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1

KR-62980: a novel peroxisome proliferator-activated receptor gamma agonist with weak adipogenic effects.  

PubMed

The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) is the target for the anti-diabetic drugs including thiazolidinediones. We report here the identification and characterization of a novel PPARgamma agonist KR-62980. KR-62980 acted as a selective PPARgamma agonist in transactivation assay with an EC50 of 15 nM. In fully differentiated 3T3-L1 adipocytes, KR-62980 induced [3H]-deoxyglucose uptake in a concentration-dependent manner in the presence of insulin. KR-62980 was weakly adipogenic with little induction of aP2 mRNA, and was able to antagonize the adipogenic effects of rosiglitazone in C3H10T1/2 cells. In vivo pharmacokinetic profile of KR-62980 revealed that the compound exhibited good oral bioavailability of 65% with a terminal elimination half-life of 2.5 h in the rat. Treatment of high fat diet-induced C57BL/6J mice with KR-62980 for 14 days reduced plasma glucose levels with little side effects with regard to weight gain, cardiac hypertrophy and hepatotoxicity. These results suggest that KR-62980 acts as a selective PPARgamma modulator with anti-hyperglycemic activity, and that the mechanism of actions of KR-62980 appears to be different from that of rosiglitazone with improved side effect profiles. PMID:16797489

Kim, Kwang Rok; Lee, Jeong Hyung; Kim, Seung Jun; Rhee, Sang Dal; Jung, Won Hoon; Yang, Sung-Don; Kim, Sung Soo; Ahn, Jin Hee; Cheon, Hyae Gyeong

2006-08-14

2

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

PubMed Central

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 cells. In the current study, we analyzed the range of functional activation states of human iNKT cells using a library of novel analogs of ?-galactosylceramide (?GalCer), the prototypical iNKT cell antigen. Measurement of cytokines secreted by human iNKT cell clones over a wide range of glycolipid concentrations revealed that iNKT cell ligands could be classified into functional groups, correlating with weak versus strong agonistic activity. The findings established a hierarchy for induction of different cytokines, with thresholds for secretion being consistently lowest for IL-13, higher for interferon-? (IFN?), and even higher for IL-4. These findings suggested that human iNKT cells can be intrinsically polarized to selective production of IL-13 by maintaining a low level of activation using weak agonists, whereas selective polarization to IL-4 production cannot be achieved through modulating the strength of the activating ligand. In addition, using a newly designed in vitro system to assess the ability of human iNKT cells to transactivate NK cells, we found that robust secondary induction of interferon-? secretion by NK cells was associated with strong but not weak agonist ligands of iNKT cells. These results indicate that polarization of human iNKT cell responses to Th2-like or anti-inflammatory effects may best be achieved through selective induction of IL-13 and suggest potential discrepancies with findings from mouse models that may be important in designing iNKT cell-based therapies in humans. PMID:21179412

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

2010-01-01

3

The agonism and synergistic potentiation of weak partial agonists by triethylamine in alpha 1-adrenergic receptor activation: evidence for a salt bridge as the initiating process.  

PubMed

Alpha 1-adrenergic receptor (AR) activation is thought to be initiated by disruption of a constraining interhelical salt bridge (). Disruption of this salt bridge is achieved through a competition for the aspartic acid residue in transmembrane domain three by the protonated amine of the endogenous ligand norepinephrine and a lysine residue in transmembrane domain seven. To further test this hypothesis, we investigated the possibility that a simple amine could mimic an important functional group of the endogenous ligand and break this alpha 1-AR ionic constraint leading to agonism. Triethylamine (TEA) was able to generate concentration-dependent increases of soluble inositol phosphates in COS-1 cells transiently transfected with the hamster alpha 1b-AR and in Rat-1 fibroblasts stably transfected with the human alpha 1a-AR subtype. TEA was also able to synergistically potentiate the second messenger production by weak partial alpha 1-AR agonists and this effect was fully inhibited by the alpha 1-AR antagonist prazosin. However, this synergistic potentiation was not observed for full alpha 1-AR agonists. Instead, TEA caused a parallel rightward shift of the dose-response curve, consistent with the properties of competitive antagonism. TEA specifically bound to a single population of alpha 1-ARs with a Ki of 28.7 +/- 4.7 mM. In addition, the site of binding by TEA to the alpha 1-AR is at the conserved aspartic acid residue in transmembrane domain three, which is part of the constraining salt bridge. These results indicate a direct interaction of TEA in the receptor agonist binding pocket that leads to a disruption of the constraining salt bridge, thereby initiating alpha 1-AR activation. PMID:9547369

Porter, J E; Edelmann, S E; Waugh, D J; Piascik, M T; Perez, D M

1998-04-01

4

TLR3 Agonists and Proinflammatory Antitumor Activities  

PubMed Central

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

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

2013-01-01

5

The tyrosine phosphatase Ptpn22 discriminates weak, self-peptide from strong agonist T cell receptor signals  

PubMed Central

T cells must be tolerant of self-antigens to avoid autoimmunity, but responsive to foreign-antigens to provide protection against infection. We found that in both naive and effector T cells, the tyrosine phosphatase, Ptpn22 limits T cell receptor signaling by weak agonist and self-antigens, while not impeding responses to strong agonist antigens. T cells lacking Ptpn22 show enhanced conjugate formation with antigen presenting cells pulsed with weak peptides, leading to their activation and production of inflammatory cytokines. This effect is exacerbated under conditions of lymphopenia with the formation of potent memory T cells in the absence of Ptpn22. These data address how loss of function PTPN22 alleles can lead to expansion of effector/memory T cells and a predisposition to human autoimmunity. PMID:25108421

Morrison, Vicky L.; Zamoyska, Rose

2014-01-01

6

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

E-print Network

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

Huber, Robert

7

Efficient help for autoreactive B cell activation requires CD4+ T cell recognition of an agonist peptide at the effector stage  

PubMed Central

T cell recognition of peptide/MHC complexes is flexible and can lead to differential activation, but how interactions with agonist (full activation) or partial agonist (suboptimal activation) peptides can shape immune responses in vivo is not well characterized. We investigated the effect of stimulation by agonist or partial agonist ligands during initial CD4+ T cell priming, and subsequent T-B cell cognate interactions, on antibody production by anti-chromatin B cells. We found that autoantibody production required TCR recognition of an agonist peptide at the effector stage of B cell activation. However, interaction with a weak agonist ligand at this effector stage failed to promote efficient autoantibody production, even if the CD4+ T cells were fully primed by an agonist peptide. These studies suggest that the reactivity of the TCR for a target self-peptide during CD4+ T-B cell interaction can be a critical determinant in restraining anti-chromatin autoantibody production. PMID:19662636

Hondowicz, Brian D.; Batheja, Amrita O.; Metzgar, Michele H.; Pagán, Antonio J.; Perng, Olivia A.; Willms, Simone; Caton, Andrew J.; Erikson, Jan

2010-01-01

8

PPAR ? agonist GW0742 interacts weakly with multiple nuclear receptors including the vitamin D receptor  

PubMed Central

A high throughput screening campaign was conducted to identify small molecules with the ability to inhibit the interaction between the vitamin D receptor (VDR) and steroid receptor coactivator 2. These inhibitors represent novel molecular probes to modulate gene regulation mediated by VDR. The peroxisome proliferator-activated receptor ? (PPAR?) agonist GW0742 was among the identified VDR-coactivator inhibitors and has been characterized herein as a pan nuclear receptor antagonist at concentrations higher than 12.1 µM. The highest antagonist activity for GW0742 was found for VDR and the androgen receptor (AR). Surprisingly, GW0742 behaved as PPAR agonist/antagonist activating transcription at lower concentration and inhibiting this effect at higher concentrations. A unique spectroscopic property of GW0742 was identified as well. In the presence of rhodamine-derived molecules, GW0742+ increased fluorescence intensity and fluorescence polarization at an excitation wavelength of 595 nm and emission wavelength of 615 nm in a dose dependent manner. The GW0742-inhibited NR-coactivator binding resulted in a reduced expression of five different NR target genes in LNCaP cells in the presence of agonist. Especially VDR target genes CYP24A1, IGFBP-3 and TRPV6 were negatively regulated by GW0742. GW0742 is the first VDR ligand inhibitor lacking the secosteroid structure of VDR ligand antagonists. Nevertheless, the VDR-meditated downstream process of cell differentiation was antagonized by GW0742 in HL-60 cells that were pretreated with the endogenous VDR agonist 1,25-dihydroxyvitamin D3. PMID:23713684

Nandhikonda, Premchendar; Yasgar, Adam; Baranowski, Athena M.; Sidhu, Preetpal S.; McCallum, Megan M.; Pawlak, Alan J.; Teske, Kelly; Feleke, Belaynesh; Yuan, Nina Y.; Kevin, Chinedum; Bikle, Daniel D.; Ayers, Steven D.; Webb, Paul; Rai, Ganesha; Simeonov, Anton; Jadhav, Ajit; Maloney, David; Arnold, Leggy A.

2013-01-01

9

Activation of Cyclic AMP Synthesis by Full and Partial Beta-Adrenergic Receptor Agonists in Chicken Skeletal Muscle Cells  

NASA Technical Reports Server (NTRS)

Several beta-adrenergic receptor (bAR) agonists are known to cause hypertrophy of skeletal muscle tissue. Accordingly, five bAR agonists encompassing a range in activity from strong to weak were evaluated for their ability to stimulate CAMP accumulation in embryonic chicken skeletal muscle cells in culture. Two strong agonists (epinephrine and isoproterenol), one moderate agonist (albuterol), and two weak agonists known to cause hypertrophy in animals (clenbuterol and cimaterol) were studied. Dose response curves were determined over six orders of magnitude in concentration for each agonist, and values were determined for their maximum stimulation of CAMP synthesis rate (Bmax) and the agonist concentration at which 50% stimulation of CAMP synthesis (EC50) occurred. Bmax values decreased in the following order: isoproterenol, epinephrine, albuterol, cimaterol, clenbuterol. Cimaterol and clenbuterol at their Bmax concentrations were approximately 15-fold weaker than isoproterenol in stimulating the rate of CAMP synthesis. When cimaterol and clenbuterol were added to culture media at concentrations known to cause significant muscle hypertrophy in animals, there was no detectable effect on stimulation of CAMP synthesis. Finally, these same levels of cimaterol and clenbuterol did not antagonize the stimulation of CAMP by either epinephrine or isoproterenol.

Young, R. B.; Bridge, K. Y.

2003-01-01

10

Activation of Cyclic AMP Synthesis by Full and Partial Beta-Adrenergic Receptor Agonists in Chicken Skeletal Muscle Cells  

NASA Technical Reports Server (NTRS)

Several beta-adrenergic receptor (bAR) agonists are known to cause hypertrophy of skeletal muscle tissue. Accordingly, five bAR agonists encompassing a range in activity from strong to weak were evaluated for their ability to stimulate cAMP accumulation in embryonic chicken skeletal muscle cells in culture. Two strong agonists (epinephrine and isoproterenol), one moderate agonist (albuterol), and two weak agonists known to cause hypertrophy in animals (clenbuterol and cimaterol) were studied. Dose response curves were determined over six orders of magnitude in concentration for each agonist, and values were determined for their maximum stimulation of cAMP synthesis rate (Bmax) and the agonist concentration at which 50% stimulation of cAMP synthesis (EC50) occurred. Bmax values decreased in the following order: isoproterenol, epinephrine, albuterol, cimaterol, clenbuterol. Cimaterol and clenbuterol at their Bmax concentrations were approximately 15-fold weaker than isoproterenol in stimulating the rate of cAMP synthesis. When cimaterol and clenbuterol were added to culture media at concentrations known to cause significant muscle hypertrophy in animals, there was no detectable effect on stimulation of cAMP synthesis. Finally, these same levels of cimaterol and clenbuterol did not antagonize the stimulation of cAMP by either epinephrine or isoproterenol.

Young, R. B.; Bridge, K. Y.; Cureri, Peter A. (Technical Monitor)

2002-01-01

11

Characteristics of the synergistic actions of platelet agonists.  

PubMed

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

Huang, E M; Detwiler, T C

1981-04-01

12

Cold Suppresses Agonist-induced Activation of TRPV1  

PubMed Central

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.

2011-01-01

13

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

14

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

PubMed

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

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

2006-02-14

15

Intracellular calcium strongly potentiates agonist-activated TRPC5 channels  

PubMed Central

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

Blair, Nathaniel T.; Kaczmarek, J. Stefan

2009-01-01

16

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

PubMed

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

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

2008-09-01

17

Crystal structure of constitutively active rhodopsin: How an agonist can activate its GPCR  

PubMed Central

G protein-coupled receptors (GPCRs) comprise the largest family of membrane proteins in the human genome and mediate cellular responses to an extensive array of hormones, neurotransmitters, and sensory stimuli. While some crystal structures have been determined for GPCRs, most are for modified forms, showing little basal activity, and are bound to inverse agonists or antagonists1. Consequently, these structures correspond to receptors in their inactive states. The visual pigment rhodopsin is the only GPCR for which structures exist that are thought to be in the active state2,3. However, these structures are for the apoprotein or opsin form that does not contain the agonist all-trans retinal. We present here a crystal structure for the constitutively active rhodopsin mutant E113Q4-6 in complex with a peptide derived from the C-terminus of the G protein transducin (the G?CT peptide). Importantly, the protein appears to be in an active conformation, and retinal is retained in the binding pocket after photoactivation. Comparison with the structure of ground state rhodopsin7 suggests how translocation of the retinal ?-ionone ring leads to a rotational tilt of transmembrane helix 6 (TM6), the critical conformational change upon activation8. A key feature of this conformational change is a reorganization of water mediated hydrogen-bonding networks between the retinal-binding pocket and three of the most conserved GPCR sequence motifs. For the first time we thus show how an agonist ligand can activate its GPCR. PMID:21389983

Standfuss, Jörg; Edwards, Patricia C.; D’Antona, Aaron; Fransen, Maikel; Xie, Guifu; Oprian, Daniel D.; Schertler, Gebhard F. X.

2013-01-01

18

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

Microsoft Academic Search

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

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

2001-01-01

19

Sphingosine-1-phosphate: a platelet-activating sphingolipid released from agonist-stimulated human platelets.  

PubMed

Sphingosine-1-phosphate (Sph-1-P) is the initial product of catabolism of sphingosine by sphingosine kinase and is cleaved by Sph-1-P lyase to a fatty aldehyde and ethanolamine phosphate. This phosphorylated sphingoid base is not only an intermediary catabolite, but also a bioactive lipid with important functions, including stimulation of cell proliferation in Swiss 3T3 fibroblasts and inhibition of tumor cell motility. In the present study, we examined functional roles of Sph-1-P in human platelets. Sph-1-P induced platelet shape change and aggregation reactions, although it failed to elicit secretion. Sphingosine, ceramide, sphingomyelin, and N,N-dimethylsphingosine did not mimic the positive effects of Sph-1-P on platelets. Subthreshold concentrations of Sph-1-P and weak platelet agonists such as adenosine diphosphate (ADP) and epinephrine synergistically elicited aggregation, which may be important for efficient amplification of platelet activation. Sph-1-P induced intracellular Ca2+ mobilization and the dose-response for Ca2+ release correlated closely with the concentration required for induction of shape change. On addition of [3H]sphingosine to intact platelets, the label was rapidly converted to Sph-1-P, and subsequently to ceramide and sphingomyelin. Interestingly, the Sph-1-P formed was specifically released into medium on stimulation of platelets with physiologic agonists. The amount of Sph-1-P in platelets, as measured by its conversion into radiolabeled N-acetyl-Sph-1-P, was 1.4 nmol/10(9) cells and was about four times higher than the mass of Sph present. When compared by mole percent Sph-1-P/phospholipid, the value for platelets is over 10 times higher than that for neutrophils. Our results suggest that Sph-1-P, rapidly converted from sphingosine, abundantly stored in platelets, and released on the cell activation, may play a physiologic role in thrombosis, hemostasis, and the natural wound-healing processes. PMID:7795224

Yatomi, Y; Ruan, F; Hakomori, S; Igarashi, Y

1995-07-01

20

Activation of Protease Activated Receptor 2 by Exogenous Agonist Exacerbates Early Radiation Injury in Rat Intestine  

SciTech Connect

Purpose: Protease-activated receptor-2 (PAR{sub 2}) is highly expressed throughout the gut and regulates the inflammatory, mitogenic, fibroproliferative, and nociceptive responses to injury. PAR{sub 2} is strikingly upregulated and exhibits increased activation in response to intestinal irradiation. We examined the mechanistic significance of radiation enteropathy development by assessing the effect of exogenous PAR{sub 2} activation. Methods and Materials: Rat small bowel was exposed to localized single-dose radiation (16.5 Gy). The PAR{sub 2} agonist (2-furoyl-LIGRLO-NH{sub 2}) or vehicle was injected intraperitoneally daily for 3 days before irradiation (before), for 7 days after irradiation (after), or both 3 days before and 7 days after irradiation (before-after). Early and delayed radiation enteropathy was assessed at 2 and 26 weeks after irradiation using quantitative histologic examination, morphometry, and immunohistochemical analysis. Results: The PAR{sub 2} agonist did not elicit changes in the unirradiated (shielded) intestine. In contrast, in the irradiated intestine procured 2 weeks after irradiation, administration of the PAR{sub 2} agonist was associated with more severe mucosal injury and increased intestinal wall thickness in all three treatment groups (p <.05) compared with the vehicle-treated controls. The PAR{sub 2} agonist also exacerbated the radiation injury score, serosal thickening, and mucosal inflammation (p <.05) in the before and before-after groups. The short-term exogenous activation of PAR{sub 2} did not affect radiation-induced intestinal injury at 26 weeks. Conclusion: The results of the present study support a role for PAR{sub 2} activation in the pathogenesis of early radiation-induced intestinal injury. Pharmacologic PAR{sub 2} antagonists might have the potential to reduce the intestinal side effects of radiotherapy and/or as countermeasures in radiologic accidents or terrorism scenarios.

Wang Junru; Boerma, Marjan; Kulkarni, Ashwini [Division of Radiation Health, University of Arkansas for Medical Sciences, Little Rock, AR (United States); Hollenberg, Morley D. [Department of Pharmacology and Therapeutics, University of Calgary, Calgary, AB (Canada); Department of Medicine, University of Calgary, Calgary, AB (Canada); Hauer-Jensen, Martin, E-mail: mhjensen@life.uams.ed [Division of Radiation Health, University of Arkansas for Medical Sciences, Little Rock, AR (United States); Surgical Service, Central Arkansas Veterans Healthcare System, Little Rock, AR (United States)

2010-07-15

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

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

PubMed

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

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

2011-10-01

23

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

PubMed

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

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

1996-01-01

24

Normal filopodia extension inVASP-deficient platelets upon activation by adhesive matrices or soluble agonists  

E-print Network

Normal filopodia extension inVASP-deficient platelets upon activation by adhesive matrices platelet activation with a soluble agonist or following contact with an ad- hesive substratum (1). Platelet that ADP-activated platelets undergo transformation from a smooth discoid shape, to discs extending a few

Paris-Sud XI, Université de

25

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

PubMed Central

Previous studies have established that pro-oxidative stressors suppress host immunity due to their ability to generate oxidized lipids with PAF-receptor (PAF-R) agonist activity. Although exposure to the pro-oxidative stressor cigarette smoke (CS) is known to exert immunomodulatory effects, little is known regarding the role of platelet-activating factor (PAF) in these events. The current studies sought to determine the role of PAF-R signaling in CS-mediated immunomodulatory effects. We demonstrate that CS exposure induces the generation of a transient PAF-R agonistic activity in the blood of mice. CS exposure inhibits contact hypersensitivity in a PAF-R-dependent manner as PAF-R-deficient mice were resistant to these effects. Blocking PAF-R agonist production either by systemic antioxidants or treatment with serum PAF-acetyl hydrolase enzyme blocked both the CS-mediated generation of PAF-R-agonists and PAF-R dependent inhibition of CHS reactions, indicating a role for oxidized glycerophosphocholines with PAF-R agonistic activity in this process. In addition, cyclooxygenase-2 (COX-2) inhibition did not block PAF-R agonist production but prevented CS-induced inhibition of CHS. This suggests that COX-2 acts downstream of the PAF-R in mediating CS-induced systemic immunosuppression. Moreover, CS-exposure induced a significant increase in the expression of the regulatory T cell reporter gene in FoxP3EGFP mice but not in FoxP3EGFP mice on a PAF-R-deficient background. Finally, Treg depletion via anti-CD25 antibodies blocked CS-mediated inhibition of CHS, indicating the potential involvement of Tregs in CS-mediated systemic immunosuppression. These studies provide the first evidence that the pro-oxidative stressor CS can modulate cutaneous immunity via the generation of PAF-R agonists produced through lipid oxidation. PMID:23355733

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

2013-01-01

26

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

2013-03-01

27

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

PubMed Central

Beta2-adrenoreceptor agonists (?2-agonists) are primarily bronchodilators, targeting airway smooth muscle and providing critical symptomatic relief in conditions such as bronchial asthma and chronic obstructive pulmonary disease. These agents also possess broad-spectrum, secondary, anti-inflammatory properties. These are mediated largely, though not exclusively, via interactions with adenylyl cyclase-coupled ?2-adrenoreceptors on a range of immune and inflammatory cells involved in the immunopathogenesis of acute and chronic inflammatory disorders of the airways. The clinical relevance of the anti-inflammatory actions of ?2-agonists, although often effective in the experimental setting, remains contentious. The primary objectives of the current review are: firstly, to assess the mechanisms, both molecular and cell-associated, that may limit the anti-inflammatory efficacy of ?2-agonists; secondly, to evaluate pharmacological strategies, several of which are recent and innovative, that may overcome these limitations. These are preceded by a consideration of the various types of ?2-agonists, their clinical applications, and spectrum of anti-inflammatory activities, particularly those involving adenosine 3?,5?-cyclic adenosine monophosphate-activated protein kinase-mediated clearance of cytosolic calcium, and altered gene expression in immune and inflammatory cells. PMID:24285920

Theron, Annette J; Steel, Helen C; Tintinger, Gregory R; Feldman, Charles; Anderson, Ronald

2013-01-01

28

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

PubMed

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

Farley, Nicole-Marie M; Mihic, S John

2015-05-01

29

Despite substantial degradation, 2-arachidonoylglycerol is a potent full efficacy agonist mediating CB1 receptor-dependent G-protein activation in rat cerebellar membranes  

PubMed Central

Two endocannabinoids, arachidonoyl ethanolamide (AEA) and 2-arachidonoylglycerol (2-AG) bind and activate G-protein-coupled cannabinoid receptors, but limited data exist on their relative ability to activate G-proteins. Here we assess agonist potency and efficacy of various cannabinoids, including 2-AG, HU-310 (2-arachidonoyl glyceryl ether, a third putative endocannabinoid), HU-313 (another ether analogue of 2-AG), AEA, R-methanandamide (an enzymatically stable analogue of AEA), and CP-55,940 at rat brain CB1 receptors using agonist-stimulated [35S]-GTP?S binding to cerebellar membranes and whole brain sections. Degradation of endocannabinoids under experimental conditions was monitored by HPLC. To enhance efficacy differences, agonist dose-response curves were generated using increasing GDP concentrations. At 10?6?M GDP, all compounds, except HU-313, produced full agonists responses ?2.5 fold over basal. The superior efficacy of 2-AG over all other compounds became evident by increasing GDP (10?5 and 10?4?M). In membrane incubations, 2-AG was degraded by 85% whereas AEA and HU-310 were stable. Pretreatment of membranes with phenylmethylsulphonyl fluoride inhibited 2-AG degradation, resulting in 2 fold increase in agonist potency. Such pretreatment had no effect on AEA potency. Responses in brain sections were otherwise consistent with membrane binding data, but 2-AG evoked only a weak signal in brain sections, apparently due to more extensive degradation. These data establish that even under conditions of substantial degradation, 2-AG is a full efficacy agonist, clearly more potent than AEA, in mediating CB1 receptor-dependent G-protein activity in native membranes. PMID:11588122

Savinainen, Juha R; Järvinen, Tomi; Laine, Krista; Laitinen, Jarmo T

2001-01-01

30

Discovery and structure-activity relationships of pyrazolodiazepine derivatives as the first small molecule agonists of the Drosophila sex peptide receptor.  

PubMed

In behavioral research, the sex peptide receptor in Drosophila melanogaster (DrmSPR) is the most interesting G protein-coupled receptor (GPCR) and is involved in post-mating responses such as increased egg-laying and decreased receptivity of the female; during these responses, the receptors are activated by a specific natural peptide agonist (sex peptide, SP). To discover small molecule agonists for DrmSPR, a compound library based on a pyrazolodiazepine scaffold, which was previously reported as a potential privileged structure, was screened. Structure-activity relationship (SAR) studies of the hit compounds, which exhibited weak agonistic effects (69-72% activation at 100?M), were explored through the synthesis of various analogs with substituents at the R1, R2, R3 and R4 positions of the pyrazolodiazepine skeleton. As a result, compounds 21 and 31 of the 6-benzyl pyrazolodiazepine derivative series were found to be small molecule agonists for DrmSPR with EC50 values of 3-4?M. PMID:25797164

Kim, Joeng-Hyun; Jeong, Pyeong-Hwa; Lee, Ju-Yeon; Lee, Jae-Hyuk; Kim, Young-Joon; Kim, Yong-Chul

2015-04-15

31

Estrogenic Agonist Activity of ICI 182,780 (Faslodex) in Hippocampal Neurons: Implications for Basic Science  

E-print Network

primary hippocampal neurons. We first investigated the neuroprotective efficacy of ICI 182,780 against-regulated kinase 1/2 and Akt (protein kinase B) and significantly increased expres- sion of spinophilin and Bcl-2Estrogenic Agonist Activity of ICI 182,780 (Faslodex) in Hippocampal Neurons: Implications

Brinton, Roberta Diaz

32

NICOTINE EFFECTS ON THE ACTIVITY OF MICE EXPOSED PRENATALLY TO THE NICOTINIC AGONIST ANATOXIN-A.  

EPA Science Inventory

Considerable research has shown long-lasting effects of early exposure in experimental animals to nicotine. Anatoxin-a is produced by cyanobacteria and has been shown to be a potent nicotinic agonist. This experiment evaluated the motor activity of adult mice, and their respons...

33

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

34

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

Microsoft Academic Search

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

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

2010-01-01

35

Accessory Cell Mediated Activation of Porcine NK Cells by TLR7 and TLR8 Agonists  

Technology Transfer Automated Retrieval System (TEKTRAN)

The induction of innate immune responses by toll-like receptor (TLR) agonists is the subject of intense investigation in many different species. In large part, this reflects the potential of such compounds to be effective vaccine adjuvants. For that reason, we analyzed the activation of innate cells...

36

Discovery of a new series of potent prostacyclin receptor agonists with in vivo activity in rat.  

PubMed

The design and synthesis of two closely related series of prostacyclin receptor agonist compounds that showed excellent human IP receptor potency and efficacy is described. Compounds from this series showed in vivo activity after SC dosing in the monocrotaline model of PAH in rat. PMID:25666818

Tran, Thuy-Anh; Shin, Young-Jun; Kramer, Bryan; Choi, Juyi; Zou, Ning; Vallar, Pureza; Martens, Peter; Douglas Boatman, P; Adams, John W; Ramirez, Juan; Shi, Yunqing; Morgan, Michael; Unett, David J; Chang, Steve; Shu, Hsin-Hui; Tung, Shiu-Feng; Semple, Graeme

2015-03-01

37

Triphenylethylene antiestrogens induce uterine vascular endothelial growth factor expression via their partial estrogen agonist activity  

Microsoft Academic Search

Estradiol induces vascular endothelial growth factor (VEGF) expression in the rat uterus and this may contribute to the hyperemia and increased vascularity produced by estrogens in this target tissue. Triphenylethylene antiestrogens such as tamoxifen have mixed agonist\\/antagonist activity and their specific effects are tissue and gene specific. These drugs exhibit primarily antiestrogenic actions in mammary tissue and are thus used

Salman M Hyder; Constance Chiappetta; George M Stancel

1997-01-01

38

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

PubMed Central

The activation characteristics of synaptic and extrasynaptic GABAA receptors are important for shaping the profile of phasic and tonic inhibition in the central nervous system, which will critically impact on the activity of neuronal networks. Here, we study in isolation the activity of three agonists, GABA, muscimol and 4,5,6,7-tetrahydoisoxazolo[5,4-c]pyridin-3(2H)-one (THIP), to further understand the activation profiles of ?1?3?2, ?4?3?2 and ?4?3? receptors that typify synaptic- and extrasynaptic-type receptors expressed in the hippocampus and thalamus. The agonists display an order of potency that is invariant between the three receptors, which is reliant mostly on the agonist dissociation constant. At ? subunit-containing extrasynaptic-type GABAA receptors, both THIP and muscimol additionally exhibited, to different degrees, superagonist behaviour. By comparing whole-cell and single channel currents induced by the agonists, we provide a molecular explanation for their different activation profiles. For THIP at high concentrations, the unusual superagonist behaviour on ?4?3? receptors is a consequence of its ability to increase the duration of longer channel openings and their frequency, resulting in longer burst durations. By contrast, for muscimol, moderate superagonist behaviour was caused by reduced desensitisation of the extrasynaptic-type receptors. The ability to specifically increase the efficacy of receptor activation, by selected exogenous agonists over that obtained with the natural transmitter, may prove to be of therapeutic benefit under circumstances when synaptic inhibition is compromised or dysfunctional. PMID:20176630

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

2010-01-01

39

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

PubMed

The activation characteristics of synaptic and extrasynaptic GABA(A) receptors are important for shaping the profile of phasic and tonic inhibition in the central nervous system, which will critically impact on the activity of neuronal networks. Here, we study in isolation the activity of three agonists, GABA, muscimol and 4,5,6,7-tetrahydoisoxazolo[5,4-c]pyridin-3(2H)-one (THIP), to further understand the activation profiles of alpha 1 beta 3 gamma 2, alpha 4 beta 3 gamma 2 and alpha 4 beta 3 delta receptors that typify synaptic- and extrasynaptic-type receptors expressed in the hippocampus and thalamus. The agonists display an order of potency that is invariant between the three receptors, which is reliant mostly on the agonist dissociation constant. At delta subunit-containing extrasynaptic-type GABA(A) receptors, both THIP and muscimol additionally exhibited, to different degrees, superagonist behaviour. By comparing whole-cell and single channel currents induced by the agonists, we provide a molecular explanation for their different activation profiles. For THIP at high concentrations, the unusual superagonist behaviour on alpha 4 beta 3 delta receptors is a consequence of its ability to increase the duration of longer channel openings and their frequency, resulting in longer burst durations. By contrast, for muscimol, moderate superagonist behaviour was caused by reduced desensitisation of the extrasynaptic-type receptors. The ability to specifically increase the efficacy of receptor activation, by selected exogenous agonists over that obtained with the natural transmitter, may prove to be of therapeutic benefit under circumstances when synaptic inhibition is compromised or dysfunctional. PMID:20176630

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

2010-04-15

40

Natural product agonists of peroxisome proliferator-activated receptor gamma (PPAR?): a review.  

PubMed

Agonists of the nuclear receptor PPAR? are therapeutically used to combat hyperglycaemia associated with the metabolic syndrome and type 2 diabetes. In spite of being effective in normalization of blood glucose levels, the currently used PPAR? agonists from the thiazolidinedione type have serious side effects, making the discovery of novel ligands highly relevant. Natural products have proven historically to be a promising pool of structures for drug discovery, and a significant research effort has recently been undertaken to explore the PPAR?-activating potential of a wide range of natural products originating from traditionally used medicinal plants or dietary sources. The majority of identified compounds are selective PPAR? modulators (SPPARMs), transactivating the expression of PPAR?-dependent reporter genes as partial agonists. Those natural PPAR? ligands have different binding modes to the receptor in comparison to the full thiazolidinedione agonists, and on some occasions activate in addition PPAR? (e.g. genistein, biochanin A, sargaquinoic acid, sargahydroquinoic acid, resveratrol, amorphastilbol) or the PPAR?-dimer partner retinoid X receptor (RXR; e.g. the neolignans magnolol and honokiol). A number of in vivo studies suggest that some of the natural product activators of PPAR? (e.g. honokiol, amorfrutin 1, amorfrutin B, amorphastilbol) improve metabolic parameters in diabetic animal models, partly with reduced side effects in comparison to full thiazolidinedione agonists. The bioactivity pattern as well as the dietary use of several of the identified active compounds and plant extracts warrants future research regarding their therapeutic potential and the possibility to modulate PPAR? activation by dietary interventions or food supplements. PMID:25083916

Wang, Limei; Waltenberger, Birgit; Pferschy-Wenzig, Eva-Maria; Blunder, Martina; Liu, Xin; Malainer, Clemens; Blazevic, Tina; Schwaiger, Stefan; Rollinger, Judith M; Heiss, Elke H; Schuster, Daniela; Kopp, Brigitte; Bauer, Rudolf; Stuppner, Hermann; Dirsch, Verena M; Atanasov, Atanas G

2014-11-01

41

Natural product agonists of peroxisome proliferator-activated receptor gamma (PPAR?): a review  

PubMed Central

Agonists of the nuclear receptor PPAR? are therapeutically used to combat hyperglycaemia associated with the metabolic syndrome and type 2 diabetes. In spite of being effective in normalization of blood glucose levels, the currently used PPAR? agonists from the thiazolidinedione type have serious side effects, making the discovery of novel ligands highly relevant. Natural products have proven historically to be a promising pool of structures for drug discovery, and a significant research effort has recently been undertaken to explore the PPAR?-activating potential of a wide range of natural products originating from traditionally used medicinal plants or dietary sources. The majority of identified compounds are selective PPAR? modulators (SPPARMs), transactivating the expression of PPAR?-dependent reporter genes as partial agonists. Those natural PPAR? ligands have different binding modes to the receptor in comparison to the full thiazolidinedione agonists, and on some occasions activate in addition PPAR? (e.g. genistein, biochanin A, sargaquinoic acid, sargahydroquinoic acid, resveratrol, amorphastilbol) or the PPAR?-dimer partner retinoid X receptor (RXR; e.g. the neolignans magnolol and honokiol). A number of in vivo studies suggest that some of the natural product activators of PPAR? (e.g. honokiol, amorfrutin 1, amorfrutin B, amorphastilbol) improve metabolic parameters in diabetic animal models, partly with reduced side effects in comparison to full thiazolidinedione agonists. The bioactivity pattern as well as the dietary use of several of the identified active compounds and plant extracts warrants future research regarding their therapeutic potential and the possibility to modulate PPAR? activation by dietary interventions or food supplements. PMID:25083916

Wang, Limei; Waltenberger, Birgit; Pferschy-Wenzig, Eva-Maria; Blunder, Martina; Liu, Xin; Malainer, Clemens; Blazevic, Tina; Schwaiger, Stefan; Rollinger, Judith M.; Heiss, Elke H.; Schuster, Daniela; Kopp, Brigitte; Bauer, Rudolf; Stuppner, Hermann; Dirsch, Verena M.; Atanasov, Atanas G.

2014-01-01

42

Recovery of brain biomarkers following peroxisome proliferator-activated receptor agonist neuroprotective treatment before ischemic stroke  

PubMed Central

Background Lipid lowering agent such as agonists of peroxisome proliferator-activated receptors (PPAR) are suggested as neuroprotective agents and may protect from the sequelae of brain ischemic stroke. Although the demonstration is not clearly established in human, the underlying molecular mechanism may be of interest for future therapeutic purposes. To this end, we have used our well established rodent model of ischemia-reperfusion pre-treated or not with fenofibrate or atorvastatin and performed a differential proteomics analyses of the brain and analysed the protein markers which levels returned to “normal” following pre-treatments with PPAR? agonists. Results In order to identify potential therapeutic targets positively modulated by pre-treatment with the PPAR? agonists, two-dimensional gel electrophoresis proteome profiles between control, ischemia-reperfusion and pre-treated or not, were compared. The polypeptide which expression was altered following ischemia – reperfusion but whose levels remain unchanged after pre-treatment were characterized by mass spectrometry and further investigated by Western-blotting and immunohistochemistry. A series of 28 polypeptides were characterized among which the protein disulfide isomerase reduction – a protein instrumental to the unfolded protein response system - was shown to be reduced following PPAR? agonists treatment while it was strongly increased in ischemia-reperfusion. Conclusions Pre-treatment with PPAR? agonist or atorvastatin show potential neuroprotective effects by inhibiting the PDI overexpression in conjunction with the preservation of other neuronal markers, several of which are associated with the regulation of protein homeostasis, signal transduction and maintenance of synaptic plasticity. This proteomic study therefore suggests that neuroprotective effect of PPAR? agonists supposes the preservation of the expression of several proteins essential for the maintenance of protein homeostasis not necessarily directly linked to PPAR? known-regulated targets. PMID:24944524

2014-01-01

43

Orthogonal activation of the reengineered A3 adenosine receptor (neoceptor) using tailored nucleoside agonists  

PubMed Central

An alternative approach to overcome the inherent lack of specificity of conventional agonist therapy can be the reengineering of the GPCRs and their agonists. A reengineered receptor (neoceptor) could be selectively activated by a modified agonist, but not by the endogenous agonist. Assisted by rhodopsin-based molecular modeling, we pinpointed mutations of the A3 adenosine receptor (AR) for selective affinity enhancement following complementary modifications of adenosine. Ribose modifications examined included, at 3?: amino, aminomethyl, azido, guanidino, ureido; and at 5?: uronamido, azidodeoxy. N6-variations included: 3-iodobenzyl, 5-chloro-2-methyloxybenzyl, and methyl. An N6-3-iodobenzyl-3?-ureido adenosine derivative 10 activated phospholipase C in COS-7 cells (EC50=0.18 ?M) or phospholipase D in chick primary cardiomyocytes mediated by a mutant (H272E), but not the wild-type, A3AR. The affinity enhancements for 10 and the corresponding 3?-acetamidomethyl analogue 6 were >100-fold and >20-fold, respectively. 10 concentration-dependently protected cardiomyocytes transfected with the neoceptor against hypoxia. Unlike 10, adenosine activated the wild-type A3AR (EC50 of 1.0 ?M), but had no effect on the H272E mutant A3AR (100 ?M). Compound 10 was inactive at human A1, A2A, and A2BARs. The orthogonal pair comprising an engineered receptor and a modified agonist should be useful for elucidating signaling pathways and could be therapeutically applied to diseases following organ-targeted delivery of the neoceptor gene. PMID:16640329

Gao, Zhan-Guo; Duong, Heng T.; Sonin, Tatiana; Kim, Soo-Kyung; Van Rompaey, Philippe; Van Calenbergh, Serge; Mamedova, Liaman; Kim, Hea Ok; Kim, Myong Jung; Kim, Ae Yil; Liang, Bruce T.; Jeong, Lak Shin; Jacobson, Kenneth A.

2012-01-01

44

Are fish oil omega-3 long-chain fatty acids and their derivatives peroxisome proliferator-activated receptor agonists?  

Microsoft Academic Search

BACKGROUND: Peroxisome proliferator-activated receptors (PPAR?, PPAR?, and PPAR?) are physiological sensors for glucose and lipid homeostasis. They are also the targets of synthetic drugs; such as fibrates as PPAR? agonists which lower lipid level, and glitazones as PPAR? agonists which lower glucose level. As diabetes and metabolic diseases are often associated with high blood glucose and lipid levels, drugs that

Osman ABSM Gani

2008-01-01

45

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

SciTech Connect

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. - Highlights: • We investigated the agonist/antagonist activities of BPS, BPF, BPA, TCBPA and TBBPA. • The direct interaction of these compounds with hER?, hER?, hAR and hPXR was studied. • BPA congeners and derivatives were found to disrupt multiple NRs. • Further evaluation of their role as endocrine-disrupting chemicals is needed.

Molina-Molina, José-Manuel, E-mail: molinajm@ugr.es [Laboratory of Medical Investigations, San Cecilio University Hospital, University of Granada, Cíber en Epidemiología y Salud Pública (CIBERESP), Granada E-18071 (Spain); Amaya, Esperanza [Laboratory of Medical Investigations, San Cecilio University Hospital, University of Granada, Cíber en Epidemiología y Salud Pública (CIBERESP), Granada E-18071 (Spain); Grimaldi, Marina [INSERM, U896, Montpellier F-34298 (France); Université de Montpellier I, Montpellier F-34298 (France); Sáenz, José-María; Real, Macarena; Fernández, Mariana F. [Laboratory of Medical Investigations, San Cecilio University Hospital, University of Granada, Cíber en Epidemiología y Salud Pública (CIBERESP), Granada E-18071 (Spain); Balaguer, Patrick [INSERM, U896, Montpellier F-34298 (France); Université de Montpellier I, Montpellier F-34298 (France); Olea, Nicolás [Laboratory of Medical Investigations, San Cecilio University Hospital, University of Granada, Cíber en Epidemiología y Salud Pública (CIBERESP), Granada E-18071 (Spain)

2013-10-01

46

Activation of Dendritic Cells by the Novel Toll-Like Receptor 3 Agonist RGC100  

PubMed Central

Toll-like receptor (TLR) 3 agonists emerged as attractive candidates for vaccination strategies against tumors and pathogens. An important mechanism of action of such agonists is based on the activation of TLR3-expressing dendritic cells (DCs), which display a unique capacity to induce and stimulate T-cell responses. In this context, it has been demonstrated that targeting of TLR3 by double-stranded RNA such as poly(I:C) results in potent activation of DCs. Major disadvantages of poly(I:C) comprise its undefined chemical structure and very poor homogeneity, with subsequent unpredictable pharmacokinetics and high toxicity. In the present study, we evaluated the physicochemical properties and biological activity of the novel TLR3 agonist RGC100. RGC100 has a defined chemical structure, with a defined length (100?bp) and molecular weight (64.9?KDa) and a good solubility. RGC100 is stable in serum and activates myeloid DCs through TLR3 targeting, as evidenced by gene silencing experiments. Activation of mouse and human myeloid CD1c+ DCs by RGC100 leads to secretion of several proinflammatory cytokines. In addition, RGC100 improves the ability of CD1c+ DCs to stimulate T-cell proliferation. Due to its physicochemical properties and its immunostimulatory properties, RGC100 may represent a promising adjuvant for prophylactic and therapeutic vaccination strategies. PMID:24454470

Wehner, Rebekka; Schwarze, Anett; Petzold, Christiane; Schmitz, Marc

2013-01-01

47

Peroxisome proliferator-activated receptor agonists modulate neuropathic pain: a link to chemokines?  

PubMed Central

Chronic pain presents a widespread and intractable medical problem. While numerous pharmaceuticals are used to treat chronic pain, drugs that are safe for extended use and highly effective at treating the most severe pain do not yet exist. Chronic pain resulting from nervous system injury (neuropathic pain) is common in conditions ranging from multiple sclerosis to HIV-1 infection to type II diabetes. Inflammation caused by neuropathy is believed to contribute to the generation and maintenance of neuropathic pain. Chemokines are key inflammatory mediators, several of which (MCP-1, RANTES, MIP-1?, fractalkine, SDF-1 among others) have been linked to chronic, neuropathic pain in both human conditions and animal models. The important roles chemokines play in inflammation and pain make them an attractive therapeutic target. Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear receptors known for their roles in metabolism. Recent research has revealed that PPARs also play a role in inflammatory gene repression. PPAR agonists have wide-ranging effects including inhibition of chemokine expression and pain behavior reduction in animal models. Experimental evidence suggests a connection between the pain ameliorating effects of PPAR agonists and suppression of inflammatory gene expression, including chemokines. In early clinical research, one PPAR? agonist, palmitoylethanolamide (PEA), shows promise in relieving chronic pain. If this link can be better established, PPAR agonists may represent a new drug therapy for neuropathic pain. PMID:25191225

Freitag, Caroline M.; Miller, Richard J.

2014-01-01

48

Modeling active electrolocation in weakly electric fish  

E-print Network

In this paper, we provide a mathematical model for the electrolocation in weakly electric fishes. We first investigate the forward complex conductivity problem and derive the approximate boundary conditions on the skin of the fish. Then we provide a dipole approximation for small targets away from the fish. Based on this approximation, we obtain a non-iterative location search algorithm using multi-frequency measurements. We present numerical experiments to illustrate the performance and the stability of the proposed multi-frequency location search algorithm. Finally, in the case of disk- and ellipse-shaped targets, we provide a method to reconstruct separately the conductivity, the permittivity, and the size of the targets from multi-frequency measurements.

Habib Ammari; Thomas Boulier; Josselin Garnier

2013-03-06

49

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

PubMed

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

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

2015-01-22

50

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. PMID:22738238

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

51

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. PMID:22353334

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

2012-01-01

52

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. PMID:22994402

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

2012-01-01

53

Phosphorylation/dephosphorylation of androgen receptor as a determinant of androgen agonistic or antagonistic activity.  

PubMed

Protein phosphorylation/dephosphorylation is an important posttranslational modification that plays a critical role in signal transduction. The androgen receptor (AR) is under such control. We demonstrate that androgen receptor phosphorylation determines whether or not AR ligands perform as agonists or antagonists in LNCaP cells. Androgen receptor ligands (such as dihydrotestosterone and beta-estradiol) stimulate receptor expression and phosphorylation and, as a result, they act as agonists or partial agonists. In contrast, agents such as bicalutamide and estramustine inhibit the receptor phosphorylation and act as antagonists. This model is supported by gene expression and transactivation assays. Significant increases in levels of both mRNA and protein of prostate-specific antigen (PSA), a natural AR target gene, occur following the treatment of LNCaP cells with DHT, beta-estradiol, or hydroxyflutamide. In contrast, exposure of LNCaP cells to bicalutamide or estramustine results in a sharp decrease of PSA expression. Agonistic or antagonistic effect of these compounds on PSA expression parallels the level of phosphorylated, but not dephosphorylated androgen receptors. These agonistic or antagonistic effects are also observed in HeLa cells transfected with wild-type AR expression plasmid (pAR0) and AR-driven luciferase expression plasmid GRE-tk-LUC in the presence of different groups of AR blockers. Our data indicate that the functional status of androgen receptors is strongly correlated with the phosphorylation status of the receptors, and that the phosphorylated androgen receptor is the form of the receptor transcriptionally active in regulation. Thus the androgen receptor phosphorylation/dephosphorylation may serve as a new molecular target for screening androgen antagonists for the treatment of prostate cancer. PMID:10334909

Wang, L G; Liu, X M; Kreis, W; Budman, D R

1999-05-27

54

Chemical Communication in Scarab Beetles: Reciprocal Behavioral Agonist-Antagonist Activities of Chiral Pheromones  

Microsoft Academic Search

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

Walter Soares Leal

1996-01-01

55

Molecular Mechanism in Activation of Glutathione System by Ropinirole, a Selective Dopamine D2 Agonist  

Microsoft Academic Search

We have previously reported that ropinirole, a non-ergot dopamine agonist, has neuroprotective effects against 6-hydroxydopamine in mice based on in vivo antioxidant properties such as the glutathione (GSH)-activating effect. In the present study, we determined that the effects of ropinirole on the level of expression of GSH-related enzyme mRNA, these enzymes were shown to regulate GSH contents in the brain.

Ken-ichi Tanaka; Ikuko Miyazaki; Naoko Fujita; MdEmdadul Haque; Masato Asanuma; Norio Ogawa

2001-01-01

56

Peroxisome Proliferator-Activated Receptor-? Agonists Suppress the Production of IL-12 Family Cytokines by Activated Glia1  

PubMed Central

The IL-12 family of cytokines, which include IL-12, IL-23, and IL-27, play critical roles in the differentiation of Th1 cells and are believed to contribute to the development of multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Relatively little is known concerning the expression of IL-12 family cytokines by cells of the CNS, the affected tissue in MS. Previously, we and others demonstrated that peroxisome proliferator-activated receptor (PPAR)-? agonists suppress the development of EAE, alter T cell proliferation and phenotype, and suppress the activation of APCs. The present studies demonstrated that PPAR-? agonists, including the naturally occurring 15-deoxy-?12,14-PGJ2 and the synthetic thiazoladinedione rosiglitazone, inhibited the induction of IL-12p40, IL-12p70 (p35/p40), IL-23 (p19/p40), and IL-27p28 proteins by LPS-stimulated primary microglia. In primary astrocytes, LPS induced the production of IL-12p40, IL-23, and IL-27p28 proteins. However, IL-12p70 production was not detected in these cells. The 15-deoxy-?12,14-PGJ2 potently suppressed IL-12p40, IL-23, and IL-27p28 production by primary astrocytes, whereas rosiglitazone suppressed IL-23 and IL-27p28, but not IL-12p40 in these cells. These novel observations suggest that PPAR-? agonists modulate the development of EAE, at least in part, by inhibiting the production of IL-12 family cytokines by CNS glia. In addition, we demonstrate that PPAR-? agonists inhibit TLR2, MyD88, and CD14 expression in glia, suggesting a possible mechanism by which these agonists modulate IL-12 family cytokine expression. Collectively, these studies suggest that PPAR-? agonists may be beneficial in the treatment of MS. PMID:17237441

Xu, Jihong; Drew, Paul D.

2008-01-01

57

MBX-102/JNJ39659100, a novel peroxisome proliferator-activated receptor-ligand with weak transactivation activity retains antidiabetic properties in the absence of weight gain and edema.  

PubMed

MBX-102/JNJ39659100 (MBX-102) is in clinical development as an oral glucose-lowering agent for the treatment of type 2 diabetes. MBX-102 is a nonthiazolidinedione (TZD) selective partial agonist of peroxisome proliferator-activated receptor (PPAR)-gamma that is differentiated from the TZDs structurally, mechanistically, preclinically and clinically. In diabetic rodent models, MBX-102 has insulin-sensitizing and glucose-lowering properties comparable to TZDs without dose-dependent increases in body weight. In vitro, in contrast with full PPAR-gamma agonist treatment, MBX-102 fails to drive human and murine adipocyte differentiation and selectively modulates the expression of a subset of PPAR-gamma target genes in mature adipocytes. Moreover, MBX-102 does not inhibit osteoblastogenesis of murine mesenchymal cells. Compared with full PPAR-gamma agonists, MBX-102 displays differential interactions with the PPAR-gamma ligand binding domain and possesses reduced ability to recruit coactivators. Interestingly, in primary mouse macrophages, MBX-102 displays enhanced antiinflammatory properties compared with other PPAR-gamma or alpha/gamma agonists, suggesting that MBX-102 has more potent transrepression activity. In summary, MBX-102 is a selective PPAR-gamma modulator with weak transactivation but robust transrepression activity. MBX-102 exhibits full therapeutic activity without the classical PPAR-gamma side effects and may represent the next generation insulin sensitizer. PMID:19389808

Gregoire, Francine M; Zhang, Fang; Clarke, Holly J; Gustafson, Thomas A; Sears, Dorothy D; Favelyukis, Svetlana; Lenhard, James; Rentzeperis, Dennis; Clemens, L Edward; Mu, Yi; Lavan, Brian E

2009-07-01

58

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

PubMed

Targeting the complement component 3a receptor (C3aR) with selective agonists or antagonists is believed to be a viable therapeutic option for several diseases such as stroke, heart attack, reperfusion injuries, and rheumatoid arthritis. We designed a number of agonists, partial agonists, and antagonists of C3aR using our two-stage de novo protein design framework. Of the peptides tested using a degranulation assay in C3aR-transfected rat basophilic leukemia cells, two were prominent agonists (EC(50) values of 25.3 and 66.2 nM) and two others were partial agonists (IC(50) values of 15.4 and 26.1 nM). Further testing of these lead compounds in a calcium flux assay in U937 cells yielded similar results although with reduced potencies compared to transfected cells. The partial agonists also displayed full antagonist activity when tested in a C3aR inhibition assay. In addition, the electrostatic potential profile was shown to potentially discriminate between full agonists and partial agonists. PMID:22500977

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

2012-05-10

59

Partial agonistic activity of R- and S-enantiomers of 8-OH-DPAT at 5-HT1A receptors.  

PubMed Central

In this study, the 5-HT1A agonistic activity of R- and S-enantiomers of the prototypical 5-HT1A agonist 8-OH-DPAT was investigated using in vivo microiontophoresis and the hypothermic response in rats. Both the R- and S-enantiomers suppressed current-dependently the firing activity of dorsal hippocampus CA3 pyramidal neurons. The number of spikes suppressed/nA of R-(+)-OH-DPAT was about 2-fold greater than that of S-(-)-OH-DPAT, which indicates greater agonistic activity of the R-enantiomer. The determination of the effectiveness of 5-HT in suppressing the firing activity of CA3 pyramidal neurons prior to and during application of either the R- or S-enantiomer showed that both compounds antagonized the effect of 5-HT, thus demonstrating their partial agonistic activity. Racemic 8-OH-DPAT produced a dose-dependent hypothermia which was attenuated by the 5-HT1A antagonist pindolol, but not by the nonselective 5-HT antagonist methysergide. Similarly, both R- and S-enantiomers induced a dose-dependent hypothermia, which was greater and longer lasting in the case of R-(+)-OH-DPAT when compared to S-(-)-OH-DPAT. In conclusion, R-(+)-OH-DPAT, displayed a greater agonistic activity at 5-HT1A receptors than S-(-)-OH-DPAT, both in suppressing firing activity of CA3 pyramidal neurons and in decreasing body temperature. Nevertheless, both compounds behaved as partial agonists. PMID:8820175

Hadrava, V; Blier, P; de Montigny, C

1996-01-01

60

Agonist and antagonist activity during voluntary upper-limb movement in patients with stroke.  

PubMed

Forty-four patients with hemiplegia following stroke and 10 nondisabled subjects were studied to examine the contributions inadequate motor unit recruitment and co-contraction attributable to impaired antagonist inhibition play in the movement disorder of the hemiplegic arm. Electromyographic data were recorded from agonist and antagonist muscles while subjects attempted six specified tasks. Data from subjects who could complete the tasks were compared with those who could not complete the tasks. Differences between the two groups were found in the electromyographic data obtained from the agonist muscles. Electromyographic values were consistently and significantly lower in patients who were unable to complete the tasks than in patients who were able to complete the tasks. In the antagonist muscles, a significant difference was noted only once; in this case, the EMG values were again lower in the group of patients who were unable to complete the task. Inadequate recruitment of agonists, not increased activity in the antagonists, was a consistent finding in patients who were unable to carry out the movement tasks. This study theoretically supports aiming treatment efforts at improving motoneuron recruitment rather than reducing activity in antagonists while retraining arm function. PMID:1508970

Gowland, C; deBruin, H; Basmajian, J V; Plews, N; Burcea, I

1992-09-01

61

Agonist activity of LSD and lisuride at cloned 5HT2A and 5HT2C receptors  

Microsoft Academic Search

Evidence from studies with phenylisopropylamine hallucinogens indicates that the 5HT2A receptor is the likely target for the initiation of events leading to hallucinogenic activity associated with LSD?and related\\u000a drugs. Recently, lisuride (a purported non-hallucinogenic congener of LSD) was reported to be a potent antagonist at the 5HT2C receptor and an agonist at the 5HT2A receptor. LSD exhibited agonist activity at

Christina T. Egan; Katharine Herrick-Davis; Keith Miller; Richard A. Glennon; M. Teitler

1998-01-01

62

Unique efficacy of Toll-like receptor 8 agonists in activating human neonatal antigen-presenting cells.  

PubMed

Newborns are prone to microbial infection and have poor memory responses to multiple antigens. We have previously shown that human neonatal blood monocytes exhibit impaired TNF-alpha responses to most known TLR agonists, including the pure TLR7 agonist imiquimod. Surprisingly, however, neonatal TNF-alpha responses to the imiquimod congener R-848 (TLR 7/8) were fully intact. We now show that TLR8 agonists, including R-848 (TLR7/8), the imidazoquinoline congeners 3M-003 (TLR7/8) and 3M-002 (TLR8), as well as single-stranded viral RNAs (TLR8) induced robust production of the Th1-polarizing cytokines TNF-alpha and IL-12 from neonatal antigen-presenting cells (APCs) that substantially exceeds responses induced by TLR-2, -4, or -7 (alone) agonists. TLR8 agonists also effectively induced up-regulation of the costimulatory molecule CD40 on neonatal and adult myeloid dendritic cells (DCs). The strong activity of TLR8 agonists correlates with their induction of p38 MAP kinase phosphorylation and with degradation of IkappaB-alpha in both neonatal and adult monocytes. We conclude that TLR8 agonists are uniquely efficacious in activating costimulatory responses in neonatal APCs and suggest that these agents are promising candidate adjuvants for enhancing immune responses in human newborns. PMID:16638933

Levy, Ofer; Suter, Eugénie E; Miller, Richard L; Wessels, Michael R

2006-08-15

63

Gene alterations by peroxisome proliferator-activated receptor ? agonists in human colorectal cancer cells  

PubMed Central

The peroxisome proliferator-activated receptor ? (PPAR?) is a nuclear transcription factor that controls the genes involved in metabolism and carcinogenesis. In the present study, we examined the alteration of gene expression in HCT-116 human colorectal cancer cells by PPAR? agonists: MCC-555 (5 µM), rosiglitazone (5 µM), and 15-deoxy-?12,14-prostaglandin J2 (1 µM). The long-oligo microarray data revealed a list of target genes commonly induced (307 genes) and repressed (32 genes) by tested PPAR? agonists. These genes were analyzed by Onto-Express software and KEGG pathway analysis and revealed that PPAR? agonists are involved in cell proliferation, focal adhesion, and several signaling pathways. Eight genes were selected to confirm the microarray data by RT-PCR and real-time PCR, from which CSTA, DAP13, TAF12, RIS1, CDKN3 and MAGOH were up-regulated, and KLHL11 and NCOA2 were down-regulated. This study elucidates the commonly induced genes modulated by tested PPAR? ligands involved in the different signaling pathways and metabolisms, probably mediated in a PPAR?-dependent manner in colorectal cancer cells and helps to better understand the pleiotropic actions of PPAR? ligands. PMID:18360708

Cekanova, Maria; Yuan, Joshua S.; Li, Xiuoon; Kim, Kyubo; Baek, Seung Joon

2008-01-01

64

Positive Allosteric Modulators Differentially Affect Full versus Partial Agonist Activation of the Glycine Receptor  

PubMed Central

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

2012-01-01

65

Serotonin 5-HT2C receptor agonist promotes hypophagia via downstream activation of melanocortin 4 receptors.  

