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Sample records for ahr antagonist ch-223191

  1. Genetic and pharmacological analysis identifies a physiological role for the AHR in epidermal differentiation

    PubMed Central

    van den Bogaard, Ellen; Podolsky, Michael; Smits, Jos; Cui, Xiao; John, Christian; Gowda, Krishne; Desai, Dhimant; Amin, Shantu; Schalkwijk, Joost; Perdew, Gary H.

    2015-01-01

    Stimulation of the aryl hydrocarbon receptor (AHR) by xenobiotics is known to affect epidermal differentiation and skin barrier formation. The physiological role of endogenous AHR signaling in keratinocyte differentiation is not known. We used murine and human skin models to address the hypothesis that AHR activation is required for normal keratinocyte differentiation. Using transcriptome analysis of Ahr-/- and Ahr+/+ murine keratinocytes, we found significant enrichment of differentially expressed genes linked to epidermal differentiation. Primary Ahr-/- keratinocytes showed a significant reduction in terminal differentiation gene and protein expression, similar to Ahr+/+ keratinocytes treated with AHR antagonists GNF351 and CH223191, or the selective AHR modulator (SAhRM), SGA360. In vitro keratinocyte differentiation led to increased AHR levels and subsequent nuclear translocation, followed by induced CYP1A1 gene expression. Monolayer cultured primary human keratinocytes treated with AHR antagonists also showed an impaired terminal differentiation program. Inactivation of AHR activity during human skin equivalent development severely impaired epidermal stratification, terminal differentiation protein expression and stratum corneum formation. As disturbed epidermal differentiation is a main feature of many skin diseases, pharmacological agents targeting AHR signaling or future identification of endogenous keratinocyte-derived AHR ligands should be considered as potential new drugs in dermatology. PMID:25602157

  2. TCDD and omeprazole prime platelets through the aryl hydrocarbon receptor (AhR) non-genomic pathway.

    PubMed

    Pombo, Mónica; Lamé, Michael W; Walker, Naomi J; Huynh, Danh H; Tablin, Fern

    2015-05-19

    The role of the aryl hydrocarbon receptor (AhR) in hemostasis has recently gained increased attention. Here, we demonstrate, by qRT-PCR and western blot, that human platelets express both AhR mRNA and AhR protein. AhR protein levels increase in a dose dependent manner when incubated with either 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or omeprazole. Treatment of platelets with puromycin blocks increased AhR protein synthesis in the presence of AhR activators. Additionally, treatment of platelets with either activator results in phosphorylation of p38MAPK and cPLA2, two key signaling molecules in platelet activation pathways. Using the AhR competitive inhibitors alpha naphthoflavone and CH-223191, we show that phosphorylation of p38MAPK is AhR dependent. Further, inhibition of p38MAPK blocks downstream cPLA2 phosphorylation induced by TCDD or omeprazole. Treatment with AhR activators results in platelet priming, as demonstrated by increased platelet aggregation, which is inhibited by AhR antagonists. Our data support a model of the platelet AhR non-genomic pathway in which treatment with AhR activators results in increased expression of the AhR, phosphorylation of p38MAPK and cPLA2, leading to platelet priming in response to agonist. PMID:25797602

  3. AHR-11797: a novel benzodiazepine antagonist

    SciTech Connect

    Johnson, D.N.; Kilpatrick, B.F.; Hannaman, P.K.

    1986-03-01

    AHR-11797(5,6-dihydro-6-methyl-1-phenyl-/sup 3/H-pyrrolo(3,2,1-ij)quinazolin-3-one) displaced /sup 3/H-flunitrazepam (IC/sub 50/ = 82 nM) and /sup 3/H-Ro 15-1877 (IC/sub 50/ = 104 nM) from rat brain synaptosomes. AHR-11797 did not protect mice from seizures induced by maximal electroshock or subcutaneous Metrazol (scMET), nor did it induce seizures in doses up to the lethal dose. However, at 31.6 mg/kg, IP, it significantly increased the anticonvulsant ED/sub 50/ of chlordiazepoxide (CDPX) from 1.9 to 31.6 mg/kg, IP. With 56.7 mg/kg, IP, of AHR-11797, CDPX was inactive in doses up to 100 mg/kg, IP. AHR-11797 did not significantly increase punished responding in the Geller and Seifter conflict procedure, but it did attenuate the effects of diazepam. Although the compound is without anticonvulsant or anxiolytic activity, it did have muscle relaxant properties. AHR-11797 blocked morphine-induced Straub tail in mice (ED/sub 50/ = 31 mg/kg, IP) and it selectively suppressed the polysnaptic linguomandibular reflex in barbiturate-anesthetized cats. The apparent muscle relaxant activity of AHR-11797 suggests that different receptor sites are involved for muscle relaxant vs. anxiolytic/anticonvulsant activities of the benzodiazepines.

  4. Inhibition of the aryl hydrocarbon receptor prevents Western diet-induced obesity. Model for AHR activation by kynurenine via oxidized-LDL, TLR2/4, TGFβ, and IDO1.

    PubMed

    Moyer, Benjamin J; Rojas, Itzel Y; Kerley-Hamilton, Joanna S; Hazlett, Haley F; Nemani, Krishnamurthy V; Trask, Heidi W; West, Rachel J; Lupien, Leslie E; Collins, Alan J; Ringelberg, Carol S; Gimi, Barjor; Kinlaw, William B; Tomlinson, Craig R

    2016-06-01

    Obesity is an increasingly urgent global problem, yet, little is known about its causes and less is known how obesity can be effectively treated. We showed previously that the aryl hydrocarbon receptor (AHR) plays a role in the regulation of body mass in mice fed Western diet. The AHR is a ligand-activated nuclear receptor that regulates genes involved in a number of biological pathways, including xenobiotic metabolism and T cell polarization. This study was an investigation into whether inhibition of the AHR prevents Western diet-based obesity. Male C57Bl/6J mice were fed control and Western diets with and without the AHR antagonist α-naphthoflavone or CH-223191, and a mouse hepatocyte cell line was used to delineate relevant cellular pathways. Studies are presented showing that the AHR antagonists α-naphthoflavone and CH-223191 significantly reduce obesity and adiposity and ameliorates liver steatosis in male C57Bl/6J mice fed a Western diet. Mice deficient in the tryptophan metabolizing enzyme indoleamine 2,3-dioxygenase 1 (IDO1) were also resistant to obesity. Using an AHR-directed, luciferase-expressing mouse hepatocyte cell line, we show that the transforming growth factor β1 (TGFβ1) signaling pathway via PI3K and NF-κB and the toll-like receptor 2/4 (TLR2/4) signaling pathway stimulated by oxidized low-density lipoproteins via NF-κB, each induce luciferase expression; however, TLR2/4 signaling was significantly reduced by inhibition of IDO1. At physiological levels, kynurenine but not kynurenic acid (both tryptophan metabolites and known AHR agonists) activated AHR-directed luciferase expression. We propose a hepatocyte-based model, in which kynurenine production is increased by enhanced IDO1 activity stimulated by TGFβ1 and TLR2/4 signaling, via PI3K and NF-κB, to perpetuate a cycle of AHR activation to cause obesity; and inhibition of the AHR, in turn, blocks the cycle's output to prevent obesity. The AHR with its broad ligand binding specificity

  5. Benzo[ghi]perylene activates the AHR pathway to exert biological effects on the NL-20 human bronchial cell line.

    PubMed

    Zaragoza-Ojeda, Montserrat; Eguía-Aguilar, Pilar; Perezpeña-Díazconti, Mario; Arenas-Huertero, Francisco

    2016-08-10

    Polycyclic aromatic hydrocarbons (PAH) are produced by incomplete combustion of organic material. In the Mexico City atmosphere, the most abundant PAH is benzo[ghi]perylene (BghiP), a gasoline combustion marker. At present, there are no reports of the effects of BghiP on human bronchial cells, so the aim of the study was to evaluate the effects in vitro of BghiP on the NL-20 cell line. Results showed that BghiP induced the formation of small vesicles throughout the cytoplasm, with absence of nuclear fragmentation. At 48h exposition, damage in cell membrane increased significantly at 1.24μg/mL of BghiP (p<0.05). Immunocytochemistry revealed that BghiP provokes nuclear translocation of AhR receptor, which indicates that this compound can induce transcription of genes via receptor binding (AhR pathway activation). BghiP induced a two-fold increase (p<0.05) in the expression of AhR and CYP4B1 (a lung-specific pathway effector). In the presence of the receptor antagonist CH-223191, the loss of viability, the nuclear translocation and the overexpression of genes decreased, though this did not prevent the formation of vesicles. BghiP induced oxidative stress and in presence of the receptor antagonist this increased significantly. In conclusion, BghiP can activate the overexpression of AhR and CYP4B1, and the effects are abated by the AhR receptor antagonist. This is the first report to prove that BghiP utilizes the AhR pathway to exert its toxic effects on the NL-20 human bronchial cell line . PMID:27234499

  6. Aryl hydrocarbon receptor-driven signals inhibit collagen synthesis in the gut.

    PubMed

    Monteleone, Ivan; Zorzi, Francesca; Marafini, Irene; Di Fusco, Davide; Dinallo, Vincenzo; Caruso, Roberta; Izzo, Roberta; Franzè, Eleonora; Colantoni, Alfredo; Pallone, Francesco; Monteleone, Giovanni

    2016-04-01

    Fibrostrictures (FS) are a major complication of Crohn's disease (CD). Pathogenesis of FS is not fully understood, but activation of fibroblasts and excessive collagen deposition are crucial in the development of FS. Here, we investigated the role of aryl hydrocarbon receptor (AhR) in intestinal fibrosis. AhR RNA and protein expression were evaluated in intestinal fibroblasts of CD patients and controls. CD fibroblasts were stimulated with TGF-β1 or TNF-α in the presence or absence of the AhR activator Ficz, an AhR antagonist CH223191, or a specific AhR-silencing RNA. In CD fibroblasts, TGF-β1 and TNF-α increased Col1A1, Col3A1 and α-SMA transcripts and collagen secretion and this effect was reduced by Ficz and upregulated by CH22319. TGF-β1 or TNF-α induced activation of p38 and ERK1/2 MAP kinases was decreased by Ficz and increased by CH223191. The inhibitory effect of Ficz on Map kinase activation and collagen induction was abolished by AhR silencing. To assess the role of AhR in vivo, mice with trinitrobenzene-sulfonic-acid induced colonic fibrosis were given Ficz or CH223191. Mice given either Ficz or CH223191 produced less or more collagen respectively as compared with control mice. Our results indicate that AhR is a negative regulator of profibrotic signals in the gut. PMID:26786786

  7. The aryl hydrocarbon receptor (AhR) mediates resistance to apoptosis induced in breast cancer cells.

    PubMed

    Bekki, Kanae; Vogel, Helena; Li, Wen; Ito, Tomohiro; Sweeney, Colleen; Haarmann-Stemmann, Thomas; Matsumura, Fumio; Vogel, Christoph F A

    2015-05-01

    The aryl hydrocarbon receptor (AhR) is well known as a ligand binding transcription factor regulating various biological effects. Previously we have shown that long-term exposure to estrogen in breast cancer cells caused not only down regulation of estrogen receptor (ER) but also overexpression of AhR. The AhR interacts with several cell signaling pathways associated with induction of tyrosine kinases, cytokines and growth factors which may support the survival roles of AhR escaping from apoptosis elicited by a variety of apoptosis inducing agents in breast cancer. In this study, we studied the anti-apoptotic role of AhR in different breast cancer cells when apoptosis was induced by exposure to UV light and chemotherapeutic agents. Activation of AhR by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in AhR overexpressing breast cancer cells effectively suppressed the apoptotic response induced by UV-irradiation, doxorubicin, lapatinib and paclitaxel. The anti-apoptotic response of TCDD was uniformly antagonized by the treatment with 3'methoxy-4'nitroflavone (MNF), a specific antagonist of AhR. TCDD's survival action of apoptosis was accompanied with the induction of well-known inflammatory genes, such as cyclooxygenase-2 (COX-2) and NF-κB subunit RelB. Moreover, TCDD increased the activity of the immunosuppressive enzyme indoleamine 2, 3-dioxygenase (IDO), which metabolizes tryptophan to kynurenine (Kyn) and mediates tumor immunity. Kyn also acts as an AhR ligand like TCDD, and kyn induced an anti-apoptotic response in breast cancer cells. Accordingly, our present study suggests that AhR plays a pivotal role in the development of breast cancer via the suppression of apoptosis, and provides an idea that the use of AhR antagonists with chemotherapeutic agents may effectively synergize the elimination of breast cancer cells. PMID:25987214

  8. The aryl hydrocarbon receptor agonist 2,3,7,8-tetrachloro-dibenzo-p-dioxin (TCDD) alters early embryonic development in a rat IVF exposure model

    PubMed Central

    Petroff, Brian K.; Valdez, Kelli E.; Brown, Sara B.; Piasecka, Joanna; Albertini, David F.

    2011-01-01

    Aryl hydrocarbon receptor (AHR) ligands, including 2,3,7,8-tetrachloro-dibenzo-p-dioxin (TCDD), accelerate reproductive senescence and one proposed target is the early embryo. To discriminate between direct effects on the oocyte and early embryo and those mediated by complex ovarian interactions with TCDD, IVF was carried out in the presence of TCDD (10, 100 nM) and the aryl hydrocarbon antagonist CH-223191 (1 μM) combined factorially. TCDD-induced Cyp1a1 mRNA expression was absent in 2-cell embryos; however morulae exhibit dose-dependent Cyp1a1 expression. TCDD induced accumulation of sperm in the perivitelline space and displacement of blastomere nuclei. At 100 nM TCDD, aberrations in cytokinesis and nuclear positioning were observed 2-cell embryos and morula and these effects were reversed in the presence of CH-223191. Our data suggest that acute exposure to TCDD has direct effects on early development in the rat that permit discrimination of AHR- mediated and AHR-independent mechanisms through which environmental toxicants impair mammalian reproduction. PMID:21835239

  9. Selective suppression of the human aryl hydrocarbon receptor function can be mediated through binding interference at the C-terminal half of the receptor.

    PubMed

    Ren, Lina; Thompson, John D; Cheung, Michael; Ngo, Katherine; Sung, Sarah; Leong, Scott; Chan, William K

    2016-05-01

    The human aryl hydrocarbon receptor is a cytosolic signaling molecule which affects immune response and aberrant cell growth. Canonical signaling of the receptor requires the recruitment of coactivators to the promoter region to remodel local chromatin structure. We predicted that interference of this recruitment would block the aryl hydrocarbon receptor function. To prove that, we employed phage display to identify nine peptides of twelve-amino-acid in length which target the C-terminal half of the human aryl hydrocarbon receptor, including the region where coactivators bind. Eight 12mer peptides, in the form of GFP fusion, suppressed the ligand-dependent transcription of six AHR target genes (cyp1a1, cyp1a2, cyp1b1, ugt1a1, nqo1, and ahrr) in different patterns in Hep3B cells, whereas the AHR antagonist CH-223191 suppressed all these target genes similarly. Three of the 12mer peptides (namely 11-3, 1-7, and 7-3) suppressed the 3MC-induced, CYP1A1-dependent EROD activity and the ROS production caused by benzo[a]pyrene. These 12mer peptides suppressed the AHR function synergistically with CH-223191. In conclusion, we provide evidence that targeting the C-terminal half of the human aryl hydrocarbon receptor is a viable, new approach to selectively block the receptor function. PMID:26970402

  10. Species-Specific Differential AhR Expression Protects Human Neural Progenitor Cells against Developmental Neurotoxicity of PAHs

    PubMed Central

    Gassmann, Kathrin; Abel, Josef; Bothe, Hanno; Haarmann-Stemmann, Thomas; Merk, Hans F.; Quasthoff, Kim N.; Rockel, Thomas Dino; Schreiber, Timm; Fritsche, Ellen

    2010-01-01

    Background Because of their lipophilicity, persistent organic pollutants (POPs) cross the human placenta, possibly affecting central nervous system development. Most POPs are known aryl hydrocarbon receptor (AhR) ligands and activators of AhR signaling. Therefore, AhR activation has been suggested to cause developmental neurotoxicity (DNT). Objective We studied the effects of AhR ligands on basic processes of brain development in two comparative in vitro systems to determine whether AhR-activation is the underlying mechanism for reported DNT of POPs in humans. Methods We employed neurosphere cultures based on human neural progenitor cells (hNPCs) and wild-type and AhR-deficient mouse NPCs (mNPCs) and studied the effects of different AhR agonists [3-methylcholanthrene (3-MC), benzo(a)pyrene [B(a)P], and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)] and an antagonist [3′-methoxy-4′-nitroflavone (MNF)] on neurosphere development. Moreover, we analyzed expression of AhR and genes involved in AhR signaling. Results In contrast to wild-type mNPCs, hNPCs and AhR-deficient mNPCs were insensitive to AhR agonism or antagonism. Although AhR modulation attenuated wild-type mNPC proliferation and migration, hNPCs and AhR-deficient mNPCs remained unaffected. Results also suggest that species-specific differences resulted from nonfunctional AhR signaling in hNPCs. Conclusion Our findings suggest that in contrast to wild-type mNPCs, hNPCs were protected against polycyclic aromatic hydrocarbon–induced DNT because of an absence of AhR. This difference may contribute to species-specific differences in sensitivity to POPs. PMID:20570779

  11. AhR signalling and dioxin toxicity.

    PubMed

    Sorg, Olivier

    2014-10-15

    Dioxins are a family of molecules associated to several industrial accidents such as Ludwigshafen in 1953 or Seveso in 1976, to the Agent Orange used during the war of Vietnam, and more recently to the poisoning of the former president of Ukraine, Victor Yushchenko. These persistent organic pollutants are by-products of industrial activity and bind to an intracellular receptor, AhR, with a high potency. In humans, exposure to dioxins, in particular 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces a cutaneous syndrome known as chloracne, consisting in the development of many small skin lesions (hamartoma), lasting for 2-5 years. Although TCDD has been classified by the WHO as a human carcinogen, its carcinogenic potential to humans is not clearly demonstrated. It was first believed that AhR activation accounted for most, if not all, biological properties of dioxins. However, certain AhR agonists found in vegetables do not induce chloracne, and other chemicals, in particular certain therapeutic agents, may induce a chloracne-like syndrome without activating AhR. It is time to rethink the mechanism of dioxin toxicity and analyse in more details the biological events following exposure to these compounds and other AhR agonists, some of which have a very different chemical structure than TCDD. In particular various food-containing AhR agonists are non-toxic and may on the contrary have beneficial properties to human health. PMID:24239782

  12. In vitro and in silico evaluation of transactivation potencies of avian AHR1 and AHR2 by endogenous ligands: Implications for the physiological role of avian AHR2.

    PubMed

    Kim, In-Sung; Hwang, Ji-Hee; Hirano, Masashi; Iwata, Hisato; Kim, Eun-Young

    2016-09-01

    Aryl hydrocarbon receptor (AHR) is well conserved from invertebrates to vertebrates, and it mediates the toxic effects of exogenous ligands, including dioxins. Recent studies reported that AHRs activated by endogenous ligands play critical roles in mammalian physiological homeostasis. Avian species possess at least two AHR isoforms (AHR1 and AHR2), which exhibit species- and isoform-specific transactivation potencies to exogenous ligands, whereas mammals possess a single AHR. To delineate the profiles and roles of endogenous ligands for avian AHR isoforms, we investigated in vitro transactivation potencies of avian AHRs (AHR1 and AHR2 from the jungle crow, Corvus macrorhynchos; common cormorant, Phalacrocorax carbo; and black-footed albatross, Phoebastria nigripes) treated with the endogenous tryptophan metabolites 6-formylindolo [3,2-b] carbazole (FICZ), l-kynurenine (l-Kyn), kynurenic acid (KYNA), and indoxyl sulfate (IS). Furthermore, we analyzed the binding mode of these ligands to each avian AHR isoform by in silico docking simulations. The EC50 of FICZ (0.009-0.032nM) was similar regardless of the species or isoform of AHR. The estimated in silico binding mode of FICZ to AHRs was well conserved in both isoforms. The transactivation potencies of avian AHRs to other tryptophan metabolites were 10(5)-10(7) fold lower than those for FICZ, and EC50 values varied in a species- and isoform-specific manner. This was consistent with poor conservation of the binding mode of l-Kyn, KYNA, and IS predicted in in silico docking simulations. Our results suggest that in avian species, FICZ is the most potent endogenous AHR ligand, and that AHR1 and AHR2 are physiologically functional. PMID:27060260

  13. Evodiamine as a novel antagonist of aryl hydrocarbon receptor

    SciTech Connect

    Yu, Hui; Tu, Yongjiu; Zhang, Chun; Fan, Xia; Wang, Xi; Wang, Zhanli; Liang, Huaping

    2010-11-05

    Research highlights: {yields} Evodiamine interacted with the AhR. {yields} Evodiamine inhibited the specific binding of [{sup 3}H]-TCDD to the AhR. {yields} Evodiamine acts as an antagonist of the AhR. -- Abstract: Evodiamine, the major bioactive alkaloid isolated from Wu-Chu-Yu, has been shown to interact with a wide variety of proteins and modify their expression and activities. In this study, we investigated the interaction between evodiamine and the aryl hydrocarbon receptor (AhR). Molecular modeling results revealed that evodiamine directly interacted with the AhR. Cytosolic receptor binding assay also provided the evidence that evodiamine could interact with the AhR with the K{sub i} value of 28.4 {+-} 4.9 nM. In addition, we observed that evodiamine suppressed the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induced nuclear translocation of the AhR and the expression of CYP1A1 dose-dependently. These results suggested that evodiamine was able to bind to the AhR as ligand and exhibit antagonistic effects.

  14. The aryl hydrocarbon receptor (AHR) transcription factor regulates megakaryocytic polyploidization

    PubMed Central

    Lindsey, Stephan; T. Papoutsakis, Eleftherios

    2012-01-01

    Summary We propose that the aryl hydrocarbon receptor (AHR) is a novel transcriptional regulator of megakaryopoietic polyploidization. Functional evidence was obtained that AHR impacts in vivo megakaryocytic differentiation and maturation; compared to wild-type mice, AHR-null mice had lower platelet counts, fewer numbers of newly synthesized platelets, increased bleeding times and lower-ploidy megakaryocytes (Mks). AHR mRNA increased 3·6-fold during ex vivo megakaryocytic differentiation, but reduced or remained constant during parallel isogenic granulocytic or erythroid differentiation. We interrogated the role of AHR in megakaryopoiesis using a validated Mk model of megakaryopoiesis, the human megakaryoblastic leukaemia CHRF cell line. Upon CHRF Mk differentiation, AHR mRNA and protein levels increased, AHR protein shifted from the cytoplasm to the nucleus and AHR binding to its consensus DNA binding sequence increased. Protein and mRNA levels of the AHR transcriptional target HES1 also increased. Mk differentiation of CHRF cells where AHR or HES1 was knocked-down using RNAi resulted in lower ploidy distributions and cells that were incapable of reaching ploidy classes ≥16n. AHR knockdown also resulted in increased DNA synthesis of lower ploidy cells, without impacting apoptosis. Together, these data support a role for AHR in Mk polyploidization and in vivo platelet function, and warrant further detailed investigations. PMID:21226706

  15. Arylhydrocarbon receptor (AhR) activation in airway epithelial cells induces MUC5AC via reactive oxygen species (ROS) production.

    PubMed

    Chiba, Takahito; Uchi, Hiroshi; Tsuji, Gaku; Gondo, Hisaki; Moroi, Yoichi; Furue, Masutaka

    2011-02-01

    The dioxins and dioxin-like compounds in cigarette smoke regulate various immunological responses via the arylhydrocarbon receptor (AhR). These environmental toxicants are known to cause bronchitis, asthma, chronic obstructive pulmonary disease (COPD), and lung cancer. Recent studies have demonstrated that AhR activation upregulates the expression of mucin 5AC, oligomeric mucus/gel-forming (MUC5AC) in the airway epithelial cell line. However, the mechanism for the production of mucin has not been clarified. In this study, we investigated the role and pathway of AhR in airway epithelial cells by using selective agonists and antagonists. After stimulation with or without benzopyrene (B[a]P), an AhR agonist, MUC5AC expression was measured by real-time RT-PCR. The mechanism of AhR-induced MUC5AC expression in airway epithelial cells was studied in terms of the production of cytokine and reactive oxygen species (ROS). Treatment with B[a]P increased ROS generation in NCI-H₂₉₂ cells. Furthermore, B[a]P-induced MUC5AC upregulation and mucin production were inhibited by AhR siRNA or the use of an antioxidative agent. These results suggest that the AhR-induced increase of mucin production is partially mediated by ROS generation. An antioxidant therapy approach may help to cure AhR-induced mucus hypersecretory diseases. PMID:20709182

  16. Immunological Relevance of the Coevolution of IDO1 and AHR

    PubMed Central

    Jaronen, Merja; Quintana, Francisco J.

    2014-01-01

    The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor initially identified because of its role in controlling the cellular response to environmental molecules. More recently, AHR has been shown to play a crucial role in controlling innate and adaptive immune responses through several mechanisms, one of which is the regulation of tryptophan metabolism. Indoleamine-2,3-dioxygenase (IDO) and tryptophan-2,3-dioxygenase (TDO) are considered rate-limiting enzymes in the tryptophan catabolism and play important roles in the regulation of the immunity. Moreover, AHR and IDO/TDO are closely interconnected: AHR regulates IDO and TDO expression, and kynurenine produced by IDO/TDO is an AHR agonist. In this review, we propose to examine the relationship between AHR and IDO/TDO and its relevance for the regulation of the immune response in health and disease. PMID:25368620

  17. TOXICITY OF AHR AGONISTS TO FISH EARLY LIFE STAGES

    EPA Science Inventory

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

  18. AHR signaling in prostate growth, morphogenesis, and disease

    PubMed Central

    Vezina, Chad M.; Lin, Tien-Min; Peterson, Richard E.

    2010-01-01

    Most evidence of aryl hydrocarbon receptor (AHR) signaling in prostate growth, morphogenesis, and disease stems from research using 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) to pharmacologically activate the AHR at various stages of development. This review discusses effects of TCDD on prostate morphogenesis and highlights interactions between AHR and other signaling pathways during normal and aberrant prostate growth. Although AHR signaling modulates estrogen and androgen signaling in other tissues, crosstalk between these steroid hormone receptors and AHR signaling cannot account for actions of TCDD on prostate morphogenesis. Instead, the AHR appears to act within a cooperative framework of developmental signals to regulate timing and patterning of prostate growth. Inappropriate activation of AHR signaling as a result of early life TCDD exposure disrupts the balance of these signals, impairs prostate morphogenesis, and has an imprinting effect on the developing prostate that predisposes to prostate disease in adulthood. Mechanisms of AHR signaling in prostate growth and disease are only beginning to be unraveled and recent studies have revealed its interactions with WNT5A, retinoic acid, fibroblast growth factor 10, and vascular endothelial growth factor signaling pathways. PMID:18977204

  19. A Structural Switch between Agonist and Antagonist Bound Conformations for a Ligand-Optimized Model of the Human Aryl Hydrocarbon Receptor Ligand Binding Domain

    PubMed Central

    Perkins, Arden; Phillips, Jessica L.; Kerkvliet, Nancy I.; Tanguay, Robert L.; Perdew, Gary H.; Kolluri, Siva K.; Bisson, William H.

    2014-01-01

    The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that regulates the expression of a diverse group of genes. Exogenous AHR ligands include the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), which is a potent agonist, and the synthetic AHR antagonist N-2-(1H-indol-3yl)ethyl)-9-isopropyl-2-(5-methylpyridin-3-yl)-9H-purin-6-amine (GNF351). As no experimentally determined structure of the ligand binding domain exists, homology models have been utilized for virtual ligand screening (VLS) to search for novel ligands. Here, we have developed an “agonist-optimized” homology model of the human AHR ligand binding domain, and this model aided in the discovery of two human AHR agonists by VLS. In addition, we performed molecular dynamics simulations of an agonist TCDD-bound and antagonist GNF351-bound version of this model in order to gain insights into the mechanics of the AHR ligand-binding pocket. These simulations identified residues 307–329 as a flexible segment of the AHR ligand pocket that adopts discrete conformations upon agonist or antagonist binding. This flexible segment of the AHR may act as a structural switch that determines the agonist or antagonist activity of a given AHR ligand. PMID:25329374

  20. Characterizing the role of endothelin-1 in the progression of cardiac hypertrophy in aryl hydrocarbon receptor (AhR) null mice

    SciTech Connect

    Lund, Amie K.; Goens, M. Beth; Nunez, Bethany A.; Walker, Mary K. . E-mail: mkwalker@unm.edu

    2006-04-15

    The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor characterized to play a role in detection and adaptation to environmental stimuli. Genetic deletion of AhR results in hypertension, and cardiac hypertrophy and fibrosis, associated with elevated plasma angiotensin II (Ang II) and endothelin-1 (ET-1), thus AhR appears to contribute to cardiovascular homeostasis. In these studies, we tested the hypothesis that ET-1 mediates cardiovascular pathology in AhR null mice via ET{sub A} receptor activation. First, we determine the time courses of cardiac hypertrophy, and of plasma and tissue ET-1 expression in AhR wildtype and null mice. AhR null mice exhibited increases in heart-to-body weight ratio and age-related expression of cardiac hypertrophy markers, {beta}-myosin heavy chain ({beta}-MHC), and atrial natriuretic factor (ANF), which were significant at 2 months. Similarly, plasma and tissue ET-1 expression was significantly elevated at 2 months and increased further with age. Second, AhR null mice were treated with ET{sub A} receptor antagonist, BQ-123 (100 nmol/kg/day), for 7, 28, or 58 days and blood pressure, cardiac fibrosis, and cardiac hypertrophy assessed, respectively. BQ-123 for 7 days significantly reduced mean arterial pressure in conscious, catheterized mice. BQ-123 for 28 days significantly reduced the histological appearance of cardiac fibrosis. Treatment for 58 days significantly reduced cardiac mass, assessed by heart weight, echocardiography, and {beta}-MHC and ANF expression; and reduced cardiac fibrosis as determined by osteopontin and collagen I mRNA expression. These findings establish ET-1 and the ET{sub A} receptor as primary determinants of hypertension and cardiac pathology in AhR null mice.

  1. AhR sensing of bacterial pigments regulates antibacterial defence.

    PubMed

    Moura-Alves, Pedro; Faé, Kellen; Houthuys, Erica; Dorhoi, Anca; Kreuchwig, Annika; Furkert, Jens; Barison, Nicola; Diehl, Anne; Munder, Antje; Constant, Patricia; Skrahina, Tatsiana; Guhlich-Bornhof, Ute; Klemm, Marion; Koehler, Anne-Britta; Bandermann, Silke; Goosmann, Christian; Mollenkopf, Hans-Joachim; Hurwitz, Robert; Brinkmann, Volker; Fillatreau, Simon; Daffe, Mamadou; Tümmler, Burkhard; Kolbe, Michael; Oschkinat, Hartmut; Krause, Gerd; Kaufmann, Stefan H E

    2014-08-28

    The aryl hydrocarbon receptor (AhR) is a highly conserved ligand-dependent transcription factor that senses environmental toxins and endogenous ligands, thereby inducing detoxifying enzymes and modulating immune cell differentiation and responses. We hypothesized that AhR evolved to sense not only environmental pollutants but also microbial insults. We characterized bacterial pigmented virulence factors, namely the phenazines from Pseudomonas aeruginosa and the naphthoquinone phthiocol from Mycobacterium tuberculosis, as ligands of AhR. Upon ligand binding, AhR activation leads to virulence factor degradation and regulated cytokine and chemokine production. The relevance of AhR to host defence is underlined by heightened susceptibility of AhR-deficient mice to both P. aeruginosa and M. tuberculosis. Thus, we demonstrate that AhR senses distinct bacterial virulence factors and controls antibacterial responses, supporting a previously unidentified role for AhR as an intracellular pattern recognition receptor, and identify bacterial pigments as a new class of pathogen-associated molecular patterns. PMID:25119038

  2. Identification of aryl hydrocarbon receptor signaling pathways altered in TCDD-treated red seabream embryos by transcriptome analysis.

    PubMed

    Iida, Midori; Fujii, Satoshi; Uchida, Masaya; Nakamura, Hiroshi; Kagami, Yoshihiro; Agusa, Tetsuro; Hirano, Masashi; Bak, Su-Min; Kim, Eun-Young; Iwata, Hisato

    2016-08-01

    2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) induces a broad spectrum of toxic effects including craniofacial malformation and neural damage in fish embryos. These effects are mainly mediated by the aryl hydrocarbon receptor (AHR). However, the mode of action between TCDD-induced AHR activation and adverse outcomes is not yet understood. To provide a comprehensive picture of the AHR signaling pathway in fish embryos exposed to TCDD, red seabream (Pagrus major) embryos were treated with graded concentrations of TCDD (0.3-37nM) in seawater, or with a mixture of TCDD and 500nM CH223191, an AHR-specific antagonist. The transcriptome of red seabream embryos was analyzed using a custom-made microarray with 6000 probes specifically prepared for this species. A Jonckheere-Terpstra test was performed to screen for genes that demonstrated altered mRNA expression levels following TCDD exposure. The signals of 1217 genes (as human homologs) were significantly altered in a TCDD concentration-dependent manner (q-value<0.2). Notably, the TCDD-induced alteration in mRNA expression was alleviated by co-exposure to CH223191, suggesting that the mRNA expression level of these genes was regulated by AHR. To identify TCDD-activated pathways, the microarray data were further subjected to gene set enrichment analysis (GSEA) and functional protein-protein interaction (PPI) network analysis. GSEA demonstrated that the effects of TCDD on sets of genes involved calcium, mitogen-activated protein kinase (MAPK), actin cytoskeleton, chemokine, T cell receptor, melanoma, vascular endothelial growth factor (VEGF), axon guidance, and renal cell carcinoma signaling pathways. These results suggest the hypotheses that TCDD induces immunosuppression via the calcium, MAPK, chemokine, and T cell receptor signaling pathways, neurotoxicity via VEGF signaling, and axon guidance alterations and teratogenicity via the dysregulation of the actin cytoskeleton and melanoma and renal cell carcinoma signaling

  3. PCB126 Inhibits Adipogenesis of Human Preadipocytes

    PubMed Central

    Gadupudi, Gopi; Gourronc, Francoise A.; Ludewig, Gabriele; Robertson, Larry W.; Klingelhutz, Aloysius J.

    2014-01-01

    Emerging evidence indicates that persistent organic pollutants (POPs), including polychlorinated biphenyls (PCBs), are involved in the development of diabetes. Dysfunctional adipocytes play a significant role in initiating insulin resistance. Preadipocytes make up a large portion of adipose tissue and are necessary for the generation of functional mature adipocytes through adipogenesis. PCB126 is a dioxin-like PCB and a potent aryl hydrocarbon receptor (AhR) agonist. We hypothesized that PCB126 may be involved in the development of diabetes through disruption of adipogenesis. Using a newly developed human preadipocyte cell line called NPAD (Normal PreADipocytes), we found that exposure of preadipocytes to PCB126 resulted in significant reduction in their subsequent ability to fully differentiate into adipocytes, more so than when the cells were exposed to PCB126 during differentiation. Reduction in differentiation by PCB126 was associated with downregulation of transcript levels of a key adipocyte transcription factor, PPARγ, and late adipocyte differentiation genes. An AhR antagonist, CH223191, blocked this effect. These studies indicate that preadipocytes are particularly sensitive to the effects of PCB126 and suggest that AhR activation inhibits PPARγ transcription and subsequent adipogenesis. Our results validate the NPAD cell line as a useful model for studying the effects of POPs on adipogenesis. PMID:25304490

  4. Simulator for SUPO, a Benchmark Aqueous Homogeneous Reactor (AHR)

    SciTech Connect

    Klein, Steven Karl; Determan, John C.

    2015-10-14

    A simulator has been developed for SUPO (Super Power) an aqueous homogeneous reactor (AHR) that operated at Los Alamos National Laboratory (LANL) from 1951 to 1974. During that period SUPO accumulated approximately 600,000 kWh of operation. It is considered the benchmark for steady-state operation of an AHR. The SUPO simulator was developed using the process that resulted in a simulator for an accelerator-driven subcritical system, which has been previously reported.

  5. Khellin and Visnagin Differentially Modulate AHR Signaling and Downstream CYP1A Activity in Human Liver Cells

    PubMed Central

    Proksch, Peter; Abel, Josef; Dvorak, Zdenek; Haarmann-Stemmann, Thomas

    2013-01-01

    Khellin and visnagin are two furanochromones that can be frequently found in ethnomedical formulations in Asia and the Middle East. Both compounds possess anti-inflammatory and analgesic properties, therefore modern medicine uses these compounds or structurally related derivatives for treatment of vitiligo, bronchial asthma and renal colics. Despite their frequent usage, the potential toxic properties of visnagin and khellin are not well characterized up-to-now. Many natural compounds modulate the expression and activity of cytochrome P450 1A1 (CYP1A1), which is well-known to bioactivate pro-carcinogens. The expression of this enzyme is controlled by the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor and regulator of drug metabolism. Here, we investigated the influence of both furanochromones on AHR signaling in human HepG2 hepatocarcinoma cells and primary human hepatocytes. Both compounds transactivated xenobiotic response element (XRE)-driven reporter gene activity in a dose-dependent manner and induced CYP1A1 transcription in HepG2 cells and primary hepatocytes. The latter was abolished in presence of a specific AHR antagonist. CYP1A enzyme activity assays done in HepG2 cells and primary hepatocytes revealed an inhibition of enzyme activity by both furanochromones, which may become relevant regarding the metabolism of xenobiotics and co-administered therapeutic drugs. The observed induction of several other members of the AHR gene battery, whose gene products are involved in regulation of cell growth, differentiation and migration, indicates that a further toxicological characterization of visnagin and khelllin is urgently required in order to minimize potential drug-drug interactions and other toxic side-effects that may occur during therapeutic usage of these furanochromones. PMID:24069365

  6. Calcium antagonists.

    PubMed

    Grossman, Ehud; Messerli, Franz H

    2004-01-01

    Calcium antagonists were introduced for the treatment of hypertension in the 1980s. Their use was subsequently expanded to additional disorders, such as angina pectoris, paroxysmal supraventricular tachycardias, hypertrophic cardiomyopathy, Raynaud phenomenon, pulmonary hypertension, diffuse esophageal spasms, and migraine. Calcium antagonists as a group are heterogeneous and include 3 main classes--phenylalkylamines, benzothiazepines, and dihydropyridines--that differ in their molecular structure, sites and modes of action, and effects on various other cardiovascular functions. Calcium antagonists lower blood pressure mainly through vasodilation and reduction of peripheral resistance. They maintain blood flow to vital organs, and are safe in patients with renal impairment. Unlike diuretics and beta-blockers, calcium antagonists do not impair glucose metabolism or lipid profile and may even attenuate the development of arteriosclerotic lesions. In long-term follow-up, patients treated with calcium antagonists had development of less overt diabetes mellitus than those who were treated with diuretics and beta-blockers. Moreover, calcium antagonists are able to reduce left ventricular mass and are effective in improving anginal pain. Recent prospective randomized studies attested to the beneficial effects of calcium antagonists in hypertensive patients. In comparison with placebo, calcium antagonist-based therapy reduced major cardiovascular events and cardiovascular death significantly in elderly hypertensive patients and in diabetic patients. In several comparative studies in hypertensive patients, treatment with calcium antagonists was equally effective as treatment with diuretics, beta-blockers, or angiotensin-converting enzyme inhibitors. From these studies, it seems that a calcium antagonist-based regimen is superior to other regimens in preventing stroke, equivalent in preventing ischemic heart disease, and inferior in preventing congestive heart failure

  7. Hexachlorobenzene induces cell proliferation, and aryl hydrocarbon receptor expression (AhR) in rat liver preneoplastic foci, and in the human hepatoma cell line HepG2. AhR is a mediator of ERK1/2 signaling, and cell cycle regulation in HCB-treated HepG2 cells.

