioglitazone and 15?deoxy??(12,14)?prostaglandin J2 (15d?PGJ2), as well as their combinations with the PPAR?? antagonist GW9662. MTT assay was used to determine the antiproliferative effects. Cell cycle analysis was conducted by flow cytometry. The mRNA and protein expression were detected by reverse transcriptase polymerase chain reaction (RT?PCR) and western blot, respectively. The invasive ability of cells was determined by the BD BioCoat Matrige invasion chamber. Results Pioglitazone and 15d?PGJ2 inhibited the proliferation of both colon cancer cell lines in a dose?dependent manner. This growth inhibitory effect was reversed by GW9662. Results from flow cytometry demonstrated G1 arrest following treatment with pioglitazone and 15d?PGJ2. The expression of matrix metalloproteinase?7 (MMP?7) was only detected in LS174T cells, while its tissue inhibitor?1 (TIMP?1) was expressed in both colon cancer cells. 15d?PGJ2 and pioglitazone downregulated MMP?7 expression and upregulated TIMP?1 expression. PPAR?? agonists can only inhibit invasive activity of LS174T cells. Conclusions PPAR?? agonists have inhibitory effects on the proliferation of colon cancer cell lines associated with G1 cell cycle arrest and invasive activity. The latter effect is demonstrated in certain cell lines through the down?regulation of MMP?7 synthesis.

Shen, Dan; Deng, Changsheng; Zhang, Ming

2007-01-01

105

Activation of the G-protein-coupled receptor 119: a conformation-based hypothesis for understanding agonist response.  

PubMed

The synthesis and properties of the bridged piperidine (oxaazabicyclo) compounds 8, 9, and 11 are described. A conformational analysis of these structures is compared with the representative GPR119 ligand 1. These results and the differences in agonist pharmacology are used to formulate a conformation-based hypothesis to understand activation of the GPR119 receptor. We also show for these structures that the agonist pharmacology in rat masks the important differences in human pharmacology. PMID:21361292

McClure, Kim F; Darout, Etzer; Guimarães, Cristiano R W; DeNinno, Michael P; Mascitti, Vincent; Munchhof, Michael J; Robinson, Ralph P; Kohrt, Jeffrey; Harris, Anthony R; Moore, Dianna E; Li, Bryan; Samp, Lacey; Lefker, Bruce A; Futatsugi, Kentaro; Kung, Daniel; Bonin, Paul D; Cornelius, Peter; Wang, Ruduan; Salter, Eben; Hornby, Sam; Kalgutkar, Amit S; Chen, Yue

2011-03-01

106

Limited Cooperation between Peroxisome Proliferator-Activated Receptors and Retinoid X Receptor Agonists in Sebocyte Growth and Development  

Microsoft Academic Search

We have found that sebaceous epithelial cell (sebocyte) differentiation is induced by cognate ligand-agonists of either peroxisome proliferator-activated receptors (PPARs) or retinoid X receptors (RXRs). In this study, we tested the hypothesis that PPAR-RXR cooperation is used in sebocytes as was reported to occur in gene transfection systems and liposarcoma cells through PPAR–RXR heterodimerization. PPAR agonists at maximally effective concentrations

Mi-Jung Kim; Dianne Deplewski; Nancy Ciletti; Serge Michel; Uwe Reichert; Robert L. Rosenfield

2001-01-01

107

Cyclothiazide binding to functionally active AMPA receptor reveals genuine allosteric interaction with agonist binding sites.  

PubMed

The agonist, [3H](-)[S]-1-(2-amino-2-carboxyethyl)-5-fluoro-pyrimidine-2,4-dione ([3H](S)F-Willardiine) binding to functional alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors of resealed plasma membrane vesicles and nerve endings freshly isolated from the rat cerebral cortex displayed two binding sites (K(D1)=33+/-7 nM, B(MAX1)=1.6+/-0.3 pmol/mg protein, K(D2)=720+/-250 nM and B(MAX2)=7.8+/-4.0 pmol/mg protein). The drug which impairs AMPA receptor desensitisation, 6-chloro-3,4-dihydro-3-(2-norbornene-5-yl)-2H-1,2,4-benzothiadiazine-7-sulphonamide-1,1-dioxide (cyclothiazide, CTZ) fully displaced the [3H](S)F-Willardiine binding at a concentration of 500 microM. In the presence of 100 microM CTZ (K(I(CTZ))=60+/-6 microM), both the antagonist [3H]-1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo(F)quinoxaline-7-sulfonamide ([3H]NBQX: K(D)=24+/-4 nM, B(MAX)=12.0+/-0.1 pmol/mg protein) and the high-affinity agonist binding showed similar affinity reduction ([3H](S)F-Willardiine: K(D)=140+/-19 nM, B(MAX)=2.9+/-0.5 pmol/mg protein; [3H]NBQX: K(D)=111+/-34 nM, B(MAX)=12+/-3 pmol/mg protein). To disclose structural correlates underlying genuine allosteric binding interactions, molecular mechanics calculations of CTZ-induced structural changes were performed with the use of PDB data on extracellular GluR2 binding domain dimeric crystals available by now. Hydrogen-bonding and root mean square (rms) values of amino acid residues recognising receptor agonists showed minor alterations in the agonist binding sites itself. Moreover, CTZ binding did not affect dimeric subunit structures significantly. These findings indicated that the structural changes featuring the non-desensitised state could possibly occur to a further site of the extracellular GluR2 binding domain. The increase of agonist efficacy on allosteric CTZ binding may be interpreted in terms of a mechanism involving AMPA receptor desensitisation sequential to activation. PMID:14602090

Kovács, Ilona; Simon, Agnes; Szárics, Eva; Barabás, Péter; Héja, László; Nyikos, Lajos; Kardos, Julianna

2004-03-01

108

Activity of recombinant trypsin isoforms on human proteinase-activated receptors (PAR): mesotrypsin cannot activate epithelial PAR-1, -2, but weakly activates brain PAR-1.  

PubMed

Trypsin-like serine proteinases trigger signal transduction pathways through proteolytic cleavage of proteinase-activated receptors (PARs) in many tissues. Three members, PAR-1, PAR-2 and PAR-4, are trypsin substrates, as trypsinolytic cleavage of the extracellular N terminus produces receptor activation. Here, the ability of the three human pancreatic trypsin isoforms (cationic trypsin, anionic trypsin and mesotrypsin (trypsin IV)) as recombinant proteins was tested on PARs. Using fura 2 [Ca(2+)](i) measurements, we analyzed three human epithelial cell lines, HBE (human bronchial epithelial), A549 (human pulmonary epithelial) and HEK (human embryonic kidney)-293 cells, which express functional PAR-1 and PAR-2. Human mesotrypsin failed to induce a PAR-mediated Ca(2+) response in human epithelial cells even at high concentrations. In addition, mesotrypsin did not affect the magnitude of PAR activation by subsequently added bovine trypsin. In HBE cells, which like A549 cells express high PAR-2 levels with negligible PAR-1 levels (<11%), half-maximal responses were seen for both cationic and anionic trypsins at about 5 nM. In the epithelial cells, mesotrypsin did not activate PAR-2 or PAR-1, whereas both anionic and cationic trypsins were comparable activators. We also investigated human astrocytoma 1321N1cells, which express PAR-1 and some PAR-3, but no PAR-2. High concentrations (>100 nM) of mesotrypsin produced a relatively weak Ca(2+) signal, apparently through PAR-1 activation. Half-maximal responses were observed at 60 nM mesotrypsin, and at 10-20 nM cationic and anionic trypsins. Using a desensitization assay with PAR-2-AP, we confirmed that both cationic and anionic trypsin isoforms cause [Ca(2+)](i) elevation in HBE cells mainly through PAR-2 activation. Desensitization of PAR-1 with thrombin receptor agonist peptide in 1321N1 cells demonstrated that all three recombinant trypsin isoforms act through PAR-1.Thus, the activity of human cationic and anionic trypsins on PARs was comparable to that of bovine pancreatic trypsin. Mesotrypsin (trypsin IV), in contrast to cationic and anionic trypsin, cannot activate or disable PARs in human epithelial cells, demonstrating that the receptors are no substrates for this isoenzyme. On the other hand, mesotrypsin activates PAR-1 in human astrocytoma cells. This might play a role in protection/degeneration or plasticity processes in the human brain. PMID:16231009

Grishina, Zoryana; Ostrowska, Ewa; Halangk, Walter; Sahin-Tóth, Miklós; Reiser, Georg

2005-12-01

109

Activity of recombinant trypsin isoforms on human proteinase-activated receptors (PAR): mesotrypsin cannot activate epithelial PAR-1, -2, but weakly activates brain PAR-1  

PubMed Central

Trypsin-like serine proteinases trigger signal transduction pathways through proteolytic cleavage of proteinase-activated receptors (PARs) in many tissues. Three members, PAR-1, PAR-2 and PAR-4, are trypsin substrates, as trypsinolytic cleavage of the extracellular N terminus produces receptor activation. Here, the ability of the three human pancreatic trypsin isoforms (cationic trypsin, anionic trypsin and mesotrypsin (trypsin IV)) as recombinant proteins was tested on PARs. Using fura 2 [Ca2+]i measurements, we analyzed three human epithelial cell lines, HBE (human bronchial epithelial), A549 (human pulmonary epithelial) and HEK (human embryonic kidney)-293 cells, which express functional PAR-1 and PAR-2. Human mesotrypsin failed to induce a PAR-mediated Ca2+ response in human epithelial cells even at high concentrations. In addition, mesotrypsin did not affect the magnitude of PAR activation by subsequently added bovine trypsin. In HBE cells, which like A549 cells express high PAR-2 levels with negligible PAR-1 levels (<11%), half-maximal responses were seen for both cationic and anionic trypsins at about 5?nM. In the epithelial cells, mesotrypsin did not activate PAR-2 or PAR-1, whereas both anionic and cationic trypsins were comparable activators. We also investigated human astrocytoma 1321N1cells, which express PAR-1 and some PAR-3, but no PAR-2. High concentrations (>100?nM) of mesotrypsin produced a relatively weak Ca2+ signal, apparently through PAR-1 activation. Half-maximal responses were observed at 60?nM mesotrypsin, and at 10–20?nM cationic and anionic trypsins. Using a desensitization assay with PAR-2-AP, we confirmed that both cationic and anionic trypsin isoforms cause [Ca2+]i elevation in HBE cells mainly through PAR-2 activation. Desensitization of PAR-1 with thrombin receptor agonist peptide in 1321N1 cells demonstrated that all three recombinant trypsin isoforms act through PAR-1. Thus, the activity of human cationic and anionic trypsins on PARs was comparable to that of bovine pancreatic trypsin. Mesotrypsin (trypsin IV), in contrast to cationic and anionic trypsin, cannot activate or disable PARs in human epithelial cells, demonstrating that the receptors are no substrates for this isoenzyme. On the other hand, mesotrypsin activates PAR-1 in human astrocytoma cells. This might play a role in protection/degeneration or plasticity processes in the human brain.

Grishina, Zoryana; Ostrowska, Ewa; Halangk, Walter; Sahin-Toth, Miklos; Reiser, Georg

2005-01-01

110

Gating of TRPM8 channels activated by cold and chemical agonists in planar lipid bilayers  

PubMed Central

The TRPM8 ion channel is a major sensor of environmental cold temperatures. It is activated by cold and chemical agonists, such as menthol and icilin. The activation of these channels both by cold and cooling agents requires the presence of the membrane phospholipid, phosphatidylinositol 4,5-bisphosphate (PIP2). The mechanism of TRPM8 activation by physical and chemical factors is unknown and the involvement of cellular signaling pathways has been considered. Here we have characterized the gating mechanism of the rat TRPM8 reconstituted in planar lipid bilayers and its activation by different stimuli. In this system the influence of cellular signaling pathways can be excluded. We found that TRPM8 activated by cold exhibits steep temperature dependence (Q10?40), and the channel openings are accompanied by large changes in entropy and enthalpy, suggesting a substantial conformation change. TRPM8 channel behavior upon menthol and icilin activation was distinguishable and the effect of icilin depended on the presence of calcium on the intracellular side of the protein. Here we also demonstrate that PIP2 is the prime factor that impacts the gating of TRPM8 and other phosphoinositides are less efficient in supporting channel activity. Menthol increases the potency of PIP2 to activate the channels, and increases binding of phosphoinositides to the full-length channel protein. Our data demonstrate conclusively that TRPM8 is gated by cold and its chemical agonists directly, and that dependence of its gating on PIP2 is a result of direct specific interactions with the lipid.

Zakharian, Eleonora; Cao, Chike; Rohacs, Tibor

2010-01-01

111

Involvement of Asn-293 in stereospecific agonist recognition and in activation of the beta 2-adrenergic receptor.  

PubMed Central

To investigate the molecular mechanism for stereospecific binding of agonists to beta 2-adrenergic receptors we used receptor models to identify potential binding sites for the beta-OH-group of the ligand, which defines the chiral center. Ser-165, located in transmembrane helix IV, and Asn-293, situated in the upper half of transmembrane helix VI, were identified as potential binding sites. Mutation of Ser-165 to Ala did not change the binding of either isoproterenol isomer as revealed after transient expression in human embryonic kidney (HEK)-293 cells. In contrast, a receptor mutant in which Asn-293 was replaced by Leu showed substantial loss of stereospecific isoproterenol binding. Adenylyl cyclase stimulation by this mutant after stable expression in CHO cells confirmed the substantial loss of stereospecificity for isoproterenol. In a series of agonists the loss of affinity in the Leu-293 mutant receptor was strongly correlated with the intrinsic activity of the compounds. Full agonists showed a 10-30-fold affinity loss, whereas partial agonists had almost the same affinity for both receptors. Stereospecific recognition of antagonists was unaltered in the Leu-293 mutant receptor. These data indicate a relationship between stereospecificity and intrinsic activity of agonists and suggest that Asn-293 is important for both properties of the agonist-receptor interaction. Images Fig. 1 Fig. 2

Wieland, K; Zuurmond, H M; Krasel, C; Ijzerman, A P; Lohse, M J

1996-01-01

112

A selective peroxisome proliferator-activated receptor ? agonist promotes reverse cholesterol transport  

PubMed Central

The peroxisome proliferator-activated receptors (PPARs) are dietary lipid sensors that regulate fatty acid and carbohydrate metabolism. The hypolipidemic effects of the fibrate drugs and the antidiabetic effects of the glitazone drugs in humans are due to activation of the ? (NR1C1) and ? (NR1C3) subtypes, respectively. By contrast, the therapeutic potential of the ? (NR1C2) subtype is unknown, due in part to the lack of selective ligands. We have used combinatorial chemistry and structure-based drug design to develop a potent and subtype-selective PPAR? agonist, GW501516. In macrophages, fibroblasts, and intestinal cells, GW501516 increases expression of the reverse cholesterol transporter ATP-binding cassette A1 and induces apolipoprotein A1-specific cholesterol efflux. When dosed to insulin-resistant middle-aged obese rhesus monkeys, GW501516 causes a dramatic dose-dependent rise in serum high density lipoprotein cholesterol while lowering the levels of small-dense low density lipoprotein, fasting triglycerides, and fasting insulin. Our results suggest that PPAR? agonists may be effective drugs to increase reverse cholesterol transport and decrease cardiovascular disease associated with the metabolic syndrome X.

Oliver, William R.; Shenk, Jennifer L.; Snaith, Mike R.; Russell, Caroline S.; Plunket, Kelli D.; Bodkin, Noni L.; Lewis, Michael C.; Winegar, Deborah A.; Sznaidman, Marcos L.; Lambert, Millard H.; Xu, H. Eric; Sternbach, Daniel D.; Kliewer, Steven A.; Hansen, Barbara C.; Willson, Timothy M.

2001-01-01

113

Protection from liver fibrosis by a peroxisome proliferator-activated receptor ? agonist.  

PubMed

Peroxisome proliferator-activated receptor delta (PPAR?), a member of the nuclear receptor family, is emerging as a key metabolic regulator with pleiotropic actions on various tissues including fat, skeletal muscle, and liver. Here we show that the PPAR? agonist KD3010, but not the well-validated GW501516, dramatically ameliorates liver injury induced by carbon tetrachloride (CCl(4)) injections. Deposition of extracellular matrix proteins was lower in the KD3010-treated group than in the vehicle- or GW501516-treated group. Interestingly, profibrogenic connective tissue growth factor was induced significantly by GW501516, but not by KD3010, following CCl(4) treatment. The hepatoprotective and antifibrotic effect of KD3010 was confirmed in a model of cholestasis-induced liver injury and fibrosis using bile duct ligation for 3 wk. Primary hepatocytes treated with KD3010 but not GW501516 were protected from starvation or CCl(4)-induced cell death, in part because of reduced reactive oxygen species production. In conclusion, our data demonstrate that an orally active PPAR? agonist has hepatoprotective and antifibrotic effects in animal models of liver fibrosis, suggesting a possible mechanistic and therapeutic approach in treating patients with chronic liver diseases. PMID:22538808

Iwaisako, Keiko; Haimerl, Michael; Paik, Yong-Han; Taura, Kojiro; Kodama, Yuzo; Sirlin, Claude; Yu, Elizabeth; Yu, Ruth T; Downes, Michael; Evans, Ronald M; Brenner, David A; Schnabl, Bernd

2012-04-25

114

Design, synthesis, and evaluation of potent, structurally novel peroxisome proliferator-activated receptor (PPAR) delta-selective agonists.  

PubMed

A series of 3-(4-alkoxyphenyl)propanoic acid derivatives was prepared as candidate peroxisome proliferator-activated receptor (PPAR) delta-selective agonists, based on our previously discovered potent human PPARalpha/delta dual agonist TIPP-401 as a lead compound. Structure-activity relationship studies clearly indicated the importance of the chain length of the alkoxy group at the 4-position, and the n-butoxy compound exhibited the most potent PPARdelta transactivation activity and highest PPARdelta selectivity. The (S)-enantiomer of a representative compound exhibited extremely potent PPARdelta transactivation activity, comparable with or somewhat superior to that of the known PPARdelta-selective agonist, GW-501516. The representative compound regulated the expression of genes involved in lipid and glucose homeostasis, and should be useful not only as a chemical tool to study PPARdelta function, but also as a candidate drug for the treatment of metabolic syndrome. PMID:17532641

Kasuga, Jun-Ichi; Nakagome, Izumi; Aoyama, Atsushi; Sako, Kumiko; Ishizawa, Michiyasu; Ogura, Michitaka; Makishima, Makoto; Hirono, Shuichi; Hashimoto, Yuichi; Miyachi, Hiroyuki

2007-05-13

115

Discovery of a nortropanol derivative as a potent and orally active GPR119 agonist for type 2 diabetes.  

PubMed

The lead optimization studies of a series of GPR119 agonists incorporating a nortropanol scaffold are described. Extensive structure-activity relationship (SAR) studies of the lead compound 20f led to the identification of compound 36j as a potent, single digit nanomolar GPR119 agonist with high agonist activity. Compound 36j was orally active in lowering blood glucose levels in a mouse oral glucose tolerance test and increased plasma insulin levels in a rat hyperglycemic model. It showed good to excellent pharmacokinetic properties in rats and monkeys and no untoward activities in counter-screen assays. Compound 36j demonstrated an attractive in vitro and in vivo profile for further development. PMID:21536438

Xia, Yan; Chackalamannil, Samuel; Greenlee, William J; Jayne, Charles; Neustadt, Bernard; Stamford, Andrew; Vaccaro, Henry; Xu, Xiaoying Lucy; Baker, Hana; O'Neill, Kim; Woods, Morgan; Hawes, Brian; Kowalski, Tim

2011-04-14

116

The orthosteric agonist 2-chloro-5-hydroxyphenylglycine activates mGluR5 and mGluR1 with similar efficacy and potency  

PubMed Central

Background The efficacy, potency, and selectivity of the compound 2-Chloro-5-hydroxyphenylglycine (CHPG), a nominally selective agonist for metabotropic glutamate receptor 5 (mGluR5), were examined with select mGluRs by examining their ability to induce modulation of the native voltage dependent ion channels in isolated sympathetic neurons from the rat superior cervical ganglion (SCG). SCG neurons offer a null mGluR-background in which specific mGluR subtypes can be made to express via intranuclear cDNA injection. Results Consistent with previous reports, CHPG strongly activated mGluR5b expressed in SCG neurons with an apparent EC50 around 60??M. Surprisingly, CHPG also activated two mGluR1 splice variants with a similar potency as at mGluR5 when calcium current inhibition was used as an assay for receptor function. No effect of 1?mM CHPG was seen in cells expressing mGluR2 or mGluR4, suggesting that CHPG only activates group I mGluRs (mGluR1 and 5). CHPG was also able to induce modulation of M-type potassium current through mGluR1, but not as consistently as glutamate. Since this channel is modulated through a Gq-dependent pathway, these data indicate that CHPG may exhibit some biased agonist properties on mGluR1. Closer examination of the voltage-independent, Gq-mediated component of mGluR-induced calcium current modulation data confirmed that some biased agonism was evident, but the effect was weak and inconsistent. Conclusions These data contrast with the established literature which suggests that CHPG is a selective mGluR5 agonist. Instead, CHPG appears to act equally well as an agonist at mGluR1. While some weak biased agonism was observed with CHPG acting on mGluR1, but not mGluR5, favoring Gi/o signaling over Gq/11, this effect does not appear sufficient to fully explain the discrepancies in the literature.

2012-01-01

117

Heavy X-Ray Absorption in Soft X-Ray-weak Active Galactic Nuclei  

Microsoft Academic Search

Recent ROSAT studies have identified a significant population of active galactic nuclei (AGNs) that are notably faint in soft X-rays relative to their optical fluxes. Are these AGNs intrinsically X-ray weak or are they highly absorbed? Brandt, Laor, & Wills have systematically examined the optical and UV spectral properties of a well-defined sample of these soft X-ray-weak (SXW) AGNs drawn

S. C. Gallagher; W. N. Brandt; A. Laor; M. Elvis; S. Mathur; Beverley J. Wills; N. Iyomoto

2001-01-01

118

Central role of liver in anticancer and radioprotective activities of Toll-like receptor 5 agonist  

PubMed Central

Vertebrate Toll-like receptor 5 (TLR5) recognizes bacterial flagellin proteins and activates innate immune responses to motile bacteria. In addition, activation of TLR5 signaling can inhibit growth of TLR5-expressing tumors and protect normal tissues from radiation and ischemia-reperfusion injuries. To understand the mechanisms behind these phenomena at the organismal level, we assessed nuclear factor kappa B (NF-?B) activation (indicative of TLR5 signaling) in tissues and cells of mice treated with CBLB502, a pharmacologically optimized flagellin derivative. This identified the liver and gastrointestinal tract as primary CBLB502 target organs. In particular, liver hepatocytes were the main cell type directly and specifically responding to systemic administration of CBLB502 but not to that of the TLR4 agonist LPS. To assess CBLB502 impact on other pathways, we created multireporter mice with hepatocytes transduced in vivo with reporters for 46 inducible transcription factor families and found that along with NF-?B, CBLB502 strongly activated STAT3-, phenobarbital-responsive enhancer module (PREM), and activator protein 1 (AP-1–) -driven pathways. Livers of CBLB502-treated mice displayed induction of numerous immunomodulatory factors and massive recruitment of various types of immune cells. This led to inhibition of growth of liver metastases of multiple tumors regardless of their TLR5 status. The changed liver microenvironment was not, however, hepatotoxic, because CBLB502 induced resistance to Fas-mediated apoptosis in normal liver cells. Temporary occlusion of liver blood circulation prevented CBLB502 from protecting hematopoietic progenitors in lethally irradiated mice, indicating involvement of a factor secreted by responding liver cells. These results define the liver as the key mediator of TLR5-dependent effects in vivo and suggest clinical applications for TLR5 agonists as hepatoprotective and antimetastatic agents.

Burdelya, Lyudmila G.; Brackett, Craig M.; Kojouharov, Bojidar; Gitlin, Ilya I.; Leonova, Katerina I.; Gleiberman, Anatoli S.; Aygun-Sunar, Semra; Veith, Jean; Johnson, Christopher; Haderski, Gary J.; Stanhope-Baker, Patricia; Allamaneni, Shyam; Skitzki, Joseph; Zeng, Ming; Martsen, Elena; Medvedev, Alexander; Scheblyakov, Dmitry; Artemicheva, Nataliya M.; Logunov, Denis Y.; Gintsburg, Alexander L.; Naroditsky, Boris S.; Makarov, Sergei S.; Gudkov, Andrei V.

2013-01-01

119

Cannabilactones: a novel class of CB2 selective agonists with peripheral analgesic activity.  

PubMed

The identification of the CB2 cannabinoid receptor has provided a novel target for the development of therapeutically useful cannabinergic molecules. We have synthesized benzo[ c]chromen-6-one analogs possessing high affinity and selectivity for this receptor. These novel compounds are structurally related to cannabinol (6,6,9-trimethyl-3-pentyl-6 H-benzo[ c]chromen-1-ol), a natural constituent of cannabis with modest CB2 selectivity. Key pharmacophoric features of the new selective agonists include a 3-(1',1'-dimethylheptyl) side chain and a 6-oxo group on the cannabinoid tricyclic structure that characterizes this class of compounds as "cannabilactones." Our results suggest that the six-membered lactone pharmacophore is critical for CB2 receptor selectivity. Optimal receptor subtype selectivity of 490-fold and subnanomolar affinity for the CB2 receptor is exhibited by a 9-hydroxyl analog 5 (AM1714), while the 9-methoxy analog 4b (AM1710) had a 54-fold CB2 selectivity. X-ray crystallography and molecular modeling show the cannabilactones to have a planar ring conformation. In vitro testing revealed that the novel compounds are CB2 agonists, while in vivo testing of cannabilactones 4b and 5 found them to possess potent peripheral analgesic activity. PMID:18038967

Khanolkar, Atmaram D; Lu, Dai; Ibrahim, Mohab; Duclos, Richard I; Thakur, Ganesh A; Malan, T Phillip; Porreca, Frank; Veerappan, Vijayabaskar; Tian, Xiaoyu; George, Clifford; Parrish, Damon A; Papahatjis, Demetris P; Makriyannis, Alexandros

2007-11-27

120

Disruption of agonist and ligand activity in an AMPA glutamate receptor splice-variable domain deletion mutant.  

PubMed

The mechanisms by which agonists and other ligands bind ligand-gated ion channels are important determinants of function in neurotransmitter receptors. The partial agonist, kainic acid (KA) activates a less desensitized, and more robust AMPA receptor (AMPAR) current than full agonists, glutamate or AMPA. Cyclothiazide (CTZ), the allosteric modulator of AMPARs, potentiates receptor currents by inhibiting receptor desensitization resulting from agonist activation. We have constructed an AMPAR GluR1 subunit deletion mutant GluR1L3T(Delta739-784) by deleting the splice-variable "flip/flop" region of the L3 domain in the wild-type receptor and compared its function to that of the wild-type GluR1 receptor and an AMPAR substitution mutant GluR1A782N. When compared to GluR1, the potency of glutamate activation of GluR1L3T was increased, in contrast to a decrease in potency of activation and reduced sensitivity to optimal concentrations of KA. Furthermore, GluR1L3T was totally insensitive to CTZ potentiation of KA and glutamate-activated currents in Xenopus laevis oocytes. The potency of glutamate and KA activation of GluR1A782N was not significantly different from that of the wild-type GluR1 receptor although the mutant receptor currents were more sensitive to CTZ potentiation than the wild-type receptor current. This result is an indication that glutamate and KA binding to the agonist (S1/S2) domain on AMPAR can be modulated by an expendable splice-variable region of the receptor. Moreover, the effect of the allosteric modulator, CTZ on agonist activation of AMPAR can also be modified by a non-conserved amino acid residue substitution within the splice-variable "flip/flop" region. PMID:18585685

Johnson, Wayne D; Parandaman, Vijaya; Onaivi, Emmanuel S; Taylor, Robert E; Akinshola, B Emmanuel

2008-05-23

121

Synthesis and P2Y2 Receptor Agonist Activities of Uridine 5'-Phosphonate Analogues  

PubMed Central

We explored the influence of modifications of uridine 5’-methylenephosphonate on biological activity at the human P2Y2 receptor. Key steps in the synthesis of a series of 5-substituted uridine 5’-methylenephosphonates were the reaction of a suitably protected uridine 5’-aldehyde with [(diethoxyphosphinyl)methylidene]triphenylphosphorane, C-5 bromination and a Suzuki–Miyaura coupling. These analogues behaved as selective agonists at the P2Y2 receptor, with three analogues exhibiting potencies in the submicromolar range. Although maximal activities observed with the phosphonate analogues were much less than observed with UTP, high concentrations of the phosphonates had no effect on the stimulatory effect of UTP. These results suggest that these phosphonates bind to an allosteric site of the P2Y2 receptor.

Van Poecke, Sara; Barrett, Matthew O.; Kumar, T. Santhosh; Sinnaeve, Davy; Martins, Jose C.; Jacobson, Kenneth A.; Harden, T. Kendall; Van Calenbergh, Serge

2012-01-01

122

Potent adjuvantic activity of a CCR1-agonistic bis-quinoline.  

PubMed

A bis-quinoline compound, (7-chloro-N-(4-(7-chloroquinolin-4-ylamino)butyl)quinolin-4-amine; RE-660) was found to have C-C chemokine receptor type 1 (CCR1)-agonistic properties. RE-660 displayed strong adjuvantic activity in mice when co-administered with bovine ?-lactalbumin used as a model subunit protein antigen. RE-660 evoked a balanced Th1 (IgG2)/Th2 (IgG1) antibody profile, and the quality of antibodies elicited by the bis-quinoline was found to be superior to that evoked by glucopyranosyl lipid A by surface plasmon resonance experiments. No evidence of proinflammatory activity was observed in human blood ex vivo models. In preliminary acute toxicity studies, the compound was found to be of lower toxicity than chloroquine in mice, and was non-mutagenic in an Ames screen. PMID:22104149

Ukani, Rehman; Lewis, Tyler C; Day, Timothy P; Wu, Wenyan; Malladi, Subbalakshmi S; Warshakoon, Hemamali J; David, Sunil A

2011-11-09

123

Potent Adjuvantic Activity of a CCR1-agonistic Bis-Quinoline  

PubMed Central

A bis-quinoline compound, (7-chloro-N-(4-(7-chloroquinolin-4-ylamino)butyl)quinolin-4-amine; RE-660) was found to have C-C chemokine receptor type 1 (CCR1)-agonistic properties.RE-660 displayed strong adjuvantic activity in mice when co-administered with bovine ?-lactalbumin used as a model subunit protein antigen. RE-660 evoked a balanced Th1 (IgG2)/Th2 (IgG1) antibody profile, and the quality of antibodies elicited by the bis-quinoline was found to be superior to that evoked by glucopyranosyl lipid A by surface plasmon resonance experiments. No evidence of proinflammatory activity was observed in human blood ex vivo models. In preliminary acute toxicity studies, the compound was found to be of lower toxicity than chloroquine in mice, and was non-mutagenic in an Ames screen.

Ukani, Rehman; Lewis, Tyler C.; Day, Timothy P.; Wu, Wenyan; Malladi, Subbalakshmi S.; Warshakoon, Hemamali J.; David, Sunil A.

2011-01-01

124

Antibodies to a peptide from the maize auxin-binding protein have auxin agonist activity.  

PubMed

The major auxin-binding protein in maize membranes is thought to function as a physiological receptor. From earlier information, including the use of site-directed irreversible inhibitors, several of the amino acids likely to form part of the active auxin-binding site were provisionally assigned. Inspection of the amino acid sequence of the auxin-binding protein showed a short region containing all but one of these amino acids. We find that antisera raised against a synthetic peptide encompassing this region recognize all isoforms of the maize auxin-binding protein together with homologous polypeptides in other species. We further find that the antibodies hyperpolarize protoplast transmembrane potential in an auxin-like manner. We conclude that these antibodies display auxin agonist activity and that we have identified an essential portion of the auxin-binding site. PMID:1323130

Venis, M A; Napier, R M; Barbier-Brygoo, H; Maurel, C; Perrot-Rechenmann, C; Guern, J

1992-08-01

125

Antibodies to a peptide from the maize auxin-binding protein have auxin agonist activity.  

PubMed Central

The major auxin-binding protein in maize membranes is thought to function as a physiological receptor. From earlier information, including the use of site-directed irreversible inhibitors, several of the amino acids likely to form part of the active auxin-binding site were provisionally assigned. Inspection of the amino acid sequence of the auxin-binding protein showed a short region containing all but one of these amino acids. We find that antisera raised against a synthetic peptide encompassing this region recognize all isoforms of the maize auxin-binding protein together with homologous polypeptides in other species. We further find that the antibodies hyperpolarize protoplast transmembrane potential in an auxin-like manner. We conclude that these antibodies display auxin agonist activity and that we have identified an essential portion of the auxin-binding site. Images

Venis, M A; Napier, R M; Barbier-Brygoo, H; Maurel, C; Perrot-Rechenmann, C; Guern, J

1992-01-01

126

Modulation of spontaneous activity in the overactive bladder: the role of P2Y agonists.  

PubMed

Spinal cord transection (SCT) leads to an increase in spontaneous contractile activity in the isolated bladder that is reminiscent of an overactive bladder syndrome in patients with similar damage to the central nervous system. An increase in interstitial cell number in the suburothelial space between the urothelium and detrusor smooth muscle layer occurs in SCT bladders, and these cells elicit excitatory responses to purines and pyrimidines such as ATP, ADP, and UTP. We have investigated the hypothesis that these agents underlie the increase in spontaneous activity. Rats underwent lower thoracic spinal cord transection, and their bladder sheets or strips, with intact mucosa except where specified, were used for experiments. Isometric tension was recorded and propagating Ca(2+) and membrane potential (E(m)) waves were recorded by fluorescence imaging using photodiode arrays. SCT bladders were associated with regular spontaneous contractions (2.9 ± 0.4/min); ADP, UTP, and UDP augmented the amplitude but not their frequency. With strips from such bladders, a P2Y(6)-selective agonist (PSB0474) exerted similar effects. Fluorescence imaging of bladder sheets showed that ADP or UTP increased the conduction velocity of Ca(2+)/E(m) waves that were confined to regions of the bladder wall with an intact mucosa. When transverse bladder sections were used, Ca(2+)/E(m) waves originated in the suburothelial space and propagated to the detrusor and urothelium. Analysis of wave propagation showed that the suburothelial space exhibited properties of an electrical syncitium. These experiments are consistent with the hypothesis that P2Y-receptor agonists increase spontaneous contractile activity by augmenting functional activity of the cellular syncitium in the suburothelial space. PMID:22357922

Fry, C H; Young, J S; Jabr, R I; McCarthy, C; Ikeda, Y; Kanai, A J

2012-02-22

127

Subpallial and hypothalamic areas activated following sexual and agonistic encounters in male chickens.  

PubMed

Male sexual and agonistic behaviors are controlled by the common social behavior network, involving subpallial and hypothalamic brain areas. In order to understand how this common network generates different behavioral outcomes, induction of FOS protein was used to examine the patterns of neuronal activation in adult male chickens following interaction with a female or a male. Males were subjected to one of the following treatments: handling control, non-contact interaction with a female, contact interaction with a live female, a taxidermy female model or another male. The number of FOS-immunoreactive (FOS-ir) cells, and the area and immunostaining density of individual cells were quantified in the medial preoptic nucleus (POM), medial extended amygdala (nucleus taeniae of the amygdala, TnA, and dorsolateral and ventromedial subdivisions of the medial portion of the bed nucleus of stria terminalis, BSTM1 and BSTM2, respectively), lateral septum (SL), hypothalamic paraventricular nucleus (PVN), bed nucleus of the pallial commissure (NCPa) and ventrolateral thalamic nucleus (VLT). An increase in FOS-ir cells following appetitive sexual behavior was found in BSTM2 and NCPa. Copulation augmented FOS-ir in POM, SL, VLT, and PVN. Intermale interactions increased FOS-ir in all examined brain regions except the TnA and BSTM. Within the SL, copulatory and agonistic behavior activated spatially segregated cell groups. In the PVN, different social behaviors induced significant changes in the distribution of FOS-ir cell sizes suggesting activation of heterogeneous subpopulations of cells. Collectively, behavioral outcomes of male-female and male-male interactions are associated with a combination of common and site-specific patterns of neural activation. PMID:20600197

Xie, Jingjing; Kuenzel, Wayne J; Anthony, Nicholas B; Jurkevich, Alexander

2010-06-17

128

Satellite observations of the impact of weak volcanic activity on marine clouds  

Microsoft Academic Search

Because emissions from weak volcanic eruptions tend to remain in the low troposphere, they may have a significant radiative impact through the indirect effect on clouds. However, this type of volcanic activity is underreported and its global impact has been assessed only by model simulations constrained with very limited observations. First observations of the impact of high-latitude active volcanoes on

Santiago Gassó

2008-01-01

129

Peroxisome Proliferator-Activated Receptor-? Agonists Prevent In Vivo Remodeling of Human Artery Induced by Alloreactive T Cells  

PubMed Central

Background Ligands activating the transcription factor peroxisome proliferator–activated receptor-? (PPAR?) have antiinflammatory effects. Vascular rejection induced by allogeneic T cells can be responsible for acute and chronic graft loss. Studies in rodents suggest that PPAR? agonists may inhibit graft vascular rejection, but human T-cell responses to allogeneic vascular cells differ from those in rodents, and the effects of PPAR? in human transplantation are unknown. Methods and Results We tested the effects of PPAR? agonists on human vascular graft rejection using a model in which human artery is interposed into the abdominal aorta of immunodeficient mice, followed by adoptive transfer of allogeneic (to the artery donor) human peripheral blood mononuclear cells. Interferon-?–dependent rejection ensues within 4 weeks, characterized by intimal thickening, T-cell infiltrates, and vascular cell activation, a response resembling clinical intimal arteritis. The PPAR? agonists 15-deoxy-prostaglandin-J2, ciglitazone, and pioglitazone reduced intimal expansion, intimal infiltration of CD45RO+ memory T cells, and plasma levels of inflammatory cytokines. The PPAR? antagonist GW9662 reversed the protective effects of PPAR? agonists, confirming the involvement of PPAR?-mediated pathways. In vitro, pioglitazone inhibited both alloantigen-induced proliferation and superantigen-induced transendothelial migration of memory T cells, indicating the potential mechanisms of PPAR? effects. Conclusion Our results suggest that PPAR? agonists inhibit allogeneic human memory T cell responses and may be useful for the treatment of vascular graft rejection.

Tobiasova, Zuzana; Zhang, Lufeng; Yi, Tai; Qin, Linfeng; Manes, Thomas D.; Kulkarni, Sanjay; Lorber, Marc I.; Rodriguez, Frederick C.; Choi, Je-Min; Tellides, George; Pober, Jordan S.; Kawikova, Ivana; Bothwell, Alfred L.M.

2012-01-01

130

N-desmethylclozapine, an allosteric agonist at muscarinic 1 receptor, potentiates N-methyl-D-aspartate receptor activity  

Microsoft Academic Search

The molecular and neuronal substrates conferring on clozapine its unique and superior efficacy in the treatment of schizophrenia remain elusive. The interaction of clozapine with many G protein-coupled receptors is well documented but less is known about its biologically active metabolite, N-desmethylclozapine. Recent clinical and preclinical evidences of the antipsychotic activity of the muscarinic agonist xanomeline prompted us to investigate

Cyrille Sur; Pierre J. Mallorga; Marion Wittmann; Marlene A. Jacobson; Danette Pascarella; Jacinta B. Williams; Philip E. Brandish; Douglas J. Pettibone; Edward M. Scolnick; P. Jeffrey Conn

2003-01-01

131

Preclinical activity of eltrombopag (SB-497115), an oral, nonpeptide thrombopoietin receptor agonist.  

PubMed

Eltrombopag is a first-in-class, orally bioavailable, small-molecule, nonpeptide agonist of the thrombopoietin receptor (TpoR), which is being developed as a treatment for thrombocytopenia of various etiologies. In vitro studies have demonstrated that the activity of eltrombopag is dependent on expression of TpoR, which activates the signaling transducers and activators of transcription (STAT) and mitogen-activated protein kinase signal transduction pathways. The objective of this preclinical study is to determine if eltrombopag interacts selectively with the TpoR to facilitate megakaryocyte differentiation in platelets. Functional thrombopoietic activity was demonstrated by the proliferation and differentiation of primary human CD34(+) bone marrow cells into CD41(+) megakaryocytes. Measurements in platelets in several species indicated that eltrombopag specifically activates only the human and chimpanzee STAT pathways. The in vivo activity of eltrombopag was demonstrated by an increase of up to 100% in platelet numbers when administered orally (10 mg/kg per day for 5 days) to chimpanzees. In conclusion, eltrombopag interacts selectively with the TpoR without competing with Tpo, leading to the increased proliferation and differentiation of human bone marrow progenitor cells into megakaryocytes and increased platelet production. These results suggest that eltrombopag and Tpo may be able to act additively to increase platelet production. PMID:19038790

Erickson-Miller, Connie L; Delorme, Evelyne; Tian, Shin-Shay; Hopson, Christopher B; Landis, Amy J; Valoret, Elizabeth I; Sellers, Teresa S; Rosen, Jon; Miller, Stephen G; Luengo, Juan I; Duffy, Kevin J; Jenkins, Julian M

2009-02-01

132

Structure-dependent activity of glycyrrhetinic acid derivatives as peroxisome proliferator-activated receptor {gamma} agonists in colon cancer cells.  

PubMed

Glycyrrhizin, a pentacyclic triterpene glycoside, is the major phytochemical in licorice. This compound and its hydrolysis product glycyrrhetinic acid have been associated with the multiple therapeutic properties of licorice extracts. We have investigated the effects of 2-cyano substituted analogues of glycyrrhetinic acid on their cytotoxicities and activity as selective peroxisome proliferator-activated receptor gamma (PPARgamma) agonists. Methyl 2-cyano-3,11-dioxo-18beta-olean-1,12-dien-30-oate (beta-CDODA-Me) and methyl 2-cyano-3,11-dioxo-18alpha-olean-1,12-dien-30-oate (alpha-CDODA-Me) were more cytotoxic to colon cancer cells than their des-cyano analogues and introduction of the 2-cyano group into the pentacyclic ring system was necessary for the PPARgamma agonist activity of alpha-CDODA-Me and beta-CDODA-Me isomers. However, in mammalian two-hybrid assays, both compounds differentially induced interactions of PPARgamma with coactivators, suggesting that these isomers, which differ only in the stereochemistry at C18 which affects conformation of the E-ring, are selective receptor modulators. This selectivity in colon cancer cells was shown for the induction of two proapoptotic proteins, namely caveolin-1 and the tumor-suppressor gene Krüppel-like factor-4 (KLF-4). beta-CDODA-Me but not alpha-CDODA-Me induced caveolin-1 in SW480 colon cancer cells, whereas caveolin-1 was induced by both compounds in HT-29 and HCT-15 colon cancer cells. The CDODA-Me isomers induced KLF-4 mRNA levels in HT-29 and SW480 cells but had minimal effects on KLF-4 expression in HCT-15 cells. These induced responses were inhibited by cotreatment with a PPARgamma antagonist. This shows for the first time that PPARgamma agonists derived from glycyrrhetinic acid induced cell-dependent caveolin-1 and KLF-4 expression through receptor-dependent pathways. PMID:17513608

Chintharlapalli, Sudhakar; Papineni, Sabitha; Jutooru, Indira; McAlees, Alan; Safe, Stephen

2007-05-01

133

Differential behavioral response to dopamine D2 agonists by sexually naive, sexually active, and sexually inactive male rats.  

PubMed

This study was performed with male rats categorized as sexually naive (SN), sexually active (SA), or sexually inactive (SI). In a first experiment the effects of dopamine (DA) D2 agonist SND 919 (0.05, 1, and 10 mg/kg) on the copulatory behavior of SN, SA and SI rats were assessed. In a second experiment the DA D2 agonist B-HT 920 (0.2 mg/kg) was used, and examination was limited to SN and SA rats. The effects exerted on stretching-yawning, penile erection, and sedation by the same compounds at the same doses in these three rat categories were also investigated. The main findings were that SND 919 and B-HT 920 facilitated ejaculation in SA rats, and that the rats that were different as regards level of sexual activity exhibited different behavioral responses to the two DA agonists. PMID:8864270

Giuliani, D; Ferrari, F

1996-08-01

134

Magnesium Ions and Opioid Agonist Activity in Streptozotocin-Induced Hyperalgesia  

Microsoft Academic Search

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

Magdalena Bujalska; Ewelina Malinowska; Helena Makulska-Nowak

2008-01-01

135

Comparative study of human and mouse pregnane X receptor agonistic activity in 200 pesticides using in vitro reporter gene assays.  

PubMed

The nuclear receptor, pregnane X receptor (PXR), is a ligand-dependent transcription factor that regulates genes involved in xenobiotic metabolism. Recent studies have shown that PXR activation may affect energy metabolism as well as the endocrine and immune systems. In this study, we characterized and compared the agonistic activities of a variety of pesticides against human PXR (hPXR) and mouse PXR (mPXR). We tested the hPXR and mPXR agonistic activity of 200 pesticides (29 organochlorines, 11 diphenyl ethers, 56 organophosphorus pesticides, 12 pyrethroids, 22 carbamates, 12 acid amides, 7 triazines, 7 ureas, and 44 others) by reporter gene assays using COS-7 simian kidney cells. Of the 200 pesticides tested, 106 and 93 activated hPXR and mPXR, respectively, and a total of 111 had hPXR and/or mPXR agonistic activity with greater or lesser inter-species differences. Although all of the pyrethroids and most of the organochlorines and acid amides acted as PXR agonists, a wide range of pesticides with diverse structures also showed hPXR and/or mPXR agonistic activity. Among the 200 pesticides, pyributicarb, pretilachlor, piperophos and butamifos for hPXR, and phosalone, prochloraz, pendimethalin, and butamifos for mPXR, acted as particularly potent activators at low concentrations in the order of 10??-10?? M. In addition, we found that several organophosphorus oxon- and pyributicarb oxon-metabolites decreased PXR activation potency compared to their parent compounds. These results suggest that a large number of structurally diverse pesticides and their metabolites possess PXR-mediated transcriptional activity, and their ability to do so varies in a species-dependent manner in humans and mice. PMID:21115097

Kojima, Hiroyuki; Sata, Fumihiro; Takeuchi, Shinji; Sueyoshi, Tatsuya; Nagai, Tadanori

2010-11-27

136

Identity of endogenous NMDAR glycine site agonist in amygdala is determined by synaptic activity level.  