PubMed

The neurotransmitter serotonin (5-hydroxytryptamine) is a well-established modulator of energy balance. Both pharmacological and genetic evidence implicate the serotonin 2C receptor (5-HT(2C)R) as a critical receptor mediator of serotonin's effects on ingestive behavior. Here we characterized the effect of the novel and selective 5-HT(2C)R agonist BVT.X on energy balance in obese and lean mice and report that BVT.X significantly reduces acute food intake without altering locomotor activity or oxygen consumption. In an effort to elucidate the mechanism of this effect, we examined the chemical phenotype of 5-HT(2C)R-expressing neurons in a critical brain region affecting feeding behavior, the arcuate nucleus of the hypothalamus. We show that 5-HT(2C)Rs are coexpressed with neurons containing proopiomelanocortin, known to potently affect appetite, in the arcuate nucleus of the hypothalamus of the mouse. We then demonstrate that prolonged infusion with BVT.X in obese mice significantly increases Pomc mRNA and reduces body weight, percent body fat, and initial food intake. To evaluate the functional importance of melanocortin circuitry in the effect of BVT.X on ingestive behavior, we assessed mice with disrupted melanocortin pathways. We report that mice lacking the melanocortin 4 receptor are not responsive to BVT.X-induced hypophagia, demonstrating that melanocortins acting on melanocortin 4 receptor are a requisite downstream pathway for 5-HT(2C)R agonists to exert effects on food intake. The data presented here not only indicate that the novel 5-HT(2C)R agonist BVT.X warrants further investigation as a treatment for obesity but also elucidate specific neuronal pathways potently affecting energy balance through which 5-HT(2C)R agonists regulate ingestive behavior. PMID:18039773

Lam, Daniel D; Przydzial, Magdalena J; Ridley, Simon H; Yeo, Giles S H; Rochford, Justin J; O'Rahilly, Stephen; Heisler, Lora K

2008-03-01

66

Bis(ammonio)alkane-type agonists of muscarinic acetylcholine receptors: synthesis, in vitro functional characterization, and in vivo evaluation of their analgesic activity.  

PubMed

In this study, we synthesized and tested in vitro and in vivo two groups of bis(ammonio)alkane-type compounds, 6a-9a and 6b-9b, which incorporate the orthosteric muscarinic agonist iperoxo into a molecular fragment of the M2-selective allosteric modulators W84 and naphmethonium. The agonist potency and efficacy of these hybrid derivatives at M1, M2 and M3 muscarinic receptor subtypes and their anticholinesterase activity were evaluated on isolated tissue preparations. Their analgesic action was then assayed in vivo in the acetic acid writhing test and the occurrence of peripheral and central cholinergic side effects was also determined. The investigated hybrids behaved as potent muscarinic agonists and weak cholinesterase inhibitors. These effects were more pronounced for bisquaternary salts bearing the naphmethonium moiety than for the W84-containing analogs, and resulted in a significant analgesic activity in vivo. A promising profile was displayed by the naphmethonium-related compound 8b, which combined the most potent antinociception among the test compounds with the absence of relevant cholinergic side effects. PMID:24534538

Matera, Carlo; Flammini, Lisa; Quadri, Marta; Vivo, Valentina; Ballabeni, Vigilio; Holzgrabe, Ulrike; Mohr, Klaus; De Amici, Marco; Barocelli, Elisabetta; Bertoni, Simona; Dallanoce, Clelia

2014-03-21

67

Protein Kinase D Isoforms Are Activated in an Agonist-specific Manner in Cardiomyocytes*  

PubMed Central

Protein kinase D (PKD) exists as a family of structurally related enzymes that are activated through similar phosphorylation-dependent mechanisms involving protein kinase C (PKC). While individual PKD isoforms could in theory mediate distinct biological functions, previous studies identify a high level of functional redundancy for PKD1 and PKD2 in various cellular contexts. This study shows that PKD1 and PKD2 are activated in a stimulus-specific manner in neonatal cardiomyocytes. The ?1-adrenergic receptor agonist norepinephrine selectively activates PKD1, thrombin and PDGF selectively activate PKD2, and endothelin-1 and PMA activate both PKD1 and PKD2. PKC activity is implicated in the ?1-adrenergic receptor pathway that activates PKD1 and the thrombin- and PDGF-dependent pathways that activate PKD2. Endothelin-1 activates PKD via both rapid PKC-dependent and more sustained PKC-independent mechanisms. The functional consequences of PKD activation were assessed by tracking phosphorylation of CREB and cardiac troponin I (cTnI), two physiologically relevant PKD substrates in cardiomyocytes. We show that overexpression of an activated PKD1-S744E/S748E transgene increases CREB-Ser133 and cTnI-Ser23/Ser24 phosphorylation, but agonist-dependent pathways that activate native PKD1 or PKD2 selectively increase CREB-Ser133 phosphorylation; there is no associated increase in cTnI-Ser23/Ser24 phosphorylation. Gene silencing studies provide unanticipated evidence that PKD1 down-regulation leads to a compensatory increase in PKD2 activity and that down-regulation of PKD1 (alone or in combination with PKD2) leads to an increase in CREB-Ser133 phosphorylation. Collectively, these studies identify distinct roles for native PKD1 and PKD2 enzymes in stress-dependent pathways that influence cardiac remodeling and the progression of heart failure. PMID:21156805

Guo, Jianfen; Gertsberg, Zoya; Ozgen, Nazira; Sabri, Abdelkarim; Steinberg, Susan F.

2011-01-01

68

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. PMID:3028557

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

1987-01-01

69

Activation of Protease Activated Receptor 2 (PAR2) by an Exogenous Agonist Exacerbates Early Radiation Injury in Rat Intestine  

PubMed Central

Purpose Protease-activated receptor-2 (PAR2) is highly expressed throughout the gut and regulates inflammatory, mitogenic, fibroproliferative, and nociceptive responses to injury. PAR2 is strikingly upregulated and exhibits increased activation in response to intestinal irradiation. We examined the mechanistic significance of in radiation enteropathy development by assessing the effect of exogenous PAR2 activation. Methods and Materials Rat small bowel was exposed to localized single-dose radiation (16.5 Gy). The PAR2 agonist (2-furoyl-LIGRLO-NH2) or vehicle was injected intraperitoneally daily for 3 days before irradiation (“before”), for 7 days after irradiation (“after”), or both 3 days before and 7 days after irradiation (“before-after”). Early and delayed radiation enteropathy was assessed 2 and 26 weeks after irradiation by quantitative histology, morphometry, and immuno-histochemical analysis. Results The PAR2 agonist did not elicit changes in unirradiated (shielded) intestine. In contrast, in irradiated intestine procured 2 weeks after irradiation, administration of PAR2 agonist was associated with more sever mucosal injury and increased intestinal wall thickness in all 3 treatment groups (p < 0.05) compared to vehicle-treated controls. The PAR2 agonist also exacerbated radiation injury score, serosal thickening, and mucosal inflammation (p < 0.05) in the before and the before-after groups. Short term exogenous activation of PAR2 did not impact radiation-induced intestinal injury at 26 weeks. Conclusions This study supports a role for PAR2 activation in the pathogenesis of early radiation-induced intestinal injury. Pharmacological PAR2 antagonists may have the potential to reduce intestinal side effects of radiation therapy and/or as countermeasures in radiological accidents or terrorism scenarios. PMID:20610041

Wang, Junru; Boerma, Marjan; Kulkarni, Ashwini; Hollenberg, Morley D.; Hauer-Jensen, Martin

2010-01-01

70

Polyyne Hybrid Compounds from Notopterygium incisum with Peroxisome Proliferator-Activated Receptor Gamma Agonistic Effects  

PubMed Central

In the search for peroxisome proliferator-activated receptor gamma (PPAR?) active constituents from the roots and rhizomes of Notopterygium incisum, 11 new polyacetylene derivatives (1–11) were isolated. Their structures were elucidated by NMR and HRESIMS as new polyyne hybrid molecules of falcarindiol with sesquiterpenoid or phenylpropanoid moieties, named notoethers A–H (1–8) and notoincisols A–C (9–11), respectively. Notoincisol B (10) and notoincisol C (11) represent two new carbon skeletons. When tested for PPAR? activation in a luciferase reporter assay with HEK-293 cells, notoethers A–C (1–3), notoincisol A (9), and notoincisol B (10) showed promising agonistic activity (EC50 values of 1.7 to 2.3 ?M). In addition, notoincisol A (9) exhibited inhibitory activity on NO production of stimulated RAW 264.7 macrophages. PMID:25333853

2014-01-01

71

Cyanidin is an agonistic ligand for peroxisome proliferator-activated receptor-alpha reducing hepatic lipid.  

PubMed

To investigate the underlying mechanism of targets of cyanidin, a flavonoid, which exhibits potent anti-atherogenic activities in vitro and in vivo, a natural chemical library that identified potent agonistic activity between cyanidin and peroxisome proliferator-activated receptors (PPAR) was performed. Cyanidin induced transactivation activity in all three PPAR subtypes in a reporter gene assay and time-resolved fluorescence energy transfer analyses. Cyanidin also bound directly to all three subtypes, as assessed by surface plasmon resonance experiments, and showed the greatest affinity to PPAR?. These effects were confirmed by measuring the expression of unique genes of each PPAR subtype. Cyanidin significantly reduced cellular lipid concentrations in lipid-loaded steatotic hepatocytes. In addition, transcriptome profiling in lipid-loaded primary hepatocytes revealed that the net effects of stimulation with cyanidin on lipid metabolic pathways were similar to those elicited by hypolipidemic drugs. Cyanidin likely acts as a physiological PPAR? agonist and potentially for PPAR?/? and ?, and reduces hepatic lipid concentrations by rewiring the expression of genes involved in lipid metabolic pathways. PMID:23228689

Jia, Yaoyao; Kim, Jin-Young; Jun, Hee-Jin; Kim, Sun-Joong; Lee, Ji-Hae; Hoang, Minh Hien; Kim, Hyun Sook; Chang, Hyo Ihl; Hwang, Kwang-Yeon; Um, Soo-Jong; Lee, Sung-Joon

2013-04-01

72

Chloride conductance activated by external agonists and internal messengers in rat peritoneal mast cells.  

PubMed Central

1. Stimulation of mast cells by externally applied secretagogues activated a slowly developing membrane current. With high external and low internal chloride (Cl-) concentrations, the current reversed at about -40 mV, but when external Cl- was made equal to internal Cl-, the reversal potential shifted to about 0 mV, demonstrating that the current carrier was Cl-. 2. In addition to external agonists, internally applied cyclic AMP and high concentrations of intracellular calcium [Ca2+]i could also activate the Cl- current. However, elevated [Ca2+]i produced only slow and incomplete activation. This suggests that the Cl- current is not directly Ca2+ activated. Also, activation of Cl- current by external agonists and by cyclic AMP was unimpaired when [Ca2+]i was clamped to low levels with internal ethylene glycol bis-N,N,N',N'-tetraacetic acid (EGTA), indicating that elevated [Ca2+]i is not necessary for activation of the Cl- current. Although activation by cyclic AMP was faster than that produced by elevated [Ca2+]i, it still required tens of seconds; thus the effect of cyclic AMP was also likely to be indirect. 3. Internal guanosine 5'-O-(3-thiotriphosphate) (GTP-gamma-S) could also activate the Cl- current, suggesting the involvement of a G protein in the control of the current. 4. The variance associated with the Cl- current was small, and noise analysis gave a lower limit of about 1-2 pS for the single-channel conductance. The Cl- current was reduced by 4,4'-diisothiocyano-2,2'-stilbenedisulphonate (DIDS), and during DIDS blockade, the variance of the current increased. This suggests that DIDS enters and blocks the open channel. 5. Activation of the Cl- current would make the membrane potential negative following stimulation of a mast cell, thus providing a driving force for entry of external calcium via the stimulation-induced influx pathways described in the preceding paper (Matthews, Neher & Penner, 1989). PMID:2559969

Matthews, G; Neher, E; Penner, R

1989-01-01

73

PPAR-gamma agonist increase gefitinib's antitumor activity through PTEN expression.  

PubMed

Gefitinib exhibits antitumor activity in patient with non-small cell lung cancer (NSCLC). However, only 10-20% of patients exhibit clinical response to this drug. The molecular mechanisms underlying gefitinib sensitivity remain unknown. Peroxisome proliferators-activated receptor-gamma (PPAR-gamma) plays roles in the regulation of cellular differentiation and growth. This regulation was mediated by increasing Phosphatase and tensin homologue deleted on chromosome Ten (PTEN) levels. PTEN plays a role in the modulation of the phosphatidylinositol 3-kinase pathway (PI3K), which is involved in cell proliferation and survival. This study investigated the effects of PPAR-gamma agonist (rosiglitazone) on the expression of PTEN, as well as EGFR tyrosine kinase inhibitor (gefitinib)'s antitumor activity in A549 cells. The treatment of A549 cells with rosiglitazone reduced the growth of A549 cells in a dose-dependent manner, and facilitated the anti-proliferative effects of gefitinib. PPAR-gamma and PTEN expression were found to have increased in the gefitinib- and rosiglitazone-treated cells. This suggests that PPAR-gamma agonist (rosiglitazone) potentiated gefitinib's anti-proliferative effects by increased of PTEN expression, and suggest that PPAR-gamma ligands may serve as potential therapeutic agents for NSCLC. PMID:16386327

Lee, Sung Yong; Hur, Gyu Young; Jung, Ki Hwan; Jung, Hye Cheol; Lee, Sang Yeub; Kim, Je Hyeong; Shin, Chol; Shim, Jae Jeong; In, Kwang Ho; Kang, Kyung Ho; Yoo, Se Hwa

2006-03-01

74

Androgen receptor antagonist versus agonist activities of the fungicide vinclozolin relative to hydroxyflutamide.  

PubMed

The mechanism of antiandrogenic activity of vinclozolin (3-(3,5-dichlorophenyl)-5-methyl-5-vinyloxazolidine-2,4-dione), a dicarboximide fungicide under investigation for its potential adverse effects on human male reproduction, was investigated using recombinant human androgen receptor (AR). The two primary metabolites of vinclozolin in plants and mammals are M1 (2-[[3,5-dichlorophenyl)-carbamoyl]oxy]-2-methyl-3-butenoic acid) and M2 (3',5'-dichloro-2-hydroxy-2-methylbut-3-enanilide). Both metabolites, in a dose-dependent manner, target AR to the nucleus and inhibit androgen-induced transactivation mediated by the mouse mammary tumor virus promoter. M2 is a 50-fold more potent inhibitor than M1 and only 2-fold less than hydroxyflutamide. In the presence of dihydrotestosterone (50 nM), M2 (0.2-10 microM) inhibits androgen-induced AR binding to androgen response element DNA. In the absence of dihydrotestosterone, concentrations of 10 microM M2 or hydroxyflutamide promote AR binding to androgen response element DNA and activation of transcription. Agonist activities of M2 and hydroxyflutamide occur at 10-fold lower concentrations with the mutant AR (Thr877 to Ala) endogenous to LNCaP human prostate cancer cells. The results indicate that androgen antagonists can act as agonists, depending on ligand binding affinity, concentration, and the presence of competing natural ligands. PMID:7650017

Wong, C; Kelce, W R; Sar, M; Wilson, E M

1995-08-25

75

Synthesis and SAR studies of benzyl ether derivatives as potent orally active S1P? agonists.  

PubMed

We report herein the synthesis and structure-activity relationships (SAR) of a series of benzyl ether compounds as an S1P? receptor modulator. From our SAR studies, the installation of substituents onto the central benzene ring of 2a was revealed to potently influence the S1P? and S1P? agonistic activities, in particular, an ethyl group on the 2-position afforded satisfactory S1P?/S1P? selectivity. These changes of the S1P? and S1P? agonistic activities caused by the alteration of substituents on the 2-position were reasonably explained by a docking study using an S1P? X-ray crystal structure and S1P? homology modeling. We found that compounds 2b and 2e had a potent in vivo immunosuppressive efficacy along with acceptable S1P?/S1P? selectivity, and confirmed that these compounds had less in vivo bradycardia risk through the evaluation of heart rate change after oral administration of the compounds (30 mg/kg, p.o.) in rats. PMID:24909680

Tsuji, Takashi; Suzuki, Keisuke; Nakamura, Tsuyoshi; Goto, Taiji; Sekiguchi, Yukiko; Ikeda, Takuya; Fukuda, Takeshi; Takemoto, Toshiyasu; Mizuno, Yumiko; Kimura, Takako; Kawase, Yumi; Nara, Futoshi; Kagari, Takashi; Shimozato, Takaichi; Yahara, Chizuko; Inaba, Shinichi; Honda, Tomohiro; Izumi, Takashi; Tamura, Masakazu; Nishi, Takahide

2014-08-01

76

Ocular pharmacokinetics and hypotensive activity of PF-04475270, an EP4 prostaglandin agonist in preclinical models.  

PubMed

Prostaglandins are widely used to lower intraocular pressure (IOP) as part of the treatment regimen for glaucoma. While FP and EP2 agonists are known to lower IOP, we investigated the ocular hypotensive activity and ocular drug distribution of PF-04475270, a novel EP4 agonist following topical administration in normotensive Beagle dogs. PF-04475270 is a prodrug of CP-734432, which stimulated cAMP formation in HEK293 cells expressing EP4 receptor and beta-lactamase activity in human EP4 expressing CHO cells transfected with a cAMP response element (CRE) with an EC(50) of 1 nM. Prodrug conversion and transcorneal permeability were assessed in rabbit corneal homogenates and a human corneal epithelial cell (cHCE) model. The compound underwent rapid hydrolysis to CP-734432 in corneal homogenates, and exhibited good permeability in the cHCE model. The descending order of ocular exposure to CP-734432 after topical dosing of PF-04475270 in dogs was as follows: cornea > aqueous humor >or= iris/ciliary body. When administered q.d., PF-04475270 lowered IOP effectively in the dog IOP model both after single and multiple days of dosing. A maximum decrease in IOP with PF-04475270 was between 30 and 45% at 24h post-dose relative to that observed with vehicle. In conclusion, PF-04475270 is a novel ocular hypotensive compound which is bioavailable following topical dosing, effectively lowering IOP in dogs. EP4 agonists could be considered as potential targets for lowering IOP for the treatment of glaucoma and ocular hypertension. PMID:19445930

Prasanna, Ganesh; Fortner, Jay; Xiang, Cathie; Zhang, Eric; Carreiro, Samantha; Anderson, Scott; Sartnurak, Soisurin; Wu, Grace; Gukasyan, Hovhannes; Niesman, Michael; Nair, Sajiv; Rui, Eugene; Lafontaine, Jennifer; Almaden, Chau Doan; Wells, Peter; Krauss, Achim

2009-11-01

77

Peroxisome proliferator-activated receptor agonists modulate heart function in transgenic mice with lipotoxic cardiomyopathy.  

PubMed

hLpL(GPI) transgenic mice that overexpress human lipoprotein lipase (hLpL) with a glycosylphosphatidylinositol anchor on cardiomyocytes develop lipotoxic cardiomyopathy associated with increased cardiac uptake of plasma lipids. We hypothesized that peroxisome proliferator-activated receptor (PPAR)alpha, PPARgamma, or a PPARalpha/gamma agonist would alter cardiac function by modulating lipid uptake by the heart. hLpL(GPI) mice were administered rosiglitazone (10 mg/kg/day), fenofibrate (100 mg/kg/day), or DRF2655, an alkoxy propanoic acid analog (10 mg/kg/day), for 16 days. Rosiglitazone reduced plasma triglyceride (TG) from 107.63 +/- 6.98 to 77.61 +/- 3.98 mg/dl, whereas fenofibrate had no effect. DRF2655 reduced TG to 33.17 +/- 4.12 mg/dl. Rosiglitazone and DRF2655 decreased heart TG and total cholesterol; fenofibrate had no effect. Molecular markers for cardiac dysfunction, atrial natriuretic factor, brain natriuretic peptide, and tumor necrosis factor-alpha were decreased with rosiglitazone and increased with fenofibrate. Echocardiographic measurements showed reduced fractional shortening and increased left ventricular systolic dimension with fenofibrate. No changes in these parameters were observed with rosiglitazone or DRF2655 treatment. Muscle-specific carnitine palmitoyltransferase-1 and fatty acid transporter protein-1 gene expression were increased with fenofibrate and DRF2655 treatment; no change in expression of these genes was noted with rosiglitazone treatment. Rosiglitazone and DRF2655 reduced TG uptake by the heart, and fenofibrate treatment increased fatty acid uptake. Thus, in a lipotoxic cardiomyopathy mouse model, a PPARgamma agonist reduced cardiac lipid and markers of cardiomyopathy, whereas an agonist of PPARalpha did not improve cardiac lipids and worsened heart function. These changes were paralleled by alterations in heart lipid uptake. Overall, PPAR activators exhibit differential effects in this model of lipotoxic dilated cardiomyopathy. PMID:15671204

Vikramadithyan, Reeba K; Hirata, Kumiko; Yagyu, Hiroaki; Hu, Yunying; Augustus, Ayanna; Homma, Shunichi; Goldberg, Ira J

2005-05-01

78

Pharmacological characterization of a novel liver X receptor agonist with partial LXR? activity and a favorable window in nonhuman primates.  

PubMed

Liver X Receptors (LXRs) ? and ? are nuclear hormone receptors that regulate multiple genes involved in reverse cholesterol transport (RCT) and are potential drug targets for atherosclerosis. However, full pan agonists also activate lipogenic genes, resulting in elevated plasma and hepatic lipids. We report the pharmacology of BMS-779788 [2-(2-(1-(2-chlorophenyl)-1-methylethyl)-1-(3'-(methylsulfonyl)-4-biphenylyl)-1H-imidazol-4-yl)-2-propanol], a potent partial LXR agonist with LXR? selectivity, which has an improved therapeutic window in the cynomolgus monkey compared with a full pan agonist. BMS-779788 induced LXR target genes in blood in vivo with an EC50 = 610 nM, a value similar to its in vitro blood gene induction potency. BMS-779788 was 29- and 12-fold less potent than the full agonist T0901317 in elevating plasma triglyceride and LDL cholesterol, respectively, with similar results for plasma cholesteryl ester transfer protein and apolipoprotein B. However, ABCA1 and ABCG1 mRNA inductions in blood, which are critical for RCT, were comparable. Increased liver triglyceride was observed after 7-day treatment with BMS-779788 at the highest dose tested and was nearly identical to the dose response for plasma triglyceride, consistent with the central role of liver LXR in these lipogenic effects. Dose-dependent increases in biliary cholesterol and decreases in phospholipid and bile acid occurred in BMS-779788-treated animals, similar to LXR agonist effects reported in mouse. In summary, BMS-779788, a partial LXR? selective agonist, has decreased lipogenic potential compared with a full pan agonist in cynomolgus monkeys, with similar potency in the induction of genes known to stimulate RCT. This provides support in nonhuman primates for improving LXR agonist therapeutic windows by limiting LXR? activity. PMID:25467132

Kirchgessner, Todd G; Martin, Richard; Sleph, Paul; Grimm, Denise; Liu, Xiaoqin; Lupisella, John; Smalley, James; Narayanan, Rangaraj; Xie, Yinong; Ostrowski, Jacek; Cantor, Glenn H; Mohan, Raju; Kick, Ellen

2015-02-01

79

Human muscarinic receptors expressed in A9L and CHO cells: activation by full and partial agonists.  

PubMed Central

1. A comparative study of receptor activation by ten full and partial muscarinic agonists was undertaken on the five subtypes of human muscarinic receptors expressed at similar receptor densities in Chinese hamster ovary (CHO-K1) cells. In addition, m1, m2 and m3 receptors were expressed in mouse fibroblast A9L cells in order to compare the influences of cell type on agonist activation of these receptors. 2. Receptor-effector coupling efficiencies were greater in CHO than A9L cells and agonists displayed greater potencies and similar or greater intrinsic activities at CHOm1 and CHOm3 than A9Lm1 and A9Lm3 receptors. Although m2 receptor density was 6 fold higher in A9L than CHO cells, carbachol elicited significantly greater inhibition of adenosine 3':5'-cyclic monophosphate (cyclic AMP) formation in CHOm2 cells. These data suggest that not only receptor density but receptor-effector coupling and/or coupling efficiencies play significant roles in agonist-induced responses. 3. In CHO cells, receptor-effector coupling efficiencies were m3 = m1 > m5. Although CHOm5 receptors were the least efficiently coupled, some partial agonists displayed higher intrinsic efficacies at m5 than m3 receptors suggesting that, in CHO cells, m5 and m3 receptors may activate different G proteins and/or effectors to stimulate inositol monophosphate (IP1) formation. 4. McN-A-343 was a functionally selective m4 agonist. It had little or no agonist activity at m3 receptors expressed in either A9L or CHO cells.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7620715

Richards, M H; van Giersbergen, P L

1995-01-01

80

TLR9 activation of Stat3 constrains its agonist-based immunotherapy  

PubMed Central

Although toll-like receptor (TLR) agonists, such as CpG, are used as immunotherapeutic agents in clinical trials for cancer and infectious diseases, their effects are limited and the underlying mechanism(s) that restrains CpG efficacy remains obscure. Here we demonstrate that signal transducer and activator of transcription 3 (Stat3) plays a key role in downmodulating CpG’s immunostimulatory effects. In the absence of IL-6 and IL-10 induction, CpG directly activates Stat3 within minutes through TLR9. Ablating Stat3 in hematopoietic cells results in rapid activation of innate immunity by CpG, with enhanced production of interferon-?, tumor necrosis factor-?, interleukin-12, and activation of macrophages, neutrophils and natural killer cells marked with Stat1 activation. Innate immune responses induced by CpG in mice with a Stat3-ablated hematopoietic system cause potent antitumor effects, leading to eradication of large (> 1 cm) B16 melanoma tumors within 72h. Moreover, ablating Stat3 in myeloid cells increases CpG-induced dendritic cell maturation, T cell activation, generation of tumor antigen-specific T cells and long-lasting antitumor immunity. A critical role of Stat3 in mediating immunosuppression by certain cytokines and growth factors in the tumor microenvironment has been recently documented. By demonstrating direct and rapid activation of Stat3 by TLR agonists, we identify a second level of Stat3-mediated immunosuppression. Our results further suggest that targeting Stat3 can drastically improve CpG-based immunotherapeutic approaches. PMID:19258507

Kortylewski, Marcin; Kujawski, Maciej; Herrmann, Andreas; Yang, Chunmei; Wang, Lin; Liu, Yong; Salcedo, Rosalba; Yu, Hua

2009-01-01

81

Assessing the agonist profiles of the prostacyclin analogues treprostinil and naxaprostene, particularly their DP1 activity.  

PubMed

In this study, the inhibitory profiles of the prostacyclin analogues treprostinil and naxaprostene on several isolated smooth muscle preparations have been investigated. Treprostinil was an agonist for prostanoid DP1, EP2 and IP receptors, but not EP4 receptors; its DP1 potency was only 3-4 times less than PGD2 itself. Naxaprostene was much more selective for IP receptors and tended towards partial agonism. Treprostinil is a 13,14-dihydro analogue and the role of conformation around C12-15 in controlling agonist specificity is debated; the synthesis of new analogues is proposed and possible clinical usage discussed. In terms of selective prostanoid antagonists employed, BW-A868C/MK-0524 (DP1), ACA-23 (EP2) and GW-627368 (EP4) were found fit for purpose. However, the IP antagonist RO-1138452 was compromised by ?1 and ?2-adrenoceptor-mediated contractile activity on rat tail artery and anti-muscarinic activity on mouse trachea. There is a need for IP receptor antagonists with better selectivity and higher affinity. PMID:25542069

Syed, Nawazish-I-Husain; Jones, Robert L

2015-04-01

82

5-HT4 receptor agonists enhance both cholinergic and nitrergic activities in human isolated colon circular muscle.  

PubMed

Previous studies have demonstrated mixed inhibitory and facilitatory effects of 5-hydroxytryptamine-4 (5-HT(4)) receptor agonists on electrical field stimulation (EFS)-induced responses in human isolated colon. Here we report three types of responses to EFS in human isolated colon circular muscle: monophasic cholinergic contraction during EFS, biphasic response (nitrergic relaxation during EFS followed by cholinergic contraction after termination of EFS) and triphasic response (cholinergic contraction followed by nitrergic relaxation during EFS and a tachykininergic contraction after EFS). The effects of two 5-HT(4) receptor agonists, prucalopride and tegaserod were then investigated on monophasic responses only. Each compound inhibited contractions during EFS in a concentration-dependent manner. In the presence of N(omega)-nitro-l-arginine methyl ester (l-NAME) however, prucalopride and tegaserod enhanced the contractions in a concentration-dependent manner. In strips where the tone was elevated with substance-P and treated with scopolamine, EFS-induced relaxations were enhanced by the two agonists. The above observed effects by the two agonists were abolished by 5-HT(4) receptor antagonist SB-204070. The two agonists did not alter the tone raised by substance-P in the presence of scopolamine and l-NAME and did not affect carbachol-induced contractions in the presence of tetrodotoxin. These results suggest that in the circular muscle of human colon, 5-HT(4) receptor agonists simultaneously facilitate the activity of neurones which release the inhibitory and excitatory neurotransmitters, nitric oxide and acetylcholine respectively. PMID:16918765

Cellek, S; John, A K; Thangiah, R; Dass, N B; Bassil, A K; Jarvie, E M; Lalude, O; Vivekanandan, S; Sanger, G J

2006-09-01

83

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

84

Tetrapeptide CCK agonists: structure-activity studies on modifications at the N-terminus.  

PubMed

We had reported earlier on a novel series of potent and selective tetrapeptide cholecystokinin-A (CCK-A) agonists of the general structure Boc-Trp-Lys[epsilon-Y]-Asp-N(R)PheNH2 [Y = amides, ureas; R = H, Me] that were potent anorectic agents in rats. In an effort to optimize the potency, selectivity, stability, and efficacy of our lead candidate A-71623 [R = Me, Y = o-tolylaminocarbonyl; Tac] toward development of a clinical candidate, we have explored a series of analogues in which the N-terminal Boc functionality was systematically replaced with various amides, ureas, carbamates, and sulfonamides of differing size, hydrophobicity, and stereoelectronic properties. In general, these analogues maintained good potency and selectivity for the CCK-A receptor (guinea pig pancreas), as well as potent anorectic activity in rats. Those analogues exhibiting equal or superior activity compared to A-71623 but differing physicochemical properties may represent superior drug candidates. PMID:8295219

Elliott, R L; Kopecka, H; Bennett, M J; Shue, Y K; Craig, R; Lin, C W; Bianchi, B R; Miller, T R; Witte, D G; Stashko, M A

1994-01-21

85

A novel natural Nrf2 activator with PPAR?-agonist (monascin) attenuates the toxicity of methylglyoxal and hyperglycemia  

SciTech Connect

Methylglyoxal (MG) is a toxic-glucose metabolite and a major precursor of advanced glycation endproducts (AGEs). MG has been reported to result in inflammation by activating receptor for AGEs (RAGE). We recently found that Monascus-fermented metabolite monascin acts as a novel natural peroxisome proliferator-activated receptor-? (PPAR?) agonist that improves insulin sensitivity. We investigated the metabolic, biochemical, and molecular abnormalities characteristic of type 2 diabetes in MG-treated Wistar rats treated with oral administration of monascin or rosiglitazone. Monascin (a novel PPAR? agonist) activated nuclear factor-erythroid 2-related factor 2 (Nrf2) and down-regulated hyperinsulinmia in oral glucose tolerance test (OGTT). Monascin was able to elevate glyoxalase-1 expression via activation of hepatic Nrf2, hence, resulting in MG metabolism to D-lactic acid and protected from AGEs production in MG-treated rats. Rosiglitazone did not activate Nrf2 nor glyoxalase expression to lower serum and hepatic AGEs levels. Monascin acts as a novel natural Nrf2 activator with PPAR?-agonist activity were confirmed by Nrf2 and PPAR? reporter assays in Hep G2 cells. These findings suggest that monascin acts as an anti-diabetic and anti-oxidative stress agent to a greater degree than rosiglitazone and thus may have therapeutic potential for the prevention of diabetes. - Highlights: • Monascin acts as a PPARgamma agonist. • Monascin activates Nrf2 and AMPK. • Monascin promotes MG metabolism into D-lactic acid. • Monascin attenuates inflammation and diabetes in vivo.

Hsu, Wei-Hsuan; Lee, Bao-Hong; Chang, Yu-Ying [Department of Biochemical Science and Technology, College of Life Science, National Taiwan University, No. 1, Sec. 4, Roosevelt Road, Taipei 10617, Taiwan (China); Hsu, Ya-Wen [SunWay Biotechnology Company, Taipei, Taiwan (China); Pan, Tzu-Ming, E-mail: tmpan@ntu.edu.tw [Department of Biochemical Science and Technology, College of Life Science, National Taiwan University, No. 1, Sec. 4, Roosevelt Road, Taipei 10617, Taiwan (China)

2013-11-01

86

Mapping the agonist-binding site of GABAB type 1 subunit sheds light on the activation process of GABAB receptors.  

PubMed

The gamma-amino-n-butyric acid type B (GABA(B)) receptor is composed of two subunits, GABA(B)1 and GABA(B)2, belonging to the family 3 heptahelix receptors. These proteins possess two domains, a seven transmembrane core and an extracellular domain containing the agonist binding site. This binding domain is likely to fold like bacterial periplasmic binding proteins that are constituted of two lobes that close upon ligand binding. Here, using molecular modeling and site-directed mutagenesis, we have identified residues in the GABA(B)1 subunit that are critical for agonist binding and activation of the heteromeric receptor. Our data suggest that two residues (Ser(246) and Asp(471)) located within lobe I form H bonds and a salt bridge with carboxylic and amino groups of GABA, respectively, demonstrating the pivotal role of lobe I in agonist binding. Interestingly, our data also suggest that a residue within lobe II (Tyr(366)) interacts with the agonists in a closed form model of the binding domain, and its mutation into Ala converts the agonist baclofen into an antagonist. These data demonstrate the pivotal role played by the GABA(B)1 subunit in the activation of the heteromeric GABA(B) receptor and are consistent with the idea that a closed state of the binding domain of family 3 receptors is required for their activation. PMID:10986293

Galvez, T; Prezeau, L; Milioti, G; Franek, M; Joly, C; Froestl, W; Bettler, B; Bertrand, H O; Blahos, J; Pin, J P

2000-12-29

87

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

2010-10-01

88

Insights into ligand-elicited activation of human constitutive androstane receptor based on novel agonists and three-dimensional quantitative structure-activity relationship.  

PubMed

The human constitutive androstane receptor (CAR, NR1I3) is an important regulator of xenobiotic metabolism and other physiological processes. So far, only few CAR agonists are known and no explicit mechanism has been proposed for their action. Thus, we aimed to generate a 3D QSAR model that could explain the molecular determinants of CAR agonist action. To obtain a sufficient number of agonists that cover a wide range of activity, we applied a virtual screening approach using both structure- and ligand-based methods. We identified 27 novel human CAR agonists on which a 3D QSAR model was generated. The model, complemented by coregulator recruitment and mutagenesis results, suggests a potential activation mechanism for human CAR and may serve to predict potential activation of CAR for compounds emerging from drug development projects or for chemicals undergoing toxicological risk assessment. PMID:18983136

Jyrkkärinne, Johanna; Windshügel, Björn; Rönkkö, Toni; Tervo, Anu J; Küblbeck, Jenni; Lahtela-Kakkonen, Maija; Sippl, Wolfgang; Poso, Antti; Honkakoski, Paavo

2008-11-27

89

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

90

Preclinical Activity of Eltrombopag (SB-497115), an Oral, Nonpeptide Thrombopoietin Receptor Agonist  

PubMed Central

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

2009-01-01

91

Catalposide is a natural agonistic ligand of peroxisome proliferator-activated receptor-{alpha}  

SciTech Connect

Highlights: Black-Right-Pointing-Pointer Catalposide is a novel ligand for PPAR{alpha}. Black-Right-Pointing-Pointer Cell stimulated with catalposide improved fatty acid uptake, regulated target genes in fatty acid {beta}-oxidation and synthesis. Black-Right-Pointing-Pointer Catalposdie reduces hepatic triacylglycerides. Black-Right-Pointing-Pointer Theses demonstrate catalposide could ameliorate hyperlipidemia and hepatic steatosis. -- Abstract: Peroxisome proliferator-activated receptor-alpha (PPAR{alpha}) is a nuclear receptor that regulates the expression of genes related to cellular lipid uptake and oxidation. Thus, PPAR{alpha} agonists may be important in the treatment of hypertriglyceridemia and hepatic steatosis. In this study, we demonstrated that catalposide is a novel natural PPAR{alpha} agonist, identified from reporter gene assay-based activity screening with approximately 900 natural plant and seaweed extracts. Results of time-resolved fluorescence resonance energy transfer analyses suggested that the compound interacted directly with the ligand-binding domain of PPAR{alpha}. Cultured hepatocytes stimulated with catalposide exhibited significantly reduced cellular triglyceride concentrations, by 21%, while cellular uptake of fatty acids was increased, by 70% (P < 0.05). Quantitative PCR analysis revealed that the increase in cellular fatty acid uptake was due to upregulation of fatty acid transporter protein-4 (+19% vs. the control) in cells stimulated with catalposide. Additionally, expression of genes related to fatty acid oxidation and high-density lipoprotein metabolism were upregulated, while that of genes related to fatty acid synthesis were suppressed. In conclusion, catalposide is hypolipidemic by activation of PPAR{alpha} via a ligand-mediated mechanism that modulates the expression of in lipid metabolism genes in hepatocytes.

Lee, Ji Hae; Jun, Hee-jin; Hoang, Minh-Hien; Jia, Yaoyao [Division of Food Bioscience and Technology, College of Life Sciences and Biotechnology, Korea University, Seoul 136-713 (Korea, Republic of) [Division of Food Bioscience and Technology, College of Life Sciences and Biotechnology, Korea University, Seoul 136-713 (Korea, Republic of); Department of Biotechnology, Graduate School of Life Sciences and Biotechnology, Korea University, Seoul 136-713 (Korea, Republic of); Han, Xiang Hua [College of Pharmacy, Chungbuk National University, Cheongju, Chungbuk 361-763 (Korea, Republic of)] [College of Pharmacy, Chungbuk National University, Cheongju, Chungbuk 361-763 (Korea, Republic of); Lee, Dong-Ho [Department of Biotechnology, Graduate School of Life Sciences and Biotechnology, Korea University, Seoul 136-713 (Korea, Republic of)] [Department of Biotechnology, Graduate School of Life Sciences and Biotechnology, Korea University, Seoul 136-713 (Korea, Republic of); Lee, Hak-Ju [Division of Green Business Management, Department of Forest Resources Utilization, Korean Forest Research Institute, Seoul 130-712 (Korea, Republic of)] [Division of Green Business Management, Department of Forest Resources Utilization, Korean Forest Research Institute, Seoul 130-712 (Korea, Republic of); Hwang, Bang Yeon, E-mail: byhwang@chungbuk.ac.kr [College of Pharmacy, Chungbuk National University, Cheongju, Chungbuk 361-763 (Korea, Republic of); Lee, Sung-Joon, E-mail: junelee@korea.ac.kr [Division of Food Bioscience and Technology, College of Life Sciences and Biotechnology, Korea University, Seoul 136-713 (Korea, Republic of) [Division of Food Bioscience and Technology, College of Life Sciences and Biotechnology, Korea University, Seoul 136-713 (Korea, Republic of); Department of Biotechnology, Graduate School of Life Sciences and Biotechnology, Korea University, Seoul 136-713 (Korea, Republic of)

2012-06-15

92

Agonist-induced T cell receptor down-regulation: molecular requirements and dissociation from T cell activation.  

PubMed

T cell receptor (TCR) down-regulation is a consequence of specific receptor engagement and plays an important role in modulating the T cell response. We have investigated the role of protein kinase C (PKC) and protein tyrosine kinases (PTK) in the induction of TCR down-regulation. We report that the mutation of S126 in the CD3-gamma chain that is known to inhibit phorbol-12-myristate 13-acetate-induced TCR down-regulation does not affect down-regulation induced by a specific agonist. In addition, agonist-induced TCR down-regulation is not affected by blockade or depletion of PKC, neither by blockade or lack of PTK, while the same treatments efficiently interfere with T cell activation. These results demonstrate that TCR down-regulation is induced by early events which follow specific engagement by an agonist and can be dissociated from those required for full T cell activation. PMID:9247590

Salio, M; Valitutti, S; Lanzavecchia, A

1997-07-01

93

Liver X Receptor Agonists Augment Human Islet Function through Activation of Anaplerotic Pathways and Glycerolipid/Free Fatty Acid Cycling*  

PubMed Central

Recent studies in rodent models suggest that liver X receptors (LXRs) may play an important role in the maintenance of glucose homeostasis and islet function. To date, however, no studies have comprehensively examined the role of LXRs in human islet biology. Human islets were isolated from non-diabetic donors and incubated in the presence or absence of two synthetic LXR agonists, TO-901317 and GW3965, under conditions of low and high glucose. LXR agonist treatment enhanced both basal and stimulated insulin secretion, which corresponded to an increase in the expression of genes involved in anaplerosis and reverse cholesterol transport. Furthermore, enzyme activity of pyruvate carboxylase, a key regulator of pyruvate cycling and anaplerotic flux, was also increased. Whereas LXR agonist treatment up-regulated known downstream targets involved in lipogenesis, we observed no increase in the accumulation of intra-islet triglyceride at the dose of agonist used in our study. Moreover, LXR activation increased expression of the genes encoding hormone-sensitive lipase and adipose triglyceride lipase, two enzymes involved in lipolysis and glycerolipid/free fatty acid cycling. Chronically, insulin gene expression was increased after treatment with TO-901317, and this was accompanied by increased Pdx-1 nuclear protein levels and enhanced Pdx-1 binding to the insulin promoter. In conclusion, our data suggest that LXR agonists have a direct effect on the islet to augment insulin secretion and expression, actions that should be considered either as therapeutic or unintended side effects, as these agents are developed for clinical use. PMID:20007976

Ogihara, Takeshi; Chuang, Jen-Chieh; Vestermark, George L.; Garmey, James C.; Ketchum, Robert J.; Huang, Xiaolun; Brayman, Kenneth L.; Thorner, Michael O.; Repa, Joyce J.; Mirmira, Raghavendra G.; Evans-Molina, Carmella

2010-01-01

94

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

95

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. PMID:23405231

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

2013-01-01

96

Identification of a potent synthetic FXR agonist with an unexpected mode of binding and activation  

SciTech Connect

The farnesoid X receptor (FXR), a member of the nuclear hormone receptor family, plays important roles in the regulation of bile acid and cholesterol homeostasis, glucose metabolism, and insulin sensitivity. There is intense interest in understanding the mechanisms of FXR regulation and in developing pharmaceutically suitable synthetic FXR ligands that might be used to treat metabolic syndrome. We report here the identification of a potent FXR agonist (MFA-1) and the elucidation of the structure of this ligand in ternary complex with the human receptor and a coactivator peptide fragment using x-ray crystallography at 1.9-{angstrom} resolution. The steroid ring system of MFA-1 binds with its D ring-facing helix 12 (AF-2) in a manner reminiscent of hormone binding to classical steroid hormone receptors and the reverse of the pose adopted by naturally occurring bile acids when bound to FXR. This binding mode appears to be driven by the presence of a carboxylate on MFA-1 that is situated to make a salt-bridge interaction with an arginine residue in the FXR-binding pocket that is normally used to neutralize bound bile acids. Receptor activation by MFA-1 differs from that by bile acids in that it relies on direct interactions between the ligand and residues in helices 11 and 12 and only indirectly involves a protonated histidine that is part of the activation trigger. The structure of the FXR:MFA-1 complex differs significantly from that of the complex with a structurally distinct agonist, fexaramine, highlighting the inherent plasticity of the receptor.

Soisson, Stephen M.; Parthasarathy, Gopalakrishnan; Adams, Alan D.; Sahoo, Soumya; Sitlani, Ayesha; Sparrow, Carl; Cui, Jisong; Becker, Joseph W. (Merck)

2008-07-08

97

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

PubMed

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. PMID:22988116

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

2012-10-01

98

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. PMID:22988116

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

2012-01-01

99

The platelet-stimulating effect of adrenaline through alpha 2-adrenergic receptors requires simultaneous activation by a true stimulatory platelet agonist. Evidence that adrenaline per se does not induce human platelet activation in vitro.  

PubMed

The stimulating effect of adrenaline on human platelet phospholipase C (PLC) activation and responses in vitro (shape change, aggregation and dense granule secretion) was investigated with respect to its dependence on exogenously added agonists. All experiments were performed with human gel-filtered platelets pretreated with acetylsalicylic acid to prevent endogenous stimulation by the arachidonate pathway. (1) Preliminary experiments demonstrated the presence of trace amounts of extracellular ADP (0.05-0.58 microM) in non-stimulated platelet suspensions; ADP was effectively converted to ATP by the enzyme system creatine phosphate (CP)/creatine phosphokinase (CPK). (2) The adrenaline-induced optical aggregation and single particle (platelet) disappearance in the presence of trace amounts of ADP were almost abolished by the ADP-scavenger system CP/CPK. (3) The response of CP/CPK-treated thrombin- or platelet-activating factor (PAF)-stimulated platelets was markedly increased by a subsequent addition of adrenaline. When hirudin or BN 50726 was added just prior to adrenaline to terminate the activation by thrombin or PAF, respectively, the stimulating effect of adrenaline was also abolished. (4) CP/CPK-treated, PAF-stimulated platelets rapidly developed decreased responsiveness to a subsequent addition of PAF. When adrenaline was added instead of a second addition of PAF, the stimulating effect of adrenaline was gradually decreased and prevented in parallel with the homologous desensitization of PAF. (5) The weak platelet agonist serotonin by itself induced only shape change in CP/CPK-treated platelets. Adrenaline failed to enhance the extent of this serotonin-induced platelet activation. (6) These results strongly suggest that adrenaline per se is not a platelet agonist in vitro but acts to enhance the stimulation induced by true agonists. PMID:8259557

Steen, V M; Holmsen, H; Aarbakke, G

1993-09-01

100

4-Hydroxydocosahexaenoic acid, a potent peroxisome proliferator-activated receptor ? agonist alleviates the symptoms of DSS-induced colitis  

Microsoft Academic Search

(5E,7Z,10Z,13Z,16Z,19Z)-4-Hydroxy-5,7,10,13,16,19-docosahexaenoic acid (4-OHDHA) is a potential agonist of peroxisome proliferator-activated receptor-? (PPAR?) and antidiabetic agent as has been previously reported. As PPAR? agonists may also have anti-inflammatory functions, in this study, we investigated whether 4-OHDHA has an inhibitory effect on expression of inflammatory genes in vitro and whether 4-OHDHA could relieve the symptoms of dextran sodium sulfate (DSS)-induced colitis in

Keiko Yamamoto; Yuichi Ninomiya; Mioko Iseki; Yutaka Nakachi; Yukiko Kanesaki-Yatsuka; Yu Yamanoue; Toshimasa Itoh; Yasuho Nishii; Nikolai Petrovsky; Yasushi Okazaki

2008-01-01

101

Agonist Activated PKC?II Translocation and Modulation of Cardiac Myocyte Contractile Function  

PubMed Central

Elevated protein kinase C ?II (PKC?II) expression develops during heart failure and yet the role of this isoform in modulating contractile function remains controversial. The present study examines the impact of agonist-induced PKC?II activation on contractile function in adult cardiac myocytes. Diminished contractile function develops in response to low dose phenylephrine (PHE, 100?nM) in controls, while function is preserved in response to PHE in PKC?II-expressing myocytes. PHE also caused PKC?II translocation and a punctate distribution pattern in myocytes expressing this isoform. The preserved contractile function and translocation responses to PHE are blocked by the inhibitor, LY379196 (30?nM) in PKC?II-expressing myocytes. Further analysis showed downstream protein kinase D (PKD) phosphorylation and phosphatase activation are associated with the LY379196-sensitive contractile response. PHE also triggered a complex pattern of end-target phosphorylation in PKC?II-expressing myocytes. These patterns are consistent with bifurcated activation of downstream signaling activity by PKC?II. PMID:23756828

Hwang, Hyosook; Robinson, Dustin; Rogers, Julie B.; Stevenson, Tamara K.; Lang, Sarah E.; Sadayappan, Sakthivel; Day, Sharlene M.; Sivaramakrishnan, Sivaraj; Westfall, Margaret V.

2013-01-01

102

Characterization of AhR agonists reveals antagonistic activity in European herring gull (Larus argentatus) eggs.  

PubMed

European herring gull (Larus argentatus) eggs from two Norwegian islands, Musvær in the south east and Reiaren in Northern Norway, were screened for dioxins, furans, and dioxin-like and selected non-dioxin-like polychlorinated biphenyls (PCBs), and subjected to non-target analysis to try to identify the aryl hydrocarbon receptor (AhR) agonists, responsible for elevated levels measured using the dioxin responsive chemically activated luciferase expression (DR-CALUX) assay. Eggs from Musvær contained chemically calculated toxic equivalent (WHO TEQ) levels of between 109 and 483pgTEQ/glw, and between 82 and 337pgTEQ/glw was determined in eggs from Reiaren. In particular PCB126 contributed highly to the total TEQ (69-82%). In 19 of the 23 samples the calculated WHO TEQ was higher than the TEQCALUX. Using CALUX specific relative effect potencies (REPs), the levels were lower at between 77 and 292pg/glw in eggs from Musvær and between 55 and 223pg/glw in eggs from Reiaren, which was higher than the TEQCALUX in 16 of the 23 samples. However, the means of the REP values and the TEQCALUX were not significantly different. This suggests the presence of compounds that can elicit antagonist effects, with a low binding affinity to the AhR. Non-target analysis identified the presence of hexachlorobenzene (HCB) (quantified at 9.6-185pg/glw) but neither this compound nor high concentrations of PCB126 and non-dioxin-like PCBs could explain the differences between the calculated TEQ or REP values and the TEQCALUX. Even though, for most AhR agonists, the sensitivity of herring gulls is not known, the reported levels can be considered to represent a risk for biological effects in the developing embryo, compared to LC50 values in chicken embryos. For human consumers of herring gull eggs, these eggs contain TEQ levels up to four times higher than the maximum tolerable weekly intake. PMID:25666281

Muusse, Martine; Christensen, Guttorm; Gomes, Tânia; Ko?an, Anton; Langford, Katherine; Tollefsen, Knut Erik; Va?ková, Lenka; Thomas, Kevin V

2015-05-01

103

A selective metabotropic glutamate receptor 7 agonist: Activation of receptor signaling via an allosteric site modulates stress parameters in vivo  

PubMed Central

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 conservation within the family, but no selective pharmacological tool was known. Here we characterize an mGluR7-selective agonist, N,N?-dibenzhydrylethane-1,2-diamine dihydrochloride (AMN082), which directly activates receptor signaling via an allosteric site in the transmembrane domain. At transfected mammalian cells expressing mGluR7, AMN082 potently inhibits cAMP accumulation and stimulates GTP?S binding (EC50-values, 64-290 nM) with agonist efficacies comparable with those of l-2-amino-4-phosphonobutyrate (L-AP4) and superior to those of l-glutamate. AMN082 (?10 ?M) failed to show appreciable activating or inhibitory effects at other mGluR subtypes and selected ionotropic GluRs. Chimeric receptor studies position the binding site of AMN082 in the transmembrane region of mGluR7, and we demonstrate that this allosteric agonist has little, if any, effect on the potency of orthosteric ligands. Here we provide evidence for full agonist activity mediated by the heptahelical domain of family 3 G protein-coupled receptors (which have mGluR-like structure) that may lead to drug development opportunities. Further, AMN082 is orally active, penetrates the blood-brain barrier, and elevates the plasma stress hormones corticosterone and corticotropin in an mGluR7-dependent fashion. Therefore, AMN082 is a valuable tool for unraveling the role of mGluR7 in stress-related CNS disorders. PMID:16339898

Mitsukawa, Kayo; Yamamoto, Rina; Ofner, Silvio; Nozulak, Joachim; Pescott, Oliver; Lukic, Snezana; Stoehr, Natacha; Mombereau, Cedric; Kuhn, Rainer; McAllister, Kevin H.; van der Putten, Herman; Cryan, John F.; Flor, Peter J.

2005-01-01

104

Modulating potency: Physicochemical characteristics are a determining factor of TLR4-agonist nanosuspension activity.  

PubMed

Activity of adjuvanted vaccines is difficult to predict in vitro and in vivo. The wide compositional and conformational range of formulated adjuvants, from aluminum salts to oil-in-water emulsions, makes comparisons between physicochemical and immunological properties difficult. Even within a formulated adjuvant class, excipient selection and concentration can alter potency and physicochemical properties of the mixture. Complete characterization of physicochemical properties of adjuvanted vaccine formulations and relationship to biological response is necessary to move beyond a guess-and-check paradigm toward directed development. Here we present a careful physicochemical characterization of a two-component nanosuspension containing synthetic TLR-4 agonist glucopyranosyl lipid adjuvant (GLA) and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) at various molar ratios. Physicochemical properties were compared with potency, as measured by stimulation of cytokine production in human whole blood. We found a surprising, nonlinear relationship between physicochemical properties and GLA-DPPC ratios that corresponded well with changes in biological activity. We discuss these data in light of the current understanding of TLR4 activation and the conformation-potency relationship in development of adjuvanted vaccines. PMID:24464844

Dowling, Quinton M; Sivananthan, Sandra J; Guderian, Jeff A; Moutaftsi, Magdalini; Chesko, James D; Fox, Christopher B; Vedvick, Thomas S; Kramer, Ryan M

2014-03-01

105

High-affinity peroxisome proliferator-activated receptor ?/?-specific ligands with pure antagonistic or inverse agonistic properties.  

PubMed

Peroxisome proliferator-activated receptor ?/? (PPAR?/?) is a ligand-regulated nuclear receptor with essential functions in metabolism and inflammation. We have synthesized a new derivative [methyl 3-(N-(4-(hexylamino)-2-methoxyphenyl)sulfamoyl)thiophene-2-carboxylate (ST247) structurally related to the published PPAR?/? inhibitory ligand methyl 3-(N-(2-methoxy-4-(phenylamino)phenyl)sulfamoyl)thiophene-2-carboxylate (GSK0660). ST247 has a higher affinity to PPAR?/? than GSK0660, and at equimolar concentrations, it more efficiently 1) induces the interaction with corepressors both in vitro and in vivo, 2) inhibits the agonist-induced transcriptional activity of PPAR?/?, and 3) down-regulates basal level expression of the peroxisome proliferator responsive element-driven PPAR?/? target gene ANGPTL4. Methyl 3-(N-(4-(tert-butylamino)-2-methoxyphenyl)sulfamoyl)thiophene-2-carboxylate (PT-S58), another high-affinity derivative from our series, also efficiently inhibits agonist-induced transcriptional activation, but in contrast to ST247, it does not enhance the interaction of PPAR?/? with corepressors. PT-S58 rather prevents corepressor recruitment triggered by the inverse agonist ST247. These findings classify ST247 as an inverse agonist, whereas PT-S58 is the first pure PPAR?/? antagonist described to date. It is noteworthy that ST247 and PT-S58 are also effective on PPRE-independent functions of PPAR?/?: in monocytic cells, both ligands modulate expression of the activation marker CCL2 in the opposite direction as an established PPAR?/? agonist. The possibility to differentially modulate specific functions of PPAR?/? makes these novel compounds invaluable tools to advance our understanding of PPAR?/? biology. PMID:21862691

Naruhn, Simone; Toth, Philipp M; Adhikary, Till; Kaddatz, Kerstin; Pape, Veronika; Dörr, Stefanie; Klebe, Gerhard; Müller-Brüsselbach, Sabine; Diederich, Wibke E; Müller, Rolf

2011-11-01

106

Effects of ?1-adrenoceptor agonist phenylephrine on swelling-activated chloride currents in human atrial myocytes.  

PubMed

Swelling-activated chloride currents (ICl.swell) play an important role in cardiac electrophysiology and arrhythmogenesis. However, the regulation of these currents has not been clarified to date. In this research, we focused on the function of phenylephrine, an ?1-adrenoceptor agonist, in the regulation of I(Cl.swell) in human atrial myocytes. We recorded I(Cl.swell) evoked by a hypotonic bath solution with the whole-cell patch-clamp technique. We found that I(Cl.swell) increased over time, and it was difficult to achieve absolute steady state. Phenylephrine potentiated I(Cl.swell) from -1.00 ± 0.51 pA/pF at -90 mV and 2.58 ± 1.17 pA/pF at +40 mV to -1.46 ± 0.70 and 3.84 ± 1.67 pA/pF, respectively (P < 0.05, n = 6), and the upward trend in ICl.swell was slowed after washout. This effect was concentration-dependent, and the ?1-adrenoceptor antagonist prazosin shifted the dose-effect curve rightward. Addition of prazosin or the protein kinase C (PKC) inhibitor bisindolylmaleimide (BIM) attenuated the effect of phenylephrine. The PKC activator phorbol 12,13-dibutyrate (PDBu) activated I(Cl.swell) from -1.69 ± 1.67 pA/pF at -90 mV and 5.58 ± 6.36 pA/pF at +40 mV to -2.41 ± 1.95 pA/pF and 7.05 ± 6.99 pA/pF, respectively (P < 0.01 at -90 mV and P < 0.05 at +40 mV; n = 6). In conclusion, the ?1-adrenoceptor agonist phenylephrine augmented I(Cl.swell), a result that differs from previous reports in other animal species. The effect was attenuated by BIM and mimicked by PDBu, which indicates that phenylephrine might modulate I(Cl,swell) in a PKC-dependent manner. PMID:25155614

Li, Yetao; Du, Xinling

2015-02-01

107

Structural determinants of A(3) adenosine receptor activation: nucleoside ligands at the agonist/antagonist boundary.  