    PubMed

    de Tomaso Portaz, Ana Clara; Caimi, Giselle Romero; Sánchez, Marcela; Chiappini, Florencia; Randi, Andrea S; Kleiman de Pisarev, Diana L; Alvarez, Laura

    2015-10-01

    are mediated by ERK1/2. Pretreatment with an AhR antagonist, prevented HCB-induced PCNA protein levels, ERK1/2 phosphorylation and alterations in cell cycle distribution. These results demonstrate that HCB-induced HepG2 proliferation and cell cycle progression depend on ERK1/2 phosphorylation which is mediated by the AhR. Our results provide a clue to the molecular events involved in the mechanism of action of HCB-induced hepatocarcinogenesis. PMID:26219504

  8. Disruption of Aryl Hydrocarbon Receptor Homeostatic Levels during Embryonic Stem Cell Differentiation Alters Expression of Homeobox Transcription Factors that Control Cardiomyogenesis

    PubMed Central

    Wang, Qin; Chen, Jing; Ko, Chia-I; Fan, Yunxia; Carreira, Vinicius; Chen, Yinglei; Xia, Ying; Medvedovic, Mario

    2013-01-01

    Background: The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that regulates the expression of xenobiotic detoxification genes and is a critical mediator of gene–environment interactions. Many AHR target genes identified by genome-wide gene expression profiling have morphogenetic functions, suggesting that AHR may play a role in embryonic development. Objectives: To characterize the developmental functions of the AHR, we studied the consequences of AHR activation by the agonist 2,3,7,8-tetrachlorodibenzo-p-doxin (TCDD), and the result of its repression by the antagonists 6,2,4-trimethoxyflavone and CH 223191 or by short-hairpin RNA (shRNA)-mediated Ahr knockdown during spontaneous differentiation of embryonic stem (ES) cells into cardiomyocytes. Methods: We generated an AHR-positive cardiomyocyte lineage differentiated from mouse ES cells that expresses puromycin resistance and enhanced green fluorescent protein (eGFP) under the control of the Cyp1a1 (cytochrome P450 1a1) promoter. We used RNA sequencing (RNA.Seq) to analyze temporal trajectories of TCDD-dependent global gene expression in these cells during differentiation. Results: Activation, inhibition, and knockdown of Ahr significantly inhibited the formation of contractile cardiomyocyte nodes. Global expression analysis of AHR-positive cells showed that activation of the AHR/TCDD axis disrupted the concerted expression of genes that regulate multiple signaling pathways involved in cardiac and neural morphogenesis and differentiation, including dozens of genes encoding homeobox transcription factors and Polycomb and trithorax group proteins. Conclusions: Disruption of AHR expression levels resulted in gene expression changes that perturbed cardiomyocyte differentiation. The main function of the AHR during development appears to be the coordination of a complex regulatory network responsible for attainment and maintenance of cardiovascular homeostasis. Citation: Wang Q, Chen J

  9. Cardiac myocyte-specific AHR activation phenocopies TCDD-induced toxicity in zebrafish.

    PubMed

    Lanham, Kevin A; Plavicki, Jessica; Peterson, Richard E; Heideman, Warren

    2014-09-01

    Exposure of zebrafish embryos to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) activates the zebrafish aryl hydrocarbon receptor 2 (AHR) to produce developmental and cardiovascular toxicity. AHR is found in the heart; however, AHR activation by TCDD is not confined to the heart and occurs throughout the organism. In order to understand the cause of cardiotoxicity, we constructed a constitutively active AHR (caAHR) based on the zebrafish AHR2 and expressed it specifically in cardiomyocytes. We show that AHR activation within the cardiomyocytes can account for the heart failure induced by TCDD. Expression of the caAHR within the heart produced cardiac malformations, loss of circulation, and pericardial edema. The heart-specific activation of AHR reproduced several other well-characterized endpoints of TCDD toxicity outside of the cardiovascular system, including defects in swim bladder and craniofacial development. This work identifies a single cellular site of TCDD action, the myocardial cell, that can account for the severe cardiovascular collapse observed following early life stage exposure to TCDD, and contributes to other forms of toxicity. PMID:25037585

  10. Cardiac Myocyte-Specific AHR Activation Phenocopies TCDD-Induced Toxicity in Zebrafish

    PubMed Central

    Lanham, Kevin A.; Plavicki, Jessica; Peterson, Richard E.; Heideman, Warren

    2014-01-01

    Exposure of zebrafish embryos to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) activates the zebrafish aryl hydrocarbon receptor 2 (AHR) to produce developmental and cardiovascular toxicity. AHR is found in the heart; however, AHR activation by TCDD is not confined to the heart and occurs throughout the organism. In order to understand the cause of cardiotoxicity, we constructed a constitutively active AHR (caAHR) based on the zebrafish AHR2 and expressed it specifically in cardiomyocytes. We show that AHR activation within the cardiomyocytes can account for the heart failure induced by TCDD. Expression of the caAHR within the heart produced cardiac malformations, loss of circulation, and pericardial edema. The heart-specific activation of AHR reproduced several other well-characterized endpoints of TCDD toxicity outside of the cardiovascular system, including defects in swim bladder and craniofacial development. This work identifies a single cellular site of TCDD action, the myocardial cell, that can account for the severe cardiovascular collapse observed following early life stage exposure to TCDD, and contributes to other forms of toxicity. PMID:25037585

  11. Combination effects of AHR agonists and Wnt/β-catenin modulators in zebrafish embryos: Implications for physiological and toxicological AHR functions

    SciTech Connect

    Wincent, Emma; Stegeman, John J.; Jönsson, Maria E.

    2015-04-15

    Wnt/β-catenin signaling regulates essential biological functions and acts in developmental toxicity of some chemicals. The aryl hydrocarbon receptor (AHR) is well-known to mediate developmental toxicity of persistent dioxin-like compounds (DLCs). Recent studies indicate a crosstalk between β-catenin and the AHR in some tissues. However the nature of this crosstalk in embryos is poorly known. We observed that zebrafish embryos exposed to the β-catenin inhibitor XAV939 display effects phenocopying those of the dioxin-like 3,3′,4,4′,5-pentachlorobiphenyl (PCB126). This led us to investigate the AHR interaction with β-catenin during development and ask whether developmental toxicity of DLCs involves antagonism of β-catenin signaling. We examined phenotypes and transcriptional responses in zebrafish embryos exposed to XAV939 or to a β-catenin activator, 1-azakenpaullone, alone or with AHR agonists, either PCB126 or 6-formylindolo[3,2-b]carbazole (FICZ). Alone 1-azakenpaullone and XAV939 both were embryo-toxic, and we found that in the presence of FICZ, the toxicity of 1-azakenpaullone decreased while the toxicity of XAV939 increased. This rescue of 1-azakenpaullone effects occurred in the time window of Ahr2-mediated toxicity and was reversed by morpholino-oligonucleotide knockdown of Ahr2. Regarding PCB126, addition of either 1-azakenpaullone or XAV939 led to lower mortality than with PCB126 alone but surviving embryos showed severe edemas. 1-Azakenpaullone induced transcription of β-catenin-associated genes, while PCB126 and FICZ blocked this induction. The data indicate a stage-dependent antagonism of β-catenin by Ahr2 in zebrafish embryos. We propose that the AHR has a physiological role in regulating β-catenin during development, and that this is one point of intersection linking toxicological and physiological AHR-governed processes.

  12. Molecular and functional characterization of a novel aryl hydrocarbon receptor isoform, AHR1β, in the chicken (Gallus gallus).

    PubMed

    Lee, Jin-Seon; Iwabuchi, Kohei; Nomaru, Koji; Nagahama, Nobumasa; Kim, Eun-Young; Iwata, Hisato

    2013-12-01

    Dioxins including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) cause toxic effects through activation of the aryl hydrocarbon receptor (AHR)-mediated signaling pathway. Our previous studies have investigated the function of 2 AHR isoforms (AHR1 and AHR2) in avian species and identified a third AHR in the chicken (Gallus gallus) genome. Knowledge of multiple avian AHRs is indispensable to understand molecular mechanisms of AHR-mediated toxic effects and establish risk assessment framework for environmental AHR ligands in avian species. In this study, we successfully isolated a third novel AHR1-like cDNA from chicken and designated it as chicken AHR1 beta (ckAHR1β). The mRNA expression of ckAHR1β was primarily detected in the liver, and the hepatic protein expression was confirmed by Western blotting. Although mRNA expression of ckAHR1β was not altered by in ovo TCDD exposure, ckAHR1β exhibited specific binding to [(3)H]TCDD, TCDD-dependent nuclear translocation, and interaction with xenobiotic responsive elements (XREs) and AHR nuclear translocators (ARNTs). In vitro XRE-driven reporter gene assays revealed ckAHR1β-mediated transactivation of TCDD in a dose-dependent manner, showing a 10-fold reduced sensitivity (high EC50) compared with that mediated by ckAHR1. The mutation of Val(371) to Ser(371) in the ligand-binding domain of ckAHR1β shifted the TCDD-EC50 toward the value observed in ckAHR1, indicating the critical roles of the amino acid in sensitivity. Furthermore, ckAHR1β-mediated transactivation of TCDD was enhanced by 17β-estradiol (E2)-activated chicken estrogen receptor α (ckERα), suggesting a positive cross talk between ckERα and ckAHR1β signaling pathway. Both TCDD-induced and its enhanced activities by E2 were suppressed by the ckAHR repressor in a manner similar to ckAHR1. Collectively, our findings discover the role of ckAHR1β in dioxin toxicity and give an insight into the evolutionary history of the AHR signaling pathway. PMID:23997109

  13. Use of natural AhR ligands as potential therapeutic modalities against inflammatory disorders.

    PubMed

    Busbee, Philip B; Rouse, Michael; Nagarkatti, Mitzi; Nagarkatti, Prakash S

    2013-06-01

    The aim of this review is to discuss research involving ligands for the aryl hydrocarbon receptor (AhR) and their role in immunomodulation. While activation of the AhR is well known for its ability to regulate the biochemical and toxic effects of environmental chemicals, more recently an exciting discovery has been made indicating that AhR ligation can also regulate T-cell differentiation, specifically through activation of Foxp3(+) regulatory T cells (Tregs) and downregulation of the proinflammatory Th17 cells. Such findings have opened new avenues of research on the possibility of targeting the AhR to treat inflammatory and autoimmune diseases. Specifically, this review will discuss the current research involving natural and dietary AhR ligands. In addition, evidence indicating the potential use of these ligands in regulating inflammation in various diseases will be highlighted. The importance of the AhR in immunological processes can be illustrated by expression of this receptor on a majority of immune cell types. In addition, AhR signaling pathways have been reported to influence a number of genes responsible for mediating inflammation and other immune responses. As interest in the AhR and its ligands increases, it seems prudent to consolidate current research on the contributions of these ligands to immune regulation during the course of inflammatory diseases. PMID:23731446

  14. Use of natural AhR ligands as potential therapeutic modalities against inflammatory disorders

    PubMed Central

    Busbee, Philip B; Rouse, Michael; Nagarkatti, Mitzi; Nagarkatti, Prakash S

    2014-01-01

    The aim of this review is to discuss research involving ligands for the aryl hydrocarbon receptor (AhR) and their role in immunomodulation. While activation of the AhR is well known for its ability to regulate the biochemical and toxic effects of environmental chemicals, more recently an exciting discovery has been made indicating that AhR ligation can also regulate T-cell differentiation, specifically through activation of Foxp3+ regulatory T cells (Tregs) and downregulation of the proinflammatory Th17 cells. Such findings have opened new avenues of research on the possibility of targeting the AhR to treat inflammatory and autoimmune diseases. Specifically, this review will discuss the current research involving natural and dietary AhR ligands. In addition, evidence indicating the potential use of these ligands in regulating inflammation in various diseases will be highlighted. The importance of the AhR in immunological processes can be illustrated by expression of this receptor on a majority of immune cell types. In addition, AhR signaling pathways have been reported to influence a number of genes responsible for mediating inflammation and other immune responses. As interest in the AhR and its ligands increases, it seems prudent to consolidate current research on the contributions of these ligands to immune regulation during the course of inflammatory diseases. PMID:23731446

  15. 76 FR 80447 - Eighth Meeting: RTCA Special Committee 219: Attitude and Heading Reference Systems (AHRS)

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-12-23

    ... Federal Aviation Administration Eighth Meeting: RTCA Special Committee 219: Attitude and Heading Reference...). ACTION: Notice of RTCA Special Committee 219: Attitude and Heading Reference Systems (AHRS). SUMMARY: The...: Attitude and Heading Reference Systems (AHRS). DATES: The meeting will be held January 24-26, 2012, from...

  16. 75 FR 49550 - Fifth Meeting: RTCA Special Committee 219: Attitude and Heading Reference System (AHRS)

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-08-13

    ... Federal Aviation Administration Fifth Meeting: RTCA Special Committee 219: Attitude and Heading Reference...: Notice of RTCA Special Committee 219: Attitude and Heading Reference System (AHRS). SUMMARY: The FAA is... Heading Reference System (AHRS). DATES: The meeting will be held September 14-16, 2010 from 9 a.m. to 5...

  17. Potential protective mechanisms of aryl hydrocarbon receptor (AHR) signaling in benign prostatic hyperplasia.

    PubMed

    Mehta, Vatsal; Vezina, Chad M

    2011-01-01

    The aryl hydrocarbon receptor (AHR) is an evolutionarily conserved ligand activated transcription factor best known for its role in mediating toxic responses to dioxin-like environmental contaminants. However, AHR signaling has also emerged as an active participant in processes of normal development and disease progression. Here, we review the role of AHR signaling in prostate development and disease processes, with a particular emphasis on benign prostatic hyperplasia (BPH). Inappropriate AHR activation has recently been associated with a decreased risk of symptomatic BPH in humans and has been shown to impair prostate development and disrupt endocrine signaling in rodents. We highlight known physiological responses to AHR activation in prostate and other tissues and discuss potential mechanisms by which it may act in adult human prostate to protect against symptomatic BPH. PMID:21684673

  18. Accurate Orientation Estimation Using AHRS under Conditions of Magnetic Distortion

    PubMed Central

    Yadav, Nagesh; Bleakley, Chris

    2014-01-01

    Low cost, compact attitude heading reference systems (AHRS) are now being used to track human body movements in indoor environments by estimation of the 3D orientation of body segments. In many of these systems, heading estimation is achieved by monitoring the strength of the Earth's magnetic field. However, the Earth's magnetic field can be locally distorted due to the proximity of ferrous and/or magnetic objects. Herein, we propose a novel method for accurate 3D orientation estimation using an AHRS, comprised of an accelerometer, gyroscope and magnetometer, under conditions of magnetic field distortion. The system performs online detection and compensation for magnetic disturbances, due to, for example, the presence of ferrous objects. The magnetic distortions are detected by exploiting variations in magnetic dip angle, relative to the gravity vector, and in magnetic strength. We investigate and show the advantages of using both magnetic strength and magnetic dip angle for detecting the presence of magnetic distortions. The correction method is based on a particle filter, which performs the correction using an adaptive cost function and by adapting the variance during particle resampling, so as to place more emphasis on the results of dead reckoning of the gyroscope measurements and less on the magnetometer readings. The proposed method was tested in an indoor environment in the presence of various magnetic distortions and under various accelerations (up to 3 g). In the experiments, the proposed algorithm achieves <2° static peak-to-peak error and <5° dynamic peak-to-peak error, significantly outperforming previous methods. PMID:25347584

  19. Aryl Hydrocarbon Receptor Ligand 5F 203 Induces Oxidative Stress That Triggers DNA Damage in Human Breast Cancer Cells

    PubMed Central

    McLean, Lancelot S.; Watkins, Cheri N.; Campbell, Petreena; Zylstra, Dain; Rowland, Leah; Amis, Louisa H.; Scott, Lia; Babb, Crystal E.; Livingston, W. Joel; Darwanto, Agus; Davis, Willie L.; Senthil, Maheswari; Sowers, Lawrence C.; Brantley, Eileen

    2015-01-01

    Breast tumors often show profound sensitivity to exogenous oxidative stress. Investigational agent 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (5F 203) induces aryl hydrocarbon receptor (AhR)-mediated DNA damage in certain breast cancer cells. Since AhR agonists often elevate intracellular oxidative stress, we hypothesize that 5F 203 increases reactive oxygen species (ROS) to induce DNA damage, which thwarts breast cancer cell growth. We found that 5F 203 induced single-strand break formation. 5F 203 enhanced oxidative DNA damage that was specific to breast cancer cells sensitive to its cytotoxic actions, as it did not increase oxidative DNA damage or ROS formation in nontumorigenic MCF-10A breast epithelial cells. In contrast, AhR agonist and procarcinogen benzo[a]pyrene and its metabolite, 1,6-benzo[a]pyrene quinone, induced oxidative DNA damage and ROS formation, respectively, in MCF-10A cells. In sensitive breast cancer cells, 5F 203 activated ROS-responsive kinases: c-Jun-N-terminal kinase (JNK) and p38 mitogen activated protein kinase (p38). AhR antagonists (alpha-naphthoflavone, CH223191) or antioxidants (N-acetyl-l-cysteine, EUK-134) attenuated 5F 203-mediated JNK and p38 activation, depending on the cell type. Pharmacological inhibition of AhR, JNK, or p38 attenuated 5F 203-mediated increases in intracellular ROS, apoptosis, and single-strand break formation. 5F 203 induced the expression of cytoglobin, an oxidative stress-responsive gene and a putative tumor suppressor, which was diminished with AhR, JNK, or p38 inhibition. Additionally, 5F 203-mediated increases in ROS production and cytoglobin were suppressed in AHR100 cells (AhR ligand-unresponsive MCF-7 breast cancer cells). Our data demonstrate 5F 203 induces ROS-mediated DNA damage at least in part via AhR, JNK, or p38 activation and modulates the expression of oxidative stress-responsive genes such as cytoglobin to confer its anticancer action. PMID:25781201

  20. INSIGHTS FROM AHR AND ARNT GENE KNOCKOUT STUDIES REGARDING RESPONSES TO TCDD AND REGULATION OF NORMAL EMBRYONIC DEVELOPMENT

    EPA Science Inventory

    The aryl hydrocarbon receptor (AhR) and the AhR nuclear translocator (ARNT) are members of the Per-ARNT-Sim (PAS) family of proteins. The AhR binds members of the chemical family that includes dioxins, furans and coplanar polychlorinated biphenyls (PCBs). A ligand-AhR-ARNT comp...

  1. ACTH Antagonists.

    PubMed

    Clark, Adrian John; Forfar, Rachel; Hussain, Mashal; Jerman, Jeff; McIver, Ed; Taylor, Debra; Chan, Li

    2016-01-01

    Adrenocorticotropin (ACTH) acts via a highly selective receptor that is a member of the melanocortin receptor subfamily of type 1 G protein-coupled receptors. The ACTH receptor, also known as the melanocortin 2 receptor (MC2R), is unusual in that it is absolutely dependent on a small accessory protein, melanocortin receptor accessory protein (MRAP) for cell surface expression and function. ACTH is the only known naturally occurring agonist for this receptor. This lack of redundancy and high degree of ligand specificity suggests that antagonism of this receptor could provide a useful therapeutic aid and a potential investigational tool. Clinical situations in which this could be useful include (1) Cushing's disease and ectopic ACTH syndrome - especially while preparing for definitive treatment of a causative tumor, or in refractory cases, or (2) congenital adrenal hyperplasia - as an adjunct to glucocorticoid replacement. A case for antagonism in other clinical situations in which there is ACTH excess can also be made. In this article, we will explore the scientific and clinical case for an ACTH antagonist, and will review the evidence for existing and recently described peptides and modified peptides in this role. PMID:27547198

  2. ACTH Antagonists

    PubMed Central

    Clark, Adrian John; Forfar, Rachel; Hussain, Mashal; Jerman, Jeff; McIver, Ed; Taylor, Debra; Chan, Li

    2016-01-01

    Adrenocorticotropin (ACTH) acts via a highly selective receptor that is a member of the melanocortin receptor subfamily of type 1 G protein-coupled receptors. The ACTH receptor, also known as the melanocortin 2 receptor (MC2R), is unusual in that it is absolutely dependent on a small accessory protein, melanocortin receptor accessory protein (MRAP) for cell surface expression and function. ACTH is the only known naturally occurring agonist for this receptor. This lack of redundancy and high degree of ligand specificity suggests that antagonism of this receptor could provide a useful therapeutic aid and a potential investigational tool. Clinical situations in which this could be useful include (1) Cushing’s disease and ectopic ACTH syndrome – especially while preparing for definitive treatment of a causative tumor, or in refractory cases, or (2) congenital adrenal hyperplasia – as an adjunct to glucocorticoid replacement. A case for antagonism in other clinical situations in which there is ACTH excess can also be made. In this article, we will explore the scientific and clinical case for an ACTH antagonist, and will review the evidence for existing and recently described peptides and modified peptides in this role. PMID:27547198

  3. In Silico Identification of an Aryl Hydrocarbon Receptor Antagonist with Biological Activity In Vitro and In Vivo

    PubMed Central

    Parks, Ashley J.; Pollastri, Michael P.; Hahn, Mark E.; Stanford, Elizabeth A.; Novikov, Olga; Franks, Diana G.; Haigh, Sarah E.; Narasimhan, Supraja; Ashton, Trent D.; Hopper, Timothy G.; Kozakov, Dmytro; Beglov, Dimitri; Vajda, Sandor; Schlezinger, Jennifer J.

    2014-01-01

    The aryl hydrocarbon receptor (AHR) is critically involved in several physiologic processes, including cancer progression and multiple immune system activities. We, and others, have hypothesized that AHR modulators represent an important new class of targeted therapeutics. Here, ligand shape–based virtual modeling techniques were used to identify novel AHR ligands on the basis of previously identified chemotypes. Four structurally unique compounds were identified. One lead compound, 2-((2-(5-bromofuran-2-yl)-4-oxo-4H-chromen-3-yl)oxy)acetamide (CB7993113), was further tested for its ability to block three AHR-dependent biologic activities: triple-negative breast cancer cell invasion or migration in vitro and AHR ligand–induced bone marrow toxicity in vivo. CB7993113 directly bound both murine and human AHR and inhibited polycyclic aromatic hydrocarbon (PAH)– and TCDD-induced reporter activity by 75% and 90% respectively. A novel homology model, comprehensive agonist and inhibitor titration experiments, and AHR localization studies were consistent with competitive antagonism and blockade of nuclear translocation as the primary mechanism of action. CB7993113 (IC50 3.3 × 10−7 M) effectively reduced invasion of human breast cancer cells in three-dimensional cultures and blocked tumor cell migration in two-dimensional cultures without significantly affecting cell viability or proliferation. Finally, CB7993113 effectively inhibited the bone marrow ablative effects of 7,12-dimethylbenz[a]anthracene in vivo, demonstrating drug absorption and tissue distribution leading to pharmacological efficacy. These experiments suggest that AHR antagonists such as CB7993113 may represent a new class of targeted therapeutics for immunomodulation and/or cancer therapy. PMID:25159092

  4. Identification and expression of aryl hydrocarbon receptors (AhR1 and AhR2) provide insight in an evolutionary context regarding sensitivity of white sturgeon (Acipenser transmontanus) to dioxin-like compounds.

    PubMed

    Doering, Jon A; Wiseman, Steve; Beitel, Shawn C; Giesy, John P; Hecker, Markus

    2014-05-01

    Sturgeons are ancient fishes, which are endangered in many parts of the world. Due to their benthic nature and longevity, sturgeon are at great risk of exposure to bioaccumulative contaminants such as dioxin-like compounds (DLCs). Despite their endangered status, little research has been conducted to characterize the relative sensitivity of sturgeons to DLCs. Proper assessment of risk of DLCs posed to these fishes therefore, requires a better understanding of this sensitivity and the factors that are driving it. Adverse effects associated with exposure to DLCs are mediated by the aryl hydrocarbon receptor (AhR). This study identified and characterized two distinct AhRs, AhR1 and AhR2, in white sturgeon (Acipenser transmontanus) for the first time as a first step in studying the relative sensitivities of sturgeons to DLCs. Furthermore, tissue-specific expression of both AhRs under basal conditions and in response to exposure to the model DLC, β-naphthoflavone (βNF), was determined. The sequence of amino acids of AhR1 of white sturgeon had greater similarity to AhRs of tetrapods, including amphibians, birds, and mammals, than to AhR1s of other fishes. The sequence of amino acids in the ligand binding domain of the AhR1 had greater than 80% similarity to AhRs known to bind DLCs and was less similar to AhRs not known to bind DLCs. AhR2 of white sturgeon had greatest similarity to AhR2 of other fishes. Profiles of expression of AhR1 and AhR2 in white sturgeon were distinct from those known in other fishes and appear more similar to profiles observed in birds. Expressions of both AhR1 and AhR2 of white sturgeon were greatest in liver and heart, which are target organs for DLCs. Furthermore, abundances of transcripts of AhR1 and AhR2 in all tissues from white sturgeon were greater than controls (up to 35-fold) following exposure to βNF. Based upon both AhRs having similar abundances of transcript in target organs of DLC toxicity, both AhRs being up-regulated following

  5. Aryl hydrocarbon receptor-dependent regulation of miR-196a expression controls lung fibroblast apoptosis but not proliferation

    SciTech Connect

    Hecht, Emelia; Zago, Michela; Sarill, Miles; Rico de Souza, Angela; Gomez, Alvin; Matthews, Jason; Hamid, Qutayba; Eidelman, David H.; Baglole, Carolyn J.

    2014-11-01

    The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor implicated in the regulation of apoptosis and proliferation. Although activation of the AhR by xenobiotics such as dioxin inhibits the cell cycle and control apoptosis, paradoxically, AhR expression also promotes cell proliferation and survival independent of exogenous ligands. The microRNA (miRNA) miR-196a has also emerged as a regulator of proliferation and apoptosis but a relationship between the AhR and miR-196a is not known. Therefore, we hypothesized that AhR-dependent regulation of endogenous miR-196a expression would promote cell survival and proliferation. Utilizing lung fibroblasts from AhR deficient (AhR{sup −/−}) and wild-type (AhR{sup +/+}) mice, we show that there is ligand-independent regulation of miRNA, including low miR-196a in AhR{sup −/−} cells. Validation by qRT-PCR revealed a significant decrease in basal expression of miR-196a in AhR{sup −/−} compared to AhR{sup +/+} cells. Exposure to AhR agonists benzo[a]pyrene (B[a]P) and FICZ as well as AhR antagonist CH-223191 decreased miR-196a expression in AhR{sup +/+} fibroblasts concomitant with decreased AhR protein levels. There was increased proliferation only in AhR{sup +/+} lung fibroblasts in response to serum, corresponding to a decrease in p27{sup KIP1} protein, a cyclin-dependent kinase inhibitor. Increasing the cellular levels of miR-196a had no effect on proliferation or expression of p27{sup KIP1} in AhR{sup −/−} fibroblasts but attenuated cigarette smoke-induced apoptosis. This study provides the first evidence that AhR expression is essential for the physiological regulation of cellular miRNA levels- including miR-196a. Future experiments designed to elucidate the functional relationship between the AhR and miR-196a may delineate additional novel ligand-independent roles for the AhR. - Highlights: • The AhR controls proliferation and apoptosis in lung cells. • The AhR regulates the

  6. Estrogenic and AhR activities in dissolved phase and suspended solids from wastewater treatment plants.

    PubMed

    Dagnino, Sonia; Gomez, Elena; Picot, Bernadette; Cavaillès, Vincent; Casellas, Claude; Balaguer, Patrick; Fenet, Hélène

    2010-05-15

    The distribution of estrogen receptor (ERalpha) and Aryl Hydrocarbon Receptor (AhR) activities between the dissolved phase and suspended solids were investigated during wastewater treatment. Three wastewater treatment plants with different treatment technologies (waste stabilization ponds (WSPs), trickling filters (TFs) and activated sludge supplemented with a biofilter system (ASB)) were sampled. Estrogenic and AhR activities were detected in both phases in influents and effluents. Estrogenic and AhR activities in wastewater influents ranged from 41.8 to 79 ng/L E(2) Eq. and from 37.9 to 115.5 ng/L TCDD Eq. in the dissolved phase and from 5.5 to 88.6 ng/g E(2) Eq. and from 15 to 700 ng/g TCDD Eq. in the suspended solids. For both activities, WSP showed greater or similar removal efficiency than ASB and both were much more efficient than TF which had the lowest removal efficiency. Moreover, our data indicate that the efficiency of removal of ER and AhR activities from the suspended solid phase was mainly due to removal of suspended solids. Indeed, ER and AhR activities were detected in the effluent suspended solid phase indicating that suspended solids, which are usually not considered in these types of studies, contribute to environmental contamination by endocrine disrupting compounds and should therefore be routinely assessed for a better estimation of the ER and AhR activities released in the environment. PMID:20303573

  7. Pityriazepin and other potent AhR ligands isolated from Malassezia furfur yeast.

    PubMed

    Mexia, Nikitia; Gaitanis, Georgios; Velegraki, Aristea; Soshilov, Anatoly; Denison, Michael S; Magiatis, Prokopios

    2015-04-01

    Malassezia furfur yeast strains isolated from diseased human skin preferentially biosynthesize indole alkaloids which can be detected in the human skin and are highly potent activators of the aryl hydrocarbon receptor (AhR) and AhR-dependent gene expression. Chemical analysis of an EtOAc extract of a M. furfur strain obtained from diseased human skin and grown on l-tryptophan agar revealed several known AhR active tryptophan metabolites along with a previously unidentified compound, pityriazepin. While its structure resembled that of the known alkaloid pityriacitrin, the comprised pyridine ring had been transformed into an azepinone. The indoloazepinone scaffold of pityriazepin is extremely rare in nature and has only been reported once previously. Pityriazepin, like the other isolated compounds, was found to be a potent activator of the AhR-dependent reporter gene assay in recombinant cell lines derived from four different species, although significant species differences in relative potency were observed. The ability of pityriazepin to competitively bind to the AhR and directly stimulate AhR DNA binding classified it as a new naturally-occurring potent AhR agonist. M. furfur produces an expanded collection of extremely potent naturally occurring AhR agonists, which produce their biological effects in a species-specific manner. PMID:25721496

  8. Pityriazepin and other potent AhR ligands isolated from Malassezia furfur yeast

    PubMed Central

    Mexia, Nikitia; Gaitanis, George; Velegraki, Aristea; Soshilov, Anatoly; Denison, Michael S.; Magiatis, Prokopios

    2015-01-01

    Malassezia furfur yeast strains isolated from diseased human skin preferentially biosynthesize indole alkaloids which can be detected in human skin and are highly potent activators of the aryl hydrocarbon receptor (AhR) and AhR-dependent gene expression. Chemical analysis of an EtOAc extract of a M. furfur strain obtained from diseased human skin and grown on L-tryptophan agar revealed several known AhR active tryptophan metabolites along with a previously unidentified compound, pityriazepin. While its structure resembled that of the known alkaloid pityriacitrin, the comprised pyridine ring had been transformed into an azepinone. The indoloazepinone scaffold of pityriazepin is extremely rare in nature and has only been reported once previously. Pityriazepin, like the other isolated compounds, was found to be a potent activator of the AhR-dependent reporter gene assays in recombinant cell lines derived from four different species, although significant species differences in relative potency was observed. The ability of pityriazepin to competitively bind to the AhR and directly stimulate AhR DNA binding classified it as a new naturally-occurring potent AhR agonist. Malassezia furfur produces an expanded collection of extremely potent naturally occurring AhR agonists, which produce their biological effects in a species-specific manner.1 PMID:25721496

  9. Characterization testing of a 40 Ahr bipolar nickel hydrogen battery

    NASA Technical Reports Server (NTRS)

    Brewer, Jeffrey C.; Manzo, Michelle A.; Gahn, Randall F.

    1989-01-01

    In a continuing effort to develop NiH2 bipolar technology to a point where it can be used efficiently in space flight, testing of a second 40 Ahr, 10-cell bipolar battery has begun. This battery has undergone extensive characterization testing to determine the effects of such operating parameters as charge and discharge rates, temperature, and pressure. The fundamental design of this actively cooled bipolar battery is the same as the first battery. Most of the individual components, however, are from different manufacturers. Different testing procedures as well as certain unique battery characteristics make it difficult to directly compare the two sets of results. In general, the performance of this battery throughout characterization produced expected results. The main differences seen between the first and second batteries occurred during the high-rate discharge portion of the test matrix. The first battery also had poor high-rate discharge results, although better than those of the second battery. Minor changes were made to the battery frame design used for the first battery in an attempt to allow better gas access to the reaction sites for the second build and hopefully improve performance. The changes, however, did not improve the performance of the second battery and could have possibly contributed to the poorer performance that was observed. There are other component differences that could have contributed to the poorer performance of the second battery. The H2 electrode in the second battery was constructed with a Goretex backing which could have limited the high-rate current flow. The gas screen in the second battery had a larger mesh which again could have limited the high-rate current flow. Small scale 2 x 2 batteries are being tested to evaluate the effects of the component variations.

  10. A constitutive active MAPK/ERK pathway due to BRAFV600E positively regulates AHR pathway in PTC.

    PubMed

    Occhi, Gianluca; Barollo, Susi; Regazzo, Daniela; Bertazza, Loris; Galuppini, Francesca; Guzzardo, Vincenza; Jaffrain-Rea, Marie Lise; Vianello, Federica; Ciato, Denis; Ceccato, Filippo; Watutantrige-Fernando, Sara; Bisognin, Andrea; Bortoluzzi, Stefania; Pennelli, Gianmaria; Boscaro, Marco; Scaroni, Carla; Mian, Caterina

    2015-10-13

    The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor mediating the toxicity and tumor-promoting properties of dioxin. AHR has been reported to be overexpressed and constitutively active in a variety of solid tumors, but few data are currently available concerning its role in thyroid cancer. In this study we quantitatively explored a series of 51 paired-normal and papillary thyroid carcinoma (PTC) tissues for AHR-related genes. We identified an increased AHR expression/activity in PTC, independently from its nuclear dimerization partner and repressor but strictly related to a constitutive active MAPK/ERK pathway. The AHR up-regulation followed by an increased expression of AHR target genes was confirmed by a meta-analysis of published microarray data, suggesting a ligand-independent active AHR pathway in PTC. In-vitro studies using a PTC-derived cell line (BCPAP) and HEK293 cells showed that BRAFV600E may directly modulate AHR localization, induce AHR expression and activity in an exogenous ligand-independent manner. The AHR pathway might represent a potential novel therapeutic target for PTC in the clinical practice. PMID:26392334

  11. The AhR agonist VAF347 augments retinoic acid-induced differentiation in leukemia cells.

    PubMed

    Ibabao, Christopher N; Bunaciu, Rodica P; Schaefer, Deanna M W; Yen, Andrew

    2015-01-01

    In binary cell-fate decisions, driving one lineage and suppressing the other are conjoined. We have previously reported that aryl hydrocarbon receptor (AhR) promotes retinoic acid (RA)-induced granulocytic differentiation of lineage bipotent HL-60 myeloblastic leukemia cells. VAF347, an AhR agonist, impairs the development of CD14(+)CD11b(+) monocytes from granulo-monocytic (GM) stage precursors. We thus hypothesized that VAF347 propels RA-induced granulocytic differentiation and impairs D3-induced monocytic differentiation of HL-60 cells. Our results show that VAF347 enhanced RA-induced cell cycle arrest, CD11b integrin expression and neutrophil respiratory burst. Granulocytic differentiation is known to be driven by MAPK signaling events regulated by Fgr and Lyn Src-family kinases, the CD38 cell membrane receptor, the Vav1 GEF, the c-Cbl adaptor, as well as AhR, all of which are embodied in a putative signalsome. We found that the VAF347 AhR ligand regulates the signalsome. VAF347 augments RA-induced expression of AhR, Lyn, Vav1, and c-Cbl as well as p47(phox). Several interactions of partners in the signalsome appear to be enhanced: Fgr interaction with c-Cbl, CD38, and with pS259c-Raf and AhR interaction with c-Cbl and Lyn. Thus, we report that, while VAF347 impedes monocytic differentiation induced by 1,25-dihydroxyvitamin D3, VAF347 promotes RA-induced differentiation. This effect seems to involve but not to be limited to Lyn, Vav1, c-Cbl, AhR, and Fgr. PMID:25941627

  12. An altered hydrotropic response (ahr1) mutant of Arabidopsis recovers root hydrotropism with cytokinin

    PubMed Central

    Saucedo, Manuel; Ponce, Georgina; Campos, María Eugenia; Eapen, Delfeena; García, Edith; Luján, Rosario; Sánchez, Yoloxóchitl; Cassab, Gladys I.

    2012-01-01

    Roots are highly plastic and can acclimate to heterogeneous and stressful conditions. However, there is little knowledge of the effect of moisture gradients on the mechanisms controlling root growth orientation and branching, and how this mechanism may help plants to avoid drought responses. The aim of this study was to isolate mutants of Arabidopsis thaliana with altered hydrotropic responses. Here, altered hydrotropic response 1 (ahr1), a semi-dominant allele segregating as a single gene mutation, was characterized. ahr1 directed the growth of its primary root towards the source of higher water availability and developed an extensive root system over time. This phenotype was intensified in the presence of abscisic acid and was not observed if ahr1 seedlings were grown in a water stress medium without a water potential gradient. In normal growth conditions, primary root growth and root branching of ahr1 were indistinguishable from those of the wild type (wt). The altered hydrotropic growth of ahr1 roots was confirmed when the water-rich source was placed at an angle of 45° from the gravity vector. In this system, roots of ahr1 seedlings grew downward and did not display hydrotropism; however, in the presence of cytokinins, they exhibited hydrotropism like those of the wt, indicating that cytokinins play a critical role in root hydrotropism. The ahr1 mutant represents a valuable genetic resource for the study of the effects of cytokinins in the differential growth of hydrotropism and control of lateral root formation during the hydrotropic response. PMID:22442413

  13. Regulation of zebrafish CYP3A65 transcription by AHR2

    SciTech Connect

    Chang, Chin-Teng; Chung, Hsin-Yu; Su, Hsiao-Ting; Tseng, Hua-Pin; Tzou, Wen-Shyong; Hu, Chin-Hwa

    2013-07-15

    CYP3A proteins are the most abundant CYPs in the liver and intestines, and they play a pivotal role in drug metabolism. In mammals, CYP3A genes are induced by various xenobiotics through processes mediated by PXR. We previously identified zebrafish CYP3A65 as a CYP3A ortholog that is constitutively expressed in gastrointestinal tissues, and is upregulated by treatment with dexamethasone, rifampicin or tetrachlorodibenzo-p-dioxin (TCDD). However, the underlying mechanism of TCDD-mediated CYP3A65 transcription is unclear. Here we generated two transgenic zebrafish, Tg(CYP3A65S:EGFP) and Tg(CYP3A65L:EGFP), which contain 2.1 and 5.4 kb 5′ flanking sequences, respectively, of the CYP3A65 gene upstream of EGFP. Both transgenic lines express EGFP in larval gastrointestinal tissues in a pattern similar to that of the endogenous CYP3A65 gene. Moreover, EGFP expression can be significantly induced by TCDD exposure during the larval stage. In addition, EGFP expression can be stimulated by kynurenine, a putative AHR ligand produced during tryptophan metabolism. AHRE elements in the upstream regulatory region of the CYP3A65 gene are indispensible for basal and TCDD-induced transcription. Furthermore, the AHR2 DNA and ligand-binding domains are required to mediate effective CYP3A65 transcription. AHRE sequences are present in the promoters of many teleost CYP3 genes, but not of mammalian CYP3 genes, suggesting that AHR/AHR2-mediated transcription is likely a common regulatory mechanism for teleost CYP3 genes. It may also reflect the different environments that terrestrial and aquatic organisms encounter. - Highlights: • Tg(CYP3A65:EGFP) and CYP3A65 exhibits identical expression pattern. • CYP3A65 can be significantly induced by TCDD or kynurenine. • The AHRE elements are required to mediate CYP3A65 transcription. • The AHR2 DNA and ligand-binding domains are required for CYP3A65 transcription. • AHRE elements are present in many teleost CYP3 genes, but not in

  14. The Evolving Role of the Aryl Hydrocarbon Receptor (AHR) in the Normophysiology of Hematopoiesis

    PubMed Central

    Lindsey, Stephan; Papoutsakis, Eleftherios T.