PubMed

Mechanisms of N-methyl-D-aspartate receptor-dependent synaptic plasticity contribute to the acquisition and retention of conditioned fear memory. However, synaptic rules which may determine the extent of N-methyl-D-aspartate receptor activation in the amygdala, a key structure implicated in fear learning, remain unknown. Here we show that the identity of the N-methyl-D-aspartate receptor glycine site agonist at synapses in the lateral nucleus of the amygdala may depend on the level of synaptic activation. Tonic activation of N-methyl-D-aspartate receptors at synapses in the amygdala under low activity conditions is supported by ambient D-serine, whereas glycine may be released from astrocytes in response to afferent impulses. The release of glycine may decode the increases in afferent activity levels into enhanced N-methyl-D-aspartate receptor-mediated synaptic events, serving an essential function in the induction of N-methyl-D-aspartate receptor-dependent long-term potentiation in fear conditioning pathways. PMID:23612301

Li, Yan; Sacchi, Silvia; Pollegioni, Loredano; Basu, Alo C; Coyle, Joseph T; Bolshakov, Vadim Y

2013-01-01

137

Distinct roles of metabotropic glutamate receptor dimerization in agonist activation and G-protein coupling  

PubMed Central

The eight metabotropic glutamate receptors (mGluRs) are key modulators of synaptic transmission and are considered promising targets for the treatment of various brain disorders. Whereas glutamate acts at a large extracellular domain, allosteric modulators have been identified that bind to the seven transmembrane domain (7TM) of these dimeric G-protein-coupled receptors (GPCRs). We show here that the dimeric organization of mGluRs is required for the modulation of active and inactive states of the 7TM by agonists, but is not necessary for G-protein activation. Monomeric mGlu2, either as an isolated 7TM or in full-length, purified and reconstituted into nanodiscs, couples to G proteins upon direct activation by a positive allosteric modulator. However, only a reconstituted full-length dimeric mGlu2 activates G protein upon glutamate binding, suggesting that dimerization is required for glutamate induced activation. These data show that, even for such well characterized GPCR dimers like mGluR2, a single 7TM is sufficient for G-protein coupling. Despite this observation, the necessity of dimeric architecture for signaling induced by the endogenous ligand glutamate confirms that the central core of signaling complex is dimeric.

El Moustaine, Driss; Granier, Sebastien; Doumazane, Etienne; Scholler, Pauline; Rahmeh, Rita; Bron, Patrick; Mouillac, Bernard; Baneres, Jean-Louis; Rondard, Philippe; Pin, Jean-Philippe

2012-01-01

138

Identification of PPARgamma Partial Agonists of Natural Origin (II): In Silico Prediction in Natural Extracts with Known Antidiabetic Activity  

PubMed Central

Background Natural extracts have played an important role in the prevention and treatment of diseases and are important sources for drug discovery. However, to be effectively used in these processes, natural extracts must be characterized through the identification of their active compounds and their modes of action. Methodology/Principal Findings From an initial set of 29,779 natural products that are annotated with their natural source and using a previously developed virtual screening procedure (carefully validated experimentally), we have predicted as potential peroxisome proliferators-activated receptor gamma (PPAR?) partial agonists 12 molecules from 11 extracts known to have antidiabetic activity. Six of these molecules are similar to molecules with described antidiabetic activity but whose mechanism of action is unknown. Therefore, it is plausible that these 12 molecules could be the bioactive molecules responsible, at least in part, for the antidiabetic activity of the extracts containing them. In addition, we have also identified as potential PPAR? partial agonists 10 molecules from 16 plants with undescribed antidiabetic activity but that are related (i.e., they are from the same genus) to plants with known antidiabetic properties. None of the 22 molecules that we predict as PPAR? partial agonists show chemical similarity with a group of 211 known PPAR? partial agonists obtained from the literature. Conclusions/Significance Our results provide a new hypothesis about the active molecules of natural extracts with antidiabetic properties and their mode of action. We also suggest plants with undescribed antidiabetic activity that may contain PPAR? partial agonists. These plants represent a new source of potential antidiabetic extracts. Consequently, our work opens the door to the discovery of new antidiabetic extracts and molecules that can be of use, for instance, in the design of new antidiabetic drugs or functional foods focused towards the prevention/treatment of type 2 Diabetes Mellitus.

Guasch, Laura; Sala, Esther; Mulero, Miquel; Valls, Cristina; Salvado, Maria Josepa; Pujadas, Gerard; Garcia-Vallve, Santiago

2013-01-01

139

Binding affinity of nonsteroidal ecdysone agonists against the ecdysone receptor complex determines the strength of their molting hormonal activity.  

PubMed

N-tert-Butyl-N,N'-dibenzoylhydrazine and its analogs are nonsteroidal ecdysone agonists that exhibit insect molting hormonal and larvicidal activities. The interaction mode of those ecdysone agonists with the heterodimer of the ecdysone receptor and ultraspiracle has not been fully elucidated. We expressed the ecdysone receptor B1 and the ultraspiracle of the lepidopteran, Chilo suppressalis, using an in vitro transcription/translation system and confirmed, using gel-shift assays, that the proteins function as ecdysone receptors. We also analyzed their ligand-binding affinity. A potent ecdysteroid, ponasterone A, specifically bound to the ecdysone receptor with low affinity (KD = 55 nm), and the specific binding was dramatically increased (KD = 1.2 nm) in the presence of the ultraspiracle. For seven nonsteroidal ecdysone agonists and five ecdysteroids, the binding activity to the in vitro-translated ecdysone receptor-ultraspiracle complex was linearly correlated with the binding activity to the inherent receptor protein in the cell-free preparation of C. suppressalis integument. The binding to the ecdysone receptor-ultraspiracle complex for a series of compounds was highly correlated with their molting hormonal activity, indicating that the binding affinity of nonsteroidal ecdysone agonists to the ecdysone receptor-ultraspiracle complex primarily determines the strength of their molting hormonal activity. PMID:14519121

Minakuchi, Chieka; Nakagawa, Yoshiaki; Kamimura, Manabu; Miyagawa, Hisashi

2003-10-01

140

Effects of structural modifications of N-CPM-normorphine derivatives on agonist and antagonist activities in isolated organs.  

PubMed

The agonistic and antagonistic properties of N-cyclopropylmethyl (N-CPM) morphine derivatives were observed in mouse vas deferens (MVD), longitudinal muscle of guinea pig ileum (GPI) and rabbit vas deferens (LVD). In MVD the K(e) values of the titled compounds (N-CPM-morphine, N-CPM-isomorphine, N-CPM-dihydromorphine, N-CPM-dihydroisomorpPhine, N-CPM-dihydromorphone and naltrexone) were measured for mu-, kappa- and delta-receptors using normorphine, ethylketocyclazocine (EKC) and D-Pen2-D-Pen5-enkephaline (DPDPE) as selective agonists on the receptors, respectively. For mu-receptors of MVD the tested compounds showed similar affinity. For kappa-receptors the non-iso-6-OH derivatives possessed much less affinity than the iso-derivatives. Similar difference could be observed for delta-receptors. The agonistic activities of these compounds in MVD were observed to be between 0-20% of the inhibition of muscle contractions. In GPI the compounds except naltrexone possessed strong agonistic activities effectively antagonized by nor-binaltorphimine (nor-BNI) (K(e) of nor-BNI was 0.23 nM) suggesting that they were strong kappa-receptor agonists. We investigated these agents in LVD too, which contains kappa-receptors, but they did not produce any agonist potencies. It raises the possibility that the kappa-receptor subtypes of LVD and MVD are different from the kappa-receptor subtype of GPI or the vasa deferentia contain much fewer kappa-receptors than GPI and the intrinsic activities of these compounds are too small to reach the 50% inhibition of the contractions. PMID:14535623

Riba, P; Tóth, Z; Hosztafi, S; Friedmann, T; Fürst, S

2003-01-01

141

Discovery and biological evaluation of novel 4-amino-2-phenylpyrimidine derivatives as potent and orally active GPR119 agonists.  

PubMed

Novel 4-amino-2-phenylpyrimidine derivatives were synthesized and evaluated as GPR119 agonists. Optimization of the substituents on the phenyl ring at the 2-position and the amino group at the 4-position led to the identification of 3,4-dihalogenated and 2,4,5-trihalogenated phenyl derivatives showing potent GPR119 agonistic activity. The advanced analog (2R)-3-{[2-(4-chloro-2,5-difluorophenyl)-6-ethylpyrimidin-4-yl]amino}propane-1,2-diol (24g) was found to improve glucose tolerance at 1mg/kg po in mice and to show excellent pharmacokinetic profiles in mice and monkeys. Compound 24g also showed an excellent antidiabetic effect in diabetic kk/Ay mice after one week of single daily treatment. These results demonstrate that novel GPR119 agonist 24g improves glucose tolerance not only by enhancing glucose-dependent insulin secretion but also by preserving pancreatic ?-cell function. PMID:22836190

Negoro, Kenji; Yonetoku, Yasuhiro; Misawa-Mukai, Hana; Hamaguchi, Wataru; Maruyama, Tatsuya; Yoshida, Shigeru; Takeuchi, Makoto; Ohta, Mitsuaki

2012-07-06

142

Sundaicumones A and B, polyprenylated acylphloroglucinol derivatives from Calophyllumsundaicum with weak activity against the glucocorticoid receptor.  

PubMed

Bioassay-directed fractionation using a glucocorticoid receptor assay led to the isolation of two new, weakly active polyprenylated acylphloroglucinol derivatives, sundaicumones A (1) and B (2), from the leaves of Calophyllum sundaicum collected in Singapore. The structures of 1 and 2, which were established by spectroscopic methods, contain a 3-substituted hexanoic acid unit not previously reported in other polyprenylated acylphloroglucinols. PMID:16643060

Cao, Shugeng; Low, Kia-Ngee; Glover, Robert P; Crasta, Sharon C; Ng, Siewbee; Buss, Antony D; Butler, Mark S

2006-04-01

143

Antinociceptive activity of ?4?2* neuronal nicotinic receptor agonist A-366833 in experimental models of neuropathic and inflammatory pain  

Microsoft Academic Search

Nerve injury, diabetes and cancer therapies are often associated with painful neuropathy. The mechanism underlying neuropathic pain remains poorly understood. The current therapies have limited efficacy and are associated with dose-limiting side effects. Compounds which act at nicotinic acetylcholine receptors have also been reported to show antinociceptive activity. Among those, tebanicline (ABT-594) a potent nicotinic acetylcholine receptor agonist demonstrated analgesic

Ramakrishna Nirogi; Pradeep Jayarajan; Renny Abraham; Dhanalakshmi Shanmuganathan; Mohammed Abdul Rasheed; Praveen Kumar Royapalley; Venkatesh Goura

2011-01-01

144

Discovery of a novel class of zwitterionic, potent, selective and orally active S1P? direct agonists.  

PubMed

Amido-1,3,4-thiadiazoles have been identified as a novel structural class of potent and selective sphingosine-1-phosphate receptor subtype 1 agonists. Starting from a micromolar HTS hit with the help of an in-house homology model, robust structural-activity relationships were developed to yield compounds with good selectivity and excellent in vivo efficacy in rat models. PMID:23141913

Aguilar, Nuria; Mir, Marta; Grima, Pedro M; López, Manel; Segarra, Victor; Esteban, Laia; Moreno, Imma; Godessart, Nuria; Tarrasón, Gema; Domenech, Teresa; Vilella, Dolors; Armengol, Clara; Córdoba, Mònica; Sabaté, Mar; Casals, Daniel; Domínguez, Maria

2012-10-11

145

Glycosylation of Pramlintide: Synthetic Glycopeptides that Display In Vitro and In Vivo Activities as Amylin Receptor Agonists.  

PubMed

Sweet medicine: Glycosylated analogues of pramlintide, in which specific Asn residues bear extended N-glycan structures, may be accessed by a combination of solid-phase peptide synthesis and highly efficient enzymatic glycosylation (see scheme; ENGases=endo-?-N-acetylglucosaminidases). Glycopeptides display both in vitro and in vivo activity as amylin receptor agonists and effect 'smoothing' of blood glucose. PMID:24123422

Tomabechi, Yusuke; Krippner, Guy; Rendle, Phillip M; Squire, Marie A; Fairbanks, Antony J

2013-10-07

146

An assessment of the partial agonist activity of Ro 31-1118, flusoxolol and pindolol in man.  

PubMed Central

1. The effects of single oral doses of three beta-adrenoceptor partial agonists (Ro 31-1118, flusoxolol and pindolol), two beta-adrenoceptor antagonists (propranolol and atenolol), two beta-adrenoceptor agonists (salbutamol and prenalterol) and placebo on sleeping heart rate, quality of sleep, supine heart rate, exercise heart rate, blood pressure, forearm blood flow and finger tremor were studied in eight healthy male volunteers. 2. Sleeping heart rate was increased by Ro 31-1118, flusoxolol, pindolol, salbutamol and prenalterol and decreased by propranolol and atenolol. 3. None of the drugs studied affected quality of sleep. 4. Supine heart rate was increased by flusoxolol, prenalterol and salbutamol, unaffected by Ro 31-1118 and pindolol and reduced by propranolol and atenolol. 5. Exercise heart rate was reduced by both beta-adrenoceptor antagonists and the three partial agonists and unaffected by salbutamol and prenalterol. 6. Systolic blood pressure was increased by Ro 31-1118, flusoxolol, salbutamol and prenalterol, unaffected by pindolol and reduced by propranolol and atenolol. Diastolic blood pressure was reduced by salbutamol and prenalterol. 7. Forearm blood flow was increased by Ro 31-1118, salbutamol and prenalterol, unchanged by pindolol and flusoxolol and decreased by atenolol and propranolol. 8. Finger tremor was increased by Ro 31-1118, flusoxolol, pindolol, salbutamol, and prenalterol. 9. beta-adrenoceptor partial agonists have different effects on the cardiovascular system and finger tremor to beta-adrenoceptor antagonists. 10. While Ro 31-1118 and flusoxolol are antagonists mainly at the beta 1-adrenoceptor they have agonist activity at both beta 1- and beta 2 adrenoceptors. 11. While pindolol is a non-selective antagonist its agonist activity is mainly at the beta 2-adrenoceptor.

McCaffrey, P M; Riddell, J G; Shanks, R G

1987-01-01

147

Ablation of weak emphysematous visceral pleura by an ultrasonically activated device for spontaneous pneumothorax.  

PubMed

Staple bullectomy is widely performed for the thoracoscopic treatment of spontaneous pneumothorax. When weak emphysematous change was observed to extend to the whole pleura around the localized bulla, weak emphysematous pleura always remain around the stapler after bullectomy. Such cases along with weak pleural surfaces around staplers belong to the groups at high risk of postoperative recurrence. We performed thoracoscopic ablation using an ultrasonically activated device (USAD) for such lesions and studied the efficacy. From April 2002 to December 2006, a total of 85 surgeries for spontaneous pneumothorax were performed in this hospital, of which 34 cases underwent ablation with a USAD for a weak pleural surface. No complications due to ablation were observed. Recurrence was observed in four subjects, but the cause of recurrence was the regeneration of a bulla outside the range of the ablation and was unrelated to the ablation itself. Moreover, significant white pleural thickening was observed at the ablation sites, demonstrating a stiffening effect of the weak visceral pleura. Ablation using a USAD is a safe and easy operative method, and it is an appropriate operative system as a stiffening procedure for a visceral pleura. PMID:21388985

Funai, Kazuhito; Suzuki, Kazuya; Shimizu, Kei; Shiiya, Norihiko

2011-03-09

148

Full and Partial Agonists of Thromboxane Prostanoid Receptor Unveil Fine Tuning of Receptor Superactive Conformation and G Protein Activation  

PubMed Central

The intrahelical salt bridge between E/D3.49 and R3.50 within the E/DRY motif on helix 3 (H3) and the interhelical hydrogen bonding between the E/DRY and residues on H6 are thought to be critical in stabilizing the class A G protein-coupled receptors in their inactive state. Removal of these interactions is expected to generate constitutively active receptors. This study examines how neutralization of E3.49/6.30 in the thromboxane prostanoid (TP) receptor alters ligand binding, basal, and agonist-induced activity and investigates the molecular mechanisms of G protein activation. We demonstrate here that a panel of full and partial agonists showed an increase in affinity and potency for E129V and E240V mutants. Yet, even augmenting the sensitivity to detect constitutive activity (CA) with overexpression of the receptor or the G protein revealed resistance to an increase in basal activity, while retaining fully the ability to cause agonist-induced signaling. However, direct G protein activation measured through bioluminescence resonance energy transfer (BRET) indicates that these mutants more efficiently communicate and/or activate their cognate G proteins. These results suggest the existence of additional constrains governing the shift of TP receptor to its active state, together with an increase propensity of these mutants to agonist-induced signaling, corroborating their definition as superactive mutants. The particular nature of the TP receptor as somehow “resistant” to CA should be examined in the context of its pathophysiological role in the cardiovascular system. Evolutionary forces may have favored regulation mechanisms leading to low basal activity and selected against more highly active phenotypes.

Perenna, Alessandro; Ambrosio, Manuela; Accomazzo, Maria Rosa; Gales, Celine; Chini, Bice; Rovati, G. Enrico

2013-01-01

149

On-line screening of conformationally constrained nicotines and anabasines for agonist activity at the alpha3beta4- and alpha4beta2-nicotinic acetylcholine receptors using immobilized receptor-based liquid chromatographic stationary phases.  

PubMed

Liquid chromatography columns containing stationary phases based upon immobilized nicotinic acetylcholine receptors (nAChRs) were used to screen a series of conformationally constrained nicotine and anabasine derivatives for agonist activity. The alpha3beta4 nAChR and alpha4beta2 nAChR subtypes were used to prepare the chromatographic columns and [(3)H] epibatidine dihydrochloride ([(3)H] EB) was used as the marker ligand. Single displacement experiments were conducted with the test ligands and with nicotine and carbachol. Nicotine was used as an internal control for compounds with agonist activity and carbachol was used as an internal control for compounds with very weak agonistic activity (K(d) > 4700 nM for alpha3beta4). The displacement of [(3)H] EB by each of the test compounds and internal controls was calculated and expressed as Deltaml. Functional studies were then conducted using a stably transfected cell line that expresses the alpha3beta4 nAChR and EC(50) values were determined for the test compounds and the internal controls. A comparison of the Deltaml and EC(50) values indicated that 9/11 compounds had been correctly identified as agonists or non-agonists of the alpha3beta4 nAChR. A similar comparison could not be made for the alpha4beta2 nAChR, since the intact cell line was not available for testing. The results of the study suggest that the immobilized nAChR columns can be used for the rapid on-line screening of compounds for their relative affinities for the immobilized receptor and as an initial determination of qualitative functional activities. PMID:15556538

Moaddel, Ruin; Jozwiak, Krzysztof; Yamaguchi, Rika; Cobello, Christopher; Whittington, Kevin; Sarkar, Tarun K; Basak, Sankar; Wainer, Irving W

2004-12-25

150

Biological characterization of a novel class of toll-like receptor 7 agonists designed to have reduced systemic activity  

PubMed Central

BACKGROUND AND PURPOSE Toll-like receptor 7 (TLR7) agonists have potential in the treatment of allergic diseases. However, the therapeutic utility of current low molecular weight TLR7 agonists is limited by their systemic activity, resulting in unwanted side effects. We have developed a series of TLR7-selective ‘antedrugs’, including SM-324405 and AZ12441970, which contain an ester group rapidly cleaved in plasma to reduce systemic exposure. EXPERIMENTAL APPROACH Agonist activity at TLR7 of the parent ester and acid metabolite was assessed in vitro in reporter cells and primary cells from a number of species. Pharmacokinetics following a dose to the lungs was assessed in mice and efficacy evaluated in vivo with a mouse allergic airway model. KEY RESULTS Compounds were selective agonists for TLR7 with no crossover to TLR8 and were metabolically unstable in plasma with the acid metabolite showing substantially reduced activity in a number of assays. The compounds inhibited IL-5 production and induced IFN-?, which mediated the inhibition of IL-5. When dosed into the lung the compounds were rapidly metabolized and short-term exposure of the ‘antedrug’ was sufficient to activate the IFN pathway. AZ12441970 showed efficacy in a mouse allergic airway model with minimal induction of systemic IFN-?, consistent with the low plasma levels of compound. CONCLUSIONS AND IMPLICATIONS The biological and metabolic profiles of these TLR7-selective agonist ‘antedrug’ compounds are consistent with a new class of compound that could be administered locally for the treatment of allergic diseases, while reducing the risk of systemic side effects. LINKED ARTICLE This article is commented on by Kaufman and Jacoby, pp. 569–572 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476-5381.2011.01758.x

Biffen, M; Matsui, H; Edwards, S; Leishman, AJ; Eiho, K; Holness, E; Satterthwaite, G; Doyle, I; Wada, H; Fraser, NJ; Hawkins, SL; Aoki, M; Tomizawa, H; Benjamin, AD; Takaku, H; McInally, T; Murray, CM

2012-01-01

151

AKR-501 (YM477) a novel orally-active thrombopoietin receptor agonist.  

PubMed

Thrombopoietin (TPO) is the principal physiologic regulator of platelet production. We have searched for small molecule compounds that mimic the action of TPO by using human TPO receptor-expressed in Ba/F3 cells, resulting in the discovery of AKR-501 (YM477). AKR-501 specifically targeted the TPO receptor and stimulated megakaryocytopoiesis throughout the development and maturation of megakaryocytes just as rhTPO did. AKR-501, however, was shown to be effective only in humans and chimpanzees with high species specificity. Therefore, we examined the in vivo platelet-increasing effect of AKR-501 in human platelet producing non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice transplanted with human fetal liver CD34(+) cells. Daily oral administration of AKR-501 dose-dependently increased the number of human platelets in these mice, with significance achieved at doses of 1 mg/kg and above. The peak unbound plasma concentrations of AKR-501 after administration at 1 mg/kg in NOD/SCID mice were similar to those observed following administration of an active oral dose in human subjects. These results suggest that AKR-501 is an orally-active TPO receptor agonist that may be useful in the treatment of patients with thrombocytopenia. PMID:19183407

Fukushima-Shintani, Mari; Suzuki, Ken-ichi; Iwatsuki, Yoshiyuki; Abe, Masaki; Sugasawa, Keizo; Hirayama, Fukushi; Kawasaki, Tomihisa; Nakahata, Tatsutoshi

2009-01-16

152

Multivalent porous silicon nanoparticles enhance the immune activation potency of agonistic CD40 antibody.  

PubMed

One of the fundamental paradigms in the use of nanoparticles to treat disease is to evade or suppress the immune system in order to minimize systemic side effects and deliver sufficient nanoparticle quantities to the intended tissues. However, the immune system is the body's most important and effective defense against diseases. It protects the host by identifying and eliminating foreign pathogens as well as self-malignancies. Here we report a nanoparticle engineered to work with the immune system, enhancing the intended activation of antigen presenting cells (APCs). We show that luminescent porous silicon nanoparticles (LPSiNPs), each containing multiple copies of an agonistic antibody (FGK45) to the APC receptor CD40, greatly enhance activation of B cells. The cellular response to the nanoparticle-based stimulators is equivalent to a 30-40 fold larger concentration of free FGK45. The intrinsic near-infrared photoluminescence of LPSiNPs is used to monitor degradation and track the nanoparticles inside APCs. PMID:22689074

Gu, Luo; Ruff, Laura E; Qin, Zhengtao; Corr, Maripat; Hedrick, Stephen M; Sailor, Michael J

2012-06-12

153

Regulation of neuronal activation by Alpha2A adrenergic receptor agonist.  

PubMed

Stress factors induce neuronal activation in brain areas that are related to anxiety and fear. High doses of caffeine induce neuronal activation with Ca2+ influx followed by expression of the immediate early gene c-fos. In the present study, we investigated c-Fos protein expression in stress-responsive brain areas induced by caffeine, as well as the role of alpha2A receptor in the regulation of neuronal activation. Immunohistochemical analysis showed that an acute effect of caffeine induced c-Fos protein expression in the hippocampus, the bed nucleus of stria terminalis (BNST), the lateral septum, the basolateral and central amygdala, the paraventricular hypothalamic nucleus (PVN), the locus coeruleus, and the lateral parabrachial nucleus (LPBN). However, c-Fos expression was attenuated after repeated treatment of caffeine, spaced 24 h apart, compared to a single acute effect. Alpha2A receptor activation with the agonist guanfacine attenuated the acute effect of caffeine in terms of c-Fos expression in neurons in the CA1-CA3 areas of hippocampus, the locus coeruleus and the LPBN as compared with effect of caffeine alone, whereas the number of c-Fos expressing neurons increased in the lateral septum, the dorsal BNST, the central amygdala, and the PVN, areas that are densely innervated by noradrenergic neurons. Guanfacine alone induced c-Fos protein expression in neurons in the central amygdala, the dorsal BNST, the PVN, the LPBN, and the caudal nucleus of the solitary tract. Guanfacine alone also induced phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) in neurons expressing c-Fos in the dorsal BNST, the central amygdala, and the LPBN. These results suggest that alpha2A receptor activation modulates synaptic transmission in neuronal circuits that are correlated with stress in vivo. PMID:21191826

Savchenko, Valentina L; Boughter, John D

2010-12-30

154

Synthesis and structure-activity relationship of fused-pyrimidine derivatives as a series of novel GPR119 agonists.  

PubMed

A series of fused-pyrimidine derivatives have been discovered as potent and orally active GPR119 agonists. A combination of the fused-pyrimidine structure and 4-chloro-2,5-difluorophenyl group provided the 5,7-dihydrothieno[3,4-d]pyrimidine 6,6-dioxide derivative 14a as a highly potent GPR119 agonist. Further optimization of the amino group at the 4-position in the pyrimidine ring led to the identification of 2-{1-[2-(4-chloro-2,5-difluorophenyl)-6,6-dioxido-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl]piperidin-4-yl}acetamide (16b) as an advanced analog. Compound 16b was found to have extremely potent agonistic activity and improved glucose tolerance at 0.1 mg/kg po in mice. We consider compound 16b and its analogs to have clear utility in exploring the practicality of GPR119 agonists as potential therapeutic agents for the treatment of type 2 diabetes mellitus. PMID:23010456

Negoro, Kenji; Yonetoku, Yasuhiro; Moritomo, Ayako; Hayakawa, Masahiko; Iikubo, Kazuhiko; Yoshida, Shigeru; Takeuchi, Makoto; Ohta, Mitsuaki

2012-09-07

155

Agonist-evoked calcium entry in vascular smooth muscle cells requires IP 3 receptor-mediated activation of TRPC1  

Microsoft Academic Search

Transient receptor potential canonical (TRPC) proteins have been proposed to function as plasma membrane Ca2+ channels activated by store depletion and\\/or by receptor stimulation. However, their role in the increase in cytosolic Ca2+ activated by contractile agonists in vascular smooth muscle is not yet elucidated. The present study was designed to investigate the functional and molecular properties of the Ca2+

Khalid Tai; Marie-Christine Hamaide; Huguette Debaix; Philippe Gailly; Maurice Wibo; Nicole Morel

2008-01-01

156

The effects of agonist and antagonist muscle activation on the knee extension moment–angle relationship in adults and children  

Microsoft Academic Search

The present study examined the effect of agonist activation and antagonist co-activation on the shape of the knee extension\\u000a moment–angle relationship in adults and children. Isometric knee extension maximum voluntary contractions (MVCs) were performed\\u000a at every 5° of knee flexion between 55° and 90° (full extension = 0°) by ten men, ten women, ten boys and ten girls. For each\\u000a trial, the

Thomas D. O’Brien; Neil D. Reeves; Vasilios Baltzopoulos; David A. Jones; Constantinos N. Maganaris

2009-01-01

157

A Peroxisome Proliferator-Activated Receptor Agonist Reduces Infarct Size in Transient but Not in Permanent Ischemia  

Microsoft Academic Search

Background and Purpose—Activators of peroxisome proliferator-activated receptor- (PPAR), a member of the PPAR family, increase levels of CuZn-superoxide dismutase (SOD) in cultured endothelium, suggesting a mechanism by which it may exert its protective effect within the brain. These properties raise the question of whether a PPAR agonist may be neuroprotective in models of ischemia without reperfusion, in which oxidative injury

Tomokazu Shimazu; Ikuo Inoue; Nobuo Araki; Yoshio Asano; Masahiko Sawada; Daisuke Furuya; Harumitsu Nagoya; Joel H. Greenberg

2010-01-01

158

Peroxisome proliferator-activated receptor ? agonist, HPP593, prevents renal necrosis under chronic ischemia.  

PubMed

The Goldblatt's 2 kidney 1 clip (2K1C) rat animal model of renovascular hypertension is characterized by ischemic nephropathy of the clipped kidney. 2K1C rats were treated with a specific peroxisome proliferator-activated receptor ? (PPAR?) agonist, HPP593. Clipped kidneys from untreated rats developed tubular and glomerular necrosis and massive interstitial, periglomerular and perivascular fibrosis. HPP593 kidneys did not exhibit any histochemical features of necrosis; fibrotic lesions were present only in perivascular areas. Necrosis in the untreated clipped kidneys was associated with an increased oxidative stress, up regulation and mitochondrial translocation of the pro-death protein BNIP3 specifically in tubules. In the kidneys of HPP593-treated rats oxidative stress was attenuated and BNIP3 protein decreased notably in the mitochondrial fraction when compared to untreated animals. In untreated clipped kidneys, mitochondria were dysfunctional as revealed by perturbations in the levels of MCAD, COXIV, TFAM, and Parkin proteins and AMPK activation, while in HPP593-treated rats these proteins remained at the physiological levels. Nuclear amounts of oxidative stress-responsive proteins, NRF1 and NRF2 were below physiological levels in treated kidneys. Mitochondrial biogenesis and autophagy were inhibited similarly in both treated and untreated 2K1C kidneys as indicated by a decrease in PGC1-? and deficiency of the autophagy-essential proteins LC3-II and ATG5. However, HPP593 treatment resulted in increased accumulation of p62 protein, an autophagic substrate and an enhancer of NRF2 activity. Therefore, inhibition of BNIP3 activation by the preservation of mitochondrial function and control of oxidative stress by PPAR? is the most likely mechanism to account for the prevention of necrotic death in the kidney under conditions of persistent ischemia. PMID:23691217

Fedorova, Larisa V; Sodhi, Komal; Gatto-Weis, Cara; Puri, Nitin; Hinds, Terry D; Shapiro, Joseph I; Malhotra, Deepak

2013-05-15

159

Dopamine agonist cabergoline inhibits levodopa-induced caspase activation in 6-OHDA-lesioned mice  

Microsoft Academic Search

Levodopa therapy is the gold standard for symptomatic treatment of Parkinson's disease (PD), but levodopa and\\/or dopamine (DA)-induced neurotoxicity have been reported in both in vitro and in vivo experimental studies. To clarify the beneficial effects of combining DA agonists with levodopa in PD, the present study examines the effects of cabergoline, a DA agonist, on the levodopa-induced abnormal increase

Ken-ichi Tanaka; Norio Ogawa

2005-01-01

160

Gene Expression Profile of Adipocyte Differentiation and Its Regulation by Peroxisome Proliferator-Activated Receptor  Agonists  

Microsoft Academic Search

PPAR is an adipocyte-specific nuclear hormone receptor. Agonists of PPAR, such as thiazolidinediones (TZDs), pro- mote adipocyte differentiation and have insulin-sensitizing effects in animals and diabetic patients. Affymetrix oligonu- cleotide arrays representing 6347 genes were employed to profile the gene expression responses of mature 3T3-L1 adi- pocytes and differentiating preadipocytes to a TZD PPAR agonist in vitro. The expression of

DAVID L. GERHOLD; FRANKLIN LIU; GUOQIANG JIANG; ZHIHUA LI; JIAN XU; MEIQING LU; JEFFREY R. SACHS; ANSUMAN BAGCHI; ARTHUR FRIDMAN; DANIEL J. HOLDER; THOMAS W. DOEBBER; JOEL BERGER; ALEX ELBRECHT; DAVID E. MOLLER; BEI B. ZHANG

2002-01-01

161

Influence of the Mesocortical Dopaminergic System on Activity, Food Hoarding, Social–Agonistic Behavior, and Spatial Delayed Alternation in Male Rats  

Microsoft Academic Search

In order to assess the behavioral role of the dopaminergic mesocortical input to the prefrontal cortex, bilateral lesions were made in the ventral tegmental area (VTA). The possibility of a functional recovery by the administration of a dopamine agonist was examined. General activity, food hoarding, social–agonistic behavior, and spatial delayed alternation performance were recorded in rats with VTA lesions and

C. J. Stam; J. P. C. de Bruin; A. M. van Haelst; J. van der Gugten; A. Kalsbeek

1989-01-01

162

Peroxisome proliferator-activated receptor-? agonists repress epithelial sodium channel expression in the kidney  

PubMed Central

Thiazolidinediones (TZDs), known as peroxisome proliferator-activated receptor (PPAR) agonists, are used to treat type 2 diabetes. However, ?5% of patients experience the treatment-limiting side effect of edema. Studies have implicated activation of the epithelial sodium channel (ENaC) as a cause of TZD-induced fluid retention, although there have been conflicting reports. The goal of this study was to resolve the role of PPAR? in control of ENaC isoforms in the kidney. Herein, we demonstrate in mice that rosiglitazone (RGZ), a PPAR? ligand, increases body weight and abdominal fat pad fluid content and reduces hematocrit. Seven days of RGZ decreases ENaC? and ENaC? mRNA and ENaC? protein expression in the kidney cortex, and acute treatment for 5 h with pioglitazone, another potent TZD, does not increase renal ENaC isoform mRNA or protein expression. Pioglitazone also decreases ENaC? and ENaC? mRNA expression in a cortical collecting duct cell line. As no direct transcriptional studies had been conducted, we examined the PPAR?-dependent regulation of ENaC. Pioglitazone represses ENaC? promoter activity, and this repression is partially relieved by inhibition of protein synthesis. Chromatin immunoprecipitation assays revealed that repression is associated with a decrease in histone H4K5 acetylation at the proximal ENaC? promoter. In summary, TZDs do not increase ENaC mRNA expression in the kidney, and in fact repress the ENaC? promoter via an indirect transcriptional mechanism.

Borsting, Emily; Cheng, Vicki Pei-Chun; Glass, Chris K.; Vallon, Volker

2012-01-01

163

Preferential activation of the vagal nodose nociceptive subtype by TRPA1 agonists in the guinea pig esophagus  

PubMed Central

Background The TRPA1 receptor is directly activated by a wide range of chemicals including many endogenous molecules relevant for esophageal pathophysiology. We addressed the hypothesis that the TRPA1 agonists differentially activate esophageal nociceptive subtypes depending on their embryological source (neural crest or epibranchial placodes). Methods Single cell RT-PCR and whole cell patch clamp recordings were performed on the vagal neurons retrogradely labeled from the guinea pig esophagus. Extracellular recordings were made in the isolated innervated esophagus preparation ex vivo. Key results Single cell RT-PCR revealed that the majority of the nodose (placodes-derived) and jugular (neural crest-derived) TRPV1-positive esophageal nociceptors express TRPA1. Single fiber recording showed that the TRPA1 agonists allyl-isothiocyanate (AITC) and cinnamaldehyde were effective in inducing robust action potential discharge in the nerve terminals of nodose nociceptors, but had far less effect in jugular nociceptors (approximately fivefold less). Higher efficacy of the TRPA1 agonists to activate nodose nociceptors was confirmed in the isolated esophagus-labeled vagal neurons in the whole cell patch clamp studies. Similarly to neural crest-derived vagal jugular nociceptors, the spinal DRG nociceptors that are also neural crest-derived were only modestly activated by allyl-isothiocyanate. Conclusions & Inferences We conclude that the TRPA1 agonists are substantially more effective activators of the placodes-derived than the neural crest-derived esophageal nociceptors. Our data predict that in esophageal diseases the presence of endogenous TRPA1 activators will be preferentially signaled by the vagal nodose nociceptors.

Brozmanova, M; Ru, F; Surdenikova, L; Mazurova, L; Taylor-Clark, T; Kollarik, M.

2011-01-01

164

Proteinase-Activated Receptor-2 Agonist Activates Anti-Influenza Mechanisms and Modulates IFN?-Induced Antiviral Pathways in Human Neutrophils  

PubMed Central

Proteinase-activated receptor-2 (PAR2) is expressed by human leukocytes and participates in the development of inflammatory diseases. Recent studies demonstrated an ability of PAR2 agonist to enhance IFN?-induced antiviral responses of human leukocytes. However, the precise cellular antiviral defense mechanisms triggered in leukocytes after stimulation with IFN? and/or PAR2 agonist remain elusive. Therefore, we aimed to identify neutrophil defense mechanisms involved in antiviral resistance. Here we demonstrated that PAR2 agonist enhanced IFN?-related reduction of influenza A virus (IAV) replication in human neutrophils. PAR2-mediated decrease in IAV replication was associated with reduced NS-1 transcription. Moreover, PAR2-dependent neutrophil activation resulted in enhanced myeloperoxidase degranulation and extracellular myeloperoxidase disrupted IAV. The production of ROS was elevated in response to PAR2 activation. Interestingly, IFN? did not influence both effects: PAR2 agonist-triggered myeloperoxidase (MPO) release and reactive oxygen species (ROS) production, which are known to limit IAV infections. In contrast, orthomyxovirus resistance gene A (MxA) protein expression was synergistically elevated through PAR2 agonist and IFN? in neutrophils. Altogether, these findings emphasize two PAR2-controlled antiviral mechanisms that are independent of or modulated by IFN?.

Shpacovitch, Victoria; Ehrhardt, Christina; Fastrich, Michaela; Goerge, Tobias; Ludwig, Stephan; Steinhoff, Martin

2013-01-01

165

Whole blood cytokine attenuation by cholinergic agonists ex vivo and relationship to vagus nerve activity in rheumatoid arthritis  

PubMed Central

Objective The central nervous system regulates innate immunity in part via the cholinergic anti-inflammatory pathway, a neural circuit that transmits signals in the vagus nerve that suppress pro-inflammatory cytokine production by an ?-7 nicotinic acetylcholine receptors (?7nAChR) dependent mechanism. Vagus nerve activity is significantly suppressed in patients with autoimmune diseases, including rheumatoid arthritis (RA). It has been suggested that stimulating the cholinergic anti-inflammatory pathway may be beneficial to patients, but it remains theoretically possible that chronic deficiencies in this pathway will render these approaches ineffective. Methods Here we addressed the hypothesis that inflammatory cells from RA patients can respond to cholinergic agonists with reduced cytokine production in the setting of reduced vagus nerve activity. Results Measurement of RR interval variability (heart rate variability, HRV), in RA patients (n =13) and healthy controls (n = 10) revealed that vagus nerve activity was significantly depressed in patients. Whole blood cultures stimulated by exposure to endotoxin produced significantly less tumour necrosis factor in samples from RA patients as compared to healthy controls. Addition of cholinergic agonists (nicotine and GTS-21) to the stimulated whole blood cultures however significantly suppressed cytokine production to a similar extent in patients and healthy controls. Conclusion These findings suggest that it is possible to pharmacologically target the ?7nAChR dependent control of cytokine release in RA patients with suppressed vagus nerve activity. As ?7nAChR agonists ameliorate the clinical course of collagen induced arthritis in animals, it may be possible in the future to explore whether ?7nAChR agonists can improve clinical activity in RA patients.

Bruchfeld, A.; Goldstein, R. S.; Chavan, S.; Patel, N. B.; Rosas-Ballina, M.; Kohn, N.; Qureshi, A. R.; Tracey, K. J.

2010-01-01

166

Cerebral radioprotection by pentobarbital: Dose-response characteristics and association with GABA agonist activity  

SciTech Connect

Pentobarbital reduces cerebral radiation toxicity; however, the mechanism of this phenomenon remains unknown. As an anesthetic and depressant of cerebral metabolism, pentobarbital induces its effects on the central nervous system by stimulating the binding of gamma-aminobutyric acid (GABA) to its receptor and by inhibiting postsynaptic excitatory amino acid activity. The purpose of this study is to investigate the role of these actions as well as other aspects of the radioprotective activity of pentobarbital. Fischer 344 rats were separated into multiple groups and underwent two dose-response evaluations. In one set of experiments to examine the relationship of radioprotection to pentobarbital dose, a range of pentobarbital doses (0 to 75 mg/kg) were given intraperitoneally prior to a constant-level radiation dose (70 Gy). In a second series of experiments to determine the dose-response relationship of radiation protection to radiation dose, a range of radiation doses (10 to 90 Gy) were given with a single pentobarbital dose. Further groups of animals were used to evaluate the importance of the timing of pentobarbital administration, the function of the (+) and (-) isomers of pentobarbital, and the role of an alternative GABA agonist (diazepam). In addition, the potential protective effects of alternative methods of anesthesia (ketamine) and induction of cerebral hypometabolism (hypothermia) were examined. Enhancement of survival time from acute radiation injury due to high-dose single-fraction whole-brain irradiation was maximal with 60 mg/kg of pentobarbital, and occurred over the range of all doses examined between 30 to 90 Gy. Protection was seen only in animals that received the pentobarbital before irradiation. Administration of other compounds that enhance GABA binding (Saffan and diazepam) also significantly enhanced survival time.

Olson, J.J.; Friedman, R.; Orr, K.; Delaney, T.; Oldfield, E.H. (National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD (USA))

1990-05-01

167

Locally expressed LHRH receptors mediate the oncostatic and antimetastatic activity of LHRH agonists on melanoma cells.  

PubMed

Malignant melanoma is a tumor known for its uncontrollable growth and aggressive metastatic behavior. The mean survival time for patients with a metastatic melanoma is estimated to be less than 6 months, tumor cells being refractory to the conventional chemotherapy. A better understanding of the mechanisms regulating melanoma growth and progression might help increase the number of therapeutic options for this pathology. In this paper, we have shown that LHRH receptors are present in the BLM melanoma cell line, both at mRNA and at protein level; a potent LHRH agonist (LHRH-A; Zoladex) binds to these receptors with high affinity. BLM cells also express the mRNA for LHRH, indicating the presence of an autocrine LHRH-based system in melanoma cells. The treatment of BLM cells with LHRH-A dose-dependently inhibited cell proliferation; this effect was found to be specific because it was completely abrogated by the simultaneous treatment of the cells with a LHRH antagonist. Similar observations could be obtained in another melanoma cell line (Me15392). The activation of LHRH receptors, by means of LHRH-A, also reduced the ability of melanoma cells to invade a reconstituted basement membrane (Matrigel) and to migrate through a Boyden's chamber in response to a chemotactic stimulus. These data represent the first report that 1) LHRH and LHRH receptors are expressed in melanoma tumor cells; and 2) the activation of tumor LHRH receptors reduces both the proliferation and the metastatic potential of melanoma cells. It is suggested that the expression of LHRH receptors might represent a new diagnostic marker for the detection and progression of melanoma. These receptors might also be considered as a possible molecular target for a hormone-based therapeutic approach to this tumor. PMID:12161512

Moretti, Roberta M; Montagnani Marelli, Marina; Van Groeninghen, Johan C; Limonta, Patrizia

2002-08-01

168

Agonist properties of pindolol at h5HT 1A receptors coupled to mitogen-activated protein kinase  

Microsoft Academic Search

At h5-HT1A receptors, stably transfected into Chinese Hamster Ovary Cells (CHO-h5-HT1A), the selective 5-HT1A receptor agonist, (+)8-hydroxy-dipropyl-amino-tetralin, ((+)8-OH-DPAT), transiently activated mitogen-activated protein kinase (MAPK) with a pEC50 of 8.5. The arylalkylamine, (?)-pindolol, also behaved as an agonist with a maximal effect of 57% relative to (+)8-OH-DPAT (100%), and with a pEC50 of 7.2. The selective 5-HT1A receptor antagonist, N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridinyl)cyclo-hexane carboxamide

Mark J Millan; Adrian Newman-Tancredi; Delphine Duqueyroix; Didier Cussac

2001-01-01

169

The GABAA agonist THIP produces slow wave sleep and reduces spindling activity in NREM sleep in humans  

Microsoft Academic Search

Recent studies in the rat demonstrated that systemic administration of muscimol and THIP, both selective GABAA receptor agonists, elevates slow wave activity in the EEG during non-rapid eye movement (NREM) sleep. In this placebo-controlled\\u000a study, we assessed the influence of an oral dose of 20?mg THIP on nocturnal sleep in young healthy humans. Compared to placebo,\\u000a THIP increased slow wave

Johannes Faulhaber; Axel Steiger; Marike Lancel

1997-01-01

170

Endocrine pharmacological characterization of progesterone antagonists and progesterone receptor modulators with respect to PR-agonistic and antagonistic activity  

Microsoft Academic Search

Studies were conducted to assess progesterone antagonists (PAs) and progesterone receptor modulators (PRMs) with respect to PR agonistic and antagonistic activities in vivo. These properties are not always adequately reflected in transactivation in vitro models. Studies were performed in pregnant rats, estrogen-primed rabbits (McPhail -Test), and cycling and pregnant guinea pigs. Tested compounds included mifepristone (RU486), onapristone, J867, J956, J1042,

Walter Elger; Julia Bartley; Birgitt Schneider; Günther Kaufmann; Gerd Schubert; Kristof Chwalisz

2000-01-01

171

PPAR Agonists Amplify iNOS Expression While Inhibiting NF B: Implications for Mesangial Cell Activation by Cytokines  

Microsoft Academic Search

In acute inflammation, the transcription factor NF-B is activated and increases the expression of multiple pro- inflammatory genes. Agonists of peroxisome proliferator acti- vated receptors (PPAR) have been reported to exert antiinflam- matory effects in various systems. In keeping with such an antiinflammatory role, it was found that several PPAR ago- nists, including Wy14,643, clofibrate, carbaprostacyclin, and ciglitazone inhibited NF-B

EVA CERNUDA-MOROLLON; FERNANDO RODRIGUEZ-PASCUAL; PETER KLATT; SANTIAGO LAMAS; DOLORES PEREZ-SALA

2002-01-01

172

Tesaglitazar, a Dual Peroxisome Proliferator- Activated Receptor Agonist (PPAR?\\/?), Improves Metabolic Abnormalities and Reduces Renal Injury in Obese Zucker Rats  

Microsoft Academic Search

Metabolic syndrome increases the risk of developing diabetes as well as cardiovascular and kidney diseases. This research studied the effects of tesaglitazar, a dual-acting peroxisome proliferator-activated receptor (PPAR)?\\/? agonist, on metabolic abnormalities and kidney injury in obese Zucker rats (OZR). Lean Zucker rats (LZR) and OZR were used as control groups. Tesaglitazar (1 ?mol\\/kg\\/day) was given for 8 weeks in

Jie Liao; Zohreh Soltani; Philip Ebenezer; Angel A. Isidro-Carrión; Rubin Zhang; Arshad Asghar; Erwin Aguilar; Joseph Francis; Xuejiao Hu; León Ferder; Efrain Reisin

2010-01-01

173

3-Acetoxyandrost-1,5-diene-17-ethylene ketal functions as a potent antiandrogen with marginal agonist activity  

Microsoft Academic Search

The majority of available antiandrogens have been reported to possess agonist activity to induce prostate-specific antigen, which might result in antiandrogen withdrawal syndrome. Here we report the identification of 3-acetoxyandrost-1,5-diene-17-ethyl- ene ketal (ADEK) from dehydroepiandrosterone metabolites and derivatives as a potent antiandrogen. We found ADEK could interrupt androgen binding to the androgen receptor (AR) and suppress androgen-induced transactivations of WT

Hiroshi Miyamoto; Padma Marwah; Ashok Marwah; Henry Lardy; Chawnshang Chang

174

Modulating ?-Opioid Receptor Phosphorylation Switches Agonist-dependent Signaling as Reflected in PKC? Activation and Dendritic Spine Stability*  

PubMed Central

A new role of G protein-coupled receptor (GPCR) phosphorylation was demonstrated in the current studies by using the ?-opioid receptor (OPRM1) as a model. Morphine induces a low level of receptor phosphorylation and uses the PKC? pathway to induce ERK phosphorylation and receptor desensitization, whereas etorphine, fentanyl, and [d-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (DAMGO) induce extensive receptor phosphorylation and use the ?-arrestin2 pathway. Blocking OPRM1 phosphorylation (by mutating Ser363, Thr370 and Ser375 to Ala) enabled etorphine, fentanyl, and DAMGO to use the PKC? pathway. This was not due to the decreased recruitment of ?-arrestin2 to the receptor signaling complex, because these agonists were unable to use the PKC? pathway when ?-arrestin2 was absent. In addition, overexpressing G protein-coupled receptor kinase 2 (GRK2) decreased the ability of morphine to activate PKC?, whereas overexpressing dominant-negative GRK2 enabled etorphine, fentanyl, and DAMGO to activate PKC?. Furthermore, by overexpressing wild-type OPRM1 and a phosphorylation-deficient mutant in primary cultures of hippocampal neurons, we demonstrated that receptor phosphorylation contributes to the differential effects of agonists on dendritic spine stability. Phosphorylation blockage made etorphine, fentanyl, and DAMGO function as morphine in the primary cultures. Therefore, agonist-dependent phosphorylation of GPCR regulates the activation of the PKC pathway and the subsequent responses.