PubMed

Mutagenesis of the human A(3) adenosine receptor (AR) suggested that certain amino acid residues contributed differently to ligand binding and activation processes. Here we demonstrated that various adenosine modifications, including adenine substitution and ribose ring constraints, also contributed differentially to these processes. The ligand effects on cyclic AMP production in intact CHO cells expressing the A(3)AR and in receptor binding were compared. Notably, the simple 2-fluoro group alone or 2-chloro in combination with N(6)-substitution dramatically diminished the efficacy of adenosine derivatives, even converting agonist into antagonist. Other affinity-increasing substitutions, including N(6)-(3-iodobenzyl) 4 and the (Northern)-methanocarba 15, also reduced efficacy, except in combination with a flexible 5'-uronamide. 2-Cl-N(6)-(3-iodobenzyl) derivatives, both in the (N)-methanocarba (i.e., of the Northern conformation) and riboside series 18 and 5, respectively, were potent antagonists with little residual agonism. Ring-constrained 2',3'-epoxide derivatives in both riboside and (N)-methanocarba series 13 and 21, respectively, and a cyclized (spiral) 4',5'-uronamide derivative 14 were synthesized and found to be human A(3)AR antagonists. 14 bound potently at both human (26 nM) and rat (49 nM) A(3)ARs. A rhodopsin-based A(3)AR model, containing all domains except the C-terminal region, indicated separate structural requirements for receptor binding and activation for these adenosine analogues. Ligand docking, taking into account binding of selected derivatives at mutant A(3)ARs, featured interactions of TM3 (His95) with the adenine moiety and TMs 6 and 7 with the ribose 5'-region. The 5'-OH group of antagonist N(6)-(3-iodobenzyl)-2-chloroadenosine 5 formed a H-bond with N274 but not with S271. The 5'-substituent of nucleoside antagonists moved toward TM7 and away from TM6. The conserved Trp243 (6.48) side chain, involved in recognition of the classical (nonnucleoside) A(3)AR antagonists but not adenosine-derived ligands, displayed a characteristic movement exclusively upon docking of agonists. Thus, A(3)AR activation appeared to require flexibility at the 5'- and 3'-positions, which was diminished in (N)-methanocarba, spiro, and epoxide analogues, and was characteristic of ribose interactions at TM6 and TM7. PMID:12238926

Gao, Zhan-Guo; Kim, Soo-Kyung; Biadatti, Thibaud; Chen, Wangzhong; Lee, Kyeong; Barak, Dov; Kim, Seong Gon; Johnson, Carl R; Jacobson, Kenneth A

2002-09-26

108

Central activation of the sympathetic nervous system including the adrenals in anaesthetized guinea pigs by the muscarinic agonist talsaclidine  

Microsoft Academic Search

Talsaclidine, a novel M1-receptor selective muscarinic agonist for cholinergic substitution therapy of Alzheimer’s disease, activates the sympathetic\\u000a nervous system in guinea pigs and dogs at the orthosympathic ganglia and the paraganglionic adrenals. Results from guinea\\u000a pigs provide indirect evidence for an additional central site of action. The present investigation in anaesthetized and vagotomized\\u000a guinea pigs intended to demonstrate central activation

A. Walland; M. P. Pieper

1998-01-01

109

BAY 41-2272, a soluble guanylate cyclase agonist, activates human mononuclear phagocytes  

PubMed Central

BACKGROUND AND PURPOSE Phagocyte function is critical for host defense against infections. Defects in phagocytic function lead to several primary immunodeficiencies characterized by early onset of recurrent and severe infections. In this work, we further investigated the effects of BAY 41-2272, a soluble guanylate cyclase (sGC) agonist, on the activation of human peripheral blood monocytes (PBM) and THP-1 cells. EXPERIMENTAL APPROACH THP-1 cells and PBM viability was evaluated by methylthiazoletetrazolium assay; reactive oxygen species production by lucigenin chemiluminescence; gene and protein expression of NAPDH oxidase components by qRT-PCR and Western blot analysis, respectively; phagocytosis and microbicidal activity by co-incubation, respectively, with zymosan and Escherichia coli; and cytokine release by elisa. KEY RESULTS BAY 41-2272, compared with the untreated group, increased spreading of monocytes by at least 35%, superoxide production by at least 50%, and gp91PHOX and p67PHOX gene expression 20 to 40 times, in both PBM and THP-1 cells. BAY 41-2272 also augmented phagocytosis of zymosan particles threefold compared with control, doubled microbicidal activity against E. coli and enhanced the release of TNF-? and IL-12p70 by both PBM and THP-1 cells. Finally, by inhibiting sGC with ODQ, we showed that BAY 41-2272-induced superoxide production and phagocytosis is not dependent exclusively on sGC activation. CONCLUSIONS AND IMPLICATIONS In addition to its ability to induce vasorelaxation and its potential application for therapy of vascular diseases, BAY 41-2272 was shown to activate human mononuclear phagocytes. Hence, it is a novel pro-inflammatory drug that may be useful for controlling infections in the immunocompromised host. PMID:22044316

Soeiro-Pereira, PV; Falcai, A; Kubo, CA; Oliveira-Júnior, EB; Marques, OC; Antunes, E; Condino-Neto, A

2012-01-01

110

The effects of glutamate receptor agonists and antagonists on mouse hypothalamic and hippocampal neuronal activity shown through manganese enhanced MRI.  

PubMed

Manganese enhanced MRI (MEMRI) is an imaging paradigm that can be used to assess neuronal activity in vivo. Here we investigate, through the use of MEMRI, the influence of receptor dynamics on neuronal activity in the hypothalamus and hippocampus focusing on the glutamate receptor signalling system. We demonstrate that intraperitoneal (i.p.) administration of monosodium glutamate (MSG) and the ionotropic glutamate receptor (iGluR) agonists NMDA and AMPA resulted in significantly increased signal intensity (SI) in the arcuate nucleus (ARC), the suprachiasmatic nucleus (SCN) and the CA3 region of the hippocampus of mice consistent with increased neuronal activity. Administration of the NMDA receptor antagonist MK-801 resulted in significantly decreased SI in the paraventricular nucleus (PVN) consistent with decreased neuronal activity. Co-administration of MSG and the AMPA receptor antagonist NBQX attenuated the increase in SI observed in the ARC from MSG alone, suggesting MEMRI may be applicable to the study of receptor dynamics in vivo. We also observed that administration of the various iGluR agonists and antagonists modulated SI in the lateral ventricle and that high dose MSG (300 mg) caused a hitherto unseen enhancement in SI in the entire cortical/subarachnoid region. In conclusion, MEMRI reveals changes in neuronal activity in response to iGluR agonists and antagonists in the CNS in vivo as well as revealing multifaceted effects beyond those attributable to neuronal activity alone. PMID:21925279

Hankir, Mohammed K; Parkinson, James R; Bloom, Stephen R; Bell, Jimmy D

2012-01-16

111

Peroxisome Proliferator-Activated Receptor ? Agonist, HPP593, Prevents Renal Necrosis under Chronic Ischemia  

PubMed Central

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

2013-01-01

112

Adaptability and selectivity of human peroxisome proliferator-activated receptor (PPAR) pan agonists revealed from crystal structures.  

PubMed

Peroxisome proliferator-activated receptors (PPARs) belong to the nuclear hormone receptor family, which is defined as transcriptional factors that are activated by the binding of ligands to their ligand-binding domains (LBDs). Although the three PPAR subtypes display different tissue distribution patterns and distinct pharmacological profiles, they all are essentially related to fatty-acid and glucose metabolism. Since the PPARs share similar three-dimensional structures within the LBDs, synthetic ligands which simultaneously activate two or all of the PPARs could be potent candidates in terms of drugs for the treatment of abnormal metabolic homeostasis. The structures of several PPAR LBDs were determined in complex with synthetic ligands, derivatives of 3-(4-alkoxyphenyl)propanoic acid, which exhibit unique agonistic activities. The PPARalpha and PPARgamma LBDs were complexed with the same pan agonist, TIPP-703, which activates all three PPARs and their crystal structures were determined. The two LBD-ligand complex structures revealed how the pan agonist is adapted to the similar, but significantly different, ligand-binding pockets of the PPARs. The structures of the PPARdelta LBD in complex with an alpha/delta-selective ligand, TIPP-401, and with a related delta-specific ligand, TIPP-204, were also determined. The comparison between the two PPARdelta complexes revealed how each ligand exhibits either a ;dual selective' or ;single specific' binding mode. PMID:19622862

Oyama, Takuji; Toyota, Kenji; Waku, Tsuyoshi; Hirakawa, Yuko; Nagasawa, Naoko; Kasuga, Jun Ichi; Hashimoto, Yuichi; Miyachi, Hiroyuki; Morikawa, Kosuke

2009-08-01

113

NMDA receptor activation strengthens weak electrical coupling in mammalian brain.  

PubMed

Electrical synapses are formed by gap junctions and permit electrical coupling, which shapes the synchrony of neuronal ensembles. Here, we provide a direct demonstration of receptor-mediated strengthening of electrical coupling in mammalian brain. Electrical coupling in the inferior olive of rats was strengthened by activation of NMDA-type glutamate receptors (NMDARs), which were found at synaptic loci and at extrasynaptic loci 20-100 nm proximal to gap junctions. Electrical coupling was strengthened by pharmacological and synaptic activation of NMDARs, whereas costimulation of ionotropic non-NMDAR glutamate receptors transiently antagonized the effect of NMDAR activation. NMDAR-dependent strengthening (1) occurred despite increased input conductance, (2) induced Ca(2+)-influx microdomains near dendritic spines, (3) required activation of the Ca(2+)/calmodulin-dependent protein-kinase II, (4) was restricted to neurons that were weakly coupled, and (5) thus strengthened coupling, mainly between nonadjacent neurons. This provided a mechanism to expand the synchronization of rhythmic membrane potential oscillations by chemical neurotransmitter input. PMID:24656255

Turecek, Josef; Yuen, Genevieve S; Han, Victor Z; Zeng, Xiao-Hui; Bayer, K Ulrich; Welsh, John P

2014-03-19

114

NMDA RECEPTOR ACTIVATION STRENGTHENS WEAK ELECTRICAL COUPLING IN MAMMALIAN BRAIN  

PubMed Central

SUMMARY Electrical synapses are formed by gap junctions and permit electrical coupling that shapes the synchrony of neuronal ensembles. Here, we provide the first direct demonstration of receptormediated strengthening of electrical coupling in mammalian brain. Electrical coupling in the inferior olive of rats was strengthened by activation of NMDA-type glutamate-receptors (NMDARs), which were found at synaptic loci and at extrasynaptic loci 20–100 nm proximal to gap junctions. Electrical coupling was strengthened by pharmacological and synaptic activation of NMDARs, while co-stimulation of ionotropic non-NMDAR glutamate-receptors transiently antagonized the effect of NMDAR activation. NMDAR-dependent strengthening (i) occurred despite increased input conductance, (ii) induced Ca2+-influx microdomains near dendritic spines, (iii) required activation of the Ca2+/calmodulin-dependent protein-kinase II, (iv) was restricted to neurons that were weakly coupled, and thus, (v) strengthened coupling mainly between non-adjacent neurons. This provided a mechanism to expand the synchronization of rhythmic membrane potential oscillations by chemical neurotransmitter input. PMID:24656255

Turecek, Josef; Yuen, Genevieve S.; Han, Victor Z.; Zeng, Xiao-Hui; Bayer, K. Ulrich; Welsh, John P.

2014-01-01

115

Polyacetylenes from Notopterygium incisum–New Selective Partial Agonists of Peroxisome Proliferator-Activated Receptor-Gamma  

PubMed Central

Peroxisome proliferator-activated receptor gamma (PPAR?) is a key regulator of glucose and lipid metabolism and therefore an important pharmacological target to combat metabolic diseases. Since the currently used full PPAR? agonists display serious side effects, identification of novel ligands, particularly partial agonists, is highly relevant. Searching for new active compounds, we investigated extracts of the underground parts of Notopterygium incisum, a medicinal plant used in traditional Chinese medicine, and observed significant PPAR? activation using a PPAR?-driven luciferase reporter model. Activity-guided fractionation of the dichloromethane extract led to the isolation of six polyacetylenes, which displayed properties of selective partial PPAR? agonists in the luciferase reporter model. Since PPAR? activation by this class of compounds has so far not been reported, we have chosen the prototypical polyacetylene falcarindiol for further investigation. The effect of falcarindiol (10 µM) in the luciferase reporter model was blocked upon co-treatment with the PPAR? antagonist T0070907 (1 µM). Falcarindiol bound to the purified human PPAR? receptor with a Ki of 3.07 µM. In silico docking studies suggested a binding mode within the ligand binding site, where hydrogen bonds to Cys285 and Glu295 are predicted to be formed in addition to extensive hydrophobic interactions. Furthermore, falcarindiol further induced 3T3-L1 preadipocyte differentiation and enhanced the insulin-induced glucose uptake in differentiated 3T3-L1 adipocytes confirming effectiveness in cell models with endogenous PPAR? expression. In conclusion, we identified falcarindiol-type polyacetylenes as a novel class of natural partial PPAR? agonists, having potential to be further explored as pharmaceutical leads or dietary supplements. PMID:23630612

Liu, Xin; Noha, Stefan M.; Malainer, Clemens; Kramer, Matthias P.; Cocic, Amina; Kunert, Olaf; Schinkovitz, Andreas; Heiss, Elke H.; Schuster, Daniela

2013-01-01

116

Development of a Peptide-Derived Orally-Active Kappa-Opioid Receptor Agonist Targeting Peripheral Pain  

PubMed Central

Kappa-opioid agonists are particularly efficacious in the treatment of peripheral pain but suffer from central nervous system (CNS)-mediated effects that limit their development. One promising kappa-agonist is the peptidic compound CR665. Although not orally available, CR665 given i.v. exhibits high peripheral to CNS selectivity and benefits patients with visceral and neuropathic pain. In this study we have generated a series of derivatives of CR665 and screened them for oral activity in the acetic acid-induced rat writhing assay for peripheral pain. Five compounds were further screened for specificity of activation of kappa receptors as well as agonism and antagonism at mu and delta receptors, which can lead to off-target effects. All active derivatives engaged the kappa receptor with EC50s in the low nM range while agonist selectivity for kappa over mu or delta was >11,000-200,000-fold. No antagonist activity was detected. One compound was chosen for further analysis (Compound 9). An oral dose response of 9 in rats yielded an EC50 of 4.7 mg/kg, approaching a druggable level for an oral analgesic. To assess the peripheral selectivity of this compound an i.v. dose response in rats was assessed in the writhing assay and hotplate assay (an assay of CNS-mediated pain). The EC50 in the writhing assay was 0.032 mg/kg while no activity was detectable in the hotplate assay at doses as high as 30 mg/kg, indicating a peripheral selectivity of >900-fold. We propose that compound 9 is a candidate for development as an orally-available peripherally-restricted kappa agonist. PMID:24222801

Hughes, Jr, Francis M.; Shaner, Brooke E.; Brower, Justin O.; Woods, R. Jeremy; Dix, Thomas A.

2013-01-01

117

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. PMID:20337855

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

2010-01-01

118

Peroxisome Proliferator-Activated Receptor? Agonists Differentially Regulate Inhibitor of DNA Binding Expression in Rodents and Human Cells  

PubMed Central

Inhibitor of DNA binding (Id2) is a helix-loop-helix (HLH) transcription factor that participates in cell differentiation and proliferation. Id2 has been linked to the development of cardiovascular diseases since thiazolidinediones, antidiabetic agents and peroxisome proliferator-activated receptor (PPAR) gamma agonists, have been reported to diminish Id2 expression in human cells. We hypothesized that PPAR? activators may also alter Id2 expression. Fenofibrate diminished hepatic Id2 expression in both late pregnant and unmated rats. In 24 hour fasted rats, Id2 expression was decreased under conditions known to activate PPAR?. In order to determine whether the fibrate effects were mediated by PPAR?, wild-type mice and PPAR?-null mice were treated with Wy-14,643 (WY). WY reduced Id2 expression in wild-type mice without an effect in PPAR?-null mice. In contrast, fenofibrate induced Id2 expression after 24 hours of treatment in human hepatocarcinoma cells (HepG2). MK-886, a PPAR? antagonist, did not block fenofibrate-induced activation of Id2 expression, suggesting a PPAR?-independent effect was involved. These findings confirm that Id2 is a gene responsive to PPAR? agonists. Like other genes (apolipoprotein A-I, apolipoprotein A-V), the opposite directional transcriptional effect in rodents and a human cell line further emphasizes that PPAR? agonists have different effects in rodents and humans. PMID:22701468

González, María del Carmen; Corton, J. Christopher; Acero, Nuria; Muñoz-Mingarro, Dolores; Quirós, Yolanda; Álvarez-Millán, Juan José; Herrera, Emilio; Bocos, Carlos

2012-01-01

119

Peroxisome proliferator-activated receptor? agonists differentially regulate inhibitor of DNA binding expression in rodents and human cells.  

PubMed

Inhibitor of DNA binding (Id2) is a helix-loop-helix (HLH) transcription factor that participates in cell differentiation and proliferation. Id2 has been linked to the development of cardiovascular diseases since thiazolidinediones, antidiabetic agents and peroxisome proliferator-activated receptor (PPAR) gamma agonists, have been reported to diminish Id2 expression in human cells. We hypothesized that PPAR? activators may also alter Id2 expression. Fenofibrate diminished hepatic Id2 expression in both late pregnant and unmated rats. In 24 hour fasted rats, Id2 expression was decreased under conditions known to activate PPAR?. In order to determine whether the fibrate effects were mediated by PPAR?, wild-type mice and PPAR?-null mice were treated with Wy-14,643 (WY). WY reduced Id2 expression in wild-type mice without an effect in PPAR?-null mice. In contrast, fenofibrate induced Id2 expression after 24 hours of treatment in human hepatocarcinoma cells (HepG2). MK-886, a PPAR? antagonist, did not block fenofibrate-induced activation of Id2 expression, suggesting a PPAR?-independent effect was involved. These findings confirm that Id2 is a gene responsive to PPAR? agonists. Like other genes (apolipoprotein A-I, apolipoprotein A-V), the opposite directional transcriptional effect in rodents and a human cell line further emphasizes that PPAR? agonists have different effects in rodents and humans. PMID:22701468

González, María Del Carmen; Corton, J Christopher; Acero, Nuria; Muñoz-Mingarro, Dolores; Quirós, Yolanda; Alvarez-Millán, Juan José; Herrera, Emilio; Bocos, Carlos

2012-01-01

120

Distinct mechanisms of glucose lowering by specific agonists for peroxisomal proliferator activated receptor gamma and retinoic acid X receptors.  

PubMed

Agonists for the nuclear receptor peroxisomal proliferator-activated receptor-gamma (PPARgamma) and its heterodimeric partner, retinoid X receptor (RXR), are effective agents for the treatment of type 2 diabetes. To gain insight into the antidiabetic action of these compounds, we treated female Zucker diabetic rats (ZFF) with AGN194204, which we show to be a homodimer-specific RXR agonist, or the PPARgamma agonist, troglitazone. Hyperinsulinemic-euglycemic clamps in ZFF showed that troglitazone and AGN194204 reduced basal endogenous glucose production (EGP) approximately 30% and doubled the insulin suppression of EGP. AGN194204 had no effect on peripheral glucose utilization, whereas troglitazone increased insulin-stimulated glucose utilization by 50%, glucose uptake into skeletal muscle by 85%, and de novo skeletal muscle glycogen synthesis by 300%. Troglitazone increased skeletal muscle Irs-1 and phospho-Akt levels following in vivo insulin treatment, whereas AGN194204 increased hepatic Irs-2 and insulin stimulated phospho-Akt in liver. Gene profiles of AGN194204-treated mouse liver analyzed by Ingenuity Pathway Analysis identified increases in fatty acid synthetic genes, including Srebp-1 and fatty acid synthase, a pathway previously shown to be induced by RXR agonists. A network of down-regulated genes containing Foxa2, Foxa3, and G-protein subunits was identified, and decreases in these mRNA levels were confirmed by quantitative reverse transcription-PCR. Treatment of HepG2 cells with AGN194204 resulted in inhibition of glucagon-stimulated cAMP accumulation suggesting the G-protein down-regulation may provide an additional mechanism for hepatic insulin sensitization by RXR. These studies demonstrate distinct molecular events lead to insulin sensitization by high affinity RXR and PPARgamma agonists. PMID:16179348

Li, Xiangquan; Hansen, Polly A; Xi, Li; Chandraratna, Roshantha A S; Burant, Charles F

2005-11-18

121

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

122

Identification of the human receptor activity-modifying protein 1 domains responsible for agonist binding specificity.  

PubMed

When co-expressed with receptor activity-modifying protein (RAMP) 1, calcitonin receptor-like receptor (CRLR) can function as a receptor for both calcitonin gene-related peptide (CGRP) and adrenomedullin (AM). To investigate the structural determinants of ligand binding specificity, we examined the extracellular domain of human (h) RAMP1 using various deletion mutants. Co-expression of the hRAMP1 mutants with hCRLR in HEK-293 cells revealed that deletion of residues 91-94, 96-100, or 101-103 blocked [125I]CGRP binding and completely abolished intracellular cAMP accumulation normally elicited by CGRP or AM. On the other hand, the deletion of residues 78-80 or 88-90 significantly attenuated only AM-evoked responses. In all of these cases, the receptor heterodimers were fully expressed at the cell surface. Substituting alanine for residues 91-103 one at a time had little effect on CGRP-induced responses, indicating that although this segment is essential for high affinity agonist binding to the receptors, none of the residues directly interacts with either CGRP or AM. This finding suggests that RAMPs probably determine ligand specificity by contributing to the structure of the ligand-binding pocket or by allosteric modulation of the conformation of the receptor. Interestingly, the L94A mutant up-regulated surface expression of the receptor heterodimer to a greater degree than wild-type hRAMP1, thereby increasing CGRP binding and signaling. L94A also significantly increased cell surface expression of the hRAMP1 deletion mutant D101-103 when co-transfected with hCRLR, and expression of a L94A/D101-103 double mutant markedly attenuated the activity of endogenous RAMP1 in HEK-293T cells. PMID:12684503

Kuwasako, Kenji; Kitamura, Kazuo; Nagoshi, Yasuko; Cao, Yuan-Ning; Eto, Tanenao

2003-06-20

123

Effects of peripheral ?, ?, and ?-opioid receptor agonists on the levels of anxiety and motor activity of rats.  

PubMed

The effects of intragastric administration of ?-, ?, and ?-opioid receptor agonists DAMGO, DADLE, and ICI 204,448, respectively, on the anxiety and motor activity of rats in an elevated plus-maze were studied. Peripheral administration of ICI 204,448 produced an anxiolytic effect, but had no effect on motor activity of rats. DAMGO and DADLE reduced motor activity; DADLE also increased anxiety. The data on the opposite effects of ICI 204,448 and DADLE on anxiety confirmed our previous hypothesis on the interactions between the central and peripheral components of the endogenous opioid system. PMID:23113268

Alexeeva, E V; Nazarova, G A; Sudakov, S K

2012-09-01

124

Peroxisome proliferator-activated receptor-gamma agonist rosiglitazone attenuates postincisional pain by regulating macrophage polarization  

SciTech Connect

Highlights: Black-Right-Pointing-Pointer Rosiglitazone attenuated postincisional pain. Black-Right-Pointing-Pointer Rosiglitazone alters macrophage polarization to F4/80{sup +}CD206{sup +} M2 macrophages at the incisional sites. Black-Right-Pointing-Pointer Transplantation of rosiglitazone-treated macrophages produced analgesic effects. -- Abstract: Acute inflammation triggered by macrophage infiltration to injured tissue promotes wound repair and may induce pain hypersensitivity. Peroxisome proliferator-activated receptor {gamma} (PPAR){gamma} signaling is known to regulate heterogeneity of macrophages, which are often referred to as classically activated (M1) and alternatively activated (M2) macrophages. M1 macrophages have considerable antimicrobial activity and produce a wide variety of proinflammatory cytokines. In contrast, M2 macrophages are involved in anti-inflammatory and homeostatic functions linked to wound healing and tissue repair. Although it has been suggested that PPAR{gamma} agonists attenuate pain hypersensitivity, the molecular mechanism of macrophage-mediated effects of PPAR{gamma} signaling on pain development has not been explored. In this study, we investigated the link between the phenotype switching of macrophage polarization induced by PPAR{gamma} signaling and the development of acute pain hypersensitivity. Local administration of rosiglitazone significantly ameliorated hypersensitivity to heat and mechanical stimuli, and paw swelling. Consistent with the down-regulation of nuclear factor {kappa}B (NF{kappa}B) phosphorylation by rosiglitazone at the incisional sites, the number of F4/80{sup +}iNOS{sup +} M1 macrophages was decreased whereas numbers of F4/80{sup +}CD206{sup +} M2 macrophages were increased in rosiglitazone-treated incisional sites 24 h after the procedure. In addition, gene induction of anti-inflammatory M2-macrophage-associated markers such as arginase1, FIZZ1 and interleukin (IL)-10 were significantly increased, whereas M1-macrophage-related molecules such as integrin {alpha}X, IL-1{beta}, MIP2{alpha} and leptin were decreased at rosiglitazone-treated incisional sites. Moreover, transplantation of rosiglitazone-treated peritoneal macrophages into the incisional sites significantly attenuated hyperalgesia. We speculate that local administration of rosiglitazone significantly alleviated the development of postincisional pain, possibly through regulating macrophage polarity at the inflamed site. PPAR{gamma} signaling in macrophages may be a potential therapeutic target for the treatment of acute pain development.

Hasegawa-Moriyama, Maiko, E-mail: hase-mai@m3.kufm.kagoshima-u.ac.jp [Department of Anesthesiology and Critical Care Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520 (Japan)] [Department of Anesthesiology and Critical Care Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520 (Japan); Ohnou, Tetsuya; Godai, Kohei; Kurimoto, Tae; Nakama, Mayo; Kanmura, Yuichi [Department of Anesthesiology and Critical Care Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520 (Japan)] [Department of Anesthesiology and Critical Care Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520 (Japan)

2012-09-14

125

5HT 1A agonists induce hippocampal theta activity in freely moving cats: role of presynaptic 5HT 1A receptors  

Microsoft Academic Search

Electrical activity in the dorsal hippocampus was recorded in freely moving cats in response to intravenous administration of 5-HT1A agonist and antagonist drugs. Administration of low doses of the selective 5-HT1A agonists 8-OH-DPAT (5–20 ?g\\/kg) and ipsapirone (20–100 ?g\\/kg) produced rhythmic slow activity (theta) in the hippocampal EEG within 30 s. Similar effects were observed with BMY 7378 (20 and

Franco Marrosu; Casimir A. Fornal; Christine W. Metzler; Barry L. Jacobs

1996-01-01

126

Exploring pharmacological activities and signaling of morphinans substituted in position 6 as potent agonists interacting with the ? opioid receptor  

PubMed Central

Background Opioid analgesics are the most effective drugs for the treatment of moderate to severe pain. However, they also produce several adverse effects that can complicate pain management. The ? opioid (MOP) receptor, a G protein-coupled receptor, is recognized as the opioid receptor type which primarily mediates the pharmacological actions of clinically used opioid agonists. The morphinan class of analgesics including morphine and oxycodone are of main importance as therapeutically valuable drugs. Though the natural alkaloid morphine contains a C-6-hydroxyl group and the semisynthetic derivative oxycodone has a 6-carbonyl function, chemical approaches have uncovered that functionalizing position 6 gives rise to a range of diverse activities. Hence, position 6 of N-methylmorphinans is one of the most manipulated sites, and is established to play a key role in ligand binding at the MOP receptor, efficacy, signaling, and analgesic potency. We have earlier reported on a chemically innovative modification in oxycodone resulting in novel morphinans with 6-acrylonitrile incorporated substructures. Results This study describes in vitro and in vivo pharmacological activities and signaling of new morphinans substituted in position 6 with acrylonitrile and amido functions as potent agonists and antinociceptive agents interacting with MOP receptors. We show that the presence of a 6-cyano group in N-methylmorphinans has a strong influence on the binding to the opioid receptors and post-receptor signaling. One 6-cyano-N-methylmorphinan of the series was identified as the highest affinity and most selective MOP agonist, and very potent in stimulating G protein coupling and intracellular calcium release through the MOP receptor. In vivo, this MOP agonist showed to be greatly effective against thermal and chemical nociception in mice with marked increased antinociceptive potency than the lead molecule oxycodone. Conclusion Development of such novel chemotypes by targeting position 6 provides valuable insights on ligand-receptor interaction and molecular mode of action, and may aid in identification of opioid therapeutics with enhanced analgesic properties and fewer undesirable effects. PMID:25059282

2014-01-01

127

Phosphorylation\\/Dephosphorylation of Androgen Receptor as a Determinant of Androgen Agonistic or Antagonistic Activity  

Microsoft Academic Search

Protein phosphorylation\\/dephosphorylation is an important posttranslational modification that plays a critical role in signal transduction. The androgen receptor (AR) is under such control. We demonstrate that androgen receptor phosphorylation determines whether or not AR ligands perform as agonists or antagonists in LNCaP cells. Androgen receptor ligands (such as dihydrotestosterone and ?-estradiol) stimulate receptor expression and phosphorylation and, as a result,

Long G. Wang; Xiao M. Liu; Willi Kreis; Daniel R. Budman

1999-01-01

128

Diabetes or peroxisome proliferator-activated receptor alpha agonist increases mitochondrial thioesterase I activity in heart  

Technology Transfer Automated Retrieval System (TEKTRAN)

Peroxisome proliferator-activated receptor alpha (PPAR alpha) is a transcriptional regulator of the expression of mitochondrial thioesterase I (MTE-I) and uncoupling protein 3 (UCP3), which are induced in the heart at the mRNA level in response to diabetes. Little is known about the regulation of pr...

129

Design, synthesis, and structure-activity relationship of novel opioid ? receptor selective agonists: ?-iminoamide derivatives with an azabicyclo[2.2.2]octene skeleton.  

PubMed

The ?-iminoamide derivative, 4b was designed and synthesized as a novel agonist selective for the opioid ? receptor. The amide was constrained to an orientation horizontal to the F-ring of the azabicyclo[2.2.2]octane skeleton, which remarkably improved its affinity, selectivity, and agonistic activity for the ? receptor. This finding was newly established by chemical modification of the nitrogen atom at the 8-position in the azabicyclo[2.2.2]octane skeleton. This modification would never have been found with KNT-63, a derivation of oxabicyclo[2.2.2]octane. These results may provide valuable information for the future development of novel ? selective agonists. PMID:25283554

Watanabe, Yoshikazu; Kitazawa, Shota; Fujii, Hideaki; Nemoto, Toru; Hirayama, Shigeto; Iwai, Takashi; Gouda, Hiroaki; Hirono, Shuichi; Nagasea, Hiroshi

2014-11-01

130

Peroxisome proliferator-activated receptor-? agonist fenofibrate regulates IL-12 family cytokine expression in the CNS: relevance to multiple sclerosis  

PubMed Central

The interleukin-12 (IL-12) family of cytokines which includes IL-12, IL-23, and IL-27 play critical roles in T cell differentiation and are important modulators of multiple sclerosis and experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. Previously, we demonstrated that peroxisome proliferator-activated receptor (PPAR) -? agonists suppress the development of EAE. The present studies demonstrated that the PPAR-? agonist fenofibrate inhibited the secretion of IL-12p40, IL-12p70 (p35/p40), IL-23 (p19/p40), and IL-27p28 by lipopolysaccharide-stimulated microglia. The cytokines interferon-? and tumor necrosis factor-? also stimulated IL-12 p40 and IL-27 p28 expression by microglia, which was suppressed by fenofibrate. Furthermore, fenofibrate inhibited microglial expression of CD14 which plays a critical role in TLR signaling, suggesting a mechanism by which this PPAR-? agonist regulates the production of these pro-inflammatory molecules. In addition, fenofibrate suppressed the secretion of IL-12p40, IL-23, and IL-27p28 by lipopolysaccharide-stimulated astrocytes. Importantly, fenofibrate suppression of EAE was associated with decreased expression of IL-12 family cytokine mRNAs as well as mRNAs encoding TLR4, CD14, and MyD88 known to play critical roles in MyD88-dependent TLR signaling. These novel observations suggest that PPAR-? agonists including fenofibrate may modulate the development of EAE, at least in part, by suppressing the production of IL-12 family cytokines and MyD88-dependent signaling. PMID:17727629

Xu, Jihong; Racke, Michael K.; Drew, Paul D.

2008-01-01

131

Amyloid-? pathology and APOE genotype modulate retinoid X receptor agonist activity in vivo.  

PubMed

Previous data demonstrate that bexarotene (Bex), retinoid X receptor (RXR) agonist, reduces soluble and insoluble amyloid-? (A?) in Alzheimer disease (AD)-transgenic mice either by increasing the levels of mouse apolipoprotein E (apoE) or increasing ABCA1/ABCG1-induced apoE lipoprotein association/lipidation. However, although the mechanism of action of RXR agonists remains unclear, a major concern for their use is human (h)-APOE4, the greatest AD genetic risk factor. If APOE4 imparts a toxic gain-of-function, then increasing apoE4 may increase soluble A?, likely the proximal AD neurotoxin. If the APOE4 loss-of-function is lipidation of apoE4, then induction of ABCA1/ABCG1 may be beneficial. In novel EFAD-Tg mice (overexpressing h-A?42 with h-APOE), levels of soluble A? (A?42 and oligomeric A?) are highest in E4FAD hippocampus (HP) > E3FAD-HP > E4FAD cortex (CX) > E3FAD-CX, whereas levels of lipoprotein-associated/lipidated apoE have the opposite pattern (6 months). In E4FAD-HP, short-term RXR agonist treatment (Bex or LG100268; 5.75-6 months) increased ABCA1, apoE4 lipoprotein-association/lipidation, and apoE4/A? complex, decreased soluble A?, and increased PSD95. In addition, hydrogel delivery, which mimics low sustained release, was equally effective as gavage for Bex and LG100268. RXR agonists induced no beneficial effects in the E4FAD-HP in a prevention protocol (5-6 months) and actually increased soluble A? levels in E3FAD-CX and E4FAD-CX with the short-term protocol, possibly the result of systemic hepatomegaly. Thus, RXR agonists address the loss-of-function associated with APOE4 and exacerbated by A? pathology, i.e. low levels of apoE4 lipoprotein association/lipidation. Further studies are vital to address whether RXR agonists are an APOE4-specific AD therapeutic and the systemic side effects that limit translational application. PMID:25217640

Tai, Leon M; Koster, Kevin P; Luo, Jia; Lee, Sue H; Wang, Yue-ting; Collins, Nicole C; Ben Aissa, Manel; Thatcher, Gregory R J; LaDu, Mary Jo

2014-10-31

132

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. PMID:21299227

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

2011-01-01

133

Differential Pathway Coupling of the Activated Insulin Receptor Drives Signaling Selectivity by XMetA, an Allosteric Partial Agonist Antibody.  

PubMed

The monoclonal antibody XMetA is an allosteric partial agonist of the insulin receptor (IR), which activates the metabolic Akt kinase signaling pathway while having little or no effect on the mitogenic extracellular signal-regulated kinase (ERK) signaling pathway. To investigate the nature of this selective signaling, we have conducted a detailed investigation of XMetA to evaluate specific phosphorylation and activation of IR, Akt, and ERK in Chinese hamster ovary cell lines expressing either the short or long isoform of the human IR. Insulin activated both pathways, but the phosphorylation of Akt was more sensitive to the hormone than the phosphorylation of ERK. Maximally effective concentrations of XMetA elicited phosphorylation patterns similar to 40-100 pM insulin, which were sufficient for robust Akt phosphorylation, but had little effect on ERK phosphorylation. These data indicate that the preferential signaling of XMetA is due to an innate difference in pathway sensitivity of Akt versus ERK responses to IR activation and partial agonism by XMetA, rather than a separate pathway-biased mechanism. The metabolic selectivity of partial IR agonists like XMetA, if recapitulated in vivo, may be a desirable feature of therapeutic agents designed to regulate blood glucose levels while minimizing undesirable outcomes of excessive IR mitogenic activation. PMID:25613982

Bedinger, Daniel H; Goldfine, Ira D; Corbin, John A; Roell, Marina K; Adams, Sean H

2015-04-01

134

Chemical synthesis, docking studies and biological effects of a pan peroxisome proliferator-activated receptor agonist and cyclooxygenase inhibitor.  

PubMed

The compound (5Z)-5-[(5-bromo-1H-indol-3-yl)methylene]-3-(4-chlorobenzyl)-thiazolidine-2,4-dione (LYSO-7) was synthesised in order to obtain a new type of anti-inflammatory drug, designed with hybrid features to inhibit cyclooxygenase (COX) and also to activate peroxisome proliferator-activated receptor (PPAR). Results obtained from docking (in silico) studies corroborated with experimental data, showing the potential affinity between the studied ligand and targets. The specificity of LYSO-7 for COX-enzymes was detected by the inhibition of COX-1 and COX-2 activities by 30% and 20%, respectively. In transactivation reporter gene assays LYSO-07 showed a pan partial agonist effect on the three PPAR subtypes (PPAR?, PPAR? and PPAR?/?). The agonist action on PPAR? was also observed by a pharmacological approach, as the reduction in the Escherichia coli lipopolysaccharide (LPS)-induced interleukin 1 beta (IL-1?) secretion and nitric oxide (NO) production by mouse neutrophils was blocked by GW9962, a specific PPAR? antagonist. Additionally, the in vivo effect was measured by reduced carrageenan-induced neutrophil influx into the subcutaneous tissue of mice. Taken together, these data show that LYSO-7 displays a potent in vivo anti-inflammatory effect during the innate acute response, which is dependent on its associated COX inhibitory activities and PPAR activation. PMID:23305993

Santin, José Roberto; Uchôa, Flávia D T; Lima, Maria do Carmo A; Rabello, Marcelo M; Machado, Isabel Daufenback; Hernandes, Marcelo Z; Amato, Angelica A; Milton, Flora Aparecida; Webb, Paul; Neves, Francisco de Assis Rocha; Galdino, Suely L; Pitta, Ivan Rocha; Farsky, Sandra H P

2013-03-12

135

Toll-Like Receptor 8 Agonist and Bacteria Trigger Potent Activation of Innate Immune Cells in Human Liver  

PubMed Central

The ability of innate immune cells to sense and respond to impending danger varies by anatomical location. The liver is considered tolerogenic but is still capable of mounting a successful immune response to clear various infections. To understand whether hepatic immune cells tune their response to different infectious challenges, we probed mononuclear cells purified from human healthy and diseased livers with distinct pathogen-associated molecules. We discovered that only the TLR8 agonist ssRNA40 selectively activated liver-resident innate immune cells to produce substantial quantities of IFN-?. We identified CD161Bright mucosal-associated invariant T (MAIT) and CD56Bright NK cells as the responding liver-resident innate immune cells. Their activation was not directly induced by the TLR8 agonist but was dependent on IL-12 and IL-18 production by ssRNA40-activated intrahepatic monocytes. Importantly, the ssRNA40-induced cytokine-dependent activation of MAIT cells mirrored responses induced by bacteria, i.e., generating a selective production of high levels of IFN-?, without the concomitant production of TNF-? or IL-17A. The intrahepatic IFN-? production could be detected not only in healthy livers, but also in HBV- or HCV-infected livers. In conclusion, the human liver harbors a network of immune cells able to modulate their immunological responses to different pathogen-associated molecules. Their ability to generate a strong production of IFN-? upon stimulation with TLR8 agonist opens new therapeutic opportunities for the treatment of diverse liver pathologies. PMID:24967632

Ussher, James E.; Sandalova, Elena; Tang, Xin-Zi; Tan-Garcia, Alfonso; To, Natalie; Hong, Michelle; Chia, Adeline; Gill, Upkar S.; Kennedy, Patrick T.; Tan, Kai Chah; Lee, Kang Hoe; De Libero, Gennaro; Gehring, Adam J.; Willberg, Christian B.; Klenerman, Paul; Bertoletti, Antonio

2014-01-01

136

Toll-like receptor 8 agonist and bacteria trigger potent activation of innate immune cells in human liver.  

PubMed

The ability of innate immune cells to sense and respond to impending danger varies by anatomical location. The liver is considered tolerogenic but is still capable of mounting a successful immune response to clear various infections. To understand whether hepatic immune cells tune their response to different infectious challenges, we probed mononuclear cells purified from human healthy and diseased livers with distinct pathogen-associated molecules. We discovered that only the TLR8 agonist ssRNA40 selectively activated liver-resident innate immune cells to produce substantial quantities of IFN-?. We identified CD161(Bright) mucosal-associated invariant T (MAIT) and CD56(Bright) NK cells as the responding liver-resident innate immune cells. Their activation was not directly induced by the TLR8 agonist but was dependent on IL-12 and IL-18 production by ssRNA40-activated intrahepatic monocytes. Importantly, the ssRNA40-induced cytokine-dependent activation of MAIT cells mirrored responses induced by bacteria, i.e., generating a selective production of high levels of IFN-?, without the concomitant production of TNF-? or IL-17A. The intrahepatic IFN-? production could be detected not only in healthy livers, but also in HBV- or HCV-infected livers. In conclusion, the human liver harbors a network of immune cells able to modulate their immunological responses to different pathogen-associated molecules. Their ability to generate a strong production of IFN-? upon stimulation with TLR8 agonist opens new therapeutic opportunities for the treatment of diverse liver pathologies. PMID:24967632

Jo, Juandy; Tan, Anthony T; Ussher, James E; Sandalova, Elena; Tang, Xin-Zi; Tan-Garcia, Alfonso; To, Natalie; Hong, Michelle; Chia, Adeline; Gill, Upkar S; Kennedy, Patrick T; Tan, Kai Chah; Lee, Kang Hoe; De Libero, Gennaro; Gehring, Adam J; Willberg, Christian B; Klenerman, Paul; Bertoletti, Antonio

2014-06-01

137

Comparison of human B cell activation by TLR7 and TLR9 agonists  

Microsoft Academic Search

BACKGROUND: Human B cells and plasmacytoid dendritic cells (pDC) are the only cells known to express both TLR7 and TLR9. Plasmacytoid dendritic cells are the primary IFN-? producing cells in response to TLR7 and TLR9 agonists. The direct effects of TLR7 stimulation on human B cells is less understood. The objective of this study was to compare the effects of

John A Hanten; John P Vasilakos; Christie L Riter; Lori Neys; Kenneth E Lipson; Sefik S Alkan; Woubalem Birmachu

2008-01-01

138

Cell type-dependent agonist/antagonist activities of polybrominated diphenyl ethers.  

PubMed

There have been many concerns expressed regarding the possible adverse effects of thyroid hormone-disrupting chemicals including polychlorinated biphenyls and polybrominated diphenyl ethers (PBDEs), since thyroid hormones play crucial roles in normal vertebrate development. A vast amount of PBDEs have been used as flame retardants for the last two decades and our environment has been contaminated with them. Some PBDEs, especially hydroxylated PBDEs, reportedly show an affinity to the thyroid hormone receptor (TR) and act as thyroid hormone agonists, but in other studies they were reported to inhibit the actions of thyroid hormones. Therefore, in the present study, we investigated the binding affinities of PBDEs and their metabolites to TR and their ability to induce thyroid hormone-responsive transcription using luciferase reporter gene assays in two different cell lines, a pituitary cell line, MtT/E-2, and Chinese hamster ovary (CHO) cells. The binding assay showed that many of the examined PBDEs have significant affinity to TR. Interestingly, some of these PBDEs, such as 4'-OH-BDE-17 and 2'-OH-BDE-28, acted as agonists in the reporter gene assay in MtT/E-2 cells, while they acted as antagonists in CHO cells. Our results demonstrated that whether PBDEs and their metabolites are TR agonists or antagonists depends on the cell type used in the assay, which may suggest that the thyroid hormone-disrupting actions of PBDEs differ among target tissues or species. PMID:24076165

Nakamura, N; Matsubara, K; Sanoh, S; Ohta, S; Uramaru, N; Kitamura, S; Yamaguchi, M; Sugihara, K; Fujimoto, N

2013-11-25

139

Inhibition of indoleamine 2,3-dioxygenase activity enhances the anti-tumour effects of a Toll-like receptor 7 agonist in an established cancer model.  

PubMed

Toll-like receptor (TLR) agonists have been shown to have anti-tumour activity in basic research and clinical studies. However, TLR agonist monotherapy does not sufficiently eliminate tumours. Activation of the innate immune response by TLR agonists is effective at driving adaptive immunity via interleukin-12 (IL-12) or IL-1, but is counteracted by the simultaneous induction of immunosuppressive cytokines and other molecules, including IL-10, transforming growth factor-?, and indoleamine 2,3-dioxygenase (IDO). In the present study, we evaluated the anti-cancer effect of the TLR7 agonist, imiquimod (IMQ), in the absence of IDO activity. The administration of IMQ in IDO knockout (KO) mice inoculated with tumour cells significantly suppressed tumour progression compared with that in wild-type (WT) mice, and improved the survival rate. Moreover, injection with IMQ enhanced the tumour antigen-specific T helper type 1 response in IDO-KO mice with tumours. Combination therapy with IMQ and an IDO inhibitor also significantly inhibited tumour growth. Our results indicated that the enhancement of IDO expression with TLR agonists in cancer treatment might impair host anti-tumour immunity while the inhibition of IDO could enhance the therapeutic efficacy of TLR agonists via the increase of T helper type 1 immune response. PMID:25322876

Ito, Hiroyasu; Ando, Tatsuya; Arioka, Yuko; Saito, Kuniaki; Seishima, Mitsuru

2015-04-01

140

Toll-like Receptor-8 Agonistic Activities in C2, C4, and C8 Modified Thiazolo[4,5-c]quinolines  

PubMed Central

Toll-like receptor (TLR)-8 agonists typified by the 2-alkylthiazolo[4,5-c]quinolin-4-amine (CL075) chemotype are uniquely potent in activating adaptive immune responses by inducing robust production of T helper 1-polarizing cytokines, suggesting that TLR8-active compounds could be promising candidate vaccine adjuvants, especially for neonatal vaccines. Alkylthiazoloquinolines with methyl, ethyl, propyl and butyl groups at C2 displayed comparable TLR8-agonistic potencies; activity diminished precipitously in the C2-pentyl compound, and higher homologues were inactive. The C2-butyl compound was unique in possessing substantial TLR7-agonistic activity. Analogues with branched alkyl groups at C2 displayed poor tolerance of terminal steric bulk. Virtually all modifications at C8 led to abrogation of agonistic activity. Alkylation on the C4-amine was not tolerated, whereas N-acyl analogues with short acyl groups (other than acetyl) retained TLR8 agonistic activity, but were substantially less water-soluble. Immunization in rabbits with a model subunit antigen adjuvanted with the lead C2-butyl thiazoloquinoline showed enhancements of antigen-specific antibody titers. PMID:23314908

Kokatla, Hari Prasad; Yoo, Euna; Salunke, Deepak B.; Sil, Diptesh; Ng, Cameron F.; Balakrishna, Rajalakshmi; Malladi, Subbalakshmi S.; Fox, Lauren M.; David, Sunil A.

2013-01-01

141

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

142

Repeated morphine treatment-mediated hyperalgesia, allodynia and spinal glial activation are blocked by co-administration of a selective cannabinoid receptor type-2 agonist  

PubMed Central

Spinal glial activation has been implicated in sustained morphine-mediated paradoxical pain sensitization. Since activation of glial CB2 cannabinoid receptors attenuates spinal glial activation in neuropathies, we hypothesized that CB2 agonists may also attenuate sustained morphine–mediated spinal glial activation and pain sensitization. Our data indicate that co-administration of a CB2-selective agonist (AM 1241) attenuates morphine (intraperitoneal; twice daily; 6 days)-mediated thermal hyperalgesia and tactile allodynia in rats. A CB2 (AM 630) but not a CB1 (AM 251) antagonist mitigated this effect. AM 1241 co-treatment also attenuated spinal astrocyte and microglial marker and pro-inflammatory mediator (IL-1?, TNF?) immunoreactivities in morphine-treated rats, suggesting that CB2 agonists may be useful to prevent the neuroinflammatory consequences of sustained morphine treatment. PMID:22285397

Tumati, Suneeta; Largent-Milnes, Tally M; Keresztes, Attila; Ren, Jiyang; Roeske, William R; Vanderah, Todd W.; Varga, Eva V

2012-01-01

143

Synthesis, pharmacological characterization, and structure-activity relationship studies of small molecular agonists for the orphan GPR88 receptor.  

PubMed

GPR88 is an orphan G-protein-coupled receptor (GPCR) enriched in the striatum. Genetic deletion and gene expression studies have suggested that GPR88 plays an important role in the regulation of striatal functions and is implicated in psychiatric disorders. The signal transduction pathway and receptor functions of GPR88, however, are still largely unknown due to the lack of endogenous and synthetic ligands. In this paper, we report the synthesis of a GPR88 agonist 2-PCCA and its pure diastereomers, which were functionally characterized in both transiently and stably expressing GPR88 HEK293 cells. 2-PCCA inhibited isoproterenol-stimulated cAMP accumulation in a concentration-dependent manner in cells expressing GPR88 but not in the control cells, suggesting that the observed cAMP inhibition is mediated through GPR88 and that GPR88 is coupled to G?i. 2-PCCA did not induce calcium mobilization in GPR88 cells, indicating no G?q-mediated response. A structure-activity relationship (SAR) study of 2-PCCA was also conducted to explore the key structural features for GPR88 agonist activity. PMID:24793972

Jin, Chunyang; Decker, Ann M; Huang, Xi-Ping; Gilmour, Brian P; Blough, Bruce E; Roth, Bryan L; Hu, Yang; Gill, Joseph B; Zhang, X Peter

2014-07-16

144

14?-O-Cinnamoylnaltrexone and related dihydrocodeinones are mu opioid receptor partial agonists with predominant antagonist activity  

PubMed Central

14-O-cinnamoyl esters of naltrexone (6) were synthesised and evaluated in isolated tissue assays in vitro and in vivo in mouse antinociceptive assays. Their predominant opioid receptor activity was mu receptor (MOR) antagonism but the unsubstituted cinnamoyl derivative (6a) and the p-methylcinnamoyl derivative (6c) had partial MOR agonist activity in vitro and in vivo. When compared to the equivalent 14-cinnamoylaminomorphinones (5) the cinnamoyloxy morphinones (6) as MOR antagonists had shorter duration of action and were less effective as pseudoirreversible antagonists. The antinociceptive activity of the cinnamoyloxycodeinones (7) was not significantly greater than that of the morphinones (6) but they showed no evidence of any pseudoirreversible MOR antagonism. In both respects these profiles differed from those of the equivalent 14-cinnamoylaminocodeinones (4). PMID:19253983

Moynihan, H.; Jales, A.R.; Greedy, B.M.; Rennison, D.; Broadbear, J.H.; Purington, L.; Traynor, J.R.; Woods, J.H.; Lewis, J.W; Husbands, S.M.

2011-01-01

145

The benzodiazepine diazepam potentiates responses of ?1?2?2 ?-aminobutyric acid type A receptors activated by either ?-aminobutyric acid or allosteric agonists  

PubMed Central

Background The ?-aminobutyric acid type A receptor is target for several anesthetics, anticonvulsants, anxiolytics and sedatives. Neurosteroids, barbiturates and etomidate both potentiate responses to ?-aminobutyric acid (GABA) and allosterically activate the receptor. We examined the ability of a benzodiazepine, diazepam, to potentiate responses to allosteric agonists. Methods The ?-aminobutyric acid type A receptors were expressed in human embryonic kidney 293 cells, and studied using whole-cell and single-channel patch clamp. The receptors were activated by the orthosteric agonist GABA, and allosteric agonists pentobarbital, etomidate and alfaxalone. Results Diazepam is equally potent at enhancing responses to orthosteric and allosteric agonists. Diazepam EC50s were 25±4, 26±6, 33±6, and 26±3 nM for receptors activated by GABA, pentobarbital, etomidate, and alfaxalone, respectively (mean±S.D., 5–6 cells at each condition). Mutations to the benzodiazepine-binding site (?1(H101C), ?2(R144C), ?2(R197C)) reduced or removed potentiation for all agonists, and an inverse agonist at the benzodiazepine site reduced responses to all agonists. Single-channel data elicited by GABA demonstrate that in the presence of 1 ?M diazepam the prevalence of the longest open-time component is increased from 13±7 (mean±S.D., n=5 patches) to 27±8 % (n=3 patches) and the rate of channel closing is decreased from 129±28 s?1 to 47±6 s?1 (mean±S.D.) Conclusions We conclude that benzodiazepines do not act by enhancing affinity of the orthosteric site for GABA but rather by increasing channel gating efficacy. The results also demonstrate the presence of significant interactions between allosteric activators and potentiators, raising a possibility of effects on dosage requirements or changes in side effects. PMID:23407108

Li, Ping; Eaton, Megan M.; Steinbach, Joe Henry; Akk, Gustav

2013-01-01

146

The oxidative stress mediator 4-hydroxynonenal is an intracellular agonist of the nuclear receptor peroxisome proliferator-activated receptor-?/? (PPAR?/?)  

PubMed Central

Liver insufficiency and damage is a major cause of death and disease worldwide and may result from exposure to environmental toxicants, specific combinations or dosages of pharmaceuticals and microbial metabolites. The generation of reactive intermediates, in particular 4-hydroxynonenal (4-HNE), is a common event in liver damage caused by a variety of hepatotoxic drugs and solvents. The peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that are involved in the transcriptional regulation of lipid metabolism as well as other biological functions. Importantly, we have observed that the PPAR?/??/? mouse is more susceptible to chemically-induced hepatotoxicity than its wildtype counterpart, and our objective in this study was to elucidate the mechanism(s) by which PPAR?/? confers protection to hepatocytes. We hypothesized that PPAR?/? plays a protective role by responding to toxic lipids and altering gene expression accordingly. In support, oxidized-VLDL and constituents including 13-S-hydroxyoctadeca-dienoic acid (13(S)-HODE) and 4-HNE are PPAR?/? ligands. A structure-activity relationship was established where 4-HNE and 4-hydroperoxynonenal (4-HpNE) enhanced the activity of the PPAR?/? subtype while 4-hyroxy-hexenal (4-HHE), 4-oxo-2-Nonenal (4-ONE), and trans-4,5-epoxy-2(E)-decenal did not activate this receptor. Increasing PPAR?/? activity with a synthetic agonist decreased sensitivity of hepatocytes to 4-HNE and other toxic agents, whereas inhibition of this receptor had the opposite result. Gene expression microarray analysis identified several important PPAR?/?-regulated detoxification enzymes involved in 4-HNE metabolism that are regulated at the transcript level. This research established 4-HNE as an endogenous modulator of PPAR?/? activity and raises the possibility that agonists of this nuclear receptor may be utilized to prevent or treat liver disease associated with oxidative damage. PMID:17382197

Coleman, Jeffrey D.; Prabhu, K. Sandeep; Thompson, Jerry T.; Reddy, P. Sreenivasula; Peters, Jeffrey M.; Peterson, Blake R.; Reddy, C. Channa; Vanden Heuvel, John P.

2007-01-01

147

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

2013-05-01

148

Long-Acting ?2-Agonists Increase Fluticasone Propionate-Induced Mitogen-Activated Protein Kinase Phosphatase 1 (MKP-1) in Airway Smooth Muscle Cells  

PubMed Central

Mitogen-activated protein kinase phosphatase 1 (MKP-1) represses MAPK-driven signalling and plays an important anti-inflammatory role in asthma and airway remodelling. Although MKP-1 is corticosteroid-responsive and increased by cAMP-mediated signalling, the upregulation of this critical anti-inflammatory protein by long-acting ?2-agonists and clinically-used corticosteroids has been incompletely examined to date. To address this, we investigated MKP-1 gene expression and protein upregulation induced by two long-acting ?2-agonists (salmeterol and formoterol), alone or in combination with the corticosteroid fluticasone propionate (abbreviated as fluticasone) in primary human airway smooth muscle (ASM) cells in vitro. ?2-agonists increased MKP-1 protein in a rapid but transient manner, while fluticasone induced sustained upregulation. Together, long-acting ?2-agonists increased fluticasone-induced MKP-1 and modulated ASM synthetic function (measured by interleukin 6 (IL-6) and interleukin 8 (IL-8) secretion). As IL-6 expression (like MKP-1) is cAMP/adenylate cyclase-mediated, the long-acting ?2-agonist formoterol increased IL-6 mRNA expression and secretion. Nevertheless, when added in combination with fluticasone, ?2-agonists significantly repressed IL-6 secretion induced by tumour necrosis factor ? (TNF?). Conversely, as IL-8 is not cAMP-responsive, ?2-agonists significantly inhibited TNF?-induced IL-8 in combination with fluticasone, where fluticasone alone was without repressive effect. In summary, long-acting ?2-agonists increase fluticasone-induced MKP-1 in ASM cells and repress synthetic function of this immunomodulatory airway cell type. PMID:23533638

Manetsch, Melanie; Rahman, Md. Mostafizur; Patel, Brijeshkumar S.; Ramsay, Emma E.; Rumzhum, Nowshin N.; Alkhouri, Hatem; Ge, Qi; Ammit, Alaina J.