    2012-01-01

    In addition to its role as a toxicological signal mediator, the Aryl Hydrocarbon Receptor (AHR) is also a transcription factor known to regulate cellular responses to oxidative stress and inflammation through transcriptional regulation of molecules involved in the signaling of nucear factor-erythroid 2-related factor-2 (Nrf2), p53 (TRP53), retinoblastoma (RB1), and NFκB. Recent research suggests that AHR activation of these signaling pathways may provide the molecular basis for understanding AHR’s evolving role in endogenous developmental functions during hematopoietic stem-cell maintenance and differentiation. Recent developments into the hematopoietic roles for AHR are reviewed, aiming to reconcile divergent findings as to the endogenous function of AHR in hematopoiesis. Potential mechanistic explanations for AHR’s involvement in hematopoietic differentiation are discussed, focusing on its known role as a cell cycle mediator and its interactions with Hypoxia-inducible transcription factor-1 alpha (HIF1-α). Understanding the physiological mechanisms of AHR activation and signaling have far reaching implications ranging from explaining the action of various toxicological agents to providing novel ways to expand stem cell populations ex vivo for use in transplant therapies. PMID:22628113

  15. Tryptamine serves as a proligand of the AhR transcriptional pathway whose activation is dependent of monoamine oxidases.

    PubMed

    Vikström Bergander, Linda; Cai, Wen; Klocke, Bernward; Seifert, Martin; Pongratz, Ingemar

    2012-09-01

    The function of the aryl hydrocarbon receptor (AhR) in mediating the biological effect to environmental pollutants is well established. However, accumulated evidence indicates a wide range of physiological and pathological functions mediated by the AhR, suggesting the existence of endogenous AhR ligand(s). The nature of an AhR ligand remain elusive; however, it is known that the AhR is activated by several compounds, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin or the tryptophan photoproduct 6-formylindolo[3,2-b]carbazole. In this study, we show that physiological concentrations of tryptamine (TA) lead to induction of cytochrome P4501A1 transcription through an AhR-dependent mechanism. In addition, we show that activation of the AhR by TA requires a functional monoamino oxidase system, suggesting that TA acts as an AhR proligand possibly by converting to a high-affinity AhR ligand. Taken together, we show a possible mechanism, through which AhR signaling is activated by endogenous conversion of TA involving monoamine oxidases. PMID:22865928

  16. Genetic variation at aryl hydrocarbon receptor (AHR) loci in populations of Atlantic killifish (Fundulus heteroclitus) inhabiting polluted and reference habitats

    PubMed Central

    2014-01-01

    Background The non-migratory killifish Fundulus heteroclitus inhabits clean and polluted environments interspersed throughout its range along the Atlantic coast of North America. Several populations of this species have successfully adapted to environments contaminated with toxic aromatic hydrocarbon pollutants such as polychlorinated biphenyls (PCBs). Previous studies suggest that the mechanism of resistance to these and other “dioxin-like compounds” (DLCs) may involve reduced signaling through the aryl hydrocarbon receptor (AHR) pathway. Here we investigated gene diversity and evidence for positive selection at three AHR-related loci (AHR1, AHR2, AHRR) in F. heteroclitus by comparing alleles from seven locations ranging over 600 km along the northeastern US, including extremely polluted and reference estuaries, with a focus on New Bedford Harbor (MA, USA), a PCB Superfund site, and nearby reference sites. Results We identified 98 single nucleotide polymorphisms within three AHR-related loci among all populations, including synonymous and nonsynonymous substitutions. Haplotype distributions were spatially segregated and F-statistics suggested strong population genetic structure at these loci, consistent with previous studies showing strong population genetic structure at other F. heteroclitus loci. Genetic diversity at these three loci was not significantly different in contaminated sites as compared to reference sites. However, for AHR2 the New Bedford Harbor population had significant FST values in comparison to the nearest reference populations. Tests for positive selection revealed ten nonsynonymous polymorphisms in AHR1 and four in AHR2. Four nonsynonymous SNPs in AHR1 and three in AHR2 showed large differences in base frequency between New Bedford Harbor and its reference site. Tests for isolation-by-distance revealed evidence for non-neutral change at the AHR2 locus. Conclusion Together, these data suggest that F. heteroclitus populations in reference

  17. In silico predictive studies of mAHR congener binding using homology modelling and molecular docking.

    PubMed

    Panda, Roshni; Cleave, A Suneetha Susan; Suresh, P K

    2014-09-01

    The aryl hydrocarbon receptor (AHR) is one of the principal xenobiotic, nuclear receptor that is responsible for the early events involved in the transcription of a complex set of genes comprising the CYP450 gene family. In the present computational study, homology modelling and molecular docking were carried out with the objective of predicting the relationship between the binding efficiency and the lipophilicity of different polychlorinated biphenyl (PCB) congeners and the AHR in silico. Homology model of the murine AHR was constructed by several automated servers and assessed by PROCHECK, ERRAT, VERIFY3D and WHAT IF. The resulting model of the AHR by MODWEB was used to carry out molecular docking of 36 PCB congeners using PatchDock server. The lipophilicity of the congeners was predicted using the XLOGP3 tool. The results suggest that the lipophilicity influences binding energy scores and is positively correlated with the same. Score and Log P were correlated with r = +0.506 at p = 0.01 level. In addition, the number of chlorine (Cl) atoms and Log P were highly correlated with r = +0.900 at p = 0.01 level. The number of Cl atoms and scores also showed a moderate positive correlation of r = +0.481 at p = 0.01 level. To the best of our knowledge, this is the first study employing PatchDock in the docking of AHR to the environmentally deleterious congeners and attempting to correlate structural features of the AHR with its biochemical properties with regards to PCBs. The result of this study are consistent with those of other computational studies reported in the previous literature that suggests that a combination of docking, scoring and ranking organic pollutants could be a possible predictive tool for investigating ligand-mediated toxicity, for their subsequent validation using wet lab-based studies. PMID:23081860

  18. Regulation of zebrafish CYP3A65 transcription by AHR2.

    PubMed

    Chang, Chin-Teng; Chung, Hsin-Yu; Su, Hsiao-Ting; Tseng, Hua-Pin; Tzou, Wen-Shyong; Hu, Chin-Hwa

    2013-07-15

    CYP3A proteins are the most abundant CYPs in the liver and intestines, and they play a pivotal role in drug metabolism. In mammals, CYP3A genes are induced by various xenobiotics through processes mediated by PXR. We previously identified zebrafish CYP3A65 as a CYP3A ortholog that is constitutively expressed in gastrointestinal tissues, and is upregulated by treatment with dexamethasone, rifampicin or tetrachlorodibenzo-p-dioxin (TCDD). However, the underlying mechanism of TCDD-mediated CYP3A65 transcription is unclear. Here we generated two transgenic zebrafish, Tg(CYP3A65S:EGFP) and Tg(CYP3A65L:EGFP), which contain 2.1 and 5.4 kb 5' flanking sequences, respectively, of the CYP3A65 gene upstream of EGFP. Both transgenic lines express EGFP in larval gastrointestinal tissues in a pattern similar to that of the endogenous CYP3A65 gene. Moreover, EGFP expression can be significantly induced by TCDD exposure during the larval stage. In addition, EGFP expression can be stimulated by kynurenine, a putative AHR ligand produced during tryptophan metabolism. AHRE elements in the upstream regulatory region of the CYP3A65 gene are indispensible for basal and TCDD-induced transcription. Furthermore, the AHR2 DNA and ligand-binding domains are required to mediate effective CYP3A65 transcription. AHRE sequences are present in the promoters of many teleost CYP3 genes, but not of mammalian CYP3 genes, suggesting that AHR/AHR2-mediated transcription is likely a common regulatory mechanism for teleost CYP3 genes. It may also reflect the different environments that terrestrial and aquatic organisms encounter. PMID:23624173

  19. Screening a mouse liver gene expression compendium identifies modulators of the aryl hydrocarbon receptor (AhR).

    PubMed

    Oshida, Keiyu; Vasani, Naresh; Thomas, Russell S; Applegate, Dawn; Gonzalez, Frank J; Aleksunes, Lauren M; Klaassen, Curtis D; Corton, J Christopher

    2015-10-01

    The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that mediates the biological and toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), dioxin-like compounds (DLC) as well as some drugs and endogenous tryptophan metabolites. Short-term activation of AhR can lead to hepatocellular steatosis, and chronic activation can lead to liver cancer in mice and rats. Analytical approaches were developed to identify biosets in a genomic database in which AhR activity was altered. A set of 63 genes was identified (the AhR gene expression biomarker) that was dependent on AhR for regulation after exposure to TCDD or benzo[a]pyrene and includes the known AhR targets Cyp1a1 and Cyp1b1. A fold-change rank-based test (Running Fisher's test; p-value ≤ 10(-4)) was used to evaluate the similarity between the AhR biomarker and a test set of 37 and 41 biosets positive or negative, respectively for AhR activation. The test resulted in a balanced accuracy of 95%. The rank-based test was used to identify factors that activate or suppress AhR in an annotated mouse liver/mouse primary hepatocyte gene expression database of ∼ 1850 comparisons. In addition to the expected activation of AhR by TCDD and DLC, AhR was activated by AP20189 and phenformin. AhR was suppressed by phenobarbital and 1,4-Bis[2-(3,5-dichloropyridyloxy)] benzene (TCPOBOP) in a constitutive activated receptor (CAR)-dependent manner and pregnenolone-16α-carbonitrile in a pregnane X receptor (PXR)-dependent manner. Inactivation of individual genes in nullizygous models led to AhR activation (Pxr, Ghrhr, Taf10) or suppression (Ahr, Ilst6st, Hnf1a). This study describes a novel screening strategy for identifying factors in mouse liver that perturb AhR in a gene expression compendium. PMID:26215100

  20. Toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in developing red seabream (Pagrus major) embryo: an association of morphological deformities with AHR1, AHR2 and CYP1A expressions.

    PubMed

    Yamauchi, Masanobu; Kim, Eun-Young; Iwata, Hisato; Shima, Yasuhiro; Tanabe, Shinsuke

    2006-11-16

    The toxicity of dioxins such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is mainly mediated by the aryl hydrocarbon receptor (AHR), which regulates the multiple target genes including cytochrome P4501A (CYP1A). In general, bony fishes, which possess at least two distinct AHRs are one of the most sensitive vertebrates to TCDD in early life stage. However, the physiological and toxicological roles of piscine multiple AHRs are not fully understood, especially in marine fish. To understand which AHR is responsible for TCDD toxicity in a marine fish species, we characterized the early life stage toxicity related to the expression of AHRs and CYP1A in red seabream (Pagrus major). The embryos at 10h post-fertilization (hpf) were treated with 0-100 microg/L TCDD for 80 min waterborne exposure. TCDD dose-dependently elicited developmental toxicities including mortality, yolk sac edema, retarded body growth, spinal deformity, reduced heart rate, shortened snout, underdeveloped fin, heart, and lower jaw. Intriguingly, hemorrhage and pericardium edema, typical TCDD developmental defects noticed in other fish species, were not found in red seabream until test termination. The EC(egg)50s for yolk sac edema, underdeveloped fin, and spinal deformity were 170, 240, and 340 pg/g, respectively. The LC(egg)50 was 360 pg/g embryo, indicating that this species is one of the most sensitive fishes to TCDD toxicity. The expression levels of rsAHR1, rsAHR2 and CYP1A mRNAs were also determined in different developmental stages. The rsAHR2 mRNA expression dose-dependently increased following TCDD exposure, while rsAHR1 mRNA level was not altered. Level of rsAHR2 mRNA measured by two-step real-time PCR was 30 times higher than rsAHR1 in embryos treated with the highest dose. Temporal patterns of rsAHR2 and CYP1A mRNAs were similar in TCDD-treated embryos, representing a significant positive correlation between rsAHR2 and CYP1A mRNA levels, but not between rsAHR1 and CYP1A. In comparison of

  1. Metabolic control of type 1 regulatory (Tr1) cell differentiation by AHR and HIF1-α

    PubMed Central

    Mascanfroni, Ivan D.; Takenaka, Maisa C.; Yeste, Ada; Patel, Bonny; Wu, Yan; Kenison, Jessica E.; Siddiqui, Shafiuddin; Basso, Alexandre S.; Otterbein, Leo E.; Pardoll, Drew M.; Pan, Fan; Priel, Avner; Clish, Clary B.; Robson, Simon C.; Quintana, Francisco J.

    2015-01-01

    Our understanding of the pathways that regulate lymphocyte metabolism, as well as the effects of metabolism and its products on the immune response, is still limited. We report that a metabolic program controlled by the transcription factors hypoxia inducible factor-1α (HIF1-α) and aryl hydrocarbon receptor (AHR) supports the differentiation of type 1 regulatory (Tr1) cells. HIF1-α controls the early metabolic reprograming of Tr1 cells. At later time points, AHR promotes HIF1-α degradation and takes control of Tr1 cell metabolism. Extracellular adenosine triphosphate (eATP) and hypoxia, linked to inflammation, trigger AHR inactivation by HIF1-α and inhibit Tr1 cell differentiation. Conversely, CD39 promotes Tr1 cell differentiation by depleting eATP. CD39 also contributes to Tr1 suppressive activity by generating adenosine in cooperation with CD73 expressed by responder T cells and antigen presenting cells. These results suggest that HIF1-α and AHR integrate immunological, metabolic and environmental signals to regulate the immune response. PMID:26005855

  2. EXPRESSION OF AHR AND ARNT MRNA IN CULTURED HUMAN ENDOMETRIAL EXPLANTS EXPOSED TO TCDD

    EPA Science Inventory

    Expression of AhR and ARNT mRNA in cultured human endometrial explants exposed to TCDD.

    Pitt JA, Feng L, Abbott BD, Schmid J, Batt RE, Costich TG, Koury ST, Bofinger DP.

    Curriculum in Toxicology, University of North Carolina, Chapel Hill, NC 27599, USA.

    Endom...

  3. AHR2 mediates cardiac teratogenesis of polycyclic aromatic hydrocarbons and PCB-126 in Atlantic killifish (Fundulus heteroclitus)

    PubMed Central

    Clark, Bryan W.; Matson, Cole W.; Jung, Dawoon; Di Giulio, Richard T.

    2010-01-01

    Exposure of developing fish to polycyclic aromatic hydrocarbons (PAHs) and halogenated aromatic hydrocarbons (HAHs) results in a suite of defects including cardiac malformation, pericardial and yolk sac edema, craniofacial defects, and hemorrhaging. Several populations of Atlantic killifish or mummichog (Fundulus heteroclitus) on the Atlantic coast of the United States are resistant to the developmental and acute toxicity caused by PAHs and HAHs; this has made Fundulus a valuable model for studying aryl hydrocarbon sensitivity and adaptation. In order to further increase the utility of Fundulus, better understanding of the components of the molecular pathways governing aryl hydrocarbon response in Fundulus is required. The aryl hydrocarbon receptor (AHR) is known to mediate many of the toxic responses to PAHs and HAHs. A single AHR has been identified in mammals, but Fundulus has two AHRs and their relative roles are not clear. In the current study, translation-blocking and splice-junction morpholino gene knockdown was used to determine the roles of AHR1 and AHR2 in mediating cardiac teratogenesis induced by β-naphthoflavone (BNF), benzo[k]fluoranthene (BkF), and 3, 3′, 4, 4′, 5-pentachlorobiphenyl (PCB-126). Here we report that AHR2 and not AHR1 knockdown resulted in rescue of teratogenicity induced by BNF, BkF, and PCB-126. These data demonstrate that AHR2 is the primary mediator of cardiac teratogenesis caused by multiple aryl hydrocarbons in Fundulus and suggest that suppression of the AHR pathway through modulation of AHR2 is a plausible mechanism for PAH resistance in adapted fish. Additionally, this is the first reported use of splice-junction morpholinos in Fundulus. PMID:20605646

  4. Progesterone, as well as 17β-estradiol, is important for regulating AHR battery homoeostasis in the rat uterus.

    PubMed

    Rataj, Felicitas; Möller, Frank Josef; Jähne, Maria; Hönscheid, Pia; Zierau, Oliver; Vollmer, Günter; Kretzschmar, Georg

    2015-03-01

    Several studies indicate that the aryl hydrocarbon receptor (AHR), which plays an important role in mediating the toxicity of many industrial chemicals, plays an important role in the physiology of female reproductive tract organs. This makes it likely that the AHR and additional components of the AHR signalling pathway are under the control of female sex steroids. In a previous study, we could already demonstrate the regulation of many members of the AHR battery by 17β-estradiol (E2) in the uterus of rats. In this study, we addressed the potential role of progesterone (P4) in this context. In a comparative approach using ovariectomized rats which were treated for 3 days with either vehicle control, E2, progesterone (P4) or the combination of both hormones in addition to sham-operated animals, we could demonstrate that in addition to E2, P4 is also an important factor in regulating AHR signalling in the rat uterus. P4 has effects similar to E2 on uterine Ahr, Arnt and Arnt2 mRNA levels, resulting in a downregulation of these genes, while the E2-mediated downregulation of key AHR response genes Cyp1a1, Gsta2 and Ugt1 is completely antagonized by P4. As with E2, P4 leads to an increase in uterine AHR levels, especially in the endometrial epithelium despite the decrease in corresponding mRNA levels. This indicates a complex gene-specific regulatory network involving E2, P4 and possibly AHR itself to maintain all components of the AHR signalling cascade at the required levels during all stages of the oestrous cycle and pregnancy. PMID:24777823

  5. Aryl Hydrocarbon Receptor (AhR) Regulates Silica-Induced Inflammation But Not Fibrosis

    PubMed Central

    Beamer, Celine A.; Seaver, Benjamin P.; Shepherd, David M.

    2012-01-01

    The aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, is responsible for mediating a variety of pharmacological and toxicological effects caused by halogenated aromatic hydrocarbons such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). However, recent evidence has revealed that the AhR also has numerous physiological roles aside from xenobiotic metabolism, including regulation of immune and inflammatory signaling as well as normal development and homeostasis of several organs. To investigate the role of the AhR in crystalline silica (SiO2)–induced inflammation and fibrosis, C57Bl/6 and AhR−/− mice were exposed to SiO2 or vehicle. Similarly, C57Bl/6 mice were exposed to SiO2 and TCDD either simultaneously or sequentially to assess whether AhR activation alters inflammation and fibrosis. SiO2-induced acute lung inflammation was more severe in AhR−/− mice; however, the fibrotic response of AhR−/− mice was attenuated compared with C57Bl/6 mice. In a model of chronic SiO2 exposure, AhR activation by TCDD in C57Bl/6 mice resulted in reduced inflammation; however, the fibrotic response was not affected. Bone marrow–derived macrophages (BMM) from AhR−/− mice also produced higher levels of cytokines and chemokines in response to SiO2. Analysis of gene expression revealed that BMM derived from AhR−/− mice exhibit increased levels of pro-interleukin (IL)-1β, IL-6, and Bcl-2, yet decreased levels of signal transducers and activators of transcription (STAT)2, STAT5a, and serpin B2 (Pai-2) in response to SiO2. PMID:22273745

  6. AhR modulates the IL-22-producing cell proliferation/recruitment in imiquimod-induced psoriasis mouse model.

    PubMed

    Cochez, Perrine M; Michiels, Camille; Hendrickx, Emilie; Van Belle, Astrid B; Lemaire, Muriel M; Dauguet, Nicolas; Warnier, Guy; de Heusch, Magali; Togbe, Dieudonnée; Ryffel, Bernhard; Coulie, Pierre G; Renauld, Jean-Christophe; Dumoutier, Laure

    2016-06-01

    IL-22 has a detrimental role in skin inflammatory processes, for example in psoriasis. As transcription factor, AhR controls the IL-22 production by several cell types (i.e. Th17 cells). Here, we analyzed the role of Ahr in IL-22 production by immune cells in the inflamed skin, using an imiquimod-induced psoriasis mouse model. Our results indicate that IL-22 is expressed in the ear of imiquimod-treated Ahr(-/-) mice but less than in wild-type mice. We then studied the role of AhR on three cell populations known to produce IL-22 in the skin: γδ T cells, Th17 cells, and ILC3, and a novel IL-22-producing cell type identified in this setting: CD4(-) CD8(-) TCRβ(+) T cells. We showed that AhR is required for IL-22 production by Th17, but not by the three other cell types, in the imiquimod-treated ears. Moreover, AhR has a role in the recruitment of γδ T cells, ILC3, and CD4(-) CD8(-) TCRβ(+) T cells into the inflamed skin or in their local proliferation. Taken together, AhR has a direct role in IL-22 production by Th17 cells in the mouse ear skin, but not by γδ T cells, CD4(-) CD8(-) TCRβ(+) T cells and ILCs. PMID:27000947

  7. Malformation of certain brain blood vessels caused by TCDD activation of Ahr2/Arnt1 signaling in developing zebrafish

    PubMed Central

    Teraoka, Hiroki; Ogawa, Akira; Kubota, Akira; Stegeman, John J.; Peterson, Richard E.; Hiraga, Takeo

    2011-01-01

    2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) causes various signs of toxicity in early life stages of vertebrates through activation of the aryl hydrocarbon receptor (AHR). The AHR also plays important roles in normal development in mice, and AHR-/- mice show abnormal development of vascular structures in various blood vessels. Our previous studies revealed that Ahr type 2 (Ahr2) activation by TCDD and β-naphthoflavone (BNF) caused a significant decrease in blood flow in the dorsal midbrain of zebrafish embryos. Here we report effects of TCDD exposure on the morphology of some blood vessels in the head of developing zebrafish. TCDD caused concentration-dependent anatomical rearrangements in the shape of the prosencephalic artery in zebrafish larvae. In contrast, no major vascular defects were recognized in the trunk and tail regions following exposure to TCDD at least at the concentrations used. Essentially, the same observations were also confirmed in BNF-exposed larvae. Knock-down of either Ahr2 or Ahr nuclear translocator type 1 (Arnt1) by morpholino oligonucleotides (MOs) protected larvae against abnormal shape of the prosencephalic artery caused by TCDD and BNF. On the other hand, knock-down of Ahr2 or Arnt1 in vehicle-exposed zebrafish larvae had no clear effect on morphology of the prosencephalic artery or trunk vessels. Ascorbic acid, an antioxidant, protected against the TCDD-induced decrease in blood flow through the prosencephalic artery, but not the abnormal morphological changes in the shape of this artery. These results indicate that activation of Ahr2/Arnt1 pathway by TCDD and BNF affects the shape of certain blood vessels in the brain of developing zebrafish. PMID:20554057

  8. Cancer-promoting and Inhibiting Effects of Dietary Compounds: Role of the Aryl Hydrocarbon Receptor (AhR)

    PubMed Central

    Powell, Joann B.; Ghotbaddini, Maryam

    2014-01-01

    Polyaromatic hydrocarbons, heterocyclic aromatic amines and dioxin-like compounds are environmental carcinogens shown to initiate cancer in a number of tissue types including prostate and breast. These environmental carcinogens elicit their effects through interacting with the aryl hydrocarbon receptor (AhR), a ligand activated transcription factor. Naturally occurring compounds found in fruits and vegetables shown to have anti-carcinogenic effects also interact with the AhR. This review explores dietary and environmental exposure to chemical carcinogens and beneficial natural compounds whose effects are elicited by the AhR. PMID:25258701

  9. Hop (Humulus lupulus L.) Extract and 6-Prenylnaringenin Induce P450 1A1 Catalyzed Estrogen 2-Hydroxylation

    PubMed Central

    2016-01-01

    Humulus lupulus L. (hops) is a popular botanical dietary supplement used by women as a sleep aid and for postmenopausal symptom relief. In addition to its efficacy for menopausal symptoms, hops can also modulate the chemical estrogen carcinogenesis pathway and potentially protect women from breast cancer. In the present study, an enriched hop extract and the key bioactive compounds [6-prenylnarigenin (6-PN), 8-prenylnarigenin (8-PN), isoxanthohumol (IX), and xanthohumol (XH)] were tested for their effects on estrogen metabolism in breast cells (MCF-10A and MCF-7). The methoxyestrones (2-/4-MeOE1) were analyzed as biomarkers for the nontoxic P450 1A1 catalyzed 2-hydroxylation and the genotoxic P450 1B1 catalyzed 4-hydroxylation pathways, respectively. The results indicated that the hop extract and 6-PN preferentially induced the 2-hydroxylation pathway in both cell lines. 8-PN only showed slight up-regulation of metabolism in MCF-7 cells, whereas IX and XH did not have significant effects in either cell line. To further explore the influence of hops and its bioactive marker compounds on P450 1A1/1B1, mRNA expression and ethoxyresorufin O-dealkylase (EROD) activity were measured. The results correlated with the metabolism data and showed that hop extract and 6-PN preferentially enhanced P450 1A1 mRNA expression and increased P450 1A1/1B1 activity. The aryl hydrocarbon receptor (AhR) activation by the isolated compounds was tested using xenobiotic response element (XRE) luciferase construct transfected cells. 6-PN was found to be an AhR agonist that significantly induced XRE activation and inhibited 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induced XRE activity. 6-PN mediated induction of EROD activity was also inhibited by the AhR antagonist CH223191. These data show that the hop extract and 6-PN preferentially enhance the nontoxic estrogen 2-hydroxylation pathway through AhR mediated up-regulation of P450 1A1, which further emphasizes the importance of

  10. Hop (Humulus lupulus L.) Extract and 6-Prenylnaringenin Induce P450 1A1 Catalyzed Estrogen 2-Hydroxylation.

    PubMed

    Wang, Shuai; Dunlap, Tareisha L; Howell, Caitlin E; Mbachu, Obinna C; Rue, Emily A; Phansalkar, Rasika; Chen, Shao-Nong; Pauli, Guido F; Dietz, Birgit M; Bolton, Judy L

    2016-07-18

    Humulus lupulus L. (hops) is a popular botanical dietary supplement used by women as a sleep aid and for postmenopausal symptom relief. In addition to its efficacy for menopausal symptoms, hops can also modulate the chemical estrogen carcinogenesis pathway and potentially protect women from breast cancer. In the present study, an enriched hop extract and the key bioactive compounds [6-prenylnarigenin (6-PN), 8-prenylnarigenin (8-PN), isoxanthohumol (IX), and xanthohumol (XH)] were tested for their effects on estrogen metabolism in breast cells (MCF-10A and MCF-7). The methoxyestrones (2-/4-MeOE1) were analyzed as biomarkers for the nontoxic P450 1A1 catalyzed 2-hydroxylation and the genotoxic P450 1B1 catalyzed 4-hydroxylation pathways, respectively. The results indicated that the hop extract and 6-PN preferentially induced the 2-hydroxylation pathway in both cell lines. 8-PN only showed slight up-regulation of metabolism in MCF-7 cells, whereas IX and XH did not have significant effects in either cell line. To further explore the influence of hops and its bioactive marker compounds on P450 1A1/1B1, mRNA expression and ethoxyresorufin O-dealkylase (EROD) activity were measured. The results correlated with the metabolism data and showed that hop extract and 6-PN preferentially enhanced P450 1A1 mRNA expression and increased P450 1A1/1B1 activity. The aryl hydrocarbon receptor (AhR) activation by the isolated compounds was tested using xenobiotic response element (XRE) luciferase construct transfected cells. 6-PN was found to be an AhR agonist that significantly induced XRE activation and inhibited 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induced XRE activity. 6-PN mediated induction of EROD activity was also inhibited by the AhR antagonist CH223191. These data show that the hop extract and 6-PN preferentially enhance the nontoxic estrogen 2-hydroxylation pathway through AhR mediated up-regulation of P450 1A1, which further emphasizes the importance of

  11. ROLE OF THE ARYL HYDROCARBON RECEPTOR (AHR) IN LUNG INFLAMMATION1

    PubMed Central

    Beamer, Celine A.; Shepherd, David M.

    2013-01-01

    Millions of individuals worldwide are afflicted with acute and chronic respiratory diseases, causing temporary and permanent disabilities and even death. Oftentimes, these diseases occur as a result of altered immune responses. The aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, acts as a regulator of mucosal barrier function and may influence immune responsiveness in the lungs through changes in gene expression, cell-cell adhesion, mucin production, and cytokine expression. This review updates the basic immunobiology of the AhR signaling pathway with regards to inflammatory lung diseases such as asthma, chronic obstructive pulmonary disorder, and silicosis following data in rodent models and humans. Finally, we address the therapeutic potential of targeting the in regulating inflammation during acute and chronic respiratory diseases. PMID:23963493

  12. Characterization testing of a 40 AHR bipolar nickel-hydrogen battery

    NASA Technical Reports Server (NTRS)

    Brewer, Jeffrey C.; Manzo, Michelle A.; Gemeiner, Russel P.

    1989-01-01

    Extensive characterization testing has been done on a second 40 amp-hour (Ahr), 10-cell bipolar nickel-hydrogen (Ni-H2) battery to study the effects of such operating parameters as charge and discharge rates, temperature, and pressure, on capacity, Ahr and watt-hour (Whr) efficiencies, end-of-charge (EOC) and mid-point discharge voltages. Testing to date has produced many interesting results, with the battery performing well throughout all of the test matrix except during the high-rate (5C and 10C) discharges, where poorer than expected results were observed. The exact cause of this poor performance is, as yet, unknown. Small scale 2 x 2 inch battery tests are to be used in studying this problem. Low earth orbit (LEO) cycle life testing at a 40 percent depth of discharge (DOD) and 10 C is scheduled to follow the characterization testing.

  13. Down regulation of hepatic PPARalpha function by AhR ligand.

    PubMed

    Shaban, Zein; El-Shazly, Samir; Abdelhady, Shawky; Fattouh, Ibrahim; Muzandu, Kaampwe; Ishizuka, Mayumi; Kimura, Kazuhiro; Kazusaka, Akio; Fujita, Shoichi

    2004-11-01

    Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that mediates a spectrum of toxic and biological effects of 2,3,7,8-tetrachloro dibenzo-p-dioxin (TCDD) and related compounds. Peroxisome proliferator activated receptor alpha (PPARalpha) is a nuclear receptor involved in the maintenance of lipid and glucose homeostasis. In this study we hypothesized that one of the possible mechanisms for the effect of TCDD and its related chemicals on fat metabolism could be through down regulation of PPARalpha functions. We treated Wistar rats with an AhR ligand, Sudan III (S.III), and/or PPARalpha ligand, Clofibric Acid (CA), for 3 days. We analysed the expression of one of the PPARalpha-target gene products, CYP4A protein and its mRNA. We also tested HepG2 cells with the afore-mentioned treatments and evaluated their effects on PPARalpha and RXRalpha protein. Treatment of Wistar rats with S.III was found to down regulates CYP4A protein expression and reduced its induction with CA. It also decreased mRNA expressions of CYP4A1, CYP4A2, CYP4A3 and PPARalpha. In HepG2 cells, PPARalpha and RXRalpha protein expression was decreased by S.III treatment in a dose dependent manner. Our results suggest that AhR has an inhibitory effect on PPARalpha function and a new pathway by which AhR ligands could disturb lipid metabolism. PMID:15585952

  14. A novel AhR ligand, 2AI, protects the retina from environmental stress

    PubMed Central

    Gutierrez, Mark A.; Davis, Sonnet S.; Rosko, Andrew; Nguyen, Steven M.; Mitchell, Kylie P.; Mateen, Samiha; Neves, Joana; Garcia, Thelma Y.; Mooney, Shaun; Perdew, Gary H.; Hubbard, Troy D.; Lamba, Deepak A.; Ramanathan, Arvind

    2016-01-01

    Various retinal degenerative diseases including dry and neovascular age-related macular degeneration (AMD), retinitis pigmentosa, and diabetic retinopathy are associated with the degeneration of the retinal pigmented epithelial (RPE) layer of the retina. This consequently results in the death of rod and cone photoreceptors that they support, structurally and functionally leading to legal or complete blindness. Therefore, developing therapeutic strategies to preserve cellular homeostasis in the RPE would be a favorable asset in the clinic. The aryl hydrocarbon receptor (AhR) is a conserved, environmental ligand-dependent, per ARNT-sim (PAS) domain containing bHLH transcription factor that mediates adaptive response to stress via its downstream transcriptional targets. Using in silico, in vitro and in vivo assays, we identified 2,2′-aminophenyl indole (2AI) as a potent synthetic ligand of AhR that protects RPE cells in vitro from lipid peroxidation cytotoxicity mediated by 4-hydroxynonenal (4HNE) as well as the retina in vivo from light-damage. Additionally, metabolic characterization of this molecule by LC-MS suggests that 2AI alters the lipid metabolism of RPE cells, enhancing the intracellular levels of palmitoleic acid. Finally, we show that, as a downstream effector of 2AI-mediated AhR activation, palmitoleic acid protects RPE cells from 4HNE-mediated stress, and light mediated retinal degeneration in mice. PMID:27364765

  15. A novel AhR ligand, 2AI, protects the retina from environmental stress.

    PubMed

    Gutierrez, Mark A; Davis, Sonnet S; Rosko, Andrew; Nguyen, Steven M; Mitchell, Kylie P; Mateen, Samiha; Neves, Joana; Garcia, Thelma Y; Mooney, Shaun; Perdew, Gary H; Hubbard, Troy D; Lamba, Deepak A; Ramanathan, Arvind

    2016-01-01

    Various retinal degenerative diseases including dry and neovascular age-related macular degeneration (AMD), retinitis pigmentosa, and diabetic retinopathy are associated with the degeneration of the retinal pigmented epithelial (RPE) layer of the retina. This consequently results in the death of rod and cone photoreceptors that they support, structurally and functionally leading to legal or complete blindness. Therefore, developing therapeutic strategies to preserve cellular homeostasis in the RPE would be a favorable asset in the clinic. The aryl hydrocarbon receptor (AhR) is a conserved, environmental ligand-dependent, per ARNT-sim (PAS) domain containing bHLH transcription factor that mediates adaptive response to stress via its downstream transcriptional targets. Using in silico, in vitro and in vivo assays, we identified 2,2'-aminophenyl indole (2AI) as a potent synthetic ligand of AhR that protects RPE cells in vitro from lipid peroxidation cytotoxicity mediated by 4-hydroxynonenal (4HNE) as well as the retina in vivo from light-damage. Additionally, metabolic characterization of this molecule by LC-MS suggests that 2AI alters the lipid metabolism of RPE cells, enhancing the intracellular levels of palmitoleic acid. Finally, we show that, as a downstream effector of 2AI-mediated AhR activation, palmitoleic acid protects RPE cells from 4HNE-mediated stress, and light mediated retinal degeneration in mice. PMID:27364765

  16. AhR activation underlies the CYP1A autoinduction by A-998679 in rats

    PubMed Central

    Liguori, Michael J.; Lee, Chih-Hung; Liu, Hong; Ciurlionis, Rita; Ditewig, Amy C.; Doktor, Stella; Andracki, Mark E.; Gagne, Gerard D.; Waring, Jeffrey F.; Marsh, Kennan C.; Gopalakrishnan, Murali; Blomme, Eric A. G.; Yang, Yi

    2012-01-01

    Xenobiotic-mediated induction of cytochrome P450 (CYP) drug metabolizing enzymes (DMEs) is frequently encountered in drug discovery and can influence disposition, pharmacokinetic, and toxicity profiles. The CYP1A subfamily of DMEs plays a central role in the biotransformation of several drugs and environmental chemicals. Autoinduction of drugs through CYP3A enzymes is a common mechanism for their enhanced clearance. However, autoinduction via CYP1A is encountered less frequently. In this report, an experimental compound, A-998679 [3-(5-pyridin-3-yl-1,2,4-oxadiazol-3-yl) benzonitrile], was shown to enhance its own clearance via induction of Cyp1a1 and Cyp1a2. Rats were dosed for 5 days with 30, 100, and 200 mg/kg/day A-998679. During the dosing period, the compound's plasma AUC decreased at 30 mg/kg (95%) and 100 mg/kg (80%). Gene expression analysis and immunohistochemistry of the livers showed a large increase in the mRNA and protein levels of Cyp1a, which was involved in the biotransformation of A-998679. Induction of CYP1A was confirmed in primary rat, human, and dog hepatocytes. The compound also weakly inhibited CYP1A2 in human liver microsomes. A-998679 activated the aryl hydrocarbon receptor (AhR) in a luciferase gene reporter assay in HepG2 cells, upregulated expression of genes associated with AhR activation in rat liver and enhanced nuclear migration of AhR in HepG2 cells. Collectively these results demonstrate that A-998679 is an AhR activator that induces Cyp1a1 and Cyp1a2 expression, resulting in an autoinduction phenomenon. The unique properties of A-998679, along with its novel structure distinct from classical polycyclic aromatic hydrocarbons (PAHs), may warrant its further evaluation as a tool compound for use in studies involving AhR biology and CYP1A-related mechanisms of drug metabolism and toxicity. PMID:23112805

  17. Ablating the aryl hydrocarbon receptor (AhR) in CD11c+ cells perturbs intestinal epithelium development and intestinal immunity

    PubMed Central

    Chng, Song Hui; Kundu, Parag; Dominguez-Brauer, Carmen; Teo, Wei Ling; Kawajiri, Kaname; Fujii-Kuriyama, Yoshiaki; Mak, Tak Wah; Pettersson, Sven

    2016-01-01

    Diet and microbiome derived indole derivatives are known to activate the ligand induced transcription factor, the Aryl hydrocarbon Receptor (AhR). While the current understanding of AhR biology has confirmed its role in mucosal lymphocytes, its function in intestinal antigen presenting cells (APCs) is poorly understood. Here, we report that Cre-mediated deletion of AhR in CD11c-expressing cells in C57/BL6 mice is associated with altered intestinal epithelial morphogenesis in vivo. Moreover, when co-cultured with AhR-deficient DCs ex vivo, intestinal organoids showed reduced SRY (sex determining region Y)-box 9 and increased Mucin 2 expression, which correlates with reduced Paneth cells and increased goblet cell differentiation, similar to the data obtained in vivo. Further, characterization of intestinal APC subsets, devoid of AhR, revealed an expression pattern associated with aberrant intrinsic Wnt pathway regulation. At a functional level, the loss of AhR in APCs resulted in a dysfunctional epithelial barrier, associated with a more aggressive chemically induced colitis compared to wild type animals. Our results are consistent with a model whereby the AhR signalling pathway may participate in the regulation of innate immunity through intestinal epithelium development and mucosal immunity. PMID:27068235

  18. An Assessment of Technical and Production Risks of Candidate Low-Cost Attitude/Heading Reference Systems(AHRS)

    NASA Technical Reports Server (NTRS)

    Yuchnovicz, Daniel; Burgess, Malcolm; Hammers, William

    1999-01-01

    This report provides an assessment of technical and production risks of candidate low-cost attitude/heading reference systems (AHRS) for use in the Advanced General Aviation Transport Experiments (AGATE) airplanes. A low-cost AHRS is a key component of modem "glass cockpit" flight displays for General Aviation (GA) aircraft. The technical capabilities of several candidate low-cost AHRS were examined and described along with the technical issues involved with using all solid-state components for attitude measurement. An economic model was developed which describes the expected profit, rate of return, and volume requirements for the manufacture of low-cost AHRS for GA aircraft in the 2000 to 2020 time frame. The model is the result of interviews with GA airframe manufacturers, avionics manufacturers and historical analysis of avionics of similar complexity. The model shows that a manufacturer will break even after three years of AHRS production, realizing an 18 percent rate of return (23 percent profit) on an investment of $3.5M over the 20 year period. A start-up production estimate showed costs of $6-12M for a new company to build and certify an AHRS from scratch, considered to be a high-risk proposition, versus $0.25-0.75M for an experienced avionics manufacturer to manufacture a design under license, a low-risk proposition.