Zheng, Hui; Chu, Ji; Zhang, Yuhan; Loh, Horace H.; Law, Ping-Yee

2011-01-01

175

The environmental stressor ultraviolet B radiation inhibits murine antitumor immunity through its ability to generate platelet-activating factor agonists  

PubMed Central

Ubiquitous pro-oxidative stressor ultraviolet B radiation (UVB) to human or mouse skin generates platelet-activating factor (PAF) and novel oxidatively modified glycerophosphocholines (Ox-GPCs) with PAF-receptor (PAF-R) agonistic activity. These lipids mediate systemic immunosuppression in a process involving IL-10. The current studies sought to determine the functional significance of UVB-mediated systemic immunosuppression in an established model of murine melanoma. We show that UVB irradiation augments B16F10 tumor growth and is dependent on host, but not melanoma cell; PAF-R-expression as UVB or the PAF-R agonist, carbamoyl PAF (CPAF), both promote B16F10 tumor growth in wild-type (WT) mice, independent of whether B16F10 cells express PAF-Rs, but do not augment tumor growth in Pafr ? /? mice. UVB-mediated augmentation of experimental murine tumor growth was inhibited with antioxidants, demonstrating the importance of Ox-GPC PAF-R agonists produced non-enzymatically. Host immune cells are required as CPAF-induced augmentation of tumor growth which is not seen in immunodeficient NOD SCID mice. Finally, depleting antibodies against IL-10 in WT mice or depletion of CD25-positive cells in FoxP3EGFP transgenic mice block UVB and/or CPAF-induced tumor growth supporting a requirement for IL-10 and Tregs in this process. These findings indicate that UVB-generated Ox-GPCs with PAF-R agonistic activity enhance experimental murine melanoma tumor growth through targeting host immune cells, most notably Tregs, to mediate systemic immunosuppression.

Sahu, Ravi P.; Turner, Matthew J.; DaSilva, Sonia C.; Rashid, Badri M.; Ocana, Jesus A.; Perkins, Susan M.; Konger, Raymond L.; Touloukian, Christopher E.; Kaplan, Mark H.; Travers, Jeffrey B.

2012-01-01

176

The environmental stressor ultraviolet B radiation inhibits murine antitumor immunity through its ability to generate platelet-activating factor agonists.  

PubMed

Ubiquitous pro-oxidative stressor ultraviolet B radiation (UVB) to human or mouse skin generates platelet-activating factor (PAF) and novel oxidatively modified glycerophosphocholines (Ox-GPCs) with PAF-receptor (PAF-R) agonistic activity. These lipids mediate systemic immunosuppression in a process involving IL-10. The current studies sought to determine the functional significance of UVB-mediated systemic immunosuppression in an established model of murine melanoma. We show that UVB irradiation augments B16F10 tumor growth and is dependent on host, but not melanoma cell; PAF-R-expression as UVB or the PAF-R agonist, carbamoyl PAF (CPAF), both promote B16F10 tumor growth in wild-type (WT) mice, independent of whether B16F10 cells express PAF-Rs, but do not augment tumor growth in Pafr -/- mice. UVB-mediated augmentation of experimental murine tumor growth was inhibited with antioxidants, demonstrating the importance of Ox-GPC PAF-R agonists produced non-enzymatically. Host immune cells are required as CPAF-induced augmentation of tumor growth which is not seen in immunodeficient NOD SCID mice. Finally, depleting antibodies against IL-10 in WT mice or depletion of CD25-positive cells in FoxP3(EGFP) transgenic mice block UVB and/or CPAF-induced tumor growth supporting a requirement for IL-10 and Tregs in this process. These findings indicate that UVB-generated Ox-GPCs with PAF-R agonistic activity enhance experimental murine melanoma tumor growth through targeting host immune cells, most notably Tregs, to mediate systemic immunosuppression. PMID:22542595

Sahu, Ravi P; Turner, Matthew J; DaSilva, Sonia C; Rashid, Badri M; Ocana, Jesus A; Perkins, Susan M; Konger, Raymond L; Touloukian, Christopher E; Kaplan, Mark H; Travers, Jeffrey B

2012-04-27

177

Peroxisome proliferator-activated receptor alpha agonist, clofibrate, has profound influence on myocardial fatty acid composition.  

PubMed

The hypolipidemic fibrates have been identified as agonists of the peroxisome proliferator-activated receptor alpha (PPARalpha), which plays a critical role in the regulation of cardiac fatty acid metabolism. Despite the widespread clinical use of fibrates, their role in myocardial oxidative stress and fatty acid composition is less known. In this study, male Sprague-Dawley rats were treated with either vehicle (olive oil, 1 ml/kg) or clofibrate (300 mg/kgday i.p.) for 1-14 days. Lipid peroxidation in heart homogenate was determined by thiobarbituric acid reactive substance (TBARS) assay. Results show that hearts from clofibrate-treated rats are more susceptible to FeSO(4)-induced TBARS production. The antioxidants including catalase and glutathione-related enzymes were marginally affected. We demonstrated that myocardial fatty acid composition was dramatically altered by clofibrate treatment. In hearts from clofibrate-treated rats, the principal n-6 polyunsaturated fatty acids (PUFAs), linoleic acid (C18:2 n-6) and arachidonic acid (C20:4 n-6), was significantly reduced, while the content of the principal n-3 PUFA, docosahexaenoic acid (C22:6 n-3), was markedly increased. The overall effect was to reduce n-6/n-3 ratio and increase the unsaturation extent of myocardial fatty acids. Functional study showed that hearts from clofibrate-treated rats had an improved recovery of post-ischemic contractile function and reduced ischemia/reperfusion (I/R)-induced infarct size. The data shows that clofibrate has a profound impact on cardiac fatty acid composition, which may contribute to its cardioprotective effect. PMID:16540100

Tian, Qi; Grzemski, Felicity A; Panagiotopoulos, Sianna; Ahokas, Jorma T

2006-03-15

178

Antidepressant-like activity of 5HT 1A agonists measured with the forced swim test  

Microsoft Academic Search

This study examined the abilities of 5-hydroxytryptamine (5-HT) agonists with varying selectivity for different subtypes of 5-HT receptors to produce antidepressant-like behavioral effects in the forced swim test in rats. The 5-HT1A agonists 8-OH-DPAT (0.125–1.0 mg\\/kg, SC) and tandospirone (SM-3997) (5–20 mg\\/kg, SC) both produced dose-related decreases in immobility time following subchronic treatment in rats. These effects were similar to

Scott Wieland; Irwin Lucki

1990-01-01

179

Quantitative structure-activity relationships for weak acid respiratory uncouplers to Vibrio fisheri  

SciTech Connect

Acute toxicity values of 16 organic compounds thought to elicit their response via the weak acid respiratory uncoupling mechanism of toxic action were secured from the literature. Regression analysis of toxicities revealed that a measured 5-min V. fisheri potency value can be used as a surrogate for the 30-min value. Regression analysis of toxicity versus hydrophobicity, measured as the 1-octanol/water partition coefficient (log K{sub ow}), was used to formulate a quantitative structure-activity relationship (QSAR). The equation log pT{sub 30}{sup {minus}1} = 0.489(log K{sub ow}) + 0.126 was found to be a highly predictive model. This V. fisheri QSAR is statistically similar to QSARs generated from weak acid uncoupler potency data for Pimephales promelas survivability and Tetrahymena pyriformis population growth impairment. This work, therefore, suggests that the weak acid respiratory uncoupling mechanism of toxic action is present in V. fisheri, and as such is not restricted to mitochondria-containing organisms.

Schultz, T.W. [Univ. of Tennessee, Knoxville, TN (United States). Coll. of Veterinary Medicine; Cronin, M.T.D. [Liverpool John Moores Univ. (United Kingdom). School of Pharmacy and Chemistry

1997-02-01

180

Detection of agonistic activities against five human nuclear receptors in river environments of Japan using a yeast two-hybrid assay.  

PubMed

A total of 16 water samples from four rivers in Japan were examined for their agonistic activities against five human nuclear receptors (estrogen receptor [ER] alpha, thyroid hormone receptor alpha, retinoic acid receptor [RAR] alpha, retinoid X receptor alpha, and vitamin D receptor) by using a yeast two-hybrid assay. The results suggest that the river environment is contaminated with endocrine disrupting chemicals (EDCs) that can interact with a variety of nuclear receptors and that contamination with those that have RAR agonistic activity may be more serious than contamination with well-known EDCs that act as ER agonists. PMID:19034372

Inoue, Daisuke; Nakama, Koki; Matsui, Hisae; Sei, Kazunari; Ike, Michihiko

2008-11-26

181

Organization and Activation of Sexual and Agonistic Behavior in theLeopard Gecko, Eublepharis macularius  

Microsoft Academic Search

Gonadal sex is determined by the temperature experienced during incubation in the leopard gecko (Eublepharis macularius). Furthermore, both factors, incubation temperature and gonadal sex, influence adult sexual and agonistic behavior in this species. Yet it is unclear whether such differences in behavior are irreversibly organized during development or are mediated by differences in hormone levels in adulthood. To address this

Turk Rhen; David Crews

2000-01-01

182

Isoflavones made simple - genistein's agonist activity for the beta-type estrogen receptor mediates their health benefits.  

PubMed

Soy isoflavones, the focus of much research and controversy, are often referred to as "weak estrogens". In fact, genistein is a relatively potent agonist for the recently characterized beta isoform of the estrogen receptor (ERbeta). The low nanomolar serum concentrations of unconjugated free genistein achieved with high-nutritional intakes of soy isoflavones are near the binding affinity of genistein for this receptor, but are about an order of magnitude lower than genistein's affinity for the "classical" alpha isoform of the estrogen receptor (ERalpha). Moreover, these concentrations are far too low to inhibit tyrosine kinases or topoisomerase II, in vitro activities of genistein often cited as potential mediators of its physiological effects. The thesis that these physiological effects are in fact mediated by ERbeta activation provides a satisfying rationale for genistein's clinical activities. Hepatocytes do not express ERbeta; this explains why soy isoflavones, unlike oral estrogen, neither modify serum lipids nor provoke the prothrombotic effects associated with increased risk for thromboembolic disorders. The lack of uterotrophic activity of soy isoflavones reflects the fact that ERalpha is the exclusive mediator of estrogen's impact in this regard. Vascular endothelium expresses both ERalpha and ERbeta, each of which has the potential to induce and activate nitric oxide synthase; this may account for the favorable influence of soy isoflavones on endothelial function in postmenopausal women and ovariectomized rats. The ERbeta expressed in osteoblasts may mediate the reported beneficial impact of soy isoflavones on bone metabolism. Suggestive evidence that soy-rich diets decrease prostate cancer risk, accords well with the observation that ERbeta appears to play an antiproliferative role in healthy prostate. In the breast, ERalpha promotes epithelial proliferation, whereas ERbeta has a restraining influence in this regard - consistent with the emerging view that soy isoflavones do not increase breast cancer risk, and possibly may diminish it. Premenopausal women enjoy a relative protection from kidney failure; since ERbeta is an antagonist of TGF-beta signaling in mesangial cells, soy isoflavones may have nephroprotective potential. Estrogen also appears to protect women from left ventricular hypertrophy, and recent evidence suggests that this effect is mediated by ERbeta. In conjunction with reports that isoflavones may have a modestly beneficial impact on menopausal symptoms - perhaps reflecting the presence of ERbeta in the hypothalamus - these considerations suggest that soy isoflavone regimens of sufficient potency may represent a safe and moderately effective alternative to HRT in postmenopausal women. Further clinical research is required to characterize the impact of optimal genistein intakes on endothelial and bone function in men. Studies with ERbeta-knockout mice could be helpful for clarifying whether ERbeta does indeed mediate the chief physiological effects of low nanomolar genistein. S-equol, a bacterial metabolite of daidzein, has an affinity for ERbeta nearly as high as that of genistein; whether this compound contributes meaningfully to the physiological efficacy of soy isoflavones in some individuals is still unclear. PMID:16513288

McCarty, Mark Frederick

2006-03-02

183

PPAR{gamma} agonist pioglitazone reduces matrix metalloproteinase-9 activity and neuronal damage after focal cerebral ischemia  

SciTech Connect

Pioglitazone, a peroxisome proliferator-activated receptor gamma (PPAR{gamma}) agonist, has shown protective effects against ischemic insult in various tissues. Pioglitazone is also reported to reduce matrix metalloproteinase (MMP) activity. MMPs can remodel extracellular matrix components in many pathological conditions. The current study was designed to investigate whether the neuroprotection of pioglitazone is related to its MMP inhibition in focal cerebral ischemia. Mice were subjected to 90 min focal ischemia and reperfusion. In gel zymography, pioglitazone reduced the upregulation of active form of MMP-9 after ischemia. In in situ zymograms, pioglitazone also reduced the gelatinase activity induced by ischemia. After co-incubation with pioglitazone, in situ gelatinase activity was directly reduced. Pioglitazone reduced the infarct volume significantly compared with controls. These results demonstrate that pioglitazone may reduce MMP-9 activity and neuronal damage following focal ischemia. The reduction of MMP-9 activity may have a possible therapeutic effect for the management of brain injury after focal ischemia.

Lee, Seong-Ryong [Department of Pharmacology, School of Medicine and Brain Research Institute, Keimyung University, Taegu (Korea, Republic of); Chronic Disease Research Center and Institute for Medical Science, School of Medicine, Keimyung University, Taegu (Korea, Republic of); Kim, Hahn-Young [Department of Neurology, Kunkuk University Hospital, Seoul (Korea, Republic of); Hong, Jung-Suk [Department of Pharmacology, School of Medicine and Brain Research Institute, Keimyung University, Taegu (Korea, Republic of); Department of Emergency Medicine, Ulsan University Hospital, Ulsan (Korea, Republic of); Baek, Won-Ki [Chronic Disease Research Center and Institute for Medical Science, School of Medicine, Keimyung University, Taegu (Korea, Republic of); Park, Jong-Wook [Chronic Disease Research Center and Institute for Medical Science, School of Medicine, Keimyung University, Taegu (Korea, Republic of); Department of Immunology, School of Medicine, Keimyung University, Taegu (Korea, Republic of)], E-mail: j303nih@dsmc.or.kr

2009-02-27

184

Parallel Functional Activity Profiling Reveals Valvulopathogens Are Potent 5-Hydroxytryptamine2B Receptor Agonists: Implications for Drug Safety Assessment  

PubMed Central

Drug-induced valvular heart disease (VHD) is a serious side effect of a few medications, including some that are on the market. Pharmacological studies of VHD-associated medications (e.g., fenfluramine, pergolide, methysergide, and cabergoline) have revealed that they and/or their metabolites are potent 5-hydroxytryptamine2B (5-HT2B) receptor agonists. We have shown that activation of 5-HT2B receptors on human heart valve interstitial cells in vitro induces a proliferative response reminiscent of the fibrosis that typifies VHD. To identify current or future drugs that might induce VHD, we screened approximately 2200 U.S. Food and Drug Administration (FDA)-approved or investigational medications to identify 5-HT2B receptor agonists, using calcium-based high-throughput screening. Of these 2200 compounds, 27 were 5-HT2B receptor agonists (hits); 14 of these had previously been identified as 5-HT2B receptor agonists, including seven bona fide valvulopathogens. Six of the hits (guanfacine, quinidine, xylometazoline, oxymetazoline, fenoldopam, and ropinirole) are approved medications. Twenty-three of the hits were then “functionally profiled” (i.e., assayed in parallel for 5-HT2B receptor agonism using multiple readouts to test for functional selectivity). In these assays, the known valvulopathogens were efficacious at concentrations as low as 30 nM, whereas the other compounds were less so. Hierarchical clustering analysis of the pEC50 data revealed that ropinirole (which is not associated with valvulopathy) was clearly segregated from known valvulopathogens. Taken together, our data demonstrate that patterns of 5-HT2B receptor functional selectivity might be useful for identifying compounds likely to induce valvular heart disease.

Huang, Xi-Ping; Setola, Vincent; Yadav, Prem N.; Allen, John A.; Rogan, Sarah C.; Hanson, Bonnie J.; Revankar, Chetana; Robers, Matt; Doucette, Chris

2009-01-01

185

Parallel functional activity profiling reveals valvulopathogens are potent 5-hydroxytryptamine(2B) receptor agonists: implications for drug safety assessment.  

PubMed

Drug-induced valvular heart disease (VHD) is a serious side effect of a few medications, including some that are on the market. Pharmacological studies of VHD-associated medications (e.g., fenfluramine, pergolide, methysergide, and cabergoline) have revealed that they and/or their metabolites are potent 5-hydroxytryptamine(2B) (5-HT(2B)) receptor agonists. We have shown that activation of 5-HT(2B) receptors on human heart valve interstitial cells in vitro induces a proliferative response reminiscent of the fibrosis that typifies VHD. To identify current or future drugs that might induce VHD, we screened approximately 2200 U.S. Food and Drug Administration (FDA)-approved or investigational medications to identify 5-HT(2B) receptor agonists, using calcium-based high-throughput screening. Of these 2200 compounds, 27 were 5-HT(2B) receptor agonists (hits); 14 of these had previously been identified as 5-HT(2B) receptor agonists, including seven bona fide valvulopathogens. Six of the hits (guanfacine, quinidine, xylometazoline, oxymetazoline, fenoldopam, and ropinirole) are approved medications. Twenty-three of the hits were then "functionally profiled" (i.e., assayed in parallel for 5-HT(2B) receptor agonism using multiple readouts to test for functional selectivity). In these assays, the known valvulopathogens were efficacious at concentrations as low as 30 nM, whereas the other compounds were less so. Hierarchical clustering analysis of the pEC(50) data revealed that ropinirole (which is not associated with valvulopathy) was clearly segregated from known valvulopathogens. Taken together, our data demonstrate that patterns of 5-HT(2B) receptor functional selectivity might be useful for identifying compounds likely to induce valvular heart disease. PMID:19570945

Huang, Xi-Ping; Setola, Vincent; Yadav, Prem N; Allen, John A; Rogan, Sarah C; Hanson, Bonnie J; Revankar, Chetana; Robers, Matt; Doucette, Chris; Roth, Bryan L

2009-07-01

186

The Reversal of Amphetamine-Induced Locomotor Activation by a Selective Neurotensin-1 Receptor Agonist Does Not Exhibit Tolerance  

PubMed Central

Neurotensin-1 (NT1) receptor agonists have been proposed as putative antipsychotic drugs. Recently brain penetrating NT analogues produced by stability enhancing modification of the smallest NT fragment, NT(8–13), have demonstrated antipsychotic-like efficacy after acute systemic injection in several preclinical animal tests predictive for antipsychotic efficacy. However, the evidence regarding the persistence versus tolerance of these effects after repeated administration is ambiguous. Previous studies have used compounds that non-selectively activated both NT1 and NT2 receptors, a factor which may have contributed to the ambiguity in findings regarding the emergence of tolerance. In this study, we investigated the effects of subchronic systemic administration of PD149163, a brain penetrating NT analogue with selectivity for the NT1 receptor, on amphetamine-induced locomotor activation, a classic preclinical test of antipsychotic-efficacy. Sprague Dawley rats were pretreated with eight consecutive daily subcutaneous (SC) injections of PD149163 or saline. On the ninth day rats received a pair of SC injections consisting of PD149163 or saline, followed by amphetamine (0.5mg/kg) or saline. Locomotor activity was then measured in photobeam equipped cages. The results indicated that repeated daily administration of PD149163 was able to antagonize amphetamine’s locomotor activating effect comparable to that of the first dose, despite that repeated administration of PD149163 produced an increase in baseline locomotor activity not seen after the first dose. The results do not support development of tolerance for the acute antipsychotic-like effect of NT1 agonists and thus lend support to the contention that NT1 agonists are viable candidates as putative novel antipsychotic drugs.

Feifel, David; Melendez, Gilia; Murray, Rachel J.; Tina Tran, Dan N.; Rullan, Michelle A.; Shilling, Paul D.

2009-01-01

187

Peroxisome Proliferator-Activated Receptor -?/?, -? Agonists and Resveratrol Modulate Hypoxia Induced Changes in Nuclear Receptor Activators of Muscle Oxidative Metabolism  

PubMed Central

PPAR-?, PPAR-?, and PPAR-?, and RXR in conjunction with PGC-1? and SIRT1, activate oxidative metabolism genes determining insulin sensitivity. In utero, hypoxia is commonly observed in Intrauterine Growth Restriction (IUGR), and reduced insulin sensitivity is often observed in these infants as adults. We sought to investigate how changes in oxygen tension might directly impact muscle PPAR regulation of oxidative genes. Following eight days in culture at 1% oxygen, C2C12 muscle myoblasts displayed a reduction of PGC-1?, PPAR-?, and RXR-? mRNA, as well as CPT-1b and UCP-2 mRNA. SIRT1 and PGC-1? protein was reduced, and PPAR-? protein increased. The addition of a PPAR-? agonist (L165,041) for the final 24 hours of 1% treatment resulted in increased levels of UCP-2 mRNA and protein whereas Rosiglitazone induced SIRT1, PGC-1?, RXR-?, PPAR-?, CPT-1b, and UCP-2 mRNA and SIRT1 protein. Under hypoxia, Resveratrol induced SIRT1, RXR-?, PPAR-? mRNA, and PPAR-? and UCP-2 protein. These findings demonstrate that hypoxia alters the components of the PPAR pathway involved in muscle fatty acid oxidative gene transcription and translation. These results have implications for understanding selective hypoxia adaptation and how it might impact long-term muscle oxidative metabolism and insulin sensitivity.

Regnault, Timothy R. H.; Zhao, Lin; Chiu, Jacky S. S.; Gottheil, Stephanie K.; Foran, Allison; Yee, Siu-Pok

2010-01-01

188

Structure-Activity Relationships in Nucleotide Oligomerization Domain-1 (Nod1)-Agonistic ?-Glutamyl-diaminopimelic Acid Derivatives  

PubMed Central

N-acyl-?-glutamyl-diaminopimelic acid is a prototype ligand for Nod1. We report a detailed SAR of C12-?-D-Glu-DAP. Analogues with glutaric or ?-aminobutyric acid replacing the glutamic acid show greatly attenuated Nod1-agonistic activity. Substitution of the meso-diaminopimelic (DAP) acid component with monoaminopimelic acid, L- or D-lysine, or cadaverine also results in reduced activity. The free amine on DAP is crucial. However, the N-acyl group on the D-glutamyl residue can be substituted with N-alkyl groups with full preservation of activity. The free carboxylates on the DAP and Glu components can also be esterified, resulting in more lipophilic, but active analogues. Transcriptomal profiling showed a dominant upregulation of IL-19, IL-20, IL-22, and IL-24, which may explain the pronounced Th2-polarizing activity of these compounds, and also implicate cell signaling mediated by TREM-1. These results may explain the hitherto unknown mechanism of synergy between Nod1- and TLR-agonists, and are likely to be useful in designing vaccine adjuvants.

Agnihotri, Geetanjali; Ukani, Rehman; Malladi, Subbalakshmi S.; Warshakoon, Hemamali J.; Balakrishna, Rajalakshmi; Wang, Xinkun; David, Sunil A.

2011-01-01

189

Acute fatigue impairs neuromuscular activity of anterior cruciate ligament-agonist muscles in female team handball players.  

PubMed

In sports, like team handball, fatigue has been associated with an increased risk of anterior cruciate ligament (ACL) injury. While effects of fatigue on muscle function are commonly assessed during maximal isometric voluntary contraction (MVC), such measurements may not relate to the muscle function during match play. The purpose of this study was to investigate the effect of muscle fatigue induced by a simulated handball match on neuromuscular strategy during a functional sidecutting movement, associated with the incidence of ACL injury. Fourteen female team handball players were tested for neuromuscular activity [electromyography (EMG)] during a sidecutting maneuver on a force plate, pre and post a simulated handball match. MVC was obtained during maximal isometric quadriceps and hamstring contraction. The simulated handball match consisted of exercises mimicking handball match activity. Whereas the simulated handball match induced a decrease in MVC strength for both the quadriceps and hamstring muscles (P<0.05), a selective decrease in hamstring neuromuscular activity was seen during sidecutting (P<0.05). This study shows impaired ACL-agonist muscle (i.e. hamstring) activity during sidecutting in response to acute fatigue induced by handball match play. Thus, screening procedures should involve functional movements to reveal specific fatigue-induced deficits in ACL-agonist muscle activation during high-risk phases of match play. PMID:20500560

Zebis, M K; Bencke, J; Andersen, L L; Alkjaer, T; Suetta, C; Mortensen, P; Kjaer, M; Aagaard, P

2010-05-24

190

The Novel PPAR ?/? Dual Agonist MHY 966 Modulates UVB-Induced Skin Inflammation by Inhibiting NF-?B Activity  

PubMed Central

Ultraviolet B (UVB; 290~320nm) irradiation-induced lipid peroxidation induces inflammatory responses that lead to skin wrinkle formation and epidermal thickening. Peroxisome proliferator-activated receptor (PPAR) ?/? dual agonists have the potential to be used as anti-wrinkle agents because they inhibit inflammatory response and lipid peroxidation. In this study, we evaluated the function of 2-bromo-4-(5-chloro-benzo[d]thiazol-2-yl) phenol (MHY 966), a novel synthetic PPAR ?/? dual agonist, and investigated its anti-inflammatory and anti-lipid peroxidation effects. The action of MHY 966 as a PPAR ?/? dual agonist was also determined in vitro by reporter gene assay. Additionally, 8-week-old melanin-possessing hairless mice 2 (HRM2) were exposed to 150 mJ/cm2 UVB every other day for 17 days and MHY 966 was simultaneously pre-treated every day for 17 days to investigate the molecular mechanisms involved. MHY 966 was found to stimulate the transcriptional activities of both PPAR ? and ?. In HRM2 mice, we found that the skins of mice exposed to UVB showed significantly increased pro-inflammatory mediator levels (NF-?B, iNOS, and COX-2) and increased lipid peroxidation, whereas MHY 966 co-treatment down-regulated these effects of UVB by activating PPAR ? and ?. Thus, the present study shows that MHY 966 exhibits beneficial effects on inflammatory responses and lipid peroxidation by simultaneously activating PPAR ? and ?. The major finding of this study is that MHY 966 demonstrates potential as an agent against wrinkle formation associated with chronic UVB exposure.

Park, Min Hi; Park, Ji Young; Lee, Hye Jin; Kim, Dae Hyun; Chung, Ki Wung; Park, Daeui; Jeong, Hyoung Oh; Kim, Hye Rim; Park, Chan Hum; Kim, So Ra; Chun, Pusoon; Byun, Youngjoo; Moon, Hyung Ryong; Chung, Hae Young

2013-01-01

191

The Novel PPAR ?/? Dual Agonist MHY 966 Modulates UVB-Induced Skin Inflammation by Inhibiting NF-?B Activity.  

PubMed

Ultraviolet B (UVB; 290~320nm) irradiation-induced lipid peroxidation induces inflammatory responses that lead to skin wrinkle formation and epidermal thickening. Peroxisome proliferator-activated receptor (PPAR) ?/? dual agonists have the potential to be used as anti-wrinkle agents because they inhibit inflammatory response and lipid peroxidation. In this study, we evaluated the function of 2-bromo-4-(5-chloro-benzo[d]thiazol-2-yl) phenol (MHY 966), a novel synthetic PPAR ?/? dual agonist, and investigated its anti-inflammatory and anti-lipid peroxidation effects. The action of MHY 966 as a PPAR ?/? dual agonist was also determined in vitro by reporter gene assay. Additionally, 8-week-old melanin-possessing hairless mice 2 (HRM2) were exposed to 150 mJ/cm(2) UVB every other day for 17 days and MHY 966 was simultaneously pre-treated every day for 17 days to investigate the molecular mechanisms involved. MHY 966 was found to stimulate the transcriptional activities of both PPAR ? and ?. In HRM2 mice, we found that the skins of mice exposed to UVB showed significantly increased pro-inflammatory mediator levels (NF-?B, iNOS, and COX-2) and increased lipid peroxidation, whereas MHY 966 co-treatment down-regulated these effects of UVB by activating PPAR ? and ?. Thus, the present study shows that MHY 966 exhibits beneficial effects on inflammatory responses and lipid peroxidation by simultaneously activating PPAR ? and ?. The major finding of this study is that MHY 966 demonstrates potential as an agent against wrinkle formation associated with chronic UVB exposure. PMID:24130794

Park, Min Hi; Park, Ji Young; Lee, Hye Jin; Kim, Dae Hyun; Chung, Ki Wung; Park, Daeui; Jeong, Hyoung Oh; Kim, Hye Rim; Park, Chan Hum; Kim, So Ra; Chun, Pusoon; Byun, Youngjoo; Moon, Hyung Ryong; Chung, Hae Young

2013-10-09

192

SMALL MOLECULE RECEPTOR AGONISTS AND ANTAGONISTS OF CCR3 PROVIDE INSIGHT INTO MECHANISMS OF CHEMOKINE RECEPTOR ACTIVATION  

PubMed Central

Chemokine receptor CCR3 is highly expressed by eosinophils and signals in response to binding of the eotaxin family of chemokines, which are upregulated in allergic disorders. Consequently, CCR3 blockade is of interest as a possible therapeutic approach for the treatment of allergic disease. We have described previously a bi-specific antagonist of CCR1 and CCR3 named UCB35625, which was proposed to interact with the transmembrane residues Y41, Y113 and E287 of CCR1, all of which are conserved in CCR3. Here, we show that cells expressing the CCR3 constructs Y113A and E287Q are insensitive to antagonism by UCB35625 and also exhibit impaired chemotaxis in response to CCL11/Eotaxin suggesting that these residues are important for antagonist binding and also receptor activation. Furthermore, mutation of the residue Y113 to alanine was found to turn the antagonist UCB35625 into a CCR3 agonist. Screens of small molecule libraries identified a novel specific agonist of CCR3 named CH0076989. This was able to activate eosinophils and transfectants expressing both wild-type CCR3 and a CCR1:CCR3 chimaeric receptor lacking the CCR3 amino-terminus, indicating that this region of CCR3 is not required for CH0076989 binding. A direct interaction with the transmembrane helices of CCR3 was supported by mutation of the residues Y41, Y113 and E287 which resulted in complete loss of CH0076989 activity, suggesting that the compound mimics activation by CCL11. We conclude that both agonists and antagonists of CCR3 appear to occupy overlapping sites within the transmembrane helical bundle, suggesting a fine line between agonism and antagonism of chemokine receptors.

Wise, Emma L.; Duchesnes, Cecile; da Fonseca, Paula C.A.; Allen, Rodger A.; Williams, Timothy J.; Pease, James E.

2007-01-01

193

Effects of the beta-2 adrenergic agonist zinterol on DRL behavior and locomotor activity  

Microsoft Academic Search

The purpose of the present study was to assess the behavioral effects of the beta adrenergic agonist zinterol and to determine whether its actions were mediated by beta adrenergic receptors. Zinterol reduced response rate and increased reinforcement rate of rats under a differential-reinforcement-of-low-rate schedule in a dose-dependent manner; significant decreases in response rate and increases in reinforcement rate were observed

James M. O'Donnell

1993-01-01

194

Synthetic partial agonists reveal key steps in IP3 receptor activation  

PubMed Central

Inositol 1,4,5-trisphosphate receptors (IP3R) are ubiquitous intracellular Ca2+ channels. IP3binding to the IP3-binding core (IBC) near the N-terminal initiates conformational changes that lead to opening of a pore. The mechanisms are unresolved. We synthesized 2-O-modified IP3 analogues that are partial agonists of IP3R. These are like IP3 in their interactions with the IBC, but they are less effective than IP3 in rearranging the relationship between the IBC and N-terminal suppressor domain (SD), and they open the channel at slower rates. IP3R with a mutation in the SD occupying a position similar to the 2-O-substituent of the partial agonists has a reduced open probability that is similar for full and partial agonists. Bulky or charged substituents from either the ligand or SD therefore block obligatory coupling of the IBC and SD. Analysis of ?G for ligand binding shows that IP3 is recognised by the IBC and conformational changes then propagate entirely via the SD to the pore.

Rossi, Ana M.; Riley, Andrew M.; Tovey, Stephen C.; Taufiq-Ur-Rahman; Dellis, Olivier; Taylor, Emily J. A.; Veresov, Valery G.; Potter, Barry V. L.; Taylor, Colin W.

2009-01-01

195

Inhibition of cell proliferation by potential peroxisome proliferator-activated receptor (PPAR) gamma agonists and antagonists.  

PubMed

This study was initiated to determine if potential PPAR gamma antagonists could block the inhibition of cell proliferation caused by 4-phenylbutyrate. The action of 4-phenylbutyrate differed from other PPAR gamma ligands examined in that it induces histone acetylation. Proliferation of DS19 mouse erythroleukemia cells was inhibited by PPAR gamma agonists (4-phenylbutyrate, rosiglitazone, ciglitazone and GW1929) and by potential PPAR gamma antagonists: BADGE (Biphenol A diglycidyl ether), GW9662, PD068235 and diclofenac. Combined incubations tended to exhibit additive inhibitory effects. Potential PPAR gamma agonists and antagonists inhibited the incorporation of thymidine into DNA of human prostate (PC3), colon (Caco-2) and breast (T47D) cancer cells but also affected NIH3T3 cells that have little or no expression of PPAR gamma. Lipid accumulation in T47D cells was seen after incubation with 4-phenylbutyrate and both potential PPAR gamma agonists and antagonists. The extent to which the effects of 4-phenylbutyrate on cell proliferation are mediated through PPAR gamma or induction of histone acetylation remains an open question. We conclude that potential PPAR gamma antagonists may fail to reverse the growth inhibitory effect of PPAR gamma ligands and may themselves act as growth inhibitory agents. PMID:15517883

Lea, Michael A; Sura, Monali; Desbordes, Charles

196

Inhibition of Oxidative Stress-Elicited AKT Activation Facilitates PPAR? Agonist-Mediated Inhibition of Stem Cell Character and Tumor Growth of Liver Cancer Cells  

PubMed Central

Emerging evidence suggests that tumor-initiating cells (TICs) are the most malignant cell subpopulation in tumors because of their resistance to chemotherapy or radiation treatment. Targeting TICs may be a key innovation for cancer treatment. In this study, we found that PPAR? agonists inhibited the cancer stem cell-like phenotype and attenuated tumor growth of human hepatocellular carcinoma (HCC) cells. Reactive oxygen species (ROS) initiated by NOX2 upregulation were partially responsible for the inhibitory effects mediated by PPAR? agonists. However, PPAR? agonist-mediated ROS production significantly activated AKT, which in turn promoted TIC survival by limiting ROS generation. Inhibition of AKT, by either pharmacological inhibitors or AKT siRNA, significantly enhanced PPAR? agonist-mediated inhibition of cell proliferation and stem cell-like properties in HCC cells. Importantly, in nude mice inoculated with HCC Huh7 cells, we demonstrated a synergistic inhibitory effect of the PPAR? agonist rosiglitazone and the AKT inhibitor triciribine on tumor growth. In conclusion, we observed a negative feedback loop between oxidative stress and AKT hyperactivation in PPAR? agonist-mediated suppressive effects on HCCs. Combinatory application of an AKT inhibitor and a PPAR? agonist may provide a new strategy for inhibition of stem cell-like properties in HCCs and treatment of liver cancer.

Xu, Yingqian; Li, Jingyi; Xu, Dongxu; Zhang, Li; Sun, Jiabin; Xia, Suhua; Zou, Feiyan; Liu, Yongzhong

2013-01-01

197

Pretreatment with muscarinic receptor agonist activates a calcium-inhibitable adenylate cyclase in GH3 pituitary cells.  

PubMed

We have demonstrated previously that pretreatment of GH3 pituitary cells with muscarinic agonists may induce a higher cAMP formation in response to vasoactive intestinal peptide (VIP) or forskolin. In the present study, we further examined the adenylate cyclase (AC) that may be involved. We found that carbachol-pretreatment enhanced both VIP- and forskolin-activated AC activities. The addition of calcium ions to the incubation buffer diminished this enhancing effect. Carbachol was found to induce a decrease in intracellular calcium concentration [Ca2+]i by inhibiting calcium influx through L-type Ca2+ channels. However, the incubation of cells in Ca(2+)-free buffer or in the presence of L-type Ca2+ channel blockers had no influence on forskolin-stimulated cAMP formation, although both treatments induced decreases in [Ca2+]i as carbachol did. On the other hand, incubation in the presence of LaCl3 at a low concentration not being able to enter cells, forskolin-stimulated cAMP formation as well as the enhancing effect of carbachol-pretreatment on this response, were both suppressed. Similar phenomena were observed when membrane-bound AC activities were measured in the presence of LaCl3. Taken together, these results seem to suggest that pretreatment of GH3 cells with muscarinic receptor agonist may activate a Ca(2+)-inhibitable AC for a higher stimulated response. Low intracellular calcium concentrations are essential but not sufficient for this effect. PMID:15716122

Chou, Yu-Chi; Fong, Jim C

2004-12-30

198

Inhibition of T cell activation and autoimmune diabetes using a B cell surface-linked CTLA-4 agonist  

PubMed Central

CTL-associated antigen 4 (CTLA-4) engagement negatively regulates T cell activation and function and promotes immune tolerance. However, it has been difficult to explore the biology of selective engagement of CTLA-4 in vivo because CTLA-4 shares its ligands, B7-1 and B7-2, with CD28. To address this issue, we developed a Tg mouse expressing a single-chain, membrane-bound anti–CTLA-4 Ab (scFv) on B cells. B and T cells developed normally and exhibited normal phenotype in the steady state and after activation in these mice. However, B cells from scFv Tg+ mice (sc?CTLA4+) prevented T cell proliferation and cytokine production in mixed lymphocyte reactions. Additionally, mice treated with sc?CTLA4+ B cells had decreased T cell–dependent B cell Ab production and class switching in vivo after antigen challenge. Furthermore, expression of this CTLA-4 agonist protected NOD mice from spontaneous autoimmune diabetes. Finally, this disease prevention occurred in Treg-deficient NOD.B7-1/B7-2 double-knockout mice, suggesting that the effect of the CTLA-4 agonist directly attenuates autoreactive T cell activation, not Treg activation. Together, results from this study demonstrate that selective ligation of CTLA-4 attenuates in vivo T cell responses, prevents development of autoimmunity, and represents a novel immunotherapeutic approach for the induction and maintenance of peripheral tolerance.

Fife, Brian T.; Griffin, Matthew D.; Abbas, Abul K.; Locksley, Richard M.; Bluestone, Jeffrey A.

2006-01-01

199

ADAP is required for normal ?IIb?3 activation by VWF/GP Ib-IX-V and other agonists  

PubMed Central

Interaction between von Willebrand factor (VWF) and platelet GP Ib-IX-V is required for hemostasis, in part because intracellular signals from VWF/GP Ib-IX-V activate the ligand-binding function of integrin ?IIb?3. Because they also induce tyrosine phosphorylation of the ADAP adapter, we investigated ADAP's role in GP Ib-IX-V signal transduction. Fibrinogen or ligand-mimetic POW-2 Fab binding to ?IIb?3 was stimulated by adhesion of ADAP+/+ murine platelets to dimeric VWF A1A2 but was significantly reduced in ADAP?/? platelets (P < .01). ?IIb?3 activation by ADP or a Par4 thrombin receptor agonist was also decreased in ADAP?/? platelets. ADAP stabilized the expression of another adapter, SKAP-HOM, via interaction with the latter's SH3 domain. However, no abnormalities in ?IIb?3 activation were observed in SKAP-HOM?/? platelets, which express normal ADAP levels, further implicating ADAP as a modulator of ?IIb?3 function. Under shear flow conditions over a combined surface of VWF A1A2 and fibronectin to test interactions involving GP Ib-IX-V and ?IIb?3, respectively, ADAP?/? platelets displayed reduced ?IIb?3-dependent stable adhesion. Furthermore, ADAP?/? mice demonstrated increased rebleeding from tail wounds. These studies establish ADAP as a component of inside-out signaling pathways that couple GP Ib-IX-V and other platelet agonist receptors to ?IIb?3 activation.

Kasirer-Friede, Ana; Moran, Barry; Nagrampa-Orje, Jennifer; Swanson, Ken; Ruggeri, Zaverio M.; Schraven, Burkhart; Neel, Benjamin G.; Koretzky, Gary; Shattil, Sanford J.

2007-01-01

200

The peroxisome proliferator-activated receptor-? agonist pioglitazone protects against cisplatin-induced renal damage in mice.  

PubMed

Peroxisome proliferator-activated receptor-? (PPAR-?) agonists not only improve metabolic abnormalities of diabetes and consequent diabetic nephropathy, but they also protect against non-diabetic kidney disease in experimental models. Here, we investigated the effect of PPAR-? agonist pioglitazone against acute renal injury on a cisplatin model in mice. Nephrotoxicity was induced by a single intraperitoneal (i.p.) injection of cisplatin (10?mg?kg(-1) ). Pioglitazone was administered for six consecutive days in doses of 15 or 30?mg?kg(-1) ?day(-1) , per os (p.o.), starting 3?days before cisplatin injection. Cisplatin treatment to mice induced a marked renal failure, characterized by a significant increase in serum urea and creatinine levels and alterations in renal tissue architecture. Cisplatin exposure induced oxidative stress as indicated by decreased levels of non-enzymatic antioxidant defenses [glutathione (GSH) and ascorbic acid levels] and components of the enzymatic antioxidant defenses [superoxide dismutase (SOD), catalase (CAT) glutathione peroxidase (GPx), glutathione reductase (GR) and and glutathione S-transferase(GST) activities)] in renal tissue. Administration of pioglitazone markedly protected against the increase in urea and creatinine levels and histological alterations in kidney induced by cisplatin treatment. Pioglitazone administration ameliorated GSH and ascorbic acid levels decreased by cisplatin exposure in mice. Pioglitazone protected against the inhibition of CAT, SOD, GPx, GR and GST activities induced by cisplatin in the kidneys of mice. These results indicated that pioglitazone has a protective effect against cisplatin-induced renal damage in mice. The protection is mediated by preventing the decline of antioxidant status. The results have implications in use of PPAR-? agonists in human application for protecting against drugs-induced nephrotoxicity. Copyright © 2012 John Wiley & Sons, Ltd. PMID:22987311

Jesse, Cristiano R; Bortolatto, Cristiani F; Wilhelm, Ethel A; Roman, Silvane Souza; Prigol, Marina; Nogueira, Cristina W

2012-09-14

201

The mechanism mediating the activation of acetyl-coenzyme A carboxylase-  gene transcription by the liver X receptor agonist T0-901317  

Microsoft Academic Search

In birds and mammals, agonists of the liver X re- ceptor (LXR) increase the expression of enzymes that make up the fatty acid synthesis pathway. Here, we investigate the mechanism by which the synthetic LXR agonist, T0-901317, increases the transcription of the acetyl-coenzyme A carbox- ylase-a (ACCa) gene in chick embryo hepatocyte cultures. Transfection analyses demonstrate that activation of ACCa

Saswata Talukdar; F. Bradley Hillgartner

2006-01-01

202

Allometric radial growth in muscle, comparing fibres with strong and with weak adenosine triphosphatase activity.  

PubMed Central

A large flock of male and female white turkeys (Meleagris gallopavo) was reared for 22 weeks after hatching. At two weeks intervals small groups of birds were removed from the flock and killed. Samples of sartorius muscles were taken from the bird nearest the mean weight for its group. Transverse frozen sections were tested for ATPase activity by calcium method at pH 9.4. Fibres were separated into two categories (strong-ATPase and weak-ATPase) and their mean minimum diameters were measured with a micrometer scale in the microscope eyepiece. Mean minimum diameters of different fibre types were compared using the logarithmic form of Huxley's allometric growth equation. Weak-ATPase fibres grew at a relatively faster rate than strong-ATPase fibres in both males and females (k = 1.12, P less than 0.01 and k = 1.14, P less than 0.01 respectively). Transition of muscle fibres from one histochemical type to another was not detected, so that differences in the rate of increase of mean diameters of different fibre types were attributed to allometric radial growth. The possibility that transitional fibres might make some contribution cannot, however, be totally ignored.

Swatland, H J

1979-01-01

203

Effect of sulphation on the oestrogen agonist activity of the phytoestrogens genistein and daidzein in MCF-7 human breast cancer cells  

PubMed Central

The phytoestrogens genistein, daidzein and the daidzein metabolite equol have been shown previously to possess oestrogen agonist activity. However, following consumption of soya diets, they are found in the body not only as aglycones but also as metabolites conjugated at their 4?- and 7-hydroxyl groups with sulphate. This paper describes the effects of monosulphation on the oestrogen agonist properties of these three phytoestrogens in MCF-7 human breast cancer cells in terms of their relative ability to compete with [3H]oestradiol for binding to oestrogen receptor (ER), to induce a stably transfected oestrogen-responsive reporter gene (ERE-CAT) and to stimulate cell growth. In no case did sulphation abolish activity. The 4?-sulphation of genistein reduced oestrogen agonist activity to a small extent in whole-cell assays but increased the relative binding affinity to ER. The 7-sulphation of genistein, and also of equol, reduced oestrogen agonist activity substantially in all assays. By contrast, the position of monosulphation of daidzein acted in an opposing manner on oestrogen agonist activity. Sulphation at the 4?-position of daidzein resulted in a modest reduction in oestrogen agonist activity but sulphation of daidzein at the 7-position resulted in an increase in oestrogen agonist activity. Molecular modelling and docking studies suggested that the inverse effects of sulphation could be explained by the binding of daidzein into the ligand-binding domain of the ER in the opposite orientation compared with genistein and equol. This is the first report of sulphation enhancing activity of an isoflavone and inverse effects of sulphation between individual phytoestrogens.