2013-01-01

149

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

150

Two dissimilar AT(1) agonists distinctively activate AT(1) receptors located on the luminal membrane of coronary endothelium.  

PubMed

Diverse intracoronary agonists cause cardiac effects while acting on coronary endothelial luminal membrane (CELM) receptor. Our data show: a) the presence of AT(1)R in isolated CELM and in all cardiac cell types and b) sustained intracoronary infusions of Ang II-POL, a large sized molecule (approximately 15,000 kDa) confined to the vessel lumen that can only act on CELM's AT(1)R or Ang II (approximately 1 kDa); both exert the same maximum positive inotropic (PIE) and coronary constriction (CPP). The effects of these two agonists are blocked by Losartan and by Sar-POL; a large size antagonist (approximately 15,000 kDa) that acts only on CELM. Ang II effects are transient due to desensitization and cause tachyphylaxis to Ang II and toward Ang II-POL suggesting that both Ang II and Ang II-POL act on the same receptor group. In contrast, Ang II-POL effects are sustained and do not cause tachyphylaxis. The results show that intravascular Ang II and Ang II-POL act differentially by an unknown mechanism on CELM's AT(1)R and suggest that intravascular Ang II and Ang II-POL cause PIE and CCP by activation limited to CELM's AT(1)R through an unknown mechanism that is space-confined to the CELM's AT(1)R. PMID:19643203

Castillo-Hernández, Jesús; Torres-Tirado, David; Barajas-Espinosa, Alma; Chi-Ahumada, Erika; Ramiro-Díaz, Juan; Ceballos, Guillermo; Rubio, Rafael

2009-01-01

151

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

152

A Pepducin Derived from the Third Intracellular Loop of FPR2 Is a Partial Agonist for Direct Activation of This Receptor in Neutrophils But a Full Agonist for Cross-Talk Triggered Reactivation of FPR2  

PubMed Central

We recently described a novel receptor cross-talk mechanism in neutrophils, unique in that the signals generated by the PAF receptor (PAFR) and the ATP receptor (P2Y2R) transfer formyl peptide receptor 1 (FPR1) from a desensitized (non-signaling) state back to an actively signaling state (Forsman H et al., PLoS One, 8:e60169, 2013; Önnheim K, et al., Exp Cell Res, 323?209, 2014). In addition to the G-protein coupled FPR1, neutrophils also express the closely related receptor FPR2. In this study we used an FPR2 specific pepducin, proposed to work as an allosteric modulator at the cytosolic signaling interface, to determine whether the cross-talk pathway is utilized also by FPR2. The pepducin used contains a fatty acid linked to a peptide sequence derived from the third intracellular loop of FPR2, and it activates as well as desensensitizes this receptor. We now show that neutrophils desensitized with the FPR2-specific pepducin display increased cellular responses to stimulation with PAF or ATP. The secondary PAF/ATP induced response was sensitive to FPR2-specific inhibitors, disclosing a receptor cross-talk mechanism underlying FPR2 reactivation. The pepducin induced an activity in naïve cells similar to that of a conventional FPR2 agonist, but with lower potency (partial efficacy), meaning that the pepducin is a partial agonist. The PAF- or ATP-induced reactivation was, however, much more pronounced when neutrophils had been desensitized to the pepducin as compared to cells desensitized to conventional agonists. The pepducin should thus in this respect be classified as a full agonist. In summary, we demonstrate that desensitized FPR2 can be transferred back to an actively signaling state by receptor cross-talk signals generated through PAFR and P2Y2R, and the difference in agonist potency with respect to pepducin-induced direct receptor activation and cross-talk reactivation of FPR2 puts the concept of functional selectivity in focus. PMID:25303226

Gabl, Michael; Winther, Malene; Skovbakke, Sarah Line; Bylund, Johan; Dahlgren, Claes; Forsman, Huamei

2014-01-01

153

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

2012-07-01

154

Weakly Supervised Recognition of Daily Life Activities with Wearable Sensors  

Microsoft Academic Search

This paper considers scalable and unobtrusive activity recognition using on-body sensing for context awareness in wearable computing. Common methods for activity recognition rely on supervised learning requiring substantial amounts of labeled training data. Obtaining accurate and detailed annotations of activities is challenging, preventing the applicability of these approaches in real-world settings. This paper proposes new annotation strategies that substantially reduce

Maja Stikic; Diane Larlus; Sandra Ebert; Bernt Schiele

2011-01-01

155

P2YAC?-receptor agonists enhance the proliferation of rat C6 glioma cells through activation of the p42/44 mitogen-activated protein kinase  

PubMed Central

Extracellularly added P1,P3-di(adenosine-5?) triphosphate (Ap3A), P1,P4-di(adenosine-5?) tetraphosphate (Ap4A), ATP, ADP, AMP and adenosine are growth inhibitory for rat C6 glioma cells. Analysis of nucleotide hydrolysis and the use of nucleotidase inhibitors demonstrated that the latter inhibition is due to hydrolysis of the nucleotides to adenosine.Agonists of the P2YAC?-receptor enhance the growth of C6 cells if their hydrolysis to adenosine is inhibited by pyridoxalphosphate-6-azophenyl-2?,4?-disulfonic acid (PPADS). In these conditions, the potency to stimulate cell growth parallels the ranking of the receptor agonists, i.e. 2-methylthioadenosine-5?-diphosphate (2MeSADP)>Ap3A>Ap4A. ATP and ADP are still hydrolysed in the presence of PPADS and have no proliferative effect on C6 cells.The enhanced growth is due to a P2YAC?-receptor-mediated activation of p42/44 mitogen-activated protein kinase (MAPK) as shown by immunoblotting and protein kinase assays for active MAPK and the use of the MAPK/extracellular signal-regulated kinase kinase (MEK) inhibitor PD98059.The UTP-induced enhancement of the growth of C6 cells is due to activation of MAPK by a PPADS sensitive nucleotide receptor.In conclusion, the effect of nucleotides on the growth of C6 cells is determined by ecto-nucleotidases and by activation of nucleotide receptors. Hydrolysis of nucleotides to adenosine induces growth inhibition while inhibition of the hydrolysis of agonists of the P2YAC?-receptor enhances cell growth by activation of MAPK. PMID:11564659

Claes, Patrik; Grobben, Bert; Van Kolen, Kristof; Roymans, Dirk; Slegers, Herman

2001-01-01

156

Anti-kindling Effect of Bezafibrate, a Peroxisome Proliferator-activated Receptors Alpha Agonist, in Pentylenetetrazole Induced Kindling Seizure Model  

PubMed Central

Background and Purpose: Studies in the animals suggested that Peroxisome proliferators activated receptors (PPARs) may be involved in seizure control and selective agonists of PPAR ? or PPAR ? raise seizure thresholds. The present study was contemplated with the aim of evaluating the anti kindling effects and the mechanism of bezafibrate, a Peroxisome proliferator-activated receptors ? (PPAR-?) agonist in pentylenetetrazole (PTZ) induced kindling model of seizures in rats. Methods: In a PTZ kindled Wistar rat model, different doses of bezafibrate (100 mg/kg, 200 mg/kg and 300 mg/kg) were administered intraperitoneally 30 minutes before the PTZ injection. The PTZ injection was given on alternate day till the animal became fully kindled or till 10 weeks. The parameters measured were the latency to develop kindling and incidence of kindling, histopathological study of hippocampus, hippocampal lipid peroxidation studies, serum neuron specific enolase, and hippocampal DNA fragmentation study. Results: In this study, bezafibrate significantly reduced the incidence of kindling in PTZ treated rats and exhibited a marked prolongation in the latencies to seizures. In the present study bezafibrate decreased the thiobarbituric acid-reactive substance i.e. Malondialdehyde levels, increased the reduced glutathione levels, catalase and superoxide dismutase activity in the brain. This added to its additional neuroprotective effects. Bezafibrate also reduced the neuronal damage and apoptosis in hippocampal area of the brain. Therefore bezafibrate exerted anticonvulsant properties in PTZ induced kindling model in rats. Conclusions: These findings may provide insights into the understanding of the mechanism of bezafibrate as an anti kindling agent and could offer a useful support to the basic antiepileptic therapy in preventing the development of PTZ induced seizures, suggesting its potential for therapeutic applications in temporal lobe epilepsy. PMID:25625088

Saha, Lekha; Bhandari, Swati; Bhatia, Alka; Banerjee, Dibyajyoti; Chakrabarti, Amitava

2014-01-01

157

Active-State Model of a Dopamine D2 Receptor - G?i Complex Stabilized by Aripiprazole-Type Partial Agonists  

PubMed Central

Partial agonists exhibit a submaximal capacity to enhance the coupling of one receptor to an intracellular binding partner. Although a multitude of studies have reported different ligand-specific conformations for a given receptor, little is known about the mechanism by which different receptor conformations are connected to the capacity to activate the coupling to G-proteins. We have now performed molecular-dynamics simulations employing our recently described active-state homology model of the dopamine D2 receptor-G?i protein-complex coupled to the partial agonists aripiprazole and FAUC350, in order to understand the structural determinants of partial agonism better. We have compared our findings with our model of the D2R-G?i-complex in the presence of the full agonist dopamine. The two partial agonists are capable of inducing different conformations of important structural motifs, including the extracellular loop regions, the binding pocket and, in particular, intracellular G-protein-binding domains. As G-protein-coupling to certain intracellular epitopes of the receptor is considered the key step of allosterically triggered nucleotide-exchange, it is tempting to assume that impaired coupling between the receptor and the G-protein caused by distinct ligand-specific conformations is a major determinant of partial agonist efficacy. PMID:24932547

Kling, Ralf C.; Tschammer, Nuska; Lanig, Harald; Clark, Timothy; Gmeiner, Peter

2014-01-01

158

Active reinforcement of weak soils during construction of high-capacity holding tanks  

Microsoft Academic Search

Results are presented for experimental investigations of a new method for the active ring reinforcement of a weak soil during\\u000a construction of a new generation of large holding tanks with controlled service reliability.

A. A. Zemlyanskii

2006-01-01

159

Existence of weak entropic solutions for gas chromatography system with one or two active species  

E-print Network

Existence of weak entropic solutions for gas chromatography system with one or two active species), the system of conservation laws (6) generalizes the system of chromatography which has been intensively of chromatography co

Gisclon, Marguerite

160

The inverse agonist propranolol confers no corticosteroid-sparing activity in mild-to-moderate persistent asthma.  

PubMed

The murine asthma model shows that switching off airway ?2 receptors with an inverse agonist may confer anti-inflammatory effects as well as corticosteroid-sparing activity. We have assessed for any corticosteroid-sparing effects of propranolol, an inverse agonist, added to low-dose inhaled corticosteroid (ICS) compared with higher dose ICS. A randomized double-blind placebo-controlled cross-over trial in mild-to-moderate persistent asthmatic patients was performed. After a run-in (2 weeks) on hydrofluoroalkane-beclometasone dipropionate (HFA-BDP) at 100 ?g/day (HFA-BDP100), patients received randomized treatments (4 weeks) with propranolol at 80 mg/day plus HFA-BDP at 100 ?g/day compared with placebo plus HFA-BDP at 400 ?g/day (HFA-BDP400). Propranolol was up-titrated to 80 mg/day over the initial 2 weeks. Tiotropium was co-administered until 5 days before each histamine challenge (the primary outcome). Sixteen patients completed the study [mean age, 38 years; forced expiratory volume in 1 s (FEV1), 86.4%; histamine provocative concentration causing a 20% fall in FEV1 (PC20), 1.39 mg/ml; ICS dose, 406 ?g/day]. Histamine PC20 was unchanged by adding propranolol to HFA-BDP100 compared with baseline (HFA-BDP100) {0.17 doubling dilution (dd) difference [95% confidence interval (CI): -0.58 to 0.92]}, but there was a significant improvement with HFA-BDP400 compared with both baseline [1.05 dd (95% CI: 0.43-1.66); P=0.02], and propranolol+HFA-BDP100 [0.88 dd (95% CI: 0.45-1.30); P=0.006]. Significant improvements were also observed with HFA-BDP400 for exhaled nitric oxide, blood eosinophils, serum eosinophilic cationic protein and asthma quality-of-life questionnaire symptoms compared with propranolol+HFA-BDP100. Salbutamol recovery post-challenge was partially blunted by propranolol (median prolongation 5 min; P=0.002). Domiciliary evening FEV1 also fell with propranolol+HFA-BDP100 [mean reduction from baseline 0.22 litres (95% CI: 0.10-0.34); P=0.012], whereas Asthma Control Questionnaire remained unchanged. In conclusion, the inverse agonist propranolol produced no improvements when given with low-dose ICS, whereas further significant improvements in airway hyper-responsiveness and inflammation were demonstrated with higher dose ICS. Thus, propranolol does not confer corticosteroid-sparing activity in persistent asthma. PMID:24938324

Anderson, William J; Short, Philip M; Williamson, Peter A; Manoharan, Arvind; Lipworth, Brian J

2014-12-01

161

Differences in the locomotor-activating effects of indirect serotonin agonists in habituated and non-habituated rats  

PubMed Central

The indirect serotonin (5-HT) agonist 3,4-methylenedioxymethamphetamine (MDMA) produces a distinct behavioral profile in rats consisting of locomotor hyperactivity, thigmotaxis, and decreased exploration. The indirect 5-HT agonist ?-ethyltryptamine (AET) produces a similar behavioral profile. Using the Behavioral Pattern Monitor (BPM), the present investigation examined whether the effects of MDMA and AET are dependent on the novelty of the testing environment. These experiments were conducted in Sprague-Dawley rats housed on a reversed light cycle and tested during the dark phase of the light/dark cycle. We found that racemic MDMA (RS-MDMA; 3 mg/kg, SC) increased locomotor activity in rats tested in novel BPM chambers, but had no effect on locomotor activity in rats habituated to the BPM chambers immediately prior to testing. Likewise, AET (5 mg/kg, SC) increased locomotor activity in non-habituated animals but not in animals habituated to the test chambers. These results were unexpected because previous reports indicate that MDMA has robust locomotor-activating effects in habituated animals. To further examine the influence of habituation on MDMA-induced locomotor activity, we conducted parametric studies with S-(+)-MDMA (the more active enantiomer) in habituated and non-habituated rats housed on a standard or reversed light cycle. Light cycle was included as a variable due to reported differences in sensitivity to serotonergic ligands during the dark and light phases. In confirmation of our initial studies, rats tested during the dark phase and habituated to the BPM did not show an S-(+)-MDMA (3 mg/kg, SC)-induced increase in locomotor activity, whereas non-habituated rats did. By contrast, in rats tested during the light phase, S-(+)-MDMA increased locomotor activity in both non-habituated and habituated rats, although the response in habituated animals was attenuated. The finding that habituation and light cycle interact to influence MDMA- and AET-induced hyperactivity demonstrates that there are previously unrecognized complexities associated with the behavioral effects of these drugs. PMID:22487771

Halberstadt, Adam L.; Buell, Mahálah R.; Price, Diana L.; Geyer, Mark A.

2012-01-01

162

The peroxisome proliferator-activated receptor–gamma agonist Pioglitazone improves cardiometabolic risk and renal inflammation in murine lupus*  

PubMed Central

Individuals with systemic lupus erythematosus (SLE) have a striking increase in the risk of premature atherosclerosis, a complication preceded by significant subclinical vascular damage. A proposed mechanism leading to accelerated vascular disease in SLE is an imbalance between vascular damage and repair, as patients with this disease display significant abnormalities in phenotype and function of endothelial progenitor cells. In addition, individuals with SLE have a higher incidence of insulin resistance which may further contribute to the increased cardiovascular risk. This study examined the role of the peroxisome proliferator activated receptor-gamma (PPAR-?) agonist pioglitazone in improving endothelial function, endothelial progenitor cell numbers and functional capacity, metabolic parameters and disease activity in the lupus-prone murine model New Zealand Black/ New Zealand White (NZB/NZW) F1. Ten-week old pre-nephritic female NZB/NZW F1 mice were exposed to 10 or 25 mg/kg/day of oral pioglitazone or vehicle for 15 or 24 weeks. Mice exposed to pioglitazone exhibited pronounced enhancement in endothelial-dependent vasorelaxation of thoracic aortas and in endothelial progenitor cell function, as assessed by the capacity of bone-marrow derived endothelial progenitor cells to differentiate into mature endothelial cells. Pioglitazone-treated mice showed improvement in insulin resistance, adipokine and lipid profile. Kidneys from pioglitazone-treated mice showed significant decreases in immune complex deposition, renal inflammation, T cell glomerular infiltration and intrarenal synthesis of TNF-?, IL-1? and VCAM-1. These results indicate that PPAR-? agonists could serve as important tools in the prevention of premature cardiovascular disease and organ damage in SLE. PMID:19620300

Zhao, Wenpu; Thacker, Seth G.; Hodgin, Jeffrey B.; Zhang, Hongyu; Wang, Jeffrey H.; Park, James L.; Randolph, Ann; Somers, Emily C.; Pennathur, Subramaniam; Kretzler, Matthias; Brosius, Frank C.; Kaplan, Mariana J.

2009-01-01

163

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

PubMed Central

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

2013-01-01

164

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

165

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

NASA Technical Reports Server (NTRS)

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

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

2000-01-01

166

The adenosine A2A receptor antagonist, istradefylline enhances the anti-parkinsonian activity of low doses of dopamine agonists in MPTP-treated common marmosets.  

PubMed

The adenosine A2A receptor antagonist, istradefylline, enhances anti-parkinsonian activity in patients with advanced Parkinson?s disease (PD) already treated with combinations of L-DOPA and dopamine agonist drugs but who are still exhibiting prolonged 'OFF' periods. In contrast, the effects of istradefylline on motor function when administered in combination with low dose dopamine agonist therapy in early PD are unknown. We now investigate whether istradefylline administered with a threshold dose of either the non-ergot dopamine agonist, ropinirole or the ergot dopamine agonist, pergolide enhances anti-parkinsonian activity in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated common marmoset. Both ropinirole (0.01-0.1mg/kg p.o.) and pergolide (0.003-0.1mg/kg p.o.) administered alone produced dose dependent increases in locomotor activity, a reduction in motor disability. Threshold doses of ropinirole (0.025-0.075mg/kg p.o.) and pergolide (0.01-0.075mg/kg p.o.) were then selected that in individual animals caused a small but non-significant anti-parkinsonian effect. Administration of istradefylline (10mg/kg p.o.) alone resulted in a decrease in motor disability and increase in 'ON' time but dyskinesia was not observed. Combined administration of pergolide or ropinirole with istradefylline resulted in an increase in the reversal of motor disability and increase in 'ON' time compared to that produced by either treatment alone but dyskinesia was still not observed. These results show that istradefylline is effective in improving motor function when combined with low dose dopamine agonist treatment. In early PD, this may avoid dose escalation or allow a reduction in dopamine agonist dosage without a loss of efficacy and prevent dopaminergic side-effects from becoming treatment limiting. PMID:25499739

Uchida, Shin-Ichi; Soshiroda, Kazuhiro; Okita, Eri; Kawai-Uchida, Mika; Mori, Akihisa; Jenner, Peter; Kanda, Tomoyuki

2015-01-15

167

Peroxisome proliferator-activated receptor-? (PPAR-?) agonist inhibits collagen synthesis in human hypertrophic scar fibroblasts by targeting Smad3 via miR-145.  

PubMed

The transcription factor peroxisome proliferator-activated receptor-? (PPAR-?) functions to regulate cell differentiation and lipid metabolism. Recently, its agonist has been documented to regulate extracellular matrix production in human dermal fibroblasts. This study explored the underlying molecular mechanisms and gene interactions in hypertrophic scar fibroblasts (HSFBs) in vitro. HSFBs were cultured and treated with or without PPAR-? agonist or antagonist for gene expression. Bioinformatical analysis predicted that miR-145 could target Smad3 expression. Luciferase assay was used to confirm such an interaction. The data showed that PPAR-? agonist troglitazone suppressed expression of Smad3 and Col1 in HSFBs. PPAR-? agonist induced miR-145 at the gene transcriptional level, which in turn inhibited Smad3 expression and Col1 level in HSFBs. Furthermore, ELISA data showed that Col1 level in HSFBs was controlled by a feedback regulation mechanism involved in PPAR-? agonist and antagonist-regulated expression of miR-145 and Smad3 in HSFBs. These findings indicate that PPAR-?-miR-145-Smad3 axis plays a role in regulation of collagen synthesis in HSFBs. PMID:25704091

Zhu, Hua-Yu; Li, Chao; Zheng, Zhao; Zhou, Qin; Guan, Hao; Su, Lin-Lin; Han, Jun-Tao; Zhu, Xiong-Xiang; Wang, Shu-Yue; Li, Jun; Hu, Da-Hai

2015-03-27

168

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...

169

Toll-like receptor agonists stimulate differential functional activation and cytokine and chemokine gene expression in heterophils isolated from chickens with differential innate responses  

Microsoft Academic Search

Heterophils isolated from distinct broilers (lines A and B) differ in function and cytokine gene expression profiles. Nothing is known about Toll-like receptor (TLR) expression nor functional activation and cytokine\\/chemokine gene expression of line A and B heterophils when stimulated with TLR agonists. We found that line A and B heterophils express the same range of TLRs. All the bacterial

Michael H. Kogut; Christina Swaggerty; Haiqi He; Igal Pevzner; Pete Kaiser

2006-01-01

170

Oxidant Stress Impairs In Vivo Reendothelialization Capacity of Endothelial Progenitor Cells From Patients With Type 2 Diabetes Mellitus Restoration by the Peroxisome Proliferator-Activated Receptor Agonist Rosiglitazone  

Microsoft Academic Search

Background—Endothelial progenitor cells (EPCs) are thought to contribute to endothelial recovery after arterial injury. We therefore compared in vivo reendothelialization capacity of EPCs derived from patients with diabetes mellitus and healthy subjects. Moreover, we examined the effect of treatment with the peroxisome proliferator-activated receptor- agonist rosiglitazone on oxidant stress, nitric oxide (NO) bioavailability, and the in vivo reendothelialization capacity of

Sajoscha A. Sorrentino; Ferdinand H. Bahlmann; Christian Besler; Maja Müller; Svenja Schulz; Nina Kirchhoff; Carola Doerries; Tibor Horváth; Anne Limbourg; Florian Limbourg; Danilo Fliser; Hermann Haller; Helmut Drexler; Ulf Landmesser

171

Identification of 6-octadecynoic acid from a methanol extract of Marrubium vulgare L. as a peroxisome proliferator-activated receptor ? agonist  

SciTech Connect

Highlights: •6-ODA, a rare fatty acid with a triple bond, was identified from Marrubium vulgare. •6-ODA was synthesized from petroselinic acid as a starting material. •6-ODA stimulated lipid accumulation in HSC-T6 and 3T3-L1 cells. •The first report of a fatty acid with a triple bond functioning as a PPAR? agonist. •This study sheds light on novel functions of a fatty acid with a triple bond. -- Abstract: 6-Octadecynoic acid (6-ODA), a fatty acid with a triple bond, was identified in the methanol extract of Marrubium vulgare L. as an agonist of peroxisome proliferator-activated receptor ? (PPAR?). Fibrogenesis caused by hepatic stellate cells is inhibited by PPAR? whose ligands are clinically used for the treatment of diabetes. Plant extracts of Marrubium vulgare L., were screened for activity to inhibit fibrosis in the hepatic stellate cell line HSC-T6 using Oil Red-O staining, which detects lipids that typically accumulate in quiescent hepatic stellate cells. A methanol extract with activity to stimulate accumulation of lipids was obtained. This extract was found to have PPAR? agonist activity using a luciferase reporter assay. After purification using several chromatographic methods, 6-ODA, a fatty acid with a triple bond, was identified as a candidate of PPAR? agonist. Synthesized 6-ODA and its derivative 9-octadecynoic acid (9-ODA), which both have a triple bond but in different positions, activated PPAR? in a luciferase reporter assay and increased lipid accumulation in 3T3-L1 adipocytes in a PPAR?-dependent manner. There is little information about the biological activity of fatty acids with a triple bond, and to our knowledge, this is the first report that 6-ODA and 9-ODA function as PPAR? agonists.

Ohtera, Anna; Miyamae, Yusaku; Nakai, Naomi [Graduate School of Biostudies, Kyoto University, Kyoto 606-8502 (Japan)] [Graduate School of Biostudies, Kyoto University, Kyoto 606-8502 (Japan); Kawachi, Atsushi; Kawada, Kiyokazu; Han, Junkyu; Isoda, Hiroko [Alliance for Research on North Africa (ARENA), University of Tsukuba, Ibaraki 305-8572 (Japan) [Alliance for Research on North Africa (ARENA), University of Tsukuba, Ibaraki 305-8572 (Japan); Faculty of Life and Environment, University of Tsukuba, Ibaraki 305-8572 (Japan); Neffati, Mohamed [Arid Zone Research Institute (IRA), Médenine 4119 (Tunisia)] [Arid Zone Research Institute (IRA), Médenine 4119 (Tunisia); Akita, Toru; Maejima, Kazuhiro [Nippon Shinyaku CO., LTD., Kyoto 601-8550 (Japan)] [Nippon Shinyaku CO., LTD., Kyoto 601-8550 (Japan); Masuda, Seiji; Kambe, Taiho [Graduate School of Biostudies, Kyoto University, Kyoto 606-8502 (Japan)] [Graduate School of Biostudies, Kyoto University, Kyoto 606-8502 (Japan); Mori, Naoki; Irie, Kazuhiro [Graduate School of Agriculture, Kyoto University, Kyoto 606-8502 (Japan)] [Graduate School of Agriculture, Kyoto University, Kyoto 606-8502 (Japan); Nagao, Masaya, E-mail: mnagao@kais.kyoto-u.ac.jp [Graduate School of Biostudies, Kyoto University, Kyoto 606-8502 (Japan)] [Graduate School of Biostudies, Kyoto University, Kyoto 606-8502 (Japan)

2013-10-18

172

The mineralocorticoid receptor agonist, fludrocortisone, differentially inhibits pituitary-adrenal activity in humans with psychotic major depression  

PubMed Central

Introduction Hypothalamic-pituitary-adrenal (HPA) axis dysregulation has been linked with major depression, particularly psychotic major depression (PMD), with mineralocorticoid receptors (MRs) playing a role in HPA-axis regulation and the pathophysiology of depression. Herein we hypothesize that the MR agonist fludrocortisone differentially inhibits the HPA axis of psychotic major depression subjects (PMDs), non-psychotic major depression subjects (NPMDs), and healthy control subjects (HCs). Methods Fourteen PMDs, 16 NPMDs, and 19 HCs were admitted to the Stanford University Hospital General Clinical Research Center. Serum cortisol levels were sampled at baseline and every hour from 18:00 to 23:00 h, when greatest MR activity is expected, on two consecutive nights. On the second afternoon at 16:00 h all subjects were given 0.5 mg fludrocortisone. Mean cortisol levels pre- and post-fludrocortisone and percent change in cortisol levels were computed. Results There were no significant group differences for cortisol at baseline: F (2,47) = .19, p= .83. There were significant group differences for post-fludrocortisone cortisol: F (2,47) = 5.13, p = .01, which were significantly higher in PMDs compared to HCs (p = .007), but not compared to NPMDs (p = .18). There were no differences between NPMD’s and HC’s (p= .61). Also, PMDs had a lower percent change from baseline in cortisol levels at 2200 hrs than NPMDs (p =.01) or HCs (p = .009). Conclusions Individuals with psychotic major depression compared to healthy control subjects have diminished feedback inhibition of the hypothalamic-pituitary-adrenal (HPA) axis in response to the mineralocorticoid receptor agonist fludrocortisone. To our knowledge, this is the first study to examine HPA axis response to MR stimulation in major depression (with and without psychosis), and only the third study to demonstrate that exogenously administered fludrocortisone can down-regulate the HPA axis in humans. PMID:22727477

Lembke, Anna; Gomez, Rowena; Tenakoon, Lakshika; Keller, Jennifer; Cohen, Gregory; Williams, Gordon H.; Kraemer, Fredric B.; Schatzberg, Alan F.

2012-01-01

173

Glucagon-like peptide-1 receptor agonist activation ameliorates venous thrombosis-induced arteriovenous fistula failure in chronic kidney disease.  

PubMed

High shear stress that develops in the arteriovenous fistula of chronic kidney diseases (CKD) may increase H2O2 and thromboxane A2 (TXA2) release, thereby exacerbating endothelial dysfunction, thrombosis, and neointimal hyperplasia. We investigated whether glucagon-like peptide-1 receptor agonist/exendin-4, a potentially cardiovascular protective agent, could improve TXA2-induced arteriovenous fistula injury in CKD. TXA2 administration to H2O2-exposed human umbilical vein endothelial cells increased apoptosis, senescence, and detachment; these phenotypes were associated with the downregulation of phosphorylated endothelial nitric oxide synthase/heme oxygenase-1 (eNOS/HO-1) signalling. Exendin-4 reduced H2O2/TXA2-induced endothelial injury via inhibition of apoptosis-related mechanisms and restoration of phosphorylated eNOS/HO-1 signalling. Male Wistar rats subjected to right common carotid artery-external jugular vein anastomosis were treated with exendin-4 via cervical implant osmotic pumps for 16-42 days. High shear stress induced by the arteriovenous fistula significantly increased venous haemodynamics, blood and tissue H2O2 and TXB2 levels, macrophage/monocyte infiltration, fibrosis, proliferation, and adhesion molecule-1 expression. Apoptosis was also increased due to NADPH oxidase gp91 activation and mitochondrial Bax translocation in the proximal end of the jugular vein of CKD rats. Exendin-4-treatment of rats with CKD led to the restoration of normal endothelial morphology and correction of arteriovenous fistula function. Exendin-4 treatment or thromboxane synthase gene deletion in CKD mice markedly reduced ADP-stimulated platelet adhesion to venous endothelium, and prevented venous occlusion in FeCl3-injured vessels by upregulation of HO-1. Together, these data reveal that the use of glucagon-like peptide-1 receptor agonists is an effective strategy for treatment of CKD-induced arteriovenous fistula failure. PMID:25030617

Chien, Chiang-Ting; Fan, Shih-Chen; Lin, Shao-Chieh; Kuo, Chang-Chih; Yang, Chih-Hui; Yu, Tzu-Ying; Lee, Shih-Pin; Cheng, Dai-Yu; Li, Ping-Chia

2014-11-01

174

Analgesic activity and pharmacological characterization of N-[1-phenylpyrazol-3-yl]- N-[1-(2-phenethyl)-4-piperidyl] propenamide, a new opioid agonist acting peripherally  

Microsoft Academic Search

We previously reported the synthesis of three new opioid agonists as well as their in vitro and in vivo activity [Girón, R., Abalo, R., Goicoechea, C., Martín, M.I., Callado, L.F., Cano, C., Goya, P., Jagerovic, N. 2002. Synthesis and opioid activity of new fentanyl analogs. Life Sci. 71, 1023–1034]. One of them, N-[1-phenylpyrazol-3-yl]-N-[1-(2-phenethyl)-4-piperidyl)] propenamide (IQMF-4), showed an interesting antinociceptive activity.

Carlos Goicoechea; Eva Sánchez; Carolina Cano; Nadine Jagerovic; Maria Isabel Martín

2008-01-01

175

Agonist activation of cytosolic Ca2+ in subfornical organ cells projecting to the supraoptic nucleus  

NASA Technical Reports Server (NTRS)

The subfornical organ (SFO) is sensitive to both ANG II and ACh, and local application of these agents produces dipsogenic responses and vasopressin release. The present study examined the effects of cholinergic drugs, ANG II, and increased extracellular osmolarity on dissociated, cultured cells of the SFO that were retrogradely labeled from the supraoptic nucleus. The effects were measured as changes in cytosolic calcium in fura 2-loaded cells by using a calcium imaging system. Both ACh and carbachol increased intracellular ionic calcium concentration ([Ca2+]i). However, in contrast to the effects of muscarinic receptor agonists on SFO neurons, manipulation of the extracellular osmolality produced no effects, and application of ANG II produced only moderate effects on [Ca2+]i in a few retrogradely labeled cells. The cholinergic effects on [Ca2+]i could be blocked with the muscarinic receptor antagonist atropine and with the more selective muscarinic receptor antagonists pirenzepine and 4-diphenylacetoxy-N-methylpiperdine methiodide (4-DAMP). In addition, the calcium in the extracellular fluid was required for the cholinergic-induced increase in [Ca2+]i. These findings indicate that ACh acts to induce a functional cellular response in SFO neurons through action on a muscarinic receptor, probably of the M1 subtype and that the increase of [Ca2+]i, at least initially, requires the entry of extracellular Ca2+. Also, consistent with a functional role of M1 receptors in the SFO are the results of immunohistochemical preparations demonstrating M1 muscarinic receptor-like protein present within this forebrain circumventricular organ.

Johnson, R. F.; Beltz, T. G.; Sharma, R. V.; Xu, Z.; Bhatty, R. A.; Johnson, A. K.

2001-01-01

176

Glucans exhibit weak antioxidant activity, but stimulate macrophage free radical activity.  

PubMed

Polymeric carbohydrates have been reported to modulate inflammatory responses in vitro and in vivo. Previous reports suggest that certain carbohydrate polymers, such as (1-->3)-beta-D-glucans, may possess free radical scavenging activity. If glucans are free radical scavengers then it might explain, in part, the ability of these ligands to modulate inflammatory responses. The present study examined the free radical scavenging activity of a variety of carbohydrate polymers and the effect of the polymers on free radical levels in a murine macrophage cell line. All of the carbohydrates exhibited concentration dependent antioxidant effects (EC(50) range = 807 to 43 microg/ml). However, the antioxidant activity for the carbohydrates was modest in comparison with PDTC (EC(50) = 0.13 microg/ml) and the carbohydrate concentration required for antioxidant activity was high (x EC(50) = 283 microg/ml). The antioxidant ability of the polymers was greater (p < .05) than their monosaccharide constituents, i.e., dextrose EC(50) = 807 vs. glucan sulfate EC(50) = 43 microg/ml. Coincubation of glucans with murine J774a.1 cells increased free radical levels when compared to controls. Therefore, the weak free radical scavenging activity of glucan polymers cannot explain their modulatory effect on inflammatory responses in tissue culture and/or disease models of inflammation. PMID:11182295

Tsiapali, E; Whaley, S; Kalbfleisch, J; Ensley, H E; Browder, I W; Williams, D L

2001-02-15

177

The G protein-biased ?-opioid receptor agonist RB-64 is analgesic with a unique spectrum of activities in vivo.  

PubMed

The hypothesis that functionally selective G protein-coupled receptor (GPCR) agonists may have enhanced therapeutic benefits has revitalized interest for many GPCR targets. In particular, although ?-opioid receptor (KOR) agonists are analgesic with a low risk of dependence and abuse, their use is limited by a propensity to induce sedation, motor incoordination, hallucinations, and dysphoria-like states. Several laboratories have produced a body of work suggesting that G protein-biased KOR agonists might be analgesic with fewer side effects. Although that has been an intriguing hypothesis, suitable KOR-selective and G protein-biased agonists have not been available to test this idea. Here we provide data using a G protein-biased agonist, RB-64 (22-thiocyanatosalvinorin A), which suggests that KOR-mediated G protein signaling induces analgesia and aversion, whereas ?-arrestin-2 signaling may be associated with motor incoordination. Additionally, unlike unbiased KOR agonists, the G protein-biased ligand RB-64 does not induce sedation and does not have anhedonia-like actions, suggesting that a mechanism other than G protein signaling mediates these effects. Our findings provide the first evidence for a highly selective and G protein-biased tool compound for which many, but not all, of the negative side effects of KOR agonists can be minimized by creating G protein-biased KOR agonists. PMID:25320048

White, Kate L; Robinson, J Elliott; Zhu, Hu; DiBerto, Jeffrey F; Polepally, Prabhakar R; Zjawiony, Jordan K; Nichols, David E; Malanga, C J; Roth, Bryan L

2015-01-01

178

Origin of spontaneous activity in neonatal and adult rat bladders and its enhancement by stretch and muscarinic agonists  

PubMed Central

This study examined the origin of spontaneous activity in neonatal and adult rat bladders and the effect of stretch and muscarinic agonists and antagonists on spontaneous activity. Rats were anesthetized and their bladders were excised, cannulated, and loaded with voltage- and Ca2+-sensitive dyes. Intracellular Ca2+ and membrane potential transients were mapped using photodiode arrays in whole bladders, bladder sheets, or cross-section preparations at 37°C. Intravesical pressure was recorded from whole bladders. In neonatal bladders and sheets, spontaneous Ca2+ and electrical signals arose at a site near the dome and spread in a coordinated manner throughout the bladder with different dome-to-neck conduction velocities (Ca2+: 3.7 ± 0.4 mm/s; membrane potential: 46.2 ± 3.1 mm/s). In whole bladders, optical signals were associated with spontaneous contractions (10–20 cmH2O). By contrast, in adult bladders spontaneous Ca2+ and electrical activity was uncoordinated, originating at multiple sites and was associated with smaller (2–5 cmH2O) contractions. Spontaneous contractions and optical signals were insensitive to tetrodotoxin (2 ?M) but were blocked by nifedipine (10 ?M). Stretch or low carbachol concentrations (50 nM) applied to neonatal whole bladders enhanced the amplitude (to 20–35 cmH2O) of spontaneous activity, which was blocked by atropine. Bladder cross sections revealed that Ca2+ and membrane potential transients produced by stretch or carbachol began near the urothelial-suburothelial interface and then spread to the detrusor. In conclusion, spontaneous activity in neonatal bladders, unlike activity in adult bladders, is highly organized, originating in the urothelium-suburothelium near the dome. Activity is enhanced by stretch or carbachol and this enhancement is blocked by atropine. It is hypothesized that acetylcholine is released from the urothelium during bladder filling to enhance spontaneous activity. PMID:17107944

Kanai, A.; Roppolo, J.; Ikeda, Y.; Zabbarova, I.; Tai, C.; Birder, L.; Griffiths, D.; de Groat, W.; Fry, C.

2011-01-01

179

Toll-like receptor agonists stimulate differential functional activation and cytokine and chemokine gene expression in heterophils isolated from chickens with differential innate responses.  

PubMed

Heterophils isolated from distinct broilers (lines A and B) differ in function and cytokine gene expression profiles. Nothing is known about Toll-like receptor (TLR) expression nor functional activation and cytokine/chemokine gene expression of line A and B heterophils when stimulated with TLR agonists. We found that line A and B heterophils express the same range of TLRs. All the bacterial TLR agonists, peptidoglycan, the synthetic lipoprotein Pam3CSK4, ultra-pure lipopolysaccharide, and flagellin all induced significantly greater functional activation of heterophils from line A compared to B. Only stimulation with the guanosine analog, loxoribine, (LOX) induced a significantly greater functional response in B over A. Additionally, all heterophils from line A stimulated with the bacterial TLR agonists had dramatic upregulation of pro-inflammatory cytokine and chemokine mRNA expression, whereas heterophils from line B had little or no upregulation of these genes. However, stimulation of all heterophils from line B with the bacterial TLR agonists and LOX induced a significant upregulation of IFN-alpha, with little transcription of this cytokine gene in line A heterophils. These findings suggest that the difference in heterophil functional efficiency between these parent lines is due to recognition of pathogens and activation of signaling pathways that induce innate cytokine and chemokine responses. PMID:16815069

Kogut, Michael H; Swaggerty, Christina; He, Haiqi; Pevzner, Igal; Kaiser, Pete

2006-06-01

180

Cortex Is Driven by Weak but Synchronously Active Thalamocortical Synapses  

NASA Astrophysics Data System (ADS)

Sensory stimuli reach the brain via the thalamocortical projection, a group of axons thought to be among the most powerful in the neocortex. Surprisingly, these axons account for only ~15% of synapses onto cortical neurons. The thalamocortical pathway might thus achieve its effectiveness via high-efficacy thalamocortical synapses or via amplification within cortical layer 4. In rat somatosensory cortex, we measured in vivo the excitatory postsynaptic potential evoked by a single synaptic connection and found that thalamocortical synapses have low efficacy. Convergent inputs, however, are both numerous and synchronous, and intracortical amplification is not required. Our results suggest a mechanism of cortical activation by which thalamic input alone can drive cortex.

Bruno, Randy M.; Sakmann, Bert

2006-06-01

181

Synthesis and Structure–Activity Relationships of N-Benzyl Phenethylamines as 5-HT2A/2C Agonists  

PubMed Central

N-Benzyl substitution of 5-HT2A receptor agonists of the phenethylamine structural class of psychedelics (such as 4-bromo-2,5-dimethoxyphenethylamine, often referred to as 2C-B) confer a significant increase in binding affinity as well as functional activity of the receptor. We have prepared a series of 48 compounds with structural variations in both the phenethylamine and N-benzyl part of the molecule to determine the effects on receptor binding affinity and functional activity at 5-HT2A and 5-HT2C receptors. The compounds generally had high affinity for the 5-HT2A receptor with 8b having the highest affinity at 0.29 nM but with several other compounds also exhibiting subnanomolar binding affinities. The functional activity of the compounds was distributed over a wider range with 1b being the most potent at 0.074 nM. Most of the compounds exhibited low to moderate selectivity (1- to 40-fold) for the 5-HT2A receptor in the binding assays, although one compound 6b showed an impressive 100-fold selectivity for the 5-HT2A receptor. In the functional assay, selectivity was generally higher with 1b being more than 400-fold selective for the 5-HT2A receptor. PMID:24397362

2014-01-01

182

A yeast ARS-binding protein activates transcription synergistically in combination with other weak activating factors.  

PubMed Central

ABFI (ARS-binding protein I) is a yeast protein that binds specific DNA sequences associated with several autonomously replicating sequences (ARSs). ABFI also binds sequences located in promoter regions of some yeast genes, including DED1, an essential gene of unknown function that is transcribed constitutively at a high level. ABFI was purified by specific binding to the DED1 upstream activating sequence (UAS) and was found to recognize related sequences at several other promoters, at an ARS (ARS1), and at a transcriptional silencer (HMR E). All ABFI-binding sites, regardless of origin, provided weak UAS function in vivo when examined in test plasmids. UAS function was abolished by point mutations that reduced ABFI binding in vitro. Analysis of the DED1 promoter showed that two ABFI-binding sites combine synergistically with an adjacent T-rich sequence to form a strong constitutive activator. The DED1 T-rich element acted synergistically with all other ABFI-binding sites and with binding sites for other multifunctional yeast activators. An examination of the properties of sequences surrounding ARS1 left open the possibility that ABFI enhances the initiation of DNA replication at ARS1 by transcriptional activation. Images PMID:2406570

Buchman, A R; Kornberg, R D

1990-01-01

183

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...

184

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

185

Peroxisome proliferator-activated receptor alpha agonists enhance cardiomyogenesis of mouse ES cells by utilization of a reactive oxygen species-dependent mechanism.  

PubMed

Peroxisome proliferator-activated receptors (PPARalpha, -beta and -gamma) are nuclear receptors involved in transcriptional regulation of lipid and energy metabolism. Since the energy demand increases when cardiac progenitor cells are developing rhythmic contractile activity, PPAR activation may play a critical role during cardiomyogenesis of embryonic stem (ES) cells. It is shown that ES cells express PPARalpha, -beta, and -gamma mRNA during differentiation of ES cells towards cardiac cells. Treatment with PPARalpha agonists (WY14643, GW7647, and ciprofibrate) significantly increased cardiomyogenesis and expression of the cardiac genes MLC2a, ANP, MHC-beta, MLC2v, and cardiac alpha-actin. Furthermore, WY14643 increased PPARalpha gene expression and the expression of the cardiogenic transcription factors GATA-4, Nkx2.5, DTEF-1, and MEF 2C. In contrast, the PPARalpha antagonist MK886 decreased cardiomyogenesis, whereas the PPARbeta agonist L-165,041 as well as the PPARgamma agonist GW1929 were without effects. Treatment with PPARalpha, but not PPARbeta, and PPARgamma agonists and MK886, resulted in generation of reactive oxygen species (ROS), which was inhibited in the presence of the NADPH oxidase inhibitors diphenylen iodonium (DPI) and apocynin and the free radical scavengers vitamin E and N-(2-mercapto-propionyl)-glycine (NMPG), whereas the mitochondrial complex I inhibitor rotenone was without effects. The effect of PPARalpha agonists on cardiomyogenesis of ES cells was abolished upon preincubation with free radical scavengers and NADPH oxidase inhibitors, indicating involvement of ROS in PPARalpha, mediated cardiac differentiation. In summary, our data indicate that stimulation of PPARalpha but not PPARbeta and -gamma enhances cardiomyogenesis in ES cells using a pathway that involves ROS and NADPH oxidase activity. PMID:17951219

Sharifpanah, Fatemeh; Wartenberg, Maria; Hannig, Madeleine; Piper, Hans-Michael; Sauer, Heinrich

2008-01-01

186

The FomA porin from Fusobacterium nucleatum is a Toll-like receptor 2 agonist with immune adjuvant activity.  

PubMed

Many bacterial components selectively activate immune and nonhematopoietic target cells via Toll-like receptor (TLR) signaling; modulation of such host responses defines the immune adjuvant properties of these bacterial products. For example, the outer membrane protein porins from Neisseria, Salmonella, and Shigella are known TLR2 agonists with established systemic and mucosal immune adjuvanticity. Early work indicated that the FomA porin from Fusobacterium nucleatum has immune adjuvant activity in mice. Using a purified recombinant FomA, we have verified its immune stimulatory properties and have defined a role for TLR2 signaling in its in vitro and in vivo activity. FomA induces interleukin 8 (IL-8) secretion and NF-?B-dependent luciferase activity in HEK cells expressing TLR2, IL-6 secretion, and cell surface upregulation of CD86 and major histocompatibility complex (MHC) II in primary B cells from wild-type mice, but it fails to activate cells from TLR2 knockout mice. Accordingly, the immune adjuvant activity of FomA is also TLR2 dependent. In a mouse model of immunization with ovalbumin (OVA), FomA induces enhanced production of OVA-specific IgM and IgG, including IgG1 and IgG2b antibodies, as well as enhanced secretion of IL-10 and IL-6, consistent with a Th2-type adjuvant effect. We also observe a moderate production of anti-FomA antibodies, suggesting that FomA is also immunogenic, a quality that is also TLR2 dependent. Therefore, modulation of host immune responses by FomA may be effective for targeting general host immunity not only to pathogens (as a novel TLR2 adjuvant) but also to F. nucleatum itself (as an antigen), expanding its use as a self-adjuvanted antigen in an immunization strategy against polymicrobial infections, including those by F. nucleatum. PMID:22623652

Toussi, Deana N; Liu, Xiuping; Massari, Paola

2012-07-01

187

Toll-Like Receptor Agonist Augments Virus-Like Particle-Mediated Protection from Ebola Virus with Transient Immune Activation  

PubMed Central

Identifying safe and effective adjuvants is critical for the advanced development of protein-based vaccines. Pattern recognition receptor (PRR) agonists are increasingly being explored as potential adjuvants, but there is concern that the efficacy of these molecules may be dependent on potentially dangerous levels of non-specific immune activation. The filovirus virus-like particle (VLP) vaccine protects mice, guinea pigs, and nonhuman primates from viral challenge. In this study, we explored the impact of a stabilized dsRNA mimic, polyICLC, on VLP vaccination of C57BL/6 mice and Hartley guinea pigs. We show that at dose levels as low as 100 ng, the adjuvant increased the efficacy of the vaccine in mice. Antigen-specific, polyfunctional CD4 and CD8 T cell responses and antibody responses increased significantly upon inclusion of adjuvant. To determine whether the efficacy of polyICLC correlated with systemic immune activation, we examined serum cytokine levels and cellular activation in the draining lymph node. PolyICLC administration was associated with increases in TNF?, IL6, MCP1, MIP1?, KC, and MIP1? levels in the periphery and with the activation of dendritic cells (DCs), NK cells, and B cells. However, this activation resolved within 24 to 72 hours at efficacious adjuvant dose levels. These studies are the first to examine the polyICLC-induced enhancement of antigen-specific immune responses in the context of non-specific immune activation, and they provide a framework from which to consider adjuvant dose levels. PMID:24586996

Martins, Karen A. O.; Steffens, Jesse T.; van Tongeren, Sean A.; Wells, Jay B.; Bergeron, Alison A.; Dickson, Samuel P.; Dye, John M.; Salazar, Andres M.; Bavari, Sina

2014-01-01

188

The FomA Porin from Fusobacterium nucleatum Is a Toll-Like Receptor 2 Agonist with Immune Adjuvant Activity  

PubMed Central

Many bacterial components selectively activate immune and nonhematopoietic target cells via Toll-like receptor (TLR) signaling; modulation of such host responses defines the immune adjuvant properties of these bacterial products. For example, the outer membrane protein porins from Neisseria, Salmonella, and Shigella are known TLR2 agonists with established systemic and mucosal immune adjuvanticity. Early work indicated that the FomA porin from Fusobacterium nucleatum has immune adjuvant activity in mice. Using a purified recombinant FomA, we have verified its immune stimulatory properties and have defined a role for TLR2 signaling in its in vitro and in vivo activity. FomA induces interleukin 8 (IL-8) secretion and NF-?B-dependent luciferase activity in HEK cells expressing TLR2, IL-6 secretion, and cell surface upregulation of CD86 and major histocompatibility complex (MHC) II in primary B cells from wild-type mice, but it fails to activate cells from TLR2 knockout mice. Accordingly, the immune adjuvant activity of FomA is also TLR2 dependent. In a mouse model of immunization with ovalbumin (OVA), FomA induces enhanced production of OVA-specific IgM and IgG, including IgG1 and IgG2b antibodies, as well as enhanced secretion of IL-10 and IL-6, consistent with a Th2-type adjuvant effect. We also observe a moderate production of anti-FomA antibodies, suggesting that FomA is also immunogenic, a quality that is also TLR2 dependent. Therefore, modulation of host immune responses by FomA may be effective for targeting general host immunity not only to pathogens (as a novel TLR2 adjuvant) but also to F. nucleatum itself (as an antigen), expanding its use as a self-adjuvanted antigen in an immunization strategy against polymicrobial infections, including those by F. nucleatum. PMID:22623652

Toussi, Deana N.; Liu, Xiuping

2012-01-01

189

Spot market activity remains weak as prices continue to fall  

SciTech Connect

A summary of financial data for the uranium spot market in November 1996 is provided. Price ranges for the restricted and unrestricted markets, conversion, and separative work are listed, and total market volume and new contracts are noted. Transactions made are briefly described. Deals made and pending in the spot concentrates, medium and long-term, conversion, and markets are listed for U.S. and non-U.S. buyers. Spot market activity increased in November with just over 1.0 million lbs of U3O8 equivalent being transacted compared to October`s total of 530,000 lbs of U3O8 equivalent. The restricted uranium spot market price range slipped from $15.50-$15.70/lb U3O8 last month to $14.85/lb - $15.25/lb U3O8 this month. The unrestricted uranium spot market price range also slipped to $14.85/lb - $15.00/lb this month from $15.00/lb - $15.45/lb in October. Spot prices for conversion and separative work units remained at their October levels.

NONE

1996-12-01

190

Peroxisome proliferators-activated alpha agonist treatment ameliorates hepatic damage in rats with obstructive jaundice: an experimental study  

PubMed Central

Background Peroxisome proliferators-activated receptor alpha (PPAR?) activation modulates cholesterol metabolism and suppresses bile acid synthesis. This study aims to evaluate the effect of short-term administration of fenofibrate, a PPAR? agonist, on proinflammatory cytokines, apoptosis, and hepatocellular damage in cholestasis. Methods Forty male Wistar rats were randomly divided into four groups: I = sham operated, II = bile duct ligation (BDL), III = BDL + vehicle (gum Arabic), IV = BDL + fenofibrate (100 mg/kg/day). All rats were sacrificed on 7th day after obtaining blood samples and liver tissue. Total bilirubin, aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP), gamma-glutamyl transferase, (GGT), tumor necrosis factor alpha (TNF-?), interleukin 1 beta (IL-1 ?), and total bile acid (TBA) in serum, and liver damage scores; portal inflammation, necrosis, bile duct number, in liver tissue were evaluated. Apoptosis in liver was also assessed by immunohistochemical staining. Results Fenofibrate administration significantly reduced serum total bilirubin, AST, ALT, ALP, and GGT, TNF-?, IL-1 ? levels, and TBA (P < 0.01). Hepatic portal inflammation, hepatic necrosis, number of the bile ducts and apoptosis in rats with BDL were more prominent than the sham-operated animals (P < 0.01). PPAR? induction improved all histopathologic parameters (P < 0.01), except for the number of the bile duct, which was markedly increased by fenofibrate therapy (P < 0.01). Conclusion Short-term administration of fenofibrate to the BDL rats exerts beneficial effects on hepatocellular damage and apoptosis. PMID:18045488

Cindoruk, Mehmet; Kerem, Mustafa; Karakan, Tarkan; Salman, Bulent; Akin, Okan; Alper, Murat; Erdem, Ozlem; Ünal, Selahattin

2007-01-01

191

Truncation of the peptide sequence in bifunctional ligands with mu and delta opioid receptor agonist and neurokinin 1 receptor antagonist activities  

PubMed Central

The optimization and truncation of our lead peptide-derived ligand TY005 possessing eight amino-acid residues was performed. Among the synthesized derivatives, NP30 (Tyr1-DAla2-Gly3-Phe4-Gly5-Trp6-O-[3?,5?-Bzl(CF3)2]) showed balanced and potent opioid agonist as well as substance P antagonist activities in isolated tissue-based assays, together with significant antinociceptive and antiallodynic activities in vivo. PMID:23899615

Nair, Padma; Yamamoto, Takashi; Largent-Milnes, Tally M.; Cowell, Scott; Kulkarni, Vinod; Moye, Sharif; Navratilova, Edita; Davis, Peg; Ma, Shou-Wu; Vanderah, Todd W.; Lai, Josephine; Porreca, Frank; Hruby, Victor J.

2013-01-01

192

An Agonist of Toll-Like Receptor 5 Has Radioprotective Activity in Mouse and Primate Models  

Microsoft Academic Search

The toxicity of ionizing radiation is associated with massive apoptosis in radiosensitive organs. Here, we investigate whether a drug that activates a signaling mechanism used by tumor cells to suppress apoptosis can protect healthy cells from the harmful effects of radiation. We studied CBLB502, a polypeptide drug derived from Salmonella flagellin that binds to Toll-like receptor 5 (TLR5) and activates

Lyudmila G. Burdelya; Vadim I. Krivokrysenko; Thomas C. Tallant; Evguenia Strom; Anatoly S. Gleiberman; Damodar Gupta; Oleg V. Kurnasov; Farrel L. Fort; Andrei L. Osterman; Joseph A. DiDonato; Elena Feinstein; Andrei V. Gudkov

2008-01-01

193

Isoproterenol Acts as a Biased Agonist of the Alpha-1A-Adrenoceptor that Selectively Activates the MAPK/ERK Pathway  

PubMed Central

The ?1A-AR is thought to couple predominantly to the G?q/PLC pathway and lead to phosphoinositide hydrolysis and calcium mobilization, although certain agonists acting at this receptor have been reported to trigger activation of arachidonic acid formation and MAPK pathways. For several G protein-coupled receptors (GPCRs) agonists can manifest a bias for activation of particular effector signaling output, i.e. not all agonists of a given GPCR generate responses through utilization of the same signaling cascade(s). Previous work with G?q coupling-defective variants of ?1A-AR, as well as a combination of Ca2+ channel blockers, uncovered cross-talk between ?1A-AR and ?2-AR that leads to potentiation of a G?q-independent signaling cascade in response to ?1A-AR activation. We hypothesized that molecules exist that act as biased agonists to selectively activate this pathway. In this report, isoproterenol (Iso), typically viewed as ?-AR-selective agonist, was examined with respect to activation of ?1A-AR. ?1A-AR selective antagonists were used to specifically block Iso evoked signaling in different cellular backgrounds and confirm its action at ?1A-AR. Iso induced signaling at ?1A-AR was further interrogated by probing steps along the G?q /PLC, G?s and MAPK/ERK pathways. In HEK-293/EBNA cells transiently transduced with ?1A-AR, and CHO_?1A-AR stable cells, Iso evoked low potency ERK activity as well as Ca2+ mobilization that could be blocked by ?1A-AR selective antagonists. The kinetics of Iso induced Ca2+ transients differed from typical G?q- mediated Ca2+ mobilization, lacking both the fast IP3R mediated response and the sustained phase of Ca2+ re-entry. Moreover, no inositol phosphate (IP) accumulation could be detected in either cell line after stimulation with Iso, but activation was accompanied by receptor internalization. Data are presented that indicate that Iso represents a novel type of ?1A-AR partial agonist with signaling bias toward MAPK/ERK signaling cascade that is likely independent of coupling to G?q. PMID:25606852

Copik, Alicja. J.; Baldys, Aleksander; Nguyen, Khanh; Sahdeo, Sunil; Ho, Hoangdung; Kosaka, Alan; Dietrich, Paul J.; Fitch, Bill; Raymond, John R.; Ford, Anthony P. D. W.; Button, Donald; Milla, Marcos E.

2015-01-01

194

The AMPK agonist AICAR inhibits TGF-?1 induced activation of kidney myofibroblasts.  