  19. Ablating the aryl hydrocarbon receptor (AhR) in CD11c+ cells perturbs intestinal epithelium development and intestinal immunity.

    PubMed

    Chng, Song Hui; Kundu, Parag; Dominguez-Brauer, Carmen; Teo, Wei Ling; Kawajiri, Kaname; Fujii-Kuriyama, Yoshiaki; Mak, Tak Wah; Pettersson, Sven

    2016-01-01

    Diet and microbiome derived indole derivatives are known to activate the ligand induced transcription factor, the Aryl hydrocarbon Receptor (AhR). While the current understanding of AhR biology has confirmed its role in mucosal lymphocytes, its function in intestinal antigen presenting cells (APCs) is poorly understood. Here, we report that Cre-mediated deletion of AhR in CD11c-expressing cells in C57/BL6 mice is associated with altered intestinal epithelial morphogenesis in vivo. Moreover, when co-cultured with AhR-deficient DCs ex vivo, intestinal organoids showed reduced SRY (sex determining region Y)-box 9 and increased Mucin 2 expression, which correlates with reduced Paneth cells and increased goblet cell differentiation, similar to the data obtained in vivo. Further, characterization of intestinal APC subsets, devoid of AhR, revealed an expression pattern associated with aberrant intrinsic Wnt pathway regulation. At a functional level, the loss of AhR in APCs resulted in a dysfunctional epithelial barrier, associated with a more aggressive chemically induced colitis compared to wild type animals. Our results are consistent with a model whereby the AhR signalling pathway may participate in the regulation of innate immunity through intestinal epithelium development and mucosal immunity. PMID:27068235

  20. Vasopressin receptor antagonists.

    PubMed

    Palmer, Biff F

    2015-01-01

    Arginine vasopressin (AVP) is the principal hormone involved in regulating the tonicity of body fluids. Less appreciated is the role that AVP plays in a variety of other physiologic functions including glucose metabolism, cardiovascular homeostasis, bone metabolism, and cognitive behavior. AVP receptor antagonists are now available and currently approved to treat hyponatremia. There is a great deal of interest in exploring the potential benefits that these drugs may play in blocking AVP-mediated effects in other organ systems. The purpose of this report is to provide an update on the expanding role of AVP receptor antagonists and what disease states these drugs may eventually be used for. PMID:25604388

  1. TCDD dysregulation of 13 AHR-target genes in rat liver

    SciTech Connect

    Watson, John D.; Prokopec, Stephenie D.; Smith, Ashley B.; Okey, Allan B.; Pohjanvirta, Raimo; Boutros, Paul C.

    2014-02-01

    Despite several decades of research, the complete mechanism by which 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and other xenobiotic agonists of the aryl hydrocarbon receptor (AHR) cause toxicity remains unclear. While it has been shown that the AHR is required for all major manifestations of toxicity, the specific downstream changes involved in the development of toxic phenotypes remain unknown. Here we examine a panel of 13 genes that are AHR-regulated in many species and tissues. We profiled their hepatic mRNA abundances in two rat strains with very different sensitivities to TCDD: the TCDD-sensitive Long–Evans (Turku/AB; L–E) and the TCDD-resistant Han/Wistar (Kuopio; H/W). We evaluated doses ranging from 0 to 3000 μg/kg at 19 h after TCDD exposure and time points ranging from 1.5 to 384 h after exposure to 100 μg/kg TCDD. Twelve of 13 genes responded to TCDD in at least one strain, and seven of these showed statistically significant inter-strain differences in the time course analysis (Aldh3a1, Cyp1a2, Cyp1b1, Cyp2a1, Fmo1, Nfe2l2 and Nqo1). Cyp2s1 did not respond to TCDD in either rat strain. Five genes exhibited biphasic responses to TCDD insult (Ahrr, Aldh3a1, Cyp1b1, Nfe2l2 and Nqo1), suggesting a secondary event, such as association with additional transcriptional modulators. Of the 12 genes that responded to TCDD during the dose–response analysis, none had an ED{sub 50} equivalent to that of Cyp1a1, the most sensitive gene in this study, while nine genes responded to doses at least 10–100 fold higher, in at least one strain (Ahrr (L–E), Aldh3a1 (both), Cyp1a2 (both), Cyp1b1 (both), Cyp2a1 (L–E), Inmt (both), Nfe2l2 (L–E), Nqo1 (L–E) and Tiparp (both)). These data shed new light on the association of the AHR target genes with TCDD toxicity, and in particular the seven genes exhibiting strain-specific differences represent strong candidate mediators of Type-II toxicities. - Highlights: • NanoString measured hepatic mRNA molecules

  2. TCDD dysregulation of 13 AHR-target genes in rat liver.

    PubMed

    Watson, John D; Prokopec, Stephenie D; Smith, Ashley B; Okey, Allan B; Pohjanvirta, Raimo; Boutros, Paul C

    2014-02-01

    Despite several decades of research, the complete mechanism by which 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and other xenobiotic agonists of the aryl hydrocarbon receptor (AHR) cause toxicity remains unclear. While it has been shown that the AHR is required for all major manifestations of toxicity, the specific downstream changes involved in the development of toxic phenotypes remain unknown. Here we examine a panel of 13 genes that are AHR-regulated in many species and tissues. We profiled their hepatic mRNA abundances in two rat strains with very different sensitivities to TCDD: the TCDD-sensitive Long-Evans (Turku/AB; L-E) and the TCDD-resistant Han/Wistar (Kuopio; H/W). We evaluated doses ranging from 0 to 3000μg/kg at 19h after TCDD exposure and time points ranging from 1.5 to 384h after exposure to 100μg/kg TCDD. Twelve of 13 genes responded to TCDD in at least one strain, and seven of these showed statistically significant inter-strain differences in the time course analysis (Aldh3a1, Cyp1a2, Cyp1b1, Cyp2a1, Fmo1, Nfe2l2 and Nqo1). Cyp2s1 did not respond to TCDD in either rat strain. Five genes exhibited biphasic responses to TCDD insult (Ahrr, Aldh3a1, Cyp1b1, Nfe2l2 and Nqo1), suggesting a secondary event, such as association with additional transcriptional modulators. Of the 12 genes that responded to TCDD during the dose-response analysis, none had an ED50 equivalent to that of Cyp1a1, the most sensitive gene in this study, while nine genes responded to doses at least 10-100 fold higher, in at least one strain (Ahrr (L-E), Aldh3a1 (both), Cyp1a2 (both), Cyp1b1 (both), Cyp2a1 (L-E), Inmt (both), Nfe2l2 (L-E), Nqo1 (L-E) and Tiparp (both)). These data shed new light on the association of the AHR target genes with TCDD toxicity, and in particular the seven genes exhibiting strain-specific differences represent strong candidate mediators of Type-II toxicities. PMID:24355419

  3. Opioid Antagonist Impedes Exposure.

    ERIC Educational Resources Information Center

    Merluzzi, Thomas V.; And Others

    1991-01-01

    Thirty spider-phobic adults underwent exposure to 17 phobic-related, graded performance tests. Fifteen subjects were assigned to naltrexone, an opioid antagonist, and 15 were assigned to placebo. Naltrexone had a significant effect on exposure, with naltrexone subjects taking significantly longer to complete first 10 steps of exposure and with…

  4. Spiropiperidine CCR5 antagonists.

    PubMed

    Rotstein, David M; Gabriel, Stephen D; Makra, Ferenc; Filonova, Lubov; Gleason, Shelley; Brotherton-Pleiss, Christine; Setti, Lina Q; Trejo-Martin, Alejandra; Lee, Eun Kyung; Sankuratri, Surya; Ji, Changhua; Derosier, Andre; Dioszegi, Marianna; Heilek, Gabrielle; Jekle, Andreas; Berry, Pamela; Weller, Paul; Mau, Cheng-I

    2009-09-15

    A novel series of CCR5 antagonists has been identified, utilizing leads from high-throughput screening which were further modified based on insights from competitor molecules. Lead optimization was pursued by balancing opposing trends of metabolic stability and potency. Selective and potent analogs with good pharmacokinetic properties were successfully developed. PMID:19674898

  5. The Q-rich/PST domain of the AHR regulates both ligand-induced nuclear transport and nucleocytoplasmic shuttling

    PubMed Central

    Tkachenko, Anna; Henkler, Frank; Brinkmann, Joep; Sowada, Juliane; Genkinger, Doris; Kern, Christian; Tralau, Tewes; Luch, Andreas

    2016-01-01

    The aryl hydrocarbon receptor (AHR) shuttles continuously between cytoplasm and nucleus, unless ligand-binding triggers association with the AHR nuclear translocator (ARNT) and subsequent binding to cognate DNA motifs. We have now identified Val 647 as mandatory residue for export from the nucleus and AHR-function. This residue prevents inactivation of the receptor as a consequence of nuclear sequestration via constitutive import. Concomitantly mutants lacking this residue are exclusively localised in the nucleus. Although ligands accelerate nuclear import transiently, stable nuclear transition depends on a motif adjacent to Val 647 that comprises residues 650–661. Together, this defined region within the Q-rich domain regulates intracellular trafficking of the AHR in context of both nucleocytoplasmic shuttling and receptor activation. Nuclear export therefore depends on the previously characterised N-terminal NES and the newly identified motif that includes V647. Nucleocytoplasmic distribution of full-length human AHR is further affected by a section of the PST domain that shows sequence similarities with nuclear export signals. In concert, these motifs maintain a predominant cytoplasmic compartmentalisation, receptive for ligand binding. PMID:27535013

  6. The Q-rich/PST domain of the AHR regulates both ligand-induced nuclear transport and nucleocytoplasmic shuttling.

    PubMed

    Tkachenko, Anna; Henkler, Frank; Brinkmann, Joep; Sowada, Juliane; Genkinger, Doris; Kern, Christian; Tralau, Tewes; Luch, Andreas

    2016-01-01

    The aryl hydrocarbon receptor (AHR) shuttles continuously between cytoplasm and nucleus, unless ligand-binding triggers association with the AHR nuclear translocator (ARNT) and subsequent binding to cognate DNA motifs. We have now identified Val 647 as mandatory residue for export from the nucleus and AHR-function. This residue prevents inactivation of the receptor as a consequence of nuclear sequestration via constitutive import. Concomitantly mutants lacking this residue are exclusively localised in the nucleus. Although ligands accelerate nuclear import transiently, stable nuclear transition depends on a motif adjacent to Val 647 that comprises residues 650-661. Together, this defined region within the Q-rich domain regulates intracellular trafficking of the AHR in context of both nucleocytoplasmic shuttling and receptor activation. Nuclear export therefore depends on the previously characterised N-terminal NES and the newly identified motif that includes V647. Nucleocytoplasmic distribution of full-length human AHR is further affected by a section of the PST domain that shows sequence similarities with nuclear export signals. In concert, these motifs maintain a predominant cytoplasmic compartmentalisation, receptive for ligand binding. PMID:27535013

  7. NK cells contribute to persistent airway inflammation and AHR during the later stage of RSV infection in mice.

    PubMed

    Long, Xiaoru; Xie, Jun; Zhao, Keting; Li, Wei; Tang, Wei; Chen, Sisi; Zang, Na; Ren, Luo; Deng, Yu; Xie, Xiaohong; Wang, Lijia; Fu, Zhou; Liu, Enmei

    2016-10-01

    RSV can lead to persistent airway inflammation and AHR and is intimately associated with childhood recurrent wheezing and asthma, but the underlying mechanisms remain unclear. There are high numbers of NK cells in the lung, which not only play important roles in the acute stage of RSV infection, but also are pivotal in regulating the pathogenesis of asthma. Therefore, in this study, we assumed that NK cells might contribute to persistent airway disease during the later stage of RSV infection. Mice were killed at serial time points after RSV infection to collect samples. Leukocytes in bronchoalveolar lavage fluid (BALF) were counted, lung histopathology was examined, and airway hyperresponsiveness (AHR) was measured by whole-body plethysmography. Cytokines were detected by ELISA, and NK cells were determined by flow cytometry. Rabbit anti-mouse asialo-GM-1 antibodies and resveratrol were used to deplete or suppress NK cells. Inflammatory cells in BALF, lung tissue damage and AHR were persistent for 60 days post-RSV infection. Type 2 cytokines and NK cells were significantly increased during the later stage of infection. When NK cells were decreased by the antibodies or resveratrol, type 2 cytokines, the persistent airway inflammation and AHR were all markedly reduced. NK cells can contribute to the RSV-associated persistent airway inflammation and AHR at least partially by promoting type 2 cytokines. Therefore, therapeutic targeting of NK cells may provide a novel approach to alleviating the recurrent wheezing subsequent to RSV infection. PMID:27329138

  8. Xanthines as Adenosine Receptor Antagonists

    PubMed Central

    Jacobson, Kenneth A.

    2013-01-01

    The natural plant alkaloids caffeine and theophylline were the first adenosine receptor (AR) antagonists described in the literature. They exhibit micromolar affinities and are non-selective. A large number of derivatives and analogs have subsequently been synthesized and evaluated as AR antagonists. Very potent antagonists have thus been developed with selectivity for each of the four AR subtypes. PMID:20859796

  9. Improved calibration of IMU biases in analytic coarse alignment for AHRS

    NASA Astrophysics Data System (ADS)

    Lu, Jiazhen; Lei, Chaohua; Li, Baoguo; Wen, Ting

    2016-07-01

    An improved method for the inertial measurement unit (IMU) calibration of coarse alignment for the low-accuracy attitude heading reference system (AHRS) is proposed in this paper. The sensitivities of the Euler angles with respect to the inertial sensor biases are studied based on the analytic coarse alignment principle, and the errors of earth rotation rate and local gravity in the body frame caused by initial attitude error are analyzed. Then, an improved analytic coarse alignment algorithm with accelerometer and gyro bias calibration in an arbitrary three-position is proposed. Simulation and experiment results show that the novel method can calibrate accelerometer and gyro biases, reduce Euler angle attitude error, and improve navigation precision in practical applications. Moreover, this method can be applied to other low-accuracy inertial navigation systems.

  10. Musashi-2 attenuates AHR signalling to expand human haematopoietic stem cells.

    PubMed

    Rentas, Stefan; Holzapfel, Nicholas T; Belew, Muluken S; Pratt, Gabriel A; Voisin, Veronique; Wilhelm, Brian T; Bader, Gary D; Yeo, Gene W; Hope, Kristin J

    2016-04-28

    Umbilical cord blood-derived haematopoietic stem cells (HSCs) are essential for many life-saving regenerative therapies. However, despite their advantages for transplantation, their clinical use is restricted because HSCs in cord blood are found only in small numbers. Small molecules that enhance haematopoietic stem and progenitor cell (HSPC) expansion in culture have been identified, but in many cases their mechanisms of action or the nature of the pathways they impinge on are poorly understood. A greater understanding of the molecular circuitry that underpins the self-renewal of human HSCs will facilitate the development of targeted strategies that expand HSCs for regenerative therapies. Whereas transcription factor networks have been shown to influence the self-renewal and lineage decisions of human HSCs, the post-transcriptional mechanisms that guide HSC fate have not been closely investigated. Here we show that overexpression of the RNA-binding protein Musashi-2 (MSI2) induces multiple pro-self-renewal phenotypes, including a 17-fold increase in short-term repopulating cells and a net 23-fold ex vivo expansion of long-term repopulating HSCs. By performing a global analysis of MSI2-RNA interactions, we show that MSI2 directly attenuates aryl hydrocarbon receptor (AHR) signalling through post-transcriptional downregulation of canonical AHR pathway components in cord blood HSPCs. Our study gives mechanistic insight into RNA networks controlled by RNA-binding proteins that underlie self-renewal and provides evidence that manipulating such networks ex vivo can enhance the regenerative potential of human HSCs. PMID:27121842

  11. Access Path to the Ligand Binding Pocket May Play a Role in Xenobiotics Selection by AhR

    PubMed Central

    Szöllősi, Dániel; Erdei, Áron; Gyimesi, Gergely; Magyar, Csaba; Hegedűs, Tamás

    2016-01-01

    Understanding of multidrug binding at the atomic level would facilitate drug design and strategies to modulate drug metabolism, including drug transport, oxidation, and conjugation. Therefore we explored the mechanism of promiscuous binding of small molecules by studying the ligand binding domain, the PAS-B domain of the aryl hydrocarbon receptor (AhR). Because of the low sequence identities of PAS domains to be used for homology modeling, structural features of the widely employed HIF-2α and a more recent suitable template, CLOCK were compared. These structures were used to build AhR PAS-B homology models. We performed molecular dynamics simulations to characterize dynamic properties of the PAS-B domain and the generated conformational ensembles were employed in in silico docking. In order to understand structural and ligand binding features we compared the stability and dynamics of the promiscuous AhR PAS-B to other PAS domains exhibiting specific interactions or no ligand binding function. Our exhaustive in silico binding studies, in which we dock a wide spectrum of ligand molecules to the conformational ensembles, suggest that ligand specificity and selection may be determined not only by the PAS-B domain itself, but also by other parts of AhR and its protein interacting partners. We propose that ligand binding pocket and access channels leading to the pocket play equally important roles in discrimination of endogenous molecules and xenobiotics. PMID:26727491

  12. AhR ligand Aminoflavone inhibits α6-integrin expression and breast cancer sphere-initiating capacity.

    PubMed

    Brantley, Eileen; Callero, Mariana A; Berardi, Damian E; Campbell, Petreena; Rowland, Leah; Zylstra, Dain; Amis, Louisa; Yee, Michael; Simian, Marina; Todaro, Laura; Loaiza-Perez, Andrea I; Soto, Ubaldo

    2016-06-28

    Traditional chemotherapies debulk tumors but fail to produce long-term clinical remissions due to their inability to eradicate tumor-initiating cells (TICs). This necessitates therapy with activity against the TIC niche. Αlpha6-integrin (α6-integrin) promotes TIC growth. In contrast, aryl hydrocarbon receptor (AhR) signaling activation impedes the formation of mammospheres (clusters of cells enriched for TICs). We investigated the ability of AhR agonist Aminoflavone (AF) and AF pro-drug (AFP464) to disrupt mammospheres derived from breast cancer cells and a M05 mammary mouse model of breast cancer respectively. We further examined the capacity of AF and AFP464 to exhibit anticancer activity and modulate the expression of 'stemness' genes including α6-integrin using immunofluorescence, flow cytometry and qRT-PCR analysis. AF disrupted mammospheres and prevented secondary mammosphere formation. In contrast, AF did not disrupt mammospheres derived from AhR ligand-unresponsive MCF-7 cells. AFP464 treatment suppressed M05 tumor growth and disrupted corresponding mammospheres. AF and AFP464 reduced the expression and percentage of cells that stained for 'stemness' markers including α6-integrin in vitro and in vivo respectively. These data suggest AFP464 thwarts bulk breast tumor and TIC growth via AhR agonist-mediated α6-integrin inhibition. PMID:26996297

  13. Analysis of the AHR gene proximal promoter GGGGC-repeat polymorphism in lung, breast, and colon cancer

    SciTech Connect

    Spink, Barbara C.; Bloom, Michael S.; Wu, Susan; Sell, Stewart; Schneider, Erasmus; Ding, Xinxin; Spink, David C.

    2015-01-01

    The aryl hydrocarbon receptor (AhR) regulates expression of numerous genes, including those of the CYP1 gene family. With the goal of determining factors that control AHR gene expression, our studies are focused on the role of the short tandem repeat polymorphism, (GGGGC){sub n}, located in the proximal promoter of the human AHR gene. When luciferase constructs containing varying GGGGC repeats were transfected into cancer cell lines derived from the lung, colon, and breast, the number of GGGGC repeats affected AHR promoter activity. The number of GGGGC repeats was determined in DNA from 327 humans and from 38 samples representing 5 species of non-human primates. In chimpanzees and 3 species of macaques, only (GGGGC){sub 2} alleles were observed; however, in western gorilla, (GGGGC){sub n} alleles with n = 2, 4, 5, 6, 7, and 8 were identified. In all human populations examined, the frequency of (GGGGC){sub n} was n = 4 > 5 ≫ 2, 6. When frequencies of the (GGGGC){sub n} alleles in DNA from patients with lung, colon, or breast cancer were evaluated, the occurrence of (GGGGC){sub 2} was found to be 8-fold more frequent among lung cancer patients in comparison with its incidence in the general population, as represented by New York State neonates. Analysis of matched tumor and non-tumor DNA samples from the same individuals provided no evidence of microsatellite instability. These studies indicate that the (GGGGC){sub n} short tandem repeats are inherited, and that the (GGGGC){sub 2} allele in the AHR proximal promoter region should be further investigated with regard to its potential association with lung cancer susceptibility. - Highlights: • The AHR proximal promoter contains a polymorphism, (GGGGC){sub n}, where n = 4 > 5 ≫ 2, 6 • Matched tumor and non-tumor DNA did not show (GGGGC){sub n} microsatellite instability • AHR promoter activity of a construct with (GGGGC){sub 2} was lower than that of (GGGGC){sub 4} • The frequency of (GGGGC){sub 2} in lung

  14. The Effects of Chronic Lifelong Activation of the AHR Pathway by Industrial Chemical Pollutants on Female Human Reproduction

    PubMed Central

    Vacca, Margherita; Nardelli, Claudia; Castegna, Alessandra; Arnesano, Fabio; Carella, Nicola; Depalo, Raffaella

    2016-01-01

    Environmental chemicals, such as heavy metals, affect female reproductive function. A biological sensor of the signals of many toxic chemical compounds seems to be the aryl hydrocarbon receptor (AHR). Previous studies demonstrated the environmental of heavy metals in Taranto city (Italy), an area that has been influenced by anthropogenic factors such as industrial activities and waste treatments since 1986. However, the impact of these elements on female fertility in this geographic area has never been analyzed. Thus, in the present study, we evaluated the AHR pathway, sex steroid receptor pattern and apoptotic process in granulosa cells (GCs) retrieved from 30 women, born and living in Taranto, and 30 women who are living in non-contaminated areas (control group), who were undergoing in vitro fertilization (IVF) protocol. In follicular fluids (FFs) of both groups the toxic and essential heavy metals, such as chromiun (Cr), Manganese (Mn), iron (Fe), cobalt (Co), nickel (Ni), copper (Cu), zinc (Zn), cadmium (Cd) and lead (Pb), were also analyzed. Higher levels of Cr, Fe, Zn and Pb were found in the FFs of the women from Taranto as compared to the control group, as were the levels of AHR and AHR-dependent cytochrome P450 1A1 and 1B1; while CYP19A1 expression was decreased. The anti-apoptotic process found in the GCs of women fromTaranto was associated with the highest levels of progesterone receptor membrane component 1 (PGRMC1), a novel progesterone receptor, the expression of which is subjected to AHR activated by its highest affinity ligands (e.g., dioxins) or indirectly by other environmental pollutants, such as heavy metals. In conclusion, decreased production of estradiol and decreased number of retrieved mature oocytes found in women from Taranto could be due to chronic exposure to heavy metals, in particular to Cr and Pb. PMID:27008165

  15. Genome Editing of the CYP1A1 Locus in iPSCs as a Platform to Map AHR Expression throughout Human Development

    PubMed Central

    Smith, Brenden W.; Stanford, Elizabeth A.; Sherr, David H.; Murphy, George J.

    2016-01-01

    The aryl hydrocarbon receptor (AHR) is a ligand activated transcription factor that increases the expression of detoxifying enzymes upon ligand stimulation. Recent studies now suggest that novel endogenous roles of the AHR exist throughout development. In an effort to create an optimized model system for the study of AHR signaling in several cellular lineages, we have employed a CRISPR/CAS9 genome editing strategy in induced pluripotent stem cells (iPSCs) to incorporate a reporter cassette at the transcription start site of one of its canonical targets, cytochrome P450 1A1 (CYP1A1). This cell line faithfully reports on CYP1A1 expression, with luciferase levels as its functional readout, when treated with an endogenous AHR ligand (FICZ) at escalating doses. iPSC-derived fibroblast-like cells respond to acute exposure to environmental and endogenous AHR ligands, and iPSC-derived hepatocytes increase CYP1A1 in a similar manner to primary hepatocytes. This cell line is an important innovation that can be used to map AHR activity in discrete cellular subsets throughout developmental ontogeny. As further endogenous ligands are proposed, this line can be used to screen for safety and efficacy and can report on the ability of small molecules to regulate critical cellular processes by modulating the activity of the AHR. PMID:27148368

  16. The AhR Ligand, TCDD, Regulates Androgen Receptor Activity Differently in Androgen-Sensitive versus Castration-Resistant Human Prostate Cancer Cells.

    PubMed

    Ghotbaddini, Maryam; Powell, Joann B

    2015-07-01

    The reported biological effects of TCDD include induction of drug metabolizing enzymes, wasting syndrome and tumor promotion. TCDD elicits most of its effects through binding the aryl hydrocarbon receptor (AhR). TCDD induced degradation of AhR has been widely reported and requires ubiquitination of the protein. The rapid depletion of AhR following TCDD activation serves as a mechanism to modulate AhR mediated gene induction. In addition to inducing AhR degradation, TCDD has been reported to induce degradation of hormone receptors. The studies reported here, evaluate the effect of TCDD exposure on androgen receptor (AR) expression and activity in androgen-sensitive LNCaP and castration-resistant C4-2 prostate cancer cells. Our results show that TCDD exposure does not induce AhR or AR degradation in C4-2 cells. However, both AhR and AR are degraded in LNCaP cells following TCDD exposure. In addition, TCDD enhances AR phosphorylation and induces expression of AR responsive genes in LNCaP cells. Our data reveals that TCDD effect on AR expression and activity differs in androgen-sensitive and castration-resistant prostate cancer cell models. PMID:26154658

  17. The AhR Ligand, TCDD, Regulates Androgen Receptor Activity Differently in Androgen-Sensitive versus Castration-Resistant Human Prostate Cancer Cells

    PubMed Central

    Ghotbaddini, Maryam; Powell, Joann B.

    2015-01-01

    The reported biological effects of TCDD include induction of drug metabolizing enzymes, wasting syndrome and tumor promotion. TCDD elicits most of its effects through binding the aryl hydrocarbon receptor (AhR). TCDD induced degradation of AhR has been widely reported and requires ubiquitination of the protein. The rapid depletion of AhR following TCDD activation serves as a mechanism to modulate AhR mediated gene induction. In addition to inducing AhR degradation, TCDD has been reported to induce degradation of hormone receptors. The studies reported here, evaluate the effect of TCDD exposure on androgen receptor (AR) expression and activity in androgen-sensitive LNCaP and castration-resistant C4-2 prostate cancer cells. Our results show that TCDD exposure does not induce AhR or AR degradation in C4-2 cells. However, both AhR and AR are degraded in LNCaP cells following TCDD exposure. In addition, TCDD enhances AR phosphorylation and induces expression of AR responsive genes in LNCaP cells. Our data reveals that TCDD effect on AR expression and activity differs in androgen-sensitive and castration-resistant prostate cancer cell models. PMID:26154658

  18. Selective orexin receptor antagonists.

    PubMed

    Lebold, Terry P; Bonaventure, Pascal; Shireman, Brock T

    2013-09-01

    The orexin, or hypocretin, neuropeptides (orexin-A and orexin-B) are produced on neurons in the hypothalamus which project to key areas of the brain that control sleep-wake states, modulation of food intake, panic, anxiety, emotion, reward and addictive behaviors. These neuropeptides exert their effects on a pair of G-protein coupled receptors termed the orexin-1 (OX1) and orexin-2 (OX2) receptors. Emerging biology suggests the involvement of these receptors in psychiatric disorders as they are thought to play a key role in the regulation of multiple systems. This review is intended to highlight key selective OX1 or OX2 small-molecule antagonists. PMID:23891187

  19. The aryl hydrocarbon receptor suppresses osteoblast proliferation and differentiation through the activation of the ERK signaling pathway

    SciTech Connect

    Yu, Haitao; Du, Yuxuan; Zhang, Xulong; Sun, Ying; Li, Shentao; Dou, Yunpeng; Li, Zhanguo; Yuan, Huihui; Zhao, Wenming

    2014-11-01

    Ahr activation is known to be associated with synovitis and exacerbated rheumatoid arthritis (RA), but its contributions to bone loss have not been completely elucidated. Osteoblast proliferation and differentiation are abnormal at the erosion site in RA. Here, we reported that the expression of Ahr was increased in the hind paws' bone upon collagen-induced arthritis (CIA) in mice, and the levels of Ahr were negatively correlated with bone mineral density (BMD). In addition, immunofluorescent staining showed that the high expression of Ahr was mainly localized in osteoblasts from the CIA mice compared to normal controls. Moreover, the luciferase intensity of Ahr in the nucleus increased by 12.5% in CIA osteoblasts compared to that in normal controls. In addition, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) activation of the Ahr inhibited pre-osteoblast MC3T3-E1 cellular proliferation and differentiation in a dose-dependent manner. Interestingly, the levels of alkaline phosphatase (ALP) mRNA expression in the osteoblasts of CIA mice were reduced compared to normal controls. In contrast, decreased ALP expression by activated Ahr was completely reversed after pretreatment with an Ahr inhibitor (CH-223191) in MC3T3-E1 cell lines and primary osteoblasts on day 5. Our data further showed that activation of Ahr promoted the phosphorylation of ERK after 5 days. Moreover, Ahr-dependent activation of the ERK signaling pathway decreased the levels of proliferation cells and inhibited ALP activity in MC3T3-E1 cells. These results demonstrated that the high expression of Ahr may suppress osteoblast proliferation and differentiation through activation of the ERK signaling pathway, further enabling bone erosion in CIA mice. - Highlights: • The upregulation of Ahr was localized in osteoblasts of CIA mice. • The overexpression of Ahr suppressed osteoblast development. • The Ahr activated ERK signaling pathway to exacerbate bone erosion.

  20. Calmodulin antagonists induce platelet apoptosis.

    PubMed

    Wang, Zhicheng; Li, Suping; Shi, Quanwei; Yan, Rong; Liu, Guanglei; Dai, Kesheng

    2010-04-01

    Calmodulin (CaM) antagonists induce apoptosis in various tumor models and inhibit tumor cell invasion and metastasis, thus some of which have been extensively used as anti-cancer agents. In platelets, CaM has been found to bind directly to the cytoplasmic domains of several platelet receptors. Incubation of platelets with CaM antagonists impairs the receptors-related platelet functions. However, it is still unknown whether CaM antagonists induce platelet apoptosis. Here we show that CaM antagonists N-(6-aminohexyl)-5-chloro-1-naphthalene sulfonamide (W7), tamoxifen (TMX), and trifluoperazine (TFP) induce apoptotic events in human platelets, including depolarization of mitochondrial inner transmembrane potential, caspase-3 activation, and phosphatidylserine exposure. CaM antagonists did not incur platelet activation as detected by P-selectin surface expression and PAC-1 binding. However, ADP-, botrocetin-, and alpha-thrombin-induced platelet aggregation, platelet adhesion and spreading on von Willebrand factor surface were significantly reduced in platelets pre-treated with CaM antagonists. Furthermore, cytosolic Ca(2+) levels were obviously elevated by both W7 and TMX, and membrane-permeable Ca(2+) chelator BAPTA-AM significantly reduced apoptotic events in platelets induced by W7. Therefore, these findings indicate that CaM antagonists induce platelet apoptosis. The elevation of the cytosolic Ca(2+) levels may be involved in the regulation of CaM antagonists-induced platelet apoptosis. PMID:20172594

  1. Constitutive IDO expression in human cancer is sustained by an autocrine signaling loop involving IL-6, STAT3 and the AHR.

    PubMed

    Litzenburger, Ulrike M; Opitz, Christiane A; Sahm, Felix; Rauschenbach, Katharina J; Trump, Saskia; Winter, Marcus; Ott, Martina; Ochs, Katharina; Lutz, Christian; Liu, Xiangdong; Anastasov, Natasa; Lehmann, Irina; Höfer, Thomas; von Deimling, Andreas; Wick, Wolfgang; Platten, Michael

    2014-02-28

    Indoleamine-2,3-dioxygenase (IDO) inhibitors have entered clinical trials based on their ability to restore anti-tumor immunity in preclinical studies. However, the mechanisms leading to constitutive expression of IDO in human tumors are largely unknown. Here we analyzed the pathways mediating constitutive IDO expression in human cancer. IDO-positive tumor cells and tissues showed basal phosphorylation and acetylation of STAT3 as evidenced by western blotting and immunoprecipitation. Inhibition of IL-6 or STAT3 using siRNA and/or pharmacological inhibitors reduced IDO mRNA and protein expression as well as kynurenine formation. In turn, IDO enzymatic activity activated the AHR as shown by the induction of AHR target genes. IDO-mediated AHR activation induced IL-6 expression, while inhibition or knockdown of the AHR reduced IL-6 expression. IDO activity thus sustains its own expression via an autocrine AHR-IL-6-STAT3 signaling loop. Inhibition of the AHR-IL-6-STAT3 signaling loop restored T-cell proliferation in mixed leukocyte reactions performed in the presence of IDO-expressing human cancer cells. Identification of the IDO-AHR-IL-6-STAT3 signaling loop maintaining IDO expression in human cancers reveals novel therapeutic targets for the inhibition of this core pathway promoting immunosuppression of human cancers. The relevance of the IDO-AHR-IL-6-STAT3 transcriptional circuit is underscored by the finding that high expression of its members IDO, STAT3 and the AHR target gene CYP1B1 is associated with reduced relapse-free survival in lung cancer patients. PMID:24657910

  2. Benzo[a]pyrene, 3-methylcholanthrene and beta-naphthoflavone induce oxidative stress in hepatoma hepa 1c1c7 Cells by an AHR-dependent pathway.

    PubMed

    Elbekai, Reem H; Korashy, Hesham M; Wills, Kelly; Gharavi, Negar; El-Kadi, Ayman O S

    2004-11-01

    Polycyclic aromatic hydrocarbons have been shown to cause oxidative stress in vitro and in vivo in various animal models but the mechanisms by which these compounds produce oxidative stress are unknown. In the current study we have investigated the role of the aryl hydrocarbon receptor (AHR) in the production of reactive oxygen species (ROS) by its cognate ligands and the consequent effect on cyp1a1 activity, mRNA and protein expressions. For this purpose, Hepa 1c1c7 cells wild-type (WT) and C12 mutant cells, which are AHR-deficient, were incubated with increasing concentrations of the AHR-ligands, benzo[a]pyrene (B[a]P, 0.25-25 microM), 3-methylcholanthrene (3MC, 0.1-10 microM) and beta-naphthoflavone (betaNF, 1-50 microM). The studied AHR-ligands dose-dependently increased lipid peroxidation in WT but not in C12 cells. However, only B[a]P and betaNF, at the highest concentrations tested, significantly increased H2O2 production in WT but not C12 cells. The increase in lipid peroxidation and H2O2 production by AHR-ligands were accompanied by a decrease in the cyp1a1 catalytic activity but not mRNA or protein expressions, which were significantly induced in a dose-dependent manner by all AHR-ligands, suggesting a post-translational mechanism is involved in the decrease of cyp1a1 activity. The AHR-ligand-mediated decrease in cyp1a1 activity was reversed by the antioxidant N-acetylcysteine. Our results show that the AHR-ligands induce oxidative stress by an AHR-dependent pathway. PMID:15621696

  3. TCDD promoted EMT of hFPECs via AhR, which involved the activation of EGFR/ERK signaling.

    PubMed

    Gao, Zhan; Bu, Yongjun; Liu, Xiaozhuan; Wang, Xugang; Zhang, Guofu; Wang, Erhui; Ding, Shibin; Liu, Yongfeng; Shi, Ruling; Li, Qiaoyun; Fu, Jianhong; Yu, Zengli

    2016-05-01

    One critical step of second palatal fusion is the newly formed medial epithelia seam (MES) disintegration, which involves apoptosis, epithelial to mesenchymal transition (EMT), and cell migration. Although the environmental toxicant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) produces cleft palate at high rates, little is known about the effects of TCDD exposure on the fate of palatal epithelial cells. By using primary epithelial cells isolated from human fetal palatal shelves (hFPECs), we show that TCDD increased cell proliferation and EMT, as demonstrated by increased the epithelial markers (E-cadherin and cytokeratin14) and enhanced the mesenchymal markers (vimentin and fibronectin), but had no effect on cell migration and apoptosis. TCDD exposure led to a dose-dependent increase in Slug protein expression. Coimmunoprecipitation revealed that TCDD promoted AhR to form a protein complex with Slug. ChIP assay confirmed that TCDD exposure recruited AhR to the xenobiotic responsive element of Slug promoter. Knockdown of AhR by siRNA remarkably weakened TCDD-induced binding of AhR to the XRE promoter of slug, thereby suppressed TCDD-induced vimentin. Further experiment showed that TCDD stimulated EGFR phosphorylation did not influence the TGFβ3/Smad signaling; whereas TCDD increased phosphorylation of ERK1/2 and p38 with no effect on activation of JNK. By using varieties of inhibitors, we confirmed that TCDD promoted proliferation and EMT of hFPECs via activation of EGFR/ERK pathway. These data make a novel contribution to the molecular mechanism of cleft palate by TCDD. PMID:26971374

  4. Role of endocrine disrupting chemicals in the occurrence of benign uterine leiomyomata: special emphasis on AhR tissue levels.