Pugazhendhi, D; Watson, K A; Mills, S; Botting, N; Pope, G S; Darbre, P D

2008-01-01

204

(1R, 3S)-(-)-Trans-PAT: A novel full-efficacy serotonin 5-HT2C receptor agonist with 5-HT2A and 5-HT2B receptor inverse agonist/antagonist activity  

PubMed Central

The serotonin 5-HT2A, 5-HT2B, and 5-HT2C G protein-coupled receptors signal primarily through G?q to activate phospholipase C (PLC) and formation of inositol phosphates (IP) and diacylglycerol. The human 5-HT2C receptor, expressed exclusively in the central nervous system, is involved in several physiological and psychological processes. Development of 5-HT2C agonists that do not also activate 5-HT2A or 5-HT2B receptors is challenging because transmembrane domain identity is about 75% among 5-HT2 subtypes. This paper reports 5-HT2 receptor affinity and function of (1R,3S)-(?)-trans-1-phenyl-3-dimethylamino-1,2,3,4-tetrahydronaphthalene (PAT), a small molecule that produces anorexia and weight-loss after peripheral administration to mice. (?)-Trans-PAT is a stereoselective full-efficacy agonist at human 5-HT2C receptors, plus, it is a 5-HT2A/5-HT2B inverse agonist and competitive antagonist. The Ki of (?)-trans-PAT at 5-HT2A, 5-HT2B, and 5-HT2C receptors is 410, 1200, and 37 nM, respectively. Functional studies measured activation of PLC/[3H]-IP formation in clonal cells expressing human 5-HT2 receptors. At 5-HT2C receptors, (?)-trans-PAT is an agonist (EC50 = 20 nM) comparable to serotonin in potency and efficacy. At 5-HT2A and 5-HT2B receptors, (?)-trans-PAT is an inverse agonist (IC50 = 490 and 1,000 nM, respectively) and competitive antagonist (KB = 460 and 1400 nM, respectively) of serotonin. Experimental results are interpreted in light of molecular modeling studies indicating the (?)-trans-PAT protonated amine can form an ionic bond with D3.32 of 5-HT2A and 5-HT2C receptors, but, not with 5-HT2B receptors. In addition to probing 5-HT2 receptor structure and function, (?)-trans-PAT is a novel lead regarding 5-HT2C agonist/5-HT2A inverse agonist drug development for obesity and neuropsychiatric disorders.

Booth, Raymond G.; Fang, Lijuan; Huang, Yingsu; Wilczynski, Andrzej; Sivendran, Sashikala

2009-01-01

205

Central effect of SNC 80, a selective and systemically active ?-opioid receptor agonist, on gastrointestinal propulsion in the mouse  

Microsoft Academic Search

We investigated the effects of SNC 80 ((+)-4-[?R)-?-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide), a new highly selective, non-peptidic and systemically active ?-opioid receptor agonist, on gastrointestinal and colonic propulsion in mice. Intraperitoneally (i.p.) SNC 80 (1, 10 and 30 mg\\/kg) significantly decreased gastrointestinal propulsion measured as transit of an orally administered charcoal meal. Pretreatment with the ?-opioid receptor antagonist, naltrindole (1 mg\\/kg) subcutaneously (s.c.), with

Maria Broccardo; Giovanna Improta; Alessandra Tabacco

1998-01-01

206

The CB2-preferring agonist JWH015 also potently and efficaciously activates CB1 in autaptic hippocampal neurons.  

PubMed

The G protein coupled receptors CB(1) and CB(2) are targets for the psychoactive constituents of cannabis, chief among them ?(9)-THC. They are also key components of the multifunctional endogenous cannabinoid signaling system. CB(1) and CB(2) receptors modulate a wide variety of physiological systems including analgesia, memory, mood, reward, appetite and immunity. Identification and characterization of selective CB(1) and CB(2) receptor agonists and antagonists will facilitate understanding the precise physiological and pathophysiological roles of cannabinoid receptors in these systems. This is particularly necessary in the case of CB(2) because these receptors are sparsely expressed and problematic to detect using traditional immunocytochemical approaches. 1-Propyl-2-methyl-3-(1-naphthoyl)indole (JWH015) is an aminoalkylindole that has been employed as a "CB(2)-selective" agonist in more than 40 published papers. However, we have found that JWH015 potently and efficaciously activates CB(1) receptors in neurons. Using murine autaptic hippocampal neurons, which express CB(1), but not CB(2) receptors, we find that JWH015 inhibits excitatory postsynaptic currents with an EC50 of 216nM. JWH015 inhibition is absent in neurons from CB(1)(-/-) cultures and is reversed by the CB(1) antagonist, SR141716 [200nM]. Furthermore, JWH015 partially occludes CB(1)-mediated DSE (?35% remaining), an action reversed by the CB(2) antagonist, AM630 [1 and 3?M], suggesting that high concentrations of AM630 also antagonize CB(1) receptors. We conclude that while JWH015 is a CB(2)-preferring agonist, it also activates CB(1) receptors at experimentally encountered concentrations. Thus, CB(1) agonism of JWH015 needs to be considered in the design and interpretation of experiments that use JWH015 to probe CB(2)-signaling. PMID:22921769

Murataeva, N; Mackie, K; Straiker, A

2012-08-14

207

Investigation of a Bubble Detector based on Active Electrolocation of Weakly Electric Fish  

NASA Astrophysics Data System (ADS)

Weakly electric fish employ active electrolocation for navigation and object detection. They emit an electric signal with their electric organ in the tail and sense the electric field with electroreceptors that are distributed over their skin. We adopted this principle to design a bubble detector that can detect gas bubbles in a fluid or, in principle, objects with different electric conductivity than the surrounding fluid. The evaluation of the influence of electrode diameter on detecting a given bubble size showed that the signal increases with electrode diameter. Therefore it appears that this detector will be more appropriate for large sized applications such as bubble columns than small sized applications such as bubble detectors in dialysis.

Mohan, M.; Mayekar, K.; Zhou, R.; von der Emde, G.; Bousack, H.

2013-04-01

208

Manifestation of weak ferromagnetism and photocatalytic activity in bismuth ferrite nanoparticles  

NASA Astrophysics Data System (ADS)

Bismuth ferrite (BFO) nanoparticles were synthesized by auto-ignition technique with and without adding ignition fuel such as citric acid. The presence of citric acid in the reaction mixture yielded highly-magnetic BFO/?-Fe2O3 nanocomposite. When this composite was annealed to 650°C, a single phase BFO was formed with average crystallite size of 50 nm and showed weak ferromagnetic behavior. Conversely, the phase pure BFO prepared without adding citric acid exhibited antiferromagnetism because of its larger crystallite size of around 70 nm. The visible-light driven photocatalytic activity of both the pure BFO and BFO/?-Fe2O3 nanocomposite were examined by degrading methyl orange dye. The pure BFO showed a moderate photocatalytic activity; while BFO/?-Fe2O3 nanocomposite showed enhanced activity. This could be probably due to the optimal band gap ratio between BFO and ?-Fe2O3 phases reduced the recombination of electron-hole pairs which aided in the enhancement of photocatalytic activity.

Sakar, M.; Balakumar, S.; Saravanan, P.; Jaisankar, S. N.

2013-02-01

209

Gating of transient receptor potential melastatin 8 (TRPM8) channels activated by cold and chemical agonists in planar lipid bilayers.  

PubMed

The transient receptor potential melastatin 8 (TRPM8) ion channel is a major sensor of environmental cold temperatures. It is activated by cold and chemical agonists, such as menthol and icilin. The activation of these channels both by cold and cooling agents requires the presence of the membrane phospholipid phosphatidylinositol 4,5-bisphosphate [PI(4,5)P(2)]. The mechanism of TRPM8 activation by physical and chemical factors is unknown, and the involvement of cellular signaling pathways has been considered. Here we have characterized the gating mechanism of the rat TRPM8 reconstituted in planar lipid bilayers and its activation by different stimuli. In this system, the influence of cellular signaling pathways can be excluded. We found that TRPM8 activated by cold exhibits steep temperature dependence [temperature coefficient (Q(10)) of ?40], and the channel openings are accompanied by large changes in entropy and enthalpy, suggesting a substantial conformation change. TRPM8 channel behavior upon menthol and icilin activation was distinguishable, and the effect of icilin depended on the presence of calcium on the intracellular side of the protein. Here we also demonstrate that PI(4,5)P(2) is the prime factor that impacts the gating of TRPM8 and that other phosphoinositides are less efficient in supporting channel activity. Menthol increases the potency of PI(4,5)P(2) to activate the channels and increases binding of phosphoinositides to the full-length channel protein. Our data demonstrate conclusively that TRPM8 is gated by cold and its chemical agonists directly, and that dependence of its gating on PI(4,5)P(2) is a result of direct specific interactions with the lipid. PMID:20844147

Zakharian, Eleonora; Cao, Chike; Rohacs, Tibor

2010-09-15

210

GR94839, a kappa-opioid agonist with limited access to the central nervous system, has antinociceptive activity.  

PubMed

1. The pharmacological profile of GR94839, a kappa-opioid agonist with limited access to the central nervous system, has been investigated. Its antinociceptive activity has been compared with that of GR103545, a centrally-penetrating kappa-agonist and ICI204448, the previously described peripherally-selective kappa-agonist. 2. GR94839 was a potent agonist in the rabbit vas deferens in vitro assay for kappa-opioid receptors (IC50: 1.4 +/- 0.3 nM; n = 6), but had limited activity at mu- or delta-opioid receptors. 3. In the mouse abdominal constriction test, GR94839 was 238 fold more potent when given i.c.v. (ED50: 0.008 (0.004-0.029) mg kg-1; n = 18) than when s.c. (ED50: 1.9 (0.7-3.1) mg kg-1; n = 30). In comparison, GR103545 was equipotent when given i.c.v. or s.c. 4. After intravenous administration, the maximum plasma to brain concentration-ratio attained by GR94839 was 18 compared with 2 for GR85571, a structurally-related kappa-agonist that is centrally-penetrating. 5. GR94839 inhibited the 2nd phase of the rat formalin response at doses 7 fold lower than those required to inhibit the 1st phase (ED50 vs 1st phase: 10.2 (6.7-17.1) mg kg-1, s.c.; ED50 vs 2nd phase: 1.4 (1.0-1.8) mg kg-1, s.c.; n = 18). GR103545 was equipotent against the two phases. 6. Intraplantar administration of the opioid antagonists, norbinaltorphimine (100 micrograms) or naltrexone (1 microgram), reversed the antinociceptive effect of systemic GR94839 (3 mg kg-1, s.c.) against the 2nd phase of the formalin response and intraplantar injection of GR94839 (30-100 micrograms) selectively inhibited the 2nd phase.7. GR94839 and IC1204448 reversed the hyperalgesia in the zymosan-inflamed rat paw at doses (ED50 GR94839: 2.0 (1.1-3.2) mg kg-', s.c.; ED50 IC1204448: 1.2 (0.8-1.7) mg kg-', s.c.), lower than those required to raise the noxious pressure threshold in the non-inflamed paw (EDSO GR94839: 16.4 (8.6-46.7) mg kg', s.c.; ED50 IC1204448: 68.0 (22.1-32000) mg kg', s.c.). GR103545 raised the noxious presure threshold in the inflamed and non-inflamed paws at the same doses.8. GR94839 was sedative in the rat rotarod test (ED50: 35 (12-245) mg kg-', s.c.) at doses higher than those required to inhibit the 2nd phase of the formalin response or reverse hyperalgesia in the zymosan-inflamed rat paw. The doses were comparable to those that inhibited the 1st phase of the formalin response and raised the noxious pressure threshold in the non-inflamed paw.9. The results suggest that GR94839 is a selective kappa-agonist which has antinociceptive activity against inflammatory pain at doses that produce limited central effects. These antinociceptive effects are probably mediated at peripheral opioid receptors. PMID:1327387

Rogers, H; Birch, P J; Harrison, S M; Palmer, E; Manchee, G R; Judd, D B; Naylor, A; Scopes, D I; Hayes, A G

1992-08-01

211

High throughput screening and structure-activity relationship study of potential ?2A-adrenoceptor agonists by LANCETM cAMP assay.  

PubMed

G protein-coupled receptors (GPCRs) are signaling molecules with a wide variety of skills. Members of this large family of membrane protein have been shown to regulate the activities of the different signaling pathways of the ligand specific manner. ?2-adrenoceptors (?2-ARs) are one of the GPCRs and the stimulation of them could modulate many classical effects such as hypotension, bradycardia, etc. Recently, ?2A-AR is more and more important for its role in the therapeutic applications in central nervous system (CNS) diseases.High throughput screening of ?2A-AR agonists was established by LANCETM cAMP assay from a compound library of 80,000 small-molecule compounds to find out potential human ?2A-adrenoceptor (?2A-AR) agonists that might have therapeutic effect in CNS diseases. From the preliminary and secondary screening, 37 compounds were identified as ?2AAR agonists, and six compounds among them presented more pronounced ?2A-AR stimulating activity than guanfacine, a selective ?2A-AR agonist. The study provided referred data for the development of potent ?2A-AR agonists and suggested that the existence of the parent structure (1, 2, 4-benzothiadiazine 1, 1-dioxide) bodes well for pharmaceutical development of ?2A-AR agonists. PMID:23514320

Yang, Huan; He, Ling; Yan, Ming; He, Jian-Guo; Yu, Tao

2013-06-28

212

Highly efficient biocompatible neuroprotectants with dual activity as antioxidants and P2Y receptor agonists.  

PubMed

Currently, there is a need for novel, biocompatible, and effective neuroprotectants for the treatment of neurodegenerative diseases and brain injury associated with oxidative damage. Here, we developed nucleotide-based neuroprotectants acting dually as antioxidants and P2Y-R agonists. To improve the potency, selectivity, and metabolic stability of ATP/ADP, we substituted adenine C2-position by Cl and P?/P? position by borano group, 6-9. Nucleotides 6-9 inhibited oxidation in cell-free systems (Fe(II)-H2O2), as detected by ESR (IC50 up to 175 ?M), and ABTS assay (IC50 up to 40 ?M). They also inhibited FeSO4-induced oxidative stress in PC12 cells (IC50 of 80-200 nM). 2-Cl-ADP(?-BH3), 7a, was found to be the most potent P2Y1-R agonist currently known (EC50 7 nM) and protected primary cortical neurons from FeSO4 insult (EC50 170 nM). In addition, it proved to be metabolically stable in human blood serum (t(1/2) 7 vs 1.5 h for ADP). Hence, we propose 7a as a highly promising neuroprotectant. PMID:23751098

Azran, Sagit; Förster, Daniel; Danino, Ortal; Nadel, Yael; Reiser, Georg; Fischer, Bilha

2013-06-10

213

Antinociceptive activity of ?4?2* neuronal nicotinic receptor agonist A-366833 in experimental models of neuropathic and inflammatory pain.  

PubMed

Nerve injury, diabetes and cancer therapies are often associated with painful neuropathy. The mechanism underlying neuropathic pain remains poorly understood. The current therapies have limited efficacy and are associated with dose-limiting side effects. Compounds which act at nicotinic acetylcholine receptors have also been reported to show antinociceptive activity. Among those, tebanicline (ABT-594) a potent nicotinic acetylcholine receptor agonist demonstrated analgesic effects across a broad range of preclinical models of nociceptive and neuropathic pain. Another nicotinic acetylcholine receptor agonist, 5-[(1R,5S)-3,6-Diazabicyclo[3.2.0]heptan-6-yl]nicotinonitrile (A-366833) from the same group produced significant antinociceptive effects in writhing pain (abdominal constriction), acute thermal pain (hot box), persistent chemical pain (formalin induced) and neuropathic pain. In the present study, we have demonstrated the efficacy of A-366833 in rat models of chronic constriction injury, partial sciatic nerve ligation, spinal nerve ligation, diabetes, chemotherapy induced neuropathic pain and complete Freund's adjuvant induced inflammatory pain. A-366833 (1, 3 and 6 mg/kg) produced significant antihyperalgesic effects in partial sciatic nerve ligation, chronic constriction injury and spinal nerve ligation models. In the diabetic and chemotherapy induced neuropathic models compound exerted antinociceptive activity and reduction in the mechanical hyperalgesia was observed. A-366833 dose dependently attenuated mechanical hyperalgesia in complete Freund's adjuvant induced inflammatory pain model. These results demonstrated broad-spectrum antinociceptive properties of A-366833 in both neuropathic and inflammatory pain models. PMID:21756895

Nirogi, Ramakrishna; Jabaris, Sugin Lal; Jayarajan, Pradeep; Abraham, Renny; Shanmuganathan, Dhanalakshmi; Rasheed, Mohammed Abdul; Royapalley, Praveen Kumar; Goura, Venkatesh

2011-07-03

214

Similarities and differences in activities and agonistic behavior of male Eastern grey kangaroos (Macropus giganteus) in captivity and the wild.  

PubMed

The behavior of free-ranging and captive Eastern grey kangaroos Macropus giganteus, was observed by the same observers, with similar methods and under similar vegetational/climatic conditions in a 4.2-ha enclosure at Neuwied Zoo, Germany and at Grampians National Park, Victoria, Australia. Data were collected from a zoo group of 56 animals and a free-ranging mob of 50 to 60 animals. Males were individually identified and observed: 3 large males, 9 medium males, and 10 small males in the zoo, and 8 large, 9 medium, and approximately 10 small males in the National Park were present. Activities in both situations were very similarly distributed: Feed took up less time in the zoo, resting was almost similar in both situations, alert behavior was significantly different for small and medium males, locomotor activities were similar in large males and females, autogrooming occurred significantly more in the zoo only for females. Frequencies of social interactions were slightly greater for large males and females in the zoo. Agonistic behavior in males was more frequent in the zoo situation, except for ritualized fights. Sequences of agonistic behavior were more predictable in the zoo. No differences in escalation tendencies toward potentially injurious fighting could be found. Zoo Biol 19:529-539, 2000. Copyright 2000 Wiley-Liss, Inc. PMID:11180414

Höhn, Marion; Kronschnabl, Martina; Gansloßer, Udo

2000-01-01

215

Evaluation of effectiveness of chemical and physical sewage treatment technologies for removal of retinoic acid receptor agonistic activity detected in sewage effluent.  

PubMed

Retinoic acid receptor (RAR) is a nuclear receptor involved in vertebrate morphogenesis, growth, cellular differentiation, and tissue homeostasis. Excess expression of the retinoid signaling can cause various developmental toxicities in animals and humans. We previously found that influents from sewage treatment plants (STPs) in Japan had a RAR agonistic activity and the activity cannot be removed completely by conventional biological treatments. In this study, we assessed the performance of chemical and physical sewage treatment technologies-ozonation, ultraviolet treatment, chlorination, coagulation using polyaluminium chloride (PAC) and ferric sulfate, and filtration with ultrafiltration (UF), nanofiltration (NF), and reverse osmosis (RO) membranes-in removal of RAR agonistic activity of STP effluent. All water treatment experiments were conducted in laboratory-scale reactors. The RAR agonistic activity of samples was measured using a yeast two-hybrid assay. Results showed that the effectiveness of tested technologies on the removal of RAR agonistic activity can be ranked as RO or NF > chlorination > ozonation > MF > UV > coagulation with ferric sulfate>coagulation with PAC. Furthermore, the effectiveness of chlorination might rank lower because excess reaction might bring a side effect by producing some RAR agonistic by-product(s). PMID:19542651

Inoue, D; Matsui, H; Sei, K; Hu, J; Yang, M; Aragane, J; Hirotsuji, J; Ike, M

2009-01-01

216

Screening of agonistic activities against four nuclear receptors in wastewater treatment plants in Japan using a yeast two-hybrid assay.  

PubMed

To assess the potential endocrine disruptive effects through multiple nuclear receptors (NRs), especially non-steroidal NRs, in municipal wastewater, we examined the agonistic activities on four NRs (estrogen receptor alpha, thyroid hormone receptor alpha, retinoic acid receptor alpha and retinoid X receptor alpha) of untreated and treated wastewater from municipal wastewater treatment plants (WWTPs) in Japan using a yeast two-hybrid assay. Investigation of the influent and effluent of seven WWTPs revealed that agonistic activities against steroidal and non-steroidal NRs were always detected in the influents and partially remained in the effluents. Further investigation of four WWTPs employing conventional activated sludge, pseudo-anoxic-oxic, anoxic-oxic and anaerobic-anoxic-oxic processes revealed that the ability to reduce the agonistic activity against each of the four NRs varies depending on the treatment process. These results indicated that municipal wastewater in Japan commonly contains endocrine disrupting chemicals that exert agonistic activities on steroidal and non-steroidal NRs, and that some of these chemicals are released into the natural aquatic environment. Although the results obtained in yeast assays suggested that measured levels of non-steroidal NR agonists in the effluent of WWTPs were not likely to cause any biological effect, further study is required to assess their possible risks in detail. PMID:21476351

Inoue, Daisuke; Nakama, Koki; Sawada, Kazuko; Watanabe, Taro; Matsui, Hisae; Sei, Kazunari; Nakanishi, Tsuyoshi; Ike, Michihiko

2011-01-01

217

Functional Impact of Allosteric Agonist Activity of Selective Positive Allosteric Modulators of Metabotropic Glutamate Receptor Subtype 5 in Regulating Central Nervous System Function  

PubMed Central

Positive allosteric modulators (PAMs) of metabotropic glutamate receptor subtype 5 (mGlu5) have emerged as an exciting new approach for the treatment of schizophrenia and other central nervous system (CNS) disorders. Of interest, some mGlu5 PAMs act as pure PAMs, only potentiating mGlu5 responses to glutamate whereas others [allosteric agonists coupled with PAM activity (ago-PAMs)] potentiate responses to glutamate and have intrinsic allosteric agonist activity in mGlu5-expressing cell lines. All mGlu5 PAMs previously shown to have efficacy in animal models act as ago-PAMs in cell lines, raising the possibility that allosteric agonist activity is critical for in vivo efficacy. We have now optimized novel mGlu5 pure PAMs that are devoid of detectable agonist activity and structurally related mGlu5 ago-PAMs that activate mGlu5 alone in cell lines. Studies of mGlu5 PAMs in cell lines revealed that ago-PAM activity is dependent on levels of mGlu5 receptor expression in human embryonic kidney 293 cells, whereas PAM potency is relatively unaffected by levels of receptor expression. Furthermore, ago-PAMs have no agonist activity in the native systems tested, including cortical astrocytes and subthalamic nucleus neurons and in measures of long-term depression at the hippocampal Schaffer collateral-CA1 synapse. Finally, studies with pure PAMs and ago-PAMs chemically optimized to provide comparable CNS exposure revealed that both classes of mGlu5 PAMs have similar efficacy in a rodent model predictive of antipsychotic activity. These data suggest that the level of receptor expression influences the ability of mGlu5 PAMs to act as allosteric agonists in vitro and that ago-PAM activity observed in cell-based assays may not be important for in vivo efficacy.

Noetzel, Meredith J.; Rook, Jerri M.; Vinson, Paige N.; Cho, Hyekyung P.; Days, Emily; Zhou, Y.; Rodriguez, Alice L.; Lavreysen, Hilde; Stauffer, Shaun R.; Niswender, Colleen M.; Xiang, Zixiu; Daniels, J. Scott; Jones, Carrie K.; Lindsley, Craig W.; Weaver, C. David

2012-01-01

218

Cannabinoid agonists induce contractile responses through Gi/o-dependent activation of phospholipase C in the bovine ciliary muscle.  

PubMed

This study was undertaken to investigate the effect of some cannabinoid agonists on the bovine ciliary muscle. Both anandamide and CP 55,940 (cis-3-(2-hydroxy-4-(1,1-dimethyl heptyl) phenyl)-trans-4-(3-hydroxypropyl) cyclohexanol) produced a concentration-dependent contractile response in ciliary muscle. These responses were inhibited by SR 141716A (N-[piperidin-1-yl]-5-(4-cholophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide) (0.1 and 1 microM) but not by SR 144528 (N-[1S)-endo-1,3,3-trimethyl bicyclo[2.2.1] heptan-2-yl] 5-(4-chloro-3-methylphenyl)-1-(4 methoxy benzyl)-pyrazole-3-carboxamide) (1 and 10 microM). A preincubation with G(i/o) protein inhibitor pertussis toxin (500 ng/ml) for 20 min inhibited the contractile action of anandamide and CP 55,940. In addition, the phospholipase C inhibitor U73122 (1[6-[[(17 beta)-3-methoxyestra-1,3,5(10)-trien-17-yl] amino] hexyl]-1H-pyrrole-2,5-dione) blocked the anandamide- and CP 55,940-induced contractions, whereas the protein kinase C activator, phorbol 12,13 dibutyrate (PDBu) significantly potentiated the contractions evoked by cannabinoid receptor agonists. We evaluated the binding of [(3)H]CP 55,940, which specifically labelled a single class of cannabinoid sites with affinity in low subnanomolar range (K(d)=0.6 nM) and the maximal number of binding sites of 1243 fmol/mg protein. Binding of [(3)H]CP 55,940 was inhibited by ligands having a major selectivity for cannabinoid (CB(1)) receptors. These findings provide strong evidence of the involvement of cannabinoid CB(1) receptors promoting contraction in the bovine ciliary muscle. Furthermore, the action of cannabinoid receptor agonists appears to be mediated via phospholipase C. These data also contribute to elucidate the cannabinoid CB(1) receptor pivotal role in the modulation of intraocular pressure and to show that cannabinoid receptor agonists may be regarded as potential antiglaucoma agents. PMID:15194451

Lograno, Marcello D; Romano, Maria Rosaria

2004-06-21

219

A new perspective for schizophrenia: TAAR1 agonists reveal antipsychotic- and antidepressant-like activity, improve cognition and control body weight.  

PubMed

Schizophrenia is a chronic, severe and highly complex mental illness. Current treatments manage the positive symptoms, yet have minimal effects on the negative and cognitive symptoms, two prominent features of the disease with critical impact on the long-term morbidity. In addition, antipsychotic treatments trigger serious side effects that precipitate treatment discontinuation. Here, we show that activation of the trace amine-associated receptor 1 (TAAR1), a modulator of monoaminergic neurotransmission, represents a novel therapeutic option. In rodents, activation of TAAR1 by two novel and pharmacologically distinct compounds, the full agonist RO5256390 and the partial agonist RO5263397, blocks psychostimulant-induced hyperactivity and produces a brain activation pattern reminiscent of the antipsychotic drug olanzapine, suggesting antipsychotic-like properties. TAAR1 agonists do not induce catalepsy or weight gain; RO5263397 even reduced haloperidol-induced catalepsy and prevented olanzapine from increasing body weight and fat accumulation. Finally, TAAR1 activation promotes vigilance in rats and shows pro-cognitive and antidepressant-like properties in rodent and primate models. These data suggest that TAAR1 agonists may provide a novel and differentiated treatment of schizophrenia as compared with current medication standards: TAAR1 agonists may improve not only the positive symptoms but also the negative symptoms and cognitive deficits, without causing adverse effects such as motor impairments or weight gain. PMID:22641180

Revel, F G; Moreau, J-L; Pouzet, B; Mory, R; Bradaia, A; Buchy, D; Metzler, V; Chaboz, S; Groebke Zbinden, K; Galley, G; Norcross, R D; Tuerck, D; Bruns, A; Morairty, S R; Kilduff, T S; Wallace, T L; Risterucci, C; Wettstein, J G; Hoener, M C

2012-05-29

220

Biological activities of the LXR? and ? agonist, 4?-hydroxycholesterol, and of its isomer, 4?-hydroxycholesterol, on oligodendrocytes: effects on cell growth and viability, oxidative and inflammatory status.  

PubMed

The biochemical and biological properties of 4?-hydroxycholesterol and of its isomer, 4?-hydroxycholesterol, are not well known. So, we determined the ability of 4?- and 4?-hydroxycholesterol to react with LXR? and LXR?, and we characterized the activities of these oxysterols on oligodendrocytes which are myelin synthesizing cells. The effects of 4?- and 4?-hydroxycholesterol were studied on 158N murine oligodendrocytes to assess their activities on cell growth and viability, oxidative and inflammatory status. To this end different parameters were used: cell counting with trypan blue; identification of dead cells and cell cycle analysis with propidium iodide; evaluation of mitochondrial depolarization, lysosomal membrane integrity, actin depolimerization, nuclear morphology, and superoxide anion production after staining with JC-1, acridine orange, rhodamine-phalloidin, Hoechst 33342, and dihydroethidium, respectively; evaluation of ultrastructural changes by transmission electron microscopy, and cytokine quantification with a cytometric bead array. Only 4?-hydroxycholesterol is a LXR? and ? agonist. No cytotoxic effects were found with 4?-hydroxycholesterol except a slight inhibition of cell growth at elevated concentrations. At high concentrations, 4?-hydroxycholesterol was not only able to inhibit cell growth, but also to induce cell death associated with a loss of mitochondrial transmembrane potential, dysfunctions of lysosomal membrane integrity, and superoxide anion overproduction. These side effects were lower than those observed with 7-ketocholesterol and 25-hydroxycholesterol used as positive controls. On oligodendrocyte murine primary cultures, only lysosomal membrane integrity was slightly affected under treatment with 4?- and 4?-hydroxycholesterol. So, 4?- and 4?-hydroxycholesterol have different biological activities. Their ability to induce cytotoxic effects on oligodendrocytes can be considered as weak comparatively to 7-ketocholesterol and 25-hydroxycholesterol. PMID:23220593

Nury, Thomas; Samadi, Mohammad; Varin, Alexis; Lopez, Tatiana; Zarrouk, Amira; Boumhras, Mohamed; Riedinger, Jean-Marc; Masson, David; Vejux, Anne; Lizard, Gérard

2012-12-07

221

Protein Kinase D Isoforms Are Expressed In Rat and Mouse Primary Sensory Neurons and Are activated by Agonists Of Protease-Activated Receptor 2  

PubMed Central

Serine proteases generated during injury and inflammation cleave protease-activated receptor 2 (PAR2) on primary sensory neurons to induce neurogenic inflammation and hyperalgesia. Hyperalgesia requires sensitization of transient receptor potential vanilloid (TRPV) ion channels by mechanisms involving phospholipase C and protein kinase C (PKC). The protein kinase D (PKD) serine/threonine kinases are activated by diacylglycerol and PKCs, and can phosphorylate TRPV1. Thus, PKDs may participate in novel signal transduction pathways triggered by serine proteases during inflammation and pain. However, it is not known whether PAR2 activates PKD, and the expression of PKD isoforms by nociceptive neurons is poorly characterized. Using HEK293 cells transfected with PKDs, we found that PAR2 stimulation promoted plasma membrane translocation and phosphorylation of PKD1, PKD2 and PKD3, indicating activation. This effect was partially dependent on PKC?. Using immunofluorescence and confocal microscopy, with antibodies against PKD1/PKD2, PKD3 and neuronal markers, we found that PKDs were expressed in rat and mouse dorsal root ganglia (DRG) neurons, including nociceptive neurons that expressed TRPV1, PAR2 and neuropeptides. PAR2 agonist induced phosphorylation of PKD in cultured DRG neurons, indicating PKD activation. Intraplantar injection of PAR2 agonist also caused phosphorylation of PKD in neurons of lumbar DRG, confirming activation in vivo. Thus, PKD1, PKD2 and PKD3 are expressed in primary sensory neurons that mediate neurogenic inflammation and pain transmission, and PAR2 agonists activate PKDs in HEK293 cells and DRG neurons in culture and in intact animals. PKD may be a novel component of a signal transduction pathway for protease-induced activation of nociceptive neurons and an important new target for anti-inflammatory and analgesic therapies.

Amadesi, Silvia; Grant, Andrew D.; Cottrell, Graeme S.; Vaksman, Natalya; Poole, Daniel P.; Rozengurt, Enrique; Bunnett, Nigel W.

2009-01-01

222

Effects of weak acids, UV and proton motive force inhibitors on pyrazinamide activity against Mycobacterium tuberculosis in vitro  

Microsoft Academic Search

Background: Pyrazinamide is a paradoxical frontline tuberculosis drug characterized by high sterilizing in vivo activity but poor in vitro activity. Pyrazinamide is thought to act by the entrapment of pyrazinoic acid in the bacterial cell, leading to acidification and membrane damage. Consequently, the effects of weak acids and molecules affecting membranes added to pyrazinamide were studied. Objectives: To examine the

Mary Margaret Wade; Ying Zhang

2006-01-01

223

Retinoid x receptor agonists modulate foxp3+ regulatory T cell and th17 cell differentiation with differential dependence on retinoic Acid receptor activation.  

PubMed

Retinoic acid (RA) enhances TGF-?-dependent differentiation of Foxp3(+) inducible regulatory T cells (iTregs) and inhibits Th17 differentiation by binding to the RA receptor (RAR)/retinoid X receptor (RXR) heterodimer. The major physiologic RA, all-trans-RA, binds to RAR but not to RXR at physiological concentrations. It remained unclear whether RXR-mediated stimulation affected the iTregs and Th17 differentiation. We found in this study that the RXR agonists, PA024 and tributyltin, augmented the ability of all-trans-RA or the RAR agonist Am80 to enhance CD4(+)CD25(-) T cells to acquire Foxp3 expression and suppressive function. However, they failed to enhance Foxp3 expression in the presence of the RAR antagonist LE540, suggesting that the effect depends on RAR-mediated signals. They exerted the effect largely by augmenting the ability of all-trans-RA to suppress the production of IL-4, IL-21, and IFN-? that inhibited Foxp3 expression. Agonists of peroxisome proliferator-activated receptors and liver X receptors (LXRs), permissive partners of RXR, failed to enhance Foxp3 expression. In contrast, RXR agonists and LXR agonists suppressed IL-17 expression. The RXR-mediated suppression was not canceled by blocking RAR stimulation but was likely to involve permissive activation of LXRs. All-trans-RA and an agonist of RXR or LXR additively suppressed IL-17 expression when the all-trans-RA concentration was low. RXR agonists also suppressed Ccr6 expression that is essential for Th17 cells to enter the CNS. Accordingly, tributyltin treatment of mice ameliorated experimental autoimmune encephalomyelitis through regulating Th17 cell activities. These results suggest that RXR stimulation modulates Foxp3(+) iTreg and Th17 differentiation with differential dependence on RAR-mediated stimulation. PMID:23980207

Takeuchi, Hajime; Yokota-Nakatsuma, Aya; Ohoka, Yoshiharu; Kagechika, Hiroyuki; Kato, Chieko; Song, Si-Young; Iwata, Makoto

2013-08-26

224

Pharmacological profile of the abeorphine 201-678, a potent orally active and long lasting dopamine agonist  

SciTech Connect

The central dopaminergic effects of an abeorphine derivative 201-678 were compared to those of apomorphine and bromocriptine in different model systems. After oral administration, this compound induced contralateral turning in rats with 6-hydroxydopamine induced nigral lesions and exhibited strong anti-akinetic properties in rats with 6-hydroxydopamine induced hypothalamic lesions. It decreased dopamine metabolism in striatum and cortex, but did not modify noradrenaline and serotonin metabolism in the rat brain. 201-678 counteracted the in vivo increase of tyrosine hydroxylase activity induced by ..gamma..-butyrolactone. In vitro it stimulated DA-sensitive adenylate cyclase and inhibited acetylcholine release from rat striatal slices. This compound had high affinity for /sup 3/H-dopamine and /sup 3/H-clonidine binding sites. These results indicate that 201-678 is a potent, orally active dopamine agonist with a long duration of action. Furthermore it appears more selective than other dopaminergic drugs. 29 references, 5 figures, 3 tables.

Jaton, A.L.; Giger, R.K.A.; Vigouret, J.M.; Enz, A.; Frick, W.; Closse, A.; Markstein, R.

1986-01-13

225

Weak” ultrasonic pre-treatment on anaerobic digestion of flocculated activated biosolids  

Microsoft Academic Search

This study examined how “weak” ultrasonic pre-treatment affects anaerobic digestion of waste biosolids, treated with a cationic polyelectrolyte flocculant. In relation to pre-treatment, the term “weak” used refers to the fact that the total ultrasonic energy input to biosolids is insufficient to fully disrupt its floc structure or the cell walls, as described in the literature. Methane production potential, floc

C. P Chu; D. J Lee; Bea-Ven Chang; C. S You; J. H Tay

2002-01-01

226

GLP-1R Agonist Liraglutide Activates Cytoprotective Pathways and Improves Outcomes After Experimental Myocardial Infarction in Mice  

PubMed Central

OBJECTIVE Glucagon-like peptide-1 receptor (GLP-1R) agonists are used to treat type 2 diabetes, and transient GLP-1 administration improved cardiac function in humans after acute myocardial infarction (MI) and percutaneous revascularization. However, the consequences of GLP-1R activation before ischemic myocardial injury remain unclear. RESEARCH DESIGN AND METHODS We assessed the pathophysiology and outcome of coronary artery occlusion in normal and diabetic mice pretreated with the GLP-1R agonist liraglutide. RESULTS Male C57BL/6 mice were treated twice daily for 7 days with liraglutide or saline followed by induction of MI. Survival was significantly higher in liraglutide-treated mice. Liraglutide reduced cardiac rupture (12 of 60 versus 46 of 60; P = 0.0001) and infarct size (21 ± 2% versus 29 ± 3%, P = 0.02) and improved cardiac output (12.4 ± 0.6 versus 9.7 ± 0.6 ml/min; P = 0.002). Liraglutide also modulated the expression and activity of cardioprotective genes in the mouse heart, including Akt, GSK3?, PPAR?-?, Nrf-2, and HO-1. The effects of liraglutide on survival were independent of weight loss. Moreover, liraglutide conferred cardioprotection and survival advantages over metformin, despite equivalent glycemic control, in diabetic mice with experimental MI. The cardioprotective effects of liraglutide remained detectable 4 days after cessation of therapy and may be partly direct, because liraglutide increased cyclic AMP formation and reduced the extent of caspase-3 activation in cardiomyocytes in a GLP-1R–dependent manner in vitro. CONCLUSIONS These findings demonstrate that GLP-1R activation engages prosurvival pathways in the normal and diabetic mouse heart, leading to improved outcomes and enhanced survival after MI in vivo.

Noyan-Ashraf, Mohammad Hossein; Momen, M. Abdul; Ban, Kiwon; Sadi, Al-Muktafi; Zhou, Yu-Qing; Riazi, Ali M.; Baggio, Laurie L.; Henkelman, R. Mark; Husain, Mansoor; Drucker, Daniel J.

2009-01-01

227

Thiazolidinedione Class of Peroxisome Proliferator-Activated Receptor   Agonists Prevents Neuronal Damage, Motor Dysfunction, Myelin Loss, Neuropathic Pain, and Inflammation after Spinal Cord Injury in Adult Rats  

Microsoft Academic Search

Thiazolidinediones (TZDs) are potent synthetic agonists of the ligand-activated transcription factor peroxisome proliferator- activated receptor- (PPAR). TZDs were shown to induce neuroprotection after cerebral ischemia by blocking inflamma- tion. As spinal cord injury (SCI) induces massive inflammation that precipitates secondary neuronal death, we currently ana- lyzed the therapeutic efficacy of TZDs pioglitazone and rosigli- tazone after SCI in adult rats.

Seung-Won Park; Jae-Hyuk Yi; Guruwattan Miranpuri; Irawan Satriotomo; Kellie Bowen; Daniel K. Resnick; Raghu Vemuganti

2006-01-01

228

Closure of the Venus flytrap module of mGlu8 receptor and the activation process: Insights from mutations converting antagonists into agonists  

Microsoft Academic Search

Ca2+, pheromones, sweet taste compounds, and the main neurotransmitters glutamate and -aminobutyric acid activate G protein-coupled receptors (GPCRs) that constitute the GPCR family 3. These receptors are dimers, and each subunit has a large extracellular domain called a Venus flytrap module (VFTM), where agonists bind. This module is connected to a heptahelical domain that activates G proteins. Recently, the structure

Anne-Sophie Bessis; Philippe Rondard; Florence Gaven; Isabelle Brabet; Nicolas Triballeau; Laurent Prézeau; Francine Acher; Jean-Philippe Pin

2002-01-01

229

Bezafibrate, a Peroxisome Proliferator-Activated Receptors Agonist, Decreases Body Temperature and Enhances Electroencephalogram Delta-Oscillation during Sleep in Mice  

Microsoft Academic Search

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the nu- clear receptor family. PPARs play a critical role in lipid and glucose metabolism. We examined whether chronic treat- ment with bezafibrate, a PPAR agonist, would alter sleep and body temperature (BT). Mice fed with a control diet were monitored for BT, electroencephalogram (EEG), and electromyogram for 48 h

Sachiko Chikahisa; Kumiko Tominaga; Tomoko Kawai; Kazuyoshi Kitaoka; Katsutaka Oishi; Norio Ishida; Kazuhito Rokutan; Hiroyoshi Sei

2008-01-01

230

Structure-activity relationships of 2,4-diphenyl-1H-imidazole analogs as CB2 receptor agonists for the treatment of chronic pain.  

PubMed

A series of 2,4-diphenyl-1H-imidazole analogs have been synthesized and displayed potent human CB2 agonist activity. Many of these analogs showed high functional selectivity over human CB1 receptors. The syntheses, structure-activity relationships, and selected pharmacokinetic data of these analogs are described. PMID:21115245

Yang, Shu-Wei; Smotryski, Jennifer; Matasi, Julius; Ho, Ginny; Tulshian, Deen; Greenlee, William J; Brusa, Rossella; Beltramo, Massimiliano; Cox, Kathleen

2010-11-11

231

A Novel Form of 4-1BBL Has Better Immunomodulatory Activity than an Agonistic Anti-4-1BB Ab without Ab Associated Severe Toxicity  

PubMed Central

Agonistic Abs to select costimulatory members of CD28 and TNFR family have shown efficacy in various preclinical cancer immunotherapeutic settings. However, the use of agonistic Abs is often associated with severe toxicity due to nonspecific activation of lymphocytes. We hypothesized that natural costimulatory ligands may serve as more potent and safer alternative to agonistic Abs for immunotherapy. In this communication, we focused on 4-1BBL as the molecule of choice because of the pleiotropic effects of 4-1BB signaling in the immune system and the demonstrated therapeutic efficacy of 4-1BB agonistic Abs in preclinical cancer and infection models. We report that a novel form of soluble ligand, SA-4-1BBL, delivered more potent and qualitatively different signals to T cells than an agonistic Ab. Importantly, while treatment of naïve mice with the agonistic Ab resulted in severe toxicity, as assessed by enlarged spleen and peripheral LNs, non-specific T cell proliferation, hepatitis, and systemic inflammatory cytokine production, treatment with SA-4-1BBL lacked these immune anomalies. Agonistic Ab treatment produced full toxicity in Fc?R?/? or complement C1q?/? or C3?/? knockout mice, suggesting lack of involvement of stimulatory Fc?Rs or complement system in the observed toxicity. Naïve and memory T cells served as direct targets of anti-4-1BB Ab mediated toxicity. Potent immunostimulatory activity combined with lack of toxicity rationalizes further development of soluble SA-4-1BBL as an immunomodulatory component of therapeutic vaccines against cancer and chronic infections.

Schabowsky, Rich-Henry; Elpek, Kutlu G; Madireddi, Shravan; Sharma, Rajesh K; Yolcu, Esma S.; Bandura-Morgan, Laura; Miller, Robert; MacLeod, Kathryn J; Mittler, Robert S.; Shirwan, Haval

2009-01-01

232

Activation of tongue-expressed GPR40 and GPR120 by non caloric agonists is not sufficient to drive preference in mice.  

PubMed

There is mounting evidence that, in addition to texture and olfaction, taste plays a role in the detection of long chain fatty acids. Triglycerides, the main components of oils and dietary fat, are hydrolyzed in the mouth by a lingual lipase secreted from the von Ebner gland and the released free fatty acids are detected by the taste system. GPR40 and GPR120, two fatty acid responsive G-protein-coupled receptors (GPCRs), are expressed in taste bud cells, and knockout mice lacking either of those receptors have blunted taste nerve responses to and reduced preference for fatty acids. Here we investigated whether activation of those GPCRs is sufficient to elicit fat taste and preference. Five non-fatty acid agonists of GPR40 and two non-fatty acid agonists of GPR120 activated the glossopharyngeal nerve of wild-type mice but not of knockout mice lacking the cognate receptor. In human subjects, two-alternative forced choice (2-AFC) tests, triangle tests and sensory profiling showed that non fatty acid agonists of GPR40 dissolved in water are detected in sip and spit tests and elicit a taste similar to that of linoleic acid, whereas 2-AFC tests showed that two agonists of GPR120 in water are not perceived fattier than water alone. Wild-type mice did not show any preference for five agonists of GPR40, two agonists of GPR120 and mixtures of both agonists over water in two-bottle preference tests. Together these data indicate that GPR40 mediated taste perception is not sufficient to generate preference. PMID:23831422

Godinot, N; Yasumatsu, K; Barcos, M E; Pineau, N; Ledda, M; Viton, F; Ninomiya, Y; le Coutre, J; Damak, S

2013-07-04

233

Design, synthesis, and structure-activity relationship study of bicyclic piperazine analogs of indole-3-carboxamides as novel cannabinoid CB1 receptor agonists.  

PubMed

Bicyclic piperazine derivatives were synthesized as conformationally constrained analogs of N-alkyl piperazines and were found to be potent CB1 receptor agonists. The CB1 receptor agonist activity was dependent upon the absolute configuration of the chiral center of the bicyclic ring system. Although the conformational constraint did not protect the compounds from metabolism by N-dealkylation, several bicyclic analogs were found to be more potent than the unconstrained lead compound. Compound 8b demonstrated potent antinociceptive activity in vivo. PMID:21074434

Moir, Elizabeth M; Yoshiizumi, Kazuya; Cairns, Jim; Cowley, Phillip; Ferguson, Morag; Jeremiah, Fiona; Kiyoi, Takao; Morphy, Richard; Tierney, Jason; Wishart, Grant; York, Mark; Baker, James; Cottney, Jean E; Houghton, Andrea K; McPhail, Petula; Osprey, Andrew; Walker, Glenn; Adam, Julia M

2010-10-20

234

Discovery, design and synthesis of Y-shaped peroxisome proliferator-activated receptor ? agonists as potent anti-obesity agents in vivo.  

PubMed

We have discovered and demonstrated the in vitro and in vivo PPAR?-selective activity of novel Y-shaped agonists. These compounds activated hPPAR? with EC(50) values between 1 and 523 nM. Surprisingly, compounds 10a, 11d, 11e and 11f were the most potent and most selective hPPAR? agonists with 10(4)-fold selectivity over the other two subtypes, namely, hPPAR? and hPPAR?. The PPAR? ligands 10a, 11e and 11f showed good bioavailability and in vivo efficacy. PMID:22534184

Ham, Jungyeob; Hwang, Hoosang; Kim, Euno; Kim, Jeong-Ah; Cho, Sung Jin; Ko, Jaeyoung; Lee, Woojin; Lee, Jaehwan; Holla, Harish; Banerjee, Joydeep; Kim, Seokho; Yang, Inho; Lee, Hyun Joo; Shin, Kyoungjin; Choi, Hyukjae; Nam, Sang-Jip; Tak, Jungae; Hahn, Dongyup; Oh, Taekyung; Won, Dong Hwan; Lee, Tae Gu; Choi, Jihye; Park, Mi Sun; Seok, Chaok; Chin, Jungwook; Kang, Heonjoong

2012-04-06

235

Interfacial behavior of polar, weakly polar, and nonpolar compounds bound to activated carbons.  