PubMed

Activation of interstitial myofibroblasts and excessive production of extracellular matrix proteins are common pathways that contribute to chronic kidney disease. In a number of tissues, AMP-activated kinase (AMPK) activation has been shown to inhibit fibrosis. Here, we examined the inhibitory effect of the AMPK activator, 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR), on renal fibrosis in vivo and TGF-?1-induced renal fibroblasts activation in vitro. A unilateral ureteral obstruction (UUO) model was induced in male BALB/c mice. Mice with UUO were administered AICAR (500 mg/Kg/day) or saline intraperitoneally 1 day before UUO surgery and daily thereafter. Both kidneys were harvested 7 days after surgery for further analysis. For the in vitro studies, NRK-49F rat fibroblasts were pre-incubated with AICAR before TGF-?1 stimulation. The inhibitory effects of AICAR on signaling pathways down-stream of TGF-?1 were analyzed. In UUO model mice, administration of AICAR attenuated extracellular matrix protein deposition and the expression of ?-smooth muscle actin (?-SMA), type I collagen and fibronectin. Pre-incubation of NRK-49F cells with AICAR inhibited TGF-?1-induced myofibroblast activation. Silencing of AMPK?1 by siRNA or by blocking AMPK activation with Compound C diminished the inhibitory effect of AICAR. Moreover, the inhibitory effects of AICAR on TGF-?1-mediated myofibroblast activation were associated with down-regulation of ERK 1/2 and STAT3. Our results suggest that AICAR reduces tubulointerstitial fibrosis in UUO mice and inhibits TGF-?1-induced kidney myofibroblast activation. AMPK activation by AICAR may have therapeutic potential for the treatment of renal tubulointerstitial fibrosis. PMID:25188319

Chen, Kuan-Hsing; Hsu, Hsiang-Hao; Lee, Cheng-Chia; Yen, Tzu-Hai; Ko, Yi-Ching; Yang, Chih-Wei; Hung, Cheng-Chieh

2014-01-01

195

The AMPK Agonist AICAR Inhibits TGF-?1 Induced Activation of Kidney Myofibroblasts  

PubMed Central

Activation of interstitial myofibroblasts and excessive production of extracellular matrix proteins are common pathways that contribute to chronic kidney disease. In a number of tissues, AMP-activated kinase (AMPK) activation has been shown to inhibit fibrosis. Here, we examined the inhibitory effect of the AMPK activator, 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR), on renal fibrosis in vivo and TGF-?1-induced renal fibroblasts activation in vitro. A unilateral ureteral obstruction (UUO) model was induced in male BALB/c mice. Mice with UUO were administered AICAR (500 mg/Kg/day) or saline intraperitoneally 1 day before UUO surgery and daily thereafter. Both kidneys were harvested 7 days after surgery for further analysis. For the in vitro studies, NRK-49F rat fibroblasts were pre-incubated with AICAR before TGF-?1 stimulation. The inhibitory effects of AICAR on signaling pathways down-stream of TGF-?1 were analyzed. In UUO model mice, administration of AICAR attenuated extracellular matrix protein deposition and the expression of ?-smooth muscle actin (?-SMA), type I collagen and fibronectin. Pre-incubation of NRK-49F cells with AICAR inhibited TGF-?1-induced myofibroblast activation. Silencing of AMPK?1 by siRNA or by blocking AMPK activation with Compound C diminished the inhibitory effect of AICAR. Moreover, the inhibitory effects of AICAR on TGF-?1-mediated myofibroblast activation were associated with down-regulation of ERK 1/2 and STAT3. Our results suggest that AICAR reduces tubulointerstitial fibrosis in UUO mice and inhibits TGF-?1-induced kidney myofibroblast activation. AMPK activation by AICAR may have therapeutic potential for the treatment of renal tubulointerstitial fibrosis. PMID:25188319

Chen, Kuan-Hsing; Hsu, Hsiang-Hao; Lee, Cheng-Chia; Yen, Tzu-Hai; Ko, Yi-Ching; Yang, Chih-Wei; Hung, Cheng-Chieh

2014-01-01

196

Agonists of Toll-like receptors 2 and 4 activate airway smooth muscle via mononuclear leukocytes  

Microsoft Academic Search

Rationale: Toll-like receptors 2 and 4 (TLR2, TLR4) enable cellular responsestobacteriallipoproteins,LPS,andendogenousmediators of cell damage. They have an established role in the activation of leukocytes, endothelial cells, and some smooth muscle cell types, but their roles in airway smooth muscle are uncertain. Objectives: To determine the roles of TLRs in activation of airway smooth muscle. Methods: Airway smooth muscle cells were

Gavin E Morris; Moira K B Whyte; Gillian F Martin; Peter J Jose; Steven K Dower; Ian Sabroe

2005-01-01

197

The ? opioid receptor agonist SNC80 selectively activates heteromeric ?-? opioid receptors.  

PubMed

Coexpressed and colocalized ?- and ?-opioid receptors have been established to exist as heteromers in cultured cells and in vivo. However the biological significance of opioid receptor heteromer activation is less clear. To explore this significance, the efficacy of selective activation of opioid receptors by SNC80 was assessed in vitro in cells singly and coexpressing opioid receptors using a chimeric G-protein-mediated calcium fluorescence assay, SNC80 produced a substantially more robust response in cells expressing ?-? heteromers than in all other cell lines. Intrathecal SNC80 administration in ?- and ?-opioid receptor knockout mice produced diminished antinociceptive activity compared with wild type. The combined in vivo and in vitro results suggest that SNC80 selectively activates ?-? heteromers to produce maximal antinociception. These data contrast with the current view that SNC80 selectively activates ?-opioid receptor homomers to produce antinociception. Thus, the data suggest that heteromeric ?-? receptors should be considered as a target when SNC80 is employed as a pharmacological tool in vivo. PMID:22860219

Metcalf, Matthew D; Yekkirala, Ajay S; Powers, Michael D; Kitto, Kelley F; Fairbanks, Carolyn A; Wilcox, George L; Portoghese, Philip S

2012-07-18

198

Differential Adjuvant Activities of TLR7 and TLR9 Agonists Inversely Correlate with Nitric Oxide and PGE2 Production  

PubMed Central

Activation of different pattern recognition receptors causes distinct profiles of innate immune responses, which in turn dictate the adaptive immune response. We found that mice had higher CD4+ T cell expansion to an immunogen, ovalbumin, when coadministered with CpG than with CL097 in vivo. To account for this differential adjuvanticity, we assessed the activities of CpG and CL097 on antigen-specific CD4+ T cell expansion in vitro using an OT-II CD4+ T cell/bone marrow-derived dendritic cell (DC) co-culture system. Unexpectedly, ovalbumin-stimulated expansion of OT-II CD4+ T cells in vitro was potently suppressed by both TLR agonists, with CL097 being stronger than CpG. The suppression was synergistically reversed by co-inhibition of cyclooxygenases 1 and 2, and inducible nitric oxide (NO) synthase. In addition, stimulation of OT-II CD4+ T cell/DC cultures with CL097 induced higher levels of CD4+ T cell death than stimulation with CpG, and this CD4+ T cell turnover was reversed by NO and PGE2 inhibition. Consistently, the co-cultures stimulated with CL097 produced higher levels of prostaglandin E2 (PGE2) and NO than stimulation with CpG. CL097 induced higher PGE2 production in DC cultures and higher IFN-? in the OT-II CD4+ T cell/DC cultures, accounting for the high levels of PGE2 and NO. This study demonstrates that the adjuvant activities of immunostimulatory molecules may be determined by differential induction of negative regulators, including NO and PGE2 suppressing clonal expansion and promoting cell death of CD4+ T cells. PMID:25875128

Lee, Jinhee; Martinez, Nuria; West, Kim; Kornfeld, Hardy

2015-01-01

199

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

200

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...

201

Activity of serotonin 5-HT1A receptor 'biased agonists' in rat models of Parkinson's disease and l-DOPA-induced dyskinesia.  

PubMed

Serotonin 5-HT1A receptor agonists reduce l-DOPA-induced dyskinesia (LID) in animal models of Parkinson's disease (PD). Here, we compared the effects of novel 5-HT1A receptor 'biased agonists' on LID in hemiparkinsonian rats. F13714 preferentially activates pre-synaptic 5-HT1A autoreceptors. F15599 preferentially activates cortical postsynaptic 5-HT1A heteroreceptors. The partial agonist, tandospirone, does not differentiate these receptor subpopulations. The drugs were also tested on rotational behavior, rotarod and cylinder test for evaluation of locomotor activity, motor coordination and forelimb akinesia. Finally, the effects of F13714 and F15599 on 5-HT, DA, glutamate, and GABA release were investigated by microdialysis. F13714 abolished l-DOPA-induced AIMs even at very low doses (0.02-0.04 mg/kg). This effect was reversed by the selective 5-HT1A receptor antagonist, WAY100635. F13714 also elicited ipsilateral rotations (which were blocked by WAY100635) and potentiated the rotational activity of a sub-threshold dose of l-DOPA (2 mg/kg). F13714 profoundly inhibited striatal 5-HT release on both sides of the brain, and slightly increased DA release on the intact side. F15599 inhibited the l-DOPA-induced AIMs only at a dose (0.16 mg/kg) that reduced 5-HT release. Tandospirone produced a modest attenuation of peak AIMs severity and did not elicit rotations. F13714, F15599 and tandospirone did not modify the action of l-DOPA in the cylinder test but impaired rotarod performance at the highest doses tested. Targeting 5-HT1A receptors with selective biased agonists exerts distinct effects in the rat model of PD and LID. Preferential activation of 5-HT1A autoreceptors could potentially translate to superior antidyskinetic and l-DOPA dose-sparing effects in PD patients. PMID:25645393

Iderberg, H; McCreary, A C; Varney, M A; Cenci, M A; Newman-Tancredi, A

2015-06-01

202

FXR agonist GW4064 alleviates endotoxin-induced hepatic inflammation by repressing macrophage activation  

PubMed Central

AIM: To examine the effect of farnesoid X receptor (FXR) activation by GW4064 on endotoxin-induced hepatic inflammation in nonalcoholic fatty liver disease (NAFLD) and the underlying mechanism. METHODS: Six-week-old male C57BL/6 mice were fed a normal diet or a high-fat (HF) diet for 8 wk. HF diet-fed mice were intraperitoneally injected with GW4064 (30 mg/kg) or DMSO (vehicle) once daily for a week and then sacrificed after lipopolysaccharide (LPS, 50 ?g/mouse) administration. Hepatic inflammation, levels of the macrophage marker F4/80, and apoptosis were measured at the end of the study. Additionally, the expression of proinflammatory genes involved in NAFLD (interleukin-6, interleukin-1?, interferon-?, MCP-1) were analyzed by real-time PCR in the murine macrophage cell line RAW 264.7 cultured with or without GW4064 (2 ?mol/L) before treatment with LPS. RESULTS: In patients with NAFLD, the expression of FXR was detected by immunohistochemical staining and the relation between FXR expression and NAFLD activity score (NAS) was analyzed. Activation of FXR by GW4064 alleviated hepatic inflammation induced by endotoxin in a murine NAFLD model fed an HF diet as reflected by reduced serum levels of aspartate aminotransferase and alanine aminotransferase. Apoptosis and proinflammatory cytokine levels in liver tissues were also reduced by GW4064, and GW4064 could reduce induction of proinflammatory cytokines by LPS in vitro. FXR levels were reduced in patients with non-alcoholic steatohepatitis compared with healthy controls and were negatively correlated with NAS. CONCLUSION: FXR activation attenuates LPS-induced hepatic inflammation in murine NAFLD by reducing expression of proinflammatory cytokines in macrophages. PMID:25339829

Yao, Jun; Zhou, Chun-Suo; Ma, Xiong; Fu, Bai-Qing; Tao, Li-Sheng; Chen, Miao; Xu, Ya-Ping

2014-01-01

203

Lasting modulation of in-vitro oscillatory activity with weak direct current stimulation  

E-print Network

University of New York, New York, USA December 3, 2014 Abstract Transcranial Direct Current Stimulation (t hypothesis. Introduction The number of studies on transcranial direct current stimulation (tDCS) has rapidlyLasting modulation of in-vitro oscillatory activity with weak direct current stimulation Davide

Parra, Lucas C.

204

New troglitazone derivatives devoid of PPAR? agonist activity display an increased antiproliferative effect in both hormone-dependent and hormone-independent breast cancer cell lines  

Microsoft Academic Search

Numerous recent studies indicate that most anticancer effects of PPAR? agonists like thiazolidinediones are the result of\\u000a PPAR?-independent pathways. These conclusions were obtained by several approaches including the use of thiazolidinedione derivatives\\u000a like ?2-Troglitazone (?2-TGZ) that does not activate PPAR?. Since biotinylation has been proposed as a mechanism able to increase\\u000a the specificity of drug delivery to cancer cells which

Christelle ColinStephane; Stéphane Salamone; Isabelle Grillier-Vuissoz; Michel Boisbrun; Sandra Kuntz; Julie Lecomte; Yves Chapleur; Stéphane Flament

2010-01-01

205

Comparison of the effects of NMDA and AMPA antagonists on the locomotor activity induced by selective D 1 and D 2 dopamine agonists in reserpine-treated mice  

Microsoft Academic Search

This study examined the interaction between various glutamate antagonists and selective D1 (SKF 38393) and D2 (RU 24213) dopamine agonists in the production of locomotion in the reserpine-treated mouse. Firstly, in normal mice, the NMDA channel blocker MK 801 (0.1–1.6 mg\\/kg) caused a biphasic stimulation\\/depression of locomotor activity, whereas the competitive NMDA antagonists CGP 40116 (0.25–8 mg\\/kg) and CPP (0.2–20

M. S. Starr; B. S. Starr

1994-01-01

206

[Structure-activity relationship of novel vitamin K analogues as steroid and xenobiotic receptor (SXR) agonists].  

PubMed

Vitamin K2 is a ligand for a nuclear receptor, steroid and xenobiotic receptor (SXR), that induces the gene expressions of CYP3A4. We synthesized new vitamin K analogues with the same isoprene side chains symmetrically introduced at the 2 and 3 positions of 1,4-naphthoquinone and vitamin K2 analogues with hydroxyl or phenyl groups at the ?-terminal of the side chain. The upregulation of SXR-mediated transcription of the target gene by the analogues was dependent on the length of the side chain and the hydrophobicity of the ?-terminal residues. Phenyl analogue menaquinone-3 was as active as the known SXR ligand rifampicin. PMID:22864345

Suhara, Yoshitomo; Motoyoshi, Sayaka; Hirota, Yoshihisa; Sawada, Natsumi; Nakagawa, Kimie; Tokiwa, Hiroaki; Okano, Toshio

2012-01-01

207

The spinal antinociceptive activity of the alpha 2-adrenoceptor agonist, xylazine in sheep.  

PubMed Central

1. The intrathecal administration of xylazine (100 micrograms), via a chronic indwelling, cervical intrathecal catheter, produced a marked elevation of the mechanical nociceptive thresholds in the sheep. This antinociceptive effect was abolished by the prior intrathecal administration of the alpha 2-adrenoceptor antagonist, idazoxan. 2. The intrathecal administration of the selective alpha 2-antagonists, idazoxan (100 micrograms) and RX811059 (33 micrograms), significantly attenuated the antinociceptive activity of intravenous xylazine, with a 60-65% reduction in the area under the antinociceptive curve. The intrathecal administration of the antagonists alone had no significant effect on nociceptive thresholds. 3. Examination of the distribution of tritiated idazoxan (25 microCi in 100 microliters) indicated that the site of action of the drug was limited to the cervical spinal cord after intrathecal administration. 4. These studies demonstrate that a significant proportion of the antinociceptive effect of systemically administered xylazine is mediated by spinal alpha 2-adrenoceptors. PMID:8097956

Kyles, A. E.; Waterman, A. E.; Livingston, A.

1993-01-01

208

Effects of intravenous administration of neurokinin receptor subtype-selective agonists on gonadotropin-releasing hormone pulse generator activity and luteinizing hormone secretion in goats  

PubMed Central

Recent evidence suggests that neurokinin B (NKB), a member of the neurokinin (tachykinin) peptide family, plays a pivotal role in gonadotropin-releasing hormone (GnRH) pulse generation. Three types of neurokinin receptors (NKRs), NK1R, NK2R and NK3R, are found in the brain. Although NKB preferentially binds to NK3R, other NKRs are possibly also involved in NKB action. The present study examined the effects of intravenous administration of the NKR subtype-selective agonists GR73632 (NK1R), GR64349 (NK2R), and senktide (NK3R) on GnRH pulse generator activity and luteinizing hormone (LH) secretion. Multiple-unit activity (MUA) was monitored in ovariectomized goats (n = 5) implanted with recording electrodes. Characteristic increases in MUA (MUA volleys) were considered GnRH pulse generator activity. Although three NKR agonists dose-dependently induced an MUA volley and an accompanying increase in LH secretion, the efficacy in inducing the volley markedly differed. As little as 10 nmol of senktide induced an MUA volley in all goats, whereas a dose of 1000 nmol was only effective for the NK1R and NK2R agonists in two and four goats, respectively. When the treatment failed to evoke an MUA volley, no apparent change was observed in the MUA or LH secretion. Similar effects of the NK2R and NK3R agonists were observed in the presence of estradiol. The results demonstrated that NK3R plays a predominant role in GnRH pulse generation and suggested that the contributions of NK1R and NK2R to this mechanism may be few, if any, in goats. PMID:25345909

YAMAMURA, Takashi; WAKABAYASHI, Yoshihiro; OHKURA, Satoshi; NAVARRO, Victor M.; OKAMURA, Hiroaki

2014-01-01

209

Effects of intravenous administration of neurokinin receptor subtype-selective agonists on gonadotropin-releasing hormone pulse generator activity and luteinizing hormone secretion in goats.  

PubMed

Recent evidence suggests that neurokinin B (NKB), a member of the neurokinin (tachykinin) peptide family, plays a pivotal role in gonadotropin-releasing hormone (GnRH) pulse generation. Three types of neurokinin receptors (NKRs), NK1R, NK2R and NK3R, are found in the brain. Although NKB preferentially binds to NK3R, other NKRs are possibly also involved in NKB action. The present study examined the effects of intravenous administration of the NKR subtype-selective agonists GR73632 (NK1R), GR64349 (NK2R), and senktide (NK3R) on GnRH pulse generator activity and luteinizing hormone (LH) secretion. Multiple-unit activity (MUA) was monitored in ovariectomized goats (n = 5) implanted with recording electrodes. Characteristic increases in MUA (MUA volleys) were considered GnRH pulse generator activity. Although three NKR agonists dose-dependently induced an MUA volley and an accompanying increase in LH secretion, the efficacy in inducing the volley markedly differed. As little as 10 nmol of senktide induced an MUA volley in all goats, whereas a dose of 1000 nmol was only effective for the NK1R and NK2R agonists in two and four goats, respectively. When the treatment failed to evoke an MUA volley, no apparent change was observed in the MUA or LH secretion. Similar effects of the NK2R and NK3R agonists were observed in the presence of estradiol. The results demonstrated that NK3R plays a predominant role in GnRH pulse generation and suggested that the contributions of NK1R and NK2R to this mechanism may be few, if any, in goats. PMID:25345909

Yamamura, Takashi; Wakabayashi, Yoshihiro; Ohkura, Satoshi; Navarro, Victor M; Okamura, Hiroaki

2015-02-24

210

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

211

Structural Basis for Iloprost as a Dual Peroxisome Proliferator-activated Receptor ?/? Agonist*  

PubMed Central

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? ligand-binding domain and PPAR? 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?/? by this prostacyclin analog. In addition to conserved contacts for all PPAR? 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?/? 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. PMID:21775429

Jin, Lihua; Lin, Shengchen; Rong, Hui; Zheng, Songyang; Jin, Shikan; Wang, Rui; Li, Yong

2011-01-01

212

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

213

alpha(1B)- and alpha(1D)-Adrenergic receptors exhibit different requirements for agonist and mitogen-activated protein kinase activation to regulate growth responses in rat 1 fibroblasts.  

PubMed

We compared DNA replication, protein biosynthesis, and mitogen-activated protein kinase (MAPK) activity in Rat 1 fibroblasts stably expressing either the alpha(1B)-adrenergic receptor (AR) or alpha(1D)-AR subtypes. Activation of both the alpha(1B)-AR and alpha(1D)-AR inhibited DNA synthesis (as assessed by [(3)H]thymidine incorporation). In contrast, both receptors stimulated protein biosynthesis (as measured by [(35)S]methionine incorporation) and activated extracellular signal-regulated kinase (ERK)1/2. Importantly, these responses were agonist-dependent for the alpha(1B)-AR, but were agonist-independent for the alpha(1D)-AR. Agonist activation of the alpha(1B)-AR resulted in increased p38 kinase activity, but not c-Jun NH(2)-terminal kinase (JNK) activity, whereas the alpha(1D)-AR activated JNK but not p38 kinase. Unlike ERK1/2, JNK activity was increased by agonist treatment in the alpha(1D)-AR cells. An ERK1/2-pathway inhibitor PD98059 had no effect on phenylephrine-mediated inhibition of DNA synthesis in either cell line but blocked protein biosynthesis mediated by both receptors. The p38 kinase inhibitor SB203580 blocked alpha(1B)-AR effects on [(3)H]thymidine and [(35)S]methionine incorporation in alpha(1B)-AR-expressing cells, but had no effect on alpha(1D)-AR-mediated growth responses, consistent with the inability of the alpha(1D)-AR to activate p38 kinase. Therefore, alpha(1B)- and alpha(1D)-ARs mediated similar growth responses but differ with respect to the MAPK family member involved and the requirement for agonist. PMID:11752101

Waldrop, Bruce A; Mastalerz, Diana; Piascik, Michael T; Post, Ginell R

2002-01-01

214

The QBO and weak external forcing by solar activity: A three dimensional model study  

NASA Technical Reports Server (NTRS)

A better understanding is attempted of the physical mechanisms leading to significant correlations between oscillations in the lower and middle stratosphere and solar variability associated with the sun's rotation. A global 3-d mechanistic model of the middle atmosphere is employed to investigate the effects of minor artificially induced perturbations. The aim is to explore the physical mechanisms of the dynamical response especially of the stratosphere to weak external forcing as it may result from UV flux changes due to solar rotation. First results of numerical experiments dealing about the external forcing of the middle atmosphere by solar activity were presented elsewhere. Different numerical studies regarding the excitation and propagation of weak perturbations have been continued since then. The model calculations presented are made to investigate the influence of the quasi-biennial oscillation (QBO) on the dynamical response of the middle atmosphere to weak perturbations by employing different initial wind fields which represent the west and east phase of the QBO.

Dameris, M.; Ebel, A.

1989-01-01

215

5-Hydroxytryptamine receptor activity of the dopamine receptor agonist fenoldopam in canine tracheal smooth muscle.  

PubMed

Fenoldopam is a new vasodilator undergoing clinical trials for the treatment of hypertensive emergencies. Its pharmacologic effects result from activation of vascular dopamine-1 receptors. In canine tracheal smooth muscle strips, fenoldopam caused a concentration- and calcium-dependent increase in tension, which was not antagonized by atropine, indomethacin or the dopamine-1 receptor antagonist, SCH 23390. The EC50 (1.89 x 10(-6) M) exceeded that of serotonin or acetylcholine (8.38 x 10(-8) and 8.25 x 10(-8) M, respectively). Maximum tension was similar for fenoldopam and serotonin (11.6 +/- 1.5 g, n = 7 and 13.8 +/- 0.8 g, n = 24; P greater than .2) and considerably greater for acetylcholine (20.5 +/- 1.3 g, n = 14; P less than .005). The serotonin antagonists ketanserin and methysergide reversed completely the effect of fenoldopam (5 x 10(-7) M) with IC50 values of 2.5 x 10(-9) and 2.7 x 10(-9) M, respectively. Phentolamine, rauwolscine and chlorpheniramine were also effective, but they were less potent (IC50 values 6.6 x 10(-8), 1.0 x 10(-7) and 1.7 x 10(-7) M, respectively). By contrast, only very high concentrations (IC50, 5.3 x 10(-5) M) of terazosin produced an inhibition of fenoldopam-induced tension increases. The effect of antagonists could be overcome by increasing the fenoldopam concentration. Experiments performed on strips precontracted with serotonin (5 x 10(-8) M) revealed a very similar order of potency for the five antagonists. The addition of serotonin did not increase the tension produced by supramaximal concentrations of fenoldopam (and vice-versa), whereas acetylcholine increased tension further.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1346635

Gretler, D D; Jones, K C; Murphy, M B

1992-02-01

216

A Robotic MCF-7:WS8 Cell Proliferation Assay to Detect Agonist and Antagonist Estrogenic Activity  

PubMed Central

Endocrine-disrupting chemicals with estrogenic activity (EA) or anti-EA (AEA) have been extensively reported to possibly have many adverse health effects. We have developed robotized assays using MCF-7:WS8 cell proliferation (or suppression) to detect EA (or AEA) of 78 test substances supplied by the Interagency Coordinating Committee on the Validation of Alternative Methods and the National Toxicology Program’s Interagency Center for the Evaluation of Alternative Toxicological Methods for validation studies. We also assayed ICI 182,780, a strong estrogen antagonist. Chemicals to be assayed were initially examined for solubility and volatility to determine optimal assay conditions. For both EA and AEA determinations, a Range-Finder assay was conducted to determine the concentration range for testing, followed by a Comprehensive assay. Test substances with potentially positive results from an EA Comprehensive assay were subjected to an EA Confirmation assay that evaluated the ability of ICI 182,780 to reverse chemically induced MCF-7 cell proliferation. The AEA assays examined the ability of chemicals to decrease MCF-7 cell proliferation induced by nonsaturating concentrations of 17?-estradiol (E2), relative to ICI or raloxifene, also a strong estrogen antagonist. To be classified as having AEA, a saturating concentration of E2 had to significantly reverse the decrease in cell proliferation produced by the test substance in nonsaturating E2. We conclude that our robotized MCF-7 EA and AEA assays have accuracy, sensitivity, and specificity values at least equivalent to validated test methods accepted by the U.S. Environmental Protection Agency and the Organisation for Economic Co-operation and Development. PMID:24213142

Casey, Warren

2014-01-01

217

Dihydropyridine agonist Bay K 8644 inhibits platelet activation by competitive antagonism of thromboxane A2-prostaglandin H2 receptor.  

PubMed

The dihydropyridine calcium channel antagonists, such as nifedipine, inhibit platelet aggregation in vitro and ex vivo, but the mechanism by which this occurs is uncertain. Bay K 8644 (BAY) is a substituted dihydropyridine that has effects on voltage-dependent calcium channels in cardiac and smooth muscle that are opposite the effects of nifedipine. To evaluate the mechanism responsible for dihydropyridine-induced inhibition of platelet function, we studied the in vitro effects of BAY on human platelet aggregation and secretion plus several related biochemical parameters, including cytoplasmic ionized calcium ([Ca2+]i). BAY exerted concentration-dependent effects on platelet aggregation and secretion of [14C]serotonin. BAY (1-10 microns) inhibited the second wave of platelet aggregation and secretion stimulated by adenosine diphosphate or epinephrine and blocked shape change, aggregation, and secretion induced by the thromboxane A2 (TXA2) mimic, U46619. BAY also inhibited U46619-induced phosphorylation of the approximately 40,000-dalton cytoplasmic protein substrate of protein kinase C (40K protein), formation of TXA2, and rise in [Ca2+]i, all biochemical consequences of platelet activation. The (+)-(R) enantiomer of BAY [BAY(+)] was predominantly responsible for the inhibitory effects of racemic BAY. Nifedipine had the same inhibitory effects on platelet function and biochemistry, except it was approximately 10 times less potent than BAY. Since these results suggested inhibition of the TXA2-prostaglandin H2 (PGH2) receptor, we measured binding of [3H]U46619 to intact platelets. BAY, BAY(+), and nifedipine all functioned as competitive antagonists of [3H]U46619 binding (BAY Ki = 1.47 microM). They did not inhibit binding of [3H]yohimbine to platelet alpha 2-adrenergic receptors. At 1-10 nM BAY, BAY(+) and the (-)-(S) enantiomer of BAY [BAY(-)] all resulted in slight stimulation of platelet function and biochemical events. No significant increase in [3H]U46619 binding was demonstrable, however. Therefore, dihydropyridines that function as either calcium channel agonists or antagonists in cardiac or smooth muscle exert concentration-dependent effects on platelet function. In nanomolar concentrations, they augment, and in micromolar concentrations, they inhibit platelet activation induced by TXA2 or U46619. These data indicate that dihydropyridines do not inhibit TXA2-induced platelet activation by an effect on voltage-dependent calcium channels; they define the mechanism of inhibition as competitive antagonism of the TXA2-PGH2 receptor. The mechanism responsible for augmentation of platelet activation is uncertain.(ABSTRACT TRUNCATED AT 400 WORDS) PMID:2449295

Johnson, G J; Dunlop, P C; Leis, L A; From, A H

1988-03-01

218

Pharmacokinetic properties of MH84, a ?-secretase modulator with PPAR? agonistic activity.  

PubMed

Alzheimer's disease (AD) is the most common cause of dementia. Since no causative treatment is available, new therapeutic options are utmost needed. Several pirinixic acid derivatives, including MH84 (2-((4,6-bis(4-(trifluoromethyl)phenethoxy)pyrimidin-2-yl)thio)hexanoic acid), have shown promising in vitro results as ?-secretase modulators as well as PPAR? activators as potential pharmacological compounds against AD. Using a newly developed and validated sensitive LC-MS (APCI-qTOF mass analyzer) method, the pharmacokinetic and long-term accumulating properties as well as the blood-brain-barrier permeability of MH84 were evaluated in a preclinical animal study. MH84 was administered to mice by oral gavage with a dose of 12 mg/kg. Nine time points from 0.5 to 48 h with 6 animals per point were investigated. Additionally 6 animals were fed daily, for 21 days with an identical dose to determine possible long-term accumulation in plasma and brain tissue. The sample preparation was performed by a liquid-liquid extraction on Extrelut(®) columns whereas the LC separation was operated on a MulthoHigh 100 RP 18-5 ? column (125 × 4 mm) using an isocratic mobile phase of formic acid (0.1% (v/v))-methanol mixture (11:89 (v/v)) at a flow rate of 1 ml/min. The validation confirmed the new LC-MS method to be precise, accurate and reliable. After oral application, Cmax and Tmax of unmetabolized MH84 was determined to be 10.90 ?g/ml and 3h in plasma. In brain tissue a constant level of 300 to maximum 320.64 ng/g was found after 1.5-6h. Daily gavage for 21 days did not lead to a long-term drug accumulation in the brain. The efficacy of the obtained MH84 levels needs to be investigated in further preclinical pharmacodynamic animal studies. PMID:25459941

Pellowska, M; Stein, C; Pohland, M; Merk, D; Klein, J; Eckert, G P; Schubert-Zsilavecz, M; Wurglics, M

2015-01-01

219

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

220

Identification of compounds by high-content screening that induce cytoplasmic to nuclear localization of a fluorescent estrogen receptor ? chimera and exhibit agonist or antagonist activity in vitro.  

PubMed

We have completed a robust high-content imaging screen for novel estrogen receptor ? (ER?) agonists and antagonists by quantitation of cytoplasmic to nuclear translocation of an estrogen receptor chimera in 384-well plates. The screen was very robust, with Z' values >0.7 and coefficients of variation (CV) <5%. The screen utilized a stably transfected green fluorescent protein-tagged glucocorticoid/estrogen receptor (GFP-GRER) chimera, which consisted of the N-terminus of the glucocorticoid receptor fused to the human ER? ligand binding domain. The GFP-GRER exhibited cytoplasmic localization in the absence of ER? ligands and translocated to the nucleus in response to stimulation with ER? agonists and antagonists. The BD Pathway 435 imaging system was used for image acquisition, analysis of translocation dynamics, and cytotoxicity measurements. We screened 224,891 samples from our synthetic, pure natural product libraries, prefractionated natural product extracts library, and crude natural product extracts library, which produced a 0.003% hit rate. In addition to identifying several known ER ligands, five compounds were discovered that elicited significant activity in the screen. Transactivation potential studies demonstrated that two hit compounds behave as agonists, while three compounds elicited antagonist activity in MCF-7 cells. PMID:24051224

Dull, Angie B; George, Anuja A; Goncharova, Ekaterina I; Evans, Jason R; Wamiru, Antony; Cartner, Laura K; Hager, Gordon L; McMahon, James B

2014-02-01

221

[Dopanergic agonists and schizophrenia].  

PubMed

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

Pidgeon, J F; Wolf, M A

1989-11-01

222

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. PMID:20958291

Jenkins, Laura; Alvarez-Curto, Elisa; Campbell, Kate; de Munnik, Sabrina; Canals, Meritxell; Schlyer, Sabine; Milligan, Graeme

2011-01-01

223

Pharmacological evidence of bradykinin regeneration from extended sequences that behave as peptidase–activated B2 receptor agonists  

PubMed Central

While bradykinin (BK) is known to be degraded by angiotensin converting enzyme (ACE), we have recently discovered that Met-Lys-BK-Ser-Ser is paradoxically activated by ACE. We designed and evaluated additional “prodrug” peptides extended around the BK sequence as potential ligands that could be locally activated by vascular or blood plasma peptidases. BK regeneration was estimated using the contractility of the human umbilical vein as model of vascular functions mediated by endogenous B2 receptors (B2Rs) and the endocytosis of the fusion protein B2R-green fluorescent protein (B2R-GFP) expressed in Human Embryonic Kidney 293 cells. Of three BK sequences extended by a C-terminal dipeptide, BK-His-Leu had the most desirable profile, exhibiting little direct affinity for the receptor but a significant one for ACE (as shown by competition of [3H]BK binding to B2R-GFP or of [3H]enalaprilat to recombinant ACE, respectively). The potency of the contractile effect of this analog on the vein was reduced 18-fold by the ACE inhibitor enalaprilat, pharmacologically evidencing BK regeneration in situ. BK-Arg, a potential substrate of arginine carboxypeptidases, had a low affinity for B2Rs and its potency as a contractile agent was reduced 15-fold by tissue treatment with an inhibitor of these enzymes, Plummer’s inhibitor. B2R-GFP internalization in response to 100 nM of the extended peptides recapitulated these findings, as enalaprilat selectively inhibited the effect of BK-His-Leu and Plummer’s inhibitor, that of BK-Arg. The two peptidase inhibitors did not affect BK-induced effects in either assay. The novel C-terminally extended BKs had no or very little affinity for the kinin B1 receptor (competition of [3H]Lys-des-Arg9-BK binding). The feasibility of peptidase-activated B2R agonists is illustrated by C-terminal extensions of the BK sequence. PMID:24639651

Charest-Morin, Xavier; Roy, Caroline; Fortin, Émile-Jacques; Bouthillier, Johanne; Marceau, François

2014-01-01

224

NICOTINE EFFECTS ON THE MOTOR ACTIVITY OF MICE EXPOSED PRENATALLY TO THE NICOTINIC AGONIST ANATOXIN-A.  

EPA Science Inventory

Several studies in the literature have shown that exposure of mice and rats to nicotine early in development alters its effects when the rodents are subsequently challenged with nicotine. Anatoxin-a is a nicotinic agonist produced by several genera of cyanobacteria, and has caus...

225

Evaluation of the insulin releasing and antihyperglycaemic activities of GPR55 lipid agonists using clonal beta-cells, isolated pancreatic islets and mice  

PubMed Central

Background and Purpose G-protein coupled receptor (GPR)55 is a novel lipid sensing receptor activated by both cannabinoid endogenous ligands (endocannabinoids) and other non-cannabinoid lipid transmitters. This study assessed the effects of various GPR55 agonists on glucose homeostasis. Experimental Approach Insulin secretion and changes in intracellular Ca2+ and cAMP in response to glucose and a range of GPR55 agonists [endogenous ligands (OEA, PEA), chemically synthetic cannabidiol (CBD) analogues (Abn-CBD, 0–1602), an analogue of rimonabant (AM-251) and antagonist (CBD)] were investigated in clonal BRIN-BD11 cells and mouse pancreatic islets. Cytotoxicity was assessed by LDH release, cellular localization by double-staining immunohistochemistry and in vivo effects assessed in mice. Key Results The most potent and selective GPR55 agonist was the synthetic CBD analogue, Abn-CBD (pEC50 10.33), maximum stimulation of 67% at 10?4?mol·L?1 (P < 0.001) in BRIN-BD11 cells. AM-251 (pEC50 7.0), OEA (pEC50 7.0), 0–1602 (pEC50 7.3) and PEA (pEC50 6.0) stimulated insulin secretion. Results were corroborated by islet studies, with no cytotoxic effects. Concentration-dependent insulin secretion by GPR55 agonists was glucose-sensitive and accompanied by elevations of [Ca2+]i (P < 0.01–P < 0.001) and cAMP (P < 0.05–P < 0.01). GPR55 agonists exhibited insulinotropic and glucose lowering activity in vivo. GPR55 was expressed on BRIN-BD11 cells and confined to islet beta cells with no distribution on alpha cells. Conclusion and Implications These results demonstrate GPR55 is distributed in pancreatic beta cells and is a strong activator of insulin secretion, with glucose-lowering effects in vivo. Development of agents agonizing the GPR55 receptor may have therapeutic potential in the treatment of type 2 diabetes. PMID:23992544

McKillop, A M; Moran, B M; Abdel-Wahab, Y H A; Flatt, P R

2013-01-01

226

Anti-conflict effect of 5-HT1A agonists in rats: a new model for evaluating anxiolytic-like activity.  

PubMed

A new conflict procedure was developed to study the potential anti-punishment effects of 5-HT( 1A) agonists as compared to diazepam. In this paradigm, the opportunity existed for rats to choose during punished periods between immediate, punished reinforcement and delayed, non-punished reinforcement. The results confirm that, for non-sedative doses (1 mg/kg), diazepam increases the number of punished responses. Furthermore, the present paradigm seems sensitive for the detection of 5-HT(1A) activity. Buspirone, gepirone, ipsapirone, zalospirone and 8-OH-DPAT increased responding for immediate but punished reinforcement. 1-(2-pyrimidinyl)piperazine, the common metabolite of the azapirones, does not participate in their anti-conflict effect. NAN 190, a 5-HT(1A) antagonist, was shown to block the 5-HT(1A) agonists. The findings of the present study suggest that benzodiazepines and 5-HT( 1A) agonists reduce the capacity to tolerate delays in reward. Abnormality in serotonin systems may be associated with poor impulse control. PMID:22298629

Hascoët, M; Bourin, M; Todd, K G; Coüetoux du Tertre, A

1994-01-01

227

Activation of GPR119 by fatty acid agonists augments insulin release from clonal ?-cells and isolated pancreatic islets and improves glucose tolerance in mice.  

PubMed

G-protein coupled receptor 119 (GPR119) is emerging as a potential target for the treatment of type 2 diabetes with beneficial effects on glucose homeostasis. This study assessed the insulin-secreting properties of various GPR119 agonists and the distribution of GPR119 in pancreatic islets. Endogenous ligands [oleoylethanolamide (OEA), palmitoylethanolamine (PEA)] and chemically synthetic analogues (AS-1269574, PSN-375963) were investigated in clonal BRIN-BD11 cells and mouse pancreatic islets. Secondary messenger assays such as intracellular Ca²? and cAMP in response to agonists at normoglycaemic and hyperglycaemic conditions were assessed. Cytotoxicity was assessed by LDH release. AS-1269574 was the most potent and selective agonist tested in isolated islets, with an EC?? value of 9.7×10?? mol/l, enhancing insulin release maximally by 63.2%. Stimulation was also observed with GPR119 ligands; OEA (3.0×10?? mol/l; 37.5%), PSN-375963 (2.4×10?? mol/l; 28.7%) and PEA (1.2×10?? mol/l; 22.2%). Results were corroborated by studies using BRIN-BD11 cells, which revealed augmentation of intracellular Ca²? and cAMP. Both OEA and AS-1269574 enhanced insulin release and improved glucose tolerance in vivo in NIH Swiss mice. These results demonstrate the cellular localisation of GPR119 on islet cells (? and pancreatic polypeptide cells), its activation of the ?-cell stimulus-secretion coupling pathway and glucose lowering effects in vivo. PMID:24323890

Moran, Brian M; Abdel-Wahab, Yasser H A; Flatt, Peter R; McKillop, Aine M

2014-04-01

228

Differential induction of nitric oxide, degranulation, and oxidative burst activities in response to microbial agonist stimulations in monocytes and heterophils from young commercial turkeys.  

PubMed

The toll-like receptors (TLRs) recognize microbial pathogens and pathogen-associated molecular patterns and trigger inflammatory immune responses to control the infection. Here, we examined functional innate immune responses to Salmonella enteritidis (SE, live or formalin-killed) and various TLR agonists including lipoteichoic acid (LTA) and peptidoglycan (PGN) from Staphylococcus aureus and synthetic lipoprotein Pam3CSK4 (PAM), poly I:C (synthetic double-stranded RNA analog), lipopolysaccharide (LPS) from S. enteritidis, flagellin (FGN) from S. typhimurium, loxoribine (LOX) and R837 (synthetic anti-viral compounds), and CpG oligodeoxydinucleotide (CpG ODN)by measuring antimicrobial activities including oxidative burst and degranulation in heterophils and nitric oxide production in peripheral blood monocytes. Our results demonstrate differential nitric oxide responses to TLR agonists in turkey monocytes. LTA and CpG ODN were the most potent stimuli for nitric oxide induction followed by PAM, poly I:C, and LPS, whereas FGN, PGN, LOX, R837, and control ODN stimulated little or no nitric oxide production. Live SE stimulated significantly less NO production than formalin-killed SE (FKSE). Although FKSE induced significant degranulation and oxidative burst, most TLR agonists stimulate little oxidative burst and degranulation responses in turkey heterophils. PMID:18304649

He, Haiqi; Genovese, Kenneth J; Swaggerty, Christina L; Nisbet, David J; Kogut, Michael H

2008-06-15

229

A Structure–Activity Relationship Study and Combinatorial Synthetic Approach of C-Terminal Modified Bifunctional Peptides That Are ?/? Opioid Receptor Agonists and Neurokinin 1 Receptor Antagonists  

PubMed Central

A series of bifunctional peptides with opioid agonist and substance P antagonist bioactivities were designed with the concept of overlapping pharmacophores. In this concept, the bifunctional peptides were expected to interact with each receptor separately in the spinal dorsal horn where both the opioid receptors and the NK1 receptors were found to be expressed, to show an enhanced analgesic effect, no opioid-induced tolerance, and to provide better compliance than coadministration of two drugs. Compounds were synthesized using a two-step combinatorial method for C-terminal modification. In the method, the protected C-terminal-free carboxyl peptide, Boc-Tyr(tBu)-d-Ala-Gly Phe-Pro-Leu-Trp(Boc)-OH, was synthesized as a shared intermediate using Fmoc solid phase chemistry on a 2-chlorotrityl resin. This intermediate was esterified or amidated in solution phase. The structure–activity relationships (SAR) showed that the C-terminus acted as not only a critical pharmacophore for the substance P antagonist activities, but as an address region for the opioid agonist pharmacophore that is structurally distant from the C-terminal. Among the peptides, H-Tyr-d-Ala-Gly-Phe-Pro-Leu-Trp-NH-Bzl (3) demonstrated high binding affinities at both ? and ? receptors (Ki = 10 and 0.65 nM, respectively) with efficient agonist functional activity in the mouse isolated vas deferens (MVD) and guinea pig isolated ileum (GPI) assays (IC50 = 50 and 13 nM, respectively). Compound 3 also showed a good antagonist activity in the GPI assay with substance P stimulation (Ke = 26 nM) and good affinity for the hNK1 receptor (Ki = 14 nM). Consequently, compound 3 is expected to be a promising and novel type of analgesic with bifunctional activities. PMID:18266313

Yamamoto, Takashi; Nair, Padma; Vagner, Josef; Largent-Milnes, Tally; Davis, Peg; Ma, Shou-wu; Navratilova, Edita; Moye, Sharif; Tumati, Suneeta; Lai, Josephine; Yamamura, Henry I.; Vanderah, Todd W.; Porreca, Frank; Hruby, Victor J.

2009-01-01

230

A selective inverse agonist for central cannabinoid receptor inhibits mitogen-activated protein kinase activation stimulated by insulin or insulin-like growth factor 1. Evidence for a new model of receptor/ligand interactions.  

PubMed

In the present study, we showed that Chinese hamster ovary (CHO) cells transfected with human central cannabinoid receptor (CB1) exhibit high constitutive activity at both levels of mitogen-activated protein kinase (MAPK) and adenylyl cyclase. These activities could be blocked by the CB1-selective ligand, SR 141716A, that functions as an inverse agonist. Moreover, binding studies showed that guanine nucleotides decreased the binding of the agonist CP-55,940, an effect usually observed with agonists, whereas it enhanced the binding of SR 141716A, a property of inverse agonists. Unexpectedly, we found that CB1-mediated effects of SR 141716A included inhibition of MAPK activation by pertussis toxin-sensitive receptor-tyrosine kinase such as insulin or insulin-like growth factor 1 receptors but not by pertussis toxin-insensitive receptor-tyrosine kinase such as the fibroblast growth factor receptor. We also observed similar results when cells were stimulated with Mas-7, a mastoparan analog, that directly activates the Gi protein. Furthermore, SR 141716A inhibited guanosine 5'-0-(thiotriphosphate) uptake induced by CP-55,940 or Mas-7 in CHO-CB1 cell membranes. This indicates that, in addition to the inhibition of autoactivated CB1, SR 141716A can deliver a biological signal that blocks the Gi protein and consequently abrogates most of the Gi-mediated responses. By contrast, SR 141716A had no effect on MAPK activation by insulin or IGF1 in CHO cells lacking CB1 receptors, ruling out the possibility of a direct interaction of SR 141716A with the Gi protein. This supports the notion that the Gi protein may act as a negative intracellular signaling cross-talk molecule. From these original results, which considerably enlarge the biological properties of the inverse agonist, we propose a novel model for receptor/ligand interactions. PMID:9268384

Bouaboula, M; Perrachon, S; Milligan, L; Canat, X; Rinaldi-Carmona, M; Portier, M; Barth, F; Calandra, B; Pecceu, F; Lupker, J; Maffrand, J P; Le Fur, G; Casellas, P

1997-08-29

231

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. PMID:22343625

Ahn, Kwang H.; Mahmoud, Mariam M.; Kendall, Debra A.

2012-01-01

232

Using distinct molecular signatures of human monocytes and dendritic cells to predict adjuvant activity and pyrogenicity of TLR agonists  

Microsoft Academic Search

We present a systematic study that defines molecular profiles of adjuvanticity and pyrogenicity induced by agonists of human\\u000a Toll-like receptor molecules in vitro. Using P3CSK4, Lipid A and Poly I:C as model adjuvants we show that all three molecules enhance the expansion of IFN?+\\/CD4+ T cells from their naïve precursors following priming with allogeneic DC in vitro. In contrast, co-culture

Richard Kenmoe Kamgang; Inês Ramos; Lurdes Rodrigues Duarte; Mascia Ghielmetti; Marina Freudenberg; Clemens Dahinden; Elisabetta Padovan

2008-01-01

233

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 40 mg/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 (1 mg/kg i.p.) for 21 days. 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

2013-10-01

234

Evaluation of the number of agonist molecules needed to activate a ligand-gated channel from the current rising phase.  

PubMed Central

We propose a new method for calculating the number of agonist binding sites (n) in ligand-gated receptor channels from the initial phase of the current. This method is based on the fact that the relation between the current (I) and its first-time derivative (I') at the beginning of the current reflects the number of transitions that lead to channel opening. We show that, for constant agonist concentration, the above relationship at t --> 0 provides the number of steps leading to channel opening. When the agonist concentration is not constant but rather increases linearly with time, the corresponding value can be obtained using a slightly modified procedure. The analytical results were compared with computer simulations and a good match between the two was obtained. The theoretical procedure was then validated experimentally using the nicotinic receptor, because, for this receptor, the number of binding sites is well established. Indeed, the expected number of two binding sites was obtained. The method was then tested for the quisqualate-type glutamate receptor channel from the opener muscle of crayfish. The number of this receptor's binding sites is not fully resolved. Our results suggest that, for this glutamate receptor as well, two binding sites must be occupied to open the channel. PMID:10653786

Ratner, E; Tour, O; Parnas, H

2000-01-01

235

Platelet-derived growth factor stimulates phagocytosis and blocks agonist-induced activation of the neutrophil oxidative burst: a possible cellular mechanism to protect against oxygen radical damage.  

PubMed Central

The effect of platelet-derived growth factor (PDGF) on agonist-induced activation of the superoxide-generating oxidative burst in human neutrophils was tested. PDGF had no effect on the resting level of superoxide generation but inhibited both the rate and the extent of fMet-Leu-Phe-stimulated superoxide production in a dose-dependent manner. The concentration required to inhibit the response by 50% was 95 +/- 26 pM (n = 10). PDGF also blocked activation by other receptor-mediated agonists such as the complement protein C5a and opsonized zymosan, but not by phorbol myristate acetate or arachidonate, both of which may act at postreceptor sites. The growth factor, however, had no effect on the binding of fMet-Leu-Phe to its receptor. PDGF in concentrations that blocked the oxidative burst stimulated phagocytosis of opsonized latex particles. Thus, PDGF functions as a heterologous "down-regulator" of receptor-mediated activation of the neutrophil oxidative burst and an activator of phagocytosis. A model for a feedback regulatory loop between platelets and neutrophils is proposed. PMID:3031672

Wilson, E; Laster, S M; Gooding, L R; Lambeth, J D

1987-01-01

236

Differential Effects of the Toll-Like Receptor 2 Agonists, PGN and Pam3CSK4 on Anti-IgE Induced Human Mast Cell Activation  

PubMed Central

Mast cells are pivotal in the pathogenesis of allergy and inflammation. In addition to the classical IgE-dependent mechanism involving crosslinking of the high-affinity receptor for IgE (Fc?RI), mast cells are also activated by Toll-like receptors (TLRs) which are at the center of innate immunity. In this study, we demonstrated that the response of LAD2 cells (a human mast cell line) to anti-IgE was altered in the presence of the TLR2 agonists peptidoglycan (PGN) and tripalmitoyl-S-glycero-Cys-(Lys)4 (Pam3CSK4). Pretreatment of PGN and Pam3CSK4 inhibited anti-IgE induced calcium mobilization and degranulation without down-regulation of Fc?RI expression. Pam3CSK4 but not PGN acted in synergy with anti-IgE for IL-8 release when the TLR2 agonist was added simultaneously with anti-IgE. Studies with inhibitors of key enzymes implicated in mast cell signaling revealed that the synergistic release of IL-8 induced by Pam3CSK4 and anti-IgE involved ERK and calcineurin signaling cascades. The differential modulations of anti-IgE induced mast cell activation by PGN and Pam3CSK4 suggest that dimerization of TLR2 with TLR1 or TLR6 produced different modulating actions on Fc?RI mediated human mast cell activation. PMID:25398056

Yu, Yangyang; Yip, Kwok Ho; Tam, Issan Yee San; Sam, Sze Wing; Ng, Chun Wai; Zhang, Wei; Lau, Hang Yung Alaster

2014-01-01

237

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

238

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

PubMed Central

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

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

2013-01-01

239

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. PMID:24069189

Kim, Mi-Kyung; Cho, Jin-Hwan; Lee, Jae-Jin; Cheong, Ye-Hwang; Son, Moon-Ho; Lee, Kong-Joo

2013-01-01

240

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

2010-07-01

241

Polychlorinated biphenyls (PCBs) contamination and aryl hydrocarbon receptor (AhR) agonist activity of Omega-3 polyunsaturated fatty acid supplements: implications for daily intake of dioxins and PCBs.  

PubMed

Omega-3 polyunsaturated fatty acid (n-3 PUFA) rich oils derived primarily from fish are frequently consumed as supplements. Due to the tendency of persistent organic pollutants (POPs) to accumulate in exposed organisms, n-3 PUFA supplements can contain sufficient POPs to present a risk to consumers. Here we investigated PCB concentrations and aryl hydrocarbon receptor (AhR) agonist activity in 17 n-3 PUFA supplements available in Canada. PCBs ranged from <0.8 to 793 ng g(-1) oil, with salmon- and seal-derived products yielding the highest values. AhR agonist activity from a reporter gene assay ranged from 1.3 to 72.2 pg TEQ g(-1) oil, with salmon and tuna yielding the highest values. When consumed at the recommended doses and as a supplement to the average Canadian diet, seal-derived oil can contribute to exceedance of the tolerable daily intake of 20 ng PCBs kg-BW(-1)day(-1), and salmon-, tuna-, and sea herring-derived oils can contribute to exceedance of the tolerable daily intake limit of 2.3 pg TEQ kg-BW(-1)day(-1). The beneficial properties of fish and n-3 PUFA supplements, and the results of this study suggest that it is prudent to consume supplements derived from small, cold-water fatty fish. Further research will be necessary to draw firm conclusions. PMID:20692313

Bourdon, J A; Bazinet, T M; Arnason, T T; Kimpe, L E; Blais, J M; White, P A

2010-11-01

242

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

243

Xanomeline, an M(1)/M(4) preferring muscarinic cholinergic receptor agonist, produces antipsychotic-like activity in rats and mice.  

PubMed

Xanomeline is an M(1)/M(4) preferring muscarinic receptor agonist which decreased psychotic behaviors in patients with Alzheimer's disease, suggesting that xanomeline might be useful in the treatment of psychotic symptoms in patients with schizophrenia. The purpose of the present studies was, therefore, to compare the pharmacologic profile of xanomeline with that of known antipsychotic drugs. Electrophysiologically, xanomeline, after both acute and chronic administration in rats, inhibited A10 but not A9 dopamine cells in a manner which was blocked by the muscarinic receptor antagonist scopolamine. Behaviorally, xanomeline, like haloperidol, clozapine and olanzapine, blocked dopamine agonist-induced turning in unilateral 6-hydroxydopamine-lesioned rats, as well as apomorphine-induced climbing in mice. However, unlike the dopamine antagonist antipsychotic haloperidol, xanomeline did not produce catalepsy in rats. Moreover, xanomeline, like haloperidol, clozapine and olanzapine, inhibited conditioned avoidance responding in rats, an effect which also was blocked by scopolamine. The present results thus demonstrate that xanomeline has a pharmacologic profile which is similar to that of the atypical antipsychotics clozapine and olanzapine, thus indicating that xanomeline has the potential to be a novel approach in the treatment of psychotic symptoms in patients with schizophrenia. PMID:10785583

Shannon, H E; Rasmussen, K; Bymaster, F P; Hart, J C; Peters, S C; Swedberg, M D; Jeppesen, L; Sheardown, M J; Sauerberg, P; Fink-Jensen, A

2000-05-01

244

Neuroprotective Potential of Peroxisome Proliferator Activated Receptor-? Agonist in Cognitive Impairment in Parkinson's Disease: Behavioral, Biochemical, and PBPK Profile  

PubMed Central

Parkinson's disease (PD) is a common neurodegenerative disorder affecting 1% of the population by the age of 65 years and 4-5% of the population by the age of 85 years. PD affects functional capabilities of the patient by producing motor symptoms and nonmotor symptoms. Apart from this, it is also associated with a higher risk of cognitive impairment that may lead to memory loss, confusion, and decreased attention span. In this study, we have investigated the effect of fenofibrate, a PPAR-? agonist in cognitive impairment model in PD. Bilateral intranigral administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (100?µg/1?µL/side) produced significant cognitive dysfunctions. Fenofibrate treatment at 10, 30, and 100?mg/kg for twenty-five days was found to be neuroprotective and improved cognitive impairment in MPTP-induced PD model as evident from behavioral, biochemical (MDA, GSH, TNF-?, and IL-6), immunohistochemistry (TH), and DNA fragmentation (TUNEL positive cells) studies. Further, physiologically based pharmacokinetic (PBPK) modeling study was performed using GastroPlus to characterize the kinetics of fenofibric acid in the brain. A good agreement was found between pharmacokinetic parameters obtained from the actual and simulated plasma concentration-time profiles of fenofibric acid. Results of this study suggest that PPAR-? agonist (fenofibrate) is neuroprotective in PD-induced cognitive impairment. PMID:24693279

Das, Nihar R.; Gangwal, Rahul P.; Damre, Mangesh V.; Sangamwar, Abhay T.; Sharma, Shyam S.

2014-01-01

245

Gardiquimod: a Toll-like receptor-7 agonist that inhibits HIV type 1 infection of human macrophages and activated T cells.  