    PubMed

    Bidgoli, Sepideh Arbabi; Khorasani, Hoda; Keihan, Heideh; Sadeghipour, Alireza; Mehdizadeh, Abolfazl

    2012-01-01

    Although benign uterine leiomyomata (LMA) is the most common reproductive tumor in premenopausal women, its etiology is largely unknown. We aimed in the present study to demonstrate the potential role of environmental factors with estrogenic activity in tumor etiology by focusing on the role of aryl hydrocarbon receptor (AhR) which mediates the effects of many environmental endocrine disruptors and contributes to the loss of normal ovarian function in polluted environments. This case-control study aimed to compare the interactions between AhR and lifestyle factors in a clinical setting for the first time among 138 newly diagnosed LMA patients and 138 normal controls who lived in Tehran and Mashhad, respectively, during the last 10 years. To conduct immunohistochemical studies using appropriate monoclonal antibodies, 30 cases were selected retrospectively from 2009-2011 from the pathology departments of two university hospitals in Tehran. Although the levels of sex steroid receptors were similar in adjacent myometrium and uterine leiomyomas of all cases, AhR was significantly overexpressed (p=0.034, OR=1.667) in uterine LMA and this overexpression was correlated with living in Tehran [(p=0.04, OR=16 (1.216-210.58)], smoking[P=0.04, OR=2.085 (1.29-3.371)], living near polycyclic aromative hydrocarbon producing companies [p=0.007, OR=2.22 (1.256-3.926)] and eating grilled meat [p=0.042, OR=1.28 (1.92-3.842)]. Our study contributes to the understanding of the effects of EDCs on AhR levels as well as women's health and points out possible risk factors for the development and growth of uterine LMA. It seems that the development of LMA could be the result of interactions between hormonal and environmental factors. PMID:23317198

  5. AhR signaling activation disrupts migration and dendritic growth of olfactory interneurons in the developing mouse

    PubMed Central

    Kimura, Eiki; Ding, Yunjie; Tohyama, Chiharu

    2016-01-01

    Perinatal exposure to a low level of dioxin, a ubiquitous environmental pollutant, has been shown to induce abnormalities in learning and memory, emotion, and sociality in laboratory animals later in adulthood. However, how aryl hydrocarbon receptor (AhR) signaling activation disrupts the higher brain function remains unclear. Therefore, we studied the possible effects of excessive activation of AhR signaling on neurodevelopmental processes, such as cellular migration and neurite growth, in mice. To this end, we transfected a constitutively active-AhR plasmid into stem cells in the lateral ventricle by in vivo electroporation on postnatal day 1. Transfection was found to induce tangential migration delay and morphological abnormalities in neuronal precursors in the rostral migratory stream at 6 days post-electroporation (dpe) as well as disrupt radial migration in the olfactory bulb and apical and basal dendritic growth of the olfactory interneurons in the granule cell layer at 13 and 20 dpe. These results suggest that the retarded development of interneurons by the excessive AhR signaling may at least in part explain the dioxin-induced abnormal behavioral alterations previously reported in laboratory animals. PMID:27197834

  6. AhR signaling activation disrupts migration and dendritic growth of olfactory interneurons in the developing mouse.

    PubMed

    Kimura, Eiki; Ding, Yunjie; Tohyama, Chiharu

    2016-01-01

    Perinatal exposure to a low level of dioxin, a ubiquitous environmental pollutant, has been shown to induce abnormalities in learning and memory, emotion, and sociality in laboratory animals later in adulthood. However, how aryl hydrocarbon receptor (AhR) signaling activation disrupts the higher brain function remains unclear. Therefore, we studied the possible effects of excessive activation of AhR signaling on neurodevelopmental processes, such as cellular migration and neurite growth, in mice. To this end, we transfected a constitutively active-AhR plasmid into stem cells in the lateral ventricle by in vivo electroporation on postnatal day 1. Transfection was found to induce tangential migration delay and morphological abnormalities in neuronal precursors in the rostral migratory stream at 6 days post-electroporation (dpe) as well as disrupt radial migration in the olfactory bulb and apical and basal dendritic growth of the olfactory interneurons in the granule cell layer at 13 and 20 dpe. These results suggest that the retarded development of interneurons by the excessive AhR signaling may at least in part explain the dioxin-induced abnormal behavioral alterations previously reported in laboratory animals. PMID:27197834

  7. Zebrafish Cardiotoxicity: The Effects of CYP1A Inhibition and AHR2 Knockdown Following Exposure to Weak Aryl Hydrocarbon Receptor Agonists

    PubMed Central

    Clark, Bryan William; Van Tiem Garner, Lindsey; Di Giulio, Richard Thomas

    2014-01-01

    The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that mediates many of the toxic effects of dioxin-like compounds (DLCs) and some polycyclic aromatic hydrocarbons (PAHs). Strong AHR agonists, such as certain polychlorinated biphenyls and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), cause severe cardiac teratogenesis in fish embryos. Moderately strong AHR agonists, such as benzo[a]pyrene and β-naphthoflavone, have been shown to cause similar cardiotoxic effects when coupled with a cytochrome P450 1A (CYP1A) inhibitor, such as fluoranthene (FL). We sought to determine if weak AHR agonists, when combined with a CYP1A inhibitor (FL) or CYP1A morpholino gene knockdown, are capable of causing cardiac deformities similar to moderately strong AHR agonists (Wassenberg and Di Giulio 2004; Wassenberg and Di Giulio 2004; Billiard, Timme-Laragy et al. 2006; Van Tiem and Di Giulio 2011). The weak AHR agonists included the following: carbaryl, phenanthrene, 2-methylindole, 3-methylindole, indigo, and indirubin. The results showed a complex pattern of cardiotoxic response to weak agonist inhibitor exposure and morpholino-knockdown. Danio rerio (zebrafish) embryos were first exposed to weak AHR agonists at equimolar concentrations. The agonists were assessed for their relative potency as inducers of CYP1 enzyme activity, measured by the ethoxyresorufin-o-deethylase (EROD) assay, and cardiac deformities. Carbaryl, 2-methylindole, and 3-methylindole induced the highest CYP1A activity in zebrafish. Experiments were then conducted to determine the individual cardiotoxicity of each compound. Next, zebrafish were co-exposed to each agonist (at concentrations below those determined to be cardiotoxic) and FL in combination to assess if CYP1A inhibition could induce cardiac deformities. Carbaryl, 2-methylindole, 3-methylindole, and phenanthrene significantly increased pericardial edema relative to controls when combined with FL. To further evaluate the

  8. Integration of Genome-Wide Computation DRE Search, AhR ChIP-chip and Gene Expression Analyses of TCDD-Elicited Responses in the Mouse Liver

    PubMed Central

    2011-01-01

    Background The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor (TF) that mediates responses to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Integration of TCDD-induced genome-wide AhR enrichment, differential gene expression and computational dioxin response element (DRE) analyses further elucidate the hepatic AhR regulatory network. Results Global ChIP-chip and gene expression analyses were performed on hepatic tissue from immature ovariectomized mice orally gavaged with 30 μg/kg TCDD. ChIP-chip analysis identified 14,446 and 974 AhR enriched regions (1% false discovery rate) at 2 and 24 hrs, respectively. Enrichment density was greatest in the proximal promoter, and more specifically, within ± 1.5 kb of a transcriptional start site (TSS). AhR enrichment also occurred distal to a TSS (e.g. intergenic DNA and 3' UTR), extending the potential gene expression regulatory roles of the AhR. Although TF binding site analyses identified over-represented DRE sequences within enriched regions, approximately 50% of all AhR enriched regions lacked a DRE core (5'-GCGTG-3'). Microarray analysis identified 1,896 number of TCDD-responsive genes (|fold change| ≥ 1.5, P1(t) > 0.999). Integrating this gene expression data with our ChIP-chip and DRE analyses only identified 625 differentially expressed genes that involved an AhR interaction at a DRE. Functional annotation analysis of differentially regulated genes associated with AhR enrichment identified overrepresented processes related to fatty acid and lipid metabolism and transport, and xenobiotic metabolism, which are consistent with TCDD-elicited steatosis in the mouse liver. Conclusions Details of the AhR regulatory network have been expanded to include AhR-DNA interactions within intragenic and intergenic genomic regions. Moreover, the AhR can interact with DNA independent of a DRE core suggesting there are alternative mechanisms of AhR-mediated gene regulation. PMID:21762485

  9. Ultraviolet light converts propranolol, a nonselective β-blocker and potential lupus-inducing drug, into a proinflammatory AhR ligand.

    PubMed

    Dorgham, Karim; Amoura, Zahir; Parizot, Christophe; Arnaud, Laurent; Frances, Camille; Pionneau, Cédric; Devilliers, Hervé; Pinto, Sandra; Zoorob, Rima; Miyara, Makoto; Larsen, Martin; Yssel, Hans; Gorochov, Guy; Mathian, Alexis

    2015-11-01

    UV light and some medications are known to trigger lupus erythematosus (LE). A common mechanism underlying the immunopathologic effect, resulting from exposure to these two seemingly unrelated factors, remains unknown. The aryl hydrocarbon receptor (AhR) plays a key role in the regulation of IL-22 production in humans and can be activated by both xenobiotics and naturally occurring photoproducts. A significant expansion of Th17 and Th22 cells was observed in the peripheral blood of active systemic LE (SLE) patients, compared to inactive patients and controls. We also show that propranolol, a potential lupus-inducing drug, induced stronger AhR activation in PBMCs of SLE patients than in those of controls. AhR agonist activity of propranolol was enhanced by UV light exposure. MS analysis of irradiated propranolol revealed the generation of a proinflammatory photoproduct. This compound behaves like the prototypic AhR ligand 6-formylindolo[3,2-b]carbazole, a cutaneous UV light-induced tryptophan metabolite, both promoting IL-22, IL-8, and CCL2 secretion by T-cells and macrophages. Finally, LE patients exhibit signs of cutaneous AhR activation that correlate with lesional expression of the same proinflammatory cytokines, suggesting a role for photometabolites in the induction of skin inflammation. The AhR might therefore represent a target for therapeutic intervention in LE. PMID:26354876

  10. Phenotype refinement strengthens the association of AHR and CYP1A1 genotype with caffeine consumption.

    PubMed

    McMahon, George; Taylor, Amy E; Davey Smith, George; Munafò, Marcus R

    2014-01-01

    Two genetic loci, one in the cytochrome P450 1A1 (CYP1A1) and 1A2 (CYP1A2) gene region (rs2472297) and one near the aryl-hydrocarbon receptor (AHR) gene (rs6968865), have been associated with habitual caffeine consumption. We sought to establish whether a more refined and comprehensive assessment of caffeine consumption would provide stronger evidence of association, and whether a combined allelic score comprising these two variants would further strengthen the association. We used data from between 4,460 and 7,520 women in the Avon Longitudinal Study of Parents and Children, a longitudinal birth cohort based in the United Kingdom. Self-report data on coffee, tea and cola consumption (including consumption of decaffeinated drinks) were available at multiple time points. Both genotypes were individually associated with total caffeine consumption, and with coffee and tea consumption. There was no association with cola consumption, possibly due to low levels of consumption in this sample. There was also no association with measures of decaffeinated drink consumption, indicating that the observed association is most likely mediated via caffeine. The association was strengthened when a combined allelic score was used, accounting for up to 1.28% of phenotypic variance. This was not associated with potential confounders of observational association. A combined allelic score accounts for sufficient phenotypic variance in caffeine consumption that this may be useful in Mendelian randomization studies. Future studies may therefore be able to use this combined allelic score to explore causal effects of habitual caffeine consumption on health outcomes. PMID:25075865

  11. Hexachlorobenzene stimulates uroporphyria in low affinity AHR mice without increasing CYP1A2

    SciTech Connect

    Gorman, Nadia; Trask, Heidi S.; Robinson, Susan W.; Sinclair, Jacqueline F.; Smith, Andrew G.; Sinclair, Peter R. . E-mail: psinc@dartmouth.edu

    2007-06-01

    Hexachlorobenzene (HCB), a weak ligand of the aryl hydrocarbon receptor (AHR), causes hepatic uroporphyrin (URO) accumulation (uroporphyria) in humans and animals. CYP1A2 has been shown to be necessary in the development of uroporphyria in mice. Using mice expressing the low affinity form of the AH receptor (AHRd), we investigated whether the enhancement of uroporphyria by HCB involves an obligatory increase in CYP1A2 as measured by specific enzyme assays and immunoblotting. We compared the ability of HCB, in combination with iron dextran and the porphyrin precursor, 5-aminolevulinate (ALA), to cause uroporphyria in a strain of mice (C57BL/6) which expresses the high affinity form of the receptor (AHRb{sub 1}), with three strains of mice (SWR and two 129 sublines) expressing the low affinity AHRd. In C57BL/6 mice, HCB-enhanced uroporphyria was associated with a doubling of CYP1A2. HCB treatment produced uroporphyria in iron-loaded mice expressing AHRd, even though there was little or no increase in CYP1A2. Cyp1a2(-/-) mice in a 129 background were completely resistant to HCB-induced uroporphyria, and female Hfe(-/-) 129 mice, in which the levels of hepatic CYP1A2 were half of those of the male levels, responded poorly. The effect of exogenous iron, administered in the form of iron dextran, on HCB enhancement of uroporphryia could be replicated utilizing the endogenous hepatic iron accumulated in 129 Hfe(-/-) mice. In conclusion, some minimal basal expression of CYP1A2 is essential for HCB-mediated enhancement of uroporphyria, but increases in CYP1A2 above that level are not essential.

  12. [Vitamin K antagonists overdose].

    PubMed

    Groszek, Barbara; Piszczek, Paweł

    2015-01-01

    Nowadays, anticoagulant therapy belongs to the most commonly used forms of pharmacotherapy in modern medicine. The most important representatives of anticoagulants are heparins (unfractionated heparin and low-molecular-weight heparin) and coumarin derivatives (vitamin K antagonists--VKA). Next to the many advantages of traditional oral anticoagulants may also have disadvantages. In Poland most often used two VKA: acenocoumarol and warfarin. The aim of the work is the analysis of the causes of the occurrence of bleeding disorders and symptoms of overdose VKA in patients to be hospitalized. In the years 2012 to 2014 were hospitalized 62 patients with overdose VKA (40 women and 22 men). The average age of patients was 75.3 years) and clotting disturbances and/or bleeding. At the time of the admission in all patients a significant increase in the value of the INR was stated, in 22 patients INR result was " no clot detected", on the remaining value of the INR were in the range of 7 to 13.1. On 51 patients observed different severe symptoms of bleeding (hematuria, bleeding from mucous membranes of the nose or gums ecchymoses on the extremities, bleeding from the gastrointestinal tract--as in 5 patients has led to significant anemia and transfusion of concentrated red blood cells. Up on 33 patients kidney function disorder were found--exacerbated chronic renal failure and urinary tract infection. 8 diagnosed inflammatory changes in the airways. On 13 patients, it was found a significant degree of neuropsychiatric disorders (dementia, cognitive impairment), which made impossible the understanding the sense of treatment and cooperation with the patient. In 6 patients the symptoms of overdose were probably dependent on the interaction with the congestants at the same time (change the preparation of anticoagulant, NSAIDs, antibiotics). In 2 cases, the overdose was a suicide attempt in nature. In addition to the above mentioned disorders, on two of those patients diagnosed

  13. Deficiency in Aryl Hydrocarbon Receptor (AHR) Expression throughout Aging Alters Gene Expression Profiles in Murine Long-Term Hematopoietic Stem Cells

    PubMed Central

    Bennett, John A.; Singh, Kameshwar P.; Unnisa, Zeenath; Welle, Stephen L.; Gasiewicz, Thomas A.

    2015-01-01

    Dysregulation of hematopoietic stem cell (HSC) signaling can contribute to the development of diseases of the blood system. Lack of aryl hydrocarbon receptor (AhR) has been associated with alterations in gene expression related to HSC function and the subsequent development of a myeloproliferative disorder in aging female mice. We sorted the most primitive population of HSCs with the highest stem cell potential (Long-term, or LT-HSCs) from 18-month-old AhR-null-allele (AhR-KO) and WT mice and analyzed gene expression using microarray to determine alterations in gene expression and cell signaling networks in HSCs that could potentially contribute to the aging phenotype of AhR-KO mice. Comparisons with previous array data from 8-week old mice indicated that aging alone is sufficient to alter gene expression. In addition, a significant number of gene expression differences were observed in aged LT-HSCs that are dependent on both aging and lack of AhR. Pathway analysis of these genes revealed networks related to hematopoietic stem cell activity or function. qPCR was used to confirm the differential expression of a subset of these genes, focusing on genes that may represent novel AhR targets due to the presence of a putative AhR binding site in their upstream regulatory region. We verified differential expression of PDGF-D, Smo, Wdfy1, Zbtb37 and Zfp382. Pathway analysis of this subset of genes revealed overlap between cellular functions of the novel AhR targets and AhR itself. Lentiviral-mediated knockdown of AhR in lineage-negative hematopoietic cells was sufficient to induce changes in all five of the candidate AhR targets identified. Taken together, these data suggest a role for AhR in HSC functional regulation, and identify novel HSC AhR target genes that may contribute to the phenotypes observed in AhR-KO mice. PMID:26208102

  14. Behavioral Rhythmicity of Mice Lacking AhR and Attenuation of Light-induced Phase Shift by 2,3,7,8-Tetracholordibenzo-p-dioxin

    PubMed Central

    Mukai, Motoko; Lin, Tien-Min; Peterson, Richard E.; Cooke, Paul S.; Tischkau, Shelley A.

    2008-01-01

    Transcription factors belonging to the Per/Arnt/Sim (PAS) domain family are highly conserved and many are involved in circadian rhythm regulation. One member of this family, aryl hydrocarbon receptor (AhR), is an orphan receptor whose physiological role is unknown. Recent findings have led to the hypothesis that AhR has a role in circadian rhythm, which is the focus of the present investigation. First, time-of-day dependent mRNA expression of AhR and its signaling target, cytochrome p4501A1 (Cyp1a1) was determined in C57BL/6J mice by quantitative RT-PCR. Circadian expression of AhR and Cyp1a1 was observed both in the suprachiasmatic nucleus (SCN) and liver. Next, the circadian phenotype of mice lacking AhR (AhRKO) was investigated using behavioral monitoring. Intact AhRKO mice had robust circadian rhythmicity with a similar tau under constant conditions compared to wild-type mice, but a significant difference in tau was observed between genotypes in ovariectomized female mice. Time to re-entrainment following 6-h advances or delays of the light/dark cycle was not significantly different between genotypes. However, mice exposed to the AhR agonist 2,3,7,8-tetracholorodibenzo-p-dioxin (TCDD, 1 μg/kg BW) displayed decreased phase shifts in response to light and had altered expression of Per1 and Bmal1. These results suggest that chronic activation of AhR may affect the ability of the circadian timekeeping system to adjust to alterations in environmental lighting by affecting canonical clock genes. Further studies are necessary to decipher the mechanism of how AhR agonists could disrupt light-induced phase shifts. If AhR does have a role in circadian rhythm, it may share redundant roles with other PAS domain proteins and/or the role of AhR may not be exhibited in the behavioral activity rhythm, but could be important elsewhere in the peripheral circadian system. PMID:18487412

  15. Sequence and in vitro function of chicken, ring-necked pheasant, and Japanese quail AHR1 predict in vivo sensitivity to dioxins.

    PubMed

    Farmahin, Reza; Wu, Dongmei; Crump, Doug; Hervé, Jessica C; Jones, Stephanie P; Hahn, Mark E; Karchner, Sibel I; Giesy, John P; Bursian, Steven J; Zwiernik, Matthew J; Kennedy, Sean W

    2012-03-01

    There are large differences in sensitivity to the toxic and biochemical effects of dioxins and dioxin-like compounds (DLCs) among vertebrates. Previously, we demonstrated that the difference in sensitivity between domestic chicken (Gallus gallus domesticus) and common tern (Sterna hirundo) to aryl hydrocarbon receptor 1 (AHR1)-dependent changes in gene expression following exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is based upon the identities of the amino acids at two sites within the ligand binding domain of AHR1 (chicken--highly sensitive; Ile324_Ser380 vs common tern--250-fold less sensitive than chicken; Val325_Ala381). Here, we tested the hypotheses that (i) the sensitivity of other avian species to TCDD, 2,3,4,7,8-pentachlorodibenzofuran (PeCDF), and 2,3,7,8-tetrachlorodibenzofuran (TCDF) is also determined by the amino acids at sites that are equivalent to sites 324 and 380 in chicken, and (ii) Ile324_Ala380 and Val324_Ser380 genotypes confer intermediate sensitivity to DLCs in birds. We compared ligand-induced transactivation function of full-length AHR1s from chicken, common tern, ring-necked pheasant (Phasianus colchicus; Ile324_Ala380) and Japanese quail (Coturnix japonica; Val324_Ala380), and three Japanese quail AHR1 mutants. The results support our hypothesis that avian species can be grouped into three general classes of sensitivity to DLCs. Both AHR1 genotype and in vitro transactivation assays predict in vivo sensitivity. Contrary to the assumption that TCDD is the most potent DLC, PeCDF was more potent than TCDD at activating Japanese quail (13- to 26-fold) and common tern (23- to 30-fold) AHR1. Our results support and expand previous in vitro and in vivo work that demonstrated ligand-dependent species differences in AHR1 affinity. The findings and methods will be of use for DLC risk assessments. PMID:22296185

  16. Fibroblast growth factor (Fgf) 21 is a novel target gene of the aryl hydrocarbon receptor (AhR).

    PubMed

    Cheng, Xingguo; Vispute, Saurabh G; Liu, Jie; Cheng, Christine; Kharitonenkov, Alexei; Klaassen, Curtis D

    2014-07-01

    The toxic effects of dioxins, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), mainly through activation of the aryl hydrocarbon receptor (AhR) are well documented. Fibroblast growth factor (Fgf) 21 plays critical roles in metabolic adaptation to fasting by increasing lipid oxidation and ketogenesis in the liver. The present study was performed to determine whether activation of the AhR induces Fgf21 expression. In mouse liver, TCDD increased Fgf21 mRNA in both dose- and time-dependent manners. In addition, TCDD markedly increased Fgf21 mRNA expression in cultured mouse and human hepatocytes. Moreover, TCDD increased mRNA (in liver) and protein levels (in both liver and serum) of Fgf21 in wild-type mice, but not in AhR-null mice. Chromatin immunoprecipitation assays showed that TCDD increased AhR protein binding to the Fgf21 promoter (-105/+1 base pair). Fgf21-null mice administered 200μg/kg of TCDD died within 20days, whereas wild-type mice receiving the same treatment were still alive at one month after administration. This indicates that TCDD-induced Fgf21 expression protects against TCDD toxicity. Diethylhexylphthalate (DEHP) pretreatment attenuated TCDD-induced Fgf21 expression in mouse liver and white adipose tissue, which may explain a previous report that DEHP pretreatment decreases TCDD-induced wasting. In conclusion, Fgf21 appears to be a target gene of AhR-signaling pathway in mouse and human liver. PMID:24769090

  17. Fibroblast growth factor (Fgf) 21 is a novel target gene of the aryl hydrocarbon receptor (AhR)

    SciTech Connect

    Cheng, Xingguo; Vispute, Saurabh G.; Liu, Jie; Cheng, Christine; Kharitonenkov, Alexei; Klaassen, Curtis D.

    2014-07-01

    The toxic effects of dioxins, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), mainly through activation of the aryl hydrocarbon receptor (AhR) are well documented. Fibroblast growth factor (Fgf) 21 plays critical roles in metabolic adaptation to fasting by increasing lipid oxidation and ketogenesis in the liver. The present study was performed to determine whether activation of the AhR induces Fgf21 expression. In mouse liver, TCDD increased Fgf21 mRNA in both dose- and time-dependent manners. In addition, TCDD markedly increased Fgf21 mRNA expression in cultured mouse and human hepatocytes. Moreover, TCDD increased mRNA (in liver) and protein levels (in both liver and serum) of Fgf21 in wild-type mice, but not in AhR-null mice. Chromatin immunoprecipitation assays showed that TCDD increased AhR protein binding to the Fgf21 promoter (− 105/+ 1 base pair). Fgf21-null mice administered 200 μg/kg of TCDD died within 20 days, whereas wild-type mice receiving the same treatment were still alive at one month after administration. This indicates that TCDD-induced Fgf21 expression protects against TCDD toxicity. Diethylhexylphthalate (DEHP) pretreatment attenuated TCDD-induced Fgf21 expression in mouse liver and white adipose tissue, which may explain a previous report that DEHP pretreatment decreases TCDD-induced wasting. In conclusion, Fgf21 appears to be a target gene of AhR-signaling pathway in mouse and human liver. - Highlights: • TCDD induced Fgf21 expression at both mRNA and protein levels. • Fgf21 induction by TCDD is AhR-dependent. • DEHP attenuated TCDD-induced Fgf21 expression.

  18. Sexually antagonistic genes: experimental evidence.

    PubMed

    Rice, W R

    1992-06-01

    When selection differs between the sexes, a mutation beneficial to one sex may be harmful to the other (sexually antagonistic). Because the sexes share a common gene pool, selection in one sex can interfere with the other's adaptive evolution. Theory predicts that sexually antagonistic mutations should accumulate in tight linkage with a new sex-determining gene, even when the harm to benefit ratio is high. Genetic markers and artificial selection were used to make a pair of autosomal genes segregate like a new pair of sex-determining genes in a Drosophila melanogaster model system. A 29-generation study provides experimental evidence that sexually antagonistic genes may be common in nature and will accumulate in response to a new sex-determining gene. PMID:1604317

  19. Differential Proteomics Analysis Reveals a Role for E2F2 in the Regulation of the Ahr Pathway in T Lymphocytes§

    PubMed Central

    Azkargorta, Mikel; Fullaondo, Asier; Laresgoiti, Usua; Aloria, Kerman; Infante, Arantza; Arizmendi, Jesus M.; Zubiaga, Ana M.

    2010-01-01

    E2F transcription factors (E2F1-8) are best known for their role in cell proliferation, although it is clear that they regulate many other biological processes through the transcriptional modulation of distinct target genes. However, the specific set of genes regulated by each E2F remains to be characterized. To gain insight into the molecular pathways regulated by E2F2, we have analyzed the proteome of antigen receptor–activated T cells lacking E2F2. We report that loss of E2F2 results in a deregulated Aryl-hydrocarbon-receptor pathway. Proliferating E2F2−/− T lymphocytes expressed significantly higher levels of Aip, Ahr, and Arnt relative to wild-type (WT)1 controls. The mechanism for increased levels of Aip appears straightforward, involving direct regulation of the Aip gene promoter by E2F2. Although the Ahr and Arnt promoters also bind E2F2, their regulation appears to be more complex. Nevertheless, exposure to the environmental xenobiotic 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a well-known exogenous ligand of the Ahr pathway, led to overexpression of the Ahr target gene Cyp1a1, and to increased sensitivity to TCDD-triggered apoptosis in E2F2−/− T cells compared with WT controls. These results suggest that E2F2 modulates cellular sensitivity to xenobiotic signals through the negative regulation of the Ahr pathway. PMID:20573986

  20. Structure of the C-terminal effector-binding domain of AhrC bound to its corepressor l-arginine

    SciTech Connect

    Garnett, James A.; Baumberg, Simon; Stockley, Peter G.; Phillips, Simon E. V.

    2007-11-01

    The crystal structure of the C-terminal domain hexameric core of AhrC, with bound corepressor (l-arginine), has been solved at 1.95 Å resolution. Binding of l-arginine results in a rotation between the two trimers of the hexamer, leading to the activation of the DNA-binding state. The arginine repressor/activator protein (AhrC) from Bacillus subtilis belongs to a large family of multifunctional transcription factors that are involved in the regulation of bacterial arginine metabolism. AhrC interacts with operator sites in the promoters of arginine biosynthetic and catabolic operons, acting as a transcriptional repressor at biosynthetic sites and an activator of transcription at catabolic sites. AhrC is a hexamer of identical subunits, each having two domains. The C-terminal domains form the core of the protein and are involved in oligomerization and l-arginine binding. The N-terminal domains lie on the outside of the compact core and play a role in binding to 18 bp DNA operators called ARG boxes. The C-terminal domain of AhrC has been expressed, purified and characterized, and also crystallized as a hexamer with the bound corepressor l-arginine. Here, the crystal structure refined to 1.95 Å is presented.

  1. Comparative in vitro transformation of the aromatic hydrocarbon receptor (AhR) by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and 3-methylcholanthrene (MC)

    SciTech Connect

    Riddick, D.S.; Harper, P.A.; Okey, A.B.; Riddick, D.S. )

    1992-02-26

    The induction of CYP1A1 by halogenated (e.g. TCDD) and nonhalogenated (e.g. MC) aromatic hydrocarbons is mediated by the AhR. In cytosol prepared from the mouse hepatoma cell line Hepa-1, AhR bound TCDD with 3 to 4-fold greater affinity than MC, whereas TCDD was 960-fold more potent than MC as an inducer of aryl hydrocarbon hydroxylase (AHH) activity in cultured Hepa-1 cells. The objective of this study was to compare the potency and efficacy of TCDD and MC with respect to transformation of the cytosolic AhR to its DNA-binding form. Following incubation of Hepa-1 cytosol with TCDD or MC at 30 C for 4 h, the extent of AhR transformation was assessed by measuring interaction of the AhR-ligand complex with a {sup 32}P-labeled 26-bp oligonucleotide containing a single dioxin-responsive element (DRE) consensus sequence in a gel retardation assay. Concentration-response studies indicated that TCDD and MC did not differ significantly in AhR transformation potency, but MC displayed only about 70% of the efficacy of TCDD. In vitro transformation efficacy appears to be a determinant of AHH induction efficacy, but the small difference between TCDD and MC in transformation potency does not seem adequate to explain quantitatively the large difference in AHH induction potency displayed by these ligands.

  2. The licorice flavonoid isoliquiritigenin reduces DNA-binding activity of AhR in MCF-7 cells.

    PubMed

    Wong, Tsz Yan; Lin, Shu-mei; Poon, Ching Ho; Leung, Lai K

    2014-09-25

    Licorice is derived from the rhizomes of Glycyrrhiza glabra. It has been used for confectioneries or culinary purposes. The rhizomes contain many flavonoidal compounds that have been shown to be biologically active. In the present study, effect of the licorice flavonoid isoliquiritigenin (ILN) on polycyclic aromatic hydrocarbon (PAH)-induced XRE transactivation and the downstream expression were investigated in MCF-7 cells. The environmental toxicant PAHs are pro-carcinogens and are biotransformed into their ultimate genotoxic structures by cytochrome P450 (CYP) 1 enzymes. Reporter gene assay revealed that ILN reduced XRE transactivation triggered by 7,12-dimethylbenz[α]anthracene (DMBA) or 2,3,7,8-Tetrachlorodibenzodioxin (TCDD). Our EMSA results also demonstrated that the flavonoid diminished DMBA-induced XRE binding. The reduced transactivation could be the result of a decreased amount of AhR translocating from cytosol to nucleus as shown in Western analysis. Quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) assay demonstrated that expressions of genes with XRE-containing promoters, including CYP1A1, 1A2, and 1B1, followed the same pattern of XRE transactivation. The present study illustrated that ILN might downregulate PAH-induced expressions through antagonizing AhR translocation. PMID:25110319

  3. Sequence variants at CYP1A1–CYP1A2 and AHR associate with coffee consumption

    PubMed Central

    Sulem, Patrick; Gudbjartsson, Daniel F.; Geller, Frank; Prokopenko, Inga; Feenstra, Bjarke; Aben, Katja K.H.; Franke, Barbara; den Heijer, Martin; Kovacs, Peter; Stumvoll, Michael; Mägi, Reedik; Yanek, Lisa R.; Becker, Lewis C.; Boyd, Heather A.; Stacey, Simon N.; Walters, G. Bragi; Jonasdottir, Adalbjorg; Thorleifsson, Gudmar; Holm, Hilma; Gudjonsson, Sigurjon A.; Rafnar, Thorunn; Björnsdottir, Gyda; Becker, Diane M.; Melbye, Mads; Kong, Augustine; Tönjes, Anke; Thorgeirsson, Thorgeir; Thorsteinsdottir, Unnur; Kiemeney, Lambertus A.; Stefansson, Kari

    2011-01-01

    Coffee is the most commonly used stimulant and caffeine is its main psychoactive ingredient. The heritability of coffee consumption has been estimated at around 50%. We performed a meta-analysis of four genome-wide association studies of coffee consumption among coffee drinkers from Iceland (n = 2680), the Netherlands (n = 2791), the Sorbs Slavonic population isolate in Germany (n = 771) and the USA (n = 369) using both directly genotyped and imputed single nucleotide polymorphisms (SNPs) (2.5 million SNPs). SNPs at the two most significant loci were also genotyped in a sample set from Iceland (n = 2430) and a Danish sample set consisting of pregnant women (n = 1620). Combining all data, two sequence variants significantly associated with increased coffee consumption: rs2472297-T located between CYP1A1 and CYP1A2 at 15q24 (P = 5.4 · 10−14) and rs6968865-T near aryl hydrocarbon receptor (AHR) at 7p21 (P = 2.3 · 10−11). An effect of ∼0.2 cups a day per allele was observed for both SNPs. CYP1A2 is the main caffeine metabolizing enzyme and is also involved in drug metabolism. AHR detects xenobiotics, such as polycyclic aryl hydrocarbons found in roasted coffee, and induces transcription of CYP1A1 and CYP1A2. The association of these SNPs with coffee consumption was present in both smokers and non-smokers. PMID:21357676

  4. Activation of Aryl Hydrocarbon Receptor (AhR) Leads to Reciprocal Epigenetic Regulation of FoxP3 and IL-17 Expression and Amelioration of Experimental Colitis

    PubMed Central

    Singh, Balwan; Price, Robert L.; Nagarkatti, Mitzi; Nagarkatti, Prakash S.

    2011-01-01

    Background Aryl hydrocarbon receptor (AhR), a transcription factor of the bHLH/PAS family, is well characterized to regulate the biochemical and toxic effects of environmental chemicals. More recently, AhR activation has been shown to regulate the differentiation of Foxp3+ Tregs as well as Th17 cells. However, the precise mechanisms are unclear. In the current study, we investigated the effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a potent AhR ligand, on epigenetic regulation leading to altered Treg/Th17 differentiation, and consequent suppression of colitis. Methodology/Principal Findings Dextran sodium sulphate (DSS) administration induced acute colitis in C57BL/6 mice, as shown by significant weight loss, shortening of colon, mucosal ulceration, and increased presence of CXCR3+ T cells as well as inflammatory cytokines. Interestingly, a single dose of TCDD (25 µg/kg body weight) was able to attenuate all of the clinical and inflammatory markers of colitis. Analysis of T cells in the lamina propria (LP) and mesenteric lymph nodes (MLN), during colitis, revealed decreased presence of Tregs and increased induction of Th17 cells, which was reversed following TCDD treatment. Activation of T cells from AhR+/+ but not AhR -/- mice, in the presence of TCDD, promoted increased differentiation of Tregs while inhibiting Th17 cells. Analysis of MLN or LP cells during colitis revealed increased methylation of CpG islands of Foxp3 and demethylation of IL-17 promoters, which was reversed following TCDD treatment. Conclusions/Significance These studies demonstrate for the first time that AhR activation promotes epigenetic regulation thereby influencing reciprocal differentiation of Tregs and Th17 cells, and amelioration of inflammation. PMID:21858153

  5. Disruption of period gene expression alters the inductive effects of dioxin on the AhR signaling pathway in the mouse liver

    SciTech Connect

    Qu Xiaoyu; Metz, Richard P.; Porter, Weston W.; Cassone, Vincent M.; Earnest, David J.

    2009-02-01

    The aryl hydrocarbon receptor (AhR) and AhR nuclear translocator (ARNT) are transcription factors that express Per-Arnt-Sim (PAS) DNA-binding motifs and mediate the metabolism of drugs and environmental toxins in the liver. Because these transcription factors interact with other PAS genes in molecular feedback loops forming the mammalian circadian clockworks, we determined whether targeted disruption or siRNA inhibition of Per1 and Per2 expression alters toxin-mediated regulation of the AhR signaling pathway in the mouse liver and Hepa1c1c7 hepatoma cells in vitro. Treatment with the prototypical Ahr ligand, 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), had inductive effects on the primary targets of AhR signaling, Cyp1A1 and Cyp1B1, in the liver of all animals, but genotype-based differences were evident such that the toxin-mediated induction of Cyp1A1 expression was significantly greater (2-fold) in mice with targeted disruption of Per1 (Per1{sup ldc} and Per1{sup ldc}/Per2{sup ldc}). In vitro experiments yielded similar results demonstrating that siRNA inhibition of Per1 significantly increases the TCDD-induced expression of Cyp1A1 and Cyp1B1 in Hepa1c1c7 cells. Per2 inhibition in siRNA-infected Hepa1c1c7 cells had the opposite effect and significantly decreased both the induction of these p450 genes as well as AhR and Arnt expression in response to TCDD treatment. These findings suggest that Per1 may play a distinctive role in modulating AhR-regulated responses to TCDD in the liver.

  6. Measured and predicted affinities of binding and relative potencies to activate the AhR of PAHs and their alkylated analogues.