PubMed

Detailed analysis of the interfacial behavior of water and weakly polar or nonpolar organics adsorbed alone or co-adsorbed onto activated carbons (AC) at different temperatures is a complex problem important for practical applications of adsorbents. Interaction of water, 1-decanol, and n-decane with AC possessing highly developed porosity (pore volume Vp?1.4-2.3 cm(3)/g, specific surface area S(BET)?1500-3500 m(2)/g) was studied over a broad temperature range using differential scanning calorimetry (DSC), thermoporometry, (1)H NMR spectroscopy, cryoporometry, and temperature-programmed desorption with mass-spectrometry control methods. Comparison of the pore size distributions (PSD) calculated using the DSC thermoporometry, NMR cryoporometry, and nitrogen adsorption isotherms allows us to determine localization of adsorbates in different pores, as well as changes in the PSD of AC due to freezing of adsorbates in pores. Theoretical calculations (using ab initio HF/6-31G(d,p), DFT B3LYP/6-31G(d,p), and PM7 methods) explain certain aspects of the interfacial behavior of water, decane, and decanol adsorbed onto AC that appear in the experimental data. Obtained results show strong temperature dependence (above and below the freezing point, Tf, of bulk liquids) of the interfacial behavior of adsorbates on the textural characteristics and hydrophilic/hydrophobic properties of AC and the adsorbate amounts that affect the distributions of adsorbates unfrozen at T

Gun'ko, V M; Turov, V V; Zarko, V I; Goncharuk, O V; Nychiporuk, Yu M; Kozynchenko, O P; Skubiszewska-Zi?ba, J; Leboda, R; Charmas, B; Balakin, D Yu; Ptushinskii, Yu G

2013-05-09

236

Dexamethasone prevents visceral hyperalgesia but not colonic permeability increase induced by luminal protease?activated receptor-2 agonist in rats  

PubMed Central

Background Low?grade inflammation may play a role in the pathogenesis of irritable bowel syndrome (IBS). Although corticosteroids are potent inhibitors of inflammatory processes, only one study with corticosteroids in patients with postinfectious IBS exists, which suggests that prednisolone is not an effective treatment for IBS symptoms. Aim To evaluate whether dexamethasone treatment prevents protease?activated receptor?2 (PAR?2) activation?induced visceral hyperalgesia and increased permeability in rats, and to determine whether the effects involve colonic mast cells. Methods Abdominal contractions provoked by rectal distension were recorded in rats equipped with intramuscular electrodes. Changes in visceral hypersensitivity provoked by intracolonic administration of PAR?2?activating peptide (SLIGRL; H?serine?leucine?isoleucine?glycine?arginine?leucine?OH), changes in colonic mucosal rat mast cell protease?II (RMCP?II) content, mast cell count and PAR?2 expression were measured after a 4?day treatment with dexamethasone (1?mg/day/rat intraperitoneally) or its vehicle (water). The effect of mast cell stabiliser (doxantrazole, 1?mg/kg intraperitoneally, 2?h before and 6?h after intracolonic infusion of SLIGRL) on SLIGRL?induced visceral hyperalgesia was also assessed. The effects of SLIGRL and a mast cell degranulator (compound 48/80) on the permeability of colonic strips from vehicle? or dexamethasone?treated rats were investigated in Ussing chambers. Results 4 days of dexamethasone as well as doxantrazole diminished the SLIGRL?induced hyperalgesia for all volumes of distension. This effect of dexamethasone was accompanied by a reduced responsiveness of colonic permeability to compound 48/80, and decreased RMCP?II content and mast cell number. Dexamethasone treatment did not influence colonic mucosal PAR?2 expression and permeability responsiveness to SLIGRL. Conclusions Dexamethasone treatment improves PAR?2 agonist?induced visceral hypersensitivity but does not prevent PAR?2 agonist?induced increase in colonic permeability in rats. This effect is coupled with a reduction of colonic mast cell number and RMCP?II contents.

Roka, Richard; Ait-Belgnaoui, Afifa; Salvador-Cartier, Christel; Garcia-Villar, Raphael; Fioramonti, Jean; Eutamene, Helene; Bueno, Lionel

2007-01-01

237

Satellite observations of the impact of weak volcanic activity on marine clouds  

NASA Astrophysics Data System (ADS)

Because emissions from weak volcanic eruptions tend to remain in the low troposphere, they may have a significant radiative impact through the indirect effect on clouds. However, this type of volcanic activity is underreported and its global impact has been assessed only by model simulations constrained with very limited observations. First observations of the impact of high-latitude active volcanoes on marine boundary layer clouds are reported here. These observations were made using a combination of standard derived products and visible images from the MODIS, AMSR-E and GOES detectors. Two distinctive effects are identified. When there is an existing boundary layer cloud deck, an increase in cloud brightness and a decrease in both cloud effective radius and liquid water content were observed immediately downwind of the volcanoes. The visible appearance of these "volcano tracks" resembles the effect of man-made ship tracks. When synoptic conditions favor low cloudiness, the volcano plume (or volcano cloud) increases significantly the cloud cover downwind. The volcano cloud can extend for hundreds of kilometers until mixing with background clouds. Unlike violent eruptions, the volcano clouds reported here (the Aleutian Islands in the North Pacific and the South Sandwich Islands in the South Atlantic) have retrieved microphysical properties similar to those observed in ship tracks. However, when comparing the volcano clouds from these two regions, liquid water content can decrease, increase or remain unchanged with respect to nearby unperturbed clouds. These differences suggest that composition at the source, type of eruption and meteorological conditions influence the evolution of the cloud.

Gassó, Santiago

2008-07-01

238

Peroxisome proliferator-activated receptor ? agonists inhibit T helper type 1 (Th1) and Th17 responses in experimental allergic encephalomyelitis  

PubMed Central

Multiple sclerosis (MS) is a neurological disorder that affects more than a million people world-wide. The aetiology of MS is not known and there is no medical treatment available that can cure MS. Experimental autoimmune encephalomyelitis (EAE) is a T-cell-mediated autoimmune disease model of MS. The pathogenesis of EAE/MS is a complex process involving activation of immune cells, secretion of inflammatory cytokines and destruction of myelin sheath in the central nervous system (CNS). Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptor transcription factors that regulate cell growth, differentiation and homeostasis. PPAR agonists have been used in the treatment of obesity, diabetes, cancer and inflammation. We and others have shown that PPAR?, ? and ? agonists inhibit CNS inflammation and demyelination in the EAE model of MS. In this study we show that the PPAR? agonists GW501516 and L165041 ameliorate MOGp35-55-induced EAE in C57BL/6 mice by blocking interferon (IFN)-? and interleukin (IL)-17 production by T helper type 1 (Th1) and Th17 cells. The inhibition of EAE by PPAR? agonists was also associated with a decrease in IL-12 and IL-23 and an increase in IL-4 and IL-10 expression in the CNS and lymphoid organs. These findings indicate that PPAR? agonists modulate Th1 and Th17 responses in EAE and suggest their use in the treatment of MS and other autoimmune diseases.

Kanakasabai, Saravanan; Chearwae, Wanida; Walline, Crystal C; Iams, Wade; Adams, Suzanne M; Bright, John J

2010-01-01

239

Peroxisome proliferator-activated receptor delta agonists inhibit T helper type 1 (Th1) and Th17 responses in experimental allergic encephalomyelitis.  

PubMed

Multiple sclerosis (MS) is a neurological disorder that affects more than a million people world-wide. The aetiology of MS is not known and there is no medical treatment available that can cure MS. Experimental autoimmune encephalomyelitis (EAE) is a T-cell-mediated autoimmune disease model of MS. The pathogenesis of EAE/MS is a complex process involving activation of immune cells, secretion of inflammatory cytokines and destruction of myelin sheath in the central nervous system (CNS). Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptor transcription factors that regulate cell growth, differentiation and homeostasis. PPAR agonists have been used in the treatment of obesity, diabetes, cancer and inflammation. We and others have shown that PPARgamma, alpha and delta agonists inhibit CNS inflammation and demyelination in the EAE model of MS. In this study we show that the PPARdelta agonists GW501516 and L165041 ameliorate MOGp35-55-induced EAE in C57BL/6 mice by blocking interferon (IFN)-gamma and interleukin (IL)-17 production by T helper type 1 (Th1) and Th17 cells. The inhibition of EAE by PPARdelta agonists was also associated with a decrease in IL-12 and IL-23 and an increase in IL-4 and IL-10 expression in the CNS and lymphoid organs. These findings indicate that PPARdelta agonists modulate Th1 and Th17 responses in EAE and suggest their use in the treatment of MS and other autoimmune diseases. PMID:20406305

Kanakasabai, Saravanan; Chearwae, Wanida; Walline, Crystal C; Iams, Wade; Adams, Suzanne M; Bright, John J

2010-04-06

240

Peroxisome proliferator-activated receptor-? agonist 15d-prostaglandin J2 mediates neuronal autophagy after cerebral ischemia-reperfusion injury.  

PubMed

Peroxisome proliferator-activated receptor-? (PPAR-?) has recently emerged as potential therapeutic agents for cerebral ischemia-reperfusion (I/R) injury because of anti-neuronal apoptotic actions. However, whether PPAR-? activation mediates neuronal autophagy in such conditions remains unclear. Therefore, in this study, we investigated the role of PPAR-? agonist 15-PGJ(2) on neuronal autophagy induced by I/R. The expression of autophagic-related protein in ischemic cortex such as LC3-II, Beclin 1, cathepsin-B and LAMP1 increased significantly after cerebral I/R injury. Furthermore, increased punctate LC3 labeling and cathepsin-B staining occurred in neurons. Treatment with PPAR-? agonist 15d-PGJ(2) decreased not only autophagic-related protein expression in ischemic cortex, but also immunoreactivity of LC3 and cathepsin-B in neurons. Autophagic inhibitor 3-methyladenine (3-MA) decreased LC3-II levels, reduced the infarct volume, and mimicked some protective effect of 15d-PGJ(2) against cerebral I/R injury. These results indicate that PPAR-? agonist 15d-PGJ(2) exerts neuroprotection by inhibiting neuronal autophagy after cerebral I/R injury. Although the molecular mechanisms underlying PPAR-? agonist in mediating neuronal autophagy remain to be determined, neuronal autophagy may be a new target for PPAR-? agonist treatment in cerebral I/R injury. PMID:23372817

Xu, Feng; Li, Jian; Ni, Wei; Shen, Yi-wen; Zhang, Xiao-ping

2013-01-25

241

Failure of cAMP agonists to activate rescued ?F508 CFTR in CFBE41o– airway epithelial monolayers  

PubMed Central

The cystic fibrosis transmembrane conductance regulator (CFTR) is a cyclic AMP-regulated chloride channel. Mutations in the CFTR gene result in cystic fibrosis (CF). The most common mutation, ?F508, results in endoplasmic reticulum-associated degradation (ERAD) of CFTR. ?F508 CFTR has been described as a temperature-sensitive mutation that can be rescued following growth at 27°C. In order to study the processing and function of wild-type and rescued ?F508 CFTR at the cell surface under non-polarized and polarized conditions, we developed stable cell lines expressing ?F508 or wild-type CFTR. CFBE41o– is a human airway epithelial cell line capable of forming high resistance, polarized monolayers when cultured on permeable supports, while HeLa cells are normally grown under non-polarizing conditions. Immunoprecipitation, cell surface biotinylation, immunofluorescence, and functional assays confirmed the presence of ?F508 CFTR at the cell surface in both cell lines after incubating the cells for 48 h at 27°C. However, stimulators of wild-type CFTR such as forskolin, ?2-adrenergic or A2B-adenosine receptor agonists failed to activate rescued ?F508 CFTR in CFBE41o– monolayers. Rescued ?F508 CFTR could be stimulated with genistein independent of pretreatment with cAMP signalling agonists. Interestingly, rescued ?F508 CFTR in HeLa cells could be efficiently stimulated with either forskolin or genistein to promote Cl– transport. These results indicate that ?F508 CFTR, when rescued in CFBE41o– human airway epithelial cells, is poorly responsive to signalling pathways known to regulate wild-type CFTR. Furthermore, the differences in rescue and activation of ?F508 CFTR in the two cell lines suggest that cell-type specific differences in ?F508 CFTR processing are likely to complicate efforts to identify potentiators and/or correctors of the ?F508 defect.

Bebok, Zsuzsa; Collawn, James F; Wakefield, John; Parker, William; Li, Yao; Varga, Karoly; Sorscher, Eric J; Clancy, JP

2005-01-01

242

Neonatal exposure to endocrine active compounds or an ERbeta agonist increases adult anxiety and aggression in gonadally intact male rats.  

PubMed

Endocrine active compounds (EACs) have been shown to influence a number of reproductive endpoints but less is known about how they might affect other hormone dependent behaviors including anxiety and aggression. Recent evidence suggests that these effects may be mediated through the beta form of the estrogen receptor (ERbeta). Using male Long Evans rats, we sought to determine how neonatal exposure to EACs affects anxiety and aggression in adulthood. Anxiety was assessed using the elevated plus maze and aggression was assessed 8 weeks later using the resident intruder test. To gain insight into which ER subtype (ERalpha vs ERbeta) might be mediating these effects we used agonists specific for ERalpha (1,3,5-tris(4-Hydroxyphenyl)-4-propyl-1H-pyrazole (PPT)) or ERbeta (Diarylpropionitrile (DPN)) as additional treatment groups. For these experiments the synthetic EAC bisphenol-A (BPA) and the phytoestrogen metabolite equol (EQ) were used. Male neonates were injected with either 0.05 ml sesame oil (control), 50 microg estradiol benzoate (EB), 1 mg/kg DPN, 1 mg/kg PPT, 50 microg/kg BPA, or 10 mg/kg EQ daily for 4 days beginning on the day of birth (PND 0). Compared to the oil treated controls, significantly fewer open arm entries were made by the males neonatally treated with DPN, EQ, or BPA. The DPN and EQ treated males were also more aggressive compared to the controls. These findings suggest that neonatal exposure to EACs with agonistic activity on ERbeta may influence affective behavior in adulthood, including anxiety and aggression. PMID:18308321

Patisaul, Heather B; Bateman, Heather L

2008-02-08

243

Dual Peroxisome Proliferator-Activated Receptor ?/? Agonist GFT505 Improves Hepatic and Peripheral Insulin Sensitivity in Abdominally Obese Subjects.  

PubMed

OBJECTIVE The development of new insulin sensitizers is an unmet need for the treatment of type 2 diabetes. We investigated the effect of GFT505, a dual peroxisome proliferator-activated receptor (PPAR)-?/? agonist, on peripheral and hepatic insulin sensitivity. RESEARCH DESIGN AND METHODS Twenty-two abdominally obese insulin-resistant males (homeostasis model assessment of insulin resistance >3) were randomly assigned in a randomized crossover study to subsequent 8-week treatment periods with GFT505 (80 mg/day) or placebo, followed by a two-step hyperinsulinemic-euglycemic insulin clamp with a glucose tracer to calculate endogenous glucose production (EGP). The primary end point was the improvement in glucose infusion rate (GIR). Gene expression analysis was performed on skeletal muscle biopsy specimens. RESULTS GFT505 improved peripheral insulin sensitivity, with a 21% (P = 0.048) increase of the GIR at the second insulin infusion period. GFT505 also enhanced hepatic insulin sensitivity, with a 44% (P = 0.006) increase of insulin suppression of EGP at the first insulin infusion period. Insulin-suppressed plasma free fatty acid concentrations were significantly reduced on GFT505 treatment (0.21 ± 0.07 vs. 0.27 ± 0.11 mmol/L; P = 0.006). Neither PPAR? nor PPAR? target genes were induced in skeletal muscle, suggesting a liver-targeted action of GFT505. GFT505 significantly reduced fasting plasma triglycerides (-21%; P = 0.003) and LDL cholesterol (-13%; P = 0.0006), as well as liver enzyme concentrations (?-glutamyltranspeptidase: -30.4%, P = 0.003; alanine aminotransferase: -20.5%, P = 0.004). There was no safety concern or any indication of PPAR? activation with GFT505. CONCLUSIONS The dual PPAR?/? agonist GFT505 is a liver-targeted insulin-sensitizer that is a promising drug candidate for the treatment of type 2 diabetes and nonalcoholic fatty liver disease. PMID:23715754

Cariou, Bertrand; Hanf, Rémy; Lambert-Porcheron, Stéphanie; Zaïr, Yassine; Sauvinet, Valérie; Noël, Benoit; Flet, Laurent; Vidal, Hubert; Staels, Bart; Laville, Martine

2013-05-28

244

Correlating AMPA receptor activation and cleft closure across subunits: crystal structures of the GluR4 ligand-binding domain in complex with full and partial agonists.  

PubMed

AMPA receptors are glutamate-gated ion channels that are essential mediators of synaptic signals in the central nervous system. They form tetramers that are assembled as combinations of subunits GluR1-4, each of which contains a ligand-binding domain (LBD). Crystal structures of the GluR2 LBD have revealed an agonist-binding cleft, which is located between two lobes and which acts like a Venus flytrap. In general, agonist efficacy is correlated with the extent of cleft closure. However, recent observations show that cleft closure is not the sole determinant of the relative efficacy for glutamate receptors. In addition, these studies have focused on the GluR2 subunit, which is the specific target of a physiologically important RNA-editing modification in vivo. We therefore sought to test the generality of the cleft closure-efficacy correlation for other AMPA-R subunits. Here, we present crystal structures of the GluR4(flip) LBD in complex with both full and partial agonists. As for GluR2, both agonists stabilize a closed-cleft conformation, and the partial agonist induces a smaller cleft closure than the full agonist. However, a detailed analysis of LBD-kainate interactions reveals the importance of subtle backbone conformational changes in the ligand-binding pocket in determining the magnitude of agonist-associated conformational changes. Furthermore, the GluR4 subunit exhibits a different correlation between receptor activation and LBD cleft closure than does GluR2. PMID:19102704

Gill, Avinash; Birdsey-Benson, Amanda; Jones, Brian L; Henderson, Leslie P; Madden, Dean R

2008-12-30

245

Suppression of Complex Spiral--Wave Activity in an Ionic Model of Cardiac Tissue by Weak Local Stimulations  

Microsoft Academic Search

On the basis of a quite realistic ionic Fenton--Karma model of the cardiac tissue we consider the problem of defibrillation by a local weak forcing. In contrast to other systems, this model accurately reproduces the most essential mesoscopic properties of the cardiac activity. It is shown that suppression of spiral--wave turbulent dynamics in the heart tissue may be realized by

Ekaterina Zhuchkova; Boris Radnaev; Alexander Loskutov

2006-01-01

246

Tethered Agonist Analogs as Site-Specific Probes for Domains of the Human ?7 Nicotinic Acetylcholine Receptor that Differentially Regulate Activation and Desensitization  

PubMed Central

Homomeric ?7 nicotinic acetylcholine receptors represent an important and complex pharmaceutical target. They can be activated by structurally diverse agonists and are highly likely to enter and remain in desensitized states at rates determined by the structures of the agonists. To identify structural elements regulating this function, we introduced reactive cysteines into the ?7 ligand-binding domain allowing us to bind sulfhydryl-reactive (SH) agonist analogs or control reagents onto specific positions in the ligand binding domain. We identified four ?7 mutants (S36C, L38C, W55C, and L119C) in which the tethering of the SH reagents blocked further acetylcholine-evoked activation of the receptor. However, after selective reaction with SH agonist analogs, the type II allosteric modulator N-(5-chloro-2,4-dimethoxyphenyl)-N?-(5-methyl-3-isoxazolyl-3-isoxazolyl)-urea (PNU-120596) could reactivate L119C and W55C mutants and receptors with a reduced or modified C-loop. Modified S36C and L38C mutants were insensitive to reactivation by PNU-120596, whether they were reacted with agonist analogs or alternative SH reagents. Molecular modeling showed that in the W55C and L119C mutants, the ammonium pharmacophore of the agonist analog methanethiosulfonate-ethyltrimethylammonium would be in a similar but nonidentical position underneath the C-loop. The orientation assumed by the ligand tethered to 119C was approximately 3-fold more sensitive to PNU-120596 than the alternative pose at 55C. Our results support the hypothesis that a single ligand can bind within the receptor in different ways and, depending on the specific binding pose, may variously promote activation or desensitization, or, alternatively, function as a competitive antagonist. This insight may provide a new approach for drug development.

Wang, Jingyi; Horenstein, Nicole A.; Stokes, Clare

2010-01-01

247

Effects of peroxisome proliferator-activated receptor (PPAR)-? and PPAR-? agonists on glucose and lipid metabolism in patients with type 2 diabetes mellitus  

Microsoft Academic Search

Aims\\/hypothesis  The aim of the study was to examine the effects of pioglitazone (PIO), a peroxisome proliferator-activated receptor (PPAR)-?\\u000a agonist, and fenofibrate (FENO), a PPAR-? agonist, as monotherapy and in combination on glucose and lipid metabolism.\\u000a \\u000a \\u000a \\u000a Subjects and methods  Fifteen type 2 diabetic patients received FENO (n?=?8) or PIO (n?=?7) for 3 months, followed by the addition of the other agent for 3 months

M. Bajaj; S. Suraamornkul; L. J. Hardies; L. Glass; N. Musi; R. A. DeFronzo

2007-01-01

248

Novel bisaryl substituted thiazoles and oxazoles as highly potent and selective peroxisome proliferator-activated receptor delta agonists.  

PubMed

The discovery, synthesis, and optimization of compound 1 from a high-throughput screening hit to highly potent and selective peroxisome proliferator-activated receptor delta (PPARdelta) agonists are reported. The synthesis and structure-activity relationship in this series are described in detail. On the basis of a general schematic PPAR pharmacophore model, scaffold 1 was divided into headgroup, linker, and tailgroup and successively optimized for PPAR activation using in vitro PPAR transactivation assays. A (2-methylphenoxy)acetic acid headgroup, a flexible linker, and a five-membered heteroaromatic center ring with two hydrophobic aryl substituents were required for efficient and selective PPARdelta activation. The fine-tuning of these aryl substituents led to an array of highly potent and selective compounds such as compound 38c, displaying an excellent pharmacokinetic profile in mouse. In an in vivo acute dosing model, selected members of this array were shown to induce the expression of pyruvate dehydrogenase kinase-4 (PDK4) and uncoupling protein-3 (UCP3), genes that are known to be involved in energy homeostasis and regulated by PPARdelta in skeletal muscle. PMID:19928766

Epple, Robert; Cow, Christopher; Xie, Yongping; Azimioara, Mihai; Russo, Ross; Wang, Xing; Wityak, John; Karanewsky, Donald S; Tuntland, Tove; Nguyêñ-Trân, Vân T B; Cuc Ngo, Cara; Huang, David; Saez, Enrique; Spalding, Tracy; Gerken, Andrea; Iskandar, Maya; Seidel, H Martin; Tian, Shin-Shay

2010-01-14

249

Activation of cerebral function by CS-932, a functionally selective M1 partial agonist: neurochemical characterization and pharmacological studies.  

PubMed

A newly synthesized agonist for muscarinic acetylcholine (ACh) receptors CS-932, (R)-3-(3-iso-xazoloxy)-1-azabicyclo-[2.2.2]octane hydrochloride, showed a relatively higher affinity for M1 than M2 receptors expressed in Chinese hamster ovary (CHO)-cells in comparison with ACh. CS-932 elevated the intracellular Ca2+ level only in M1-CHO cells, although ACh increased the level in both M1- and M3-CHO cells. CS-932 and ACh reduced forskolin-stimulated accumulation of cAMP in M2-CHO cells by 20% and 80%, respectively. This neurochemical profile of CS-932 indicates that the compound can activate M1-receptor-mediated functions selectively. CS-932 increased firing of cholinoceptive neurons in rat hippocampal slices, and this excitation was antagonized by pirenzepine, but not by AF-DX 116. CS-932 increased awake and decreased slow wave sleep episodes of daytime EEG in free-moving rats. It counteracted scopolamine-induced slow waves in rat cortical EEG. CS-932 also increased the power of alpha- and beta-waves, but decreased delta-wave of the cortical EEG in anesthetized monkeys. It ameliorated scopolamine-induced impairment of working memory in rats. Orally administered CS-932 had the best penetration into the brain among the muscarinic agonists tested and caused the least salivary secretion among the cholinomimetics examined. These results indicate that CS-932 has potential as a cognitive enhancer with fewer side effects in therapy for Alzheimer disease. PMID:11138727

Iwata, N; Kozuka, M; Hara, T; Kanek, T; Tonohiro, T; Sugimoto, M; Niitsu, Y; Kondo, Y; Yamamoto, T; Sakai, J; Nagano, M

2000-11-01

250

7-Hydroxy-benzopyran-4-one derivatives: a novel pharmacophore of peroxisome proliferator-activated receptor alpha and -gamma (PPARalpha and gamma) dual agonists.  

PubMed

Design, synthesis, and in vitro bioevaluation of a new class of potential dual PPARalpha and gamma agonists discovered through a structure-driven design paradigm are described. The 7-hydroxy-benzopyran-4-one moiety (includes flavones, flavanones, and isoflavones) is the key pharmacophore of these novel molecules, exhibiting similarity to the core structure of both fibrates and thiazolidinediones. New lead PPAR ligands were identified from "natraceuticals" and synthetic analogues. In total, 77 molecules, including chalcones, flavones, flavanones, isoflavones, and pyrazole derivatives, were screened and structure-activity relationship studies of the dual agonists undertaken. Compounds 68, 70, 72, and 76 were identified as novel and potent dual PPARalpha and gamma agonists. These novel molecules may have the potential to be the future leads in PPAR-related disorders, including type II diabetes mellitus and metabolic syndrome. PMID:19807106

Matin, Azadeh; Gavande, Navnath; Kim, Moon S; Yang, Nancy X; Salam, Noeris K; Hanrahan, Jane R; Roubin, Rebecca H; Hibbs, David E

2009-11-12

251

CORRELATION OF THE ANTICHOLINESTERASE ACTIVITY OF A SERIES OF ORGANOPHOSPHATES WITH THEIR ABILITY TO COMPETE WITH AGONIST BINDING TO MUSCARINIC RECEPTORS  

EPA Science Inventory

Some compounds that inhibit acetylcholinesterase (ACHE) activity compete directly with quinuclidinyl benzilate (QNB) binding, a muscarinic antagonist which binds to all subtypes equally, and with cis-methyldioxolane (CD), an agonist that binds with high affinity to the M2 subtype...

252

Effects of D 2 dopamine receptor agonist and antagonist on brain activity in the rat assessed by functional magnetic resonance imaging  

Microsoft Academic Search

The effects of D2 dopamine receptor agonist, bromocriptine (BROMO), and antagonist, haloperidol (HPD), on brain activity were investigated in rats by functional magnetic resonance imaging. T2*-weighted signal intensity was increased in the hypothalamus at 120 min after acute administration of BROMO, and in the ventral posterior and dorsomedial nuclei of the thalamus from 30 to 120 min. In contrast, the

Hirofumi Hagino; Eiichi Tabuchi; Masayoshi Kurachi; Osamu Saitoh; Yueji Sun; Takashi Kondoh; Taketoshi Ono; Kunio Torii

1998-01-01

253

Quantity of partial agonist activity for antiglucocorticoids complexed with mutant glucocorticoid receptors is constant in two different transactivation assays but not predictable from steroid structure  

Microsoft Academic Search

An unsolved question in steroid hormone action is why the amount of agonist activity displayed by antisteroids is not constant but varies with the assay conditions. Receptor mutations have provided insight into hormone action, presumably due to changes in the tertiary structure of the receptor that alter its interaction surfaces with the transcriptional machinery or\\/and co-factors. We have now employed

Nicholas J Sarlis; Suzanne F Bayly; Daniele Szapary; S. Stoney Simons

1999-01-01

254

PTEROSTILBENE AS A NEW AGONIST FOR THE PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR ALPHA ISOFORM  

Technology Transfer Automated Retrieval System (TEKTRAN)

Pterostilbene, a stilbenoid antioxidant found in blueberries, grapes, other small fruits, and in woody plants was shown to activate the peroxisome proliferator-activated receptor alpha (PPAR alpha) isoform. This nuclear receptor is proposed to mediate the activity of lipid-lowering drugs such as th...

255

The role of peroxisome proliferator-activated receptor ?, and effects of its agonist, rosiglitazone, on transient cerebral ischemic damage.  

PubMed

Peroxisome proliferator-activated receptor ? (PPAR?) is expressed in neurons and glia, and its synthetic agonist, rosiglitazone (RSG), regulates inflammatory process and has neuroprotective effects against neurological disorders. In the present study, we examined the role of PPAR? in the hippocampal CA1 region (CA1) after transient cerebral ischemia and the neuroprotective effects of RSG on ischemic damage. RSG attenuated neuronal damage in the ischemic CA1, not showing perfect neuroprotection: the RSG appeared to delay neuronal death after ischemia/reperfusion (I/R). PPAR? immunoreactivity and protein levels were increased after I/R, and most of PPAR?-immunoreactive cells colocalized with microglia, not astrocytes. In addition, RSG attenuated glial activation and increased IL-4 and IL-13 levels in the ischemic CA1. These results indicate that PPAR? increases and expresses in microglia after I/R, and that RSG delays neuronal damage by interfering with glial activations and increases anti-inflammatory cytokines in response to ischemic damage. PMID:20880548

Lee, Choong Hyun; Park, Ok Kyu; Yoo, Ki-Yeon; Byun, Kyunghee; Lee, Bonghee; Choi, Jung Hoon; Hwang, In Koo; Kim, Young-Myeong; Won, Moo-Ho

2010-09-28

256

[Design and synthesis of peroxisome proliferator-activated receptor (PPAR) delta agonists and its implication to the driving force to elicit PPAR delta selectivity].  

PubMed

A series of 3-(4-alkoxypheny)propanoic acid derivatives was prepared as candidate peroxisome proliferator-activated receptor (PPAR) delta-selective agonists, based on our previously discovered potent human PPARalpha/delta dual agonist TIPP-401 as a lead compound. Structure-activity relationship studies clearly indicated the importance of the chain length of the alkoxy group at the 4-position, and the n-butoxy compound exhibited the most potent PPARdelta transactivation activity and highest PPARdelta selectivity. The (S)-enantiomer of a representative compound (TIPP-204) exhibited extremely potent PPARdelta transactivation activity, comparable to that of the known PPARdelta-selective agonist GW-501516. To understand why TIPP-204 shows high selectivity for hPPARdelta among hPPAR subtypes, and why TIPP-401, a structurally related compound, is a hPPARalpha/delta dual agonist, computational docking of TIPP-401 to the ligand binding domains of hPPARalpha and hPPARdelta and X-ray structure analysis of TIPP-204-hPPARdelta ligand binding domain were carried out. The results allowed identification of certain amino acids as putative determinants of the hPPARdelta selectivity of TIPP-204. To confirm the significance of these amino acids, GAL4-fusion proteins of mutated hPPARdeltas and hPPARalphas were prepared, and the transactivation activity of TIPP-204 toward the mutants was evaluated. The amino acid(s) that predominantly influence the potency and selectivity of TIPP-204 are different from that of the well-known PPARdelta-selective agonist GW-501516, which belongs to a different chemical class. The significance of these amino acids was confirmed by the examination of the complex structure between TIPP-204 and hPPARdelta. The results revealed several interactions relevant to the hPPARdelta-selectivity of the two ligands and will be useful for logical hPPARdelta ligand design. PMID:19483413

Kasuga, Jun-Ichi; Oyama, Takuji; Nakagome, Izumi; Aoyama, Atsushi; Sako, Kumiko; Makishima, Makoto; Hirono, Shuichi; Morikawa, Kosuke; Hashimoto, Yuichi; Miyachi, Hiroyuki

2009-06-01

257

Differential modulation of agonist and antagonist structure activity relations for rat TRPV1 by cyclosporin A and other protein phosphatase inhibitors  

PubMed Central

The transient receptor potential V1 channel (vanilloid receptor, TRPV1) represents a promising therapeutic target for inflammatory pain and other conditions involving C-fiber sensory afferent neurons. Sensitivity of TRPV1 is known to be subject to modulation by numerous signaling pathways, in particular by phosphorylation, and we wished to determine whether TRPV1 structure-activity relations could be differentially affected. We demonstrate here that the structure activity relations of TRPV1, as determined by 45Ca2+ uptake, were substantially altered by treatment of the cells with cyclosporin A, an inhibitor of protein phosphatase 2B. Whereas the potency of resiniferatoxin for stimulation of 45Ca2+ was not altered by cyclosporin A treatment, the potencies of some other agonists were increased up to 8-fold. Among antagonists examined, potencies were reduced to a lesser extent, ranging from 1–2.5 fold. Finally, the efficacy of partial agonists was increased. In contrast to cyclosporin A, okadaic acid, an inhibitor of protein phosphatases 1 and 2A, had little effect on agonist potencies, and calyculin A, an inhibitor of protein phosphatases 1 and 2A but with somewhat different selectivity from that of okadaic acid, caused changes in structure activity relations distinct from those induced by cyclosporin A. Because phosphatase activity differentially modulates the structure activity relations of TRPV1 agonists and antagonists, our findings predict that it may be possible to design agonist and antagonists selective for TRPV1 in a specific regulatory environment. A further implication is that it may be desirable to tailor screening approaches for drug discovery to reflect the desired regulatory state of the targeted TRPV1.

Pearce, Larry V.; Toth, Attila; Ryu, HyungChul; Kang, Dong Wook; Choi, Hyun-Kyung; Jin, Mi-Kyoung; Lee, Jeewoo; Blumberg, Peter M.

2008-01-01

258

Agonist-induced desensitization of dopamine D1 receptor-stimulated adenylyl cyclase activity is temporally and biochemically separated from D1 receptor internalization.  

PubMed Central

The regulation of the dopamine D1 receptor was investigated by using c-myc epitope-tagged D1 receptors expressed in Sf9 (fall armyworm ovary) cells. Treatment of D1 receptors with 10 microM dopamine for 15 min led to a loss of the dopamine-detected high-affinity state of the receptor accompanying a 40% reduction in the ability of the receptor to mediate maximal dopamine stimulation of adenylyl cyclase activity. After 60 min of agonist exposure, 45 min after the occurrence of desensitization, 28% of the cell surface receptors were internalized into an intracellular light vesicular membrane fraction as determined by radioligand binding and supported by photoaffinity labeling, immunocytochemical staining, and immunoblot analysis. Pretreatment of cells with concanavalin A or sucrose completely blocked agonist-induced D1 receptor internalization without preventing agonist-induced desensitization, indicating a biochemical separation of these processes. Collectively, these findings indicate that the desensitization of D1 receptor-coupled adenylyl cyclase activity and D1 receptor internalization are temporarily and biochemically distinct mechanisms regulating D1 receptor function following agonist activation. Images Fig. 2 Fig. 3

Ng, G Y; Trogadis, J; Stevens, J; Bouvier, M; O'Dowd, B F; George, S R

1995-01-01

259

Peroxisome proliferator-activated receptor (PPAR) ? and PPAR? agonists modulate mitochondrial fusion-fission dynamics: relevance to reactive oxygen species (ROS)-related neurodegenerative disorders?  

PubMed

Recent studies showed that the activation of the retinoid X receptor, which dimerizes with peroxisome proliferator-activated receptors (PPARs), leads to an enhanced clearance of A? from the brain of transgenic mice model of Alzheimer's disease (AD), because an increased expression of apolipoprotein E and it main transporters. However, the effects observed must involve additional underlying mechanisms that have not been yet explored. Several studies conducted in our laboratory suggest that part of the effects observed for the PPARs agonist might involves mitochondrial function and, particularly, mitochondrial dynamics. In the present study we assessed the effects of oxidative stress challenge on mitochondrial morphology and mitochondrial dynamics-related proteins in hippocampal neurons. Using immunofluorescence, we evaluated the PPAR? co-activator 1? (PGC-1?), dynamin related protein 1 (DRP1), mitochondrial fission protein 1 (FIS1), and mitochondrial length, in order to determine if PPARs agonist pre-treatment is able to protect mitochondrial population from hippocampal neurons through modulation of the mitochondrial fusion-fission events. Our results suggest that both a PPAR? agonist (ciglitazone) and a PPAR? agonist (WY 14.643) are able to protect neurons by modulating mitochondrial fusion and fission, leading to a better response of neurons to oxidative stress, suggesting that a PPAR based therapy could acts simultaneously in different cellular components. Additionally, our results suggest that PGC-1? and mitochondrial dynamics should be further studied in future therapy research oriented to ameliorate neurodegenerative disorders, such as AD. PMID:23675519

Zolezzi, Juan M; Silva-Alvarez, Carmen; Ordenes, Daniela; Godoy, Juan A; Carvajal, Francisco J; Santos, Manuel J; Inestrosa, Nibaldo C

2013-05-13

260

Expression of active protein phosphatase 1 inhibitor-1 attenuates chronic beta-agonist-induced cardiac apoptosis  

Microsoft Academic Search

Cardiac apoptosis has been considered an important contributing factor to heart failure. Several subcellular mechanisms, including\\u000a increased protein phosphatase 1 activity, have been suggested to induce apoptosis. Protein phosphatase 1 is regulated by an\\u000a endogenous inhibitor-1 (I-1) that is activated upon phosphorylation at threonine 35 via protein kinase A. Here, we tested\\u000a whether cardiac-specific overexpression of a constitutively active (T35D,

Guoli Chen; Xiaoyang Zhou; Stela Florea; Jiang Qian; Wenfeng Cai; Zhiguo Zhang; Guo-Chang Fan; John Lorenz; Roger J. Hajjar; Evangelia G. Kranias

2010-01-01

261

Agonist induction and conformational selection during activation of a G-protein-coupled receptor  

Microsoft Academic Search

Substitutions of Asn111 of the AT1 angiotensin receptor and mutations of the corresponding amino acids in other G-protein-coupled receptors (GPCRs) cause constitutive receptor activation. Ligand binding and signalling of constitutively active mutant GPCRs are discussed and similarities and differences during the activation of amine and peptide GPCRs are identified. Studies using the AT1 receptor suggest that conformational selection is not

László Hunyady; Georges Vauquelin; Patrick Vanderheyden

2003-01-01

262

Isolated neuronal growth cones from developing rat forebrain possess adenylate cyclase activity which can be augmented by various receptor agonists.  

PubMed

Isolated neuronal growth cones from neonatal rat forebrain were found to contain a high specific activity of adenylate cyclase (61 pmol cyclic AMP/min/mg protein) compared to the pelleted starting homogenate (5 pmol cyclic AMP/min/mg protein). Forskolin at 10(-4) M increased adenylate cyclase activity in both the pelleted homogenate and growth cone fraction by 70 and 217 pmol cyclic AMP/min/mg protein, respectively, over basal levels. The incremental effect of forskolin was 3-fold greater in the growth cone fraction than in the pelleted homogenate. However, relative to basal levels in each of the two fractions, forskolin increased adenylate cyclase activity in the growth cone fraction by only approx. 5-fold compared to 15-fold in the pelleted homogenate. Dopamine (10(-4) M), vasoactive intestinal polypeptide (10(-6) M) and isoproterenol (10(-5) M) also augmented adenylate cyclase activity in the two fractions. In the growth cone fraction, dopamine and vasoactive intestinal polypeptide produced a stimulation over basal levels by approx. 20 pmol cyclic AMP/min/mg protein while isoproterenol produced a stimulation of approx. 10 pmol cAMP/min/mg protein. The incremental effects of these receptor agonists in the growth cone fraction are approx. 5-fold greater than in the pelleted homogenate. The dopamine-sensitive adenylate cyclase activity in the growth cone fraction could be blocked by the compound SCH23390, a selective D1 receptor antagonist. At saturating concentrations, all combinations of dopamine, vasoactive intestinal polypeptide and isoproterenol were found to be completely additive on adenylate cyclase activity in the growth cone fraction.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2829998

Lockerbie, R O; Hervé, D; Blanc, G; Tassin, J P; Glowinski, J

1988-01-01

263

The relative contribution of affinity and efficacy to agonist activity: organ selectivity of noradrenaline and oxymetazoline with reference to the classification of drug receptors.  

PubMed Central

Oxymetazoline demonstrated a pronounced organ selectivity, when compared to noradrenaline, by being a potent full agonist in rat anococcygeus muscle and a partial agonist in rat vas deferens. Responses of rat anococcygeus muscles to oxymetazoline were relatively more sensitive to antagonism by phenoxybenzamine (Pbz) an alkylating alpha-adrenoceptor antagonist. Therefore, although oxymetazoline was more potent than noradrenaline in this tissue, after Pbz (0.3 microM for 10 min), the responses to oxymetazoline were completely inhibited while those to noradrenaline were only partially inhibited. Schild analysis with phentolamine, corynanthine, prazosin and yohimbine indicated no alpha-adrenoceptor heterogeneity within the rat anococcygeus muscle or between this tissue and rat vas deferens. Measurement of agonist Kd values and Schild analysis of oxymetazoline antagonism of responses to noradrenaline (after alkylation) confirmed the homogeneity of alpha-adrenoceptors with respect to these two agonists. The above profiles of activity would be predicted if oxymetazoline had a higher affinity but lower efficacy than noradrenaline. Experimentally this was confirmed when it was found that oxymetazoline had 5 times the affinity but 0.2 to 0.3 times the efficacy of noradrenaline. These results serve as a caveat to the use of selective receptor desensitization and/or selective receptor alkylation (or protection from alkylation) as means of differentiating drug receptors. Theoretical modelling and these experimental results indicate that high affinity/low efficacy agonists are much more sensitive to receptor coupling. The implications for therapeutic selectivity could be important in that high affinity/low efficacy agonists theoretically have a much greater potential for organ selectivity.

Kenakin, T. P.

1984-01-01

264

Peroxisome Proliferator Activated Receptor (PPAR)  Agonists Inhibit Hypertrophy of Neonatal Rat Cardiac Myocytes  

Microsoft Academic Search

The peroxisome proliferator activated receptors (PPARs) ap- pear to have beneficial effects in the cardiovascular system. PPAR has been shown previously to exert an inhibitory ef- fect on cardiac myocyte hypertrophy in vivo and in vitro. Us- ing endothelin to activate the hypertrophic program in neo- natal rat cardiac myocytes, we demonstrate that PPAR ligands (fenofibrate and WY14,643) suppress hypertrophy-

FAQUAN LIANG; FENG WANG; SUMEI ZHANG; DAVID G. GARDNER

2003-01-01

265

Intrinsic mineralocorticoid agonist activity of some nonsteroidal anti-inflammatory drugs. A postulated mechanism for sodium retention.  

PubMed Central

Because some nonsteroidal anti-inflammatory drugs (NSAID) induce salt and water retention and exhibit other steroid-like actions, studies were performed to ascertain whether these drugs possess intrinsic mineralocorticoid agonist activity. In vitro competitive binding assays utilizing tissue from adrenalectomized rats demonstrated that some NSAID can displace [3H]-aldosterone from renal cytoplasmic mineralocorticoid receptors. Displacement potency for these sites was in the sequence: aldosterone greater than spironolactone greater than phenylbutazone (PBZ) greater than aspirin (ASA) greater than indomethacin (IDM). Concentration ratios required to obtain significant displacement of [3H]aldosterone were high but clearly within the therapeutic range for PBZ and ASA but not IDM. The analogues oxyphenbutazone (OBZ) and sodium salicylate (SS) were similar in binding activity to PBZ and ASA, respectively. Lineweaver-Burk analysis revealed that the inhibition of [3H]aldosterone binding was competitive in nature. In addition, PBZ was shown to prevent the nuclear binding of [3H]aldosterone. In vivo injection of PBZ and ASA resulted in competition for [3H]aldosterone renal binding comparable to the in vitro studies. Administration of PBZ and OBZ to adrenalectomized rats resulted in significant salt retention whereas ASA and SS did not differ significantly from controls. Salt retention elicited by PBZ and OBZ was inhibited by spironolactone, a competitive mineralocorticoid antagonist. These data suggest that, despite nonsteroidal structures, PBZ and OBZ induce salt retention via a receptor-mediated mineralocorticoid pathway analogous to aldosterone action.

Feldman, D; Couropmitree, C

1976-01-01

266

Cyclic AMP enhances agonist-induced Ca2+ entry into endothelial cells by activation of potassium channels and membrane hyperpolarization.  

PubMed Central

The mechanism underlying cyclic AMP (cAMP)-mediated amplification of agonist-induced Ca2+ responses in endothelial cells was investigated in pig endothelial cells. Forskolin, adenosine and isoprenaline, as well as the membrane-permeant cAMP analogue dibutyryl cAMP, enhanced bradykinin-induced rises in intracellular free Ca2+ as well as bradykinin-induced Mn2+ entry. These agents were also found to hyperpolarize endothelial cells without increasing intracellular Ca2+ by itself, i.e. in the absence of bradykinin. Both amplification of bradykinin effects and the hyperpolarizing action was blocked by the protein kinase inhibitor H-8. The involvement of K+ channels in the hyperpolarizing effects of forskolin was consequently studied in perforated outside-out vesicles. Two different types of K+ channels were recorded, one of which had a large conductance (170 pS) and was activated by forskolin. We suggest that stimulation of endothelial adenylate cyclase results in activation of large-conductance K+ channels and consequently in membrane hyperpolarization, which in turn enhances bradykinin-induced entry of Ca2+ by increasing its electrochemical gradient.

Graier, W F; Kukovetz, W R; Groschner, K

1993-01-01

267

LRH agonist buserelin as a post-partum contraceptive: lack of biological activity of buserelin in breast milk.  

PubMed

To evaluate the possibility of using the LRH agonist buserelin as a contraceptive for lactating women we have investigated the passage of buserelin into breast milk and explored possible biological activity in the infant. Eleven mothers received 600 micrograms buserelin by nasal spray. Buserelin was measured by radioimmunoassay in the breast milk of these mothers, and values ranged from undetectable levels (less than 15 pg/ml) to 8800 pg/ml. The maximum amount of buserelin that an infant could ingest during an average feed would be 1-2 micrograms. In adult men ingestion of 600 micrograms buserelin dissolved in cows milk was without biological effect upon both serum and urinary levels of luteinizing hormone. There was no change in the levels of LH found in the urine of infants fed by women who had received 600 micrograms buserelin by nasal spray. We conclude that the small amount of buserelin passing into the breast milk of these volunteers was without biological activity when ingested by the infant. PMID:3103361

Dewart, P J; McNeilly, A S; Smith, S K; Sandow, J; Hillier, S G; Fraser, H M

1987-02-01

268

Effects of peroxisome proliferator-activated receptor ? agonists on Na+ transport and activity of the kinase SGK1 in epithelial cells from lung and kidney  

PubMed Central

Background and purpose: Peroxisome proliferator-activated receptor ? (PPAR?) agonists, such as rosiglitazone and pioglitazone, sensitize cells to insulin, and are therefore used to treat type 2 diabetes. However, in some patients, these drugs induce oedema, and the present study tests the hypothesis that this side effect reflects serum and glucocorticoid-inducible kinase 1 (SGK1)-dependent enhancement of epithelia Na+ absorption. Experimental approach: Na+ absorbing epithelial cells (H441 cells, mpkCCD cells) on permeable membranes were mounted in Ussing chambers, and the effects of rosiglitazone (2 µM) and pioglitazone (10 µM) on transepithelial Na+ absorption were quantified electrometrically. Changes in SGK1 activity were assessed by monitoring phosphorylation of residues within an endogenous protein. Key results: Both cell types absorbed Na+ via an electrogenic process that was enhanced by insulin. In mpkCCD cells, this stimulation of Na+ transport was associated with increased activity of SGK1, whereas insulin regulated Na+ transport in H441 cells through a mechanism that did not involve activation of this kinase. Rosiglitazone and pioglitazone had no discernible effect on transepithelial Na+ absorption in unstimulated or insulin-stimulated cells and failed to alter cellular SGK1 activity. Conclusions and implications: Our results do not support the view that PPAR? agonists stimulate epithelial Na+ absorption or alter the control of cellular SGK1 activity. It is therefore likely that other mechanisms are involved in PPAR?-mediated fluid retention, and a better understanding of these mechanisms may help with the identification of patients likely to develop oedema or heart failure when treated with these drugs.