PubMed

Immune response modifiers are being studied as therapeutic agents for viral infections and cancer. These molecules include agonists for the Toll-like receptors (TLR), a family of innate immune receptors. TLR7 and 8, located in cellular endosomes, bind single-stranded RNA characteristic of viral genomes, and trigger intracellular signaling pathways that induce inflammatory cytokines and antiviral innate immune factors. We studied the anti-HIV-1 effects of gardiquimod, a specific TLR7 agonist when used at concentrations below 10 ?M, in macrophages and activated peripheral blood mononuclear cells (PBMCs). Gardiquimod, added prior to or within 2 days after infection with X4, R5, or dual-tropic (R5/X4) strains of HIV-1, significantly reduced infection in these cells. Cocultures of activated PBMCs added to gardiquimod-treated and HIV-1-exposed macrophages demonstrated minimal HIV-1 replication for up to 10 days, suggesting that gardiquimod inhibited activated PBMCs viral amplification from HIV-1-exposed macrophages. Gardiquimod treatment of both activated PBMCs and macrophages induced interferon-alpha (IFN-?) transcription within hours of addition, and sustained IFN-? protein secretion for several days. Treatment of cells with a peptide inhibitor to the MyD88 adaptor protein blocked the induction of IFN-? by gardiquimod, and partially reversed the anti-HIV effects in activated PBMCs. Blocking the IFN-? receptor with a neutralizing antibody also reduced the anti-HIV effect of gardiquimod. Gardiquimod inhibited HIV-1 reverse transcriptase, an early step in the life cycle of HIV-1. These findings suggest that gardiquimod, functioning as both an immune system modifier and a reverse transcriptase inhibitor, could be developed as a novel therapeutic agent to block systemic and mucosal transmission of HIV-1. PMID:23316755

Buitendijk, Maarten; Eszterhas, Susan K; Howell, Alexandra L

2013-06-01

246

Allosteric Switching of Agonist/Antagonist Activity by a Single Point Mutation in the Interluekin-1 Receptor Antagonist, IL-1Ra  

PubMed Central

The pleiotropic pro-inflammatory cytokine interleukin (IL)-1? has co-evolved with a competitive inhibitor, IL-1 receptor antagonist (IL-1Ra). IL-1? initiates cell signaling by binding the IL-1 receptor (IL-1R) whereas IL-1Ra acts as an antagonist, blocking receptor signaling. The current paradigm for agonist/antagonist functions for these two proteins is based on the receptor–ligand interaction observed in the crystal structures of the receptor–ligand complexes. While IL-1Ra and IL-1? are structurally homologous, IL-1Ra engages only two of the three extracellular domains of the receptor, whereas IL-1? engages all three. We find that an allosteric functional switch exists within a highly conserved pocket of residues, residues 111–120. This region is maintained across all IL-1 family members and serves as a hydrophobic mini-core for IL-1? folding. A key difference across species is a conserved aromatic residue at position 117 in IL-1?, versus a conserved cysteine in IL-1Ra at the analogous position, 116. We find that the replacement of C116 with a phenylalanine switches the protein from an antagonist to an agonist despite the distant location of C116 relative to receptor interaction sites. These results suggest new ways to develop designer cytokine activity into the ?-trefoil fold and may be of general use in regulation of this large family of signaling proteins. PMID:23499887

Hailey, Kendra L.; Capraro, Dominique T.; Barkho, Sulyman; Jennings, Patricia A.

2013-01-01

247

Combination therapy of an intestine-specific inhibitor of microsomal triglyceride transfer protein and peroxisome proliferator-activated receptor ? agonist in diabetic rat.  

PubMed

We investigated effects on glucose and lipid metabolism in combination of JTT-130, a novel intestine-specific microsomal triglyceride transfer protein (MTP) inhibitor, and pioglitazone, peroxisome proliferator-activated receptor (PPAR) ? agonist. Male Zucker diabetic fatty rats were divided into 4 groups: control group, JTT-130 treatment group, pioglitazone treatment group, and combination group. The Zucker diabetic fatty rats were fed a regular powdered diet with JTT-130 and/or pioglitazone as a food admixture for 6 weeks. Effects on glucose and lipid metabolism were compared mainly between JTT-130 treatment group and combination group. JTT-130 treatment showed good glycemic control, while the plasma glucose and glycated hemoglobin levels in combination group were significantly decreased as compared with those JTT-130 treatment group. The reduction in the plasma triglyceride and free fatty acid levels in combination group was higher than that in JTT-130 treatment group, and glucose utilization was significantly elevated in adipose tissues. In Zucker diabetic fatty rats, combination treatment of JTT-130 and pioglitazone showed better glycemic control and a strong hypolipidemic action with an enhancement of insulin sensitivity. Combination therapy of MTP inhibitor and PPAR ? agonist might be more useful in the treatment of type 2 diabetes accompanied with obesity and insulin resistance. PMID:24772450

Sakata, Shohei; Mera, Yasuko; Kuroki, Yukiharu; Nashida, Reiko; Kakutani, Makoto; Ohta, Takeshi

2014-01-01

248

New benzimidazoles as thrombopoietin receptor agonists.  

PubMed

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

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

2006-03-01

249

Glucans exhibit weak antioxidant activity, but stimulate macrophage free radical activity  

Microsoft Academic Search

Polymeric carbohydrates have been reported to modulate inflammatory responses in vitro and in vivo. Previous reports suggest that certain carbohydrate polymers, such as (1?3)-?-D-glucans, may possess free radical scavenging activity. If glucans are free radical scavengers then it might explain, in part, the ability of these ligands to modulate inflammatory responses. The present study examined the free radical scavenging activity

Ekaterini Tsiapali; Sarah Whaley; John Kalbfleisch; Harry E Ensley; I. William Browder; David L Williams

2001-01-01

250

Cannabinoid receptor-2 (CB2) agonist ameliorates colitis in IL-10{sup ?/?} mice by attenuating the activation of T cells and promoting their apoptosis  

SciTech Connect

Inflammatory bowel disease (IBD) is a chronic intestinal inflammation caused by hyperactivated effector immune cells that produce pro-inflammatory cytokines. Recent studies have shown that the cannabinoid system may play a critical role in mediating protection against intestinal inflammation. However, the effect of cannabinoid receptor induction after chronic colitis progression has not been investigated. Here, we investigate the effect of cannabinoid receptor-2 (CB2) agonist, JWH-133, after chronic colitis in IL-10{sup ?/?} mice. JWH-133 effectively attenuated the overall clinical score, and reversed colitis-associated pathogenesis and decrease in body weight in IL-10{sup ?/?} mice. After JWH-133 treatment, the percentage of CD4{sup +} T cells, neutrophils, mast cells, natural killer (NK1.1) cells, and activated T cells declined in the intestinal lamina propria (LP) and mesenteric lymph nodes (MLN) of mice with chronic colitis. JWH-133 was also effective in ameliorating dextran sodium sulfate (DSS)-induced colitis. In this model, JWH-133 reduced the number and percentage of macrophages and IFN-? expressing cells that were induced during colitis progression. Treatment with aminoalkylindole 6-iodo-pravadoline (AM630), a CB2 receptor antagonist, reversed the colitis protection provided by JWH-133 treatment. Also, activated T cells were found to undergo apoptosis following JWH-133 treatment both in-vivo and in-vitro. These findings suggest that JWH-133 mediates its effect through CB2 receptors, and ameliorates chronic colitis by inducing apoptosis in activated T cells, reducing the numbers of activated T cells, and suppressing induction of mast cells, NK cells, and neutrophils at sites of inflammation in the LP. These results support the idea that the CB2 receptor agonists may serve as a therapeutic modality against IBD. -- Highlights: ? JWH-133, a cannnabinoid receptor-2 agonist ameliorates experimental colitis. ? JWH-133 suppressed inflammation and toxicity to colon by inducing T cell apoptosis. ? JWH-133 decreased mast cells, macrophages, NK cells, IFN-?{sup +} cells in the LPL. ? AM630, a cannnabinoid receptor-2 antagonist inverted the colitis defense of JWH-133. ? Cannnabinoid receptor-2 may serve as a novel therapeutic target for IBD.

Singh, Udai P.; Singh, Narendra P. [Pathology, Microbiology and Immunology, School of Medicine, University of South Carolina, Columbia, SC 29208 (United States)] [Pathology, Microbiology and Immunology, School of Medicine, University of South Carolina, Columbia, SC 29208 (United States); Singh, Balwan [National Primate Research Center, Emory University, Atlanta GA 30329 (United States)] [National Primate Research Center, Emory University, Atlanta GA 30329 (United States); Price, Robert L. [Department of Cell and Developmental Biology, University of South Carolina, Columbia, SC 29208 (United States)] [Department of Cell and Developmental Biology, University of South Carolina, Columbia, SC 29208 (United States); Nagarkatti, Mitzi [Pathology, Microbiology and Immunology, School of Medicine, University of South Carolina, Columbia, SC 29208 (United States)] [Pathology, Microbiology and Immunology, School of Medicine, University of South Carolina, Columbia, SC 29208 (United States); Nagarkatti, Prakash S., E-mail: Prakash.Nagarkatti@uscmed.sc.edu [Pathology, Microbiology and Immunology, School of Medicine, University of South Carolina, Columbia, SC 29208 (United States)

2012-01-15

251

The fungal T-2 toxin alters the activation of primary macrophages induced by TLR-agonists resulting in a decrease of the inflammatory response in the pig  

PubMed Central

T-2 toxin is known to be one of the most toxic trichothecene mycotoxins. Exposure to T-2 toxin induces many hematologic and immunotoxic disorders and is involved in immuno-modulation of the innate immune response. The objective of this work was to evaluate the effects of T-2 toxin on the activation of macrophages by different agonists of Toll-like receptors (TLR) using an in vitro model of primary porcine alveolar macrophages (PAM). Cytotoxic effects of T-2 toxin on PAM were first evaluated. An IC50 of 19.47?±?0.9753 nM was determined for the cytotoxicity of T-2 toxin. A working concentration of 3 nM of T-2 toxin was chosen to test the effect of T-2 toxin on TLR activation; this dose was not cytotoxic and did not induce apoptosis as demonstrated by Annexin/PI staining. A pre-exposure of macrophages to 3 nM of T-2 toxin decreased the production of inflammatory mediators (IL-1 beta, TNF-alpha, nitric oxide) in response to LPS and FSL1, TLR4 and TLR2/6 agonists respectively. The decrease of the pro-inflammatory response is associated with a decrease of TLR mRNA expression. By contrast, the activation of TLR7 by ssRNA was not modulated by T-2 toxin pre-treatment. In conclusion, our results suggest that ingestion of low concentrations of T-2 toxin affects the TLR activation by decreasing pattern recognition of pathogens and thus interferes with initiation of inflammatory immune response against bacteria and viruses. Consequently, mycotoxins could increase the susceptibility of humans and animals to infectious diseases. PMID:22530722

2012-01-01

252

A novel PPAR{gamma} agonist, KR62776, suppresses RANKL-induced osteoclast differentiation and activity by inhibiting MAP kinase pathways  

SciTech Connect

We investigated the effects of a novel peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) agonist, KR62776, on osteoclast differentiation and function, and on the underlying signaling pathways. KR62776 markedly suppressed differentiation into osteoclasts in various osteoclast model systems, including bone marrow mononuclear (BMM) cells and a co-culture of calvarial osteoblasts and BMM cells. KR62776 suppressed the activation of tartrate-resistant acid phosphatase (TRAP) and the expression of genes associated with osteoclast differentiation, such as TRAP, dendritic cell-specific transmembrane protein (DC-STAMP), and osteoclast-associated receptor (OSCAR). Furthermore, KR62776 reduced resorption pit formation in osteoclasts, and down-regulated genes essential for osteoclast activity, such as Src and {alpha}v{beta}3 integrin. An analysis of a signaling pathway showed that KR62776 inhibited the receptor activator of nuclear factor-{kappa}B ligand (RANKL)-induced activation of p38 mitogen-activated protein kinase (p38MAPK), extracellular regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and nuclear factor-{kappa}B (NF-{kappa}B). Together, these results demonstrate that KR62776 negatively affects osteoclast differentiation and activity by inhibiting the RANKL-induced activation of MAP kinases and NF-{kappa}B.

Park, Ju-Young [Skeletal Diseases Genome Research Center, Kyungpook National University Hospital, Daegu (Korea, Republic of); Department of Biochemistry, School of Medicine, Kyungpook National University, Daegu (Korea, Republic of); Bae, Myung-Ae; Cheon, Hyae Gyeong; Kim, Sung Soo [Center for Metabolic Syndrome Therapeutics, Korea Research Institute of Chemical Technology, Daejeon (Korea, Republic of); Hong, Jung-Min; Kim, Tae-Ho [Skeletal Diseases Genome Research Center, Kyungpook National University Hospital, Daegu (Korea, Republic of); Choi, Je-Yong [Skeletal Diseases Genome Research Center, Kyungpook National University Hospital, Daegu (Korea, Republic of); Department of Biochemistry, School of Medicine, Kyungpook National University, Daegu (Korea, Republic of); Kim, Sang-Hyun [Department of Pharmacology, School of Medicine, Kyungpook National University, Daegu (Korea, Republic of); Lim, Jiwon [Department of Oral Pathology, IHBR, School of Dentistry, Kyungpook National University, Daegu (Korea, Republic of); Choi, Chang-Hyuk [Department of Orthopaedic Surgery, School of Medicine, Catholic University of Daegu, Daegu (Korea, Republic of); Shin, Hong-In [Department of Oral Pathology, IHBR, School of Dentistry, Kyungpook National University, Daegu (Korea, Republic of); Kim, Shin-Yoon [Skeletal Diseases Genome Research Center, Kyungpook National University Hospital, Daegu (Korea, Republic of); Department of Orthopaedic Surgery, School of Medicine, Kyungpook National University, Daegu (Korea, Republic of)], E-mail: syukim@knu.ac.kr; Park, Eui Kyun [Skeletal Diseases Genome Research Center, Kyungpook National University Hospital, Daegu (Korea, Republic of); Department of Oral Pathology, IHBR, School of Dentistry, Kyungpook National University, Daegu (Korea, Republic of)], E-mail: epark@knu.ac.kr

2009-01-16

253

Development of Functionally Selective, Small Molecule Agonists at Kappa Opioid Receptors*  

PubMed Central

The kappa opioid receptor (KOR) is widely expressed in the CNS and can serve as a means to modulate pain perception, stress responses, and affective reward states. Therefore, the KOR has become a prominent drug discovery target toward treating pain, depression, and drug addiction. Agonists at KOR can promote G protein coupling and ?arrestin2 recruitment as well as multiple downstream signaling pathways, including ERK1/2 MAPK activation. It has been suggested that the physiological effects of KOR activation result from different signaling cascades, with analgesia being G protein-mediated and dysphoria being mediated through ?arrestin2 recruitment. Dysphoria associated with KOR activation limits the therapeutic potential in the use of KOR agonists as analgesics; therefore, it may be beneficial to develop KOR agonists that are biased toward G protein coupling and away from ?arrestin2 recruitment. Here, we describe two classes of biased KOR agonists that potently activate G protein coupling but weakly recruit ?arrestin2. These potent and functionally selective small molecule compounds may prove to be useful tools for refining the therapeutic potential of KOR-directed signaling in vivo. PMID:24187130

Zhou, Lei; Lovell, Kimberly M.; Frankowski, Kevin J.; Slauson, Stephen R.; Phillips, Angela M.; Streicher, John M.; Stahl, Edward; Schmid, Cullen L.; Hodder, Peter; Madoux, Franck; Cameron, Michael D.; Prisinzano, Thomas E.; Aubé, Jeffrey; Bohn, Laura M.

2013-01-01

254

Manifestation of weak ferromagnetism and photocatalytic activity in bismuth ferrite nanoparticles  

SciTech Connect

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/{gamma}-Fe{sub 2}O{sub 3} nanocomposite. When this composite was annealed to 650 Degree-Sign 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/{gamma}-Fe{sub 2}O{sub 3} nanocomposite were examined by degrading methyl orange dye. The pure BFO showed a moderate photocatalytic activity; while BFO/{gamma}-Fe{sub 2}O{sub 3} nanocomposite showed enhanced activity. This could be probably due to the optimal band gap ratio between BFO and {gamma}-Fe{sub 2}O{sub 3} phases reduced the recombination of electron-hole pairs which aided in the enhancement of photocatalytic activity.

Sakar, M.; Balakumar, S. [National Center for Nanoscience and Nanotechnology, University of Madras, Chennai - 600025 (India); Saravanan, P. [Advanced Magnetics Group, Defence Metallurgical Research Laboratory, Hyderabad - 500 058 (India); Jaisankar, S. N. [Polymer Lab, Central Leather Research Laboratory, Adyar, Chennai - 600020 (India)

2013-02-05

255

Caspase and calpain activation both contribute to sepsis-induced diaphragmatic weakness  

PubMed Central

The cecal ligation perforation (CLP) model of sepsis is known to induce severe diaphragm dysfunction, but the cellular mechanisms by which this occurs remain unknown. We hypothesized that CLP induces diaphragm caspase-3 and calpain activation, and that these two enzymes act at the level of the contractile proteins to reduce muscle force generation. Rats (n = 4/group) were subjected to 1) sham surgery plus saline (intraperitoneal); 2) CLP; 3) CLP plus administration of calpain inhibitor peptide III (12 mg/kg ip); or 4) CLP plus administration of a caspase inhibitor, zVAD-fmk (3 mg/kg). At 24 h, diaphragms were removed, and the following were determined: 1) calpain and caspase-3 activities by fluorogenic assay; 2) caspase-3 and calpain I protein levels; 3) the intact diaphragm force-frequency relationship; and 4) the force generated by contractile proteins of single, permeabilized diaphragm fibers in response to exogenous calcium. CLP significantly increased diaphragm calpain activity (P < 0.02), caspase-3 activity (P < 0.02), active calpain I protein levels (P < 0.02), and active caspase-3 protein (P < 0.02). CLP also reduced the force generated by intact diaphragm muscle (P < 0.001) and the force generated by single-fiber contractile proteins (P < 0.001). Administration of either calpain inhibitor III or zVAD-fmk markedly improved force generation of both intact diaphragm muscle (P < 0.01) and single-fiber contractile proteins (P < 0.001). CLP induces significant reductions in diaphragm contractile protein force-generating capacity. This force reduction is mediated by the combined effects of activated caspase and calpain. Inhibition of these pathways may prevent diaphragm weakness in infected patients. PMID:19661453

Wang, W.; Callahan, L. A.

2009-01-01

256

Intramolecular Fluorescence Resonance Energy Transfer (FRET) Sensors of the Orexin OX1 and OX2 Receptors Identify Slow Kinetics of Agonist Activation*  

PubMed Central

Intramolecular fluorescence resonance energy transfer (FRET) sensors able to detect changes in distance or orientation between the 3rd intracellular loop and C-terminal tail of the human orexin OX1 and OX2 G protein-coupled receptors following binding of agonist ligands were produced and expressed stably. These were directed to the plasma membrane and, despite the substantial sequence alterations introduced, in each case were able to elevate [Ca2+]i, promote phosphorylation of the ERK1/2 MAP kinases and become internalized effectively upon addition of the native orexin peptides. Detailed characterization of the OX1 sensor demonstrated that it was activated with rank order of potency orexin A > orexin B > orexin A 16–33, that it bound antagonist ligands with affinity similar to the wild-type receptor, and that mutation of a single residue, D203A, greatly reduced the binding and function of orexin A but not antagonist ligands. Addition of orexin A to individual cells expressing an OX1 sensor resulted in a time- and concentration-dependent reduction in FRET signal consistent with mass-action and potency/affinity estimates for the peptide. Compared with the response kinetics of a muscarinic M3 acetylcholine receptor sensor upon addition of agonist, response of the OX1 and OX2 sensors to orexin A was slow, consistent with a multistep binding and activation process. Such sensors provide means to assess the kinetics of receptor activation and how this may be altered by mutation and sequence variation of the receptors. PMID:22389503

Xu, Tian-Rui; Ward, Richard J.; Pediani, John D.; Milligan, Graeme

2012-01-01

257

PET imaging to non-invasively study immune activation leading to antitumor responses with a 4-1BB agonistic antibody  

PubMed Central

Background Molecular imaging with positron emission tomography (PET) may allow the non-invasive study of the pharmacodynamic effects of agonistic monoclonal antibodies (mAb) to 4-1BB (CD137). 4-1BB is a member of the tumor necrosis factor family expressed on activated T cells and other immune cells, and activating 4-1BB antibodies are being tested for the treatment of patients with advanced cancers. Methods We studied the antitumor activity of 4-1BB mAb therapy using [18 F]-labeled fluoro-2-deoxy-2-D-glucose ([18 F]FDG) microPET scanning in a mouse model of colon cancer. Results of microPET imaging were correlated with morphological changes in tumors, draining lymph nodes as well as cell subset uptake of the metabolic PET tracer in vitro. Results The administration of 4-1BB mAb to Balb/c mice induced reproducible CT26 tumor regressions and improved survival; complete tumor shrinkage was achieved in the majority of mice. There was markedly increased [18?F]FDG signal at the tumor site and draining lymph nodes. In a metabolic probe in vitro uptake assay, there was an 8-fold increase in uptake of [3H]DDG in leukocytes extracted from tumors and draining lymph nodes of mice treated with 4-1BB mAb compared to untreated mice, supporting the in vivo PET data. Conclusion Increased uptake of [18?F]FDG by PET scans visualizes 4-1BB agonistic antibody-induced antitumor immune responses and can be used as a pharmacodynamic readout to guide the development of this class of antibodies in the clinic. PMID:24829750

2013-01-01

258

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

259

Cannabinoid receptor activation correlates with the proapoptotic action of the ?2-adrenergic agonist (R,R')-4-methoxy-1-naphthylfenoterol in HepG2 hepatocarcinoma cells.  

PubMed

Inhibition of cell proliferation by fenoterol and fenoterol derivatives in 1321N1 astrocytoma cells is consistent with ?(2)-adrenergic receptor (?(2)-AR) stimulation. However, the events that result in fenoterol-mediated control of cell proliferation in other cell types are not clear. Here, we compare the effect of the ?(2)-AR agonists (R,R')-fenoterol (Fen) and (R,R')-4-methoxy-1-naphthylfenoterol (MNF) on signaling and cell proliferation in HepG2 hepatocarcinoma cells by using Western blotting and [(3)H]thymidine incorporation assays. Despite the expression of ?(2)-AR, no cAMP accumulation was observed when cells were stimulated with isoproterenol or Fen, although the treatment elicited both mitogen-activated protein kinase and phosphatidylinositol 3-kinase/Akt activation. Unexpectedly, isoproterenol and Fen promoted HepG2 cell growth, but MNF reduced proliferation together with increased apoptosis. The mitogenic responses of Fen were attenuated by 3-(isopropylamino)-1-[(7-methyl-4-indanyl)oxy]butan-2-ol (ICI 118,551), a ?(2)-AR antagonist, whereas those of MNF were unaffected. Because of the coexpression of ?(2)-AR and cannabinoid receptors (CBRs) and their impact on HepG2 cell proliferation, these G?(i)/G?(o)-linked receptors may be implicated in MNF signaling. Cell treatment with (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-napthalenylmethanone (WIN 55,212-2), a synthetic agonist of CB(1)R and CB(2)R, led to growth inhibition, whereas inverse agonists of these receptors blocked MNF mitogenic responses without affecting Fen signaling. MNF responses were sensitive to pertussis toxin. The ?(2)-AR-deficient U87MG cells were refractory to Fen, but responsive to the antiproliferative actions of MNF and WIN 55,212-2. The data indicate that the presence of the naphthyl moiety in MNF results in functional coupling to the CBR pathway, providing one of the first examples of a dually acting ?(2)-AR-CBR ligand. PMID:22776956

Paul, Rajib K; Ramamoorthy, Anuradha; Scheers, Jade; Wersto, Robert P; Toll, Lawrence; Jimenez, Lucita; Bernier, Michel; Wainer, Irving W

2012-10-01

260

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 Central

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 the 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 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 wished to test the generality of the cleft closure:efficacy correlation for other AMPA-R subunits. Here, we present crystal structures of the GluR4flip 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.

2009-01-01

261

PPAR Agonists and Cardiovascular Disease in Diabetes  

PubMed Central

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

Calkin, Anna C.; Thomas, Merlin C.

2008-01-01

262

Antidepressant-Like Activity of YL-0919: A Novel Combined Selective Serotonin Reuptake Inhibitor and 5-HT1A Receptor Agonist  

PubMed Central

It has been suggested that drugs combining activities of selective serotonin reuptake inhibitor and 5-HT1A receptor agonist may form a novel strategy for higher therapeutic efficacy of antidepressant. The present study aimed to examine the pharmacology of YL-0919, a novel synthetic compound with combined high affinity and selectivity for serotonin transporter and 5-HT1A receptors. We performed in vitro binding and function assays and in vivo behavioral tests to assess the pharmacological properties and antidepressant-like efficacy of YL-0919. YL-0919 displayed high affinity in vitro to both 5-HT1A receptor and 5-HT transporter prepared from rat cortical tissue. It exerted an inhibitory effect on forskolin-stimulated cAMP formation and potently inhibited 5-HT uptake in both rat cortical synaptosomes and recombinant cells. After acute p.o. administration, very low doses of YL-0919 reduced the immobility time in tail suspension test and forced swimming test in mice and rats, with no significant effect on locomotor activity in open field test. Furthermore, WAY-100635 (a selective 5-HT1A receptor antagonist, 0.3 mg/kg) significantly blocked the effect of YL-0919 in tail suspension test and forced swimming test. In addition, chronic YL-0919 treatment significantly reversed the depressive-like behaviors in chronically stressed rats. These findings suggest that YL-0919, a novel structure compound, exerts dual effect on the serotonergic system, as both 5-HT1A receptor agonist and 5-HT uptake blocker, showing remarkable antidepressant effects in animal models. Therefore, YL-0919 may be used as a new option for the treatment of major depressive disorder. PMID:24367588

Zhang, Li-ming; Xue, Rui; Xu, Xiao-dan; Zhao, Nan; Qiu, Zhi-kun; Wang, Xian-wang; Zhang, You-zhi; Yang, Ri-fang; Li, Yun-feng

2013-01-01

263

The quetiapine active metabolite N-desalkylquetiapine and the neurotensin NTS? receptor agonist PD149163 exhibit antidepressant-like effects on operant responding in male rats.  

PubMed

Major depressive disorder is the most common mood disorder in the United States and European Union; however, the limitations of clinically available antidepressant drugs have led researchers to pursue novel pharmacological treatments. Clinical studies have reported that monotherapy with the atypical antipsychotic drug quetiapine produces a rapid reduction in depressive symptoms that is apparent after 1 week of treatment, and it is possible that the active metabolite N-desalkylquetiapine, which structurally resembles an antidepressant drug, produces antidepressant effects. Neuropharmacological evaluations of the neurotensin NTS1 receptor agonist PD149163 suggest antidepressant efficacy, but the effects of a NTS? receptor agonist in an antidepressant animal model have yet to be reported. The present study examined the antidepressant-like effects of N-desalkylquetiapine, PD14916, quetiapine, the tricyclic antidepressant drug imipramine, the atypical antipsychotic drug risperidone, and the typical antipsychotic drug raclopride on responding in male Sprague-Dawley rats trained on a differential-reinforcement-of-low-rate 72-s operant schedule, a procedure used for screening antidepressant drugs. Quetiapine, PD149163, risperidone, and imipramine exhibited antidepressant-like effects by increasing the number of reinforcers earned, decreasing the number of responses emitted, and shifting the interresponse time (IRT) distributions to the right. N-Desalkylquetiapine produced a partial antidepressant-like effect by decreasing the number of responses emitted and producing a rightward shift in the IRT distributions, but it did not significantly alter the number of reinforcers earned. Raclopride decreased reinforcers and responses. These data suggest that N-desalkylquetiapine likely contributes to quetiapine's antidepressant efficacy and identify NTS? receptor activation as a potential novel pharmacologic strategy for antidepressant drugs. PMID:25285844

Hillhouse, Todd M; Shankland, Zachary; Matazel, Katelin S; Keiser, Ashley A; Prus, Adam J

2014-12-01

264

Desensitization of Human CRF2(a) Receptor Signaling Governed by Agonist Potency and ?Arrestin2 Recruitment  

PubMed Central

The primary goal was to determine agonist-specific regulation of CRF2(a) receptor function. Exposure of human retinoblastoma Y79 cells to selective (UCN2, UCN3 or stresscopins) and nonselective (UCN1 or sauvagine) agonists prominently desensitized CRF2(a) receptors in a rapid, concentration-dependent manner. A considerably slower rate and smaller magnitude of desensitization developed in response to the weak agonist CRF. CRF1 receptor desensitization stimulated by CRF, cortagine or stressin1-A had no effect on CRF2(a) receptor cyclic AMP signaling. Conversely, desensitization of CRF2(a) receptors by UCN2 or UCN3 did not cross-desensitize Gs-coupled CRF1 receptor signaling. In transfected HEK293 cells, activation of CRF2(a) receptors by UCN2, UCN3 or CRF resulted in receptor phosphorylation and internalization proportional to agonist potency. Neither protein kinase A nor casein kinases mediated CRF2(a) receptor phosphorylation or desensitization. Exposure of HEK293 or U2OS cells to UCN2 or UCN3 (100 nM) produced strong ?arrestin2 translocation and colocalization with membrane CRF2(a) receptors while CRF (1 µM) generated only weak ?arrestin2 recruitment. ?arrestin2 did not internalize with the receptor, however, indicating that transient CRF2(a) receptor-arrestin complexes dissociate at or near the cell membrane. Since deletion of the ?arrestin2 gene upregulated Gs-coupled CRF2(a) receptor signaling in MEF cells, a ?arrestin2 mechanism restrains Gs-coupled CRF2(a) receptor signaling activated by urocortins. We further conclude the rate and extent of homologous CRF2(a) receptor desensitization are governed by agonist-specific mechanisms affecting GRK phosphorylation, ?arrestin2 recruitment, and internalization thereby producing unique signal transduction profiles that differentially affect the stress response. PMID:23820308

Hauger, Richard L.; Olivares-Reyes, J. Alberto; Braun, Sandra; Hernandez-Aranda, Judith; Hudson, Christine C.; Gutknecht, Eric; Dautzenberg, Frank M.; Oakley, Robert H.

2013-01-01

265

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

PubMed

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

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

2011-01-13

266

CD47 Agonist Peptides Induce Programmed Cell Death in Refractory Chronic Lymphocytic Leukemia B Cells via PLC?1 Activation: Evidence from Mice and Humans  

PubMed Central

Background Chronic lymphocytic leukemia (CLL), the most common adulthood leukemia, is characterized by the accumulation of abnormal CD5+ B lymphocytes, which results in a progressive failure of the immune system. Despite intense research efforts, drug resistance remains a major cause of treatment failure in CLL, particularly in patients with dysfunctional TP53. The objective of our work was to identify potential approaches that might overcome CLL drug refractoriness by examining the pro-apoptotic potential of targeting the cell surface receptor CD47 with serum-stable agonist peptides. Methods and Findings In peripheral blood samples collected from 80 patients with CLL with positive and adverse prognostic features, we performed in vitro genetic and molecular analyses that demonstrate that the targeting of CD47 with peptides derived from the C-terminal domain of thrombospondin-1 efficiently kills the malignant CLL B cells, including those from high-risk individuals with a dysfunctional TP53 gene, while sparing the normal T and B lymphocytes from the CLL patients. Further studies reveal that the differential response of normal B lymphocytes, collected from 20 healthy donors, and leukemic B cells to CD47 peptide targeting results from the sustained activation in CLL B cells of phospholipase C gamma-1 (PLC?1), a protein that is significantly over-expressed in CLL. Once phosphorylated at tyrosine 783, PLC?1 enables a Ca2+-mediated, caspase-independent programmed cell death (PCD) pathway that is not down-modulated by the lymphocyte microenvironment. Accordingly, down-regulation of PLC?1 or pharmacological inhibition of PLC?1 phosphorylation abolishes CD47-mediated killing. Additionally, in a CLL-xenograft model developed in NOD/scid gamma mice, we demonstrate that the injection of CD47 agonist peptides reduces tumor burden without inducing anemia or toxicity in blood, liver, or kidney. The limitations of our study are mainly linked to the affinity of the peptides targeting CD47, which might be improved to reach the standard requirements in drug development, and the lack of a CLL animal model that fully mimics the human disease. Conclusions Our work provides substantial progress in (i) the development of serum-stable CD47 agonist peptides that are highly effective at inducing PCD in CLL, (ii) the understanding of the molecular events regulating a novel PCD pathway that overcomes CLL apoptotic avoidance, (iii) the identification of PLC?1 as an over-expressed protein in CLL B cells, and (iv) the description of a novel peptide-based strategy against CLL. PMID:25734483

Attout, Tarik; Boullet, Heloïse; Herbi, Linda; Vela, Laura; Barbier, Sandrine; Chateau, Danielle; Chapiro, Elise; Nguyen-Khac, Florence; Davi, Frédéric; Le Garff-Tavernier, Magali; Moumné, Roba; Sarfati, Marika; Karoyan, Philippe; Merle-Béral, Hélène; Launay, Pierre; Susin, Santos A.

2015-01-01

267

Repeated effects of the neurotensin receptor agonist PD149163 in three animal tests of antipsychotic activity: assessing for tolerance and cross-tolerance to clozapine.  

PubMed

Neurotensin is an endogenous neuropeptide closely associated with the mesolimbic dopaminergic system and shown to possess antipsychotic-like effects. In particular, acute neurotensin receptor activation can inhibit conditioned avoidance response (CAR), attenuate phencyclidine (PCP)-induced prepulse inhibition (PPI) disruptions, and reverse PCP-induced hyperlocomotion. However, few studies have examined the long term effects of repeated neurotensin receptor activation and results are inconsistent. Since clinical administration of antipsychotic therapy often requires a prolonged treatment schedule, here we assessed the effects of repeated activation of neurotensin receptors using an NTS1 receptor selective agonist, PD149163, in 3 behavioral tests of antipsychotic activity. We also investigated whether reactivity to the atypical antipsychotic clozapine was altered following prior PD149163 treatment. Using both normal and prenatally immune activated rats generated through maternal immune activation with polyinosinic:polycytidylic acid, we tested PD149163 in CAR, PCP (1.5mg/kg)-induced PPI disruption, and PCP (3.2mg/kg)-induced hyperlocomotion. For each paradigm, rats were first repeatedly tested with vehicle or PD149163 (1.0, 4.0, 8.0mg/kg, sc) along with vehicle or PCP for PPI and hyperlocomotion tests, then challenged with PD149163 after 2 drug-free days. All rats were then challenged with clozapine (5.0mg/kg, sc). During the repeated test period, PD149163 exhibited antipsychotic-like effects in all three models. On the PD149163 challenge day, prior drug treatment only caused a tolerance effect in CAR. This tolerance in CAR was transferrable to clozapine, as it enhanced clozapine tolerance in the same group of animals. Although no tolerance effect was seen in the PD149163 challenge for the PCP-induced hyperlocomotion test, the clozapine challenge showed increased sensitivity in groups previously exposed to repeated PD149163 treatment. Our findings suggest that repeated exposure to NTS1 receptor agonists can induce a dose-dependent tolerance and cross-tolerance to clozapine to some of its behavioral effects but not others. PMID:25433325

Chou, Shinnyi; Davis, Collin; Jones, Sean; Li, Ming

2015-01-01

268

Memory Enhancement Induced by Post-Training Intrabasolateral Amygdala Infusions of [beta]-Adrenergic or Muscarinic Agonists Requires Activation of Dopamine Receptors: Involvement of Right, but Not Left, Basolateral Amygdala  

ERIC Educational Resources Information Center

Previous findings indicate that the noradrenergic, dopaminergic, and cholinergic innervations of the basolateral amygdala (BLA) modulate memory consolidation. The current study investigated whether memory enhancement induced by post-training intra-BLA infusions of a [beta]-adrenergic or muscarinic cholinergic agonist requires concurrent activation

LaLumiere, Ryan T.; McGaugh, James L.

2005-01-01

269

Agonist-specific Gating of NMDA Receptors  

PubMed Central

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

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

2011-01-01

270

Spinal cannabinoid receptor type 2 agonist reduces mechanical allodynia and induces mitogen-activated protein kinase phosphatases in a rat model of neuropathic pain  

PubMed Central

Peripheral nerve injury generally results in spinal neuronal and glial plastic changes associated with chronic behavioral hypersensitivity. Spinal mitogen-activated protein kinases (MAPKs), e.g., p38 or extracellular signal-regulated kinases (ERKs), are instrumental in the development of chronic allodynia in rodents, and new p38 inhibitors have shown potential in acute and neuropathic pain patients. We have previously shown that the cannabinoid type 2 receptor agonist JWH015 inhibits ERK activity by inducing MAPK phosphatase (MKP)-1 and MKP-3 (the major regulators of MAPKs) in vitro in microglial cells. Therefore, we decided to investigate the role of these phosphatases in the mechanisms of action of JWH015 in vivo using the rat L5 nerve transection model of neuropathic pain. We observed that peripheral nerve injury reduced spinal MKP-1/3 expression and activity and that intrathecal JWH015 reduced established L5 nerve-injury-induced allodynia, enhanced spinal MKP-1/3 expression and activity, and reduced the phosphorylated form of p38 and ERK-1/2. Triptolide, a pharmacological blocker of MKP-1 and MKP-3 expression, inhibited JWH015’s effects, suggesting that JWH015 exerts its antinociceptive effects by modulating MKP-1 and MKP-3. JWH015-induced antinociception and MKP-1 and MKP-3 expression were inhibited by the cannabinoid type 2 receptor antagonist AM630. Our data suggest that MKP-1 and MKP-3 are potential targets for novel analgesic drugs. PMID:22901764

Landry, Russell P.; Martinez, Elena; DeLeo, Joyce A.; Romero-Sandoval, E. Alfonso

2012-01-01

271

Peroxisome proliferator-activated receptor alpha (PPARalpha) agonists down-regulate alpha2-macroglobulin expression by a PPARalpha-dependent mechanism.  

PubMed

Fibrates are peroxisome proliferator-activated receptor alpha (PPARalpha) ligands used to normalize lipid and glucose parameters and exert anti-inflammatory effects. The acute-phase response (APR) is an important inflammatory process. One of the most important acute-phase proteins in rats is alpha2-macroglobulin (A2Mg). Whereas normal adult rats present low serum levels, pregnant rats display high amounts. Therefore, we used pregnant rats to detect the effect of fenofibrate on hepatic A2Mg expression by RT-PCR and Northern blot. Virgin rats were used as controls. The expression of other APR genes, a known fibrate-responder gene, gamma-chain fibrinogen (gamma-Fib), and one gene from the same family as A2Mg, complement component 3 (C3), were also measured in liver. In order to determine whether the fibrate-effects were mediated by PPARalpha, wild-type mice and PPARalpha-null mice were also used and treated with WY-14,643 (WY) or di-2-ethylhexyl phthalate (DEHP). Fenofibrate depressed A2Mg expression in virgin rats, but expression was decreased more sharply in pregnant rats. Expression of C3 and gamma-Fib was diminished after treatment only in pregnant rats. On the other hand, WY, but not DEHP, reduced A2Mg and gamma-Fib expression in the livers of wild-type mice, without any effect in PPARalpha-null mice. WY or DEHP did not affect C3 expression. Therefore, A2Mg expression is modified by PPARalpha agonists not only in pregnant rats under augmented APR protein synthesis, but also in virgin rats and mice under basal conditions. Interestingly, our results also identify A2Mg as a novel PPARalpha agonist-regulated gene. PMID:19497347

González, María del Carmen; Corton, J Christopher; Cattley, Russell C; Herrera, Emilio; Bocos, Carlos

2009-08-01

272

Innate Immune Receptors in Human Airway Smooth Muscle Cells: Activation by TLR1/2, TLR3, TLR4, TLR7 and NOD1 Agonists  

PubMed Central

Background Pattern-recognition receptors (PRRs), including Toll-like receptors (TLRs), NOD-like receptors (NLRs) and RIG-I-like receptors (RLRs), recognize microbial components and trigger a host defense response. Respiratory tract infections are common causes of asthma exacerbations, suggesting a role for PRRs in this process. The present study aimed to examine the expression and function of PRRs on human airway smooth muscle cells (HASMCs). Methods Expression of TLR, NLR and RLR mRNA and proteins was determined using real-time RT-PCR, flow cytometry and immunocytochemistry. The functional responses to ligand stimulation were investigated in terms of cytokine and chemokine release, cell surface marker expression, proliferation and proteins regulating the contractile state. Results HASMCs expressed functional TLR2, TLR3, TLR4, TLR7 and NOD1. Stimulation with the corresponding agonists Pam3CSK4, poly(I:C), LPS, R-837 and iE-DAP, respectively, induced IL-6, IL-8 and GM-CSF release and up-regulation of ICAM-1 and HLA-DR, while poly(I:C) also affected the release of eotaxin and RANTES. The proliferative response was slightly increased by LPS. Stimulation, most prominently with poly(I:C), down-regulated myosin light chain kinase and cysteinyl leukotriene 1 receptor expression and up-regulated ?2-adrenoceptor expression. No effects were seen for agonist to TLR2/6, TLR5, TLR8, TLR9, NOD2 or RIG-I/MDA-5. Conclusion Activation of TLR2, TLR3, TLR4, TLR7 and NOD1 favors a synthetic phenotype, characterized by an increased ability to release inflammatory mediators, acquire immunomodulatory properties by recruiting and interacting with other cells, and reduce the contractile state. The PRRs might therefore be of therapeutic use in the management of asthma and infection-induced disease exacerbations. PMID:23861935

Månsson Kvarnhammar, Anne; Tengroth, Lotta; Adner, Mikael; Cardell, Lars-Olaf

2013-01-01

273

The delta-opioid receptor agonist DADLE at reperfusion protects the heart through activation of pro-survival kinases via EGF receptor transactivation.  

PubMed

The specific delta-opioid receptor agonist [D-Ala(2)-D-Leu(5)]enkephalin (DADLE) protects against infarction in the heart when given before ischemia. In rabbit, this protection leads to phosphorylation of the pro-survival kinases Akt and extracellular signal-regulated kinase (ERK) and is dependent on transactivation of the epidermal growth factor receptor (EGFR). DADLE reportedly protects rat hearts at reperfusion. We therefore tested whether DADLE at reperfusion could protect isolated rabbit hearts subjected to 30 min of regional ischemia and 120 min of reperfusion and whether this protection is dependent on Akt, ERK, and EGFR. DADLE (40 nM) was infused for 1 h starting 5 min before reperfusion and reduced infarct size from 31.0 +/- 2.3% in the control group to 14.6 +/- 1.6% (P = 0.01). This protection was abolished by cotreatment of the metalloproteinase inhibitor (MPI) and the EGFR inhibitor AG1478. In contrast, 20 nM DADLE, although known to be protective before ischemia, failed to protect. Western blotting revealed that DADLE's protection was correlated to increase in phosphorylation of the kinases Akt and ERK1 and -2 in reperfused hearts (2.5 +/- 0.5, 1.6 +/- 0.2, and 2.3 +/- 0.7-fold of baseline levels, P < 0.05 vs. control). The DADLE-dependent increases in Akt and ERK1/2 phosphorylation were abolished by either MPI or AG1478, confirming a signaling through the EGFR pathway. Additionally, DADLE treatment increased phosphorylation of EGFR (1.4 +/- 0.2-fold, P = 0.03 vs. control). Thus the delta-opioid agonist DADLE protects rabbit hearts at reperfusion through activation of the pro-survival kinases Akt and ERK and is dependent on the transactivation of the EGFR. PMID:17545478

Förster, Karina; Kuno, Atsushi; Solenkova, Natalia; Felix, Stephan B; Krieg, Thomas

2007-09-01

274

GPR119 agonists: a promising approach for T2DM treatment? A SWOT analysis of GPR119.  

PubMed

Ever since its advent as a promising therapeutic target for type 2 diabetes mellitus (T2DM), G-protein-coupled receptor 119 (GPR119) has received much interest from the pharmaceutical industry. This interest peaked in June 2010, when Sanofi-Aventis agreed to pay Metabolex (Cymabay Therapeutics) US$375 million for MBX-2982, which was a representative orally active GPR119 agonist. However, Sanofi-Aventis opted to terminate the deal in May 2011 and another leading GPR119 agonist, GSK1292263, had a loss of efficacy during its clinical trial. In this review, I discuss the pros and cons of GPR119 through a strengths, weaknesses, opportunities, and threats (SWOT) analysis and propose development strategies for the eventual success of a GPR119 agonist development program. PMID:24060477

Kang, Sang-Uk

2013-12-01

275

Agonist-directed trafficking of signalling at serotonin 5-HT2A, 5-HT2B and 5-HT2C-VSV receptors mediated Gq/11 activation and calcium mobilisation in CHO cells.  

PubMed

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 mobilisation. At the h5-HT2A receptor, d-lysergic acid diethylamide (LSD) and the antiparkinsonian agents lisuride, bromocriptine and pergolide exhibit a higher potency for Gq/11 activation than calcium release in contrast with all the other tested ligands such as 5-HT, mCPP and BW723C86, that show an opposite preference of signalling pathway. Comparable observations are made at h5-HT2B and h5-HT2C-VSV receptors, suggesting a similar mechanism of functional selectivity for the three serotonin receptors. Interestingly, the non-hallucinogenic compound lisuride behaves as a partial agonist for both Gq/11 activation and calcium release at the three 5-HT2 receptors, in contrast with DOI, LSD, pergolide and bromocriptine, which are known to provoke hallucinations, and behave as more efficacious agonists. Hence, a functional selectivity for Gq/11 activation together with a threshold of efficacy at h5-HT2A (and possibly h5-HT2B and/or h5-HT2C-VSV) may contribute to hallucinogenic liability. Thus, our results extend the notion of agonist-directed trafficking of receptor signalling to all the 5-HT2-receptor family and indicate that measures of Gq/11 activation versus calcium release may be useful to identify more effective therapeutic drugs with limited side effects. PMID:18703043

Cussac, Didier; Boutet-Robinet, Elisa; Ailhaud, Marie-Christine; Newman-Tancredi, Adrian; Martel, Jean-Claude; Danty, Nathalie; Rauly-Lestienne, Isabelle

2008-10-10

276

Evaluation of bactericidal activity of weakly acidic electrolyzed water (WAEW) against Vibrio vulnificus and Vibrio parahaemolyticus.  

PubMed

Vibrio parahaemolyticus and Vibriovulnificus cause severe foodborne illness in humans; thus, to reduce outbreaks of disease, it is clearly important to reduce food contamination by these pathogens. Although electrolyzed oxidizing (EO) water has been reported to exhibit strong bactericidal activities against many pathogens, it has never been tested against V. vulnificus and V. parahaemolyticus. The purpose of this study was to evaluate the bactericidal activity of weakly acidic electrolyzed water (WAEW), a type of EO water, against V. vulnificus and V. parahaemolyticus. Cell suspensions and cell cultures of both pathogens were treated for 30s with sodium hypochlorite solution containing 35mg/L available chlorine concentration (ACC) or WAEW containing 35mg/L ACC. After an initial inoculum of 5.7logCFU/mL, the number of viable V. vulnificus cells was reduced by 2.2 logs after treatment for 60s with sodium hypochlorite solution containing 35mg/L ACC, while no cells survived treatment with WAEW for 30s. Similar results were obtained for V. parahaemolyticus. Under open storage conditions, WAEW maintained bactericidal activities against cell suspensions of both strains after 5weeks but disappeared against cell cultures of the two strains after 5weeks. Under closed storage conditions, however, WAEW maintained bactericidal activities against both cell suspensions and cell cultures of each strain after 5weeks. No cells were detected in the cell suspensions and cultures when the ACC of WAEW was more than 20mg/L and treatment time was greater than 15s. Bactericidal activity of WAEW against V. vulnificus cell culture was reduced when the ACC of WAEW was less than 15mg/L but was maintained in the V. vulnificus cell suspension when the ACC of WAEW was 0.5mg/L. Thus, the bactericidal activity of WAEW was primarily affected by ACC rather than treatment time. Similar results were obtained for V. parahaemolyticus, indicating that WAEW kills these microorganisms more quickly than a chemical product such as sodium hypochlorite (NaClO), even at equivalent ACCs. PMID:20004034

Quan, Yaru; Choi, Kyoo-Duck; Chung, Donghwa; Shin, Il-Shik

2010-01-01

277

Mass-spectrometric analysis of agonist-induced retinoic acid receptor gamma conformational change.  

PubMed Central

Apo and holo forms of retinoic acid receptors, and other nuclear receptors, display differential sensitivity to proteolytic digestion that likely reflects the distinct conformational states of the free and liganded forms of the receptor. We have developed a method for rapid peptide mapping of holo-retinoic acid receptor gamma that utilizes matrix-assisted laser-desorption-ionization time-of-flight MS to identify peptide fragments that are derived from the partially proteolysed holo-receptor. The peptide maps of retinoic acid receptor gamma bound by four different agonists were identical, suggesting that all four ligands induced a similar conformational change within the ligand-binding domain of the receptor. In all cases, this agonist-induced conformational change promoted the direct association of retinoic acid receptor gamma with the transcriptional co-activator p300 and inhibited interaction of the receptor with the nuclear receptor co-repressor. SR11253, a compound previously reported to exert mixed retinoic acid receptor gamma agonist/antagonist activities in cultured cells, was found to bind directly to, but only weakly altered the protease-sensitivity of, the receptor and failed to promote interaction of the receptor with p300 or induce dissociation of receptor-nuclear receptor co-repressor complexes. This technique should be generally applicable to other members of the nuclear receptor superfamily that undergo an induced structural alteration upon agonist or antagonist binding, DNA binding and/or protein-protein interaction. PMID:11829754

Peterson, Valerie J; Barofsky, Elisabeth; Deinzer, Max L; Dawson, Marcia I; Feng, Kai-Chia; Zhang, Xiao-kun; Madduru, Machender R; Leid, Mark

2002-01-01

278

Cell death is induced by ciglitazone, a peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) agonist, independently of PPAR{gamma} in human glioma cells  

SciTech Connect

Highlights: Black-Right-Pointing-Pointer Greater than 30 {mu}M ciglitazone induces cell death in glioma cells. Black-Right-Pointing-Pointer Cell death by ciglitazone is independent of PPAR{gamma} in glioma cells. Black-Right-Pointing-Pointer CGZ induces cell death by the loss of MMP via decreased Akt. -- Abstract: Peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) regulates multiple signaling pathways, and its agonists induce apoptosis in various cancer cells. However, their role in cell death is unclear. In this study, the relationship between ciglitazone (CGZ) and PPAR{gamma} in CGZ-induced cell death was examined. At concentrations of greater than 30 {mu}M, CGZ, a synthetic PPAR{gamma} agonist, activated caspase-3 and induced apoptosis in T98G cells. Treatment of T98G cells with less than 30 {mu}M CGZ effectively induced cell death after pretreatment with 30 {mu}M of the PPAR{gamma} antagonist GW9662, although GW9662 alone did not induce cell death. This cell death was also observed when cells were co-treated with CGZ and GW9662, but was not observed when cells were treated with CGZ prior to GW9662. In cells in which PPAR{gamma} was down-regulated cells by siRNA, lower concentrations of CGZ (<30 {mu}M) were sufficient to induce cell death, although higher concentrations of CGZ ( Greater-Than-Or-Slanted-Equal-To 30 {mu}M) were required to induce cell death in control T98G cells, indicating that CGZ effectively induces cell death in T98G cells independently of PPAR{gamma}. Treatment with GW9662 followed by CGZ resulted in a down-regulation of Akt activity and the loss of mitochondrial membrane potential (MMP), which was accompanied by a decrease in Bcl-2 expression and an increase in Bid cleavage. These data suggest that CGZ is capable of inducing apoptotic cell death independently of PPAR{gamma} in glioma cells, by down-regulating Akt activity and inducing MMP collapse.

Lee, Myoung Woo; Kim, Dae Seong; Kim, Hye Ryung; Kim, Hye Jin; Yang, Jin Mo; Ryu, Somi; Noh, Yoo Hun; Lee, Soo Hyun; Son, Meong Hi; Jung, Hye Lim; Yoo, Keon Hee [Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of)] [Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of); Koo, Hong Hoe, E-mail: hhkoo@skku.edu [Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of); Sung, Ki Woong, E-mail: kwsped@skku.edu [Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of)

2012-01-06

279

Pyrexia, anorexia, adipsia, and depressed motor activity in rats during systemic inflammation induced by the Toll-like receptors-2 and -6 agonists MALP-2 and FSL-1.  

PubMed

Macrophage-activating lipopeptide-2 (MALP-2) from Mycoplasma fermentans has been identified as a pathogen-associated molecular pattern of Mycoplasmas that causes activation of the innate immune system through the activation of the heterodimeric Toll-like receptors (TLRs)-2 and -6. The aim of this study was to characterize the ability of MALP-2 and a synthetic analog fibroblast-stimulating lipopeptide-1 (FSL-1; represents the NH2-terminal sequence of a lipoprotein from M. salivarium) to act as exogenous pyrogens, to induce formation of cytokines (endogenous pyrogens), and to cause sickness behavior, such as depressed motor activity, anorexia, and adipsia. For this purpose, body temperature, activity, food intake, and water intake were recorded for 3 days by use of telemetry devices in several groups of rats treated with MALP-2/FSL-1 or the respective control solutions. Intraperitoneal injections of FSL-1 caused fever at doses of 10 or 100 microg/kg, which was preceded by a pronounced phase of hypothermia in response to a dose of 1,000 microg/kg. The maximal fever (a peak of 1.5 degrees C above baseline) was caused by the 100 microg/kg dose with almost identical responses to both MALP-2 and FSL-1. Fever was accompanied by pronounced rises of the proinflammatory cytokines TNF and IL-6 in plasma. Treatment with the TLR-2 and -6 agonists further induced a dose-dependent manifestation of anorexia and adipsia, as well as a reduction of motor activity. We could thus demonstrate that activation of TLR-2 and -6 can induce systemic inflammation in rats accompanied by the classical signs of brain-controlled illness responses. PMID:16154916

Hübschle, Thomas; Mütze, Jörg; Mühlradt, Peter F; Korte, Stefan; Gerstberger, Rüdiger; Roth, Joachim

2006-01-01

280

Dual-acting peptide with prolonged glucagon-like peptide-1 receptor agonist and glucagon receptor antagonist activity for the treatment of type 2 diabetes.  

PubMed

Type 2 diabetes is characterized by reduced insulin secretion from the pancreas and overproduction of glucose by the liver. Glucagon-like peptide-1 (GLP-1) promotes glucose-dependent insulin secretion from the pancreas, while glucagon promotes glucose output from the liver. Taking advantage of the homology between GLP-1 and glucagon, a GLP-1/glucagon hybrid peptide, dual-acting peptide for diabetes (DAPD), was identified with combined GLP-1 receptor agonist and glucagon receptor antagonist activity. To overcome its short plasma half-life DAPD was PEGylated, resulting in dramatically prolonged activity in vivo. PEGylated DAPD (PEG-DAPD) increases insulin and decreases glucose in a glucose tolerance test, evidence of GLP-1 receptor agonism. It also reduces blood glucose following a glucagon challenge and elevates fasting glucagon levels in mice, evidence of glucagon receptor antagonism. The PEG-DAPD effects on glucose tolerance are also observed in the presence of the GLP-1 antagonist peptide, exendin(9-39). An antidiabetic effect of PEG-DAPD is observed in db/db mice. Furthermore, PEGylation of DAPD eliminates the inhibition of gastrointestinal motility observed with GLP-1 and its analogues. Thus, PEG-DAPD has the potential to be developed as a novel dual-acting peptide to treat type 2 diabetes, with prolonged in vivo activity, and without the GI side-effects. PMID:17283237

Claus, Thomas H; Pan, Clark Q; Buxton, Joanne M; Yang, Ling; Reynolds, Jennifer C; Barucci, Nicole; Burns, Michael; Ortiz, Astrid A; Roczniak, Steve; Livingston, James N; Clairmont, Kevin B; Whelan, James P

2007-02-01

281

Electromyographic assessment of the activity of the masticatory using the agonist contract-antagonist relax technique (AC) and contract-relax technique (CR).  

PubMed

Proprioceptive neuromuscular facilitation (PNF) techniques are a group of therapeutic procedures that may be used to cause relaxation of muscles. Studies have found controversial results when applying these techniques. The aim of the present study was to evaluate the effectiveness of masticatory muscle relaxation through the use of the contract-relax technique (CR) when compared with the agonist contract-antagonist relax technique (AC). A convenience sample of 30 students was recruited for this study. The CR and the AC techniques were applied to the subjects in order to cause relaxation of the masticatory muscles. Electromyography activity of all muscles was registered. Two way ANOVA with repeated measures analysis demonstrated that both the AC technique and the CR technique did not decrease the EMG activity of masticatory muscles (P>0.05). Instead, both techniques caused an increase in electromyographic activity of the masticatory muscles. Based on the results obtained from this study, both the CR and the AC techniques were not effective in causing relaxation of the masticatory muscles. The purported physiological mechanisms of PNF techniques, which stated that they act through reciprocal inhibition and autogenic inhibition causing muscular relaxation, are not supported by this study. PMID:16226048

Olivo, Susan Armijo; Magee, David J

2006-05-01

282

Peroxisome proliferator activator receptor-gamma agonists and 15-deoxy-Delta(12,14)(12,14)-PGJ(2) induce apoptosis in normal and malignant B-lineage cells.  

PubMed

The research described herein evaluates the expression and functional significance of peroxisome proliferator activator receptor-gamma (PPAR-gamma) on B-lineage cells. Normal mouse B cells and a variety of B lymphoma cells reflective of stages of B cell differentiation (e.g., 70Z/3, CH31, WEHI-231, CH12, and J558) express PPAR-gamma mRNA and, by Western blot analysis, the 67-kDa PPAR-gamma protein. 15-Deoxy-Delta(12,14)-PGJ(2) (15d-PGJ(2)), a PPAR-gamma agonist, has a dose-dependent antiproliferative and cytotoxic effect on normal and malignant B cells as shown by [(3)H]thymidine and 3-[4,5-dimethylthiazol-2-yl]-2, 5-diphenyltetrazolium bromide assays. Only PPAR-gamma agonists (thiazolidinediones), and not PPAR-alpha agonists, mimicked the effect of 15d-PGJ(2) on B-lineage cells, indicating that the mechanism by which 15d-PGJ(2) negatively affects B-lineage cells involves in part PPAR-gamma. The mechanism by which PPAR-gamma agonists induce cytotoxicity is via apoptosis, as shown by annexin V staining and as confirmed by DNA fragmentation detected using the TUNEL assay. Interestingly, addition of PGF(2alpha), which was not known to affect lymphocytes, dramatically attenuated the deleterious effects of PPAR-gamma agonists on B lymphomas. Surprisingly, 15d-PGJ(2) induced a massive increase in nuclear mitogen-activated protein kinase activation, and pretreatment with PGF(2alpha) blunted the mitogen-activated protein kinase activation. This is the first study evaluating PPAR-gamma expression and its significance on B lymphocytes. PPAR-gamma agonists may serve as a counterbalance to the stimulating effects of other PGs, namely PGE(2), which promotes B cell differentiation. Finally, the use of PGs, such as 15d-PGJ(2), and synthetic PPAR-gamma agonists to induce apoptosis in B-lineage cells may lead to the development of novel therapies for fatal B lymphomas. PMID:11120820

Padilla, J; Kaur, K; Cao, H J; Smith, T J; Phipps, R P

2000-12-15

283

Non-equivalent ligand selectivity of agonist sites in (?4?2)2?4 nicotinic acetylcholine receptors: a key determinant of agonist efficacy.  