    PubMed

    Lee, Sangwoo; Shin, Woong-Hee; Hong, Seongjin; Kang, Habyeong; Jung, Dawoon; Yim, Un Hyuk; Shim, Won Joon; Khim, Jong Seong; Seok, Chaok; Giesy, John P; Choi, Kyungho

    2015-11-01

    Polycyclic aromatic hydrocarbons (PAHs) and their alkylated forms are important components of crude oil. Both groups of PAHs have been reported to cause dioxin-like responses, mediated by aryl hydrocarbon receptor (AhR). Thus, characterization of binding affinity to the AhR of unsubstituted or alkylated PAHs is important to understand the toxicological consequences of oil contamination on ecosystems. We investigated the potencies of major PAHs of crude oil, e.g., chrysene, phenanthrene and dibenzothiophene, and their alkylated forms (n=17) to upregulate expression of AhR-mediated processes by use of the H4IIE-luc transactivation bioassay. In addition, molecular descriptors of different AhR activation potencies among PAHs were investigated by use of computational molecular docking models. Based on responses of the H4IIE-luc in vitro assay, it was shown that potencies of PAHs were determined by alkylation in addition to the number and conformation of rings. Potencies of AhR-mediated processes were generally greater when a chrysene group was substituted, especially in 1-methyl-chrysene. Significant negative correlations were observed between the in vitro dioxin-like potency measured in H4IIE-luc cells and the binding distance estimated from the in silico modeling. The difference in relative potency for AhR activation observed among PAHs and their alkylated forms could be explained by differences among binding distances in the ligand binding domain of the AhR caused by alkylation. The docking model developed in the present study may have utility in predicting risks of environmental contaminants of which toxicities are mediated by AhR binding. PMID:26037956

  7. Aminoflavone, a ligand of the Aryl Hydrocarbon Receptor (AhR), inhibits HIF-1α expression in an AhR-independent fashion

    PubMed Central

    Terzuoli, Erika; Puppo, Maura; Rapisarda, Annamaria; Uranchimeg, Badarch; Cao, Liang; Burger, Angelika M.; Ziche, Marina; Melillo, Giovanni

    2010-01-01

    Aminoflavone (AF), the active component of a novel anticancer agent (AFP464) in phase I clinical trials, is a ligand of the aryl hydrocarbon receptor (AhR). AhR dimerizes with HIF-1β/ARNT, which is shared with HIF-1α, a transcription factor critical for the response of cells to oxygen deprivation. To address whether pharmacological activation of the AhR pathway might be a potential mechanism for inhibition of HIF-1, we tested the effects of AF on HIF-1 expression. AF inhibited HIF-1α transcriptional activity and protein accumulation in MCF-7 cells. However, inhibition of HIF-1α by AF was independent from a functional AhR pathway. Indeed, AF inhibited HIF-1α expression in AhR100 cells, in which the AhR pathway is functionally impaired, yet did not induce cytotoxicity, providing evidence that these effects are mediated by distinct signaling pathways. Moreover, AF was inactive in MDA-MB-231 cells, yet inhibited HIF-1α in MDA-MB-231 cells transfected with the SULT1A1 gene. AF inhibited HIF-1α mRNA expression by approximately 50%. Notably, actinomycin-D completely abrogated the ability of AF to down-regulate HIF-1α mRNA, indicating that active transcription was required for the inhibition of HIF-1α expression. Finally, AF inhibited HIF-1α protein accumulation and the expression of HIF-1-target genes in MCF-7 xenografts. These results demonstrate that AF inhibits HIF-1α in an AhR-independent fashion and they unveil additional activities of AF that may be relevant for its further clinical development. PMID:20736373

  8. Baicalein induces G1 arrest in oral cancer cells by enhancing the degradation of cyclin D1 and activating AhR to decrease Rb phosphorylation

    SciTech Connect

    Cheng, Ya-Hsin; Li, Lih-Ann; Lin, Pinpin; Cheng, Li-Chuan; Hung, Chein-Hui; Chang, Nai Wen; Lin, Chingju

    2012-09-15

    Baicalein is a flavonoid, known to have anti-inflammatory and anti-cancer effects. As an aryl hydrocarbon receptor (AhR) ligand, baicalein at high concentrations blocks AhR-mediated dioxin toxicity. Because AhR had been reported to play a role in regulating the cell cycle, we suspected that the anti-cancer effect of baicalein is associated with AhR. This study investigated the molecular mechanism involved in the anti-cancer effect of baicalein in oral cancer cells HSC-3, including whether such effect would be AhR-mediated. Results revealed that baicalein inhibited cell proliferation and increased AhR activity in a dose-dependent manner. Cell cycle was arrested at the G1 phase and the expression of CDK4, cyclin D1, and phosphorylated retinoblastoma (pRb) was decreased. When the AhR was suppressed by siRNA, the reduction of pRb was partially reversed, accompanied by a decrease of cell population at G1 phase and an increase at S phase, while the reduction of cyclin D1 and CDK4 did not change. This finding suggests that the baicalein activation of AhR is indeed associated with the reduction of pRb, but is independent of the reduction of cyclin D1 and CDK4. When cells were pre-treated with LiCl, the inhibitor of GSK-3β, the decrease of cyclin D1 was blocked and the reduction of pRb was recovered. The data indicates that in HSC-3 the reduction of pRb is both mediated by baicalein through activation of AhR and facilitation of cyclin D1 degradation, which causes cell cycle arrest at the G1 phase, and results in the inhibition of cell proliferation. -- Highlights: ► Baicalein causes the G1 phase arrest by decreasing Rb phosphorylation. ► Baicalein modulates AhR-mediated cell proliferation. ► Both AhR activation and cyclin D1 degradation results in hypophosphorylation of Rb. ► Baicalein facilitates cyclin D1 degradation by signalling the GSK-3β pathway.

  9. In Utero and Lactational Exposure to PCBs in Mice: Adult Offspring Show Altered Learning and Memory Depending on Cyp1a2 and Ahr Genotypes

    PubMed Central

    Curran, Christine P.; Genter, Mary Beth; Patel, Krishna V.; Schaefer, Tori L.; Skelton, Matthew R.; Williams, Michael T.; Vorhees, Charles V.

    2011-01-01

    Background: Both coplanar and noncoplanar polychlorinated biphenyls (PCBs) exhibit neurotoxic effects in animal studies, but individual congeners do not always produce the same effects as PCB mixtures. Humans genetically have > 60-fold differences in hepatic cytochrome P450 1A2 (CYP1A2)-uninduced basal levels and > 12-fold variability in aryl hydrocarbon receptor (AHR)affinity; because CYP1A2 is known to sequester coplanar PCBs and because AHR ligands include coplanar PCBs, both genotypes can affect PCB response. Objectives: We aimed to develop a mouse paradigm with extremes in Cyp1a2 and Ahr genotypes to explore genetic susceptibility to PCB-induced developmental neurotoxicity using an environmentally relevant mixture of PCBs. Methods: We developed a mixture of eight PCBs to simulate human exposures based on their reported concentrations in human tissue, breast milk, and food supply. We previously characterized specific differences in PCB congener pharmacokinetics and toxicity, comparing high-affinity–AHR Cyp1a2 wild-type [Ahrb1_Cyp1a2(+/+)], poor-affinity–AHR Cyp1a2 wild-type [Ahrd_Cyp1a2(+/+)], and high-affinity–AHR Cyp1a2 knockout [Ahrb1_Cyp1a2(–/–)] mouse lines [Curran CP, Vorhees CV, Williams MT, Genter MB, Miller ML, Nebert DW. 2011. In utero and lactational exposure to a complex mixture of polychlorinated biphenyls: toxicity in pups dependent on the Cyp1a2 and Ahr genotypes. Toxicol Sci 119:189–208]. Dams received a mixture of three coplanar and five noncoplanar PCBs on gestational day 10.5 and postnatal day (PND) 5. In the present study we conducted behavioral phenotyping of exposed offspring at PND60, examining multiple measures of learning, memory, and other behaviors. Results: We observed the most significant deficits in response to PCB treatment in Ahrb1_Cyp1a2(–/–) mice, including impaired novel object recognition and increased failure rate in the Morris water maze. However, all PCB-treated genotypes showed significant differences on

  10. The aryl hydrocarbon receptor-mediated disruption of vitellogenin synthesis in the fish liver: Cross-talk between AHR- and ERα-signalling pathways

    PubMed Central

    Bemanian, Vahid; Male, Rune; Goksøyr, Anders

    2004-01-01

    Background In the fish liver, the synthesis of egg yolk protein precursor vitellogenin (VTG) is under control of the estrogen receptor alpha (ERα). Environmental contaminants such as 2,3,7,8-tetrachloro-dibenzo-p-dioxin (TCDD) are suspected to have antiestrogenic effects. The aryl hydrocarbon receptor (AHR) is the initial cellular target for TCDD and related compounds. The AHR is a ligand-activated transcription factor that stimulates the expression of the genes encoding xenobiotic metabolizing enzymes, such as cytochrome P450 1A (CYP1A). In this study, the effects of activation of AHR on the hepatic expression of VTG and ERα genes, in primary cultured salmon hepatocytes, have been investigated. Results The expression of the genes encoding VTG and ERα were strongly induced by 17β-estradiol (E2). However, the expression of VTG was disrupted by exposure of the cells to TCDD while CYP1A expression was enhanced. The effect of TCDD on VTG and CYP1A expression was annulled by the AHR-inhibitor α-naphthoflavone. Furthermore, exposure of the cells to TCDD abolished E2-induced accumulation of ERα mRNA. The AHR-mediated inhibitory effects on the expression of the VTG and ERα genes may occur at transcriptional and/or post-transcriptional levels. Nuclear run-off experiments revealed that simultaneous exposure of the cells to E2 and TCDD strongly inhibited the initiation of transcription of the VTG and ERα genes. In addition, inhibition of RNA synthesis by actinomycin D treatment showed that post-transcriptional levels of VTG and ERα mRNAs were not significantly altered upon treatment of the cells with TCDD. These results suggested that activation of AHR may inhibit the transactivation capacity of the ERα. Further, electrophoretic mobility shift assays using nuclear extracts prepared from cells treated for one or two hours with E2, alone or in mixture with TCDD, showed a strong reduction in the DNA binding activities upon TCDD treatment. These results also suggested

  11. A TDO2-AhR signaling axis facilitates anoikis resistance and metastasis in triple-negative breast cancer.

    PubMed

    D'Amato, Nicholas C; Rogers, Thomas J; Gordon, Michael A; Greene, Lisa I; Cochrane, Dawn R; Spoelstra, Nicole S; Nemkov, Travis G; D'Alessandro, Angelo; Hansen, Kirk C; Richer, Jennifer K

    2015-11-01

    The ability of a cancer cell to develop resistance to anoikis, a programmed cell death process triggered by substratum detachment, is a critical step in the metastatic cascade. Triple-negative breast cancers (TNBC) exhibit higher rates of metastasis after diagnosis, relative to estrogen-positive breast cancers, but while TNBC cells are relatively more resistant to anoikis, the mechanisms involved are unclear. Through gene expression and metabolomic profiling of TNBC cells in forced suspension culture, we identified a molecular pathway critical for anchorage-independent cell survival. TNBC cells in suspension upregulated multiple genes in the kynurenine pathway of tryptophan catabolism, including the enzyme tryptophan 2,3-dioxygenase (TDO2), in an NF-κB-dependent manner. Kynurenine production mediated by TDO2 in TNBC cells was sufficient to activate aryl hydrocarbon receptor (AhR), an endogenous kynurenine receptor. Notably, pharmacologic inhibition or genetic attenuation of TDO2 or AhR increased cellular sensitivity to anoikis, and also reduced proliferation, migration, and invasion of TNBC cells. In vivo, TDO2 inhibitor-treated TNBC cells inhibited colonization of the lung, suggesting that TDO2 enhanced metastatic capacity. In clinical specimens of TNBC, elevated expression of TDO2 was associated with increased disease grade, estrogen receptor-negative status, and shorter overall survival. Our results define an NF-κB-regulated signaling axis that promotes anoikis resistance, suggest functional connections with inflammatory modulation by the kynurenine pathway, and highlight TDO2 as an attractive target for treatment of this aggressive breast cancer subtype. PMID:26363006

  12. A high-resolution structure of the DNA-binding domain of AhrC, the arginine repressor/activator protein from Bacillus subtilis

    SciTech Connect

    Garnett, James A.; Baumberg, Simon; Stockley, Peter G.; Phillips, Simon E. V.

    2007-11-01

    The structure of the winged helix–turn–helix DNA-binding domain of AhrC has been determined at 1.0 Å resolution. The largely hydrophobic β-wing shows high B factors and may mediate the dimer interface in operator complexes. In Bacillus subtilis the concentration of l-arginine is controlled by the transcriptional regulator AhrC, which interacts with 18 bp DNA operator sites called ARG boxes in the promoters of arginine biosynthetic and catabolic operons. AhrC is a 100 kDa homohexamer, with each subunit having two domains. The C-terminal domains form the core, mediating intersubunit interactions and binding of the co-repressor l-arginine, whilst the N-terminal domains contain a winged helix–turn–helix DNA-binding motif and are arranged around the periphery. The N-terminal domain of AhrC has been expressed, purified and characterized and it has been shown that the fragment still binds DNA operators as a recombinant monomer. The DNA-binding domain has also been crystallized and the crystal structure refined to 1.0 Å resolution is presented.

  13. Species-specific relative AHR1 binding affinities of 2,3,4,7,8-pentachlorodibenzofuran explain avian species differences in its relative potency.

    PubMed

    Farmahin, Reza; Jones, Stephanie P; Crump, Doug; Hahn, Mark E; Giesy, John P; Zwiernik, Matthew J; Bursian, Steven J; Kennedy, Sean W

    2014-04-01

    Results of recent studies showed that 2,3,4,7,8-pentachlorodibenzofuran (PeCDF) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) are equipotent in domestic chicken (Gallus gallus domesticus) while PeCDF is more potent than TCDD in ring-necked pheasant (Phasianus colchicus) and Japanese quail (Coturnix japonica). To elucidate the mechanism(s) underlying these differences in relative potency of PeCDF among avian species, we tested the hypothesis that this is due to species-specific differential binding affinity of PeCDF to the aryl hydrocarbon receptor 1 (AHR1). Here, we modified a cell-based binding assay that allowed us to measure the binding affinity of dioxin-like compounds (DLCs) to avian AHR1 expressed in COS-7 (fibroblast-like cells). The results of the binding assay show that PeCDF and TCDD bind with equal affinity to chicken AHR1, but PeCDF binds with greater affinity than TCDD to pheasant (3-fold) and Japanese quail (5-fold) AHR1. The current report introduces a COS-7 whole-cell binding assay and provides a mechanistic explanation for differential relative potencies of PeCDF among species of birds. PMID:24434118

  14. Biological effects of 6-formylindolo[3,2-b]carbazole (FICZ) in vivo are enhanced by loss of CYP1A function in an Ahr2-dependent manner.

    PubMed

    Wincent, Emma; Kubota, Akira; Timme-Laragy, Alicia; Jönsson, Maria E; Hahn, Mark E; Stegeman, John J

    2016-06-15

    6-Formylindolo[3,2-b]carbazole (FICZ) is a potent aryl hydrocarbon receptor (AHR) agonist that is efficiently metabolized by AHR-regulated cytochrome P4501 enzymes. FICZ is a proposed physiological AHR ligand that induces its own degradation as part of a regulatory negative feedback loop. In vitro studies in cells show that CYP1 inhibition in the presence of FICZ results in enhanced AHR activation, suggesting that FICZ accumulates in the cell when its metabolism is blocked. We used zebrafish (Danio rerio) embryos to investigate the in vivo effects of FICZ when CYP1A is knocked down or inhibited. Embryos were injected with morpholino antisense oligonucleotides targeting CYP1A (CYP1A-MO), Ahr2, or a combination of both. FICZ exposure of non-injected embryos or embryos injected with control morpholino had little effect. In CYP1A-MO-injected embryos, however, FICZ dramatically increased mortality, incidence and severity of pericardial edema and circulation failure, reduced hatching frequency, blocked swim bladder inflation, and strongly potentiated expression of Ahr2-regulated genes. These effects were substantially reduced in embryos with a combined knockdown of Ahr2 and CYP1A, indicating that the toxicity was mediated at least partly by Ahr2. Co-exposure to the CYP1 inhibitor alpha-naphthoflavone (αNF) and FICZ had similar effects as the combination of CYP1A-MO and FICZ. HPLC analysis of FICZ-exposed embryos showed increased levels of FICZ after concomitant CYP1A-MO injection or αNF co-exposure. Together, these results show that a functioning CYP1/AHR feedback loop is crucial for regulation of AHR signaling by a potential physiological ligand in vivo and further highlights the role of CYP1 enzymes in regulating biological effects of FICZ. PMID:27112072

  15. Ahr2-dependence of PCB126 effects on the swim bladder in relation to expression of CYP1 and cox-2 genes in developing zebrafish

    SciTech Connect

    Jönsson, Maria E.; Kubota, Akira; Timme-Laragy, Alicia R.; Woodin, Bruce; Stegeman, John J.

    2012-12-01

    The teleost swim bladder is assumed a homolog of the tetrapod lung. Both swim bladder and lung are developmental targets of persistent aryl hydrocarbon receptor (AHR) agonists; in zebrafish (Danio rerio) the swim bladder fails to inflate with exposure to 3,3′,4,4′,5-pentachlorobiphenyl (PCB126). The mechanism for this effect is unknown, but studies have suggested roles of cytochrome P450 1 (CYP1) and cyclooxygenase 2 (Cox-2) in some Ahr-mediated developmental effects in zebrafish. We determined relationships between swim bladder inflation and CYP1 and Cox-2 mRNA expression in PCB126-exposed zebrafish embryos. We also examined effects on β-catenin dependent transcription, histological effects, and Ahr2 dependence of the effect of PCB126 on swim bladder using morpholinos targeting ahr2. One-day-old embryos were exposed to waterborne PCB126 or carrier (DMSO) for 24 h and then held in clean water until day 4, a normal time for swim bladder inflation. The effects of PCB126 were concentration-dependent with EC{sub 50} values of 1.4 to 2.0 nM for induction of the CYP1s, 3.7 and 5.1 nM (or higher) for cox-2a and cox-2b induction, and 2.5 nM for inhibition of swim bladder inflation. Histological defects included a compaction of the developing bladder. Ahr2-morpholino treatment rescued the effect of PCB126 (5 nM) on swim bladder inflation and blocked induction of CYP1A, cox-2a, and cox-2b. With 2 nM PCB126 approximately 30% of eleutheroembryos failed to inflate the swim bladder, but there was no difference in CYP1 or cox-2 mRNA expression between those embryos and embryos showing inflated swim bladder. Our results indicate that PCB126 blocks swim bladder inflation via an Ahr2-mediated mechanism. This mechanism seems independent of CYP1 or cox-2 mRNA induction but may involve abnormal development of swim bladder cells. -- Highlights: ► PCB126 caused cellular changes in the developing swim bladder. ► Swim bladder inflation was not related to expression of CYP1 or cox

  16. AHR2 knockdown prevents PAH-mediated cardiac toxicity and XRE- and ARE-associated gene induction in zebrafish (Danio rerio)

    SciTech Connect

    Van Tiem, Lindsey A.; Di Giulio, Richard T.

    2011-08-01

    Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental contaminants often present in aquatic systems as complex mixtures. Embryonic fish are sensitive to the developmental toxicity of some PAHs, but the exact mechanisms involved in this toxicity are still unknown. This study explored the role of the aryl hydrocarbon receptor (AHR) in the oxidative stress response of zebrafish to the embryotoxicity of select PAHs. Embryos were exposed to two PAHs, benzo[k]fluoranthene (BkF; a strong AHR agonist) and fluoranthene (FL; a cytochrome P4501A (CYP1A) inhibitor), alone and in combination. CYP1A, CYP1B1, CYP1C1, and redox-responsive genes glutathione s-transferase pi 2 (GSTp2), glutathione peroxidase 1 (GPx1), the glutamate-cysteine ligase catalytic subunit (GCLc), MnSOD and CuZnSOD mRNA expression was examined. CYP1 activity was measured via an in vivo ethoxyresorufin-O-deethlyase (EROD) activity assay, and the area of the pericardium was measured as an index of cardiotoxicity. BkF or FL alone caused no deformities whereas BkF + FL resulted in extreme pericardial effusion. BkF induced CYP activity above controls and co-exposure with FL inhibited this activity. BkF induced expression of all three CYPs, GSTp2, and GCLc. BkF + FL caused greater than additive induction of the three CYPs, GSTp2, GPx1, and GCLc but had no effect on MnSOD or CuZnSOD. AHR2 knockdown protected against the cardiac deformities caused by BkF + FL and significantly inhibited the induction of the CYPs, GSTp2, GPx1, and GCLc after BkF + FL compared to non-injected controls. These results further show the protective role of AHR2 knockdown against cardiotoxic PAHs and the role of AHR2 as a mediator of redox-responsive gene induction. - Research Highlights: > Co-exposure of the PAHs BkF and FL causes cardiotoxicity in zebrafish. > BkF and FL co-exposure upregulates certain XRE- and ARE-associated genes. > AHR2 knockdown prevents the deformities caused by BkF and FL co-exposure. > AHR2

  17. Deciphering Dimerization Modes of PAS Domains: Computational and Experimental Analyses of the AhR:ARNT Complex Reveal New Insights Into the Mechanisms of AhR Transformation

    PubMed Central

    Corrada, Dario; Soshilov, Anatoly A.; Denison, Michael S.

    2016-01-01

    The Aryl hydrocarbon Receptor (AhR) is a transcription factor that mediates the biochemical response to xenobiotics and the toxic effects of a number of environmental contaminants, including dioxins. Recently, endogenous regulatory roles for the AhR in normal physiology and development have also been reported, thus extending the interest in understanding its molecular mechanisms of activation. Since dimerization with the AhR Nuclear Translocator (ARNT) protein, occurring through the Helix-Loop-Helix (HLH) and PER-ARNT-SIM (PAS) domains, is needed to convert the AhR into its transcriptionally active form, deciphering the AhR:ARNT dimerization mode would provide insights into the mechanisms of AhR transformation. Here we present homology models of the murine AhR:ARNT PAS domain dimer developed using recently available X-ray structures of other bHLH-PAS protein dimers. Due to the different reciprocal orientation and interaction surfaces in the different template dimers, two alternative models were developed for both the PAS-A and PAS-B dimers and they were characterized by combining a number of computational evaluations. Both well-established hot spot prediction methods and new approaches to analyze individual residue and residue-pairwise contributions to the MM-GBSA binding free energies were adopted to predict residues critical for dimer stabilization. On this basis, a mutagenesis strategy for both the murine AhR and ARNT proteins was designed and ligand-dependent DNA binding ability of the AhR:ARNT heterodimer mutants was evaluated. While functional analysis disfavored the HIF2α:ARNT heterodimer-based PAS-B model, most mutants derived from the CLOCK:BMAL1-based AhR:ARNT dimer models of both the PAS-A and the PAS-B dramatically decreased the levels of DNA binding, suggesting this latter model as the most suitable for describing AhR:ARNT dimerization. These novel results open new research directions focused at elucidating basic molecular mechanisms underlying the

  18. AHR2 knockdown prevents PAH-mediated cardiac toxicity and XRE- and ARE-associated gene induction in zebrafish (Danio rerio)

    PubMed Central

    Van Tiem, Lindsey A.; Di Giulio, Richard T.

    2011-01-01

    Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental contaminants often present in aquatic systems as complex mixtures. Embryonic fish are sensitive to the developmental toxicity of some PAHs, but the exact mechanisms involved in this toxicity are still unknown. This study explored the role of the aryl hydrocarbon receptor (AHR) in the oxidative stress response of zebrafish to the embryotoxicity of select PAHs. Embryos were exposed to two PAHs, benzo[k]fluoranthene (BkF; a strong AHR agonist) and fluoranthene (FL; a cytochrome P4501A (CYP1A) inhibitor), alone and in combination. CYP1A, CYP1B1, CYP1C1, and redox-responsive genes glutathione s-transferase pi 2 (GSTp2), glutathione peroxidase 1 (GPx1), the glutamate-cysteine ligase catalytic subunit (GCLc), MnSOD and CuZnSOD mRNA expression was examined. CYP1 activity was measured via an in vivo ethoxyresorufin-O-deethlyase (EROD) activity assay, and the area of the pericardium was measured as an index of cardiotoxicity. BkF or FL alone caused no deformities whereas BkF + FL resulted in extreme pericardial effusion. BkF induced CYP activity above controls and co-exposure with FL inhibited this activity. BkF induced expression of all three CYPs, GSTp2, and GCLc. BkF + FL caused greater than additive induction of the three CYPs, GSTp2, GPx1, and GCLc but had no effect on MnSOD or CuZnSOD. AHR2 knockdown protected against the cardiac deformities caused by BkF + FL and significantly inhibited the induction of the CYPs, GSTp2, GPx1 and GCLc after BkF + FL compared to non-injected controls. These results further show the protective role of AHR2 knockdown against cardiotoxic PAHs and the role of AHR2 as a mediator of redox-responsive gene induction. PMID:21600235

  19. Evaluation of the Enterococcus faecalis Biofilm-Associated Virulence Factors AhrC and Eep in Rat Foreign Body Osteomyelitis and In Vitro Biofilm-Associated Antimicrobial Resistance

    PubMed Central

    Frank, Kristi L.; Vergidis, Paschalis; Brinkman, Cassandra L.; Greenwood Quaintance, Kerryl E.; Barnes, Aaron M. T.; Mandrekar, Jayawant N.; Schlievert, Patrick M.; Dunny, Gary M.; Patel, Robin

    2015-01-01

    Enterococcus faecalis can cause healthcare-associated biofilm infections, including those of orthopedic devices. Treatment of enterococcal prosthetic joint infection is difficult, in part, due to biofilm-associated antimicrobial resistance. We previously showed that the E. faecalis OG1RF genes ahrC and eep are in vitro biofilm determinants and virulence factors in animal models of endocarditis and catheter-associated urinary tract infection. In this study, we evaluated the role of these genes in a rat acute foreign body osteomyelitis model and in in vitro biofilm-associated antimicrobial resistance. Osteomyelitis was established for one week following the implantation of stainless steel orthopedic wires inoculated with E. faecalis strains OG1RF, ΩahrC, and ∆eep into the proximal tibiae of rats. The median bacterial loads recovered from bones and wires did not differ significantly between the strains at multiple inoculum concentrations. We hypothesize that factors present at the infection site that affect biofilm formation, such as the presence or absence of shear force, may account for the differences in attenuation in the various animal models we have used to study the ΩahrC and ∆eep strains. No differences among the three strains were observed in the planktonic and biofilm antimicrobial susceptibilities to ampicillin, vancomycin, daptomycin, linezolid, and tetracycline. These findings suggest that neither ahrC nor eep directly contribute to E. faecalis biofilm-associated antimicrobial resistance. Notably, the experimental evidence that the biofilm attachment mutant ΩahrC displays biofilm-associated antimicrobial resistance suggests that surface colonization alone is sufficient for E. faecalis cells to acquire the biofilm antimicrobial resistance phenotype. PMID:26076451

  20. Evaluation of the Enterococcus faecalis Biofilm-Associated Virulence Factors AhrC and Eep in Rat Foreign Body Osteomyelitis and In Vitro Biofilm-Associated Antimicrobial Resistance.

    PubMed

    Frank, Kristi L; Vergidis, Paschalis; Brinkman, Cassandra L; Greenwood Quaintance, Kerryl E; Barnes, Aaron M T; Mandrekar, Jayawant N; Schlievert, Patrick M; Dunny, Gary M; Patel, Robin

    2015-01-01

    Enterococcus faecalis can cause healthcare-associated biofilm infections, including those of orthopedic devices. Treatment of enterococcal prosthetic joint infection is difficult, in part, due to biofilm-associated antimicrobial resistance. We previously showed that the E. faecalis OG1RF genes ahrC and eep are in vitro biofilm determinants and virulence factors in animal models of endocarditis and catheter-associated urinary tract infection. In this study, we evaluated the role of these genes in a rat acute foreign body osteomyelitis model and in in vitro biofilm-associated antimicrobial resistance. Osteomyelitis was established for one week following the implantation of stainless steel orthopedic wires inoculated with E. faecalis strains OG1RF, ΩahrC, and ∆eep into the proximal tibiae of rats. The median bacterial loads recovered from bones and wires did not differ significantly between the strains at multiple inoculum concentrations. We hypothesize that factors present at the infection site that affect biofilm formation, such as the presence or absence of shear force, may account for the differences in attenuation in the various animal models we have used to study the ΩahrC and ∆eep strains. No differences among the three strains were observed in the planktonic and biofilm antimicrobial susceptibilities to ampicillin, vancomycin, daptomycin, linezolid, and tetracycline. These findings suggest that neither ahrC nor eep directly contribute to E. faecalis biofilm-associated antimicrobial resistance. Notably, the experimental evidence that the biofilm attachment mutant ΩahrC displays biofilm-associated antimicrobial resistance suggests that surface colonization alone is sufficient for E. faecalis cells to acquire the biofilm antimicrobial resistance phenotype. PMID:26076451

  1. Mixed-ligand copper(II) complexes activate aryl hydrocarbon receptor AhR and induce CYP1A genes expression in human hepatocytes and human cell lines.

    PubMed

    Kubešová, Kateřina; Dořičáková, Aneta; Trávníček, Zdeněk; Dvořák, Zdeněk

    2016-07-25

    The effects of four copper(II) mixed-ligand complexes [Cu(qui1)(L)]NO3·H2O (1-3) and [Cu(qui2)(phen)]NO3 (4), where qui1=2-phenyl-3-hydroxy-4(1H)-quinolinone, Hqui2=2-(4-amino-3,5-dichlorophenyl)-N-propyl-3-hydroxy-4(1H)-quinolinone-7-carboxamide, L=1,10-phenanthroline (phen) (1), 5-methyl-1,10-phenanthroline (mphen) (2), bathophenanthroline (bphen) (3), on transcriptional activities of steroid receptors, nuclear receptors and xenoreceptors have been studied. The complexes (1-4) did not influence basal or ligand-inducible activities of glucocorticoid receptor, androgen receptor, thyroid receptor, pregnane X receptor and vitamin D receptor, as revealed by gene reporter assays. The complexes 1 and 2 dose-dependently induced luciferase activity in stable gene reporter AZ-AhR cell line, and this induction was reverted by resveratrol, indicating involvement of aryl hydrocarbon receptor (AhR) in the process. The complexes 1, 2 and 3 induced CYP1A1 mRNA in LS180 cells and CYP1A1/CYP1A2 in human hepatocytes through AhR. Electrophoretic mobility shift assay EMSA showed that the complexes 1 and 2 transformed AhR in its DNA-binding form. Collectively, we demonstrate that the complexes 1 and 2 activate AhR and induce AhR-dependent genes in human hepatocytes and cancer cell lines. In conclusion, the data presented here might be of toxicological importance, regarding the multiple roles of AhR in human physiology and pathophysiology. PMID:27180721

  2. Endothelin receptors and their antagonists.

    PubMed

    Maguire, Janet J; Davenport, Anthony P

    2015-03-01

    All three members of the endothelin (ET) family of peptides, ET-1, ET-2, and ET-3, are expressed in the human kidney, with ET-1 being the predominant isoform. ET-1 and ET-2 bind to two G-protein-coupled receptors, ETA and ETB, whereas at physiological concentrations ET-3 has little affinity for the ET(A) receptor. The human kidney is unusual among the peripheral organs in expressing a high density of ET(B). The renal vascular endothelium only expresses the ET(B) subtype and ET-1 acts in an autocrine or paracrine manner to release vasodilators. Endothelial ETB in kidney, as well as liver and lungs, also has a critical role in scavenging ET-1 from the plasma. The third major function is ET-1 activation of ET(B) in in the nephron to reduce salt and water re-absorption. In contrast, ET(A) predominate on smooth muscle, causing vasoconstriction and mediating many of the pathophysiological actions of ET-1. The role of the two receptors has been delineated using highly selective ET(A) (BQ123, TAK-044) and ET(B) (BQ788) peptide antagonists. Nonpeptide antagonists, bosentan, macitentan, and ambrisentan, that are either mixed ET(A)/ET(B) antagonists or display ET(A) selectivity, have been approved for clinical use but to date are limited to pulmonary hypertension. Ambrisentan is in clinical trials in patients with type 2 diabetic nephropathy. This review summarizes ET-receptor antagonism in the human kidney, and considers the relative merits of selective versus nonselective antagonism in renal disease. PMID:25966344

  3. Tachykinin antagonists and the airways.

    PubMed

    Joos, G F; Kips, J C; Peleman, R A; Pauwels, R A

    1995-01-01

    There is now convincing evidence for the presence of substance P (SP) and neurokinin A (NKA) in human airway nerves. Studies on autopsy tissue, on bronchoalveolar lavage fluid and on sputum suggest that SP may be present in increased amounts in the asthmatic airway. Substance P and NKA are potent bronchoconstrictors of human airways, asthmatics being more sensitive than normal persons. The major enzyme responsible for the degradation of the tachykinins, the neutral endopeptidase, is present in the airways and is involved in the breakdown of exogenously administered SP and NKA, both in normal and asthmatic persons. Other, less well documented airway effects of SP and NKA include mucus secretion, vasodilation and plasma extravasation, as well as the chemoattraction and stimulation of various cells presumed to be involved in asthmatic airway inflammation. NK2 receptors and, to a lesser extent, NK1 receptors have been shown to be involved in bronchoconstriction, whereas NK1 receptors were found to be involved in mucus secretion, microvascular leakage and vasodilatation, and in most of the effects on inflammatory cells. The first clinical trial with FK224, a peptide NK1 and NK2 receptor antagonist, and CP99994, a nonpeptide NK1 receptor antagonist, are negative. However, FK224 failed to block the bronchoconstrictor effect of NKA in asthmatics and the dose of CP99994, needed to antagonize tachykinin effects in man, remains to be determined. PMID:7543746

  4. Long-acting muscarinic antagonists.

    PubMed

    Melani, Andrea S

    2015-01-01

    Chronic obstructive pulmonary disease (COPD) is a major cause of death and disability worldwide. Inhaled bronchodilators are the mainstay of COPD pharmacological treatment. Long-acting muscarinic antagonists (LAMAs) are a major class of inhaled bronchodilators. Some LAMA/device systems with different characteristics and dosing schedules are currently approved for maintenance therapy of COPD and a range of other products are being developed. They improve lung function and patient-reported outcomes and reduce acute bronchial exacerbations with good safety. LAMAs are used either alone or associated with long-acting β₂-agonists, eventually in fixed dose combinations. Long-acting β₂-agonist/LAMA combinations assure additional benefits over the individual components alone. The reader will obtain a view of the safety and efficacy of the different LAMA/device systems in COPD patients. PMID:26109098

  5. A new alcohol antagonist: Phaclofen

    SciTech Connect

    Allan, A.M. ); Harris, R.A. )

    1989-01-01

    The ability of the GABA{sub B} receptor antagonist, phaclofen to alter behavioral effects of ethanol was evaluated by loss of righting reflex (sleep time), motor incoordination (bar holding), spontaneous locomotion (open field activity) and hypothermia. Pretreatment with phaclofen significantly decreased the effects of ethanol on motor incoordination, locomotor activity and hypothermia. However, phaclofen had no effect on either pentobarbital- or diazepam-induced motor incoordination. Phaclofen slightly increased the ED{sub 50} for loss of the righting reflex but did not alter either the duration of reflex loss produced by ethanol or blood ethanol levels at awakening. Our results suggest phaclofen is rapidly inactivated resulting in difficulty in observing antagonism of long duration ethanol effects. These findings suggest that the GABA{sub B} system may play a role in mediating several important actions of ethanol.

  6. Client Perceptions of Two Antagonist Programs.

    ERIC Educational Resources Information Center

    Capone, Thomas A.; And Others

    1980-01-01

    Reports results of a questionnaire administered to participants in an antagonist drug outpatient clinic and an antagonist drug work-release program to obtain awareness of acceptance of the program participants. Naltrexone patients recommended an alternative method of administering the drug and changing the money system to award deserving inmates…

  7. Effects of carcinogenic versus non-carcinogenic AHR-active PAHs and their mixtures: lessons from ecological relevance.

    PubMed

    Martins, Marta; Santos, José M; Diniz, Mário S; Ferreira, Ana M; Costa, Maria H; Costa, Pedro M

    2015-04-01

    Polycyclic aromatic hydrocarbons (PAHs) are priority environmental mutagens and carcinogens that occur in the aquatic environment as mixtures rather than the individual compounds for which guidelines are issued. The present work aimed at understanding the interaction effects between carcinogenic and non-carcinogenic PAHs in a model marine fish (Dicentrarchus labrax) in realistic scenarios. Laboratory assays under ecologically-relevant parameters were conducted for 28 days with sediments spiked with low-moderate concentrations (250-800ngg(-1)) of two model PAHs, phenanthrene (non-carcinogenic) and benzo[b]fluoranthene (carcinogenic to experimental animals). Both PAHs induced hepatic histopathological changes that indicate metabolic failure and inflammation, especially in animals exposed to mixtures. Phenanthrene elicited biochemical changes better related to oxidative stress (lipid peroxidation, glutathione and glutathione S-transferase activity) and CYP function, whereas B[b]F disrupted metabolic responses and defences to toxicological challenge. Conversely, mixed PAHs yielded lesions and responses that, altogether, are compatible with the AHR dependent pathway (the basis of PAH mutagenicity), potentially generating supra-additive effects. Nonetheless, the low, ecologically-relevant, concentrations of PAHs diluted dose and time-response relations. Overall, although seemingly predicting the risk of individual PAHs, environmental guidelines may not apply to mixtures by underestimating adverse effects, which calls for a redefinition of standards when determining the true risk of toxicants under realistic circumstances. PMID:25704830

  8. Preferential induction of the AhR gene battery in HepaRG cells after a single or repeated exposure to heterocyclic aromatic amines

    SciTech Connect

    Dumont, Julie Josse, Rozenn Lambert, Carine Antherieu, Sebastien Laurent, Veronique Loyer, Pascal Robin, Marie-Anne Guillouzo, Andre

    2010-11-15

    2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) are two of the most common heterocyclic aromatic amines (HAA) produced during cooking of meat, fish and poultry. Both HAA produce different tumor profiles in rodents and are suspected to be carcinogenic in humans. In order to better understand the molecular basis of HAA toxicity, we have analyzed gene expression profiles in the metabolically competent human HepaRG cells using pangenomic oligonucleotide microarrays, after either a single (24-h) or a repeated (28-day) exposure to 10 {mu}M PhIP or MeIQx. The most responsive genes to both HAA were downstream targets of the arylhydrocarbon receptor (AhR): CYP1A1 and CYP1A2 after both time points and CYP1B1 and ALDH3A1 after 28 days. Accordingly, CYP1A1/1A2 induction in HAA-treated HepaRG cells was prevented by chemical inhibition or small interference RNA-mediated down-regulation of the AhR. Consistently, HAA induced activity of the CYP1A1 promoter, which contains a consensus AhR-related xenobiotic-responsive element (XRE). In addition, several other genes exhibited both time-dependent and compound-specific expression changes with, however, a smaller magnitude than previously reported for the prototypical AhR target genes. These changes concerned genes mainly related to cell growth and proliferation, apoptosis, and cancer. In conclusion, these results identify the AhR gene battery as the preferential target of PhIP and MeIQx in HepaRG cells and further support the hypothesis that intake of HAA in diet might increase human cancer risk.