Wilson, Stuart M; Mansley, Morag K; Getty, Jennet; Husband, Elaine M; Inglis, Sarah K; Hansen, Michael K

2010-01-01

269

Delta-9-tetrahydrocannabinol differentially suppresses emesis versus enhanced locomotor activity produced by chemically diverse dopamine D2/D3 receptor agonists in the least shrew (Cryptotis parva).  

PubMed

The principal psychoactive component of marijuana, delta-9-tetrahydrocannabinol (Delta9-THC), suppresses nausea and vomiting in cancer patients caused by chemotherapeutics such as cisplatin. Cisplatin induces vomiting via a number of emetic stimuli, including dopamine. Currently, there is controversy as to whether Delta9-THC can prevent emesis produced by dopaminergic agonists such as apomorphine. The present investigation utilizes the least shrew to evaluate the antiemetic potential and the cannabinoid receptor by which Delta9-THC may prevent emesis produced by four dopamine receptor agonists with differing selectivity for D2 and D3 receptors, i.e., a nonselective dopamine receptor agonist (apomorphine), a D2-preferring receptor agonist (quinpirole), and two D3-preferring receptor agonists (quinelorane and 7-OH DPAT). In addition, relative to its antiemetic doses, the motor suppressive doses of Delta9-THC in dopamine D2/D3-receptor-agonist-treated shrews were also evaluated. Thus, different groups of shrews were injected with either vehicle (V) or varying doses of Delta9-THC [0.5, 1, 2.5, 5, or 10 mg/kg, intraperitoneal (i.p.)] 10 min prior to administration of a 2 mg/kg dose of one of the four cited D2/D3 agonists. Immediately after the last injection, the frequency of vomiting for each shrew was recorded for the next 30 min. To investigate which cannabinoid receptor is involved in the antiemetic action of Delta9-THC, various doses of the CB1 receptor antagonist SR 141716A [0, 5, 10, and 20 mg/kg, subcutaneous (s.c.)] were administered to shrews 10 min prior to an injection of a fully effective antiemetic dose of Delta9-THC (5 mg/kg, i.p.). Ten minutes later, each treated shrew was administered with a 2 mg/kg dose of apomorphine. The emesis frequency was recorded for the next 30 min. For locomotor studies, different groups of shrews received either vehicle or various doses of Delta9-THC (0, 5, 10, 20, or 30 mg/kg) 10 min prior to an injection of vehicle or a 2 mg/kg dose of one of the four D2/D3 receptor agonists. The triad of motor behaviors (spontaneous locomotor activity, total duration of movement, and rearing frequency) were recorded for the next 30 min by a computerized video tracking system. Delta9-THC dose-dependently attenuated the frequency of emesis as well as fully protecting shrews from vomiting produced by each one of the four cited dopamine D2/D3 receptor agonists with ID50s ranging from 1 to 4 mg/kg. SR 141716A reversed the antiemetic activity of Delta9-THC against apomorphine-induced emesis. Delta9-THC also differentially suppressed the triad of motor activities in dopamine D2/D3-receptor-agonist-treated shrews with ID50s ranging from 7 to 21 mg/kg. The results suggest that Delta9-THC prevents emesis via cannabinoid CB1 receptors in a potent and dose-dependent manner in D2/D3-receptor-agonist-treated shrews at doses well below those which cause significant motor depression. PMID:15652378

Darmani, Nissar A; Crim, Jennifer L

2004-12-08

270

The JAK2V617 mutation induces constitutive activation and agonist hypersensitivity in basophils from patients with polycythemia vera  

PubMed Central

Background The JAK2V617F mutation has been associated with constitutive and enhanced activation of neutrophils, while no information is available concerning other leukocyte subtypes. Design and Methods We evaluated correlations between JAK2V617F mutation and the count of circulating basophils, the number of activated CD63+ basophils, their response in vitro to agonists as well as the effects of a JAK2 inhibitor. Results We found that basophil count was increased in patients with JAK2V617F -positive myeloproliferative neoplasms, particularly in those with polycythemia vera, and was correlated with the V617F burden. The burden of V617F allele was similar in neutrophils and basophils from patients with polycythemia vera, while total JAK2 mRNA content was remarkably greater in the basophils; however, the content of JAK2 protein in basophils was not increased. The number of CD63+ basophils was higher in patients with polycythemia vera than in healthy subjects or patients with essential thrombocythemia or primary myelofibrosis and was correlated with the V617F burden. Ultrastructurally, basophils from patients with polycythemia vera contained an increased number of granules, most of which were empty suggesting cell degranulation in vivo. Ex vivo experiments revealed that basophils from patients with polycythemia vera were hypersensitive to the priming effect of interleukin-3 and to f-MLP-induced activation; pre-treatment with a JAK2 inhibitor reduced polycythemia vera basophil activation. Finally, we found that the number of circulating CD63+ basophils was significantly greater in patients suffering from aquagenic pruritus, who also showed a higher V617F allele burden. Conclusions These data indicate that the number of constitutively activated and hypersensitive circulating basophils is increased in polycythemia vera, underscoring a role of JAK2V617F in these cells’ abnormal function and, putatively, in the pathogenesis of pruritus.

Pieri, Lisa; Bogani, Costanza; Guglielmelli, Paola; Zingariello, Maria; Rana, Rosa Alba; Bartalucci, Niccolo; Bosi, Alberto; Vannucchi, Alessandro M.

2009-01-01

271

Stimulation of the p38 Mitogen-activated Protein Kinase Pathway in Neonatal Rat Ventricular Myocytes by the G Protein-coupled Receptor Agonists, Endothelin1 and Phenylephrine: A Role in Cardiac Myocyte Hypertrophy?  

Microsoft Academic Search

We examined the activation of the p38 mito- gen-activated protein kinase (p38-MAPK) pathway by the G protein-coupled receptor agonists, endothelin-1 and phenylephrine in primary cultures of cardiac myo- cytes from neonatal rat hearts. Both agonists increased the phosphorylation (activation) of p38-MAPK by z 12-fold. A p38-MAPK substrate, MAPK-activated protein kinase 2 (MAPKAPK2), was activated approxi- mately fourfold and 10 m

Angela Clerk; Ashour Michael; Peter H. Sugden

1998-01-01

272

Regulation of Agonist - and Antagonist - Mediated Activation of Human Progesterone Receptors by Phosphorylation.  

National Technical Information Service (NTIS)

Phosphoprotein progesterone receptor (PR) is a key mediator of sex hormone progesterone, which regulates the development and differentiation of many organs including mammary glands. Aberrant activity of PR may be involved in breast cancer development. We ...

Y. Zhang

1997-01-01

273

Regulation of Neuronal Activation by Alpha2A Adrenergic Receptor Agonist  

Microsoft Academic Search

Stress factors induce neuronal activation in brain areas that are related to anxiety and fear. High doses of caffeine induce\\u000a neuronal activation with Ca2+ influx followed by expression of the immediate early gene c-fos. In the present study, we investigated c-Fos protein expression in stress-responsive brain areas induced by caffeine, as\\u000a well as the role of alpha2A receptor in the

Valentina L. Savchenko; John D. Boughter

274

Benzydamine inhibits monocyte migration and MAPK activation induced by chemotactic agonists  

PubMed Central

The present study was aimed to investigate the effect of benzydamine, an anti-inflammatory drug devoid of activity on arachidonic acid metabolism, on monocyte chemotaxis and to define the possible biochemical correlates of activity. Benzydamine inhibited monocyte chemotaxis in response to three classes of chemoattractants: the prototypic CC-chemokine CCL2 (MCP-1), the microbial product fMLP and the complement cascade component C5a. The effect was dose-dependent with IC50's of 100, 50 and 45 ?M for MCP-1/CCL2, fMLP and C5a, respectively. At the dose of 100 ?M, the effect resulted in a 50±10% inhibition of MCP-1/CCL2-induced chemotaxis and 53±6 and 54±5% inhibitions of chemotaxis in response of fMLP and C5a, respectively (n=3). Receptor expression as well as calcium fluxes in response to chemoattractants were not affected by benzydamine. Benzydamine strongly inhibited chemoattractant-induced activation of the mitogen-activated protein kinase (MAPK) ERK1/2, and of its upstream activator kinase MEK1/2. ERK1/12 activation in response to chemoattractants was 89–98% inhibited by a 100 ?M concentration of benzydamine with an IC50 of 30 ?M. Under the same experimental conditions, pretreatment with 100 ?M benzydamine caused a 75–89% inhibition of p38 activation (IC50 25 ?M). These results indicate that the anti-inflammatory activity of benzydamine is exerted at multiple levels, including monocyte migration to chemotactic factors associated to a blockage of ERK and p38 MAPK pathways.

Riboldi, Elena; Frascaroli, Giada; Transidico, Pietro; Luini, Walter; Bernasconi, Sergio; Mancini, Francesca; Guglielmotti, Angelo; Milanese, Claudio; Pinza, Mario; Sozzani, Silvano; Mantovani, Alberto

2003-01-01

275

Peroxisome proliferator-activated receptor-gamma agonist is protective in podocyte injury-associated sclerosis  

Microsoft Academic Search

We have previously observed increased expression of peroxisome proliferator-activated receptor gamma (PPAR?) in podocytes in both rat and human sclerotic conditions. The aim of the present study was to investigate whether activation of PPAR? can attenuate podocyte injury-associated glomerulosclerosis in vivo. Puromycin aminonucleoside nephropathy was induced in Sprague–Dawley rats. The animals then either received no further treatment (control group (CONT));

H-C Yang; L-J Ma; J Ma; A B Fogo

2006-01-01

276

New synthetic analogs of lipid A as lipopolysaccharide agonists or antagonists of B lymphocyte activation.  

PubMed

We have studied the ability of synthetic analogs of lipid A to mimic lipopolysaccharide (LPS) for activation of 70Z/3 pre-B cells (expression of surface Igs) or to antagonize this effect. The results indicate that the presence of glucosamine (mono- or disaccharide) as a 'backbone' for the attachment of fatty acids is not necessary for activation of cells of the B lineage. Phosphate groups are not necessary either. Other structural features such as the configuration of particular asymmetric carbons, and the distance between an anionic group and an N-acyl chain, seem to be much more critical parameters for activation of B cells. Among the synthetic lipids which were unable to activate 70Z/3 cells, one compound, consisting of N,N-acylated and bisphosphorylated 2,3-dideoxy-2,3-diamino-D-glucose, behaved as a specific LPS antagonist and blocked also the activation triggered by the other synthetic inducers. The influence of the synthetic lipids on the entry of mature mouse B lymphocytes into the G1A phase of the cell cycle (cell enlargement) was also investigated. A high correlation was observed between the potency to activate pre-B cells and the ability to induce blast formation in mature B cells. PMID:1591221

Pedron, T; Girard, R; Eustache, J; Bulusu, A R; Macher, I; Radzyner-Vyplel, H; Stütz, P L; Chaby, R

1992-04-01

277

Activation of Nociceptin/Orphanin FQ Peptide Receptors Disrupts Visual but Not Auditory Sensorimotor Gating in BALB/cByJ Mice: Comparison to Dopamine Receptor Agonists  

PubMed Central

Nociceptin/orphanin FQ (N/OFQ) peptide and its receptor (NOP receptor) have been implicated in a host of brain functions and diseases, but the contribution of this neuropeptide system to behavioral processes of relevance to psychosis has not been investigated. We examined the effect of the NOP receptor antagonists, Compound 24 and J-113397, and the synthetic agonist, Ro64-6198, on time function (2–2000?ms prepulse–pulse intervals) of acoustic (80?dB/10?ms prepulse) and visual (1000?Lux/20?ms prepulse) prepulse inhibition of startle reflex (PPI), a preattentive sensory filtering mechanism that is central to perceptual and mental integration. The effects of the dopamine D1-like receptor agonist, SKF-81297, the D2-like receptor agonist, quinelorane, and the mixed D1/D2 agonist, apomorphine, were studied for comparison. When acoustic stimulus was used as prepulse, BALB/cByJ mice displayed a monotonic time function of PPI, and consistent with previous studies, apomorphine and SKF-81279 induced PPI impairment, whereas quinelorane had no effect. None of the NOP receptor ligands was effective on acoustic PPI. When flash light was used as prepulse, BALB/cByJ mice displayed a bell-shaped time function of PPI and all dopamine agonists were active. Ro64-6198 was also effective in reducing visual PPI. NOP receptor antagonists showed no activity but blocked disruptive effect of Ro64-6198. Finally, coadministration of the typical antipsychotic, haloperidol, attenuated PPI impairment induced by Ro64-6198, revealing involvement of a dopaminergic component. These findings show that pharmacological stimulation of NOP or dopamine D2-like receptors is more potent in disrupting visual than acoustic PPI in mice, whereas D1-like receptor activation disrupts both. They further suggest that dysfunction of N/OFQ transmission may be implicated in the pathogenesis of psychotic manifestations.

Ces, Aurelia; Reiss, David; Walter, Ondine; Wichmann, Jurgen; Prinssen, Eric P; Kieffer, Brigitte L; Ouagazzal, Abdel-Mouttalib

2012-01-01

278

Activation of nociceptin/orphanin FQ peptide receptors disrupts visual but not auditory sensorimotor gating in BALB/cByJ mice: comparison to dopamine receptor agonists.  

PubMed

Nociceptin/orphanin FQ (N/OFQ) peptide and its receptor (NOP receptor) have been implicated in a host of brain functions and diseases, but the contribution of this neuropeptide system to behavioral processes of relevance to psychosis has not been investigated. We examined the effect of the NOP receptor antagonists, Compound 24 and J-113397, and the synthetic agonist, Ro64-6198, on time function (2-2000?ms prepulse-pulse intervals) of acoustic (80?dB/10?ms prepulse) and visual (1000?Lux/20?ms prepulse) prepulse inhibition of startle reflex (PPI), a preattentive sensory filtering mechanism that is central to perceptual and mental integration. The effects of the dopamine D1-like receptor agonist, SKF-81297, the D2-like receptor agonist, quinelorane, and the mixed D1/D2 agonist, apomorphine, were studied for comparison. When acoustic stimulus was used as prepulse, BALB/cByJ mice displayed a monotonic time function of PPI, and consistent with previous studies, apomorphine and SKF-81279 induced PPI impairment, whereas quinelorane had no effect. None of the NOP receptor ligands was effective on acoustic PPI. When flash light was used as prepulse, BALB/cByJ mice displayed a bell-shaped time function of PPI and all dopamine agonists were active. Ro64-6198 was also effective in reducing visual PPI. NOP receptor antagonists showed no activity but blocked disruptive effect of Ro64-6198. Finally, coadministration of the typical antipsychotic, haloperidol, attenuated PPI impairment induced by Ro64-6198, revealing involvement of a dopaminergic component. These findings show that pharmacological stimulation of NOP or dopamine D2-like receptors is more potent in disrupting visual than acoustic PPI in mice, whereas D1-like receptor activation disrupts both. They further suggest that dysfunction of N/OFQ transmission may be implicated in the pathogenesis of psychotic manifestations. PMID:21881568

Ces, Aurelia; Reiss, David; Walter, Ondine; Wichmann, Jürgen; Prinssen, Eric P; Kieffer, Brigitte L; Ouagazzal, Abdel-Mouttalib

2011-08-31

279

Thermotolerant Campylobacter with no or weak catalase activity isolated from dogs  

Microsoft Academic Search

ThermotolerantCampylobacter strains isolated from dog feces were characterized by phenotypical tests, DNA base composition, and DNA-DNA-hybridization. Out of 98 strains, 63 were catalase negative or weakly reacting (CNW); they were found in diarrheic as well as in healthy dogs. The CNW strains were all nalidixic-acid sensitive, hippurate negative, and grew at 42°C but not at 25°C. Seven strains were further

Karin Sandstedt; Jan Ursing; Mats Walder

1983-01-01

280

Blunted cGMP response to agonists and enhanced glomerular cyclic 3?,5?-nucleotide phosphodiesterase activities in experimental congestive heart failure  

Microsoft Academic Search

Blunted cGMP response to agonists and enhanced glomerular cyclic 3?,5?-nucleotide phosphodiesterase activities in experimental congestive heart failure. The natriuretic peptide (NP) and nitric oxide (NO) systems are activated in congestive heart failure (CHF), resulting in increased synthesis of cGMP, which serves as a second messenger for both humoral systems. These two regulatory systems play functional roles in the preservation of

Thanom Supaporn; Sharon M Sandberg; Daniel D Borgeson; Denise M Heublein; Andreas Luchner; Chi-Ming Wei; Thomas P Dousa; John C Burnett

1996-01-01

281

NS-1: a novel partial peroxisome proliferator-activated receptor ? agonist to improve insulin sensitivity and metabolic profile.  

PubMed

Peroxisome proliferator-activated receptor (PPAR) ? is known to be a key regulator of insulin resistance. We characterized the pharmacological profiles of NS-1 chemically known as (5Z)-5-[4-hydroxy-3-methoxy-phenyl) methylene] thiazolidine-2, 4-dione), as a selective partial activator of PPAR?. In transient transactivation assay in NIH3T3 cells, NS-1 showed a partial activation against human PPAR? with an EC (50) of 0.91 ?M without activating human PPAR? and PPAR?. In adipocyte differentiation assay, NS-1 induced adipocyte differentiation, which was ~25-fold weaker inducer of GPDH activities than pioglitazone and also showed weak adipogenic activity in C3H10T1/2 pluripotent stem cells using Oil Red O staining. NS-1 showed good in vivo pharmacokinetic profiles in C57BL/6J mice at 30 mg/kg oral dose with Cmax-26 ?M, terminal elimination half-life- 2.5h and bioavailability of 85%. Furthermore, NS-1 significantly improved hyperglycemia and insulin resistance in DIO animals when orally administered at a dose of 30 mg/kg/day for 45 days without significant weight gain. Overall, these studies suggest that NS-1 improves insulin resistance in such animal models through activation of PPAR?-mediated transcriptional activity and that it would be a new therapeutic candidate with potential for the treatment of type 2 diabetic patients. PMID:22484334

Chaudhary, Sumit; Dube, Aakanksha; Kothari, Vishal; Sachan, Narsingh; Upasani, Chandrashekhar Devidas

2012-03-30

282

Structure-activity relationships in toll-like receptor-2 agonistic diacylthioglycerol lipopeptides.  

PubMed

The N-termini of bacterial lipoproteins are acylated with a (S)-(2,3-bisacyloxypropyl)cysteinyl residue. Lipopeptides derived from lipoproteins activate innate immune responses by engaging Toll-like receptor 2 (TLR2) and are highly immunostimulatory and yet without apparent toxicity in animal models. The lipopeptides may therefore be useful as potential immunotherapeutic agents. Previous structure-activity relationships in such lipopeptides have largely been obtained using murine cells, and it is now clear that significant species-specific differences exist between human and murine TLR responses. We have examined in detail the role of the highly conserved Cys residue as well as the geometry and stereochemistry of the Cys-Ser dipeptide unit. (R)-Diacylthioglycerol analogues are maximally active in reporter gene assays using human TLR2. The Cys-Ser dipeptide unit represents the minimal part-structure, but its stereochemistry was found not to be a critical determinant of activity. The thioether bridge between the diacyl and dipeptide units is crucial, and replacement by an oxoether bridge results in a dramatic decrease in activity. PMID:20302301

Wu, Wenyan; Li, Rongti; Malladi, Subbalakshmi S; Warshakoon, Hemamali J; Kimbrell, Matthew R; Amolins, Michael W; Ukani, Rehman; Datta, Apurba; David, Sunil A

2010-04-22

283

Structure-Activity Relationships in Toll-like Receptor-2 agonistic Diacylthioglycerol Lipopeptides  

PubMed Central

The N-termini of bacterial lipoproteins are acylated with a (S)-(2,3-bisacyloxypropyl)cysteinyl residue. Lipopeptides derived from lipoproteins activate innate immune responses by engaging Toll-like receptor 2 (TLR2), and are highly immunostimulatory and yet without apparent toxicity in animal models. The lipopeptides may therefore be useful as potential immunotherapeutic agents. Previous structure-activity relationships in such lipopeptides have largely been obtained using murine cells and it is now clear that significant species-specific differences exist between human and murine TLR responses. We have examined in detail the role of the highly conserved Cys residue as well as the geometry and stereochemistry of the Cys-Ser dipeptide unit. (R)-diacylthioglycerol analogues are maximally active in reporter gene assays using human TLR2. The Cys-Ser dipeptide unit represents the minimal part-structure, but its stereochemistry was found not to be a critical determinant of activity. The thioether bridge between the diacyl and dipeptide units is crucial, and replacement by an oxoether bridge results in a dramatic decrease in activity.

Wu, Wenyan; Li, Rongti; Malladi, Subbalakshmi S.; Warshakoon, Hemamali J.; Kimbrell, Matthew R.; Amolins, Michael W.; Ukani, Rehman; Datta, Apurba; David, Sunil A.

2010-01-01

284

Synthesis and cannabinoid activity of 1-substituted-indole-3-oxadiazole derivatives: novel agonists for the CB1 receptor.  

PubMed

An exploratory chemical effort has been undertaken to develop a novel series of compounds as selective CB(1) agonists. It is hoped that compounds of this type will have clinical utility in pain control, and cerebral ischaemia following stroke or traumatic head injury. We report here medicinal chemistry studies directed towards the investigation of a series of 1-substituted-indole-3-oxadiazoles as potential CB(1) agonists. PMID:17582659

Moloney, Gerard P; Angus, James A; Robertson, Alan D; Stoermer, Martin J; Robinson, Michael; Wright, Christine E; McRae, Ken; Christopoulos, Arthur

2007-05-06

285

Some implications of receptor theory for in vivo assessment of agonists, antagonists and inverse agonists  

PubMed Central

Drug effects can be classified into three major phenotypes: agonist, antagonist and inverse agonist. Agonist and inverse agonist effects are associated with receptor activation and inactivation, respectively, whereas antagonism implies that a drug produces no effect when administered alone but blocks the effects of agonists and inverse agonists. Attention has only recently begun to focus on the theoretical and clinical implications of inverse agonists, and studies of inverse agonism have also stimulated revisions in receptor theory. This commentary addresses two specific issues related to the application of receptor theory to studies of inverse agonists in vivo. First, principles of receptor theory suggest that increasing drug doses produce a graded pharmacological stimulus that is transduced by receptor-containing tissue into a biological response. However, assays vary in their ability to detect those responses, and any given assay provides only a narrow window on the full range of underlying drug effects. Consequently, in vivo assessment of inverse agonists will benefit from development of assays sensitive to graded inverse agonist effects. Second, detection of inverse agonist effects requires some preexisting level of receptor activity (or tone). This tone can result from at least two sources: (a) endogenous ligands for the receptor, or (b) constitutive receptor activity. Strategies for discriminating these two sources of tone will also contribute to the in vivo assessment of inverse agonist effects. Studies with intermediate efficacy ligands may be especially helpful in this regard, because their effects are differentially influenced by endogenous agonist tone versus constitutive receptor tone.

Negus, S. Stevens

2007-01-01

286

Biostable agonists that match or exceed activity of native insect kinins on recombinant arthropod GPCRs  

Technology Transfer Automated Retrieval System (TEKTRAN)

The multifunctional arthropod insect kinins share the evolutionarily conserved C-terminal pentapeptide motif Phe-X1-X2-Trp-Gly-NH2, where X1 = His, Asn, Ser, or Tyr and X2 = Ser, Pro, or Ala. Insect kinins regulate diuresis in many species of insects. Compounds with similar biological activity cou...

287

Mitochondrial impairment by PPAR agonists and statins identified via immunocaptured OXPHOS complex activities and respiration  

Microsoft Academic Search

Mitochondrial impairment is increasingly implicated in the etiology of toxicity caused by some thiazolidinediones, fibrates, and statins. We examined the effects of members of these drug classes on respiration of isolated rat liver mitochondria using a phosphorescent oxygen sensitive probe and on the activity of individual oxidative phosphorylation (OXPHOS) complexes using a recently developed immunocapture technique. Of the six thiazolidinediones

Sashi Nadanaciva; James A. Dykens; Autumn Bernal; Roderick A. Capaldi; Yvonne Will

2007-01-01

288

Agonist and Antagonist Muscle EMG Activity Pattern Changes with Skill Acquisition.  

ERIC Educational Resources Information Center

|Using electromyography (EMG), researchers studied changes in the control of biceps and triceps brachii muscles that occurred as women college students learned two elbow flexion tasks. Data on EMG activity, angular kinematics, training, and angular displacement were analyzed. (Author/PP)|

Engelhorn, Richard

1983-01-01

289

TRIF Is a Critical Negative Regulator of TLR Agonist Mediated Activation of Dendritic Cells In Vivo  

Microsoft Academic Search

Despite recent advances in developing and licensing adjuvants, there is a great need for more potent formulations to enhance immunogenicity of vaccines. An Eimeria tenella derived antigen (rEA) augments immune responses against several pathogens in animal models and recently was confirmed to be safe for human use. In this study, we have analyzed the molecular mechanisms underlying rEA activity in

Sergey S. Seregin; Yasser A. Aldhamen; Daniel M. Appledorn; Charles F. Aylsworth; Sarah Godbehere; Chyong-Jy Joyce Liu; Dionisia Quiroga; Andrea Amalfitano

2011-01-01

290

Expression level and agonist-binding affect the turnover, ubiquitination and complex formation of peroxisome proliferator activated receptor beta.  

PubMed

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily that modulate target gene expression in response to fatty acid ligands. Their regulation by post-translational modifications has been reported but is poorly understood. In the present study, we investigated whether ligand binding affects the turnover and ubiquitination of the PPARbeta subtype (also known as PPARdelta). Our data show that the ubiquitination and degradation of PPARbeta is not significantly influenced by the synthetic agonist GW501516 under conditions of moderate PPARbeta expression. By contrast, the overexpression of PPARbeta dramatically enhanced its degradation concomitant with its polyubiquitination and the formation of high molecular mass complexes containing multiple, presumably oligomerized PPARbeta molecules that lacked stoichiometical amounts of the obligatory PPARbeta dimerization partner, retinoid X receptor. The formation of these apparently aberrant complexes, as well as the ubiquitination and destabilization of PPARbeta, were strongly inhibited by GW501516. Our findings suggest that PPARbeta is subject to complex post-translational regulatory mechanisms that partly may serve to safeguard the cell against deregulated PPARbeta expression. Furthermore, our data have important implications regarding the widespread use of overexpression systems to evaluate the function and regulation of PPARs. PMID:17803688

Rieck, Markus; Wedeken, Lena; Müller-Brüsselbach, Sabine; Meissner, Wolfgang; Müller, Rolf

2007-09-04

291

Coupling of agonist binding to effector domain activation in metabotropic glutamate-like receptors.  

PubMed

Many membrane receptors are made of a ligand binding domain and an effector domain mediating intracellular signaling. This is the case for the metabotropic glutamate-like G-protein-coupled receptors. How ligand binding leads to the active conformation of the effector domain in such receptors is largely unknown. Here, we used an evolutionary trace analysis and mutagenesis to identify critical residues involved in the allosteric coupling between the Venus flytrap ligand binding domain (VFT) and the heptahelical G-protein activating domain of the metabotropic glutamate-like receptors. We have shown that a conserved interdomain disulfide bridge is required for this allosteric interaction. Taking into account that these receptors are homodimers, this finding provides important new information explaining how the different conformations of the dimer of VFT lead to different signaling of such dimeric receptors. PMID:16787923

Rondard, Philippe; Liu, Jianfeng; Huang, Siluo; Malhaire, Fanny; Vol, Claire; Pinault, Alexia; Labesse, Gilles; Pin, Jean-Philippe

2006-06-20

292

Phospholipid-esterified Eicosanoids Are Generated in Agonist-activated Human Platelets and Enhance Tissue Factor-dependent Thrombin Generation*  

PubMed Central

Here, a group of specific lipids, comprising phosphatidylethanolamine (PE)- or phosphatidylcholine (PC)-esterified 12S-hydroxyeicosatetraenoic acid (12S-HETE), generated by 12-lipoxygenase was identified and characterized. 12S-HETE-PE/PCs were formed within 5 min of activation by thrombin, ionophore, or collagen. Esterified HETE levels generated in response to thrombin were 5.85 ± 1.42 (PE) or 18.35 ± 4.61 (PC), whereas free was 65.5 ± 17.6 ng/4 × 107 cells (n = 5 separate donors, mean ± S.E.). Their generation was stimulated by triggering protease-activated receptors-1 and -4 and signaling via Ca2+ mobilization secretory phospholipase A2, platelet-activating factor-acetylhydrolase, src tyrosine kinases, and protein kinase C. Stable isotope labeling showed that they form predominantly by esterification that occurs on the same time scale as free acid generation. Unlike free 12S-HETE that is secreted, esterified HETEs remain cell-associated, with HETE-PEs migrating to the outside of the plasma membrane. 12-Lipoxygenase inhibition attenuated externalization of native PE and phosphatidylserine and HETE-PEs. Platelets from a patient with the bleeding disorder, Scott syndrome, did not externalize HETE-PEs, and liposomes supplemented with HETE-PC dose-dependently enhanced tissue factor-dependent thrombin generation in vitro. This suggests a role for these novel lipids in promoting coagulation. Thus, oxidized phospholipids form by receptor/agonist mechanisms, not merely as an undesirable consequence of vascular and inflammatory disease.

Thomas, Christopher P.; Morgan, Lloyd T.; Maskrey, Benjamin H.; Murphy, Robert C.; Kuhn, Hartmut; Hazen, Stanley L.; Goodall, Alison H.; Hamali, Hassan A.; Collins, Peter W.; O'Donnell, Valerie B.

2010-01-01

293

Quantitative structure activity relationship (QSAR) of N 6 -substituted adenosine receptor agonists as potential antihypertensive agents  

Microsoft Academic Search

Quantitative structure activity relationship studies are indubitably of great importance in modern chemistry. In pursuit of\\u000a better antihypertensive agents, QSAR studies were performed on a series of 48 N\\u000a 6-substituted adenosines analogs. The models were developed using multiple linear regression (MLR) and partial least square\\u000a (PLS) with many descriptors like electronic, topological, and lipophilic. QSAR models were evaluated for statistical

Sarvesh Paliwal; Sucheta Das; Divya Yadav; Manyata Saxena; Shailendra Paliwal

294

Dose-response of acetylcholine receptor channels opened by a flash-activated agonist in voltage-clamped rat myoballs.  

PubMed Central

Whole-cell or single-channel currents through acetylcholine (ACh) receptor channels were studied in voltage-clamped rat myoballs or in excised membrane patches from myoballs. The recording pipette contained CsCl to suppress outward currents, and tetrodotoxin was used to help suppress Na+ currents. To minimize problems associated with bath applied agonists, myoballs were bathed in a solution containing the inactive (cis) isomer of the photo-isomerizable azobenzene derivative, Bis-Q. Calibrated light flashes of varying intensity were presented to produce concentration jumps of agonist, trans-Bis-Q. The resulting whole-cell current relaxations through ACh channels approach a steady state along an exponential time course, then decline as the newly created agonist diffuses away over the next few seconds. The dose-response relationship was inferred from Hill (double-log) plots for myoballs bathed in 500 nM-cis-Bis-Q at three membrane potentials. At low agonist concentrations (less than 300 nM-trans-Bis-Q), the slope of the Hill plot averaged 1.62 at -150 mV, 1.89 at -100 mV, and 2.05 at +80 mV. These results are consistent with an apparent agonist affinity constant that decreases with membrane depolarization and shifts the responses further down on the dose-response curve. When the myoballs were bathed in higher concentrations of cis-Bis-Q (1.5-20 microM), the slope of the Hill plot was reduced at all membrane potentials, although it was still closer to two at positive potentials. This is expected from the known sigmoid shape of the dose-response relation. The shallow dependence of the Hill slope on agonist concentration suggests the presence of negative cooperativity in the over-all binding of agonist molecules. Following treatment of the membrane with dithiothreitol to reduce disulphide groups, the Hill slope for the reversibly bound agonist, trans-Bis-Q, remained near two. The kinetics of currents at hyperpolarized membrane potentials became complicated at higher agonist concentrations in a manner that was consistent with open-channel block by trans-Bis-Q; the currents showed a slow secondary increase in conductance. Averaged single-channel recordings at higher agonist concentrations resemble macroscopic relaxations under comparable conditions. Furthermore, those recordings also suggested that open channels are blocked by trans-Bis-Q at concentrations greater than 2 microM; the block depends strongly on membrane potential and increases with hyperpolarization. Currents at positive membrane potentials showed no evidence of open-channel block.(ABSTRACT TRUNCATED AT 400 WORDS)

Chabala, L D; Gurney, A M; Lester, H A

1986-01-01

295

Identification of a ?-? opioid receptor heteromer-biased agonist with antinociceptive activity.  

PubMed

G protein-coupled receptors play a pivotal role in many physiological signaling pathways. Mounting evidence suggests that G protein-coupled receptors, including opioid receptors, form dimers, and dimerization is necessary for receptor maturation, signaling, and trafficking. However, the physiological role of dimerization in vivo has not been well-explored because of the lack of tools to study these dimers in endogenous systems. To address this problem, we previously generated antibodies to ?-? opioid receptor (?OR-?OR) dimers and used them to study the pharmacology and signaling by this heteromer. We also showed that the heteromer exhibits restricted distribution in the brain and that its abundance is increased in response to chronic morphine administration. Thus, the ?OR-?OR heteromer represents a potentially unique target for the development of therapeutics to treat pain. Here, we report the identification of compounds targeting ?OR-?OR heteromers through high-throughput screening of a small-molecule library. These compounds exhibit activity in ?OR-?OR cells but not ?OR or ?OR cells alone. Among them, CYM51010 was found to be a ?OR-?OR-biased ligand, because its activity is blocked by the ?OR-?OR heteromer antibody. Notably, systemic administration of CYM51010 induced antinociceptive activity similar to morphine, and chronic administration of CYM51010 resulted in lesser antinociceptive tolerance compared with morphine. Taken together, these results suggest that CYM51010, a ?OR-?OR-biased ligand, could serve as a scaffold for the development of a unique type (heteromer-biased) of drug that is more potent and without the severe side effects associated with conventional clinical opioids. PMID:23818586

Gomes, Ivone; Fujita, Wakako; Gupta, Achla; Saldanha, Adrian S; Negri, Ana; Pinello, Christine E; Roberts, Edward; Filizola, Marta; Hodder, Peter; Devi, Lakshmi A

2013-07-01

296

Activation of airway epithelial cells by toll-like receptor agonists.  

PubMed

Toll-like receptors (TLR) play an important role in pathogen recognition and innate immunity. We investigated the presence and function of TLRs in the BEAS-2B airway epithelial cell line and primary bronchial epithelial cells. Standard real-time reverse transcriptase-polymerase chain reaction (RT-PCR) analysis and Taqman RT-PCR revealed that BEAS-2B cells express mRNA for TLR1-10. Several TLR ligands were tested for their ability to activate gene expression in BEAS-2B cells using limited microarray analyses focusing on genes of the chemokine and chemokine receptor family, cytokines, and signaling pathways. While the TLR3 ligand double-stranded RNA was the most effective epithelial activator, clear responses to flagellin, lipopolysaccharide, CpG, peptidoglycan, and zymosan were also observed. RT-PCR and/or enzyme-linked immunosorbent assay were used to confirm results obtained with microarrays for five of the induced genes: interleukin-8, serum amyloid A, TLR3, macrophage inflammatory protein-3alpha, and granulocyte-macrophage colony-stimulating factor. Stimulation of epithelial cells with double-stranded RNA induced levels of interleukin-8 exceeding 20 ng/ml and levels of serum amyloid A exceeding 80 ng/ml. Double-stranded RNA, lipopolysaccharide, zymosan A, and flagellin also induced expression of macrophage inflammatory protein-3alpha and granulocyte-macrophage colony-stimulating factor, which may facilitate immature dendritic cell migration and maturation. These results suggest that airway epithelial cells express several TLRs and that they are functionally active. Epithelial expression of TLRs may be of importance in inflammation and immunity in the airways in response to inhaled pathogens. PMID:15191912

Sha, Quan; Truong-Tran, Ai Q; Plitt, James R; Beck, Lisa A; Schleimer, Robert P

2004-06-10

297

Dual bronchodilatory and pulmonary anti-inflammatory activity of RO5024118, a novel agonist at vasoactive intestinal peptide VPAC2 receptors  

PubMed Central

BACKGROUND AND PURPOSE Vasoactive intestinal peptide is expressed in the respiratory tract and induces its effects via its receptors, VPAC1 and VPAC2. RO5024118 is a selective VPAC2 receptor agonist derived via chemical modification of an earlier VPAC2 agonist, RO0251553. In the present studies, we characterized the pharmacological activity of RO5024118. EXPERIMENTAL APPROACH Stability of RO5024118 to human neutrophil elastase was assessed. Bronchodilatory activity of RO5024118 was investigated in guinea pig and human isolated airway smooth muscle preparations and in a guinea pig bronchoconstriction model. Pulmonary anti-inflammatory activity of RO5024118 was investigated in a lipopolysaccharide mouse model and in a porcine pancreatic elastase (PPE) rat model. KEY RESULTS RO5024118 demonstrated increased stability to neutrophil elastase compared with RO0251553. In human and guinea pig isolated airway preparations, RO5024118 induced bronchodilatory effects comparable with RO0251553 and the long-acting ?-agonist salmeterol and was significantly more potent than native vasoactive intestinal peptide and the short-acting ?-agonist salbutamol. In 5-HT-induced bronchoconstriction in guinea pigs, RO5024118 exhibited inhibitory activity with similar efficacy as, and longer duration than, RO0251553. In a lipopolysaccharide-mouse model, RO5024118 inhibited neutrophil and CD8+ cells and myeloperoxidase levels. In rats, intratracheal instillation of PPE induced airway neutrophilia that was resistant to dexamethasone. Pretreatment with RO5024118 significantly inhibited PPE-induced neutrophil accumulation. CONCLUSIONS AND IMPLICATIONS These results demonstrate that RO5024118 induces dual bronchodilatory and pulmonary anti-inflammatory activity and may be beneficial in treating airway obstructive and inflammatory diseases.

Tannu, SA; Renzetti, LM; Tare, N; Ventre, JD; Lavelle, D; Lin, TA; Morschauser, A; Paciorek, J; Bolin, DR; Michel, H; Singer, L; Hargaden, M; Knowles, ID; Gardiner, P; Cazzola, M; Calzetta, L; Matera, MG; Hicks, A

2010-01-01

298

Optimization of a Small Tropomyosin-related Kinase B (TrkB) Agonist 7,8-Dihydroxyflavone Active in Mouse Models of Depression  

PubMed Central

Structure-activity relationship study shows that the catechol group in 7,8-dihdyroxyflavone, a selective small TrkB receptor agonist, is critical for the agonistic activity. To improve the poor pharmacokinetic profiles intrinsic to catechol-containing molecules and elevate the agonistic effect of the lead compound, we initiated the lead optimization campaign by synthesizing various bioisosteric derivatives. Here we show that the optimized 2-methyl-8-(4?-(pyrrolidin-1-yl)phenyl)chromeno[7,8-d]imidazol-6(1H)-one derivative possesses the enhanced TrkB stimulatory activity. Chronic oral administration of this compound significantly reduces the immobility in forced swim test and tail suspension test, two classical antidepressant behavioral animal models, which is accompanied by robust TrkB activation in hippocampus of mouse brain. Further, in vitro ADMET studies demonstrate that this compound possesses the improved features compared to the previous lead compound. Hence, this optimized compound may act as a promising lead candidate for in-depth drug development for treating various neurological disorders including depression.

Liu, Xia; Chan, Chi-Bun; Qi, Qi; Xiao, Ge; Luo, Hongbo R.; He, Xiaolin; Ye, Keqiang

2012-01-01

299

GLP-1 Receptor Agonists and the Thyroid: C-Cell Effects in Mice Are Mediated via the GLP-1 Receptor and not Associated with RET Activation  

PubMed Central

Liraglutide and exenatide are glucagon-like peptide receptor (GLP-1R) agonists used in the treatment of type 2 diabetes. Both molecules have been associated with the development of thyroid C-cell tumors after lifetime exposure in rodents. Previously, it has been reported that these tumors are preceded by increased plasma calcitonin and C-cell hyperplasia. We can now document that the murine C-cell effects are mediated via GLP-1R. Thus, 13 wk of continuous exposure to GLP-1R agonists was associated with marked increases in plasma calcitonin and in the incidence of C-cell hyperplasia in wild-type mice. In contrast, similar effects were not seen in GLP-1R knockout mice. Human C-cell cancer is often caused by activating mutations in the rearranged-during-transfection (RET) protooncogene. We developed an immunohistochemical method to assess RET activation in tissues. Liraglutide dosing to mice was not found to activate RET. Further evaluation of the signaling pathways demonstrated that liraglutide increased ribosomal S6, but not MAPK kinase, phosphorylation. These observations are consistent with effects of GLP-1R agonists on rodent C cells being mediated via mammalian target of rapamycin activation in a RET- and MAPK-independent manner.

Knauf, Jeffrey A.; Gotfredsen, Carsten; Pilling, Andrew; Sjogren, Ingrid; Andersen, S?ren; Andersen, Lene; Sietske de Boer, Anne; Manova, Katia; Barlas, Afsar; Vundavalli, Sushil; Nyborg, Niels C. Berg; Bjerre Knudsen, Lotte; Moelck, Anne Marie

2012-01-01

300

Calcium currents in the A7r5 smooth muscle-derived cell line. An allosteric model for calcium channel activation and dihydropyridine agonist action  

PubMed Central

We have investigated the gating kinetics of calcium channels in the A7r5 cell line at the level of single channels and whole cell currents, in the absence and presence of dihydropyridine (DHP) calcium channel agonists. Although latencies to first opening and macroscopic currents are strongly voltage dependent, analysis of amplitude histograms indicates that the primary open-closed transition is voltage independent. This suggests that the molecular mechanisms for voltage sensing and channel opening are distinct, but coupled. We propose a modified Monod-Wyman-Changeux (MWC) model for channel activation, where movement of a voltage sensor is analogous to ligand binding, and the closed and open channels correspond to inactive (T) and active (R) states. This model can account for the activation kinetics of the calcium channel, and is consistent with the existence of four homologous domains in the main subunit of the calcium channel protein. DHP agonists slow deactivation kinetics, shift the activation curve to more negative potentials with an increase in slope, induce intermingled fast and slow channel openings, and reduce the latency to first opening. These effects are predicted by the MWC model if we make the simple assumption that DHP agonists act as allosteric effectors to stabilize the open states of the channel.

1992-01-01

301

Self-sustained firing activities of the cortical network with plastic rules in weak AC electrical fields  

NASA Astrophysics Data System (ADS)

Both external and endogenous electrical fields widely exist in the environment of cortical neurons. The effects of a weak alternating current (AC) field on a neural network model with synaptic plasticity are studied. It is found that self-sustained rhythmic firing patterns, which are closely correlated with the cognitive functions, are significantly modified due to the self-organizing of the network in the weak AC field. The activities of the neural networks are affected by the synaptic connection strength, the external stimuli, and so on. In the presence of learning rules, the synaptic connections can be modulated by the external stimuli, which will further enhance the sensitivity of the network to the external signal. The properties of the external AC stimuli can serve as control parameters in modulating the evolution of the neural network.

Qin, Ying-Mei; Wang, Jiang; Men, Cong; Zhao, Jia; Wei, Xi-Le; Deng, Bin

2012-07-01

302

Amplified Inhibition of Stellate Cell Activation Pathways by PPAR-?, RAR and RXR Agonists.  

PubMed

Peroxisome proliferator activator receptors (PPAR) ligands such as 15-?12,13-prostaglandin L(2) [PJ] and all trans retinoic acid (ATRA) have been shown to inhibit the development of liver fibrosis. The role of ligands of retinoic X receptor (RXR) and its ligand, 9-cis, is less clear. The purpose of this study was to investigate the effects of combined treatment of the three ligends, PJ, ATRA and 9-cis, on key events during liver fibrosis in rat primary hepatic stellate cells (HSCs). We found that the anti-proliferative effect of the combined treatment of PJ, ATRA and 9-cis on HSCs was additive. Further experiments revealed that this inhibition was due to cell cycle arrest at the G0/G1 phase as demonstrated by FACS analysis. In addition, the combined treatment reduced cyclin D1 expression and increased p21 and p27 protein levels. Furthermore, we found that the three ligands down regulated the phosphorylation of mTOR and p70(S6K). The activation of HSCs was also inhibited by the three ligands as shown by inhibition of vitamin A lipid droplets depletion from HSCs. Studies using real time PCR and western blot analysis showed marked inhibition of collagen I?1 and ?SMA by the combination of the three ligands. These findings suggest that the combined use of PJ, ATRA and 9-cis causes inhibition of cell proliferation by cell cycle arrest and down-regulation of fibrotic markers to a greater extent compared to each of the ligands alone. PMID:24098526

Sharvit, Efrat; Abramovitch, Shirley; Reif, Shimon; Bruck, Rafael

2013-10-01

303

Amplified Inhibition of Stellate Cell Activation Pathways by PPAR-?, RAR and RXR Agonists  

PubMed Central

Peroxisome proliferator activator receptors (PPAR) ligands such as 15-?12,13-prostaglandin L(2) [PJ] and all trans retinoic acid (ATRA) have been shown to inhibit the development of liver fibrosis. The role of ligands of retinoic X receptor (RXR) and its ligand, 9-cis, is less clear. The purpose of this study was to investigate the effects of combined treatment of the three ligends, PJ, ATRA and 9-cis, on key events during liver fibrosis in rat primary hepatic stellate cells (HSCs). We found that the anti-proliferative effect of the combined treatment of PJ, ATRA and 9-cis on HSCs was additive. Further experiments revealed that this inhibition was due to cell cycle arrest at the G0/G1 phase as demonstrated by FACS analysis. In addition, the combined treatment reduced cyclin D1 expression and increased p21 and p27 protein levels. Furthermore, we found that the three ligands down regulated the phosphorylation of mTOR and p70S6K. The activation of HSCs was also inhibited by the three ligands as shown by inhibition of vitamin A lipid droplets depletion from HSCs. Studies using real time PCR and western blot analysis showed marked inhibition of collagen I?1 and ?SMA by the combination of the three ligands. These findings suggest that the combined use of PJ, ATRA and 9-cis causes inhibition of cell proliferation by cell cycle arrest and down-regulation of fibrotic markers to a greater extent compared to each of the ligands alone.