PubMed

The ?4?2 nicotinic acetylcholine receptor (nAChR) is the most abundant nAChR type in the brain, and this receptor type exists in alternate (?4?2)2?4 and (?4?2)2?2 forms, which are activated by agonists with strikingly differing efficacies. Recent breakthroughs have identified an additional operational agonist binding site in the (?4?2)2?4 nAChR that is responsible for the signature sensitivity of this receptor to activation by agonists, yet the structural mechanisms determining agonist efficacy at this receptor type are not yet fully understood. In this study, we characterized the ligand selectivity of the individual agonist sites of the (?4?2)2?4 nAChR to determine whether differences in agonist selectivity influence agonist efficacy. Applying the substituted cysteine accessibility method to individual agonist sites in concatenated (?4?2)2?4 receptors, we determined the agonist selectivity of the agonist sites of the (?4?2)2?4 receptor. We show that (a) accessibility of substituted cysteines to covalent modification by methanesulfonate reagent depends on the agonist site at which the modification occurs and (b) that agonists such as sazetidine-A and TC-2559 are excluded from the site at the ?4/?4 interface. Given that additional binding to the agonist site in the ?4/?4 interface increases acetylcholine efficacy and that agonists excluded from the agonist site at the ?4/?4 interface behave as partial agonists, we conclude that the ability to engage all agonist sites in (?4?2)2?4 nAChRs is a key determinant of agonist efficacy. The findings add another level of complexity to the structural mechanisms that govern agonist efficacy in heteromeric nAChRs and related ligand-gated ion channels. PMID:24936069

Mazzaferro, Simone; Gasparri, Federica; New, Karina; Alcaino, Constanza; Faundez, Manuel; Iturriaga Vasquez, Patricio; Vijayan, Ranjit; Biggin, Philip C; Bermudez, Isabel

2014-08-01

284

The TLR7/8 agonist CL097 primes N-formyl-methionyl-leucyl-phenylalanine-stimulated NADPH oxidase activation in human neutrophils: critical role of p47phox phosphorylation and the proline isomerase Pin1.  

PubMed

Superoxide anion production by the neutrophil NADPH oxidase plays a key role in host defense; however, excessive superoxide production is believed to participate to inflammatory reactions. Neutrophils express several TLR that recognize a variety of microbial motifs or agonists. The interaction between TLR and their agonists is believed to help neutrophils to recognize and eliminate the pathogen. However, the effects of some TLR agonists on the NADPH oxidase activation and the mechanisms controlling these effects have not been elucidated. In this study, we show that the TLR7/8 agonist CL097 by itself did not induce NADPH oxidase activation in human neutrophils, but induced a dramatic increase of fMLF-stimulated activation. Interestingly, CL097 induced cytochrome b558 translocation to the plasma membrane and the phosphorylation of the NADPH oxidase cytosolic component p47phox on Ser(345), Ser(328), and Ser(315). Phosphorylation of Ser(328) and Ser(315) was significantly increased in CL097-primed and fMLF-stimulated neutrophils. Phosphorylation of Ser(345), Ser(328), and Ser(315) was decreased by inhibitors of p38 MAPK and the ERK1/2 pathway. Phosphorylation of Ser(328) was decreased by a protein kinase C inhibitor. Genistein, a broad-range protein tyrosine kinase inhibitor, inhibited the phosphorylation of these serines. Our results also show that CL097 induced proline isomerase 1 (Pin1) activation and that juglone, a Pin1 inhibitor, inhibited CL097-mediated priming of fMLF-induced p47phox phosphorylation and superoxide production. These results show that the TLR7/8 agonist CL097 induces hyperactivation of the NADPH oxidase by stimulating the phosphorylation of p47phox on selective sites in human neutrophils and suggest that p38 MAPK, ERK1/2, protein kinase C, and Pin1 control this process. PMID:23002436

Makni-Maalej, Karama; Boussetta, Tarek; Hurtado-Nedelec, Margarita; Belambri, Sahra Amel; Gougerot-Pocidalo, Marie-Anne; El-Benna, Jamel

2012-11-01

285

Activation of I2-imidazoline receptors enhances supraspinal morphine analgesia in mice: a model to detect agonist and antagonist activities at these receptors  

PubMed Central

This work investigates the receptor acted upon by imidazoline compounds in the modulation of morphine analgesia. The effects of highly selective imidazoline ligands on the supraspinal antinociception induced by morphine in mice were determined.Intracerebroventricular (i.c.v.) or subcutaneous (s.c.) administration of ligands selective for the I2-imidazoline receptor, 2-BFI, LSL 60101, LSL 61122 and aganodine, and the non selective ligand agmatine, increased morphine antinociception in a dose-dependent manner. Neither moxonidine, a mixed I1-imidazoline and ?2-adrenoceptor agonist, RX821002, a potent ?2-adrenoceptor antagonist that displays low affinity at I2-imidazoline receptors, nor the selective non-imidazoline ?2-adrenoceptor antagonist RS-15385-197, modified the analgesic responses to morphine.Administration of pertussis toxin (0.25??g per mouse, i.c.v.) 6 days before the analgesic test blocked the ability of the I2-imidazoline ligands to potentiate morphine antinociception.The increased effect of morphine induced by I2-imidazoline ligands (agonists) was completely reversed by idazoxan and BU 224. Identical results were obtained with IBI, which alkylates I2-imidazoline binding sites. Thus, both agonist and antagonist properties of imidazoline ligands at the I2-imidazoline receptors were observed.Pre-treatment (30?min) with deprenyl, an irreversible inhibitor of monoamine oxidase B (IMAO-B), produced an increase of morphine antinociception. Clorgyline, an irreversible IMAO-A, given 30?min before morphine did not alter the effect of the opioid. At longer intervals (24?h) a single dose of either clorgyline or deprenyl reduced the density of I2-imidazoline receptors and prevented the I2-mediated potentiation of morphine analgesia.These results demonstrate functional interaction between I2-imidazoline and opioid receptors. The involvement of Gi-Go transducer proteins in this modulatory effect is also suggested. PMID:10781010

Sánchez-Blázquez, Pilar; Boronat, M Assumpció; Olmos, Gabriel; García-Sevilla, Jesús A; Garzón, Javier

2000-01-01

286

Activation of heat shock protein (hsp)70 and proto-oncogene expression by alpha1 adrenergic agonist in rat aorta with age.  

PubMed Central

Induction of heat shock proteins (hsp) most likely is a homeostatic mechanism in response to metabolic and environmental insults. We have investigated signal transduction mechanisms involved in alpha1, adrenergic receptor stimulation of hsp7O gene expression in isolated aortas with age. We found that alpha1 adrenergic agonists directly induced hsp70 mRNA in rat aorta in vitro; the alpha1, selective antagonist prazosin blocked this effect whereas chloroethylclonidine, an antagonist which has some selectivity for alpha1B receptors, was ineffective. This response was insensitive to pertussis toxin and was partially blocked by the protein kinase C inhibitor H7. Removal of extracellular calcium attenuated induction of hsp70 mRNA but not the induction of c-fos or c-myc. The induction of hsp70 mRNA by either norepinephrine or by phorbol dibutyrate was blunted in aortas from old (24-27 mo) rats whereas c-fos responses were not diminished in the older vessels. The hsp70 response to elevated temperature (42 degrees C) was not changed with age. Activation of hsp70 expression most likely involves a pertussis toxin insensitive G protein which activates protein kinase C, and requires extracellular calcium. With age, hsp70 gene expression induced by stimulation of alpha1 adrenergic receptors is markedly attenuated, which could modify responses to stress or vascular injury with aging. PMID:8636412

Chin, J H; Okazaki, M; Hu, Z W; Miller, J W; Hoffman, B B

1996-01-01

287

Molecular docking, molecular dynamics simulation, and structure-based 3D-QSAR studies on the aryl hydrocarbon receptor agonistic activity of hydroxylated polychlorinated biphenyls.  

PubMed

The binding interactions between hydroxylated polychlorinated biphenyls (HO-PCBs) and the aryl hydrocarbon receptor (AhR) are suspected of causing toxic effects. To understand the binding mode between HO-PCBs and AhR, and to explore the structural characteristics that influence the AhR agonistic activities of HO-PCBs, the combination of molecular docking, three-dimensional quantitative structure-activity relationship (3D-QSAR), and molecular dynamics (MD) simulations was performed. Using molecular docking, the HO-PCBs were docked into the binding pocket of AhR, which was generated by homology modeling. Comparative molecular similarity index analysis (CoMSIA) models were subsequently developed from three different alignment rules. The optimum 3D-QSAR model showed good predictive ability (q(2)=0.583, R(2)=0.913) and good mechanism interpretability. The statistical reliability of the CoMSIA model was also validated. In addition, molecular docking and MD simulations were applied to explore the binding modes between the ligands and AhR. The results obtained from this study may lead to a better understanding of the interaction mechanism between HO-PCBs and AhR. PMID:23850706

Cao, Fu; Li, Xiaolin; Ye, Li; Xie, Yuwei; Wang, Xiaoxiang; Shi, Wei; Qian, Xiangping; Zhu, Yongliang; Yu, Hongxia

2013-09-01

288

Cannabinoid receptor type 2 agonist attenuates apoptosis by activation of phosphorylated CREB-Bcl-2 pathway after subarachnoid hemorrhage in rats.  

PubMed

Early brain injury (EBI) which comprises of vasogenic edema and apoptotic cell death is an important component of subarachnoid hemorrhage (SAH) pathophysiology. This study evaluated whether cannabinoid receptor type 2 (CB2R) agonist, JWH133, attenuates EBI after SAH and whether CB2R stimulation reduces pro-apoptotic caspase-3 via up-regulation of cAMP response element-binding protein (CREB)-Bcl-2 signaling pathway. Male Sprague-Dawley rats (n=123) were subjected to SAH by endovascular perforation. Rats received vehicle or JWH133 at 1h after SAH. Neurological deficits and brain water content were evaluated at 24h after SAH. Western blot was performed to quantify phosphorylated CREB (pCREB), Bcl-2, and cleaved caspase-3 levels. Neuronal cell death was evaluated with terminal deoxynucleotidyl transferase-mediated uridine 5'-triphosphate-biotin nick end-labeling staining. Additionally, CREB siRNA was administered to manipulate the proposed pathway. JWH133 (1.0mg/kg) improved neurological deficits and reduced brain water content in left hemisphere 24h after SAH. JWH133 significantly increased activated CREB (pCREB) and Bcl-2 levels and significantly decreased cleaved caspase-3 levels in left hemisphere 24h after SAH. CREB siRNA reversed the effects of treatment. TUNEL positive neurons in the cortex were reduced with JWH133 treatment. Thus, CB2R stimulation attenuated EBI after SAH possibly through activation of pCREB-Bcl-2 pathway. PMID:25058046

Fujii, Mutsumi; Sherchan, Prativa; Soejima, Yoshiteru; Hasegawa, Yu; Flores, Jerry; Doycheva, Desislava; Zhang, John H

2014-11-01

289

Peroxisome proliferator-activated receptor {alpha} agonists modulate Th1 and Th2 chemokine secretion in normal thyrocytes and Graves' disease  

SciTech Connect

Until now, no data are present about the effect of peroxisome proliferator-activated receptor (PPAR){alpha} activation on the prototype Th1 [chemokine (C-X-C motif) ligand (CXCL)10] (CXCL10) and Th2 [chemokine (C-C motif) ligand 2] (CCL2) chemokines secretion in thyroid cells. The role of PPAR{alpha} and PPAR{gamma} activation on CXCL10 and CCL2 secretion was tested in Graves' disease (GD) and control primary thyrocytes stimulated with interferon (IFN){gamma} and tumor necrosis factor (TNF){alpha}. IFN{gamma} stimulated both CXCL10 and CCL2 secretion in primary GD and control thyrocytes. TNF{alpha} alone stimulated CCL2 secretion, while had no effect on CXCL10. The combination of IFN{gamma} and TNF{alpha} had a synergistic effect both on CXCL10 and CCL2 chemokines in GD thyrocytes at levels comparable to those of controls. PPAR{alpha} activators inhibited the secretion of both chemokines (stimulated with IFN{gamma} and TNF{alpha}) at a level higher (for CXCL10, about 60-72%) than PPAR{gamma} agonists (about 25-35%), which were confirmed to inhibit CXCL10, but not CCL2. Our data show that CCL2 is modulated by IFN{gamma} and TNF{alpha} in GD and normal thyrocytes. Furthermore we first show that PPAR{alpha} activators inhibit the secretion of CXCL10 and CCL2 in thyrocytes, suggesting that PPAR{alpha} may be involved in the modulation of the immune response in the thyroid.

Antonelli, Alessandro, E-mail: a.antonelli@med.unipi.it [Department of Internal Medicine, University of Pisa-School of Medicine, Via Roma 67, I-56100, Pisa (Italy)] [Department of Internal Medicine, University of Pisa-School of Medicine, Via Roma 67, I-56100, Pisa (Italy); Ferrari, Silvia Martina, E-mail: sm.ferrari@int.med.unipi.it [Department of Internal Medicine, University of Pisa-School of Medicine, Via Roma 67, I-56100, Pisa (Italy); Frascerra, Silvia, E-mail: lafrasce@gmail.com [Department of Internal Medicine, University of Pisa-School of Medicine, Via Roma 67, I-56100, Pisa (Italy)] [Department of Internal Medicine, University of Pisa-School of Medicine, Via Roma 67, I-56100, Pisa (Italy); Corrado, Alda, E-mail: dala_res@hotmail.it [Department of Internal Medicine, University of Pisa-School of Medicine, Via Roma 67, I-56100, Pisa (Italy)] [Department of Internal Medicine, University of Pisa-School of Medicine, Via Roma 67, I-56100, Pisa (Italy); Pupilli, Cinzia, E-mail: c.pupilli@dfc.unifi.it [Endocrinology Unit, Azienda Ospedaliera Careggi and University of Florence, Viale Morgagni 85, I-50134, Florence (Italy)] [Endocrinology Unit, Azienda Ospedaliera Careggi and University of Florence, Viale Morgagni 85, I-50134, Florence (Italy); Bernini, Giampaolo, E-mail: g.bernini@int.med.unipi.it [Department of Internal Medicine, University of Pisa-School of Medicine, Via Roma 67, I-56100, Pisa (Italy)] [Department of Internal Medicine, University of Pisa-School of Medicine, Via Roma 67, I-56100, Pisa (Italy); Benvenga, Salvatore, E-mail: s.benvenga@me.nettuno.it [Department of Clinical and Experimental Medicine, Section of Endocrinology, University of Messina, Piazza Pugliatti 1, I-98122, Messina (Italy)] [Department of Clinical and Experimental Medicine, Section of Endocrinology, University of Messina, Piazza Pugliatti 1, I-98122, Messina (Italy); Ferrannini, Ele, E-mail: eferrannini@med.unipi.it [Department of Internal Medicine, University of Pisa-School of Medicine, Via Roma 67, I-56100, Pisa (Italy)] [Department of Internal Medicine, University of Pisa-School of Medicine, Via Roma 67, I-56100, Pisa (Italy); Fallahi, Poupak, E-mail: poupak@int.med.unipi.it [Department of Internal Medicine, University of Pisa-School of Medicine, Via Roma 67, I-56100, Pisa (Italy)] [Department of Internal Medicine, University of Pisa-School of Medicine, Via Roma 67, I-56100, Pisa (Italy)

2011-07-01

290

Potentiating action of MKC-242, a selective 5-HT1A receptor agonist, on the photic entrainment of the circadian activity rhythm in hamsters  

PubMed Central

Serotonergic projections from the midbrain raphe nuclei to the suprachiasmatic nuclei (SCN) are known to regulate the photic entrainment of circadian clocks. However, it is not known which 5-hydroxytryptamine (5-HT) receptor subtypes are involved in the circadian regulation. In order to verify the role of 5-HT1A receptors, we examined the effects of 5-{3-[((2S)-1,4-benzodioxan-2-ylmethyl)amino]propoxy}-1,3-benzodioxole HCl (MKC-242), a selective 5-HT1A receptor agonist, on photic entrainment of wheel-running circadian rhythms of hamsters.MKC-242 (3?mg?kg?1, i.p.) significantly accelerated the re-entrainment of wheel-running rhythms to a new 8?h delayed or advanced light-dark cycle.MKC-242 (3?mg?kg?1, i.p.) also potentiated the phase advance of the wheel-running rhythm produced by low (5 lux) or high (60 lux) intensity light pulses. In contrast, 8-hydroxy-dipropylaminotetralin (8-OH-DPAT)(5?mg?kg?1, i.p.), a well known 5-HT1A/5-HT7 receptor agonist, only suppressed low intensity (5 lux) light-induced phase advances.The potentiating actions of MKC-242 on light pulse-induced phase advances were observed even when injected 20 or 60?min after the light exposure.The potentiating action of MKC-242 was antagonized by WAY100635, a selective 5-HT1A receptor blocker, but not by ritanserin, a 5-HT2/5-HT7 receptor blocker, indicating that MKC-242 is activating 5-HT1A receptors.Light pulse-induced c-fos expression in the SCN and the intergeniculate leaflet (IGL) were unaffected by MKC-242 (3?mg?kg?1, i.p.).HPLC analysis demonstrated that MKC-242 (3?mg?kg?1, i.p.) decreased the 5-HIAA content in the SCN.The present results suggest that presynaptic 5-HT1A receptor activation may be involved in the potentiation of photic entrainment by MKC-242 in hamsters. PMID:9863658

Moriya, T; Yoshinobu, Y; Ikeda, M; Yokota, S; Akiyama, M; Shibata, S

1998-01-01

291

Activating persulfate by Fe? coupling with weak magnetic field: performance and mechanism.  

PubMed

Weak magnetic field (WMF) and Fe(0) were proposed to activate PS synergistically (WMF-Fe(0)/PS) to degrade dyes and aromatic contaminants. The removal rates of orange G (OG) by WMF-Fe(0)/PS generally decreased with increasing initial pH (3.0-10.0) and increased with increasing Fe(0) (0.5-3.0 mM) or PS dosages (0.5-3.0 mM). Compared to its counterpart without WMF, the WMF-Fe(0)/PS process could induce a 5.4-28.2 fold enhancement in the removal rate of OG under different conditions. Moreover, the application of WMF significantly enhanced the decolorization rate and the mineralization of OG. The degradation rates of caffeine, 4-nitrophenol, benzotriazole and diuron by Fe(0)/PS were improved by 2.1-11.1 fold due to the superimposed WMF. Compared to many other sulfate radical-based advanced oxidation technologies under similar reaction conditions, WMF-Fe(0)/PS technology could degrade selected organic contaminants with much greater rates. Sulfate radical was identified to be the primary radical species responsible for the OG degradation at pH 7.0 in WMF-Fe(0)/PS process. This study unraveled that the presence of WMF accelerated the corrosion rate of Fe(0) and thus promoted the release of Fe(2+), which induced the increased production of sulfate radicals from PS and promoted the degradation of organic contaminants. Employing WMF to enhance oxidation capacity of Fe(0)/PS is a novel, efficient, promising and environmental-friendly method since it does not need extra energy and costly reagents. PMID:24934323

Xiong, Xinmei; Sun, Bo; Zhang, Jing; Gao, Naiyun; Shen, Jimin; Li, Jialing; Guan, Xiaohong

2014-10-01

292

Ombuin-3-O-?-D-glucopyranoside from Gynostemma pentaphyllum is a dual agonistic ligand of peroxisome proliferator-activated receptors ? and ?/?  

SciTech Connect

Highlights: ? Ombuin-3-O-?-D-glucopyranoside is a dual ligand for PPAR? and ?/?. ? Ombuin-3-O-?-D-glucopyranoside reduces cellular lipid levels in multiple cell types. ? Cells stimulated with ombuine up-regulated target genes in cholesterol efflux. ? Cells stimulated with ombuine regulated target fatty acid ?-oxidation and synthesis. ? Ombuin-3-O-?-D-glucopyranoside could ameliorate hyperlipidemia and hepatic steatosis. -- Abstract: We demonstrated that ombuin-3-O-?-D-glucopyranoside (ombuine), a flavonoid from Gynostemma pentaphyllum, is a dual agonist for peroxisome proliferator-activated receptors (PPARs) ? and ?/?. Using surface plasmon resonance (SPR), time-resolved fluorescence resonance energy transfer (FRET) analyses, and reporter gene assays, we showed that ombuine bound directly to PPAR? and ?/? but not to PPAR? or liver X receptors (LXRs). Cultured HepG2 hepatocytes stimulated with ombuine significantly reduced intracellular concentrations of triglyceride and cholesterol and downregulated the expression of lipogenic genes, including sterol regulatory element binding protein-1c (SREBP1c) and stearoyl-CoA desaturase-1 (SCD-1), with activation of PPAR? and ?/?. Activation of LXRs by ombuine was confirmed by reporter gene assays, however, SPR and cell-based FRET assays showed no direct binding of ombuine to either of the LXRs suggesting LXR activation by ombuine may be operated via PPAR? stimulation. Ombuine-stimulated macrophages showed significantly induced transcription of ATP binding cassette cholesterol transporter A1 (ABCA1) and G1 (ABCG1), the key genes in reverse cholesterol transport, which led to reduced cellular cholesterol concentrations. These results suggest that ombuine is a dual PPAR ligand for PPAR? and ?/? with the ability to decrease lipid concentrations by reducing lipogenic gene expression in hepatocytes and inducing genes involved in cholesterol efflux in macrophages.

Malek, Mastura Abd; Hoang, Minh-Hien; Jia, Yaoyao; Lee, Ji Hae; Jun, Hee Jin [Department of Biotechnology, Graduate School of Biotechnology, Korea University, Seoul 136-713 (Korea, Republic of) [Department of Biotechnology, Graduate School of Biotechnology, Korea University, Seoul 136-713 (Korea, Republic of); Division of Food Bioscience and Technology, College of Life Sciences and Biotechnology, Korea University, Seoul 136-713 (Korea, Republic of); Lee, Dong-Ho [Department of Biotechnology, Graduate School of Biotechnology, Korea University, Seoul 136-713 (Korea, Republic of)] [Department of Biotechnology, Graduate School of Biotechnology, Korea University, Seoul 136-713 (Korea, Republic of); Lee, Hak Ju [Division of Green Business Management, Department of Forest Resources Utilization, Korean Forest Research Institute, Seoul 130-712 (Korea, Republic of)] [Division of Green Business Management, Department of Forest Resources Utilization, Korean Forest Research Institute, Seoul 130-712 (Korea, Republic of); Lee, Chul; Lee, Myung Koo [College of Pharmacy, Chungbuk National University, Cheongju, Chungbuk 361-763 (Korea, Republic of)] [College of Pharmacy, Chungbuk National University, Cheongju, Chungbuk 361-763 (Korea, Republic of); Hwang, Bang Yeon, E-mail: byhwang@chungbuk.ac.kr [College of Pharmacy, Chungbuk National University, Cheongju, Chungbuk 361-763 (Korea, Republic of); Lee, Sung-Joon, E-mail: junelee@korea.ac.kr [Department of Biotechnology, Graduate School of Biotechnology, Korea University, Seoul 136-713 (Korea, Republic of) [Department of Biotechnology, Graduate School of Biotechnology, Korea University, Seoul 136-713 (Korea, Republic of); Division of Food Bioscience and Technology, College of Life Sciences and Biotechnology, Korea University, Seoul 136-713 (Korea, Republic of)

2013-01-25

293

NOD-like receptors and RIG-I-like receptors in human eosinophils: activation by NOD1 and NOD2 agonists  

PubMed Central

NOD-like receptors (NLRs) and RIG-I-like receptors (RLRs) are newly discovered pattern-recognition receptors. They detect substructures of bacterial peptidoglycan and viral RNA, respectively, thereby initiating an immune response. However, their role in eosinophil activation remains to be explored. The aim of this study was to characterize the expression of a range of NLRs and RLRs in purified human eosinophils and assess their functional importance. Expression of NOD1, NOD2, NLRP3, RIG-I and MDA-5 was investigated using real-time reverse transcription PCR, flow cytometry and immunohistochemistry. The effects of the corresponding agonists iE-DAP (NOD1), MDP (NOD2), alum (NLRP3) and poly(I:C)/LyoVec (RIG-I/MDA-5) were studied in terms of cytokine secretion, degranulation, survival, expression of adhesion molecules and activation markers, and chemotactic migration. Eosinophils expressed NOD1 and NOD2 mRNA and protein. Low levels of RIG-I and MDA-5 were found, whereas expression of NLRP3 was completely absent. In accordance, stimulation with iE-DAP and MDP was found to induce secretion of interleukin-8, up-regulate expression of CD11b, conversely down-regulate CD62 ligand, increase expression of CD69 and induce migration. The MDP also promoted release of eosinophil-derived neurotoxin, whereas iE-DAP failed to do so. No effects were seen upon stimulation with alum or poly(I:C)/LyoVec. Moreover, the NOD1-induced and NOD2-induced activation was mediated via the nuclear factor-?B signalling pathway and augmented by interleukin-5 and granulocyte–macrophage colony-stimulating factor, but not interferon-?. Taken together, the NLR system represents a novel pathway for eosinophil activation. The responses are enhanced in the presence of cytokines that regulate T helper type 2 immunity, suggesting that the NLRs constitute a link between respiratory infections and exacerbations of allergic disease. PMID:21978001

Kvarnhammar, Anne Månsson; Petterson, Terese; Cardell, Lars-Olaf

2011-01-01

294

Complete rescue of cerebrovascular function in aged Alzheimer's disease transgenic mice by antioxidants and pioglitazone, a peroxisome proliferator-activated receptor gamma agonist.  

PubMed

Accumulating evidence suggests that cerebrovascular dysfunction is an important factor in the pathogenesis of Alzheimer's disease (AD). Using aged ( approximately 16 months) amyloid precursor protein (APP) transgenic mice that exhibit increased production of the amyloid-beta (Abeta) peptide and severe cerebrovascular and memory deficits, we examined the capacity of in vivo treatments with the antioxidants N-acetyl-L-cysteine (NAC) and tempol, or the peroxisome proliferator-activated receptor gamma agonist pioglitazone to rescue cerebrovascular function and selected markers of AD neuropathology. Additionally, we tested the ability of pioglitazone to normalize the impaired increases in cerebral blood flow (CBF) and glucose uptake (CGU) induced by whisker stimulation, and to reverse spatial memory deficits in the Morris water maze. All compounds fully restored cerebrovascular reactivity of isolated cerebral arteries concomitantly with changes in proteins regulating oxidative stress, without reducing brain Abeta levels or Abeta plaque load. Pioglitazone, but not NAC, significantly attenuated astroglial activation and improved, albeit nonsignificantly, the reduced cortical cholinergic innervation. Furthermore, pioglitazone completely normalized the CBF and CGU responses to increased neuronal activity, but it failed to improve spatial memory. Our results are the first to demonstrate that late pharmacological intervention with pioglitazone not only overcomes cerebrovascular dysfunction and altered neurometabolic coupling in aged APP mice, but also counteracts cerebral oxidative stress, glial activation, and, partly, cholinergic denervation. Although early or combined therapy may be warranted to improve cognition, these findings unequivocally point to pioglitazone as a most promising strategy for restoring cerebrovascular function and counteracting several AD markers detrimental to neuronal function. PMID:18784309

Nicolakakis, Nektaria; Aboulkassim, Tahar; Ongali, Brice; Lecrux, Clotilde; Fernandes, Priscilla; Rosa-Neto, Pedro; Tong, Xin-Kang; Hamel, Edith

2008-09-10

295

Protective effects of a peroxisome proliferator-activated receptor-h/y agonist in experimental autoimmune encephalomyelitis  

E-print Network

autoimmune encephalomyelitis Paul E. Polak a,1 , Sergey Kalinin a,1 , Cinzia Dello Russo a , Vitaliy. Introduction Peroxisome Proliferator-Activated Receptors (PPARs) are nuclear hormone receptors. In response

Omiecinski, Curtis

296

SAR-studies of ?-secretase modulators with PPAR?-agonistic and 5-lipoxygenase-inhibitory activity for Alzheimer's disease.  

PubMed

We present the design, synthesis and biological evaluation of compounds containing a 2-(benzylidene)hexanoic acid scaffold as multi-target directed ?-secretase-modulators. Broad structural variations were undertaken to elucidate the structure-activity-relationships at the 5-position of the aromatic core. Compound 13 showed the most potent activity profile with IC50 values of 0.79?M (A?42), 0.3?M (5-lipoxygenase) and an EC50 value of 4.64?M for PPAR?-activation. This derivative is the first compound exhibiting low micromolar to nanomolar activities for these three targets. Combining ?-secretase-modulation, PPAR?-agonism and inhibition of 5-lipoxygenase in one compound could be a novel disease-modifying multi-target-strategy for Alzheimer's disease to concurrently address the causative amyloid pathology and secondary pathologies like chronic brain inflammation. PMID:25575659

Flesch, Daniel; Ness, Julia; Lamers, Christina; Dehm, Friederike; Popella, Sven; Steri, Ramona; Ogorek, Isabella; Hieke, Martina; Dannhardt, Gerd; Werz, Oliver; Weggen, Sascha; Schubert-Zsilavecz, Manfred

2015-02-15

297

Combination of a Toll-like receptor 9 agonist with everolimus interferes with the growth and angiogenic activity of renal cell carcinoma.  

PubMed

The mTOR inhibitor everolimus is currently approved for the treatment of renal cell carcinoma (RCC) and several Toll-like receptor 9 (TLR9) agonists, including immunomodulatory oligonucleotides (IMOs), have been tested for their therapeutic potential against advanced RCC. However, no clinical trials investigating the combination of mTOR inhibitors with TLR9 agonists in RCC patients have been performed to date. Our results may pave the way to translate this combinatorial approach to the clinical setting. PMID:24083076

Rosa, Roberta; Damiano, Vincenzo; Formisano, Luigi; Nappi, Lucia; Marciano, Roberta; Veneziani, Bianca Maria; De Placido, Sabino; Bianco, Roberto

2013-08-01

298

Combination of a Toll-like receptor 9 agonist with everolimus interferes with the growth and angiogenic activity of renal cell carcinoma  

PubMed Central

The mTOR inhibitor everolimus is currently approved for the treatment of renal cell carcinoma (RCC) and several Toll-like receptor 9 (TLR9) agonists, including immunomodulatory oligonucleotides (IMOs), have been tested for their therapeutic potential against advanced RCC. However, no clinical trials investigating the combination of mTOR inhibitors with TLR9 agonists in RCC patients have been performed to date. Our results may pave the way to translate this combinatorial approach to the clinical setting. PMID:24083076

Rosa, Roberta; Damiano, Vincenzo; Formisano, Luigi; Nappi, Lucia; Marciano, Roberta; Veneziani, Bianca Maria; De Placido, Sabino; Bianco, Roberto

2013-01-01

299

Correlation between thyroid hormone status and hepatic hyperplasia and hypertrophy caused by the peroxisome proliferator-activated receptor alpha agonist Wy-14,643.  

PubMed

BACKGROUND: The metabolic inhibitor rotenone inhibits hepatocellular proliferation and the incidence of liver cancer resulting from exposure to the PPARalpha agonist Wy-14,643, via unknown mechanisms. Since the absence of thyroid hormones diminishes hepatomegaly, an early biomarker for the hepatocarcinogenicity induced by PPARalpha agonists, this study was undertaken to investigate whether rotenone might interference with the ability of Wy-14,643 to alter the animal thyroid status. METHODS: Male B6C3F1 mice were given Wy-14,643 (100 ppm), rotenone (600 ppm) or a mixture of both, in the feed for 7 days. Bromodeoxyuridine (BrDU), marker of cell replication, was delivered through subcutaneously implanted osmotic mini-pumps. At the end of the experiment, sera were collected and corticosterone and thyroid hormone levels were measured by solid-phase radioimmunoassay kits. In addition, liver tissue samples were stained immunohistochemically for BrDU to determine percentages of labeled cells. Further, cell surface area was determined from images generated by a Zeiss Axioplan microscope equipped with a plan Neofluar x40 0.75 na objective. Tracings of individual hepatocyte perimeters were then analyzed and cell-surface areas were calculated using MicroMeasure FL-4000. RESULTS: Wy-14,643 caused a significant increase in liver weights, hepatocyte BrDU labeling index (LI), and hepatocyte surface area. In animals which received both Wy-14,643 and rotenone simultaneously, all of these effects were significantly less pronounced compared with mice that received Wy-14,643 alone. Rotenone alone decreased liver weights, LI and surface area. The Free Thyroid Index (FTI), which provides an accurate reflection of the animal's thyroid status, was 5.0 +/- 0.3 in control mice. In animals exposed to rotenone, these values decreased to 2.0 +/- 0.9, but in animals which received Wy-14,643, levels increased significantly to 7.7 +/- 0.9. FTI values decreased to 3.4 +/- 0.8 in mice receiving both rotenone and Wy-14,643. CONCLUSION: A strong correlation was observed between the animal thyroid status and both, hepatocyte proliferation (r2 = 0.62), and hepatocyte surface area (r2 = 0.83). These results support the hypothesis that the thyroid status of the animal plays a role in PPARalpha-induced hepatocellular proliferation and liver cell enlargement. Both these events are known to contribute to the expression of liver cancer in response to the activation of PPARalpha. PMID:15157275

Wang, C; Youssef, J; Cunningham, ML; Badr, M

2004-05-24

300

Correlation between thyroid hormone status and hepatic hyperplasia and hypertrophy caused by the peroxisome proliferator-activated receptor alpha agonist Wy-14,643  

PubMed Central

Background The metabolic inhibitor rotenone inhibits hepatocellular proliferation and the incidence of liver cancer resulting from exposure to the PPAR? agonist Wy-14,643, via unknown mechanisms. Since the absence of thyroid hormones diminishes hepatomegaly, an early biomarker for the hepatocarcinogenicity induced by PPAR? agonists, this study was undertaken to investigate whether rotenone might interference with the ability of Wy-14,643 to alter the animal thyroid status. Methods Male B6C3F1 mice were given Wy-14,643 (100 ppm), rotenone (600 ppm) or a mixture of both, in the feed for 7 days. Bromodeoxyuridine (BrDU), marker of cell replication, was delivered through subcutaneously implanted osmotic mini-pumps. At the end of the experiment, sera were collected and corticosterone and thyroid hormone levels were measured by solid-phase radioimmunoassay kits. In addition, liver tissue samples were stained immunohistochemically for BrDU to determine percentages of labeled cells. Further, cell surface area was determined from images generated by a Zeiss Axioplan microscope equipped with a plan Neofluar ×40 0.75 na objective. Tracings of individual hepatocyte perimeters were then analyzed and cell-surface areas were calculated using MicroMeasure FL-4000. Results Wy-14,643 caused a significant increase in liver weights, hepatocyte BrDU labeling index (LI), and hepatocyte surface area. In animals which received both Wy-14,643 and rotenone simultaneously, all of these effects were significantly less pronounced compared with mice that received Wy-14,643 alone. Rotenone alone decreased liver weights, LI and surface area. The Free Thyroid Index (FTI), which provides an accurate reflection of the animal's thyroid status, was 5.0 ± 0.3 in control mice. In animals exposed to rotenone, these values decreased to 2.0 ± 0.9, but in animals which received Wy-14,643, levels increased significantly to 7.7 ± 0.9. FTI values decreased to 3.4 ± 0.8 in mice receiving both rotenone and Wy-14,643. Conclusion A strong correlation was observed between the animal thyroid status and both, hepatocyte proliferation (r2 = 0.62), and hepatocyte surface area (r2 = 0.83). These results support the hypothesis that the thyroid status of the animal plays a role in PPAR?-induced hepatocellular proliferation and liver cell enlargement. Both these events are known to contribute to the expression of liver cancer in response to the activation of PPAR?. PMID:15157275

Wang, C; Youssef, J; Cunningham, ML; Badr, M

2004-01-01

301

Effect of combination treatment of S–amlodipine with peroxisome proliferator-activated receptor agonists on metabolic and cardiovascular parameters in Zucker fa/fa rats  

PubMed Central

Background Type 2 diabetes is a complex metabolic disorder characterized by hyperglycemia, impaired glucose tolerance and insulin resistance associated with dyslipidemia and hypertension. The available drugs are not sufficiently efficacious in reducing cardiovascular risk and restoring normal glucose metabolism associated with type 2 diabetes as a mono- or a combination therapy. The present study examined the combined effects of an antihypertensive (S-Amlodipine) and an insulin-sensitizing agent, peroxisome proliferator-activated receptor (PPAR) agonists (Pioglitazone and Ragaglitazar), on cardiovascular risk factors in aged diabetic and insulin-resistant Zucker fa/fa rats. Methods Following combination treatment for 14 days, blood pressure (BP), serum glucose, total cholesterol and triglycerides were measured. Aortic ring study was conducted to determine the effect of combination treatments on phenylephrine-induced vasoconstriction and acetylcholine (Ach)-induced vasorelaxation. Results In combination, S-Amlodipine and Pioglitazone significantly reduced blood glucose (115.1?±?6.6 vs. 81.7?±?4.2), BP (184.4?±?5.0 vs. 155.1?±?5.0), serum triglycerides (362.5?±?47.5 vs. 211.1?±?23.7) and glucose intolerance when compared with vehicle treated Zucker fa/fa rats. Similar results were observed with the combination of S-Amlodipine and Ragaglitazar (Triglycerides, 362.5?±?47.5 vs. 252.34?±?27.86; BP, 184.4?±?5.0 vs. 159.0?±?8.0) except for serum glucose. ACh-induced vasorelaxation in aortic rings was also superior with both of the combinations compared to individual treatment. Furthermore, there was less body weight gain and food intake with S-Amlodipine and Pioglitazone combination in Zucker fa/fa rats. S-Amlodipine itself caused significant reduction in glucose (115.1?±?6.6 vs. 89.7?±?2.7) and BP (184.4?±?5.0 vs. 156.1?±?4.0) with improvement in insulin sensitivity observed through oral glucose tolerance test. Conclusions The results suggest that a combination of PPAR agonists and S-Amlodipine has partial benefits in improving the cardiovascular risk factors such as reduction in triglyceride levels, associated with chronic type 2 diabetes, and therefore may be utilized as an approach for addressing some of these devastating metabolic syndrome complications. PMID:24673913

2014-01-01

302

Rosiglitazone, a Peroxisome Proliferator-Activated Receptor-? Agonist, Restores Alveolar and Pulmonary Vascular Development in a Rat Model of Bronchopulmonary Dysplasia  

PubMed Central

Purpose We tested whether rosiglitazone (RGZ), a peroxisome proliferator-activated receptor-? agonist, can restore alveolar development and vascular growth in a rat model of bronchopulmonary dysplasia (BPD). Materials and Methods A rat model of BPD was induced through intra-amniotic delivery of lipopolysaccharide (LPS) and postnatal hyperoxia (80% for 7 days). RGZ (3 mg/kg/d, i.p.) or vehicle was given daily to rat pups for 14 days. This model included four experimental groups: No BPD+vehicle (V), No BPD+RGZ, BPD+V, and BPD+RGZ. On D14, alveolarization, lung vascular density, and right ventricular hypertrophy (RVH) were evaluated. Results Morphometric analysis revealed that the BPD+RGZ group had significantly smaller and more complex airspaces and larger alveolar surface area than the BPD+V group. The BPD+RGZ group had significantly greater pulmonary vascular density than the BPD+V group. Western blot analysis revealed that significantly decreased levels of vascular endothelial growth factor (VEGF) and its receptor VEGFR-2 by the combined exposure to intra-amniotic LPS and postnatal hyperoxia were restored by the RGZ treatment. RVH was significantly lesser in the BPD+RGZ group than in the BPD+V group. Conclusion These results suggest that RGZ can restore alveolar and pulmonary vascular development and lessen pulmonary hypertension in a rat model of BPD. PMID:24339293

Lee, Hyun Ju; Lee, Youn Jin; Lee, Jin-A; Kim, Ee-Kyung; Kim, Han-Suk; Kim, Beyong Il; Choi, Jung-Hwan

2014-01-01

303

Inhibition of rotavirus ECwt infection in ICR suckling mice by N-acetylcysteine, peroxisome proliferator-activated receptor gamma agonists and cyclooxygenase-2 inhibitors  

PubMed Central

Live attenuated vaccines have recently been introduced for preventing rotavirus disease in children. However, alternative strategies for prevention and treatment of rotavirus infection are needed mainly in developing countries where low vaccine coverage occurs. In the present work, N-acetylcysteine (NAC), ascorbic acid (AA), some nonsteroidal anti-inflammatory drugs (NSAIDs) and peroxisome proliferator-activated receptor gamma (PPAR?) agonists were tested for their ability to interfere with rotavirus ECwt infectivity as detected by the percentage of viral antigen-positive cells of small intestinal villi isolated from ECwt-infected ICR mice. Administration of 6 mg NAC/kg every 8 h for three days following the first diarrhoeal episode reduced viral infectivity by about 90%. Administration of AA, ibuprofen, diclofenac, pioglitazone or rosiglitazone decreased viral infectivity by about 55%, 90%, 35%, 32% and 25%, respectively. ECwt infection of mice increased expression of cyclooxygenase-2, ERp57, Hsc70, NF-?B, Hsp70, protein disulphide isomerase (PDI) and PPAR? in intestinal villus cells. NAC treatment of ECwt-infected mice reduced Hsc70 and PDI expression to levels similar to those observed in villi from uninfected control mice. The present results suggest that the drugs tested in the present work could be assayed in preventing or treating rotaviral diarrhoea in children and young animals. PMID:24037197

Guerrero, Carlos Arturo; Pardo, Paula; Rodriguez, Victor; Guerrero, Rafael; Acosta, Orlando

2013-01-01

304

Peroxisome proliferator-activated receptor-gamma agonist rosiglitazone attenuates inflammatory pain through the induction of heme oxygenase-1 in macrophages.  

PubMed

Macrophage infiltration to inflammatory sites promotes tissue repair and may be involved in pain hypersensitivity. Peroxisome proliferator-activated receptor (PPAR)? signaling is known to regulate polarity of macrophages, which are often referred to as proinflammatory (M1) and antiinflammatory (M2) macrophages. We recently showed that the PPAR? agonist rosiglitazone ameliorated the development of postincisional hyperalgesia by increasing the influx of M2 macrophages to inflamed sites. It has been suggested that heme oxygenase (HO)-1, upregulated by PPAR? signaling, promotes differentiation of macrophages to M2 phenotype. In this study, we investigated how rosiglitazone alters pain hypersensitivity by a PPAR?HO-1-dependent mechanism during the course of inflammation induced by complete Freund's adjuvant. Local administration of rosiglitazone alleviated mechanical hyperalgesia, with increased gene induction of HO-1. Phenotype switching of infiltrated macrophages to M2 by rosiglitazone was reversed by an HO-1 inhibitor, tin protoporphyrin, at the inflamed sites. Direct stimulation of peritoneal macrophages with rosiglitazone also increased HO-1 induction in the presence of lipopolysaccharide/interferon-?. Moreover, rosiglitazone increased gene induction of endogenous opioid proenkephalin, both at inflamed sites and in isolated macrophages. Administration of naloxone blocked the analgesic effects of rosiglitazone. We speculate that rosiglitazone alleviated the development of inflammatory pain, possibly through regulating the M1/M2 balance at the inflamed site by a PPAR?/HO-1-dependent mechanism. PPAR? signaling in macrophages may be a potential therapeutic target for the treatment of acute pain development. PMID:23707273

Hasegawa-Moriyama, Maiko; Kurimoto, Tae; Nakama, Mayo; Godai, Kohei; Kojima, Masayasu; Kuwaki, Tomoyuki; Kanmura, Yuichi

2013-08-01

305

Lesions of area postrema and subfornical organ alter exendin-4-induced brain activation without preventing the hypophagic effect of the GLP-1 receptor agonist.  

PubMed

The mechanism and route whereby glucagon-like peptide 1 (GLP-1) receptor agonists, such as GLP-1 and exendin-4 (Ex-4), access the central nervous system (CNS) to exert their metabolic effects have yet to be clarified. The primary objective of the present study was to investigate the potential role of two circumventricular organs (CVOs), the area postrema (AP) and the subfornical organ (SFO), in mediating the metabolic and CNS-stimulating effects of Ex-4. We demonstrated that electrolytic ablation of the AP, SFO, or AP + SFO does not acutely prevent the anorectic effects of Ex-4. AP + SFO lesion chronically decreased food intake and body weight and also modulated the effect of Ex-4 on the neuronal activation of brain structures involved in the hypothalamic-pituitary-adrenal axis and glucose metabolism. The results of the study also showed that CVO lesions blunted Ex-4-induced expression of c-fos mRNA (a widely used neuronal activity marker) in 1) limbic structures (bed nucleus of the stria terminalis and central amygdala), 2) hypothalamus (paraventricular hypothalamic nucleus, supraoptic nucleus, and arcuate nucleus), and 3) hindbrain (lateral and lateral-external parabrachial nucleus, medial nucleus of the solitary tract, and ventrolateral medulla). In conclusion, although the present results do not support a role for the CVOs in the anorectic effect induced by a single injection of Ex-4, they suggest that the CVOs play important roles in mediating the actions of Ex-4 in the activation of CNS structures involved in homeostatic control. PMID:20106992

Baraboi, Elena-Dana; Smith, Pauline; Ferguson, Alastair V; Richard, Denis

2010-04-01

306

Total Synthesis and Structure-Activity Relationship Study of the Potent cAMP Signaling Agonist (-)-Alotaketal A  

PubMed Central

A detailed account of the first total synthesis of alotaketal A, a tricyclic spiroketal sesterterpenoid that potently activates the cAMP signaling pathway, is provided. The synthesis employs both intra- and intermolecular reductive allylation of esters for assembling one of the fragments and their coupling. A Hg(OAc)2-mediated allylic mercuration is used to introduce the C22-hydroxyl group. The subtle influence of substituents over the course of the spiroketalization process is revealed. The synthesis confirms the relative and absolute stereochemistry of (-)-alotaketal A and allows verification of alotaketal A’s effect over cAMP signaling using reporter-based FRET imaging assays with HEK 293T cells. Our studies also revealed alotaketal A’s unique activity in selectively targeting nuclear PKA signaling in living cells. PMID:23584129

Huang, Jinhua; Yang, Jessica R.

2013-01-01

307

Low molecular weight, non-peptidic agonists of TrkA receptor with NGF-mimetic activity  

PubMed Central

Exploitation of the biologic activity of neurotrophins is desirable for medical purposes, but their protein nature intrinsically bears adverse pharmacokinetic properties. Here, we report synthesis and biologic characterization of a novel class of low molecular weight, non-peptidic compounds with NGF (nerve growth factor)-mimetic properties. MT2, a representative compound, bound to Trk (tropomyosin kinase receptor)A chain on NGF-sensitive cells, as well as in cell-free assays, at nanomolar concentrations and induced TrkA autophosphorylation and receptor-mediated internalization. MT2 binding involved at least two amino-acid residues within TrkA molecule. Like NGF, MT2 increased phosphorylation of extracellular signal-regulated kinase1/2 and Akt proteins and production of MKP-1 phosphatase (dual specificity phosphatase 1), modulated p38 mitogen-activated protein kinase activation, sustained survival of serum-starved PC12 or RDG cells, and promoted their differentiation. However, the intensity of such responses was heterogenous, as the ability of maintaining survival was equally possessed by NGF and MT2, whereas the induction of differentiation was expressed at definitely lower levels by the mimetic. Analysis of TrkA autophosphorylation patterns induced by MT2 revealed a strong tyrosine (Tyr)490 and a limited Tyr785 and Tyr674/675 activation, findings coherent with the observed functional divarication. Consistently, in an NGF-deprived rat hippocampal neuronal model of Alzheimer Disease, MT2 could correct the biochemical abnormalities and sustain cell survival. Thus, NGF mimetics may reveal interesting investigational tools in neurobiology, as well as promising drug candidates. PMID:22764098

Scarpi, D; Cirelli, D; Matrone, C; Castronovo, G; Rosini, P; Occhiato, E G; Romano, F; Bartali, L; Clemente, A M; Bottegoni, G; Cavalli, A; De Chiara, G; Bonini, P; Calissano, P; Palamara, A T; Garaci, E; Torcia, M G; Guarna, A; Cozzolino, F

2012-01-01

308

Anxiolytic Effects and Neuroanatomical Targets of Estrogen Receptor-? (ER?) Activation by a Selective ER? Agonist in Female Mice  

PubMed Central

The dichotomous anxiogenic and anxiolytic properties of estrogens have been reported to be mediated by two distinct neural estrogen receptors (ER), ER? and ER?, respectively. Using a combination of pharmacological and genetic approaches, we confirmed that the anxiolytic actions of estradiol are mediated by ER? and extended and these observations to demonstrate the neuroanatomical targets involved in ER? activation in these behavioral responses. We examined the effects of the biologically active S-enantiomer of diarylpropionitrile (S-DPN) on anxiety-related behavioral measures, the corresponding stress hormonal response to hypothalamo-pituitary-adrenal axis reactivity, and potential sites of neuronal activation in mutant female mice carrying a null mutation for ER? gene (?ERKO). S-DPN administration significantly reduced anxiety-like behaviors in the open field, light-dark exploration, and the elevated plus maze (EPM) in ovariectomized wild-type (WT) mice, but not in their ?ERKO littermates. Stress-induced corticosterone (CORT) and ACTH were also attenuated by S-DPN in the WT mice but not in the ?ERKO mice. Using c-fos induction after elevated plus maze, as a marker of stress-induced neuronal activation, we identified the anterodorsal medial amygdala and bed nucleus of the stria terminalis as the neuronal targets of S-DPN action. Both areas showed elevated c-fos mRNA expression with S-DPN treatment in the WT but not ?ERKO females. These studies provide compelling evidence for anxiolytic effects mediated by ER?, and its neuroanatomical targets, that send or receive projections to/from the paraventricular nucleus, providing potential indirect mode of action for the control of hypothalamo-pituitary-adrenal axis function and behaviors. PMID:22186418

Oyola, Mario G.; Portillo, Wendy; Reyna, Andrea; Foradori, Chad D.; Kudwa, Andrea; Hinds, Laura; Handa, Robert J.

2012-01-01

309

Retinoid X receptor and peroxisome proliferator-activated receptor-gamma agonists cooperate to inhibit matrix metalloproteinase gene expression  

Microsoft Academic Search

INTRODUCTION: We recently described the ability of retinoid X receptor (RXR) ligand LG100268 (LG268) to inhibit interleukin-1-beta (IL-1-?)-driven matrix metalloproteinase-1 (MMP-1) and MMP-13 gene expression in SW-1353 chondrosarcoma cells. Other investigators have demonstrated similar effects in chondrocytes treated with rosiglitazone, a ligand for peroxisome proliferator-activated receptor-gamma (PPAR?), for which RXR is an obligate dimerization partner. The goals of this study

Peter S Burrage; Adam C Schmucker; Yanqing Ren; Michael B Sporn; Constance E Brinckerhoff

2008-01-01

310

Immunization of male rabbits with sheep luteal receptor to LH results in production of antibodies exhibiting hormone-agonistic and -antagonistic activities.  

PubMed

Antibodies to LH/chorionic gonadotrophin receptor (LH/CG-R; molecular weight 67 000), isolated in a homogenous state (established by SDS-PAGE and ligand blotting) from sheep luteal membrane using human CG (hCG)-Sepharose affinity chromatography, were raised in three adult male rabbits (R-I, R-II and R-III). Each of the rabbits received 20-30 micrograms of the purified receptor in Freund's complete adjuvant at a time. Primary immunization was followed by booster injection at intervals. Production of receptor antibodies was monitored by (1) determining the dilution of the serum (IgG fraction) that could specifically bind 50% of 125I-LH/CG-R added and (2) analysing sera for any change in testosterone levels. Following primary immunization and the first booster, all three rabbits exhibited a 2.5- to 6.0-fold increase in serum testosterone over basal levels and this effect was spread over a period of time (approximately 40 days) coinciding with the rise and fall of receptor antibodies. The maximal antibody titre (ED50) produced at this time ranged from 1:350 to 1:100 to below detectable limits for R-I, R-II and R-III respectively. Subsequent immunizations followed by the second booster resulted in a substantial increase in antibody titre (ED50 of 1:5000) in R-I, but this was not accompanied by any change in serum testosterone over preimmune levels, suggesting that with the progress of immunization the character of the antibody produced had also changed. Two pools of antisera from R-I collected 10 days following the booster (at day 70 (bleed I) and day 290 (bleed II)) were used in further experiments. IgG isolated from bleed I but not from bleed II antiserum showed a dose-dependent stimulation of testosterone production by mouse Leydig cells in vitro, thus confirming the in vivo hormone-mimicking activity of antibodies generated during the early immunization phase. The IgG fractions from both bleeds were, however, capable of inhibiting (1) 125I-hCG binding to crude sheep luteal membrane (EC50 of 1:70 and 1:350 for bleed I and II antisera respectively) and (2) ovine LH-stimulated testosterone production by mouse Leydig cells in vitro, indicating the presence of antagonistic antibodies irrespective of the period of time during which the rabbits were immunized. The fact that bleed I-stimulated testosterone production could be inhibited in a dose-dependent manner by the addition of IgG from bleed II to the mouse Leydig cell in vitro assay system showed that the agonistic activity is intrinsic to the bleed I antibody. The receptor antibody (bleed II) was also capable of blocking LH action in vivo, as rabbits passively (for 24 h with LH/CG-R antiserum) as well as actively (for 430 days) immunized against LH/CG-R failed to respond to a bolus injection of LH (50 micrograms). At no time, however, was the serum testosterone reduced below the basal level. This study clearly shows that, unlike with LH antibody, attempts to achieve an LH deficiency effect in vivo by resorting to immunization with holo LH receptor is difficult, as receptor antibodies exhibit both hormone-mimicking (agonistic) as well as hormone-blocking (antagonistic) activities. PMID:8882162

Jeyakumar, M; Moudgal, N R

1996-09-01

311

Ocular hypotensive activity of BOL-303259-X, a nitric oxide donating prostaglandin F2? agonist, in preclinical models.  

PubMed

The aim of the study was to investigate the ocular hypotensive activity of a nitric oxide (NO)-donating latanoprost, BOL-303259-X, following topical administration. The effect of BOL-303259-X (also known as NCX 116 and PF-3187207) on intraocular pressure (IOP) was investigated in monkeys with laser-induced ocular hypertension, dogs with naturally-occurring glaucoma and rabbits with saline-induced ocular hypertension. Latanoprost was used as reference drug. NO, downstream effector cGMP, and latanoprost acid were determined in ocular tissues following BOL-303259-X administration as an index of prostaglandin and NO-mediated activities. In primates, a maximum decrease in IOP of 31% and 35% relative to baseline was achieved with BOL-303259-X at doses of 0.036% (9 ?g) and 0.12% (36 ?g), respectively. In comparison, latanoprost elicited a greater response than vehicle only at 0.1% (30 ?g) with a peak effect of 26%. In glaucomatous dogs, IOP decreased from baseline by 44% and 10% following BOL-303259-X (0.036%) and vehicle, respectively. Latanoprost (0.030%) lowered IOP by 27% and vehicle by 9%. Intravitreal injection of hypertonic saline in rabbits increased IOP transiently. Latanoprost did not modulate this response, whereas BOL-303259-X (0.036%) significantly blunted the hypertensive phase. Following BOL-303259-X treatment, latanoprost acid was significantly elevated in rabbit and primate cornea, iris/ciliary body and aqueous humor as was cGMP in aqueous humor. BOL-303259-X lowered IOP more effectively than latanoprost presumably as a consequence of a contribution by NO in addition to its prostaglandin activity. The compound is now in clinical development for the treatment of glaucoma and ocular hypertension. PMID:21396362

Krauss, Achim H P; Impagnatiello, Francesco; Toris, Carol B; Gale, David C; Prasanna, Ganesh; Borghi, Valentina; Chiroli, Valerio; Chong, Wesley K M; Carreiro, Samantha T; Ongini, Ennio

2011-09-01

312

A Phase 1 Study of Efatutazone, an Oral Peroxisome Proliferator-Activated Receptor Gamma Agonist, Administered to Patients With Advanced Malignancies  

PubMed Central

BACKGROUND Efatutazone (CS-7017), a novel peroxisome proliferator-activated receptor gamma (PPAR?) agonist, exerts anticancer activity in preclinical models. The authors conducted a phase 1 study to determine the recommended phase 2 dose, safety, tolerability, and pharmacokinetics of efatutazone. METHODS Patients with advanced solid malignancies and no curative therapeutic options were enrolled to receive a given dose of efatutazone, administered orally (PO) twice daily for 6 weeks, in a 3 + 3 intercohort dose-escalation trial. After the third patient, patients with diabetes mellitus were excluded. Efatutazone dosing continued until disease progression or unacceptable toxicity, with measurement of efatutazone pharmacokinetics and plasma adiponectin levels. RESULTS Thirty-one patients received efatutazone at doses ranging from 0.10 to 1.15 mg PO twice daily. Dose escalation stopped when maximal impact on PPAR?-related biomarkers had been reached before any protocol-defined maximum-tolerated dose level. On the basis of a population pharmacokinetic/pharmacodynamic analysis, the recommended phase 2 dose was 0.5 mg PO twice daily. A majority of patients experienced peripheral edema (53.3%), often requiring diuretics. Three episodes of dose-limiting toxicities, related to fluid retention, were noted in the 0.10-, 0.25-, and 1.15-mg cohorts. Of 31 treated patients, 27 were evaluable for response. A sustained partial response (PR; 690 days on therapy) was observed in a patient with myxoid liposarcoma. Ten additional patients had stable disease (SD) for ?60 days. Exposures were approximately dose proportional, and adiponectin levels increased after 4 weeks of treatment at all dose levels. Immunohistochemistry of archived specimens demonstrated that PPAR? and retinoid X receptor expression levels were significantly greater in patients with SD for ?60 days or PR (P = .0079), suggesting a predictive biomarker. CONCLUSIONS Efatutazone demonstrates acceptable tolerability with evidence of disease control in patients with advanced malignancies. PMID:22570147

Pishvaian, Michael J.; Marshall, John L.; Wagner, Andrew J.; Hwang, Jimmy J.; Malik, Shakun; Cotarla, Ion; Deeken, John F.; He, A. Ruth; Daniel, Hirut; Halim, Abdel-Baset; Zahir, Hamim; Copigneaux, Catherine; Liu, Kejian; Beckman, Robert A.; Demetri, George D.