  9. Data on AHR-dependent changes in the mitochondrial proteome in response to ,3,7,8-tetrachlorodibenzo-p-dioxin.

    PubMed

    Hwang, Hye Jin; Dornbos, Peter; LaPres, John J

    2016-09-01

    The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that is the principal regulator of a cell׳s response to many polyaromatic hydrocarbons, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). To gain a better understanding of the impact of TCDD on the mitochondrial proteome, a stable isotope labeling by amino acids in cell culture (SILAC)-based proteomic analysis was performed. We used two mouse hepatoma cell lines that differ in AHR expression levels, hepa1c1c7 (AHR-expressing) and hepac12 (AHR-deficient). The cell lines were exposed to TCDD (10 nM) for 72 h; each treatment was assayed in triplicate and were analyzed as separate runs on the mass-spectrometer. Mitochondria were then isolated and mitochondrial proteins were separated by SDS-PAGE and subject to mass spectrometry. The data presented were collected from four independent SILAC experiments. Within each experiment, three isotopes were employed to compare protein ratios via mass-spectrometry: (1) light l-arginine/l-lysine HCl (Arg0, Lys0), (2) medium (15)N4-l-arginin/(13)C6l-lysine HCl (Arg4, Lys6), and (3) heavy (13)C6 (15)N4l-arginine/(13)C6 (15)N2l-lysine HCl (Arg10, Lys8). The raw data includes approximately 2500 annotated proteins. The datasets provided by this study can be a reference to other toxicologists investigating TCDD-induced mitochondrial dysfunction. The data presented here are associated with the research article, "Mitochondrial-targeted Aryl Hydrocarbon Receptor and the Impact of 2,3,7,8-Tetrachlorodibenzo-p-Dioxin on Cellular Respiration and the Mitochondrial Proteome" (Hwang et al. (2016) [1]). PMID:27331086

  10. Exposure to Diesel Exhaust Particle Extracts (DEPe) Impairs Some Polarization Markers and Functions of Human Macrophages through Activation of AhR and Nrf2

    PubMed Central

    Jaguin, Marie; Fardel, Olivier; Lecureur, Valérie

    2015-01-01

    Macrophages (MΦ), well-known to play an important role in immune response, also respond to environmental toxic chemicals such as diesel exhaust particles (DEP). Potential effects of DEPs towards MΦ polarization, a key hall-mark of MΦ physiology, remain however poorly documented. This study was therefore designed to evaluate the effects of a reference DEP extract (DEPe) on human MΦ polarization. Human blood monocytes-derived MΦ were incubated with IFNγ+LPS or IL-4 to obtain M1 and M2 subtypes, respectively; a 24 h exposure of polarizing MΦ to 10 μg/ml DEPe was found to impair expression of some macrophagic M1 and M2 markers, without however overall inhibition of M1 and M2 polarization processes. Notably, DEPe treatment increased the secretion of the M1 marker IL-8 and the M2 marker IL-10 in both MΦ subtypes, whereas it reduced lipopolysaccharide-induced IL-6 and IL-12p40 secretion in M1 MΦ. In M2 MΦ, DEPe exposure led to a reduction of CD200R expression and of CCL17, CCL18 and CCL22 secretion, associated with a lower chemotaxis of CCR4-positive cells. DEPe activated the Nrf2 and AhR pathways and induced expression of their reference target genes such as Hmox-1 and cytochrome P-4501B1 in M1 and M2 MΦ. Nrf2 or AhR silencing through RNA interference prevented DEPe-related down-regulation of IL-6. AhR silencing also inhibited the down-secretion of IL-12p40 and CCL18 in M1- and M2-DEPe-exposed MΦ, respectively. DEPs are therefore likely to alter expression of some M1 and M2 markers in an AhR- and Nrf2-dependent manner; such regulations may contribute to deleterious immune effects of atmospheric DEP. PMID:25710172

  11. TCDD and a Putative Endogenous AhR Ligand, ITE, Elicit the Same Immediate Changes in Gene Expression in Mouse Lung Fibroblasts

    PubMed Central

    Henry, Ellen C.; Welle, Stephen L.; Gasiewicz, Thomas A.

    2010-01-01

    The aryl hydrocarbon receptor (AhR), a ligand-dependent transcription factor, mediates toxicity of several classes of xenobiotics and also has important physiological roles in differentiation, reproduction, and immunity, although the endogenous ligand(s) mediating these functions is/are as yet unidentified. One candidate endogenous ligand, 2-(1′H-indolo-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE), is a potent AhR agonist in vitro, activates the murine AhR in vivo, but does not induce toxicity. We hypothesized that ITE and the toxic ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), may modify transcription of different sets of genes to account for their different toxicity. To test this hypothesis, primary mouse lung fibroblasts were exposed to 0.5μM ITE, 0.2nM TCDD, or vehicle for 4 h, and total gene expression was evaluated using microarrays. After this short-term and low-dose treatment, several hundred genes were changed significantly, and the response to ITE and TCDD was remarkably similar, both qualitatively and quantitatively. Induced gene sets included the expected battery of AhR-dependent xenobiotic-metabolizing enzymes, as well as several sets that reflect the inflammatory role of lung fibroblasts. Real time quantitative RT-qPCR assay of several selected genes confirmed these microarray data and further suggested that there may be kinetic differences in expression between ligands. These data suggest that ITE and TCDD elicit an analogous change in AhR conformation such that the initial transcription response is the same. Furthermore, if the difference in toxicity between TCDD and ITE is mediated by differences in gene expression, then it is likely that secondary changes enabled by the persistent TCDD, but not by the shorter lived ITE, are responsible. PMID:19933214

  12. Impact of AhR, CYP1A1 and GSTM1 genetic polymorphisms on TP53 R273G mutations in individuals exposed to polycyclic aromatic hydrocarbons.

    PubMed

    Gao, Meili; Li, Yongfei; Xue, Xiaochang; Long, Jiangang; Chen, Lan; Shah, Walayat; Kong, Yu

    2014-01-01

    This study was to undertaken to investigate the impacts of AhR, CYP1A1, GSTM1 genetic polymorphisms on the R273G mutation in exon 8 of the tumor suppressor p53 gene (TP53) among polycyclic aromatic hydrocarbons (PAHs) exposed to coke-oven workers. One hundred thirteen workers exposed to PAH and 82 control workers were recruited. We genotyped for polymorphisms in the AhR, CYP1A1, GSTM1, and TP53 R273G mutation in blood by PCR methods, and determined the levels of 1-hydroxypyrene as PAH exposure marker in urine using the high pressure liquid chromatography assay. We found that the distribution of alcohol users and the urinary excretion of 1-OHP in the exposed workers were significantly higher than that of the control workers (p=0.004, p<0.001, respectively). Significant differences were observed in the p53 genotype distributions of smoking subjects (p=0.01, 95%CI: 1.23-6.01) and PAH exposure (p=0.008, 95%CI: 1.24-4.48), respectively. Further, significant differences were observed in the p53 exon 8 mutations for the genetic polymorphisms of Lys/Arg for AhR (p=0.02, 95%CI: 0.70-15.86), Val/Val for CYP1A1 (p=0.04, 95%CI: 0.98-19.09) and null for GSTM1 (p=0.02, 95%CI: 1.19-6.26), respectively. Our findings indicated that polymorphisms of PAH metabolic genes, such as AhR, CYP1A1, GSTM1 polymorphisms may interact with p53 genetic variants and may contribute to PAH related cancers. PMID:24761888

  13. The tertiary structures of porcine AhR and ARNT proteins and molecular interactions within the TCDD/AhR/ARNT complex.

    PubMed

    Orlowska, Karina; Molcan, Tomasz; Swigonska, Sylwia; Sadowska, Agnieszka; Jablonska, Monika; Nynca, Anna; Jastrzebski, Jan P; Ciereszko, Renata E

    2016-06-01

    The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that can be activated by structurally diverse synthetic and natural chemicals, including toxic environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). In the present study, homology models of the porcine AhR-ligand binding domain (LBD) and the porcine aryl hydrocarbon receptor nuclear translocator-ligand binding domain (ARNT-LBD) were created on the basis of structures of closely related respective proteins i.e., human Hif-2α and ARNT. Molecular docking of TCDD to the porcine AhR-LBD model revealed high binding affinity (-8.8kcal/mol) between TCDD and the receptor. Moreover, formation of the TCDD/AhR-LBD complex was confirmed experimentally with the use of electrophoretic mobility shift assay (EMSA). It was found that TCDD (10nM, 2h of incubation) not only bound to the AhR in the porcine granulosa cells but also activated the receptor. The current study provides a framework for examining the key events involved in the ligand-dependent activation of the AhR. PMID:27288759

  14. Atropine-resistant effects of the muscarinic agonists McN-A-343 and AHR 602 on cardiac performance and the release of noradrenaline from sympathetic nerves of the perfused rabbit heart

    PubMed Central

    Fozard, J.R.; Muscholl, E.

    1974-01-01

    1 The effects of 4-(m-chlorophenylcarbamoyloxy)-2-butynyltrimethylammonium chloride (McN-A-343) and N-benzyl-3-pyrrolidyl acetate methobromide (AHR 602) on cardiac performance and noradrenaline release from terminal sympathetic fibres were measured in isolated perfused hearts of rabbits. 2 In the presence of sufficient atropine to block muscarinic receptors, high concentrations of McN-A-343 and AHR 602 caused no cardiac stimulation and there was no increase in the resting output of noradrenaline into the perfusates. 3 McN-A-343 and AHR 602 increased both the mechanical responses and the transmitter overflow evoked by electrical stimulation of the sympathetic nerves (SNS) but inhibited both parameters during perfusion with 1,1-dimethyl-4-phenylpiperazinium (DMPP). The effects were atropine-resistant and qualitatively similar to those seen with cocaine. Hexamethonium inhibited DMPP, but affected neither SNS per se nor the facilitatory effects of McN-A-343 and AHR 602 on SNS. 4 McN-A-343, cocaine and desipramine (but not AHR 602 or hexamethonium) blocked the net cardiac noradrenaline uptake and increased the positive chronotropic effect of noradrenaline. 5 Prior perfusion with concentrations of cocaine and desipramine sufficient to block uptake reduced or abolished the facilitatory effects of both McN-A-343 and AHR 602 on SNS. 6 Cocaine, McN-A-343 and AHR 602 displayed local anaesthetic properties on the guinea-pig wheal and frog nerve plexus tests, and their relative potencies in this respect were similar to those for inhibition of DMPP-evoked transmitter overflow. Hexamethonium did not produce local anaesthesia. 7 The results indicate that the facilitated release of noradrenaline after SNS and the inhibition of release after DMPP produced by McN-A-343 and AHR 602 are the result of their combined local anaesthetic action and inhibition of amine uptake. PMID:4447857

  15. Role of zebrafish cytochrome P450 CYP1C genes in the reduced mesencephalic vein blood flow caused by activation of AHR2

    SciTech Connect

    Kubota, Akira; Stegeman, John J.; Woodin, Bruce R.; Iwanaga, Toshihiko; Harano, Ryo; Peterson, Richard E.; Hiraga, Takeo; Teraoka, Hiroki

    2011-06-15

    2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) causes various signs of toxicity in early life stages of vertebrates through activation of the aryl hydrocarbon receptor (AHR). We previously reported a sensitive and useful endpoint of TCDD developmental toxicity in zebrafish, namely a decrease in blood flow in the dorsal midbrain, but downstream genes involved in the effect are not known. The present study addressed the role of zebrafish cytochrome P450 1C (CYP1C) genes in association with a decrease in mesencephalic vein (MsV) blood flow. The CYP1C subfamily was recently discovered in fish and includes the paralogues CYP1C1 and CYP1C2, both of which are induced via AHR2 in zebrafish embryos. We used morpholino antisense oligonucleotides (MO or morpholino) to block initiation of translation of the target genes. TCDD-induced mRNA expression of CYP1Cs and a decrease in MsV blood flow were both blocked by gene knockdown of AHR2. Gene knockdown of CYP1C1 by two different morpholinos and CYP1C2 by two different morpholinos, but not by their 5 nucleotide-mismatch controls, was effective in blocking reduced MsV blood flow caused by TCDD. The same CYP1C-MOs prevented reduction of blood flow in the MsV caused by {beta}-naphthoflavone (BNF), representing another class of AHR agonists. Whole-mount in situ hybridization revealed that mRNA expression of CYP1C1 and CYP1C2 was induced by TCDD most strongly in branchiogenic primordia and pectoral fin buds. In situ hybridization using head transverse sections showed that TCDD increased the expression of both CYP1Cs in endothelial cells of blood vessels, including the MsV. These results indicate a potential role of CYP1C1 and CYP1C2 in the local circulation failure induced by AHR2 activation in the dorsal midbrain of the zebrafish embryo. - Research Highlights: > We examine the roles of zebrafish CYP1C1 and CYP1C2 in TCDD developmental toxicity. > TCDD induces mRNA expression of both CYP1Cs in the mesencephalic vein. > Knockdown of each

  16. Plant Evolution: Evolving Antagonistic Gene Regulatory Networks.

    PubMed

    Cooper, Endymion D

    2016-06-20

    Developing a structurally complex phenotype requires a complex regulatory network. A new study shows how gene duplication provides a potential source of antagonistic interactions, an important component of gene regulatory networks. PMID:27326708

  17. Benzodiazepinone Derivatives as CRTH2 Antagonists.

    PubMed

    Liu, Jiwen Jim; Cheng, Alan C; Tang, H Lucy; Medina, Julio C

    2011-07-14

    Multiple CRTH2 antagonists are currently evaluated in human clinical trials for asthma and chronic obstructive pulmonary disease (COPD). During our lead optimization for CRTH2 antagonists, an observation of an intramolecular hydrogen bond in ortho-phenylsulfonamido benzophenone derivatives led to the design and synthesis of conformationally constrained benzodiazepinones as potent CRTH2 antagonists. The benzodiazepinones are 2 orders of magnitude more potent than the original flexible bisaryl ethers in our binding assay. Selected benzodiazepinones, such as compound 6, were also potent in the human eosinophil shape change assay. Analysis of the rigid conformations of these benzodiazepinones and ortho-phenylsulfonamido benzophenones provided an explanation for the structure-activity relationship and revealed the possible bound conformations to CRTH2, which may be useful for building a pharmacophore model of CRTH2 antagonists. PMID:24900341

  18. Dopamine D2-Receptor Antagonists Down-Regulate CYP1A1/2 and CYP1B1 in the Rat Liver

    PubMed Central

    Harkitis, P.; Lang, M. A.; Marselos, M.; Fotopoulos, A.; Albucharali, G.; Konstandi, M.

    2015-01-01

    Dopaminergic systems regulate the release of several hormones including growth hormone (GH), thyroid hormones, insulin, glucocorticoids and prolactin (PRL) that play significant roles in the regulation of various Cytochrome P450 (CYP) enzymes. The present study investigated the role of dopamine D2-receptor-linked pathways in the regulation of CYP1A1, CYP1A2 and CYP1B1 that belong to a battery of genes controlled by the Aryl Hydrocarbon Receptor (AhR) and play a crucial role in the metabolism and toxicity of numerous environmental toxicants. Inhibition of dopamine D2-receptors with sulpiride (SULP) significantly repressed the constitutive and benzo[a]pyrene (B[a]P)-induced CYP1A1, CYP1A2 and CYP1B expression in the rat liver. The expression of AhR, heat shock protein 90 (HSP90) and AhR nuclear translocator (ARNT) was suppressed by SULP in B[a]P-treated livers, whereas the AhRR expression was increased by the drug suggesting that the SULP-mediated repression of the CYP1 inducibility is due to inactivation of the AhR regulatory system. At signal transduction level, the D2-mediated down-regulation of constitutive CYP1A1/2 and CYP1B1 expression appears to be mediated by activation of the insulin/PI3K/AKT pathway. PRL-linked pathways exerting a negative control on various CYPs, and inactivation of the glucocorticoid-linked pathways that positively control the AhR-regulated CYP1 genes, may also participate in the SULP-mediated repression of both, the constitutive and induced CYP1 expression. The present findings indicate that drugs acting as D2-dopamine receptor antagonists can modify several hormone systems that regulate the expression of CYP1A1, CYP1A2 and CYP1B1, and may affect the toxicity and carcinogenicity outcome of numerous toxicants and pre-carcinogenic substances. Therefore, these drugs could be considered as a part of the strategy to reduce the risk of exposure to environmental pollutants and pre-carcinogens. PMID:26466350

  19. Tannins as Gibberellin Antagonists 1

    PubMed Central

    Corcoran, Mary Ritzel; Geissman, T. A.; Phinney, Bernard O.

    1972-01-01

    Fourteen chemically defined hydrolyzable tannins and six impure mixtures of either condensed or hydrolyzable tannins were found to inhibit the gibberellin-induced growth of light-grown dwarf pea seedlings. The highest ratio of tannins to gibberellic acid tested (1000: 1 by weight) inhibited from 80 to 95% of the induced growth for all tannins tested except for two monogalloyl glucose tannins which inhibited only 50% of the induced growth. The lowest ratio tested (10: 1) inhibited the induced growth by less than 25% except for the case of terchebin where 50% inhibition was found. The inhibition of gibberellin-induced growth was found to be completely reversed by increasing the amount of gibberellin in three cases tested. Tannins alone did not inhibit endogenous growth of either dwarf or nondwarf pea seedlings. Eight compounds related to tannins, including coumarin, trans-cinnamic acid, and a number of phenolic compounds were also tested as gibberellin antagonists. Most of these compounds showed some inhibition of gibberellin-induced growth, but less than that of the tannins. At the highest ratio (1000: 1) the greatest inhibition was 55%; at the lowest ratio (10: 1) no more than 17% was observed. These compounds did not inhibit endogenous growth, and the inhibition of gibberellin-induced growth could be reversed by increasing the amount of gibberellin in two cases tested. Six chemically defined tannins were found to inhibit hypocotyl growth induced by gibberellic acid in cucumber seedlings. Growth induced by indoleacetic acid in the same test was not inhibited. The highest ratio of tannin to promotor tested gave strong inhibition of gibberellic acid-induced growth, but actually enhanced the growth induced by indoleacetic acid. This difference in action suggests a specificity between the tannins and gibberellic acid. PMID:16657953

  20. Tetrahydroquinoline derivatives as opioid receptor antagonists.

    PubMed

    Zhang, Cunyu; Westaway, Susan M; Speake, Jason D; Bishop, Michael J; Goetz, Aaron S; Carballo, Luz Helena; Hu, Mike; Epperly, Andrea H

    2011-01-15

    Opioid receptors play an important role in both behavioral and homeostatic functions. We herein report tetrahydroquinoline derivatives as opioid receptor antagonists. SAR studies led to the identification of the potent antagonist 2v, endowed with 1.58nM (K(i)) functional activity against the μ opioid receptor. DMPK data suggest that novel tetrahydroquinoline analogs may be advantageous in peripheral applications. PMID:21193310

  1. Food flavonoid aryl hydrocarbon receptor-mediated agonistic/antagonistic/synergic activities in human and rat reporter gene assays.

    PubMed

    Van der Heiden, Edwige; Bechoux, Nathalie; Muller, Marc; Sergent, Thérèse; Schneider, Yves-Jacques; Larondelle, Yvan; Maghuin-Rogister, Guy; Scippo, Marie-Louise

    2009-04-01

    Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor mediating the adverse effects of dioxins and polycyclic aromatic hydrocarbons (PAHs). In this study, we investigated the genetic-, time-, dose-, species- and tissue-dependent AhR-mediated agonistic/antagonistic activities of three food flavonoids: quercetin, chrysin and genistein. To that end, four stably transfected cell lines were used in cell-based luciferase reporter gene assays: three lines were transformed with the ptKLuc vector harbouring four dioxin-responsive elements (DREs) upstream of the thymidine kinase promoter and the luciferase gene (HepG2-Luc, T-47D-Luc and H4IIE-ULg). The fourth is a patented cell line transformed with a different construct: H4IIE DR-CALUX((R)). Both H4IIE cells were compared for their genetic construction. Human hepatoma (HepG2-Luc) and human breast tumour (T-47D-Luc) cells were compared for tissue-dependent effects. Rat hepatoma (H4IIE-ULg) and human hepatoma (HepG2-Luc) cells were compared for species-dependent activities. We concluded that quercetin, chrysin and genistein act in a time-, dose-, species- and tissue-specific way. For example, genistein displayed agonistic activities when exposed to rat hepatoma cells during 6h but not after 24h. Flavonoids displayed agonistic/antagonistic activities in human breast tumour cells, depending on the exposure time, while in human hepatoma cells, only antagonistic activities of flavonoids were measured. In addition, we report, in all the cells, a synergy between an isoflavone and two food contaminants; the 2,3,7,8-tetrachlorodibenzo-p-dioxin and 3-methylcholanthrene, a PAH. In rat cells, this synergy occurred when cells were exposed to flavonoids and contaminant for 6h, while it was observed in human cells only after 24h. PMID:19286049

  2. New CYP1 genes in the frog Xenopus (Silurana) tropicalis: Induction patterns and effects of AHR agonists during development

    PubMed Central

    Jönsson, Maria E.; Berg, Cecilia; Goldstone, Jared V.; Stegeman, John J.

    2010-01-01

    The Xenopus tropicalis genome shows a single gene in each of the four cytochrome P450 1 (CYP1) subfamilies that occur in vertebrates, designated as CYP1A, CYP1B1, CYP1C1, and CYP1D1. We cloned the cDNAs of these genes and examined their expression in untreated tadpoles and in tadpoles exposed to waterborne aryl hydrocarbon receptor agonists, 3,3',4,4',5-pentachlorobiphenyl (PCB126), β-naphthoflavone (βNF), or indigo. We also examined the effects of PCB126 on expression of genes involved in stress response, cell proliferation, thyroid homeostasis, and prostaglandin synthesis. PCB126 induced CYP1A, CYP1B1, and CYP1C1 but had little effect on CYP1D1 (77-, 1.7-, 4.6- and 1.4-fold induction versus the control, respectively). βNF induced CYP1A and CYP1C1 (26- and 2.5-fold), while, under conditions used, indigo tended to induce only CYP1A (1.9-fold). The extent of CYP1 induction by PCB126 and βNF was positively correlated to the number of putative dioxin response elements 0–20 kb upstream of the start codons. No morphological effect was observed in tadpoles exposed to 1 nM-10 µM PCB126 at two days post-fertilization (dpf) and screened 20 days later. However, in 14-dpf tadpoles a slight up-regulation of the genes for PCNA, transthyretin, HSC70, Cu-Zn SOD, and Cox-2 was observed two days after exposure to 1 µM PCB126. This study of the full suite of CYP1 genes in an amphibian species reveals gene- and AHR agonist-specific differences in response, as well as a much lower sensitivity to CYP1 induction and short-term toxicity by PCB126 compared with in fish larvae. The single genes in each CYP1 subfamily may make X. tropicalis a useful model for mechanistic studies of CYP1 functions. PMID:20965207

  3. ITE and TCDD differentially regulate the vascular remodeling of rat placenta via the activation of AhR.

    PubMed

    Wu, Yanming; Chen, Xiao; Zhou, Qian; He, Qizhi; Kang, Jiuhong; Zheng, Jing; Wang, Kai; Duan, Tao

    2014-01-01

    Vascular remodeling in the placenta is essential for normal fetal development. The previous studies have demonstrated that in utero exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, an environmental toxicant) induces the intrauterine fetal death in many species via the activation of aryl hydrocarbon receptor (AhR). In the current study, we compared the effects of 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) and TCDD on the vascular remodeling of rat placentas. Pregnant rats on gestational day (GD) 15 were randomly assigned into 5 groups, and were exposed to a single dose of 1.6 and 8.0 mg/kg body weight (bw) ITE, 1.6 and 8.0 µg/kg bw TCDD, or an equivalent volume of the vehicle, respectively. The dams were sacrificed on GD20 and the placental tissues were gathered. The intrauterine fetal death was observed only in 8.0 µg/kg bw TCDD-exposed group and no significant difference was seen in either the placental weight or the fetal weight among all these groups. The immunohistochemical and histological analyses revealed that as compared with the vehicle-control, TCDD, but not ITE, suppressed the placental vascular remodeling, including reduced the ratio of the placental labyrinth zone to the basal zone thickness (at least 0.71 fold of control), inhibited the maternal sinusoids dilation and thickened the trophoblastic septa. However, no marked difference was observed in the density of fetal capillaries in the labyrinth zone among these groups, although significant differences were detected in the expression of angiogenic growth factors between ITE and TCDD-exposed groups, especially Angiopoietin-2 (Ang-2), Endoglin, Interferon-γ (IFN-γ) and placenta growth factor (PIGF). These results suggest ITE and TCDD differentially regulate the vascular remodeling of rat placentas, as well as the expression of angiogenic factors and their receptors, which in turn may alter the blood flow in the late gestation and partially resulted in

  4. ITE and TCDD Differentially Regulate the Vascular Remodeling of Rat Placenta via the Activation of AhR

    PubMed Central

    Zhou, Qian; He, Qizhi; Kang, Jiuhong; Zheng, Jing; Wang, Kai; Duan, Tao

    2014-01-01

    Vascular remodeling in the placenta is essential for normal fetal development. The previous studies have demonstrated that in utero exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, an environmental toxicant) induces the intrauterine fetal death in many species via the activation of aryl hydrocarbon receptor (AhR). In the current study, we compared the effects of 2-(1′H-indole-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) and TCDD on the vascular remodeling of rat placentas. Pregnant rats on gestational day (GD) 15 were randomly assigned into 5 groups, and were exposed to a single dose of 1.6 and 8.0 mg/kg body weight (bw) ITE, 1.6 and 8.0 µg/kg bw TCDD, or an equivalent volume of the vehicle, respectively. The dams were sacrificed on GD20 and the placental tissues were gathered. The intrauterine fetal death was observed only in 8.0 µg/kg bw TCDD-exposed group and no significant difference was seen in either the placental weight or the fetal weight among all these groups. The immunohistochemical and histological analyses revealed that as compared with the vehicle-control, TCDD, but not ITE, suppressed the placental vascular remodeling, including reduced the ratio of the placental labyrinth zone to the basal zone thickness (at least 0.71 fold of control), inhibited the maternal sinusoids dilation and thickened the trophoblastic septa. However, no marked difference was observed in the density of fetal capillaries in the labyrinth zone among these groups, although significant differences were detected in the expression of angiogenic growth factors between ITE and TCDD-exposed groups, especially Angiopoietin-2 (Ang-2), Endoglin, Interferon-γ (IFN-γ) and placenta growth factor (PIGF). These results suggest ITE and TCDD differentially regulate the vascular remodeling of rat placentas, as well as the expression of angiogenic factors and their receptors, which in turn may alter the blood flow in the late gestation and partially resulted in

  5. New CYP1 genes in the frog Xenopus (Silurana) tropicalis: Induction patterns and effects of AHR agonists during development

    SciTech Connect

    Joensson, Maria E.; Berg, Cecilia; Goldstone, Jared V.; Stegeman, John J.

    2011-01-15

    The Xenopus tropicalis genome shows a single gene in each of the four cytochrome P450 1 (CYP1) subfamilies that occur in vertebrates, designated as CYP1A, CYP1B1, CYP1C1, and CYP1D1. We cloned the cDNAs of these genes and examined their expression in untreated tadpoles and in tadpoles exposed to waterborne aryl hydrocarbon receptor agonists, 3,3',4,4',5-pentachlorobiphenyl (PCB126), {beta}-naphthoflavone ({beta}NF), or indigo. We also examined the effects of PCB126 on expression of genes involved in stress response, cell proliferation, thyroid homeostasis, and prostaglandin synthesis. PCB126 induced CYP1A, CYP1B1, and CYP1C1 but had little effect on CYP1D1 (77-, 1.7-, 4.6- and 1.4-fold induction versus the control, respectively). {beta}NF induced CYP1A and CYP1C1 (26- and 2.5-fold), while, under conditions used, indigo tended to induce only CYP1A (1.9-fold). The extent of CYP1 induction by PCB126 and {beta}NF was positively correlated to the number of putative dioxin response elements 0-20 kb upstream of the start codons. No morphological effect was observed in tadpoles exposed to 1 nM-10 {mu}M PCB126 at two days post-fertilization (dpf) and screened 20 days later. However, in 14-dpf tadpoles a slight up-regulation of the genes for PCNA, transthyretin, HSC70, Cu-Zn SOD, and Cox-2 was observed two days after exposure to 1 {mu}M PCB126. This study of the full suite of CYP1 genes in an amphibian species reveals gene- and AHR agonist-specific differences in response, as well as a much lower sensitivity to CYP1 induction and short-term toxicity by PCB126 compared with in fish larvae. The single genes in each CYP1 subfamily may make X. tropicalis a useful model for mechanistic studies of CYP1 functions.

  6. Selective Aryl Hydrocarbon Receptor Modulator 3,3'-Diindolylmethane Impairs AhR and ARNT Signaling and Protects Mouse Neuronal Cells Against Hypoxia.

    PubMed

    Rzemieniec, J; Litwa, E; Wnuk, A; Lason, W; Krzeptowski, W; Kajta, M

    2016-10-01

    The neuroprotective potential of 3,3'-diindolylmethane (DIM), which is a selective aryl hydrocarbon receptor modulator, has recently been shown in cellular and animal models of Parkinson's disease and lipopolysaccharide-induced inflammation. However, there are no data concerning the protective capacity and mechanisms of DIM action in neuronal cells exposed to hypoxia. The aim of the present study was to investigate the neuroprotective potential of DIM against the hypoxia-induced damage in mouse hippocampal cells in primary cultures, with a particular focus on DIM interactions with the aryl hydrocarbon receptor (AhR), its nuclear translocator ARNT, and estrogen receptor β (ERβ). In the present study, 18 h of hypoxia induced apoptotic processes, in terms of the mitochondrial membrane potential, activation of caspase-3, and fragmentation of cell nuclei. These effects were accompanied by substantial lactate dehydrogenase release and neuronal cell death. The results of the present study demonstrated strong neuroprotective and anti-apoptotic actions of DIM in hippocampal cells exposed to hypoxia. In addition, DIM decreased the Ahr and Arnt mRNA expression and stimulated Erβ mRNA expression level. DIM-induced mRNA alterations were mirrored by changes in protein levels, except for ERβ, as detected by ELISA, Western blotting, and immunofluorescence labeling. We also demonstrated that DIM decreased the expression of AhR-regulated CYP1A1. Using specific siRNAs, we provided evidence that impairment of AhR and ARNT, but not ERβ plays a key role in the neuroprotective action of DIM against hypoxia-induced cell damage. This study may have implication for identifying new agents that could protect neurons against hypoxia by targeting AhR/ARNT signaling. PMID:26476840

  7. Assessment of energetic costs of AhR activation by β-naphthoflavone in rainbow trout (Oncorhynchus mykiss) hepatocytes using metabolic flux analysis

    SciTech Connect

    Nault, Rance; Abdul-Fattah, Hiba; Mironov, Gleb G.; Berezovski, Maxim V.; Moon, Thomas W.

    2013-08-15

    Exposure to environmental contaminants such as activators of the aryl hydrocarbon receptor (AhR) leads to the induction of defense and detoxification mechanisms. While these mechanisms allow organisms to metabolize and excrete at least some of these environmental contaminants, it has been proposed that these mechanisms lead to significant energetic challenges. This study tests the hypothesis that activation of the AhR by the model agonist β-naphthoflavone (βNF) results in increased energetic costs in rainbow trout (Oncorhynchus mykiss) hepatocytes. To address this hypothesis, we employed traditional biochemical approaches to examine energy allocation and metabolism including the adenylate energy charge (AEC), protein synthesis rates, Na{sup +}/K{sup +}-ATPase activity, and enzyme activities. Moreover, we have used for the first time in a fish cell preparation, metabolic flux analysis (MFA) an in silico approach for the estimation of intracellular metabolic fluxes. Exposure of trout hepatocytes to 1 μM βNF for 48 h did not alter hepatocyte AEC, protein synthesis, or Na{sup +}/K{sup +}-ATPase activity but did lead to sparing of glycogen reserves and changes in activities of alanine aminotransferase and citrate synthase suggesting altered metabolism. Conversely, MFA did not identify altered metabolic fluxes, although we do show that the dynamic metabolism of isolated trout hepatocytes poses a significant challenge for this type of approach which should be considered in future studies. - Highlights: • Energetic costs of AhR activation by βNF was examined in rainbow trout hepatocytes. • Metabolic flux analysis was performed on a fish cell preparation for the first time. • Exposure to βNF led to sparing of glycogen reserves and altered enzyme activities. • Adenylate energy charge was maintained despite temporal changes in metabolism.

  8. Toxicogenomic analysis of exposure to TCDD, PCB126 and PCB153: identification of genomic biomarkers of exposure to AhR ligands

    PubMed Central

    2010-01-01

    Background Two year cancer bioassays conducted by the National Toxicology Program have shown chronic exposure to dioxin-like compounds (DLCs) to lead to the development of both neoplastic and non-neoplastic lesions in the hepatic tissue of female Sprague Dawley rats. Most, if not all, of the hepatotoxic effects induced by DLC's are believed to involve the binding and activation of the transcription factor, the aryl hydrocarbon receptor (AhR). Toxicogenomics was implemented to identify genomic responses that may be contributing to the development of hepatotoxicity in rats. Results Through comparative analysis of time-course microarray data, unique hepatic gene expression signatures were identified for the DLCs, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (100 ng/kg/day) and 3,3',4,4',5-pentachlorobiphenyl (PCB126) (1000 ng/kg/day) and the non-DLC 2,2',4,4',5,5',-hexachlorobiphenyl (PCB153) (1000 μg/kg/day). A common time independent signature of 41 AhR genomic biomarkers was identified which exhibited at least a 2-fold change in expression following subchronic (13-wk) and chronic (52-wk) p.o. exposure to TCDD and PCB126, but not the non DLC, PCB153. Real time qPCR analysis validated that 30 of these genes also exhibited at least a 2-fold change in hepatic expression at 24 hr following a single exposure to TCDD (5 μg/kg, po). Phenotypic anchoring was conducted which identified forty-six genes that were differently expressed both following chronic p.o. exposure to DLCs and in previously reported studies of cholangiocarcinoma or hepatocellular adenoma. Conclusions Together these analyses provide a comprehensive description of the genomic responses which occur in rat hepatic tissue with exposure to AhR ligands and will help to isolate those genomic responses which are contributing to the hepatotoxicity observed with exposure to DLCs. In addition, the time independent gene expression signature of the AhR ligands may assist in identifying other agents with the potential

  9. Antagonistic formation motion of cooperative agents

    NASA Astrophysics Data System (ADS)

    Lu, Wan-Ting; Dai, Ming-Xiang; Xue, Fang-Zheng

    2015-02-01

    This paper investigates a new formation motion problem of a class of first-order multi-agent systems with antagonistic interactions. A distributed formation control algorithm is proposed for each agent to realize the antagonistic formation motion. A sufficient condition is derived to ensure that all of the agents make an antagonistic formation motion in a distributed manner. It is shown that all of the agents can be spontaneously divided into several groups and that agents in the same group collaborate while agents in different groups compete. Finally, a numerical simulation is included to demonstrate our theoretical results. Project supported by the National Natural Science Foundation of China (Grant Nos. 61203080 and 61473051) and the Natural Science Foundation of Chongqing City (Grant No. CSTC 2011BB0081).

  10. Endothelin receptor antagonists in pulmonary arterial hypertension.

    PubMed

    Channick, Richard N; Sitbon, Olivier; Barst, Robyn J; Manes, Alessandra; Rubin, Lewis J

    2004-06-16

    Endothelin receptor antagonism has emerged as an important therapeutic strategy in pulmonary arterial hypertension (PAH). Laboratory and clinical investigations have clearly shown that endothelin (ET)-1 is overexpressed in several forms of pulmonary vascular disease and likely plays a significant pathogenetic role in the development and progression of pulmonary vasculopathy. Oral endothelin receptor antagonists (ERAs) have been shown to improve pulmonary hemodynamics, exercise capacity, functional status, and clinical outcome in several randomized placebo-controlled trials. Bosentan, a dual-receptor antagonist, is approved by the U.S. Food and Drug Administration for class III and IV patients with PAH, based on two phase III trials. In addition to its efficacy as sole therapy, bosentan may have a role as part of a combination of drugs such as a prostanoid or sildenafil. The selective endothelin receptor-A antagonists sitaxsentan and ambrisentan are currently undergoing investigation. PMID:15194180

  11. Histamine-2 Receptor Antagonists and Semen Quality.

    PubMed

    Banihani, Saleem A

    2016-01-01

    Histamine-2 receptor antagonists are a class of drugs used to treat the acid-related gastrointestinal diseases such as ulcer and gastro-oesophageal reflux disease. Although such drugs, especially ranitidine and famotidine, are still widely used, their effects on semen quality, and hence on male infertility, is still unclear. This MiniReview systematically addresses and summarizes the effect of histamine-2 receptor antagonists (cimetidine, ranitidine, nizatidine and famotidine) on semen quality, particularly, on sperm function. Cimetidine appears to have adverse effects on semen quality. While the effects of ranitidine and nizatidine on semen quality are still controversial, famotidine does not appear to change semen quality. Therefore, additional studies will be required to clarify whether histamine-2 receptor-independent effects of these drugs play a role in semen quality as well as further clinical studies including direct comparison of the histamine-2 receptor antagonists. PMID:26176290

  12. Different AhR binding sites of diterpenoid ligands from Andrographis paniculata caused differential CYP1A1 induction in primary culture in mouse hepatocytes.

    PubMed

    Chatuphonprasert, Waranya; Remsungnen, Tawun; Nemoto, Nobuo; Jarukamjorn, Kanokwan

    2011-12-01

    Andrographis paniculata has been employed as a folklore remedy. Andrographolide (Andro), 14-deoxy-11,12-didehydroandrographolide (DHA), andrographiside (AS), and neoandrographolide (Neo), are major diterpenoids isolated from this plant. In the present study, influence of the four diterpenoids on CYP1A1 mRNA expression was investigated in primary cultured mouse hepatocytes. Additionally, binding of these compounds to aryl hydrocarbon receptor (AhR) was examined using molecular docking analysis to clarify mechanism of CYP1A1 induction. Andro and DHA induced CYP1A1 expression by itself, and co-treatment with a CYP1A1 inducer (BNF, beta-naphthoflavone) showed a synergistic increase of CYP1A1 expression. Andro demonstrated higher enhancing activity than DHA at every similar concentration. On the other hand, Neo suppressed BNF-induced CYP1A1 expression, but AS did not modify the induction. Results from molecular docking analysis of BNF and four diterpenoids on ligand binding domain of AhR were consistent with levels of CYP1A1 mRNA expressions. Furthermore, difference of binding sites of BNF in the presence of diterpenoids might affect the synergism or inhibition of CYP1A1 expression. These results suggest that use of A. paniculata as a health supplement should be concerned in term of herb-drugs interactions or risk of carcinogenesis, according to its ability to influence CYP1A1 expression. PMID:21963808

  13. Expression of aryl hydrocarbon receptor 1 (AHR1), AHR1 nuclear translocator 1 (ARNT1) and CYP1 family monooxygenase mRNAs and their activity in chicken ovarian follicles following in vitro exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).

    PubMed

    Antos, Piotr A; Błachuta, Małgorzata; Hrabia, Anna; Grzegorzewska, Agnieszka K; Sechman, Andrzej

    2015-09-01

    The aim of this in vitro study was to determine the effect of TCDD and luteinizing hormone (LH) on mRNA expression of aryl hydrocarbon receptor 1 (AHR1), AHR1 nuclear translocator 1 (ARNT1), and the CYP1 family monooxygenases (CYP1A4, CYP1A5, CYP1B1), and to assess the basal and TCDD-induced activity of these enzymes in chicken ovarian follicles. White (WF) and yellowish (YF) prehierarchical follicles and fragments of the theca (TL) and granulosa (GL) layers of the 3 largest preovulatory follicles (F3-F1) were exposed to TCDD (10nM), ovine LH (oLH; 10ng/mL) or a combination of TCDD (10nM) and oLH (10ng/mL), and increasing doses of TCDD (0.01-100nM). AHR1 and ARNT1 mRNA transcripts were found in all examined follicles. The effect of TCDD and oLH on AHR1 and ARNT1 mRNA expression depended on the maturational state of the follicle. CYP1A4 was predominantly expressed in the GL of the F3-F1 follicles; in comparison with the WF, a higher level of CYP1A5 mRNA was found both in the GL and TL of F3-F1 follicles. Alternatively, the highest level of CYP1B1 mRNA was noticed in the WF follicles. In different developmental stages of the follicle TCDD and oLH induced a different CYP1 isoform. TCDD increased EROD and MROD activities in all the investigated ovarian follicles. In conclusion, AHR1 and ARNT1 mRNA expression indicate that the chicken ovary is a target tissue for dioxin and dioxin-like compounds. The expression of CYP1-family genes and TCDD-inducible EROD and MROD activities in ovarian follicles suggest the possibility of xenobiotic detoxification in the chicken ovary. PMID:26043675

  14. Genome-wide RNAi high-throughput screen identifies proteins necessary for the AHR-dependent induction of CYP1A1 by 2,3,7,8-tetrachlorodibenzo-p-dioxin.