Reif, Shimon; Bruck, Rafael

2013-01-01

304

A TLR2 Agonist in German Cockroach Frass Activates MMP-9 Release and is Protective Against Allergic Inflammation in Mice  

PubMed Central

The role of TLR2 in modulating experimentally induced asthma is not fully understood. We recently identified that German cockroach (GC) frass contains a TLR2 ligand allowing us to investigate the role of a TLR2 agonist in a complex real world allergen in mediating allergic airway inflammation. GC frass exposure significantly increased airway inflammation, airway hyperresponsiveness and serum IgE levels in wild type mice; however the same exposure in TLR2-deficient mice resulted in greatly exaggerated serum IgE and eosinophilia but diminished airway neutrophilia, suggesting a protective role for TLR2. Since GC frass inhalation usually induces airway neutrophilia, we queried the effect of neutrophil depletion on airway responses. Inhibition of neutrophil recruitment into the airways of naïve wild type mice prior to intratracheal inhalation of GC frass resulted in significantly increased levels of serum IgE and eosinophilia. Neutrophils are a rich source of MMP-9, and we found that MMP-9 levels were significantly increased in the airways of mice following exposure to GC frass. Importantly the levels of MMP-9 were significantly decreased in neutrophil-depleted and TLR2-deficient mice after exposure to GC frass, suggesting that TLR2 regulated MMP-9 release from neutrophils. Functionally, MMP-9-deficient mice had more acute allergic inflammation than wild type mice, suggesting that MMP-9 was protective against experimentally-induced asthma. These data suggest that TLR2 activation of neutrophils leads to release of MMP-9 which decreases allergic responses to GC frass. This suggests a protective role for TLR2 activation and MMP-9 release in the context of experimentally-induced asthma in mice.

Page, Kristen; Ledford, John R.; Zhou, Ping; Wills-Karp, Marsha

2009-01-01

305

Characterization of a novel, brain-penetrating CB1 receptor inverse agonist: metabolic profile in diet-induced obese models and aspects of central activity.  

PubMed

Pharmacologic antagonism of cannabinoid 1 receptors (CB1 receptors) in the central nervous system (CNS) suppresses food intake, promotes weight loss, and improves the metabolic profile. Since the CB1 receptor is expressed both in the CNS and in peripheral tissues, therapeutic value may be gained with CB1 receptor inverse agonists acting on receptors in both domains. The present report examines the metabolic and CNS actions of a novel CB1 receptor inverse agonist, compound 64, a 1,5,6-trisubstituted pyrazolopyrimidinone. Compound 64 showed similar or superior binding affinity, in vitro potency, and pharmacokinetic profile compared to rimonabant. Both compounds improved the metabolic profile in diet-induced obese (DIO) rats and obese cynomolgus monkeys. Weight loss tended to be greater in compound 64-treated DIO rats compared to pair-fed counterparts, suggesting that compound 64 may have metabolic effects beyond those elicited by weight loss alone. In the CNS, reversal of agonist-induced hypothermia and hypolocomotion indicated that compound 64 possessed an antagonist activity in vivo. Dosed alone, compound 64 suppressed extinction of conditioned freezing (10 mg/kg) and rapid eye movement (REM) sleep (30 mg/kg), consistent with previous reports for rimonabant, although for REM sleep, compound 64 was greater than threefold less potent than for metabolic effects. Together, these data suggested that (1) impairment of extinction learning and REM sleep suppression are classic, centrally mediated responses to CB1 receptor inverse agonists, and (2) some separation may be achievable between central and peripheral effects with brain-penetrating CB1 receptor inverse agonists while maintaining metabolic efficacy. Furthermore, chronic treatment with compound 64 contributes to evidence that peripheral CB1 receptor blockade may yield beneficial outcomes that exceed those elicited by weight loss alone. PMID:21947251

Jacobson, Laura H; Commerford, S Renee; Gerber, Sarah P; Chen, Yu Alice; Dardik, Beatriz; Chaperon, Frederique; Schwartzkopf, Chad; Nguyen-Tran, Van; Hollenbeck, Thomas; McNamara, Peter; He, Xiaohui; Liu, Hong; Seidel, H Martin; Jaton, Anne-Liese; Gromada, Jesper; Teixeira, Sandra

2011-09-25

306

Mitochondrial impairment by PPAR agonists and statins identified via immunocaptured OXPHOS complex activities and respiration  

SciTech Connect

Mitochondrial impairment is increasingly implicated in the etiology of toxicity caused by some thiazolidinediones, fibrates, and statins. We examined the effects of members of these drug classes on respiration of isolated rat liver mitochondria using a phosphorescent oxygen sensitive probe and on the activity of individual oxidative phosphorylation (OXPHOS) complexes using a recently developed immunocapture technique. Of the six thiazolidinediones examined, ciglitazone, troglitazone, and darglitazone potently disrupted mitochondrial respiration. In accord with these data, ciglitazone and troglitazone were also potent inhibitors of Complexes II + III, IV, and V, while darglitazone predominantly inhibited Complex IV. Of the six statins evaluated, lovastatin, simvastatin, and cerivastatin impaired mitochondrial respiration the most, with simvastatin and lovastatin impairing multiple OXPHOS Complexes. Within the class of fibrates, gemfibrozil more potently impaired respiration than fenofibrate, clofibrate, or ciprofibrate. Gemfibrozil only modestly inhibited Complex I, fenofibrate inhibited Complexes I, II + III, and V, and clofibrate inhibited Complex V. Our findings with the two complementary methods indicate that (1) some members of each class impair mitochondrial respiration, whereas others have little or no effect, and (2) the rank order of mitochondrial impairment accords with clinical adverse events observed with these drugs. Since the statins are frequently co-prescribed with the fibrates or thiazolidinediones, various combinations of these three drug classes were also analyzed for their mitochondrial effects. In several cases, the combination additively uncoupled or inhibited respiration, suggesting that some combinations are more likely to yield clinically relevant drug-induced mitochondrial side effects than others.

Nadanaciva, Sashi [MitoSciences, Inc., 1850 Millrace Drive, Eugene, OR 97403 (United States); Dykens, James A. [Drug Safety Research and Development, Pfizer, Inc., 10646 Science Center Drive, San Diego, CA 92121 (United States); Bernal, Autumn; Capaldi, Roderick A. [MitoSciences, Inc., 1850 Millrace Drive, Eugene, OR 97403 (United States); Will, Yvonne [Drug Safety Research and Development, Pfizer, Inc., 10646 Science Center Drive, San Diego, CA 92121 (United States)], E-mail: Yvonne.will@pfizer.com

2007-09-15

307

Structural Basis for Iloprost as a Dual Peroxisome Proliferator-activated Receptor [alpha/delta] Agonist  

SciTech Connect

Iloprost is a prostacyclin analog that has been used to treat many vascular conditions. Peroxisome proliferator-activated receptors (PPARs) are ligand-regulated transcription factors with various important biological effects such as metabolic and cardiovascular physiology. Here, we report the crystal structures of the PPAR{alpha} ligand-binding domain and PPAR{delta} ligand-binding domain bound to iloprost, thus providing unambiguous evidence for the direct interaction between iloprost and PPARs and a structural basis for the recognition of PPAR{alpha}/{delta} by this prostacyclin analog. In addition to conserved contacts for all PPAR{alpha} ligands, iloprost also initiates several specific interactions with PPARs using its unique structural groups. Structural and functional studies of receptor-ligand interactions reveal strong functional correlations of the iloprost-PPAR{alpha}/{delta} interactions as well as the molecular basis of PPAR subtype selectivity toward iloprost ligand. As such, the structural mechanism may provide a more rational template for designing novel compounds targeting PPARs with more favorable pharmacologic impact based on existing iloprost drugs.

Jin, Lihua; Lin, Shengchen; Rong, Hui; Zheng, Songyang; Jin, Shikan; Wang, Rui; Li, Yong (Pitt); (Xiamen)

2012-03-15

308

Chronic treatment with the peroxisome proliferator-activated receptor ? agonist Wy14,643 attenuates myocardial respiratory capacity and contractile function  

Microsoft Academic Search

We investigated whether chronic in vivo treatment with the peroxisome proliferator-activated receptor ? agonist Wy-14,643\\u000a attenuates cardiac contractile function by impairing mitochondrial respiration. Wy-14,643 (25 mg kg?1 day?1) was administered to Wistar rats by oral gavage for 14 consecutive days, after which ex vivo heart function, myocardial mitochondrial\\u000a respiratory capacity, and metabolic gene expression were determined. Body and heart weights were not significantly

Makhosazane Zungu; Martin E. Young; William C. Stanley; M. Faadiel Essop

2009-01-01

309

Investigation of the agonist activity of prostacyclin analogues on prostanoid EP 4 receptors using GW 627368 and taprostene: Evidence for species differences  

Microsoft Academic Search

The possibility that the prostacyclin analogues AFP-07 and cicaprost relax saphenous vein preparations of pig, guinea-pig and rabbit by simultaneously activating prostanoid EP4 and IP (prostacyclin) receptors was investigated using the high-affinity EP4 antagonist GW 627368. The IP receptor system in each preparation was suppressed with the partial agonist taprostene. The results indicate that AFP-07 and cicaprost are moderately potent

R. L. Jones; K. M. Chan

2005-01-01

310

From The Cover: A selective metabotropic glutamate receptor 7 agonist: Activation of receptor signaling via an allosteric site modulates stress parameters in vivo  

Microsoft Academic Search

Metabotropic glutamate receptor (mGluR) subtypes (mGluR1 to mGluR8) act as important pre- and postsynaptic regulators of neurotransmission in the CNS. These receptors consist of two domains, an extracellular region containing the orthosteric agonist site and a transmembrane heptahelical domain involved in G protein activation and recognition of several recently synthesized pharmacological modulators. The presynaptic receptor mGluR7 shows the highest evolutionary

Kayo Mitsukawa; Rina Yamamoto; Silvio Ofner; Joachim Nozulak; Oliver Pescott; Snezana Lukic; Natacha Stoehr; Cedric Mombereau; Rainer Kuhn; Kevin H. McAllister; Herman van der Putten; John F. Cryan; Peter J. Flor; Edward M. Scolnick

2005-01-01

311

In silico structure-based drug design approach to develop novel pharmacophore model of human peroxisome proliferator-activated receptor ? agonists  

Microsoft Academic Search

A structure-based pharmacophore generation approach was employed to identify novel structural characteristics and scaffolds\\u000a for peroxisome proliferator-activated receptor ? (PPAR?). The structure-based six feature pharmacophore hypothesis generated\\u000a in the present study signifies the importance of hydrogen bond donors, hydrogen bond acceptors and hydrophobic interaction\\u000a between the PPAR? structure and its agonists. The interaction shown by the compounds provides an important

Sarvesh Paliwal; Divya Yadav; Rakesh Yadav; Shailendra Paliwal

2011-01-01

312

Partial agonists for ?4?2 nicotinic receptors stimulate dopaminergic neuron firing with relatively enhanced maximal effects  

PubMed Central

BACKGROUND AND PURPOSE Partial agonists selective for ?4?2 nicotinic ACh receptors have been developed for smoking cessation as they induce weak activation of native ?4?2* receptors and inhibit effect of nicotine. However, it is unclear whether at brain functions there is an existence of receptor reserve that allows weak receptor activation to induce maximum physiological effects. We assessed the extent of ?4?2 partial agonist-induced increase of firing rate in dopaminergic neurons and evaluated the influence of receptor reserve. EXPERIMENTAL APPROACH The relative maximal effects and potencies of six nicotinic agonists were assessed on recombinant human ?4?2 and ?7 receptors expressed in mammalian cell lines by measuring calcium influx. Agonist-induced increase of the spontaneous firing rate of dopaminergic neurons was recorded using microelectrodes in the ventral tegmental area of rat brain slices. KEY RESULTS All ?4?2 partial and full agonists increased the firing rate concentration-dependently. Their sensitivity to subtype-selective antagonists showed predominant activation of native ?4?2* receptors. However, partial agonists with relative maximal effects as low as 33% on ?4?2 receptors maximally increased the firing rate and induced additional depolarization block of firing, demonstrating that partial activation of receptors caused the maximum increase in firing rate in the presence of a receptor reserve. CONCLUSIONS AND IMPLICATIONS Partial ?4?2 agonists induced relatively enhanced effects on the firing rate of dopaminergic neurons, and the effect was mainly attributed to the existence of native ?4?2* receptor reserve. The results have implications in the understanding of physiological effects and therapeutic efficacies of ?4?2 partial agonists.

Chen, Ying; Broad, Lisa M; Phillips, Keith G; Zwart, Ruud

2012-01-01

313

Agonist-receptor efficacy II: agonist trafficking of receptor signals  

Microsoft Academic Search

There is evidence to suggest that receptors with seven transmembrane domains can exist in G protein-activating conformations. It is not known how many activated receptor forms exist for each receptor. Furthermore, if there are multiple forms, does the chemical structure of the agonist determine which form dominates, and therefore, which response pathway is activated? This latter scheme is referred to

T. Kenakin

1995-01-01

314

Effects of weak transcranial alternating current stimulation on brain activity--a review of known mechanisms from animal studies  

PubMed Central

Rhythmic neuronal activity is ubiquitous in the human brain. These rhythms originate from a variety of different network mechanisms, which give rise to a wide-ranging spectrum of oscillation frequencies. In the last few years an increasing number of clinical research studies have explored transcranial alternating current stimulation (tACS) with weak current as a tool for affecting brain function. The premise of these interventions is that tACS will interact with ongoing brain oscillations. However, the exact mechanisms by which weak currents could affect neuronal oscillations at different frequency bands are not well known and this, in turn, limits the rational optimization of human experiments. Here we review the available in vitro and in vivo animal studies that attempt to provide mechanistic explanations. The findings can be summarized into a few generic principles, such as periodic modulation of excitability, shifts in spike timing, modulation of firing rate, and shifts in the balance of excitation and inhibition. These effects result from weak but simultaneous polarization of a large number of neurons. Whether this can lead to an entrainment or a modulation of brain oscillations, or whether AC currents have no effect at all, depends entirely on the specific dynamic that gives rise to the different brain rhythms, as discussed here for slow wave oscillations (?1 Hz) and gamma oscillations (?30 Hz). We conclude with suggestions for further experiments to investigate the role of AC stimulation for other physiologically relevant brain rhythms.

Reato, Davide; Rahman, Asif; Bikson, Marom; Parra, Lucas C.

2013-01-01

315

Mitemcinal (GM-611), an orally active motilin receptor agonist, improves delayed gastric emptying in a canine model of diabetic gastroparesis.  

PubMed

1. The aim of the present study was to evaluate the effects of mitemcinal (GM-611), an orally active motilin receptor agonist, on delayed gastric emptying in a canine model of diabetic gastroparesis and to compare these effects with those of cisapride. 2. Moderate hyperglycaemia was induced by a single intravenous injection of a mixture of streptozotocin (30 mg/kg) and alloxan (50 mg/kg). Dogs that maintained moderate hyperglycaemia (fasting plasma glucose 200-300 mg/dL) without insulin treatment were selected and gastric emptying in these dogs was determined by the paracetamol method. 3. One year after the onset of diabetes, there was no difference in the gastric emptying of normal and diabetic dogs. However, after 5 years, the diabetic dogs showed delayed gastric emptying. The motor nerve conduction velocity of the tibial nerve was significantly lower in diabetic dogs compared with normal dogs at both time points. 4. Histopathological examination at the end of the study showed that there were fewer nerve fibres in both dorsal vagal and tibial nerves of diabetic dogs compared with normal dogs. The onset of delayed gastric emptying is thought to have occurred gradually, in parallel with abnormal autonomic nerve function induced by the long period of moderate hyperglycaemia. 5. Oral administration of mitemcinal (0.125, 0.25 or 0.5 mg/kg) dose-dependently accelerated delayed gastric emptying, significant at 0.5 mg/kg, in diabetic dogs, whereas cisapride (1, 3 or 10 mg/kg) had no significant effect. These results add to the existing evidence that mitemcinal is likely to be useful for treating diabetic gastroparesis. PMID:18346169

Onoma, Mitsu; Ozaki, Ken-ichi; Yogo, Kenji; Monnai, Makoto; Muramatsu, Hiroyasu; Kamei, Kenshi; Kawabe, Yoshiki; Hayashi, Shuji; Shiga, Toshihiko; Matsuo, Saori; Suzuki, Masami; Itoh, Zen; Omura, Satoshi; Takanashi, Hisanori

2008-03-13

316

Effects of aging on agonist-activated sup 86 Rb efflux in arteries of Fischer 344 rats  

SciTech Connect

Segments of thoracic aorta (DTA), tail artery (TA), and mesenteric artery branches (MAB) were obtained from male Fischer 344 rats at ages of 1, 2, 6, 12, 24, and 30 mo and were used to determine the effects of aging on agonist-activated {sup 86}Rb (and {sup 42}K) efflux. At all three arterial sites, basal efflux decreased during development (1-6 mo), but no further changes were observed with aging (6-30 mo). The initial efflux response to 10 microM norepinephrine (NE) in the presence of 1 microM propranolol exhibited either no change (DTA) or an increase (TA and MAB) during development (1-6 mo), but all three sites showed a large decrease during aging (6-30 mo). Changes in the steady-state response to NE paralleled changes in the basal efflux at all ages and arterial sites. The initial efflux response to 75 mM K+-physiological salt solution (PSS) for the DTA in the presence of 1 microM phentolamine and 1 microM propranolol decreased during development followed by an increase during aging, whereas for the TA and MAB, there were no significant changes with age. The steady-state efflux response to K+ decreased during development at all three sites but was increased only for the DTA during aging. The steady-state efflux response to K+ was not altered for the TA and MAB during aging. Efflux responses using {sup 42}K were qualitatively similar, but rate constants were quantitatively larger than those with {sup 86}Rb at all three arterial sites and at all ages.

Cox, R.H.; Tulenko, T.N. (Univ. of Pennsylvania, Philadelphia (USA))

1989-08-01

317

Activation of the human. beta. sub 2 -interferon/hepatocyte-stimulating factor/interleukin 6 promoter by cytokines, viruses, and second messenger agonists  

SciTech Connect

The hallmark of {beta}{sub 2}-interferon (IFN-{beta}{sub 2})/hepatocyte-stimulating factor/interleukin 6 gene expression is its inducibility in different types of human cells (fibroblasts, monocytes, epithelial cells, and endothelial cells) by different stimuli, which include cytokines such as tumor necrosis factor, interleukin 1 (IL-1) and platelet-derived growth factor, different viruses, and bacterial products such as endotoxin. The activation by cytokines, viruses, and second messenger agonists of the IFN-{beta}{sub 2} promoter linked to the bacterial chloramphenicol acetyltransferase (CAT) gene was studied after transfection into HeLa cells. A chimeric gene containing IFN-{beta}{sub 2} DNA from -1180 to +13 linked to the CAT gene was inducible {approx}10-fold by phorbol 12-myristate 13-acetate (PMA), followed, in decreasing order, by pseudorabies and Sendai viruses; serum; the cytokines tumor necrosis factor, IL-1, and epidermal growth factor; the cAMP agonists BrcAMP and forskolin and the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine; poly(I){center dot}poly(C); 1,2-diacylglycerol and the calcium ionophore A23187. The region between -225 and -113 in IFN-{beta}{sub 2}, which contains DNA motifs similar to the regulatory elements in the human c-fos gene, appears to contain the major cis-acting regulatory elements responsible for the activation of the IFN-{beta}{sub 2} promoter by several different cytokines, viruses, and second messenger agonists.

Ray, A.; Tatter, S.B.; May, L.T.; Sehgal, P.B. (Rockefeller Univ., New York, NY (USA))

1988-09-01

318

Increased theta activity in quantitative electroencephalographic (QEEG) measurements during exposure to complex weak magnetic fields.  

PubMed

Previous research has shown that exposure to circumcerebral weak magnetic fields with different rates of acceleration applied in a counterclockwise rotation around the head was associated with increased estimations of subjective time and as much as a 30% increase in power within the theta range within quantitative electroencephalographic (QEEG) recordings. The largest effect was associated with magnetic fields applied with 20 ms rates of change through each of the successively stimulated, equally spaced, 8 circumcerebral solenoids. The purpose of the present study was to compare the intracerebral power spectra associated with the rotation of the same patterns in either the clockwise or counterclockwise direction. The results generally replicated previous reports and showed enhanced power over regions of the left hemisphere during clockwise rotations and over the right hemisphere during counterclockwise rotations. These results were considered congruent with the creation of "interference patterns" between the rostral-caudal generation of endogenous cerebral magnetic fields putatively associated with consciousness and the spatial direction of the applied rotating magnetic fields. PMID:19037792

Booth, J N; Koren, S A; Persinger, M A

2008-01-01

319

Agonist Anti-Human CD27 Monoclonal Antibody Induces T Cell Activation and Tumor Immunity in Human CD27-Transgenic Mice.  

PubMed

The CD70/CD27 pathway plays a significant role in the control of immunity and tolerance, and previous studies demonstrated that targeting murine CD27 (mCD27) with agonist mAbs can mediate antitumor efficacy. We sought to exploit the potential of this pathway for immunotherapy by developing 1F5, a fully human IgG1 mAb to human CD27 (hCD27) with agonist activity. We developed transgenic mice expressing hCD27 under control of its native promoter for in vivo testing of the Ab. The expression and regulation of hCD27 in hCD27-transgenic (hCD27-Tg) mice were consistent with the understood biology of CD27 in humans. In vitro, 1F5 effectively induced proliferation and cytokine production from hCD27-Tg-derived T cells when combined with TCR stimulation. Administration of 1F5 to hCD27-Tg mice enhanced Ag-specific CD8(+) T cell responses to protein vaccination comparably to an agonist anti-mCD27 mAb. In syngeneic mouse tumor models, 1F5 showed potent antitumor efficacy and induction of protective immunity, which was dependent on CD4(+) and CD8(+) T cells. The requirement of FcR engagement for the agonistic and antitumor activities of 1F5 was demonstrated using an aglycosylated version of the 1F5 mAb. These data with regard to the targeting of hCD27 are consistent with previous reports on targeting mCD27 and provide a rationale for the clinical development of the 1F5 mAb, for which studies in advanced cancer patients have been initiated under the name CDX-1127. PMID:24026078

He, Li-Zhen; Prostak, Naseem; Thomas, Lawrence J; Vitale, Laura; Weidlick, Jeffrey; Crocker, Andrea; Pilsmaker, Catherine D; Round, Sarah M; Tutt, Alison; Glennie, Martin J; Marsh, Henry; Keler, Tibor

2013-09-11

320

Agonist activation of the G protein-coupled receptor GPR35 involves transmembrane domain III and is transduced via G?13 and ?-arrestin-2  

PubMed Central

BACKGROUND AND PURPOSE GPR35 is a poorly characterized G protein-coupled receptor at which kynurenic acid has been suggested to be the endogenous ligand. We wished to test this and develop assays appropriate for the study of this receptor. EXPERIMENTAL APPROACH Human and rat orthologues of GPR35 were engineered and expressed and assays developed to assess interaction with ?-arrestin-2, activation of G?13 and agonist-induced internalization. KEY RESULTS GPR35-?-arrestin-2 interaction assays confirmed that both the endogenous tryptophan metabolite kynurenic acid and the synthetic ligand zaprinast had agonist action at each orthologue. Zaprinast was substantially more potent than kynurenic acid at each and both agonists displayed substantially greater potency at rat GPR35. Two novel thiazolidinediones also displayed agonism and displayed similar potency at each GPR35 orthologue. The three ligand classes acted orthosterically with respect to each other, suggesting overlapping binding sites and, consistent with this, mutation to alanine of the conserved arginine at position 3.36 or tyrosine 3.32 in transmembrane domain III abolished ?-arrestin-2 recruitment in response to each ligand at each orthologue. CONCLUSIONS AND IMPLICATIONS These studies indicate that ?-arrestin-2 interaction assays are highly appropriate to explore the pharmacology of GPR35 and that G?13 activation is an alternative avenue of signal generation from GPR35. Arginine and tyrosine residues in transmembrane domain III are integral to agonist recognition and function of this receptor. The potency of kynurenic acid at human GPR35 is sufficiently low, however, to question whether it is likely to be the true endogenous ligand for this receptor.

Jenkins, Laura; Alvarez-Curto, Elisa; Campbell, Kate; de Munnik, Sabrina; Canals, Meritxell; Schlyer, Sabine; Milligan, Graeme

2011-01-01

321

Synthesis and structure-activity relationship of 4-amino-2-phenylpyrimidine derivatives as a series of novel GPR119 agonists.  

PubMed

Through preparation and examination of a series of novel 4-amino-2-phenylpyrimidine derivatives as agonists for GPR119, we identified 2-(4-bromophenyl)-6-methyl-N-[2-(1-oxidopyridin-3-yl)ethyl]pyrimidin-4-amine (9t). Compound 9t improved glucose tolerance in mice following oral administration and showed good pharmacokinetic profiles in rats. PMID:22365911

Negoro, Kenji; Yonetoku, Yasuhiro; Maruyama, Tatsuya; Yoshida, Shigeru; Takeuchi, Makoto; Ohta, Mitsuaki

2012-02-10

322

Opioid receptor agonists activate pertussis toxin-sensitive G proteins and inhibit adenylyl cyclase in canine cardiac sarcolemma  

Microsoft Academic Search

Although both opioid receptors and endogenous opioids are abundant in cardiac tissues, the signal transduction pathways of opioids in cardiac sarcolemmal membranes have yet to be identified. In highly purified canine cardiac sarcolemmal membranes, binding of the opioid receptor antagonist [3H]diprenorphine and effects of µ, d and ? agonists on low Km GTPase and adenylyl cyclase were measured. Equilibrium binding

Feraydoon Niroomand; Roman A. Mura; Lucia Piacentini; Wolfgang Kübler

1996-01-01

323

Alterations in torque and hamstrings agonist and antagonist activity over repeated maximum effort, reciprocal isokinetic flexion-extension movements  

Microsoft Academic Search

Examining the effects of fatigue on hamstrings' functioning can provide useful information regarding their role in stabilizing the knee joint. The purpose of the present investigation was to determine the effect of fatiguing, maximum effort, reciprocal isokinetic flexion-extension movements on peak torque (PT) and average torque (AVT) of the knee flexors and extensors, and agonist and antagonist medial hamstrings (MH)

Ronald Croce; J. P. Miller; Michael Horvat

2008-01-01

324

Patterns of electric organ discharge activity in the weakly electric fish Brienomyrus niger L. (Mormyridae).  

PubMed

In this study we investigated the electric organ discharge (EOD) activity of the mormyrid fish Brienomyrus niger when they were not affected by conspecific EODs. The fish emitted two types of EOD patterns: phasic and tonic sequences of pulse intervals (SPIs). The phasic SPI occurred in the form of stereotyped, individual-specific bursts in EOD activity which we called scallop. Tonic SPIs varied in mean EOD repetition rate and pulse interval stability, and consisted of either regular activity with mean frequencies exceeding 10 Hz and a coefficient of variation (cv) below 15%, or variable activity with mean rates below 10 Hz and cv's of 15% and above. Individual fish predominantly generated one of the three patterns: "variable", "regular", or "scallop". Most fish emitted "variable" activity, but "regular" activity was typical of females and "scallop" of males. We suggest that these SPIs may facilitate individual recognition. The dynamics of the electromotor command system, as reflected by the fish's EOD activity, is compared with that of the well-studied mammalian inferior olive, and mechanisms for a possible self-regulatory central pattern generator are discussed. PMID:2620705

Serrier, J; Moller, P

1989-01-01

325

Tesaglitazar, a dual peroxisome proliferator-activated receptor alpha/gamma agonist, reduces atherosclerosis in female low density lipoprotein receptor deficient mice  

PubMed Central

Objective The transcription factors, peroxisome proliferator-activated receptors (PPAR) alpha (?) and gamma (?), which are involved in lipid and glucose homeostasis, also exert modulatory actions on vascular cells where they exhibit anti-inflammatory and anti-proliferative properties. Hence PPAR agonists potentially can affect atherogenesis both via metabolic effects and direct effects on the vessel wall. We tested whether the dual PPAR-?/? agonist, tesaglitazar (TZ), would reduce atherosclerosis in a non-diabetic, atherosclerosis-prone mouse model, independent of effects on plasma lipids. Methods and results Low-density lipoprotein receptor deficient (LDLr ?/?) mice were fed a Western type diet consisting of 21% butterfat and 0.15% cholesterol, with or without TZ 0.5 ?mol/kg of diet, for 12 weeks. TZ reduced atherosclerosis in the female, but not male, LDLr ?/? mice without affecting cholesterol and triglyceride levels, HDL binding to biglycan, or the inflammatory markers serum amyloid A (SAA) and serum amyloid P (SAP). TZ also decreased adiposity in both genders. Conclusions TZ reduced atherosclerosis in the female LDLr?/? mice via lipid-independent mechanisms, probably at least in part by direct actions on the vessels. The body weight changes in these mice are different from the effects of dual PPAR agonists seen in humans.

Chira, Ebele C.; McMillen, Timothy S.; Wang, Shari; Haw, Antonio; O'Brien, Kevin D.; Wight, Thomas N.; Chait, Alan

2009-01-01

326

Luteinizing hormone-releasing hormone agonists interfere with the mitogenic activity of the insulin-like growth factor system in androgen-independent prostate cancer cells.  

PubMed

We have previously shown that LHRH agonists exert a direct and specific inhibitory action on the proliferation of the androgen-independent DU 145 prostate cancer cell line; however, the cellular mechanisms mediating this antiproliferative action are not well defined. It is well known that the insulin-like growth factor (IGF) system plays a crucial role in the local regulation of the growth of androgen-independent prostate cancer. The present experiments were performed to evaluate whether LHRH agonists might exert their antimitogenic effect by interfering with the activity of the locally expressed IGF system. To this purpose, the effects of the LHRH agonist Zoladex (LHRH-A) on 1) the mitogenic action of IGF-I, 2) the tyrosine phosphorylation of type 1 IGF-I receptor (IGF-IR), 3) the concentration of IGF-IR, and 4) the secretion of IGF-binding protein-3 were studied. The results obtained show that in DU 145 cells, LHRH-A 1) counteracts the mitogenic action of IGF-I in a dose-dependent manner, 2) prevents the IGF-I-induced tyrosine phosphorylation of the IGF-IR, 3) reduces the concentration of IGF-IR without affecting its Kd value, and 4) does not affect the secretion of IGF-binding protein-3 in the conditioned medium from these cells. These data suggest that LHRH agonists may inhibit the proliferation of human androgen-independent prostate tumor cells by interfering with some of the cellular mechanisms mediating the stimulatory action of the IGF system. PMID:9886842

Marelli, M M; Moretti, R M; Dondi, D; Motta, M; Limonta, P

1999-01-01

327

New strategies for drug discovery: activation of silent or weakly expressed microbial gene clusters.  

PubMed

Genome sequencing of Streptomyces, myxobacteria, and fungi showed that although each strain contains genes that encode the enzymes to synthesize a plethora of potential secondary metabolites, only a fraction are expressed during fermentation. Interest has therefore grown in the activation of these cryptic pathways. We review current progress on this topic, describing concepts for activating silent genes, utilization of "natural" mutant-type RNA polymerases and rare earth elements, and the applicability of ribosome engineering to myxobacteria and fungi, the microbial groups known as excellent searching sources, as well as actinomycetes, for secondary metabolites. PMID:23143535

Ochi, Kozo; Hosaka, Takeshi

2012-11-11

328

The novel HSP90 inhibitor, PU-H71, suppresses glial cell activation but weakly affects clinical signs of EAE  

PubMed Central

Ansamycins are very effective HSP90 inhibitors that showed significant beneficial effects in the treatment of EAE. However, their toxicity and poor stability in solution limit their clinical use. In the present study we have characterized the anti-inflammatory properties of a novel HSP90 inhibitor, PU-H71, and tested its effects in EAE. Our findings show that PU-H71 reduced lipopolysaccharide astrocyte activation but failed to reduce the inflammatory cytokine activation. In contrast to ansamycins, PU-H71 weakly affects EAE clinical course. In conclusion, although PU-H71 displayed some anti-inflammatory properties, it appeared in vivo less effective than the more toxic HSP90 inhibitors.

Lisi, Lucia; McGuire, Susan; Sharp, Anthony; Chiosis, Gabriela; Navarra, Pierluigi; Feinstein, Douglas L.; Russo, Cinzia Dello

2013-01-01

329

Muscarinic agonists activate Ca2+ store-operated and -independent ionic currents in insulin-secreting HIT-T15 cells and mouse pancreatic beta-cells.  

PubMed

The neurotransmitter acetylcholine, a muscarinic receptor agonist, augments glucose-induced insulin secretion from pancreatic beta-cells by depolarizing the membrane to enhance voltage-gated Ca(2+) influx. To clarify the electrical events involved in this process, we measured ionic currents from a clonal beta-cell line (HIT-T15) and mouse pancreatic beta-cells. In whole-cell recordings, the muscarinic agonist carbachol (CCh) dose-dependently and reversibly activated a voltage-independent, nonselective current (whole-cell conductance 24 pS/pF, reversal potential of approximately -15 mV). The current, which we refer to as I(musc), was blocked by atropine, a muscarinic receptor antagonist, and SKF 96365, a nonspecific ion channel blocker. The magnitude of the current decreased by 52% when extracellular Na(+) was removed, but was not affected by changes in extracellular Ca(2+), confirming that I(musc) is a nonselective current. To determine if I(musc) activates following release of Ca(2+) from an intracellular store, we blocked intracellular IP(3) receptors with heparin. Carbachol still activated a current in the presence of heparin, demonstrating the presence of a Ca(2+) store-independent, muscarinic agonist-activated ionic current in HIT cells. However, the store-independent current was smaller and had a more positive reversal potential (approximately 0 mV) than the current activated by CCh under control conditions. This result indicates that heparin had blocked a component of I(musc), which likely activates following release of stored Ca(2+). Depleting IP(3)-sensitive calcium stores with thapsigargin also activated a non-selective, SKF 96365-blockable current in HIT cells. The properties of this putative store-operated current were similar to the component of I(musc) that was blocked by heparin, being voltage-independent and reversing near -30 mV. We conclude that I(musc) consists of store-operated and store-independent components, both of which may contribute to the depolarizing action of muscarinic agonists on pancreatic beta-cells. PMID:15014918

Mears, D; Zimliki, C L

2004-01-01

330

Pharmacokinetics, metabolism, and disposition of rivoglitazone, a novel peroxisome proliferator-activated receptor ? agonist, in rats and monkeys.  

PubMed

The pharmacokinetics, metabolism, and excretion of rivoglitazone [(RS)-5-{4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl)methoxy]benzyl}-1,3-thiazolidine-2,4-dione monohydrochloride], a novel thiazolidinedione (TZD) peroxisome proliferator-activated receptor ? selective agonist, were evaluated in male F344/DuCrlCrlj rats and cynomolgus monkeys. The total body clearance and volume of distribution of rivoglitazone were low in both animals (0.329-0.333 ml per min/kg and 0.125-0.131 l/kg for rats and 0.310-0.371 ml per min/kg and 0.138-0.166 l/kg for monkeys), and the plasma half-life was 4.55 to 4.84 h for rats and 6.21 to 6.79 h for monkeys. The oral bioavailability was high (>95% in rats and >76.1% in monkeys), and the exposure increased dose proportionally. After administration of [(14)C]rivoglitazone, radioactivity was mainly excreted in feces in rats, whereas radioactivity was excreted in urine and feces with the same ratio in monkeys. Because excreted rivoglitazone in urine and bile was low, metabolism was predicted to be the main contributor to total body clearance. The structures of 20 metabolites (M1-M20) were identified, and 5 initial metabolic pathways were proposed: O-demethylation, TZD ring opening, N-glucuronidation, N-demethylation, and TZD ring hydroxylation. O-Demethylation was the main metabolic pathway in both animals, but N-demethylation and TZD ring hydroxylation were observed only in monkeys. N-Glucuronide (M13) was nonenzymatically hydrolyzed to TZD ring-opened N-glucuronide (M9), and the amount of these metabolites in monkeys was larger than that in rats. In plasma, rivolitazone was observed as the main component in both animals, and O-demethyl-O-sulfate (M11) was observed as the major metabolite in rats but as many minor metabolites in monkeys. PMID:21177486

Uchiyama, Minoru; Iwabuchi, Haruo; Tsuruta, Fujiko; Abe, Koji; Takahashi, Makoto; Koda, Hiroko; Oguchi, Minoru; Okazaki, Osamu; Izumi, Takashi

2010-12-21

331

Creatine Kinase Activity Weakly Correlates to Volume Completed Following Upper Body Resistance Exercise  

ERIC Educational Resources Information Center

|In the current study, we examined the relationship between serum creatine kinase (CK) activity following upper body resistance exercise with a 1- or 3-min rest between sets. Twenty men performed two sessions, each consisting of four sets with a 10-repetition maximum load. The results demonstrated significantly greater volume for the 3-min…

Machado, Marco; Willardson, Jeffrey M.; Silva, Dailson P.; Frigulha, Italo C.; Koch, Alexander J.; Souza, Sergio C.

2012-01-01

332

Potentiation of a weakly active ricin A chain immunotoxin recognizing the neural cell adhesion molecule.  

PubMed

A ricin A chain immunotoxin, SEN36-ricin A chain, directed against the neural cell adhesion molecule (N-CAM) had no selective cytotoxic activity against three different small cell lung cancer (SCLC) cell lines in tissue culture despite expression of the target antigen on more than 98% of cells in each line detected by indirect immunofluorescence. Treatment of the SW2 SCLC cell line with suramin and interferons alpha and gamma increased the level of N-CAM expression only slightly and had no significant effect on the cytotoxic activity of the SEN36 immunotoxin. In the presence of the carboxylic ionophore monensin at a concentration of 0.1 microM, the toxicity of SEN36-ricin A chain to the SW2 cell line was enhanced by 12,000-fold. In contrast, lysosomotropic amines showed little or no potentiation of activity, suggesting that lysosomal degradation was not the major factor limiting the action of the anti-N-CAM immunotoxin. The findings of this study indicate that ricin A chain immunotoxins directed against N-CAM on SCLC are unlikely to have sufficient activity to be useful therapeutic agents in the absence of potentiating agents such as monensin, which can interfere with the normal intracellular pathways of antigen routing. PMID:1325302

Derbyshire, E J; Stahel, R A; Wawrzynczak, E J

1992-09-01

333

Toll-like receptor-9 agonists increase cyclin D1 expression partly through activation of activator protein-1 in human oral squamous cell carcinoma cells.  

PubMed

Increasing evidence suggests that malignant transformation can result from chronic infection, and Toll-like receptors (TLRs) may play an important role in this process. We have previously reported that the increased expression of TLR-9 is associated with tumor cell proliferation in oral cancer. However, the mechanisms involved have not been elucidated. The aim of this study was to investigate whether CpG-oligodeoxynucleotides (CpG-ODN), a special TLR-9 agonist, is able to exert the proliferation-promoting effect in human oral squamous cell carcinoma (OSCC), and to explore the possible underlying molecular mechanism. Flow cytometry, MTT, and colony formation assay were used to evaluate cell proliferation and cell cycle distribution. The mRNA and protein levels were analyzed by quantitative RT-PCR and Western blot assay. Luciferase reporter gene, EMSA, and ChIP assays were used to detect the activity of activator protein-1 (AP-1) and nuclear factor-?B (NF-?B) in HB cells. Results showed that CpG-ODN could stimulate proliferation of HB cells in a dose- and time-dependent manner with a promoted G(1) /S cell cycle progression. Increased cyclin D1 expression was detected in the nuclear region after CpG-ODN treatment. Moreover, CpG-ODN promoted nuclear translocation and activation of AP-1, which appeared to be required for TLR-9-mediated cyclin D1 expression and subsequently cell proliferation, but seemed to have little impact on NF-?B activity. Our results indicate that CpG-ODN stimulates tumor cell proliferation through TLR-9-mediated AP-1-activated cyclin D1 expression in OSCC HB cells. Pharmacologic inhibition of the TLR-9/AP-1/cyclin D1 pathway may be a new therapeutic approach for prevention as well as treatment of OSCC. PMID:22853846

Min, Ruan; Siyi, Li; Wenjun, Yang; Shengwen, Liu; Ow, Andrew; Lizheng, Wang; Chenping, Zhang

2012-09-14

334

Allosteric Modulator ORG27569 Induces CB1 Cannabinoid Receptor High Affinity Agonist Binding State, Receptor Internalization, and Gi Protein-independent ERK1/2 Kinase Activation*  

PubMed Central

The cannabinoid receptor 1 (CB1), a member of the class A G protein-coupled receptor family, is expressed in brain tissue where agonist stimulation primarily activates the pertussis toxin-sensitive inhibitory G protein (Gi). Ligands such as CP55940 ((1R,3R,4R)-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-4-(3- hydroxypropyl)cyclohexan-1-ol) and ?9-tetrahydrocannabinol are orthosteric agonists for the receptor, bind the conventional binding pocket, and trigger Gi-mediated effects including inhibition of adenylate cyclase. ORG27569 (5-chloro-3-ethyl-1H-indole-2-carboxylic acid [2-(4-piperidin-1-yl-phenyl)ethyl]amide) has been identified as an allosteric modulator that displays positive cooperativity for CP55940 binding to CB1 yet acts as an antagonist of G protein coupling. To examine this apparent conundrum, we used the wild-type CB1 and two mutants, T210A and T210I (D'Antona, A. M., Ahn, K. H., and Kendall, D. A. (2006) Biochemistry 45, 5606–5617), which collectively cover a spectrum of receptor states from inactive to partially active to more fully constitutively active. Using these receptors, we demonstrated that ORG27569 induces a CB1 receptor state that is characterized by enhanced agonist affinity and decreased inverse agonist affinity consistent with an active conformation. Also consistent with this conformation, the impact of ORG27569 binding was most dramatic on the inactive T210A receptor and less pronounced on the already active T210I receptor. Although ORG27569 antagonized CP55940-induced guanosine 5?-3-O-(thio)triphosphate binding, which is indicative of G protein coupling inhibition in a concentration-dependent manner, the ORG27569-induced conformational change of the CB1 receptor led to cellular internalization and downstream activation of ERK signaling, providing the first case of allosteric ligand-biased signaling via CB1. ORG27569-induced ERK phosphorylation persisted even after pertussis toxin treatment to abrogate Gi and occurs in HEK293 and neuronal cells.

Ahn, Kwang H.; Mahmoud, Mariam M.; Kendall, Debra A.

2012-01-01

335

Sickle cell vaso-occlusion causes activation of iNKT cells that is decreased by the adenosine A2A receptor agonist regadenoson.  

PubMed

Adenosine A2A receptor (A2AR) agonists reduce invariant natural killer T (iNKT) cell activation and decrease inflammation in sickle cell disease (SCD) mice. We conducted a phase 1 trial of the A2AR agonist regadenoson in adults with SCD. The target dose was 1.44 ?g/kg/h. iNKT cell activation was evaluated using antibodies targeting the p65 subunit of nuclear factor-?B (phospho-NF-?B p65), interferon-? (IFN-?), and A2AR. Regadenoson was administered to 27 adults with SCD. We examined 21 patients at steady state and 6 during painful vaso-occlusive crises (pVOC). iNKT cell activation was also measured in 14 African-American controls. During pVOC, the fraction of iNKT cells demonstrating increased phospho-NF-?B p65 and A2AR expression was significantly higher compared with controls (P < .01) and steady-state patients (P < .05). IFN-? expression was also significantly higher compared with controls (P = .02). After a 24-hour infusion of regadenoson during pVOC, phospho-NF-?B p65 activation in iNKT cells decreased compared to baseline by a median of 48% (P = .03) to levels similar to controls and steady-state SCD. No toxicities were identified. Infusional regadenoson administered to adults with SCD at 1.44 ?g/kg/h during pVOC decreases activation of iNKT cells without toxicity. PMID:23377438

Field, Joshua J; Lin, Gene; Okam, Maureen M; Majerus, Elaine; Keefer, Jeffrey; Onyekwere, Onyinye; Ross, Ainsley; Campigotto, Federico; Neuberg, Donna; Linden, Joel; Nathan, David G

2013-02-01

336

The Muscarinic M1\\/M4 Receptor Agonist Xanomeline Exhibits Antipsychotic-Like Activity in Cebus apella Monkeys  

Microsoft Academic Search

Xanomeline is a muscarinic M1\\/M4 preferring receptor agonist with little or no affinity for dopamine receptors. The compound reduces psychotic-like symptoms in patients with Alzheimer's disease and exhibits an antipsychotic-like profile in rodents without inducing extrapyramidal side effects (EPS) at therapeutically relevant doses. In the present study, we examined whether the xanomeline-induced functional dopamine antagonism found in rodent studies could

Maibritt B Andersen; Anders Fink-Jensen; Linda Peacock; Jes Gerlach; Frank Bymaster; Jens August Lundbæk; Thomas Werge

2003-01-01

337

Local Administration of Serotonin Agonists Blocks Light-Induced Phase Advances of the Circadian Activity Rhythm in the Hamster  

Microsoft Academic Search

Circadian rhythms in mammals are synchronized to environmental light-dark cycles through a direct retinal projection to the suprachiasmatic nucleus (SCN), a circadian clock. This process is thought to be modulated by other afferents to the SCN, including a dense serotonergic projection from the midbrain raphe. Previous work from this laboratory demonstrated that a systemically administered 5-hydroxytry ptamine1A\\/7 (5-HT1A\\/7) agonist 8-hydroxy-2-(di-n-propylamino)tetralin

E. T. Weber; R. L. Gannon; M. A. Rea

1998-01-01

338

Possible beneficial effect of peroxisome proliferator-activated receptor (PPAR) - ? and ? agonist against a rat model of oral dyskinesia.  