2013-01-01

313

Clozapine acts as an agonist at serotonin 2A receptors to counter MK-801-induced behaviors through a ?arrestin2-independent activation of Akt.  

PubMed

The G protein-coupled serotonin 2A receptor (5-HT2AR) is a prominent target for atypical antipsychotic drugs, such as clozapine. Although clozapine is known to inhibit 5-HT2AR signaling through G protein-dependent mechanisms, it differs from classic GPCR antagonists, in that it also induces 5-HT2AR internalization and activates Akt signaling via a 5-HT2AR-mediated event. In this regard, clozapine may also be considered a functionally selective agonist. The cognate neurotransmitter at the 5-HT2AR, serotonin, also induces 5-HT2AR internalization and Akt phosphorylation. Serotonin promotes interactions with the scaffolding and regulatory protein, ?arrestin2, which results in the recruitment and activation of Akt. These interactions prove to be critical for serotonin-induced, 5-HT2AR-mediated behavioral responses in mice. Herein, we sought to determine whether clozapine also utilizes ?arrestin2-mediated mechanisms to induce 5-HT2AR signaling, and whether this interaction contributes to its behavioral effects in mice. We demonstrate that unlike serotonin, clozapine-mediated 5-HT2AR internalization and Akt phosphorylation is independent of receptor interactions with ?arrestin2. Moreover, clozapine-mediated suppression of MK-801 and phencyclidine (PCP)-induced hyperlocomotion is ?arrestin2 independent, although it is dependent upon Akt. These results demonstrate that pharmacologically oppositional ligands, serotonin and clozapine, utilize differential mechanisms to achieve the same 5-HT2AR-meadiated downstream events: Akt phosphorylation and receptor internalization. Although ?arrestin2 has no effect on clozapine's actions in vivo, Akt phosphorylation is required for clozapine's efficacy in blocking MK-801- and PCP-induced models of schizophrenic behaviors in mice. PMID:24531562

Schmid, Cullen L; Streicher, John M; Meltzer, Herbert Y; Bohn, Laura M

2014-07-01

314

Synthesis, enantioresolution, and activity profile of chiral 6-methyl-2,4-disubs-tituted pyridazin-3(2H)-ones as potent N-formyl peptide receptor agonists  

PubMed Central

A series of chiral pyridazin-3(2H)-ones was synthesized, separated as pure enantiomers, and evaluated for N-formyl peptide receptor (FPR) agonist activity. Characterization of the purified enantiomers using combined chiral HPLC and chiroptical studies (circular dichroism, allowed unambiguous assignment of the absolute configuration for each pair of enantiomers). Evaluation of the ability of racemic mixtures and purified enantiomers to stimulate intracellular Ca2+ flux in FPR-transfected HL-60 cells and human neutrophils and to induce ?-arrestin recruitment in FPR-transfected CHO-K1 cells showed that many enantiomers were potent agonists, inducing responses in the sub-micromolar to nanomolar range. Furthermore, FPRs exhibited enantiomer selectivity, generally preferring the R-(?)-forms over the S-(+)-enantiomers. Finally, we found that elongation of the carbon chain in the chiral center of the active compounds generally increased biological activity. Thus, these studies provide important new information regarding molecular features involved in FPR ligand preference and report the identification of a novel series of FPR agonists. PMID:22607879

Cilibrizzi, Agostino; Schepetkin, Igor A.; Bartolucci, Gianluca; Crocetti, Letizia; Piaz, Vittorio Dal; Giovannoni, Maria Paola; Graziano, Alessia; Kirpotina, Liliya N.; Quinn, Mark T.; Vergelli, Claudia

2012-01-01

315

[Pharmacokinetic and analgesic properties of tabletized dosage form of RU-1205-new imidazobenzimidazole derivative with kappa agonist activity].  

PubMed

The pharmacokinetic properties of a new imidazobenzimidazole derivative, compound RU-1205, were studied after peroral administration to rabbits at a dose of 50 mg/kg as a parent substance and in coated tablet dosage form. It was found that RU-1205 tablets are characterized by high values of the relative bioavailability (105.3 +/- 11.7%). The results of hot-plate and vinegar-cramp tests showed that both the dosage form and parent substance produced the same analgesic effect. Granulated RU-1205 produced maximum analgesic effect (138.8% relative to control) within 4-h investigation and retained higher analgesic activity compared to that of parent substance (on the average by 58%, p < 0.05) up to 12 h. PMID:25322651

Spasov, A A; Smirnova, L A; Grechko, O Iu; Rashchenko, A I; Shtareva, D M; Anisimova, V A

2014-01-01

316

Crystal structure of phospholipase PA2-Vb, a protease-activated receptor agonist from the Trimeresurus stejnegeri snake venom.  

PubMed

Phospholipase A2 (PLA2) is an important component in snake venoms. Here, an acidic PLA2, designated PA2-Vb was isolated from the Trimeresurus stejnegeri snake venom. PA2-Vb acts on a protease-activated receptor (PAR-1) to evoke Ca(2+) release through the inositol 1,4,5-trisphosphate receptor (IP3R) and induces mouse aorta contraction. PAR-1, phospholipase C and IP3R inhibitors suppressed PA2-Vb-induced aorta contraction. The crystal structure reveals that PA2-Vb has the typical fold of most snake venom PLA2. Several PEG molecules bond to a positively charged pocket. The finding offers a novel pharmacological basis of the structure for investigating the PAR-1 receptor and suggests potential applications for PA2-Vb in the vascular system. PMID:25447533

Zeng, Fuxing; Zhang, Wenjuan; Xue, Nairui; Teng, Maikun; Li, Xu; Shen, Bing

2014-12-20

317

The cannabinoid receptor agonist THC attenuates weight loss in a rodent model of activity-based anorexia.  

PubMed

Anorexia nervosa (AN) is characterized by anhedonia whereby patients experience little pleasure or reward in many aspects of their lives. Reward pathways and the endocannabionid system have been implicated in the mediation of food intake. The potential to exploit these systems to reverse weight loss is investigated in a rodent model of activity-based anorexia (ABA). The effect of subchronic (6 days) ?(9)-tetrahydrocannabinol (THC) treatment (0.1, 0.5, or 2.0?mg/kg/day) was assessed on chow and high-fat diet (HFD) intake, body weight, running wheel activity (RWA) as well as thermogenesis in brown adipose tissue (BAT) and lipid metabolism in white adipose tissue (WAT). Limited time availability of food and continuous access to running wheels led to anorexia and significantly reduced body weight. THC treatment (0.5 and 2.0?mg/kg/day) transiently stimulated chow intake with a moderate effect on RWA. THC (2.0?mg/kg/day) significantly reduced body weight loss and shifted markers of thermogenesis in BAT and lipid metabolism in WAT in directions consistent with reduced energy expenditure and lipolysis. THC (2.0?mg/kg/day) combined with HFD, produced a transient increase in food intake, reduction in RWA, attenuation of body weight loss, and changes in markers of thermogensis in BAT and lipolysis in the WAT. These changes were significantly greater than those seen in vehicle (HFD), vehicle (chow), and THC (chow)-treated animals. These data show for the first time the effectiveness of the endocannabinoid system in attenuating the weight loss associated with the development of ABA via a mechanism involving reduced energy expenditure. PMID:21412227

Verty, Aaron N A; Evetts, Megan J; Crouch, Geraldine J; McGregor, Iain S; Stefanidis, Aneta; Oldfield, Brian J

2011-06-01

318

Alpha-retinals as rhodopsin chromophores--preference for the 9-Z configuration and partial agonist activity.  

PubMed

The visual pigment rhodopsin, the photosensory element of the rod photoreceptor cell in the vertebrate retina, shows in combination with an endogenous ligand, 11-Z retinal, an astonishing photochemical performance. It exhibits an unprecedented quantum yield (0.67) in a highly defined and ultrafast photoisomerization process. This triggers the conformational changes leading to the active state Meta(rhodopsin) II. Retinal is covalently bound to Lys-296 of the protein opsin in a protonated Schiff base. The resulting positive charge delocalization over the terminal part of the polyene chain of retinal creates a conjugation defect that upon photoexcitation moves to the opposite end of the polyene. Shortening the polyene as in 4,5-dehydro,5,6-dihydro (alpha), 5,6-dihydro or 7,8-dihydro-analogs might facilitate photoisomerization of a 9-Z and a 11-Z bond. Here we describe pigment analogs generated with bovine opsin and 11-Z or 9-Z 4,5-dehydro,5,6-dihydro-retinal that were further characterized by UV-Vis and FTIR spectroscopy. The preference of opsin for native 11-Z retinal over the 9-Z isomer is reversed in 4,5-dehydro,5,6-dihydro-retinal. 9-Z 4,5-dehydro,5,6-dihydro-retinal readily generated a photosensitive pigment. This modification has no effect on the quantum yield, but affects the Batho<-->blueshifted intermediate (BSI) equilibrium and leads to a strong decrease in the G-protein activation rate because of a downshift of the pK(a) of the Meta I<-->Meta II equilibrium. PMID:18346085

Wang, Yajie; Bovee-Geurts, Petra H M; Lugtenburg, Johan; DeGrip, Willem J

2008-01-01

319

Modulation of cholinephosphotransferase activity in breast cancer cell lines by Ro5-4864, a peripheral benzodiazepine receptor agonist  

SciTech Connect

Changes in phospholipid and fatty acid profile are hallmarks of cancer progression. Increase in peripheral benzodiazepine receptor expression has been implicated in breast cancer. The benzodiazepine, Ro5-4864, increases cell proliferation in some breast cancer cell lines. Biosynthesis of phosphatidylcholine (PC) has been identified as a marker for cells proliferating at high rates. Cholinephosphotransferase (CPT) is the terminal enzyme for the de novo biosynthesis of PC. We have addressed here whether Ro5-4864 facilitates some cancer causing mechanisms in breast cancer. We report that cell proliferation increases exponentially in aggressive breast cancer cell lines 11-9-1-4 and BT-549 when treated with nanomolar concentrations of Ro5-4864. This increase is seen within 24 h of treatment, consistent with the cell doubling time in these cells. Ro5-4864 also upregulates c-fos expression in breast cancer cell lines 11-9-1-4 and BT-549, while expression in non-tumorigenic cell line MCF-12A was either basal or slightly downregulated. We further examined the expression of the CPT gene in breast cancer (11-9-1-4, BT-549) and non-tumorigenic cell lines (MCF-12A, MCF-12F). We found that the CPT gene is overexpressed in breast cancer cell lines compared to the non-tumorigenic cell lines. Furthermore, the activity of CPT in forming PC is increased in the breast cancer cell lines cultured for 24 h. Additionally, we examined the CPT activity in the presence of nanomolar concentrations of Ro5-4864. Biosynthesis of PC was increased in breast cancer cell lines upon treatment. We therefore propose that Ro5-4864 facilitates PC formation, a process important in membrane biogenesis for proliferating cells.

Akech, Jacqueline [Department of Biochemistry, Meharry Medical College, Nashville, TN 37208 (United States); Roy, Somdutta Sinha [Department of Biochemistry, Meharry Medical College, Nashville, TN 37208 (United States); Das, Salil K. [Department of Biochemistry, Meharry Medical College, Nashville, TN 37208 (United States)]. E-mail: sdas@mmc.edu

2005-07-22

320

Lack of the effect of lobeglitazone, a peroxisome proliferator-activated receptor-? agonist, on the pharmacokinetics and pharmacodynamics of warfarin  

PubMed Central

Aims Lobeglitazone has been developed for the treatment of type 2 diabetes mellitus. This study was conducted to evaluate potential drug–drug interactions between lobeglitazone and warfarin, an anticoagulant with a narrow therapeutic index. Methods In this open-label, three-treatment, crossover study, 24 healthy male subjects were administered lobeglitazone (0.5 mg) for 1–12 days with warfarin (25 mg) on day 5 in one period. After a washout interval, subjects were administered warfarin (25 mg) alone in the other period. Pharmacokinetics of R- and S-warfarin and lobeglitazone, as well as pharmacodynamics of warfarin, as measured by international normalized ratio (INR) and factor VII activity, were assessed. Results The geometric mean ratios (GMRs) and 90% confidence intervals (CIs) for area under the curve from time zero to the time of the last quantifiable concentration (AUClast) for warfarin + lobeglitazone: warfarin alone were 1.0076 (90% CI: 0.9771, 1.0391) for R-warfarin and 0.9880 (90% CI: 0.9537, 1.0235) for S-warfarin. The maximum observed plasma concentration (Cmax) values were 1.0167 (90% CI: 0.9507, 1.0872) for R-warfarin and 1.0028 (90% CI: 0.9518, 1.0992) for S-warfarin, both of which were contained in the interval 0.80–1.25. Lobeglitazone had no effect on the area under the effect–time curve from time 0 to 168 hours (AUEC) of INR and factor VII activity, as demonstrated by the GMRs of 1.0091 (90% CI: 0.9872, 1.0314) and 0.9355 (90% CI: 0.9028, 0.9695), respectively. In addition, the pharmacokinetics of lobeglitazone was also unaffected by warfarin. Conclusion Concomitant administration of lobeglitazone and warfarin was well tolerated. Lobeglitazone had no meaningful effect on the pharmacokinetics or pharmacodynamics of warfarin. These findings indicate that lobeglitazone and warfarin can be coadministered without dosage adjustments for either drug. PMID:25767371

Jung, Jin Ah; Lee, Soo-Yun; Kim, Tae-Eun; Kim, Jung-Ryul; Kim, Chin; Huh, Wooseong; Ko, Jae-Wook

2015-01-01

321

Rational Drug Design Leading to the Identification of a Potent 5-HT2C Agonist Lacking 5-HT2B Activity  

PubMed Central

The 5-HT2C receptor is an attractive drug target in the quest for new therapeutics to treat a variety of human disorders. We have previously undertaken a structural optimization campaign that has led to some potent and moderately selective 5-HT2C receptor agonists. After expanding our structure–function library, we were able to combine our data sets so as to allow the design of compounds of improved selectivity and potency. We disclose herein the structural optimization of our previously reported 5-HT2B/5-HT2C agonists, which has led to the identification of a highly selective 5-HT2C agonist, (+)-trans-[2-(2-cyclopropylmethoxyphenyl)cyclopropyl]methylamine hydrochloride, with an EC50 of 55 nM and no detectable agonism at the 5-HT2B receptor. PMID:22778800

2011-01-01

322

GILA WOODPECKER AGONISTIC BEHAVIOR  

Microsoft Academic Search

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

GENE L. BRENOWITZ

323

Detection of weak forces based on noise-activated switching in bistable optomechanical systems  

NASA Astrophysics Data System (ADS)

We propose to use cavity optomechanical systems in the regime of optical bistability for the detection of weak harmonic forces. Due to the optomechanical coupling an external force on the mechanical oscillator modulates the resonance frequency of the cavity and consequently the switching rates between the two bistable branches. A large difference in the cavity output fields then leads to a strongly amplified homodyne signal. We determine the switching rates as a function of the cavity detuning from extensive numerical simulations of the stochastic master equation as appropriate for continuous homodyne detection. We develop a two-state rate equation model that quantitatively describes the slow switching dynamics. This model is solved analytically in the presence of a weak harmonic force to obtain approximate expressions for the power gain and signal-to-noise ratio that we then compare to force detection with an optomechanical system in the linear regime.

Aldana, Samuel; Bruder, Christoph; Nunnenkamp, Andreas

2014-12-01

324

Early exposure of the pregestational intrauterine and postnatal growth-restricted female offspring to a peroxisome proliferator-activated receptor-? agonist  

PubMed Central

Prenatal nutrient restriction with intrauterine growth restriction (IUGR) alters basal and glucose-stimulated insulin response and hepatic metabolic adaptation. The effect of early intervention with insulin-sensitizing peroxisome proliferator-activated receptor ? agonists was examined in the metabolically maladapted F1 pregestational IUGR offspring with a propensity toward pregnancy-induced gestational diabetes. The effect of rosiglitazone maleate [RG; 11 ?mol/day from postnatal day (PN) 21 to PN60] vs. placebo (PL) on metabolic adaptations in 2-mo-old F1 female rats subjected to prenatal (IUGR), postnatal (PNGR), or pre- and postnatal (IUGR + PNGR) nutrient restriction was investigated compared with control (CON). RG vs. PL had no effect on body weight or plasma glucose concentrations but increased subcutaneous white and brown adipose tissue and plasma cholesterol concentrations in all three experimental groups. Glucose tolerance tests with a 1:1 mixture of [2-2H2]- and [6,6-2H2]glucose in RG IUGR vs. PL IUGR revealed glucose tolerance with a lower glucose-stimulated insulin release (GSIR) and suppressed endogenous hepatic glucose production (HGP) with no difference in glucose clearance (GC) and recycling (GR). RG PNGR, although similar to PL CON, was hyperglycemic vs. PL PNGR with reduced GR but no difference in the existent low GSIR, HGP, and GC. RG IUGR + PNGR overall was no different from the PL counterpart. Insulin tolerance tests revealed perturbed recovery to baseline from the exaggerated hypoglycemia in RG vs. the PL groups with the only exception being RG PNGR where further worsening of hypoglycemia over PL PNGR was minimal with full recovery to baseline. These observations support that early intervention with RG suppressed HGP in IUGR vs. PL IUGR, without increasing GSIR similar to that seen in CON. Although RG reversed PNGR to the PL CON metabolic state, no such insulin-sensitizing effect was realized in IUGR + PNGR. PMID:20009032

Garg, Meena; Thamotharan, Manikkavasagar; Pan, Gerald; Lee, Paul W. N.

2010-01-01

325

Bezafibrate, a peroxisome proliferator-activated receptor ? agonist, decreases circulating CD14(+)CD16(+) monocytes in patients with type 2 diabetes.  

PubMed

CD14(+)CD16(+) monocytes are proinflammatory cells that produce tumor necrosis factor and interleukin (IL)-1?. The number of circulating CD14(+)CD16(+) monocytes is increased in patients with chronic renal failure or coronary artery disease. We investigated the effect of bezafibrate, a peroxisome proliferator-activated receptor ? agonist, on circulating CD14(+)CD16(+) monocytes in patients with type 2 diabetes. Using cells isolated from type 2 diabetic subjects, we also examined the in vitro expression of CD16 messenger RNA (mRNA) by mononuclear cells (MNCs) exposed to bezafibrate. The percentage of CD14(+)CD16(+) monocytes among all CD14(+) monocytes was significantly higher in subjects with impaired glucose tolerance (P < 0.01) or type 2 diabetes (P < 0.05) than in those with normal glucose tolerance. The percentage of CD14(+)CD16(+) monocytes was significantly lower in patients with type 2 diabetes who were taking bezafibrate (400 mg/d) than in patients not taking it (P < 0.01). Treatment with bezafibrate for 12 weeks significantly reduced the percentage of circulating CD14(+)CD16(+) monocytes from 45.4 ± 25.2% to 38.3 ± 21.8% (P = 0.0144). In an in vitro study, the expression of CD16 mRNA by MNCs from 6 diabetic subjects was decreased after 24 hours of treatment with 10 ?g/mL of bezafibrate (P < 0.05). Expression of IL-1? mRNA by MNCs was also decreased after 24 hours of treatment with 10 ?g/mL of bezafibrate, whereas the IL-1? level in the culture supernatant was significantly decreased after treatment of MNCs with either 1 or 10 ?g/mL of bezafibrate. In conclusion, bezafibrate decreased circulating CD14(+)CD16(+) monocytes in patients with type 2 diabetes, probably by inhibiting the expression of CD16 mRNA. PMID:25134759

Terasawa, Tomoko; Aso, Yoshimasa; Omori, Kyoko; Fukushima, Maiko; Momobayashi, Atsushi; Inukai, Toshihiko

2015-02-01

326

Induction of ovarian activity and ovulation in an induced ovulator, the maned wolf (Chrysocyon brachyurus), using GnRH agonist and recombinant LH.  

PubMed

Assisted reproductive techniques, such as ovarian manipulation and artificial insemination, are useful for enhancing genetic management of threatened wildlife maintained ex situ. In this study, we used noninvasive fecal hormone monitoring to investigate (1) the influence of pairing with a male on endocrine responses of female maned wolves (Chrysocyon brachyurus) to a GnRH agonist (deslorelin) and (2) the efficiency of recombinant LH (reLH) on ovulation induction in females housed alone. Deslorelin (2.1 mg Ovuplant) was given to females that were either paired with a male (n = 4) or housed alone (n = 7); the implant was removed 7 to 11 days postimplantation. Three of seven singleton females were injected with reLH (0.0375 mg) on the day of implant removal, whereas the remaining females (n = 4) did not receive the additional treatment. Fecal samples were collected 5 to 7 days/wk from all females starting 11 days prior to hormone insertion until at least 70 days post implant removal for a total of 11 hormone treatment cycles. Fecal estrogen and progestagen metabolites were extracted and analyzed by enzyme immunoassay. Evidence of ovulation, demonstrated by a surge of estrogen followed by a significant rise in progestagen, occurred in all paired females. Three of the four singleton females that did not receive reLH treatment exhibited no rise in progestagen after an estrogen surge. All singleton females treated with reLH exhibited a rise in fecal progestagen after injection, indicating ovulation. In conclusion, deslorelin is effective at inducing ovarian activity and ovulation in paired female maned wolves; however, exogenous reLH is needed to induce ovulation in females housed alone. The findings obtained from this study serve as a foundation for future application of artificial insemination to enhance genetic management of this threatened species ex situ. PMID:24742964

Johnson, Amy E M; Freeman, Elizabeth W; Colgin, Mark; McDonough, Caitlin; Songsasen, Nucharin

2014-07-01

327

Effects of CP-900691, a novel peroxisome proliferator-activated receptor ?, agonist on diabetic nephropathy in the BTBR ob/ob mouse.  

PubMed

Piperidine-based peroxisome proliferator-activated receptor-? agonists are agents that are efficacious in improving lipid, glycemic, and inflammatory indicators in diabetes and obesity. This study sought to determine whether CP-900691 ((S)-3-[3-(1-carboxy-1-methyl-ethoxy)-phenyl]-piperidine-1-carboxylic acid 4-trifluoromethyl-benzyl ester; CP), a member of this novel class of agents, by decreasing plasma triglycerides, could prevent diabetic nephropathy in the Black and Tan, BRachyuric (BTBR) ob/ob mouse model of type 2 diabetes mellitus. Four-week old female BTBR WT and BTBR ob/ob mice received either regular chow or one containing CP (3?mg/kg per day) for 14 weeks. CP elevated plasma high-density lipoprotein, albuminuria, and urinary excretion of 8-epi PGF(2?), a product of the nonenzymatic metabolism of arachidonic acid and whose production is elevated in oxidative stress, in BTBR WT mice. In BTBR ob/ob mice, CP reduced plasma triglycerides and non-esterified fatty acids, fasting blood glucose, body weight, and plasma interleukin-6, while concomitantly improving insulin resistance. Despite these beneficial metabolic effects, CP had no effect on elevated plasma insulin, 8-epi PGF(2?) excretion, and albuminuria, and surprisingly, did not ameliorate the development of diabetic nephropathy, having no effect on the accumulation of renal macrophages, glomerular hypertrophy, and increased mesangial matrix expansion. In addition, CP did not increase plasma high-density lipoprotein in BTBR ob/ob mice, while paradoxically increasing total cholesterol levels. These findings indicate that 8-epi PGF(2?), possibly along with hyperinsulinemia and inflammatory and dysfunctional lipoproteins, is integral to the development of diabetic nephropathy and should be considered as a potential target of therapy in the treatment of diabetic nephropathy. PMID:24955894

Askari, Bardia; Wietecha, Tomasz; Hudkins, Kelly L; Fox, Edward J; O'Brien, Kevin D; Kim, Jinkyu; Nguyen, Tri Q; Alpers, Charles E

2014-08-01

328

Effects of CP-900691, A Novel Peroxisome Proliferator-Activated Receptor ? Agonist on Diabetic Nephropathy in the BTBR ob/ob mouse  

PubMed Central

Piperidine-based peroxisome proliferator-activated receptor alpha agonists are agents that are efficacious in improving lipid, glycemic, and inflammatory indicators in diabetes and obesity. This study sought to determine whether CP-900691 ((S)-3-[3-(1-carboxy-1-methyl-ethoxy)-phenyl]-piperidine-1-carboxylic acid 4-trifluoromethyl-benzyl ester) (CP), a member of this novel class of agents, by decreasing plasma triglycerides, could prevent diabetic nephropathy in the BTBR ob/ob mouse model of type 2 diabetes mellitus. 4-week old female BTBR WT and BTBR ob/ob mice received either regular chow or one containing CP (3 mg/kg/day) for 14 weeks. CP elevated plasma high-density lipoprotein, albuminuria and urinary excretion of 8-epi PGF2?, a product of the non-enzymatic metabolism of arachidonic acid and whose production is elevated in oxidative stress, in BTBR WT mice. In BTBR ob/ob mice, CP reduced plasma triglycerides and non-esterified fatty acids, fasting blood glucose, body weight, and plasma interleukin-6, while concomitantly improving insulin resistance. Despite these beneficial metabolic effects, CP had no effect on elevated plasma insulin, 8-epi PGF2? excretion and albuminuria, and surprisingly, did not ameliorate the development of diabetic nephropathy, having no effect on the accumulation of renal macrophages, glomerular hypertrophy and increased mesangial matrix expansion. In addition, CP did not increase plasma high-density lipoprotein in BTBR ob/ob mice, while paradoxically increasing total cholesterol levels. These findings indicate that 8-epi PGF2?, possibly along with hyperinsulinemia and inflammatory and dysfunctional lipoproteins, is integral to the development of diabetic nephropathy and should be considered as a potential target of therapy in the treatment of diabetic nephropathy. PMID:24955894

Askari, Bardia; Wietecha, Tomasz; Hudkins, Kelly L.; Fox, Edward J.; O’Brien, Kevin D.; Kim, Jinkyu; Nguyen, Tri Q.; Alpers, Charles E.

2014-01-01

329

Structure-activity-relationship study of N6-(2(4-(1H-indol-5-yl)piperazin-1-yl)ethyl)-N6-propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine analogues: Development of highly selective D3 dopamine receptor agonists along with a highly potent D2/D3 agonist and their pharmacological characterization  

PubMed Central

In our effort to develop multifunctional drugs against Parkinson’s disease, a structure-activity-relationship study was carried out based on our hybrid molecular template targeting D2/D3 receptors. Competitive binding with [3H]spiroperidol was used to evaluate affinity (Ki) of test compounds. Functional activity of selected compounds in stimulating [35S]GTP?S binding was assessed in CHO-cells expressing either human D2 or D3 receptors. Our results demonstrated development of highly selective compounds for D3 receptor ((?)-40; Ki D3 = 1.84 nM, D2/D3 = 583.2, (?)-45; Ki D3 = 1.09 nM, D2/D3 = 827.5). Functional data identified (?)-40 (EC50 D2 = 114 nM and D3 = 0.26 nM, D2/D3 = 438) as one of the highest D3 selective agonists known to date. In addition, high affinity, non-selective, D3 agonist, (?)-19 (EC50 D2 = 2.96 nM and D3 = 1.26 nM), was also developed. Lead compounds with antioxidant activity were evaluated using an in vivo PD animal model. PMID:22642365

Johnson, Mark; Antonio, Tamara; Reith, Maarten E. A.; Dutta, Aloke K.

2012-01-01

330

Structure-activity relationship study of N?-(2-(4-(1H-Indol-5-yl)piperazin-1-yl)ethyl)-N?-propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine analogues: development of highly selective D3 dopamine receptor agonists along with a highly potent D2/D3 agonist and their pharmacological characterization.  

PubMed

In our effort to develop multifunctional drugs against Parkinson's disease, a structure-activity-relationship study was carried out based on our hybrid molecular template targeting D2/D3 receptors. Competitive binding with [(3)H]spiroperidol was used to evaluate affinity (K(i)) of test compounds. Functional activity of selected compounds in stimulating [(35)S]GTP?S binding was assessed in CHO cells expressing either human D2 or D3 receptors. Our results demonstrated development of highly selective compounds for D3 receptor (for (-)-40K(i), D3 = 1.84 nM, D2/D3 = 583.2; for (-)-45K(i), D3 = 1.09 nM, D2/D3 = 827.5). Functional data identified (-)-40 (EC(50), D2 = 114 nM, D3 = 0.26 nM, D2/D3 = 438) as one of the highest D3 selective agonists known to date. In addition, high affinity, nonselective D3 agonist (-)-19 (EC(50), D2 = 2.96 nM and D3 = 1.26 nM) was also developed. Lead compounds with antioxidant activity were evaluated using an in vivo PD animal model. PMID:22642365

Johnson, Mark; Antonio, Tamara; Reith, Maarten E A; Dutta, Aloke K

2012-06-28

331

Discovery of trifluoromethyl(pyrimidin-2-yl)azetidine-2-carboxamides as potent, orally bioavailable TGR5 (GPBAR1) agonists: structure-activity relationships, lead optimization, and chronic in vivo efficacy.  

PubMed

Activation of the G-protein coupled receptor (GPCR) Takeda G-protein receptor 5 (TGR5), also known as G-protein bile acid receptor 1 (GPBAR1), has been shown to play a key role in pathways associated with diabetes, metabolic syndrome, and autoimmune disease. Nipecotamide 5 was identified as an attractive starting point after a high-throughput screen (HTS) for receptor agonists. A comprehensive hit-to-lead effort culminated in the discovery of 45h as a potent, selective, and bioavailable TGR5 agonist to test in preclinical metabolic disease models. In genetically obese mice (ob/ob), 45h was as effective as a dipeptidyl peptidase-4 (DPP-4) inhibitor at reducing peak glucose levels in an acute oral glucose tolerance test (OGTT), but this effect was lost upon chronic dosing. PMID:24666203

Phillips, Dean P; Gao, Wenqi; Yang, Yang; Zhang, Guobao; Lerario, Isabelle K; Lau, Thomas L; Jiang, Jiqing; Wang, Xia; Nguyen, Deborah G; Bhat, B Ganesh; Trotter, Carol; Sullivan, Heather; Welzel, Gustav; Landry, Jannine; Chen, Yali; Joseph, Sean B; Li, Chun; Gordon, W Perry; Richmond, Wendy; Johnson, Kevin; Bretz, Angela; Bursulaya, Badry; Pan, Shifeng; McNamara, Peter; Seidel, H Martin

2014-04-24

332

TRPV4 agonists and antagonists.  

PubMed

TRPV4 belongs to the TRPV subfamily of Transient Receptor Potential (TRP) ion channels. This year marks the 10 year anniversary of the discovery of this polymodal ion channel which is activated by a variety of stimuli including warm temperatures, hypotonicity and endogenous lipids. Coupled with a widespread tissue distribution, this activation profile has resulted in a large number of disparate physiological functions for TRPV4. These range from temperature monitoring in skin keratinocytes to osmolarity sensing in kidneys, sheer stress detection in blood vessels and osteoclast differentiation control in bone. As knowledge of its physiological roles has expanded, interest in targeting TRPV4 modulation for therapeutic purposes has arisen and is now focused on several areas. First, as with related TRP channels TRPV1, TRPV3, TRPM8 and TRPA1, TRPV4 antagonism is being considered for inflammatory and neuropathic pain treatment. Recent work conducted using KO mice and agonists 4?PDD and GSK1016790A suggests bladder dysfunctions may also be targeted. Additionally, ventilator-induced lung injury has emerged as another potential indication for TRPV4 antagonists. Herein we review the known small molecule modulators of TRPV4 and relate progress made in identifying potent, selective and bioavailable agonists and antagonists to interrogate this ion channel in vivo. PMID:21671873

Vincent, Fabien; Duncton, Matthew A J

2011-01-01

333

Suzaku Observes Weak Flares from IGRJ17391-3021 Representing a Common Low-Activity State in this SFXT  

NASA Technical Reports Server (NTRS)

We present an analysis of a 37-ks observation of the supergiant fast X-ray transient (SFXT) IGRJ17391 -3021 (=XTEJ1739-302) gathered with Suzaku. The source evolved from quiescence to a low-activity level culminating in three weak flares lasting approx.3 ks each in which the peak luminosity is only a factor of 5 times that of the pre-flare luminosity. The minimum observed luminosity was 1.3 x 10(exp 33) erg/s (d/2.7 kpc)(exp 2) in the 0.5-10 keV range. The weak flares are accompanied by significant changes in the spectral parameters including a column density (N(sub H) = (4.1(+0.4/-0.5)) x 10(exp 22)/sq cm) that is approx.2-9 times the absorption measured during quiescence. Accretion of obscuring clumps of stellar wind material can explain both the small flares and the increase in NH. Placing this observation in the context of the recent Swift monitoring campaign, we find that weak-flaring episodes, or at least epochs of enhanced activity just above the quiescent level but well below the moderately bright or high-luminosity outbursts, represent more than 60+/-5% of all observations in the 0.5-10keV energy range making this the most common state in the emission behavior of IGRJ17391 -3021.

Bodaghee, A.; Tomsick, J. A.; Rodriquez, J.; Chaty, S.; Pottschmidt, K.; Walter, R.; Romano, P.

2010-01-01

334

2-Furoyl-LIGRL-NH2, a potent agonist for proteinase-activated receptor-2, as a gastric mucosal cytoprotective agent in mice.  

PubMed

1. Proteinase-activated receptor-2 (PAR(2)), expressed in capsaicin-sensitive sensory neurons, plays a protective role in gastric mucosa. The present study evaluated gastric mucosal cytoprotective effect of 2-furoyl-LIGRL-NH(2), a novel highly potent PAR(2) agonist, in ddY mice and in wild-type and PAR(2)-knockout mice of C57BL/6 background. 2. Gastric mucosal injury was created by oral administration of HCl/ethanol solution in the mice. The native PAR(2)-activating peptide SLIGRL-NH(2), administered intraperitoneally (i.p.) at 0.3-1 micromol kg(-1) in combination with amastatin, an aminopeptidase inhibitor, but not alone, revealed gastric mucosal protection in ddY mice, which was abolished by ablation of capsaicin-sensitive sensory neurons. 3. I.p. administration of 2-furoyl-LIGRL-NH(2) at 0.1 micromol kg(-1), without combined treatment with amastatin, exhibited gastric mucosal cytoprotective activity in ddY mice, the potency being much greater than SLIGRL-NH(2) in combination with amastatin. This effect was also inhibited by capsaicin pretreatment. 4. Oral administration of 2-furoyl-LIGRL-NH(2) at 0.003-0.03 micromol kg(-1) also protected against gastric mucosal lesion in a capsaicin-reversible manner in ddY mice. 5. I.p. 2-furoyl-LIGRL-NH(2) at 0.1-0.3 micromol kg(-1) caused prompt salivation in anesthetized mice, whereas its oral administration at 0.003-1 micromol kg(-1) was incapable of eliciting salivation. 6. In wild-type, but not PAR(2)-knockout, mice of C57BL/6 background, i.p. administration of 2-furoyl-LIGRL-NH(2) caused gastric mucosal protection. 7. Thus, 2-furoyl-LIGRL-NH(2) is considered a potent and orally available gastric mucosal protective agent. Our data also substantiate a role for PAR(2) in gastric mucosal protection and the selective nature of 2-furoyl-LIGRL-NH(2). PMID:15655521

Kawabata, Atsufumi; Oono, Yuko; Yonezawa, Daiki; Hiramatsu, Kaori; Inoi, Naoki; Sekiguchi, Fumiko; Honjo, Masami; Hirofuchi, Michiko; Kanke, Toru; Ishiwata, Hiroyuki

2005-01-01

335

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

336

Inhibition of tumor-necrosis-factor-alpha induced endothelial cell activation by a new class of PPAR-gamma agonists. An in vitro study showing receptor-independent effects.  

PubMed

Proinflammatory cytokines and adhesion molecules expressed by endothelial cells (ECs) play a critical role in initiating and promoting atherosclerosis. Agents that oppose these inflammatory effects in vascular cells include peroxisome proliferator-activated receptor-gamma (PPAR-gamma) ligands, including 15-deoxy-delta(12,14)-prostaglandin J2 (15d-PGJ2) and synthetic thiazolidinediones. Recently, a new structural class of potent PPAR-gamma agonists, 1,1-bis(3'-indolyl)-1-(p-substituted phenyl) methanes, has been characterized. The purpose of this study was to evaluate the anti-inflammatory effects of two PPAR-gamma-active members of this class, 1,1-bis(3'-indolyl)-1-(p-t-butylphenyl)methane (DIM-C-pPhtBu) and 1,1-bis(3'-indolyl)-1-(p-biphenyl)methane (DIM-C-pPhC(6)H(5)), in ECs in vitro. Pretreatment of ECs with DIM-C-pPhC(6)H(5), DIM-C- pPhtBu, or 15d-PGJ2 decreased tumor necrosis factor-alpha (TNF-alpha)-induced intercellular adhesion molecule (ICAM)-1 expression in a concentration-dependent manner. At a concentration of 10 microM, DIM-C-pPhtBu and DIM-C-pPhC(6)H(5) decreased ICAM-1 expression by 77.5 and 71.3%, respectively, and comparable inhibition (84.4%) was observed for 10 microM 15d-PGJ2 (p < 0.05). In contrast, 10 microM ciglitazone and DIM-C-pPhCH(3), which exhibits low PPAR-gamma agonist activity, were inactive. The two new PPAR-gamma agonists and 15d-PGJ2 also inhibited TNF-alpha-induced interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1) production in supernatants of TNF-alpha-stimulated ECs, whereas ciglitazone and DIM-C-pPhCH(3) did not decrease TNF-alpha-induced expression of these two proteins. This new structural class of PPAR-gamma agonists inhibited the expression of ICAM-1 and the production of IL-6 and MCP-1 in TNF-alpha-activated ECs at lower concentrations than other synthetic PPAR-gamma agonists, suggesting the potential clinical utility of 1,1-bis(3'-indolyl)-1-(p-substituted phenyl) methanes for decreasing endothelial inflammation. PMID:16155367

Calabrò, Paolo; Samudio, Ismael; Safe, Stephen H; Willerson, James T; Yeh, Edward T H

2005-01-01

337

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

PubMed

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

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

2009-03-26

338

A2A adenosine receptor and its modulators: overview on a druggable GPCR and on structure-activity relationship analysis and binding requirements of agonists and antagonists.  

PubMed

Since the discovery of the biological effects of adenosine, the development of potent and selective agonists and antagonists of adenosine receptors has been the subject of medicinal chemistry research for several decades, even if their clinical evaluation has been discontinued. Main problems include side effects due to the ubiquity of the receptors and the possibility of side effects, or to low brain penetration (in particular for the targeting of CNS diseases), short half-life of compounds, lack of effects. Furthermore, species differences in the affinity of ligands make difficult preclinical testing in animal models. Nevertheless, adenosine receptors continue to represent promising drug targets. A(2A) receptor has proved to be a promising pharmacological target for small synthetic ligands, and while A(2A) agonists are undergoing clinical trials for myocardial perfusion imaging and as anti-inflammatory agents, A(2A) antagonists represent an attractive field of research to discover new drugs for the treatment of neurodegenerative disorders, such as Parkinson's disease. Furthermore, the information coming from bioinformatics and molecular modeling studies for the A(2A) receptor has made easier the understanding of ligand-target interaction and the rational design of agonists and antagonists for this subtype. The aim of this review is to show an overview of the most significant steps and progresses in developing A(2A) adenosine receptor agonists and antagonists. PMID:18537675

Cristalli, G; Lambertucci, C; Marucci, G; Volpini, R; Dal Ben, D

2008-01-01

339

Chenodeoxycholic acid suppresses the activation of acetyl-coenzyme A carboxylase-  gene transcription by the liver X receptor agonist T0-901317  

Microsoft Academic Search

The therapeutic utility of liver X receptor (LXR) agonists in treating atherosclerosis is limited by an un- desired accumulation of triglycerides in the blood and liver. This effect is caused by an increase in the transcription of genes involved in fatty acid synthesis. Here, we show that the primary bile acid, chenodeoxycholic acid (CDCA), antagonizes the stimulatory effect of the

Saswata Talukdar; Sushant Bhatnagar; Sami Dridi; F. Bradley Hillgartner

2007-01-01

340

Toll-like receptor agonists in cancer therapy  

PubMed Central

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

Adams, Sylvia

2010-01-01

341

Immobilized thrombin receptor agonist peptide accelerates wound healing in mice.  

PubMed

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

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

2001-10-01

342

3-(1H-Indol-3-yl)-2-[3-(4-nitrophenyl)ureido]propanamide Enantiomers With Human Formyl-Peptide Receptor Agonist Activity: Molecular Modeling of Chiral Recognition by FPR2  

PubMed Central

N-formyl peptide receptors (FPRs) are G protein-coupled receptors (GPCRs) that play critical roles in inflammatory reactions, and FPR-specific interactions can possibly be used to facilitate the resolution of pathological inflammatory reactions. Recent studies indicated that FPRs have stereo-selective preference for chiral ligands. Here, we investigated the structure-activity relationship of 24 chiral ureidopropanamides, including previously reported compounds PD168368/PD176252 and their close analogs, and used molecular modeling to define chiral recognition by FPR2. Unlike previously reported 6-methyl-2,4-disubstituted pyridazin-3(2H)-ones, whose R-forms preferentially activated FPR1/FPR2, we found that four S-enantiomers in the seven ureidopropanamide pairs tested preferentially activated intracellular Ca2+ flux in FPR2-transfected cells, while the R-counterpart was more active in two enantiomer pairs. Thus, active enantiomers of FPR2 agonists can be in either R- or S- configurations, depending on the molecular scaffold and specific substituents at the chiral center. Using molecular modeling approaches, including field point methodology, homology modeling, and docking studies, we propose a model that can explain stereoselective activity of chiral FPR2 agonists. Importantly, our docking studies of FPR2 chiral agonists correlated well with the FPR2 pharmacophore model derived previously. We conclude that the ability of FPR2 to discriminate between the enantiomers is the consequence of the arrangement of the three asymmetric hydrophobic subpockets at the main orthosteric FPR2 binding site with specific orientation of charged regions in the subpockets. PMID:23219934

Schepetkin, Igor A.; Kirpotina, Liliya N.; Khlebnikov, Andrei I.; Leopoldo, Marcello; Lucente, Ermelinda; Lacivita, Enza; De Giorgio, Paola; Quinn, Mark T.

2012-01-01

343

Pharmacological characterization of PD 118717, a putative piperazinyl benzopyranone dopamine autoreceptor agonist.  

PubMed

PD 118717 (7-[3-[4-(2-pyrimidinyl)-1-piperazinyl]-propoxy]-2H-1- benzopyran-2-one sulfate) proved to be a dopamine (DA) D-2 autoreceptor agonist in biochemical and electrophysiological studies in rats and to exhibit an antipsychotic-like profile in behavioral tests in rodents and monkeys. In vitro binding studies indicated that PD 118717 bound selectively to DA D-2 vs. D-1 receptors and exhibited agonist binding properties (biphasic inhibitory curves and GTP shift) similar to DA. It also had significant affinity for serotonin-(5-HT)1A but not 5-HT1B and 5-HT2 receptors. PD 118717 was active in antagonizing the tau-butyrolactone-induced accumulation of dopa in rat striatum and mesolimbic regions. PD 118717 also depressed the firing of DA neurons in substantia nigra pars compacta of rats. In both of the latter tests the effects of PD 118717 were reversed by haloperidol. PD 118717 decreased brain DA metabolism, decreased DA utilization, decreased accumulation of dopa after inhibition of L-aromatic amino acid decarboxylase, stimulated serum corticosterone and inhibited stimulated serum prolactin levels. PD 118717 did not alter striatal acetylcholine levels; nor did it induce locomotor stimulation or stereotypy in normal animals, suggesting a lack of postsynaptic DA stimulation of normosensitive DA receptors. In tests designed to reveal even weak postsynaptic DA agonist effects, PD 118717 stimulated locomotor activity in 6-hydroxydopamine-lesioned animals and relatively higher doses induced a low degree of stereotyped behavior when combined with the DA D-1 agonist SKF 38393. PD 118717 decreased the accumulation of 5-hydroxytryptophan in brain, an effect probably due to an agonist action at 5-HT1A receptors. PD 118717 decreased spontaneous locomotor activity in rodents, antagonized amphetamine-stimulated hyperactivity in mice and inhibited Sidman avoidance in monkeys, effects seen with antipsychotic agents. Unlike DA antagonist antipsychotics, PD 118717 did not induce extrapyramidal dysfunction in monkeys. PD 118717 displayed behavioral activity after p.o. dosing and its effects did not show tolerance on repeated dosing. In conclusion, PD 118717 has the profile of a DA autoreceptor agonist in neurochemical and neurophysiological tests and produces effects suggestive of antipsychotic efficacy without neurological side effect liability in preclinical behavioral tests. PMID:1361570

Pugsley, T A; Christofferson, C L; Corbin, A; DeWald, H A; Demattos, S; Meltzer, L T; Myers, S L; Shih, Y H; Whetzel, S Z; Wiley, J N

1992-12-01

344

Melatonin agonists and insomnia.  

PubMed

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

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

2010-02-01

345

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

NSDL National Science Digital Library

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

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

2004-01-13

346

Anti-nociception mediated by a ? opioid receptor agonist is blocked by a ? receptor agonist  

PubMed Central

BACKGROUND AND PURPOSE The opioid receptor family comprises four structurally homologous but functionally distinct sub-groups, the ? (MOP), ? (DOP), ? (KOP) and nociceptin (NOP) receptors. As most opioid agonists are selective but not specific, a broad spectrum of behaviours due to activation of different opioid receptors is expected. In this study, we examine whether other opioid receptor systems influenced KOP-mediated antinociception. EXPERIMENTAL APPROACH We used a tail withdrawal assay in C57Bl/6 mice to assay the antinociceptive effect of systemically administered opioid agonists with varying selectivity at KOP receptors. Pharmacological and genetic approaches were used to analyse the interactions of the other opioid receptors in modulating KOP-mediated antinociception. KEY RESULTS Etorphine, a potent agonist at all four opioid receptors, was not anti-nociceptive in MOP knockout (KO) mice, although etorphine is an efficacious KOP receptor agonist and specific KOP receptor agonists remain analgesic in MOP KO mice. As KOP receptor agonists are aversive, we considered KOP-mediated antinociception might be a form of stress-induced analgesia that is blocked by the anxiolytic effects of DOP receptor agonists. In support of this hypothesis, pretreatment with the DOP antagonist, naltrindole (10 mg·kg?1), unmasked etorphine (3 mg·kg?1) antinociception in MOP KO mice. Further, in wild-type mice, KOP-mediated antinociception by systemic U50,488H (10 mg·kg?1) was blocked by pretreatment with the DOP agonist SNC80 (5 mg·kg?1) and diazepam (1 mg·kg?1). CONCLUSIONS AND IMPLICATIONS Systemic DOP receptor agonists blocked systemic KOP antinociception, and these results identify DOP receptor agonists as potential agents for reversing stress-driven addictive and depressive behaviours mediated through KOP receptor activation. LINKED ARTICLES This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2 PMID:24923251

Taylor, A M W; Roberts, K W; Pradhan, A A; Akbari, H A; Walwyn, W; Lutfy, K; Carroll, F I; Cahill, C M; Evans, C J

2015-01-01

347

Lasing in active, sub-mean-free path-sized systems with dense, random, weak scatterers  

SciTech Connect

We report enhanced emission and gain narrowing in Rhodamine 590 perchlorate dye in an aqueous suspension of polystyrene microspheres. A systematic experimental study of the threshold condition for and the gain narrowing of the stimulated emission over a wide range of dye concentrations and scatterer number densities showed several interesting features, even though the transport mean free path far exceeded the system size. The conventional diffusive-reactive approximation to radiative transfer in an inhomogeneously illuminated random amplifying medium, which is valid for a transport mean-free path much smaller than the system size, is clearly inapplicable here. We propose a new probabilistic approach for the present case of dense, random, weak scatterers involving the otherwise rare and ignorable sub-mean-free-path scatterings, now made effective by the high gain in the medium, which is consistent with experimentally observed features. {copyright} 1997 Optical Society of America

Raghavendra Prasad, B.; Sood, Ajay Kumar; Subramanian, C.K. [Department of Physics, Indian Institute of Science, Bangalore 560012 (India); Kumar, Narendra [Raman Research Institute, Bangalore 560080 (India)

1997-10-01

348

Nuclear factor kappaB (NF-kappaB) activation primes cells to a pro-inflammatory polarized response to a Toll-like receptor 7 (TLR7) agonist.  

PubMed

TLR7 (Toll-like receptor 7) mediates anti-viral immunity by recognizing ssRNA (single-stranded RNA) viruses. Small-molecular-mass TLR7 agonists have been approved, or are being evaluated, for treatment of cancers or infectious diseases. Although TLR7 is predominantly expressed in a restricted set of immune cell types, including pDCs (plasmacytoid dendritic cells), it is also expressed in non-native expressing cells (e.g. hepatocytes) under certain circumstances. To elucidate the molecular basis of TLR7 induction by pro-inflammatory stimulation and the subsequent cellular responses in these non-native TLR7-expressing cell types, we first cloned and characterized the 5'-promoter region of TLR7. The proximal region of this promoter drives the transcription of the TLR7 gene. Pro-inflammatory stimuli activated TLR 7 transcription via a NF-kappaB (nuclear factor kappaB)-binding motif in this region, and this activation could be blocked by mutation of the NF-kappaB binding site or addition of NF-kappaB inhibitors. Further studies showed that pretreatment of the Hep3B hepatocytes with TNF-alpha (tumour necrosis factor-alpha) or IL-1 (interleukin-1) rendered them responsive to TLR7 activation by a TLR7 agonist. However, distinct from TLR7 activation in pDCs, which respond to stimulation with Th1 polarized cytokine production, TLR7 induction by pro-inflammatory signals in hepatocytes reconstitutes the NF-kappaB-dependent cascade but not the IRF7 (interferon regulatory factor 7)-dependent cascade, resulting in a pro-inflammatory polarized response rather than a Th1 polarized response. These results indicate that inflammatory stimulation is capable of priming cells to respond to TLR7 agonist with an immune response that differs from that in native TLR7-expressing cells. PMID:19426145

Lee, Jongdae; Hayashi, Masaaki; Lo, Jeng-Fan; Fearns, Colleen; Chu, Wen-Ming; Luo, Yunping; Xiang, Rong; Chuang, Tsung-Hsien

2009-07-15

349

A Pilot Study of the Effects of Gonadotropin-Releasing Hormone Agonist Therapy on Brain Activation Pattern in a Man With Pedophilia  

Microsoft Academic Search

Gonadotropin-releasing hormone (GnRH) agonists, such as leuprorelin, are recommended in the patients with pedophilia at highest risk of offending. However, the cerebral mechanisms of the effects of these testosterone-decreasing drugs are poorly known. This study aimed to identify changes caused by leuprorelin in a pedophilic patient’s brain responses to pictures representing children. Clinical, endocrine, and fMRI investigations were done of

Virginie Moulier; Véronique Fonteille; Mélanie Pélégrini-Issac; Bernard Cordier; Sophie Baron-Laforêt; Emeline Boriasse; Emmanuel Durand; Serge Stoléru

2012-01-01

350

SSR180711, a Novel Selective ?7 Nicotinic Receptor Partial Agonist: (II) Efficacy in Experimental Models Predictive of Activity Against Cognitive Symptoms of Schizophrenia  

Microsoft Academic Search

SSR180711 (4-bromophenyl 1,4diazabicyclo(3.2.2) nonane-4-carboxylate, monohydrochloride) is a selective ?7 nicotinic receptor (n-AChR) partial agonist. Based on the purported implication of this receptor in cognitive deficits associated with schizophrenia, the present study assessed efficacy of SSR180711 (i.p. and p.o.) in different types of learning and memory involved in this pathology. SSR180711 enhanced episodic memory in the object recognition task in rats

Philippe Pichat; Olivier E Bergis; Jean-Paul Terranova; Alexandre Urani; Christine Duarte; Vincent Santucci; Christiane Gueudet; Carole Voltz; Régis Steinberg; Jeanne Stemmelin; Florence Oury-Donat; Patrick Avenet; Guy Griebel; Bernard Scatton

2007-01-01

351

Interactions of drugs active at opiate receptors and drugs active at alpha 2-receptors on various test systems.  

PubMed

1 The actions of the opiate receptor drugs, morphine, methionine-enkephalin (Met-enkephalin) and naloxone were compared with the actions of the alpha 2-receptor drugs, clonidine, xylazine and yohimbine on analgesic tests, in vitro bioassay (guinea-pig ileum and mouse vas deferens), and radioligand displacement studies on rat brain membrane preparations. 2. Both opiate and alpha 2-agonist drugs showed analgesic activity but whilst the alpha 2-agonist analgesic activity was antagonized by only alpha 2-antagonists, the analgesic activity of morphine was antagonized by both naloxone and yohimbine. In the in vitro tests, both groups of agonists inhibited electrically evoked activity; however in these experiments only antagonism of opiates by naloxone and alpha 2-agonists by yohimbine could be shown and it is concluded that in these systems the activity of the alpha 2-agonists is mediated via the presynaptic alpha 2-receptors only. 3 In the radioligand studies the drugs acting at alpha 2-receptors were active in the micromolar range at displacing labelled opioid ligands but opiates did not displace labelled alpha 2-ligands. 4 It is concluded that drugs which act on alpha 2-receptors interfere with the in vivo analgesic effects of opiates and weakly displace opioid radioligand binding, but opioids do not affect alpha 2 agonist analgesia and do not appear to displace alpha 2-agonist radioligand binding. PMID:6128044

Browning, S; Lawrence, D; Livingston, A; Morris, B

1982-11-01

352

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

PubMed

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

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

2005-09-01

353

A highly potent agonist to protease-activated receptor-2 reveals apical activation of the airway epithelium resulting in Ca2+-regulated ion conductance.  

PubMed

The airway epithelium provides a barrier that separates inhaled air and its various particulates from the underlying tissues. It provides key physiological functions in both sensing the environment and initiating appropriate innate immune defenses to protect the lung. Protease-activated receptor-2 (PAR2) is expressed both apically and basolaterally throughout the airway epithelium. One consequence of basolateral PAR2 activation is the rapid, Ca(2+)-dependent ion flux that favors secretion in the normally absorptive airway epithelium. However, roles for apically expressed PAR2 activation have not been demonstrated, in part due to the lack of specific, high-potency PAR2 ligands. In the present study, we used the newly developed PAR2 ligand 2at-LIGRLO(PEG3-Pam)-NH2 in combination with well-differentiated, primary cultured airway epithelial cells from wild-type and PAR2 (-/-) mice to examine the physiological role of PAR2 in the conducting airway after apical activation. Using digital imaging microscopy of intracellular Ca(2+) concentration changes, we verified ligand potency on PAR2 in primary cultured airway cells. Examination of airway epithelial tissue in an Ussing chamber showed that apical activation of PAR2 by 2at-LIGRLO(PEG3-Pam)-NH2 resulted in a transient decrease in transepithelial resistance that was due to increased apical ion efflux. We determined pharmacologically that this increase in ion conductance was through Ca(2+)-activated Cl(-) and large-conductance K(+) channels that were blocked with a Ca(2+)-activated Cl(-) channel inhibitor and clotrimazole, respectively. Stimulation of Cl(-) efflux via PAR2 activation at the airway epithelial surface can increase airway surface liquid that would aid in clearing the airway of noxious inhaled agents. PMID:25143347

Sherwood, Cara L; Daines, Michael O; Price, Theodore J; Vagner, Josef; Boitano, Scott

2014-10-15

354

Dynamical mean-field theory and weakly non-linear analysis for the phase separation of active Brownian particles  

E-print Network

Recently, we have derived an effective Cahn-Hilliard equation for the phase separation dynamics of active Brownian particles by performing a weakly non-linear analysis of the effective hydrodynamic equations for density and polarization [Phys. Rev. Lett. 112, 218304 (2014)]. Here we develop and explore this strategy in more detail and show explicitly how to get to such a large-scale, mean-field description starting from the microscopic dynamics. The effective free energy emerging from this approach has the form of a conventional Ginzburg-Landau function. On the coarsest scale, our results thus agree with the mapping of active phase separation onto that of passive fluids with attractive interactions through a global effective free energy (mobility-induced phase transition). Particular attention is pa