PubMed

Tardive dyskinesia is a type of hyperkinetic movement disorder which consists of abnormal involuntary movements, characterized by orofacial movements. Previous studies suggest that oxidative stress and neuro-inflammation play important role in the pathogenesis of TD. Recently, PPAR-? and PPAR-? have been reported as neuroprotective agent in various animal models. The present study investigated the neuroprotective effect of PPAR-? agonist, pioglitazone (20 and 40mg/kg, p.o.) and PPAR-? agonist, fenofibrate (100 and 200mg/kg, p.o.) in an animal model of oral dyskinesia. Oral dyskinesia was induced by chronic administration of haloperidol (1mg/kgi.p.) for 21days. Chronic administration of haloperidol significantly increased vacuous chewing movements, tongue protrusions, facial jerking, sniffing and grooming in rats which was dose-dependently inhibited by pioglitazone and fenofibrate. Further, it also decreased % retention of memory in an elevated plus maze test on day 22. Chronic administration of haloperidol also induced oxidative damage and neuroinflammation (TNF-? and IL-1?) in brain regions. The fenofibrate and pioglitazone were able to reverse the behavioral and biochemical changes induced by haloperidol. Further the study proposed the antioxidant and antiinflammatory effects of both PPAR agonists in this model. We concluded that administration of pioglitazone and fenofibrate individually or in combination along with antipsychotic in the treatment of schizophrenia, prevent or delay the symptoms of oral dyskinesia. PMID:23948071

Grover, Sania; Kumar, Puneet; Singh, Kuldeep; Vikram, Vir; Budhiraja, R D

2013-08-12

339

AvrRpm1 Missense Mutations Weakly Activate RPS2-Mediated Immune Response in Arabidopsis thaliana  

PubMed Central

Plants recognize microbes via specific pattern recognition receptors that are activated by microbe-associated molecular patterns (MAMPs), resulting in MAMP-triggered immunity (MTI). Successful pathogens bypass MTI in genetically diverse hosts via deployment of effectors (virulence factors) that inhibit MTI responses, leading to pathogen proliferation. Plant pathogenic bacteria like Pseudomonas syringae utilize a type III secretion system to deliver effectors into cells. These effectors can contribute to pathogen virulence or elicit disease resistance, depending upon the host plant genotype. In disease resistant genotypes, intracellular immune receptors, typically belonging to the nucleotide binding leucine-rich repeat family of proteins, perceive bacterial effector(s) and initiate downstream defense responses (effector triggered immunity) that include the hypersensitive response, and transcriptional re-programming leading to various cellular outputs that collectively halt pathogen growth. Nucleotide binding leucine-rich repeat sensors can be indirectly activated via perturbation of a host protein acting as an effector target. AvrRpm1 is a P. syringae type III effector. Upon secretion into the host cell, AvrRpm1 is acylated by host enzymes and directed to the plasma membrane, where it contributes to virulence. This is correlated with phosphorylation of Arabidopsis RIN4 in vivo. RIN4 is a negative regulator of MAMP-triggered immunity, and its modification in the presence of four diverse type III effectors, including AvrRpm1, likely enhances this RIN4 regulatory function. The RPM1 nucleotide binding leucine-rich repeat sensor perceives RIN4 perturbation in disease resistant plants, leading to a successful immune response. Here, demonstrate that AvrRpm1 has a fold homologous to the catalytic domain of poly(ADP-ribosyl) polymerase. Site-directed mutagenesis of each residue in the putative catalytic triad, His63-Tyr122-Asp185 of AvrRpm1, results in loss of both AvrRpm1-dependent virulence and AvrRpm1-mediated activation of RPM1, but, surprisingly, causes a gain of function: the ability to activate the RPS2 nucleotide binding leucine-rich repeat sensor.

Cherkis, Karen A.; Temple, Brenda R. S.; Chung, Eui-Hwan; Sondek, John; Dangl, Jeffery L.

2012-01-01

340

Experiments in Weak Acid Dissociation and Theories of Activated Rate Processes.  

NASA Astrophysics Data System (ADS)

Activated chemical reactions in condensed media constitute the most important type of chemistry near the earth's surface. With the help and intuition provided by the successes of gas phase chemistry, two technological advances, subpicosecond time-resolved spectroscopy and theoretical calculations using super computers, have brought the goal of a molecular level understanding in condensed phase chemistry closer to view. In the experimental studies, lifetime and quantum yield measurements were performed on the excited states of 1-naphthol-2-sulfonic acid potassium salt (1-ROH-2-S) and its associated anion in aqueous solutions. In comparison to 1-naphthol, the intramolecular hydrogen bonding in the sulfonate derivative sterically reduces the extramolecular proton dissociation and recombination rates. Despite the large differences between excited state rates in 1-ROH -2-S and those in 1- and 2-naphthol, proton dissociation in all these molecules is controlled by reorientational motions of the adjacent water and requires a special (H _2O)_{4+/- 1} cluster as the proton acceptor. These findings support the Robinson-Lee-Moore hydration model for proton dissociation in aqueous environments. In the theoretical studies, two generalized theories of activated chemical reactions were developed using space-dependent friction. One method used the Carmeli-Nitzan approach, which is based on a Langevin equation. The second method employed the recent theory of Pollak-Grabert-Hanggi based on a Hamiltonian approach. The latter theory gave rise to interesting scaling properties in certain limits.

Krishnan, Rajalakshmi

341

GW9662, a potent antagonist of PPAR?, inhibits growth of breast tumour cells and promotes the anticancer effects of the PPAR? agonist rosiglitazone, independently of PPAR? activation  

PubMed Central

Peroxisome proliferator-activated receptor gamma (PPAR?), a member of the nuclear receptor superfamily, is activated by several compounds, including the thiazolidinediones. In addition to being a therapeutic target for obesity, hypolipidaemia and diabetes, perturbation of PPAR? signalling is now believed to be a strategy for treatment of several cancers, including breast. Although differential expression of PPAR? is observed in tumours compared to normal tissues and PPAR? agonists have been shown to inhibit tumour cell growth and survival, the interdependence of these observations is unclear. This study demonstrated that the potent, irreversible and selective PPAR? antagonist GW9662 prevented activation of PPAR? and inhibited growth of human mammary tumour cell lines. Controversially, GW9662 prevented rosiglitazone-mediated PPAR? activation, but enhanced rather than reversed rosiglitazone-induced growth inhibition. As such, these data support the existence of PPAR?-independent pathways and question the central belief that PPAR? ligands mediate their anticancer effects via activation of PPAR?.

Seargent, Jill M; Yates, Elisabeth A; Gill, Jason H

2004-01-01

342

A potential role for nuclear factor of activated T-cells in receptor tyrosine kinase and G-protein-coupled receptor agonist-induced cell proliferation.  

PubMed Central

We have studied the role of nuclear factor of activated T-cells (NFAT) transcription factors in the induction of vascular smooth muscle cell (VSMC) growth by platelet-derived growth factor-BB (PDGF-BB) and thrombin, the receptor tyrosine kinase (RTK) and G-protein-coupled receptor (GPCR) agonists, respectively. NFATc1 but not NFATc2 or NFATc3 was translocated from the cytoplasm to the nucleus upon treatment of VSMCs with PDGF-BB or thrombin. Translocation of NFATc1 was followed by an increase in NFAT-DNA binding activity and NFAT-dependent reporter gene expression. Cyclosporin A (CsA), a potent and specific inhibitor of calcineurin, a calcium/calmodulin-dependent serine phosphatase involved in the dephosphorylation and activation of NFATs, blocked NFAT-DNA binding activity and NFAT-dependent reporter gene expression induced by PDGF-BB and thrombin. CsA also completely inhibited PDGF-BB- and thrombin-induced VSMC growth, as measured by DNA synthesis and cell number. In addition, forced expression of the NFAT-competing peptide VIVIT for calcineurin binding significantly attenuated the DNA synthesis induced by PDGF-BB and thrombin in VSMCs. Together, these findings for the first time demonstrate a role for NFATs in RTK and GPCR agonist-induced growth in VSMCs.

Yellaturu, Chandrahasa R; Ghosh, Salil K; Rao, R K; Jennings, Lisa K; Hassid, Aviv; Rao, Gadiparthi N

2002-01-01

343

Agonist-directed trafficking of signalling at serotonin 5HT 2A, 5HT 2B and 5HT 2C-VSV receptors mediated Gq\\/11 activation and calcium mobilisation in CHO cells  

Microsoft Academic Search

Several examples of agonist-directed trafficking of receptor signalling at 5-HT2A and 5-HT2C receptors have been reported that involve independent downstream transduction pathways. We now report the functional selectivity of a series of chemically diverse agonists at human (h)5-HT2A, h5-HT2B and h5-HT2C-VSV by examining two related responses, the upstream activation of Gq\\/11 proteins in comparison with its associated cascade of calcium

Didier Cussac; Elisa Boutet-Robinet; Marie-Christine Ailhaud; Adrian Newman-Tancredi; Jean-Claude Martel; Nathalie Danty; Isabelle Rauly-Lestienne

2008-01-01

344

Activation of the TNF alpha-p55 receptor induces myocyte proliferation and modulates agonist-evoked calcium transients in cultured human tracheal smooth muscle cells.  

PubMed

Evidence suggests that cytokines may modulate smooth muscle cell function in a variety of inflammatory diseases. In the present study, we characterized the specific receptor subtypes that mediate tumor necrosis factor alpha (TNF alpha) effects on myocyte proliferation and on agonist-induced calcium transients in cultured human tracheal smooth muscle cells (TSMC). Pretreatment of human TSMC with TNF alpha potentiated cytosolic calcium [(Ca2+)i] transients evoked by carbachol. In a similar manner, selective TNF alpha-p55 receptor agonists such as htr-9, an activating monoclonal antibody, or a recombinant TNF-p55 (rTNF-p55), which specifically activates the TNF alpha-p55 receptor but not the TNF alpha-p75 receptor, also augmented [Ca2+]i transients evoked by carbachol. In parallel experiments, TNF alpha, rTNF alpha-p55, and htr-9 induced human TSMC proliferation as measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. Interestingly, activation of the TNF alpha-p75 receptor with a selective agonist, recombinant TNF alpha-p75 (rTNF alpha-p75), or inhibition of the TNF alpha-p75 receptor with utr-1, an inhibitory anti-TNF alpha-p75 receptor antibody, had no effect on TNF alpha-augmented calcium transients or on myocyte growth. To further confirm the receptor specificity of these findings, immunocytochemical studies were performed using receptor-specific antibodies. These studies demonstrated marked cell-surface expression of the TNF alpha-p55 receptor compared with expression of the TNF alpha-p75 receptor on human TSMC. Taken together, our results suggest that TNF alpha modulates agonist-induced calcium transients and induces human TSMC proliferation by specific activation of the TNF alpha-p55 receptor. Further studies addressing the cellular and molecular mechanisms regulating cytokine modulation of airway smooth muscle function may provide new insight into mechanisms that induce airway hyperresponsiveness in asthma. PMID:8679222

Amrani, Y; Panettieri, R A; Frossard, N; Bronner, C

1996-07-01

345

New calcium channel agonists as potential therapeutics in Lambert-Eaton myasthenic syndrome and other neuromuscular diseases.  

PubMed

Lambert-Eaton myasthenic syndrome (LEMS) causes neuromuscular weakness as a result of an autoimmune attack on the calcium channels that normally regulate chemical transmitter release at the neuromuscular junction. Currently there are limited treatment options for patients with this and other forms of neuromuscular weakness. A novel, first-in-class calcium channel agonist that is selective for the types of voltage-gated calcium channels that regulate transmitter release at neuromuscular synapses has recently been developed. This compound (GV-58) slows deactivation (closing) of the channel, resulting in a large increase in total calcium entry during motor nerve action potential activity. This new calcium channel agonist is currently being evaluated for the treatment of neuromuscular weakness. Potential applications include development as single therapeutics, or for combination treatments. PMID:23278582

Tarr, Tyler B; Valdomir, Guillermo; Liang, Mary; Wipf, Peter; Meriney, Stephen D

2012-12-01

346

Evaluation of a novel calcium channel agonist for therapeutic potential in Lambert-Eaton myasthenic syndrome.  

PubMed

We developed a novel calcium (Ca(2+)) channel agonist that is selective for N- and P/Q-type Ca(2+) channels, which are the Ca(2+) channels that regulate transmitter release at most synapses. We have shown that this new molecule (GV-58) slows the deactivation of channels, resulting in a large increase in presynaptic Ca(2+) entry during activity. GV-58 was developed as a modification of (R)-roscovitine, which was previously shown to be a Ca(2+) channel agonist, in addition to its known cyclin-dependent kinase activity. In comparison with the parent molecule, (R)-roscovitine, GV-58 has a ?20-fold less potent cyclin-dependent kinase antagonist effect, a ?3- to 4-fold more potent Ca(2+) channel agonist effect, and ?4-fold higher efficacy as a Ca(2+) channel agonist. We have further evaluated GV-58 in a passive transfer mouse model of Lambert-Eaton myasthenic syndrome and have shown that weakened Lambert-Eaton myasthenic syndrome-model neuromuscular synapses are significantly strengthened following exposure to GV-58. This new Ca(2+) channel agonist has potential as a lead compound in the development of new therapeutic approaches to a variety of disorders that result in neuromuscular weakness. PMID:23785168

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

2013-06-19

347

Synthesis and evaluation of 2,3-dinorprostaglandins: Dinor-PGD1 and 13-epi-dinor-PGD1 are peroxisome proliferator-activated receptor ?/? dual agonists.  

PubMed

2,3-Dinorprostaglandins (dinor-PGs) have been regarded as ?-oxidation products of arachidonic-acid-derived prostaglandins, but their biological activities in mammalian cells remain unclear. On the other hand, C18 polyunsaturated fatty acids (PUFAs), such as ?-linolenic acid (GLA), have various biological activities, and dinor-PGs are speculated to be biosynthesized from GLA. Here, we synthesized dinor-PGs that may possibly be derived from GLA and examined their activities towards peroxisome proliferator-activated receptors (PPARs). Dinor-PGD1 (1) and its epimer 13-epi-dinor-PGD1 (epi-1) were found to be dual agonists for PPAR?/?, whereas PGD2 derived from arachidonic acid is selective for PPAR?. Thus, GLA-derived dinor-PGs may have unique biological roles. PMID:23566516

Sato, Ayato; Dodo, Kosuke; Makishima, Makoto; Hashimoto, Yuichi; Sodeoka, Mikiko

2013-03-21

348

The Antidepressant Amitriptyline is a TrkA and TrkB Receptor Agonist that Promotes TrkA/TrkB Heterodimerization and Has Potent Neurotrophic Activity  

PubMed Central

Neurotrophins, the cognate ligands for the Trk receptors, are homodimers and induce Trk dimerization through a symmetric bivalent mechanism. We report here that amitriptyline, an antidepressant drug, directly binds TrkA and TrkB and triggers their dimerization and activation. Amitriptyline, but not any other tricyclic or SSRI antidepressants, promotes TrkA autophosphorylation in primary neurons and induces neurite outgrowth in PC12 cells. Amitriptyline binds the extracellular domain of both TrkA and TrkB and promotes TrkA-TrkB receptor heterodimerization. Truncation of amitriptyline binding motif on TrkA abrogates the receptor dimerization by amitriptyline. Administration of amitriptyline to mice activates both receptors and significantly reduces kainic acid-triggered neuronal cell death. Inhibition of TrkA, but not TrkB, abolishes amitriptyline's neuroprotective effect without impairing its antidepressant activity. Thus, amitriptyline acts as a TrkA and TrkB agonist, and possesses marked neurotrophic activity.

Jang, Sung-Wuk; Liu, Xia; Chan, Chi-Bun; Weinshenker, David; Hall, Randy A.; Xiao, Ge; Ye, Keqiang

2009-01-01

349

Minor contribution of ATP P2 receptors to electrically-evoked electrographic seizure activity in hippocampal slices: Evidence from purine biosensors and P2 receptor agonists and antagonists.  

PubMed

While the position of adenosine as an endogenous anticonvulsant is well established, it is unclear to what extent its precursor, ATP, contributes to seizure activity via P2 receptors. In this study we have addressed this issue through the use of ATP biosensors and agonists and antagonists of ATP P2 receptors to detect the release and role of ATP, respectively, during electrically-evoked electrographic seizure-like events (eSLEs) in rat hippocampal slices. The broad-spectrum P2 receptor antagonists RB-2 and PPADS (10?M) caused a small ?30% inhibition of eSLE duration, and a reduction in intensity. This inhibition of eSLEs was partially reproduced with the P2X(1,2/3,3) antagonist NF023 (10?M), but not the P2X(7) antagonist BBG (10?M). However, the P2X receptor agonist ?,?-meATP did not enhance eSLEs, but instead reduced their duration. Furthermore, we could discern no role for P2Y(1) receptors in electrically-evoked eSLEs: both the P2Y(1) antagonist MRS2179 (10?M) and the P2Y(1) receptor agonist 2-methylthioADP (10?M) were without effect on eSLEs. Consistent with a minor role for ATP P2 receptors on eSLEs we could detect no ATP release during eSLEs, although appreciable quantities of adenosine were detected, which had a pronounced inhibitory action on eSLEs via A(1) receptors. We conclude that the role of ATP P2 receptors in modulating electrographic seizure activity is limited, at least in models such as this one requiring electrical stimulation of afferent fibres. We further conclude that the presence and action of adenosine under these conditions may primarily reflect direct release of this purine. PMID:21338615

Lopatá?, Ján; Dale, Nicholas; Frenguelli, Bruno G

2011-02-19

350

Agonist-dependent attenuation of mu-opioid receptor-mediated G-protein activation in the dorsal root ganglia of neuropathic rats.  

PubMed

Besides generally accepted lower analgesic potencies of opioids in neuropathic pain, our recent pharmacological reports have demonstrated that the effectiveness of the micro-opioid receptor (MOR) agonists in neuropathy might depends upon the chemical/structural property of these compounds (alkaloid vs. peptides). Such findings prompted us to investigate the changes in MOR mRNA expression (estimated by PCR) as well as MOR functional activity (examined by [(35)S]GTPgammaS binding) in the dorsal horn of the spinal cord and the dorsal root ganglia (DRG) of neuropathic rats at different time points after sciatic nerve ligation. We found that the spinal MOR mRNA level and agonist-stimulated [(35)S]GTPgammaS binding were not affected by nerve injury. In contrast, down-regulation of MOR mRNA in the ipsilateral side of DRG developed 3 (approximately 63% reduction) and 14 (approximately 89% reduction) days after the ligation. The decrease was paralleled with pronounced reduction in the stimulation of [(35)S]GTPgammaS binding by morphine (approximately 37-39%). Thus, neuropathy-induced specific dysfunction of MOR to activate G-protein together with changes in the MOR synthesis might be related, at least in part, to diminish analgesic efficacy of morphine in neuropathic pain. Interesting observations from current studies are linked to endomorphins (EMs), which do not affect the G protein stimulation of MOR after nerve ligation. This intriguing property of EMs, together with previously reported high analgesic efficacy of these compounds indicate that chemically/structurally different MOR agonists, particularly morphine versus EMs, may differentially interact with receptors causing distinct pharmacological effects in chronic pain. PMID:20213428

Obara, Ilona; Gunduz Cinar, Ozge; Starowicz, Katarzyna; Benyhe, Sandor; Borsodi, Anna; Przewlocka, Barbara

2010-03-06

351

Expression of the beta 2 adrenoceptor partial agonist/antagonist activity of salbutamol in states of low and high adrenergic tone.  

PubMed Central

BACKGROUND--Salbutamol exhibits partial agonist/antagonist activity at airway beta 2 receptors in vitro in that it attenuates the bronchorelaxant effect of the full agonist isoprenaline. The aim of the present study was to characterise the partial beta 2 agonist/antagonist activity of salbutamol in vivo during supine rest and exercise, in states of low and high adrenergic tone. METHODS--Eight normal subjects were randomised to receive single oral doses of salbutamol 2 mg, 4 mg, 8 mg (S2, S4, S8), placebo (PL), or propranolol 80 mg (PR). The beta 2 adrenoceptor responses were evaluated after supine rest and subsequently in response to maximal exercise. RESULTS--Salbutamol demonstrated a dose-related increase in resting heart rate and tremor and a fall in serum potassium level consistent with beta 2 agonism. On exercise, the hyperkalaemic response was augmented by propranolol compared with placebo consistent with beta 2 blockade: mean difference for delta response (95% CI) PR v PL was 0.60 (0.02 to 1.27) mmol/l. This effect also occurred with salbutamol in a dose-related fashion: S8 v PL 0.33 (0.01 to 0.71) mmol/l, S8 v S2 0.31 (-0.02 to 0.61) mmol/l. Whilst propranolol blunted exercise heart rate in keeping with beta 1 blockade, salbutamol had no effect. Exercise produced an increase in lymphocyte beta 2 receptor binding density (Bmax) which was not affected by salbutamol. Plasma levels of adrenaline and noradrenaline at peak exercise were also unaltered by salbutamol in comparison with placebo. CONCLUSIONS--In a state of low adrenergic tone at rest salbutamol produces effects consistent with beta 2 agonism. In contrast, in a state of increased adrenergic tone during exercise salbutamol produced beta 2 selective antagonism as evidenced by its effects on exercise-induced hyperkalaemia (beta 2) but not on exercise-induced tachycardia (beta 1). The effects of salbutamol on beta 2 receptor density do not explain its effects on exercise-induced hyperkalaemia since upregulation rather than downregulation was observed. This in vivo phenomenon of partial beta 2 agonist/antagonist activity of salbutamol may be of relevance in the setting of acute asthma if adrenergic tone is increased. Images

Grove, A; McFarlane, L C; Lipworth, B J

1995-01-01

352

Acute Effect on Power Output of Alternating an Agonist and Antagonist Muscle Exercise During Complex Training  

Microsoft Academic Search

The efficient coordination of agonist and antagonist muscles is one of the important early adaptations in resistance training responsible for large increases in strength. Weak antagonist muscles may limit speed of movement; consequently, strengthening them leads to an increase in agonist muscle movement speed. However, the effect of combining agonist and antagonist muscle exercises into a power training session has

Daniel Baker; Robert U. Newton

2005-01-01

353

Synthetic liver X receptor agonist T0901317 inhibits semicarbazide-sensitive amine oxidase gene expression and activity in apolipoprotein E knockout mice.  

PubMed

Semicarbazide-sensitive amine oxidase (SSAO) catalyzes oxidative deamination of primary aromatic and aliphatic amines. Increased SSAO activity has been found in atherosclerosis and diabetes mellitus. We hypothesize that the anti-atherogenic effect of liver X receptors (LXRs) might be related to the inhibition of SSAO gene expression and its activity. In this study, we investigated the effect of LXR agonist T0901317 on SSAO gene expression and its activity in apolipoprotein E knockout (apoE(-/-)) mice. Male apoE(-/-) mice (8 weeks old) were randomly divided into four groups: basal control group; vehicle group; prevention group; and treatment group. SSAO gene expression was analyzed by real-time quantitative polymerase chain reaction and its activity was determined. The activity of superoxide dismutase and content of malondialdehyde in the aorta and liver were also determined. In T0901317-treated mice, SSAO gene expression was significantly decreased in the aorta, liver, small intestine, and brain. SSAO activities in serum and in these tissues were also inhibited. The amount of superoxide dismutase in the aorta and liver of the prevention group and treatment group was significantly higher compared with the vehicle group (P<0.05). Malondialdehyde in the tissues of these two groups was significantly lower compared with the vehicle group (P<0.05). Our results showed that T0901317 inhibits SSAO gene expression and its activity in atherogenic apoE(-/-) mice. The atheroprotective effect of LXR agonist T0901317 is related to the inhibition of SSAO gene expression and its activity. PMID:18330481

Dai, Xiaoyan; Ou, Xiang; Hao, Xinrui; Cao, Dongli; Tang, Yaling; Hu, Yanwei; Li, Xiaoxu; Tang, Chaoke

2008-03-01

354

High-throughput screening of ecdysone agonists using a reporter gene assay followed by 3-D QSAR analysis of the molting hormonal activity.  

PubMed

In this study, 172 diacylhydrazine analogs were examined for their ability to activate an ecdysone (molting hormone)-dependent reporter gene in a silkworm (Bombyx mori) cell-based high-throughput screening assay. The measured EC(50) values (concentration required to cause an effect in 50% of the cells) were used to construct a 3-D QSAR model that describes the ecdysone agonist activities of the diacylhydrazine analogs. Of these compounds, 14 exhibited no activity and were excluded from the 3-D QSAR analysis. The resulting equation described approximately 74% of the activity for 158 compounds. The final equation consisted of 42% electrostatic and 58% steric effects (r(2) = 0.74 and q(2) = 0.45). Comparative molecular field analysis (CoMFA) was used to visualize the steric and electrostatic potential fields that were favorable and unfavorable for biological activity. Of particular interest was the observation that the hydrophobic parameter (logP) was not necessary for describing the observed activities, although previous studies have cited the importance of hydrophobic parameters in both classical and 3-D QSAR analyses of these compounds. Modeling studies of the B. mori ecdysone receptor supported the observed physicochemical parameters required for activity reported by the CoMFA models. Comparison of the present analysis with those performed using other lepidopteran assay systems evidenced a high degree of correlation (r(2) = 0.81 for a Sf-9 cell-based assay and r(2) = 0.89 for a Chilo suppressalis integument-based assay), indicating that it is valid to compare the results generated with the B. mori cell-based system to those generated with previous lepidopteran assays. This novel assay system is amendable to a high-throughput screening format and should greatly increase our ability to discover novel agonists of molting hormone (ecdysone) activity. PMID:16249087

Wheelock, Craig E; Nakagawa, Yoshiaki; Harada, Toshiyuki; Oikawa, Nobuhiro; Akamatsu, Miki; Smagghe, Guy; Stefanou, Dimitra; Iatrou, Kostas; Swevers, Luc

2005-10-24

355

A novel truncated glucagon-like peptide 2 (GLP-2) as a tool for analyzing GLP-2 receptor agonists.  

PubMed

Glucagon-like peptide 2 (GLP-2) is an intestinotropic peptide that binds to GLP-2 receptor (GLP-2R), a class-B G protein-coupled receptor. The GLP-2R antagonist GLP-2(3-33) has relatively high partial agonistic activity, and there are as yet no ideal known potent GLP-2R antagonists. We therefore prepared several truncated forms of human GLP-2 and characterized them by binding and reporter assays to find antagonists more potent than GLP-2(3-33). We found that GLP-2(11-33) was the most potent orthosteric GLP-2R antagonist, with binding activity almost equal to those of GLP-2 and GLP-2(3-33) and weaker intrinsic agonistic activity than GLP-2(3-33). GLP-2(11-33) retained weak agonistic activity toward human, cynomolgus monkey, dog, and Syrian hamster GLP-2Rs. However, it had no agonistic activity toward rat GLP-2R. GLP-2(11-33) potentiated the agonistic activity of an ago-allosteric modulator of GLP-2R, compound 1 (N-[1-(2,5-dichlorothiophen-3-yl)-2-(phenylsulfanyl)ethylidene]hydroxylamine), synergistically toward human GLP-2R. In the case of rat GLP-2R, GLP-2(11-33) decreased the agonistic activity of compound 1, although GLP-2 and GLP-2(3-33) increased this activity additively. These findings suggest that the binding sites of the ago-allosteric modulator and GLP-2 overlap, at least in rat GLP-2R. GLP-2(11-33) is a novel, useful tool for analyzing the mode of action of agonists and ago-allosteric modulators of GLP-2R. PMID:23782746

Yamazaki, Kazuto; Kagaya, Takaki; Watanabe, Misako; Terauchi, Hiroki; Iida, Daisuke; Fukumoto, Hironori; Suzuki, Shuichi; Arai, Tohru; Aoki, Mika; Takase, Kazuma; Seiki, Takashi; Tsukahara, Kappei; Nagakawa, Junichi

2013-06-01

356

Differential Protective Effects of Exenatide, an Agonist of GLP-1 Receptor and Piragliatin, a Glucokinase Activator in Beta Cell Response to Streptozotocin-Induced and Endoplasmic Reticulum Stresses  

PubMed Central

Background Agonists of glucagon-like peptide-1 receptor (GLP-1R) and glucokinase activators (GKA) act as antidiabetic agents by their ability protect beta cells, and stimulate insulin secretion. Oxidative and endoplasmic reticulum (ER) stresses aggravate type 2 diabetes by causing beta cell loss. It was shown that GLP-1R agonists protect beta cells from oxidative and ER stresses. On the other hand, little is known regarding how GKAs protect beta cells. We hypothesized that GKAs protect beta cells by mechanisms distinct from those underlying GLP-1R agonist and tested our hypothesis by comparing the molecular effects of exenatide, a GLP-1R agonist, and piragliatin, a GKA, on INS-1 cells under oxidative and ER-induced stresses. Methods Beta cells were treated with streptozotocin (STZ) to induce oxidative stress and with palmitate or thapsigargin (Tg) to induce ER stress respectively, and the effects of exenatide and piragliatin on these cells were investigated by: a) characterizing the kinases involved employing specific kinase inhibitors, and b) by identifying the differentially regulated proteins in response to stresses with proteomic analysis. Results Exenatide protected INS-1 cells from both ER and STZ-induced death. In contrast, piragliatin rescued the cells only from STZ-induced stress. Akt activation by exenatide appeared to contribute to its protective effects of beta cells while enhanced glucose utilization was the contributing factor in the case of piragliatin. Also, exenatide, not piragliatin, blocked changes in proteins 14-3-3?, ? and ?, and preserved the 14-3-3? levels under the ER stress. Isoform-specific modifications of 14-3-3, and the reduction of 14-3-3?, commonly associated with beta cell death were assessed. Conclusions Exenatide and piragliatin exert distinct effects on beta cell survival and thus on type 2 diabetes. This study which confirmed our hypothesis is also the first to observe specific modulation of 14-3-3 isoform in stress-induced beta cell death associated with progressive deterioration of type 2 diabetes.

Kim, Mi-Kyung; Cho, Jin-Hwan; Lee, Jae-Jin; Cheong, Ye-Hwang; Son, Moon-Ho; Lee, Kong-Joo

2013-01-01

357

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

PubMed Central

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

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

2010-01-01

358

Cevoglitazar, a novel peroxisome proliferator-activated receptor-alpha/gamma dual agonist, potently reduces food intake and body weight in obese mice and cynomolgus monkeys.  

PubMed

Cevoglitazar is a dual agonist for the peroxisome proliferator-activated receptor (PPAR)-alpha and -gamma subtypes. Dual activation of PPARalpha and -gamma is a therapeutic approach in development for the treatment of type 2 diabetes mellitus and diabetic dyslipidemia. In this report, we show that, in addition to improving insulin sensitivity and lipid metabolism like other dual PPAR agonists, cevoglitazar also elicits beneficial effects on energy homeostasis in two animal models of obesity. In leptin-deficient ob/ob mice, administration of cevoglitazar at 0.5, 1, or 2 mg/kg for 18 d led to acute and sustained, dose-dependent reduction of food intake and body weight. Furthermore, plasma levels of glucose and insulin were normalized after 7 d of cevoglitazar treatment at 0.5 mg/kg. Plasma levels of free fatty acids and triglycerides were dose-dependently reduced. In obese and insulin-resistant cynomolgus monkeys, treatment with cevoglitazar at 50 and 500 mug/kg for 4 wk lowered food intake and body weight in a dose-dependent manner. In these animals, cevoglitazar also reduced fasting plasma insulin and, at the highest dose, reduced hemoglobin A1c levels by 0.4%. These preclinical results demonstrate that cevoglitazar holds promise for the treatment of diabetes and obesity-related disorders because of its unique beneficial effect on energy balance in addition to improving glycemic and metabolic control. PMID:20484464

Chen, Hong; Dardik, Beatriz; Qiu, Ling; Ren, Xianglin; Caplan, Shari L; Burkey, Bryan; Boettcher, Brian R; Gromada, Jesper

2010-05-19

359

In vitro screening of 200 pesticides for agonistic activity via mouse peroxisome proliferator-activated receptor (PPAR){alpha} and PPAR{gamma} and quantitative analysis of in vivo induction pathway  

SciTech Connect

Peroxisome proliferator-activated receptors (PPARs) are ligand-dependent transcription factors and key regulators of lipid metabolism and cell differentiation. However, there have been few studies reporting on a variety of environmental chemicals, which may interact with these receptors. In the present study, we characterized mouse PPAR{alpha} and PPAR{gamma} agonistic activities of 200 pesticides (29 organochlorines, 11 diphenyl ethers, 56 organophosphorus pesticides, 12 pyrethroids, 22 carbamates, 11 acid amides, 7 triazines, 8 ureas and 44 others) by in vitro reporter gene assays using CV-1 monkey kidney cells. Three of the 200 pesticides, diclofop-methyl, pyrethrins and imazalil, which have different chemical structures, showed PPAR{alpha}-mediated transcriptional activities in a dose-dependent manner. On the other hand, none of the 200 pesticides showed PPAR{gamma} agonistic activity at concentrations {<=} 10{sup -5} M. To investigate the in vivo effects of diclofop-methyl, pyrethrins and imazalil, we examined the gene expression of PPAR{alpha}-inducible cytochrome P450 4As (CYP4As) in the liver of female mice intraperitoneally injected with these compounds ({<=} 300 mg/kg). RT-PCR revealed significantly high induction levels of CYP4A10 and CYP4A14 mRNAs in diclofop-methyl- and pyrethrins-treated mice, whereas imazalil induced almost no gene expressions of CYP4As. In particular, diclofop-methyl induced as high levels of CYP4A mRNAs as WY-14643, a potent PPAR{alpha} agonist. Thus, most of the 200 pesticides tested do not activate PPAR{alpha} or PPAR{gamma} in in vitro assays, but only diclofop-methyl and pyrethrins induce PPAR{alpha} agonistic activity in vivo as well as in vitro.

Takeuchi, Shinji [Hokkaido Institute of Public Health, Kita-19, Nishi-12, Kita-ku, Sapporo 060-0819 (Japan); Matsuda, Tadashi [Department of Immunology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812 (Japan); Kobayashi, Satoshi [Hokkaido Institute of Public Health, Kita-19, Nishi-12, Kita-ku, Sapporo 060-0819 (Japan); Takahashi, Tetsuo [Hokkaido Institute of Public Health, Kita-19, Nishi-12, Kita-ku, Sapporo 060-0819 (Japan); Kojima, Hiroyuki [Hokkaido Institute of Public Health, Kita-19, Nishi-12, Kita-ku, Sapporo 060-0819 (Japan)]. E-mail: kojima@iph.pref.hokkaido.jp

2006-12-15

360

Synthesis and Biological Activity of N6-(p-Sulfophenyl)alkyl and N6-Sulfoalkyl Derivatives of Adenosine: Water-Soluble and Peripherally Selective Adenosine Agonists  

PubMed Central

A series of N6-(p-sulfophenyl)alkyl and N6sulfoalkyl derivatives of adenosine was synthesized, revealing that N6-(p-sulfophenyl)adenosine (10b) is a moderately potent (Ki vs [3H]PIA in rat cortical membranes was 74 nM) and A1-selective (120-fold) adenosine agonist, of exceptional aqueous solubility of >1.5 g/mL (?3 M). Compound 10b was very potent in inhibiting synaptic potentials in gerbil hippocampal slices with an IC50 of 63 nM. At a dose of 0.1 mg/kg ip in rats, 10b inhibited lipolysis (a peripheral A1 effect) by 85% after 1 h. This in vivo effect was reversed using the peripherally selective A1-antagonist 1,3-dipropyl-8-[p-(carboxyethynyl)phenyl]xanthine (BW1433). The same dose of 10b in NIH Swiss mice (ip) was nearly inactive in locomotor depression, an effect that has been shown to be centrally mediated when elicited by lower doses of other potent adenosine agonists, such as N6-cyclohexyladenosine (CHA) (Nikodijevic et al. FEBS Lett. 1990, 261, 67). HPLC studies of biodistribution of a closely related and less potent homologue, N6-[4-(p-sulfophenyl)butyl]adenosine indicated that a 25 mg/kg ip dose in mice resulted in a plasma concentration after 30 min of 0.46 ?g/mL and no detectable drug in the brain (detection limit <0.1% of plasma level). Although 10b at doses >0.1 mg/kg in mice depressed locomotor activity, this depression was unlike the effects of CHA and was reversible by BW1433. These data suggest that 10b is a potent adenosine agonist in vivo and shows poor CNS penetration.

Jacobson, Kenneth A.; Nikodijevic, Olga; Ji, Xiao-duo; Berkich, Deborah A.; Eveleth, David; Dean, Reginald L.; Hiramatsu, Ken-Ichiro; Kassell, Neal F.; van Galen, Philip J. M.; Lee, Kevin S.; Bartus, Raymond T.; Daly, John W.; LaNoue, Kathryn F.; Maillard, Michel

2012-01-01

361

Quantification of Gi-Mediated Inhibition of Adenylyl Cyclase Activity Reveals That UDP Is a Potent Agonist of the Human P2Y14 Receptor  

PubMed Central

The P2Y14 receptor was initially identified as a G protein-coupled receptor activated by UDP-glucose and other nucleotide sugars. We have developed several cell lines that stably express the human P2Y14 receptor, allowing facile examination of its coupling to native Gi family G proteins and their associated downstream signaling pathways (J Pharmacol Exp Ther 330:162–168, 2009). In the current study, we examined P2Y14 receptor-dependent inhibition of cyclic AMP accumulation in human embryonic kidney (HEK) 293, C6 glioma, and Chinese hamster ovary (CHO) cells stably expressing this receptor. Not only was the human P2Y14 receptor activated by UDP-glucose, but it also was activated by UDP. The apparent efficacies of UDP and UDP-glucose were similar, and the EC50 values (74, 33, and 29 nM) for UDP-dependent activation of the P2Y14 receptor in HEK293, CHO, and C6 glioma cells, respectively, were similar to the EC50 values (323, 132, and 72 nM) observed for UDP-glucose. UDP and UDP-glucose also stimulated extracellular signal-regulated kinase (ERK) 1/2 phosphorylation in P2Y14 receptor-expressing HEK293 cells but not in wild-type HEK293 cells. A series of analogs of UDP were potent P2Y14 receptor agonists, but the naturally occurring nucleoside diphosphates, CDP, GDP, and ADP exhibited agonist potencies over 100-fold less than that observed with UDP. Two UDP analogs were identified that selectively activate the P2Y14 receptor over the UDP-activated P2Y6 receptor, and these molecules stimulated phosphorylation of ERK1/2 in differentiated human HL-60 promyeloleukemia cells, which natively express the P2Y14 receptor but had no effect in wild-type HL-60 cells, which do not express the receptor. We conclude that UDP is an important cognate agonist of the human P2Y14 receptor.

Carter, Rhonda L.; Fricks, Ingrid P.; Barrett, Matthew O.; Burianek, Lauren E.; Zhou, Yixing; Ko, Hyojin; Das, Arijit; Jacobson, Kenneth A.; Lazarowski, Eduardo R.

2009-01-01

362

Unusual declining phase of solar cycle 23: Weak semi-annual variations of auroral hemispheric power and geomagnetic activity  

NASA Astrophysics Data System (ADS)

Seasonal variations of geomagnetic activity during the declining phase of solar cycle 23 (SC23-D, 2002-2007) have been studied using auroral hemispheric power (HP), solar wind and interplanetary magnetic field (IMF) data and the Kp index. The well known semi-annual variations of geomagnetic activity, with peaks occurring during equinoxes, were virtually absent during SC23-D. This makes SC23-D markedly different from previous solar cycles which had clear semi-annual variations. In SC23-D, both Kp and HP had unusual peaks around the December solstice (in years 2003, 2004 and 2006) and August (in years 2004 and 2005), instead of at the equinoxes. These peaks appeared to be associated with solar wind/IMF and the consequent merging electric field peaks in the same periods. Furthermore, the absolute values and relative changes of the Kp index were much smaller in SC23-D than in other solar cycles. The very weak dynamic pressure and southward IMF in SC23-D might also limit the regular modulation effects that contribute to the occurrence of peaks in equinoxes.

Luan, Xiaoli; Wang, Wenbin; Burns, Alan G.; Solomon, Stanley C.; Zhang, Yongliang; Paxton, Larry J.

2009-11-01

363

Induction of reversible urothelial cell hyperplasia in rats by clorsulon, a flukicide with weak carbonic anhydrase inhibitory activity.  

PubMed

Clorsulon, a flukicide registered for use in treating Fasciola hepatica infections in cattle, has induced urinary bladder urothelial cell hyperplasia in rats at oral doses of 30 mg/kg/day or more. Despite previous testing at doses above this threshold, this lesion had not been found in subchronic or chronic toxicity studies in rats. After ruling out the presence of a contaminant as the causative factor in producing this lesion, a study was conducted in which clorsulon increased the pH and altered the electrolyte composition of urine, consistent with its weak carbonic anhydrase inhibitory activity. The acid/base balance of the diet markedly affected the threshold for induction of the urothelial cell hyperplasia: acidification by addition of 5% ammonium chloride to the diet reduced the incidence and severity. In additional studies it was found that the urothelial cell hyperplasia was most pronounced after 1 week of treatment compared with daily exposure for either 5 or 15 wk. The reversibility of the hyperplasia despite continued treatment confirms that the hyperplasia is not a preneoplastic lesion, a conclusion supported by negative studies of carcinogenicity in rodent bioassays of clorsulon and other drugs with carbonic anhydrase inhibitory activity. PMID:1628865

Lankas, G R; Peter, C P

1992-04-01

364

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

Microsoft Academic Search

The analgesic properties of cannabinoid receptor agonists are well characterized. However, numerous side effects limit the therapeutic potential of these agents. Here we report a synergistic antinociceptive interaction between the endogenous cannabinoid receptor agonist anandamide and the synthetic peroxisome proliferator-activated receptor-? (PPAR-?) agonist 2-(4-(2-(1-Cyclohexanebutyl)-3-cyclohexylureido)ethyl)phenylthio)-2-methylpropionic acid (GW7647) in a model of acute chemical-induced pain. Moreover, we show that anandamide synergistically interacts

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

2007-01-01

365

Calpastatin domain L is a partial agonist of the calmodulin-binding site for channel activation in Cav1.2 Ca2+ channels.  

PubMed

Cav1.2 Ca(2+) channel activity diminishes in inside-out patches (run-down). Previously, we have found that with ATP, calpastatin domain L (CSL) and calmodulin (CaM) recover channel activity from the run-down in guinea pig cardiac myocytes. Because the potency of the CSL repriming effect was smaller than that of CaM, we hypothesized that CSL might act as a partial agonist of CaM in the channel-repriming effect. To examine this hypothesis, we investigated the effect of the competitions between CSL and CaM on channel activity and on binding in the channel. We found that CSL suppressed the channel-activating effect of CaM in a reversible and concentration-dependent manner. The channel-inactivating effect of CaM seen at high concentrations of CaM, however, did not seem to be affected by CSL. In the GST pull-down assay, CSL suppressed binding of CaM to GST fusion peptides derived from C-terminal regions in a competitive manner. The inhibition of CaM binding by CSL was observed with the IQ peptide but not the PreIQ peptide, which is the CaM-binding domain in the C terminus. The results are consistent with the hypothesis that CSL competes with CaM as a partial agonist for the site in the IQ domain in the C-terminal region of the Cav1.2 channel, which may be involved in activation of the channel. PMID:21937422

Minobe, Etsuko; Asmara, Hadhimulya; Saud, Zahangir A; Kameyama, Masaki

2011-09-21

366

Intervention in autoimmunity: The potential of vitamin D receptor agonists  

Microsoft Academic Search

Vitamin D receptor (VDR) agonists are well known for their capacity to control calcium metabolism and to regulate growth and differentiation of many cell types. More recently, it has become clear that VDR agonists possess immunoregulatory properties and, in particular, pronounced pro-tolerogenic activities. VDR agonists can act directly on T cells, but DCs appear to be their primary targets. The

Luciano Adorini

2005-01-01

367

Synthesis and structure-activity relationship studies in serotonin 5-HT(1A) receptor agonists based on fused pyrrolidone scaffolds.  

PubMed

A new class of serotonin 5-HT1A receptor ligands related to NAN-190, buspirone and aripiprazole has been designed using our potent 5-HT3 receptor ligands as templates. The designed pyrrolidone derivatives 10a-n were prepared by means of the straightforward chemistry consisting in the reaction of the appropriate ?-haloester derivatives with the suitable arylpiperazinylalkylamines. The nanomolar 5-HT1A receptor affinity and the agonist-like profile shown by fused pyrrolidone derivatives 10k,m stimulated the rationalization of the interaction with an homology model of the 5-HT1A receptor and the evaluation of their selectivity profiles and the pharmacokinetic properties. Interestingly, the results of the profiling assays suggested for close congeners 10k,m a significantly divergent binding pattern with compound 10m showing an appreciable selectivity for 5-HT1AR. PMID:23466604

Cappelli, Andrea; Manini, Monica; Valenti, Salvatore; Castriconi, Federica; Giuliani, Germano; Anzini, Maurizio; Brogi, Simone; Butini, Stefania; Gemma, Sandra; Campiani, Giuseppe; Giorgi, Gianluca; Mennuni, Laura; Lanza, Marco; Giordani, Antonio; Caselli, Gianfranco; Letari, Ornella; Makovec, Francesco

2013-02-08

368

Cannabinoid agonists induce contractile responses through G i\\/o-dependent activation of phospholipase C in the bovine ciliary muscle  

Microsoft Academic Search

This study was undertaken to investigate the effect of some cannabinoid agonists on the bovine ciliary muscle. Both anandamide and CP 55,940 (cis-3-(2-hydroxy-4-(1,1-dimethyl heptyl) phenyl)-trans-4-(3-hydroxypropyl) cyclohexanol) produced a concentration-dependent contractile response in ciliary muscle. These responses were inhibited by SR 141716A (N-[piperidin-1-yl]-5-(4-cholophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide) (0.1 and 1 ?M) but not by SR 144528 (N-[1S)-endo-1,3,3-trimethyl bicyclo[2.2.1] heptan-2-yl] 5-(4-chloro-3-methylphenyl)-1-(4 methoxy benzyl)-pyrazole-3-carboxamide) (1 and 10

Marcello D Lograno; Maria Rosaria Romano

2004-01-01

369

The muscarinic M1/M4 receptor agonist xanomeline exhibits antipsychotic-like activity in Cebus apella monkeys.  

PubMed

Xanomeline is a muscarinic M(1)/M(4) preferring receptor agonist with little or no affinity for dopamine receptors. The compound reduces psychotic-like symptoms in patients with Alzheimer's disease and exhibits an antipsychotic-like profile in rodents without inducing extrapyramidal side effects (EPS) at therapeutically relevant doses. In the present study, we examined whether the xanomeline-induced functional dopamine antagonism found in rodent studies could also be observed in nonhuman primates. In addition, we studied whether the lack of EPS observed in rodents also applies to primates. To this end, we investigated the effects of xanomeline on the behavior induced by D-amphetamine and (-)-apomorphine in drug-naive Cebus apella monkeys. Antipsychotic compounds antagonize amphetamine-induced motor unrest and stereotypies in this species. Xanomeline inhibited D-amphetamine-induced motor unrest, stereotypies and arousal as well as apomorphine-induced stereotypies and arousal in drug-naive Cebus apella monkeys. Xanomeline did not induce EPS but vomiting occurred in some monkeys at high doses, in accordance with emetic events observed in Alzheimer patients following xanomeline administration. Even when xanomeline was tested in EPS-sensitized Cebus apella monkeys, EPS were not observed at the dose range of xanomeline used in the D-amphetamine-apomorphine combination study (0.5-3 mg/kg). However, when xanomeline was tested at 4 mg/kg, moderate dystonia was seen in two out of three monkeys. It is concluded that xanomeline inhibits D-amphetamine- and (-)-apomorphine-induced behavior in Cebus apella monkeys at doses that do not cause EPS. These data further substantiate that muscarinic receptor agonists may be useful in the pharmacological treatment of psychosis. PMID:12700711

Andersen, Maibritt B; Fink-Jensen, Anders; Peacock, Linda; Gerlach, Jes; Bymaster, Frank; Lundbaek, Jens August; Werge, Thomas

2003-03-26