    PubMed

    Solaimani, Parrisa; Damoiseaux, Robert; Hankinson, Oliver

    2013-11-01

    The aryl hydrocarbon receptor (AHR) has a plethora of physiological roles, and upon dysregulation, carcinogenesis can occur. One target gene of AHR encodes the xenobiotic and drug-metabolizing enzyme CYP1A1, which is inducible by the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) via the AHR. An siRNA library targeted against over 5600 gene candidates in the druggable genome was used to transfect mouse Hepa-1 cells, which were then treated with TCDD, and subsequently assayed for CYP1A1-dependent ethoxyresorufin-o-deethylase (EROD) activity. Following redundant siRNA activity (RSA) statistical analysis, we identified 93 hits that reduced EROD activity with a p value ≤ .005 and substantiated 39 of these as positive hits in a secondary screening using endoribonuclease-prepared siRNAs (esiRNAs). Twelve of the corresponding gene products were subsequently confirmed to be necessary for the induction of CYP1A1 messenger RNA by TCDD. None of the candidates were deficient in aryl hydrocarbon nuclear translocator expression. However 6 gene products including UBE2i, RAB40C, CRYGD, DCTN4, RBM5, and RAD50 are required for the expression of AHR as well as for induction of CYP1A1. We also found 2 gene products, ARMC8 and TCF20, to be required for the induction of CYP1A1, but our data are ambiguous as to whether they are required for the expression of AHR. In contrast, SIN3A, PDC, TMEM5, and CD9 are not required for AHR expression but are required for the induction of CYP1A1, implicating a direct role in Cyp1a1 transcription. Our methods, although applied to Cyp1a1, could be modified for identifying proteins that regulate other inducible genes. PMID:23997114

  15. Genome-Wide RNAi High-Throughput Screen Identifies Proteins Necessary for the AHR-Dependent Induction of CYP1A1 by 2,3,7,8-Tetrachlorodibenzo-p-dioxin

    PubMed Central

    Hankinson, Oliver

    2013-01-01

    The aryl hydrocarbon receptor (AHR) has a plethora of physiological roles, and upon dysregulation, carcinogenesis can occur. One target gene of AHR encodes the xenobiotic and drug-metabolizing enzyme CYP1A1, which is inducible by the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) via the AHR. An siRNA library targeted against over 5600 gene candidates in the druggable genome was used to transfect mouse Hepa-1 cells, which were then treated with TCDD, and subsequently assayed for CYP1A1-dependent ethoxyresorufin-o-deethylase (EROD) activity. Following redundant siRNA activity (RSA) statistical analysis, we identified 93 hits that reduced EROD activity with a p value ≤ .005 and substantiated 39 of these as positive hits in a secondary screening using endoribonuclease-prepared siRNAs (esiRNAs). Twelve of the corresponding gene products were subsequently confirmed to be necessary for the induction of CYP1A1 messenger RNA by TCDD. None of the candidates were deficient in aryl hydrocarbon nuclear translocator expression. However 6 gene products including UBE2i, RAB40C, CRYGD, DCTN4, RBM5, and RAD50 are required for the expression of AHR as well as for induction of CYP1A1. We also found 2 gene products, ARMC8 and TCF20, to be required for the induction of CYP1A1, but our data are ambiguous as to whether they are required for the expression of AHR. In contrast, SIN3A, PDC, TMEM5, and CD9 are not required for AHR expression but are required for the induction of CYP1A1, implicating a direct role in Cyp1a1 transcription. Our methods, although applied to Cyp1a1, could be modified for identifying proteins that regulate other inducible genes. PMID:23997114

  16. Azines as histamine H4 receptor antagonists.

    PubMed

    Lazewska, Dorota; Kiec-Kononowicz, Katarzyna

    2012-01-01

    Since 2000, when the histamine H4 receptor (H4R) was cloned, it has constituted an interesting target for drug development. Pharmacological studies suggest the potential utility of histamine H4R antagonists/inverse agonists in the treatment of inflammatory diseases, e.g. allergic rhinitis, asthma, atopic dermatitis, colitis, or pruritus. The first H4R ligands were non-selective compounds, but intensive chemical and pharmacological work has led to the discovery of highly potent and selective H4R antagonists (e.g. JNJ7777120, CZC-13788, PF-2988403, A-940894, A-987306). The first compound (UR-63325) has finally entered into clinical studies for the treatment of allergic respiratory diseases (completing the phase I ascending dose trial) and has been found to be safe and well tolerated. The number of scientific publications and patent applications in the H4 field is increasing annually. Among the diverse chemical structures of the H4R antagonists described a 2-aminopyrimidine scaffold is repeatedly found. This review looked at recent advances in the search for H4R antagonists as reflected in patent applications/patents and peer-reviewed publications over the last two years. The work concerns azines (mono-, di-, triazines) and their fused analogues. The chemistry and pharmacology has been described. PMID:22202103

  17. Oxazolidinones as novel human CCR8 antagonists.

    PubMed

    Jin, Jian; Wang, Yonghui; Wang, Feng; Kerns, Jeffery K; Vinader, Victoria M; Hancock, Ashley P; Lindon, Matthew J; Stevenson, Graeme I; Morrow, Dwight M; Rao, Parvathi; Nguyen, Cuc; Barrett, Victoria J; Browning, Chris; Hartmann, Guido; Andrew, David P; Sarau, Henry M; Foley, James J; Jurewicz, Anthony J; Fornwald, James A; Harker, Andy J; Moore, Michael L; Rivero, Ralph A; Belmonte, Kristen E; Connor, Helen E

    2007-03-15

    High-throughput screening of the corporate compound collection led to the discovery of a novel series of N-substituted-5-aryl-oxazolidinones as potent human CCR8 antagonists. The synthesis, structure-activity relationships, and optimization of the series that led to the identification of SB-649701 (1a), are described. PMID:17267215

  18. Differential effects of mercury, lead and copper on the constitutive and inducible expression of aryl hydrocarbon receptor (AHR)-regulated genes in cultured hepatoma Hepa 1c1c7 cells.

    PubMed

    Korashy, Hesham M; El-Kadi, Ayman O S

    2004-09-01

    Both simultaneous and sequential exposure to heavy metals and aryl hydrocarbon receptor (AHR)-ligands potentially occur in human populations, yet there have been relatively few studies of combined effects of heavy metals and AHR-ligands on AHR-regulated genes. To investigate the effects of heavy metals on AHR-regulated genes; cytochrome P450 1a1 (cyp1a1), NAD(P)H:quinone oxidoreductase (QOR) and glutathione S-transferase Ya (GST Ya), murine hepatoma Hepa 1c1c7 cells were incubated with increasing concentrations of Hg2+ (2.5-10 microM), Pb2+ (10-100 microM), and Cu2+ (1-100 microM) alone or with the AHR-ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (0.1 nM), 3-methylcholanthrene (0.25 microM), beta-naphthoflavone (10 microM), or benzo[a]pyrene (1 microM). The results clearly showed that metals alone did not significantly alter the cyp1a1 activity and protein levels but increased its mRNA expression, whereas a significant reduction in AHR ligand-mediated induction of cyp1a1 activity was observed by all metals. The decrease in cyp1a1 activity was associated with an increase, no change, or decrease in cyp1a1 mRNA and protein levels by Hg2+, Pb2+ and Cu2+ respectively, suggesting pre- and post-transcription mechanisms are involved. With respect to QOR, the activity and mRNA levels were increased by all metals in the absence or presence of an AHR-ligand, with the exception of Cu2+ which significantly decreased the induction of QOR. Differently, GST Ya activity was significantly increased by Cu2+ and Pb2+ and inhibited by Hg2+, while its mRNA was increased by Hg2+ and Pb2+ and decreased by Cu2+. All metals significantly increased the expression of heme oxygenase-1, which coincided with the changes in the phase I and phase II enzyme activities. These results demonstrate that heavy metals differentially modulate the constitutive and the inducible expression of AHR-regulated genes. PMID:15297030

  19. Discovery of novel and potent CRTH2 antagonists.

    PubMed

    Ito, Shinji; Terasaka, Tadashi; Zenkoh, Tatsuya; Matsuda, Hiroshi; Hayashida, Hisashi; Nagata, Hiroshi; Imamura, Yoshimasa; Kobayashi, Miki; Takeuchi, Makoto; Ohta, Mitsuaki

    2012-01-15

    High throughput screening of our chemical library for CRTH2 antagonists provided a lead compound 1a. Initial optimization of the lead led to the discovery of a novel, potent and orally bioavailable CRTH2 antagonist 17. PMID:22178554

  20. Tumorigenic effects of endocrine-disrupting chemicals are alleviated by licorice (Glycyrrhiza glabra) root extract through suppression of AhR expression in mammalian cells.

    PubMed

    Chu, Xiao Ting; de la Cruz, Joseph; Hwang, Seong Gu; Hong, Heeok

    2014-01-01

    Endocrine-disrupting chemicals (EDCs) have been reported to interfere with estrogen signaling. Exposure to these chemicals decreases the immune response and causes a wide range of diseases in animals and humans. Recently, many studies showed that licorice (Glycyrrhiza glabra) root extract (LRE) commonly called "gamcho" in Korea exhibits antioxidative, chemoprotective, and detoxifying properties. This study aimed to investigate the mechanism of action of LRE and to determine if and how LRE can alleviate the toxicity of EDCs. LRE was prepared by vacuum evaporation and freeze-drying after homogenization of licorice root powder that was soaked in 80% ethanol for 72 h. We used 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) as a representative EDC, which is known to induce tumors or cancers; MCF-7 breast cancer cells, used as a tumor model, were treated with TCDD and various concentrations of LRE (0, 50, 100, 200, 400 μg/mL) for 24, 48, and 72 h. As a result, TCDD stimulated MCF-7 cell proliferation, but LRE significantly inhibited TCDD-induced MCF-7 cell proliferation in a dose- and time-dependent manner. The expression of TCDD toxicity-related genes, i.e., aryl hydrocarbon receptor (AhR), AhR nuclear translocator, and cytochrome P450 1A1, was also down-regulated by LRE in a dose-dependent manner. Analysis of cell cycle distribution after treatment of MCF-7 cells with TCDD showed that LRE inhibited the proliferation of MCF-7 cells via G2/M phase arrest. Reverse transcription-polymerase chain reaction and Western blot analysis also revealed that LRE dose-dependently increased the expression of the tumor suppressor genes p53 and p27 and down-regulated the expression of cell cycle-related genes. These data suggest that LRE can mitigate the tumorigenic effects of TCDD in breast cancer cells by suppression of AhR expression and cell cycle arrest. Thus, LRE can be used as a potential toxicity-alleviating agent against EDC-mediated diseases. PMID:24998545

  1. Cytochrome P4501A induction in avian hepatocyte cultures exposed to polychlorinated biphenyls: Comparisons with AHR1-mediated reporter gene activity and in ovo toxicity

    SciTech Connect

    Manning, Gillian E.; Mundy, Lukas J.; Crump, Doug; Jones, Stephanie P.; Chiu, Suzanne; Klein, Jeff; Konstantinov, Alex; Potter, Dave; Kennedy, Sean W.

    2013-01-01

    Avian-specific toxic equivalency factors (TEFs) were developed by the World Health Organization to simplify environmental risk assessments of dioxin-like compounds (DLCs), but TEFs do not account for differences in the toxic and biochemical potencies of DLCs among species of birds. Such variability may be due to differences in species sensitivity to individual DLCs. The sensitivity of avian species to DLCs was recently associated with the identity of amino acids 324 and 380 in the aryl hydrocarbon receptor 1 (AHR1) ligand binding domain. A luciferase reporter gene (LRG) assay, measuring AHR1-mediated induction of a cytochrome P450 1A5 (CYP1A5) reporter gene, in combination with a species' AHR1 ligand binding domain sequence, were also shown to predict avian species sensitivity to polychlorinated biphenyls (PCBs) and PCB relative potency in a given species. The goals of the present study were to (1) characterize the concentration-dependent effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin and PCBs 126, 77, 105 and 118 on induction of ethoxyresorufin O-deethylase (EROD) activity and CYP1A4/5 mRNA in chicken, ring-necked pheasant and Japanese quail embryo hepatocytes and (2) compare these in vitro results to those previously generated by the LRG assay and in ovo toxicity studies. EROD activity and CYP1A4/5 mRNA expression data support and complement the findings of the LRG assay. CYP1A enzyme activity and mRNA expression were significantly correlated both with luciferase activity and in ovo toxicity induced by PCBs. Relative potency values were generally similar between the LRG and EROD assays and indicate that the relative potency of some PCBs may differ among species. -- Highlights: ► The chicken isn't the most sensitive species to CYP1A induction by PCB 105 and 118. ► The relative potency of PCBs differs between avian species. ► EROD activity was correlated with luciferase activity from the LRG assay. ► EROD activity was a better predictor of toxicity than CYP

  2. Fluorescent Human EP3 Receptor Antagonists.

    PubMed

    Tomasch, Miriam; Schwed, J Stephan; Kuczka, Karina; Meyer Dos Santos, Sascha; Harder, Sebastian; Nüsing, Rolf M; Paulke, Alexander; Stark, Holger

    2012-09-13

    Exchange of the lipophilc part of ortho-substituted cinnamic acid lead structures with different small molecule fluorophoric moieties via a dimethylene spacer resulted in hEP3R ligands with affinities in the nanomolar concentration range. Synthesized compounds emit fluorescence in the blue, green, and red range of light and have been tested concerning their potential as a pharmacological tool. hEP3Rs were visualized by confocal laser scanning microscopy on HT-29 cells, on murine kidney tissues, and on human brain tissues and functionally were characterized as antagonists on human platelets. Inhibition of PGE2 and collagen-induced platelet aggregation was measured after preincubation with novel hEP3R ligands. The pyryllium-labeled ligand 8 has been shown as one of the most promising structures, displaying a useful fluorescence and highly affine hEP3R antagonists. PMID:24900547

  3. Vasopressin receptor antagonists: Characteristics and clinical role.

    PubMed

    Rondon-Berrios, Helbert; Berl, Tomas

    2016-03-01

    Hyponatremia, the most common electrolyte disorder in hospitalized patients is associated with increased risk of mortality even when mild and apparently asymptomatic. Likewise morbidity manifested as attention deficits, gait disturbances, falls, fractures, and osteoporosis is more prevalent in hyponatremic subjects. Hyponatremia also generates a significant financial burden. Therefore, it is important to explore approaches that effectively and safely treat hyponatremia. Currently available strategies are physiologically sound and affordable but lack evidence from clinical trials and are limited by variable efficacy, slow response, and/or poor compliance. The recent emergence of vasopressin receptor antagonists provides a class of drugs that target the primary pathophysiological mechanism, namely vasopressin mediated impairment of free water excretion. This review summarizes the historical development, pharmacology, clinical trials supporting efficacy and safety, shortcomings, as well as practical suggestions for the use of vasopressin receptor antagonists. PMID:27156765

  4. Preclinical pharmacology of alpha1-adrenoceptor antagonists.

    PubMed

    Martin, D J

    1999-01-01

    The implication of a single adrenoceptor subtype in the contractility of prostatic and urethral smooth muscle cells led to the concept that drugs with selectivity for this subtype may exhibit functional uroselectivity. Comparison of the affinities of the alpha1-adrenoceptor antagonists revealed that few compounds show selectivity for one of the three cloned alpha1-adrenoceptor subtypes (alpha1a/A, alpha1b/B, alpha1d/D) whereas most of them had a similar affinity for the three subtypes. Moreover, data supporting a relationship between selectivity for the alpha1a/A-adrenoceptor subtype and functional uroselectivity are still lacking and recent data challenged the relevance of the selectivity for a given cloned alpha1-adrenoceptor subtype in predicting functional uroselectivity. In vivo data showed that alpha1-adrenoceptor antagonists without adrenoceptor subtype selectivity, like alfuzosin or to a minor extent doxazosin, showed functional uroselectivity whereas prazosin and terazosin were not shown to be uroselective. Compounds considered to be selective for the alpha1a/A-adrenoceptor, like tamsulosin or 5-Me-urapidil, did not show functional uroselectivity since they modified urethral and blood pressures in a manner which was not correlated to their selectivity for the cloned alpha1-adrenoceptor subtypes. Meanwhile, the identification in prostatic tissue, of a new sub-family of alpha1-adrenoceptors with low affinity for prazosin and denominated alpha1L gave rise to numerous studies. However, its functional role as well as the affinity of the known antagonists for this receptor subtype remains to be clarified. In conclusion, the existing alpha1-adrenoceptor antagonists have different pharmacological profiles in vivo which are yet not predictable from their receptor pharmacology based on the actual state of knowledge of the alpha1-adrenoceptor classification. PMID:10393471

  5. Aryl hydrocarbon receptor (AhR) activation during pregnancy, and in adult nulliparous mice, delays the subsequent development of DMBA-induced mammary tumors

    PubMed Central

    Wang, Tao; Gavin, Heather M.; Arlt, Volker M.; Lawrence, B. Paige; Fenton, Suzanne E.; Medina, Daniel; Vorderstrasse, Beth A.

    2010-01-01

    TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin), the prototypic ligand for the aryl hydrocarbon receptor (AhR), promotes tumor formation in some model systems. However with regard to breast cancer, epidemiological and animal studies are inconclusive as to whether exposure increases tumor incidence or may instead be protective. We have previously reported that mice exposed to TCDD during pregnancy have impaired differentiation of mammary tissue, including decreased branching and poor development of lobuloalveolar structures. Because normal pregnancy-induced mammary differentiation may protect against subsequent neoplastic transformation, we hypothesized that TCDD-treated mice would be more susceptible to chemical carcinogenesis after parturition. To test this, mice were treated with TCDD or vehicle during pregnancy. Four weeks later, DMBA (7,12-dimethylbenz[a]anthracene) was administered to induce mammary tumor formation. Contrary to our hypothesis, TCDD-exposed parous mice showed a four-week delay in tumor formation relative to controls, and had a lower tumor incidence throughout the 27-week time course. The same results were obtained in nulliparous mice given TCDD and DMBA on the same schedule. We next addressed whether the delayed tumor incidence was a reflection of decreased tumor initiation, by testing the formation of DMBA-DNA adducts and preneoplastic lesions, induction of cytochrome P450s, and cell proliferation. None of these markers of tumor initiation differed between vehicle- and TCDD-treated animals. The expression of CXCL12 and CXCR4 was also measured to address their possible role in tumorigenesis. Taken together, our results suggest that AhR activation by TCDD slows the promotion of preneoplastic lesions to overt mammary tumors. PMID:20521247

  6. Amino acid sequence of the AhR1 ligand-binding domain predicts avian sensitivity to dioxin like compounds: in vivo verification in European starlings.

    PubMed

    Eng, Margaret L; Elliott, John E; Jones, Stephanie P; Williams, Tony D; Drouillard, Ken G; Kennedy, Sean W

    2014-12-01

    Research has demonstrated that the sensitivity of avian species to the embyrotoxic effects of dioxin-like compounds can be predicted by the amino acid identities at two key sites within the ligand-binding domain of the aryl hydrocarbon receptor 1 (AhR1). The domestic chicken (Gallus gallus domesticus) has been established as a highly sensitive species to the toxic effects of dioxin-like compounds. Results from genotyping and in vitro assays predict that the European starling (Sturnus vulgaris) is also highly sensitive to dioxin-like compound toxicity. The objective of the present study was to test that prediction in vivo. To do this, we used egg injections in field nesting starlings with 3,3',4,4',5-pentachlorobiphenyl (PCB-126), a dioxin-like polychlorinated biphenyl. Eggs were dosed with either the vehicle control or 1 of 5 doses (1.4, 7.1, 15.9, 32.1, and 52.9 ng PCB-126/g egg). A dose-dependent increase in embryo mortality occurred, and the median lethal dose (LD50; 95% confidence interval [CI]) was 5.61 (2.33-9.08) ng/g. Hepatic CYP1A4/5 messenger RNA (mRNA) expression in hatchlings also increased in a dose-dependent manner, with CYP1A4 being more induced than CYP1A5. No effect of dose on morphological measures was seen, and we did not observe any overt malformations. These results indicate that, other than the chicken, the European starling is the most sensitive species to the effects of PCB-126 on avian embryo mortality reported to date, which supports the prediction of relative sensitivity to dioxin-like compounds based on amino acid sequence of the AhR1. PMID:25209921

  7. Medicinal chemistry of competitive kainate receptor antagonists.

    PubMed

    Larsen, Ann M; Bunch, Lennart

    2011-02-16

    Kainic acid (KA) receptors belong to the group of ionotropic glutamate receptors and are expressed throughout in the central nervous system (CNS). The KA receptors have been shown to be involved in neurophysiological functions such as mossy fiber long-term potentiation (LTP) and synaptic plasticity and are thus potential therapeutic targets in CNS diseases such as schizophrenia, major depression, neuropathic pain and epilepsy. Extensive effort has been made to develop subtype-selective KA receptor antagonists in order to elucidate the physiological function of each of the five subunits known (GluK1-5). However, to date only selective antagonists for the GluK1 subunit have been discovered, which underlines the strong need for continued research in this area. The present review describes the structure-activity relationship and pharmacological profile for 10 chemically distinct classes of KA receptor antagonists comprising, in all, 45 compounds. To the medicinal chemist this information will serve as reference guidance as well as an inspiration for future effort in this field. PMID:22778857

  8. Calcium antagonists and their mode of action

    PubMed Central

    Nayler, Winifred G.; Dillon, J. S.

    1986-01-01

    1 The Ca2+ antagonists are a novel group of drugs useful in management of a variety of cardiac disorders. They differ from one another in terms of their chemistry, tissue specificity and selectivity. As a group, however, they share the common property of slowing Ca2+ entry through voltage-activated, ion-selective channels. Some of them exhibit other properties, including that of interfering with Na+ transport. At least one of them, diltiazem, has an intracellular action. 2 Specific high and low affinity binding sites have been identified for two of the major groups of Ca2+-antagonists, with the binding sites for verapamil and its derivatives being distinct from those which can be occupied by the dihydropyridines. The number (Bmax) and affinity (KD) of these binding sites changes under certain pathological conditions—including a reduction in ischaemia and in spontaneous hypertension, an increase in the latter, at present, only demonstrated for the dihydropyridine binding sites. 3 The sensitivity of a particular tissue to these drugs will depend upon a number of factors including the number of binding sites that are present, the contribution made by the Ca2+ entering through the voltage-activated channels to the functioning of the tissue, and properties which are peculiar to a particular type of Ca2+ antagonist, for example, whether, as in the case of verapamil, they exhibit use-dependence. PMID:3019374

  9. The Sexually Antagonistic Genes of Drosophila melanogaster

    PubMed Central

    Innocenti, Paolo; Morrow, Edward H.

    2010-01-01

    When selective pressures differ between males and females, the genes experiencing these conflicting evolutionary forces are said to be sexually antagonistic. Although the phenotypic effect of these genes has been documented in both wild and laboratory populations, their identity, number, and location remains unknown. Here, by combining data on sex-specific fitness and genome-wide transcript abundance in a quantitative genetic framework, we identified a group of candidate genes experiencing sexually antagonistic selection in the adult, which correspond to 8% of Drosophila melanogaster genes. As predicted, the X chromosome is enriched for these genes, but surprisingly they represent only a small proportion of the total number of sex-biased transcripts, indicating that the latter is a poor predictor of sexual antagonism. Furthermore, the majority of genes whose expression profiles showed a significant relationship with either male or female adult fitness are also sexually antagonistic. These results provide a first insight into the genetic basis of intralocus sexual conflict and indicate that genetic variation for fitness is dominated and maintained by sexual antagonism, potentially neutralizing any indirect genetic benefits of sexual selection. PMID:20305719

  10. AhR activation by 6-formylindolo[3,2-b]carbazole and 2,3,7,8-tetrachlorodibenzo-p-dioxin inhibit the development of mouse intestinal epithelial cells.

    PubMed

    Park, Joo-Hung; Choi, Ah-Jeong; Kim, Soo-Ji; Cheong, Seon-Woo; Jeong, So-Yeon

    2016-04-01

    The intestinal epithelium plays a central role in immune homeostasis in the intestine. AhR, a ligand-activated transcription factor, plays an important role in diverse physiological processes. The intestines are exposed to various exogenous and endogenous AhR ligands. Thus, AhR may regulate the intestinal homeostasis, directly acting on the development of intestinal epithelial cells (IEC). In this study, we demonstrated that 6-formylindolo[3,2-b]carbazole (FICZ) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) inhibited the in vitro development of mouse intestinal organoids. The number of Paneth cells in the small intestine and the depth of crypts of the small and large intestines were reduced in mice administrated with FICZ. Immunohistochemical and flow cytometric assays revealed that AhR was highly expressed in Lgr5(+) stem cells. FICZ inhibited Wnt signaling lowering the level of β-catenin protein. Gene expression analyses demonstrated that FICZ increased expression of Lgr5, Math1, BMP4, and Indian Hedgehog while inhibiting that of Lgr4. PMID:26950395

  11. From the Cover: Glutamate antagonists limit tumor growth

    NASA Astrophysics Data System (ADS)

    Rzeski, Wojciech; Turski, Lechoslaw; Ikonomidou, Chrysanthy

    2001-05-01

    Neuronal progenitors and tumor cells possess propensity to proliferate and to migrate. Glutamate regulates proliferation and migration of neurons during development, but it is not known whether it influences proliferation and migration of tumor cells. We demonstrate that glutamate antagonists inhibit proliferation of human tumor cells. Colon adenocarcinoma, astrocytoma, and breast and lung carcinoma cells were most sensitive to the antiproliferative effect of the N-methyl-D-aspartate antagonist dizocilpine, whereas breast and lung carcinoma, colon adenocarcinoma, and neuroblastoma cells responded most favorably to the -amino-3-hydroxy-5-methyl-4-isoxazole-propionate antagonist GYKI52466. The antiproliferative effect of glutamate antagonists was Ca2+ dependent and resulted from decreased cell division and increased cell death. Morphological alterations induced by glutamate antagonists in tumor cells consisted of reduced membrane ruffling and pseudopodial protrusions. Furthermore, glutamate antagonists decreased motility and invasive growth of tumor cells. These findings suggest anticancer potential of glutamate antagonists.

  12. Management of calcium channel antagonist overdose.

    PubMed

    Salhanick, Steven D; Shannon, Michael W

    2003-01-01

    Calcium channel antagonists are used primarily for the treatment of hypertension and tachyarrhythmias. Overdose of calcium channel antagonists can be lethal. Calcium channel antagonists act at the L-type calcium channels primarily in cardiac and vascular smooth muscle preventing calcium influx into cells with resultant decreases in vascular tone and cardiac inotropy and chronotropy. The L-type calcium channel is a complex structure and is thus affected by a large number of structurally diverse antagonists. In the setting of overdose, patients may experience vasodilatation and bradycardia leading to a shock state. Patients may also be hyperglycaemic and acidotic due to the blockade of L-type calcium channels in the pancreatic islet cells that affect insulin secretion. Aggressive therapy is warranted in the setting of toxicity. Gut decontamination with charcoal, or whole bowel irrigation or multiple-dose charcoal in the setting of extended-release products is indicated. Specific antidotes include calcium salts, glucagon and insulin. Calcium salts may be given in bolus doses or may be employed as a continuous infusion. Care should be exercised to avoid the administration of calcium in the setting of concomitant digoxin toxicity. Insulin administration has been used effectively to increase cardiac inotropy and survival. The likely mechanism involves a shift to carbohydrate metabolism in the setting of decreased availability of carbohydrates due to decreased insulin secretion secondary to blockade of calcium channels in pancreatic islet cells. Glucose should be administered as well to maintain euglycaemia. Supportive care including the use of phosphodiesterase inhibitors, adrenergic agents, cardiac pacing, balloon pump or extracorporeal bypass is frequently indicated if antidotal therapy is not effective. Careful evaluation of asymptomatic patients, including and electrocardiogram and a period of observation, is indicated. Patients ingesting a nonsustained

  13. AHR-related activities in a creosote-adapted population of adult atlantic killifish, Fundulus heteroclitus, two decades post-EPA superfund status at the Atlantic Wood Site, Portsmouth, VA USA.

    PubMed

    Wojdylo, Josephine V; Vogelbein, Wolfgang; Bain, Lisa J; Rice, Charles D

    2016-08-01

    Atlantic killifish, Fundulus heteroclitus, are adapted to creosote-based PAHs at the US EPA Superfund site known as Atlantic Wood (AW) on the southern branch of the Elizabeth River, VA USA. Subsequent to the discovery of the AW population in the early 1990s, these fish were shown to be recalcitrant to CYP1A induction by PAHs under experimental conditions, and even to the time of this study, killifish embryos collected from the AW site are resistant to developmental deformities typically associated with exposure to PAHs in reference fish. Historically, however, 90 +% of the adult killifish at this site have proliferative hepatic lesions including cancer of varying severity. Several PAHs at this site are known to be ligands for the aryl hydrocarbon receptor (AHR). In this study, AHR-related activities in AW fish collected between 2011 and 2013 were re-examined nearly 2 decades after first discovery. This study shows that CYP1A mRNA expression is three-fold higher in intestines of AW killifish compared to a reference population. Using immunohistochemistry, CYP1A staining in intestines was uniformly positive compared to negative staining in reference fish. Livers of AW killifish were examined by IHC to show that CYP1A and AHR2 protein expression reflect lesions-specific patterns, probably representing differences in intrinsic cellular physiology of the spectrum of proliferative lesions comprising the hepatocarcinogenic process. We also found that COX2 mRNA expression levels were higher in AW fish livers compared to those in the reference population, suggesting a state of chronic inflammation. Overall, these findings suggest that adult AW fish are responsive to AHR signaling, and do express CYP1A and AHR2 proteins in intestines at a level above what was observed in the reference population. PMID:27262937

  14. Time-dependent transcriptomic and biochemical responses of 6-formylindolo[3,2-b]carbazole (FICZ) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) are explained by AHR activation time.

    PubMed

    Farmahin, Reza; Crump, Doug; O'Brien, Jason M; Jones, Stephanie P; Kennedy, Sean W

    2016-09-01

    6-Formylindolo[3,2-b]carbazole (FICZ) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) are ligands of the aryl hydrocarbon receptor (AHR) and bind to the AHR with high affinity. Until recently, TCDD was considered to be the most potent AHR agonist, but several recent studies indicate that FICZ binds with greater affinity to the AHR than TCDD. To advance our understanding of the similarities and differences of the effects of FICZ and TCDD exposure in chicken embryo hepatocyte (CEH) cultures, we compared relative expression changes of 27 dioxin-responsive genes by the use of a chicken PCR array, porphyrin accumulation and ethoxyresorufin-O-deethylase (EROD) activity at different time points. In addition, an egg injection study was performed to assess the effects of FICZ on the developing chicken embryo. The results of the current study showed: (1) mean EROD-derived relative potency values for FICZ compared to TCDD changed as a function of time (i.e. 9, 0.004, 0.0008 and 0.00008 at 3, 8, 24, and 48h, respectively) in CEH cultures; (2) FICZ exposure did not result in porphyrin accumulation in CEH cultures; (3) concordance between gene expression profiles for FICZ and TCDD was time- and concentration-dependent, and (4) no mortality or morphological abnormalities were observed in chicken embryos injected with 0.87ng FICZ/g egg into the air cell. The results presented herein suggest that while FICZ and TCDD share similar molecular targets, transient versus sustained AHR activation by FICZ and TCDD result in differential transcriptomic responses. Moreover, rapid metabolism of FICZ in hepatocytes resulted in a significant decrease in the induction of EROD activity. PMID:27301797

  15. Promoter analysis of TCDD-inducible genes in a thymic epithelial cell line indicates the potential for cell-specific transcription factor crosstalk in the AhR response

    SciTech Connect

    Frericks, Markus; Burgoon, Lyle D.; Zacharewski, Timothy R.; Esser, Charlotte

    2008-10-15

    Activation of the aryl hydrocarbon receptor (AhR{sup 1}) by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) elicits severe immunosuppression accompanied by thymic atrophy. Previous evidence suggests that TCDD targets both thymocytes and thymic epithelial cells. The AhR induces cell-specific changes in gene transcription via binding to the dioxin response element DRE; however, the underlying specificity-mechanisms, in particular with regard to the role of promoter element context, and possible transcription factor crosstalk remain poorly understood. Global gene expression in the cortical thymic epithelial cell line ET at 2, 4, and 6 h following 5 nM TCDD exposure resulted in differential regulation of 201 genes. JASPAR and TRANSFAC mapped the statistically over-represented promoter elements in the regulated genes to specific transcription factor binding sites, suggesting a regulatory role in AhR signaling. Over-represented elements included the xenobiotic response element XRE, NF{kappa}B-Rel, HRE, PPAR{gamma}, GR, PAX-4 and estrogen receptor binding sites. Co-treatment experiments with TCDD and CoCl{sub 2}, to induce hypoxia, or TCDD and 17-{beta}-estradiol (E2) indicated crosstalk between AhR and Hif or ER, in agreement with other experimental models. The computational identification of TFBS and the demonstration of interaction confirm their interactions with AhR signaling and suggest that the other over-represented elements may also be important in the immunosuppressive effects elicited by TCDD. In conclusion, we demonstrated the importance of promoter element cooperation in the shaping of a cell-specific AhR response. Our findings regarding the transcriptional changes in cortical epithelial cells are congruent with the well-known thymotoxic TCDD-phenotype, and useful in new hypothesis generation of the role of cortical TECs in TCDD toxicity.

  16. Classification of dopamine, serotonin, and dual antagonists by decision trees.

    PubMed

    Kim, Hye-Jung; Choo, Hyunah; Cho, Yong Seo; Koh, Hun Yeong; No, Kyoung Tai; Pae, Ae Nim

    2006-04-15

    Dopamine antagonists (DA), serotonin antagonists (SA), and serotonin-dopamine dual antagonists (Dual) are being used as antipsychotics. A lot of dopamine and serotonin antagonists reveal non-selective binding affinity against these two receptors because the antagonists share structurally common features originated from conserved residues of binding site of the aminergic receptor family. Therefore, classification of dopamine and serotonin antagonists into their own receptors can be useful in the designing of selective antagonist for individual therapy of antipsychotic disorders. Data set containing 1135 dopamine antagonists (D2, D3, and D4), 1251 serotonin antagonists (5-HT1A, 5-HT2A, and 5-HT2C), and 386 serotonin-dopamine dual antagonists was collected from the MDDR database. Cerius2 descriptors were employed to develop a classification model for the 2772 compounds with antipsychotic activity. LDA (linear discriminant analysis), SIMCA (soft independent modeling of class analogy), RP (recursive partitioning), and ANN (artificial neural network) algorithms successfully classified the active class of each compound at the average 73.6% and predicted at the average 69.8%. The decision trees from RP, the best model, were generated to identify and interpret those descriptors that discriminate the active classes more easily. These classification models could be used as a virtual screening tool to predict the active class of new candidates. PMID:16387502

  17. Pharmacodynamic properties of leukotriene receptor antagonists.

    PubMed

    Nicosia, S

    1999-06-01

    Leukotrienes (LTs) are among the most important mediators of asthma; cysteine-containing LTs (cysteinyl-LTs, i.e. LTC4, LTD4 and LTE4) are very potent bronchoconstrictors and participate in the inflammatory component of asthma by inducing mucus hypersecretion, plasma extravasation, mucosal oedema and eosinophil recruitment. Therefore, compounds able to inhibit either the formation or the action of LTs are potential antiasthma drugs and, at present, the cysteinyl-LT receptor antagonists (LTRAs) appear to be the most promising. The receptors for cysteinyl-LTs, termed CysLT receptors, are heterogeneous; at least two different classes have so far been recognized, named CysLT1 (blocked by the so-called classical antagonists, such as FPL 55712, ICI 198,615, ICI 204,219, SK&F 104353, MK-476 and others) and CysLT2 (insensitive to the classical antagonists, but sensitive to BAY u9773). The authors' results indicate that even more receptor subclasses might exist in human airways, which discriminate between LTC4 and LTD4, both asthma mediators. Among the many LTRAs, zafirlukast (Accolate, ICI 204,219), montelukast (Singulair, MK-476) and pranlukast (Onon, ONO-1078) are available for clinical use. All the LTRAs are able to inhibit LTD4-induced bronchoconstriction in humans, albeit with different potencies. With respect to antigen challenge, all of them inhibit the early phase of response, whereas only the most recently developed and potent ones are effective in the late phase. LTRAs are effective in asthma triggered by exercise, cold or aspirin. Furthermore, although they are not bronchodilators per se, they increase basal forced expiratory volume in one second in patients with mild-to-moderate asthma, indicating that, in these individuals, constant cysteinyl-LT release contributes to maintaining increased bronchial tone. Finally, the effect of LTRAs is additive to that of beta-agonists and is potentiated by antihistamine compounds. In conclusion, the available results clearly

  18. Novel paramagnetic AT1 receptor antagonists.

    PubMed

    Tan, Nichole P H; Taylor, Michelle K; Bottle, Steven E; Wright, Christine E; Ziogas, James; White, Jonathan M; Schiesser, Carl H; Jani, Nitya V

    2011-11-28

    Novel paramagnetic selective angiotensin AT(1) receptor antagonists (sartans) bearing nitroxides (3, 4) have been prepared and their pharmacology evaluated in vitro as well as in vivo. Compounds 3, 4 proved to be effective sartans with pK(B) estimates in the range 6.2-9.1. In addition, the sodium salt (11) of 4 (R = Bu) is able to protect against vascular injury in hypertensive rats as determined by its ability to attenuate the development of intimal thickening caused by balloon injury of the carotid artery. PMID:21963998

  19. Mineralocorticoid receptor antagonists and endothelial function

    PubMed Central

    Maron, Bradley A.; Leopold, Jane A.

    2010-01-01

    Hyperaldosteronism has been associated with endothelial dysfunction and impaired vascular reactivity in patients with hypertension or congestive heart failure. The mineralocorticoid receptor (MR) antagonists spironolactone and eplerenone have been shown to reduce morbidity and mortality, in part, by ameliorating the adverse effects of aldosterone on vascular function. Although spironolactone and eplerenone are increasingly utilized in patients with cardiovascular disease, widespread clinical use is limited by the development of gynecomastia with spironolactone and hyperkalemia with both agents. This suggests that the development of newer agents with favorable side effect profiles is warranted. PMID:18729003

  20. Agonists and antagonists for P2 receptors

    PubMed Central

    Jacobson, Kenneth A.; Costanzi, Stefano; Joshi, Bhalchandra V.; Besada, Pedro; Shin, Dae Hong; Ko, Hyojin; Ivanov, Andrei A.; Mamedova, Liaman

    2015-01-01

    Recent work has identified nucleotide agonists selective for P2Y1, P2Y2 and P2Y6 receptors and nucleotide antagonists selective for P2Y1, P2Y12 and P2X1 receptors. Selective non-nucleotide antagonists have been reported for P2Y1, P2Y2, P2Y6, P2Y12, P2Y13, P2X2/3/P2X3 and P2X7 receptors. For example, the dinucleotide INS 37217 (Up4dC) potently activates the P2Y2 receptor, and the non-nucleotide antagonist A-317491 is selective for P2X2/3/P2X3 receptors. Nucleotide analogues in which the ribose moiety is substituted by a variety of novel ring systems, including conformation-ally locked moieties, have been synthesized as ligands for P2Y receptors. The focus on conformational factors of the ribose-like moiety allows the inclusion of general modifications that lead to enhanced potency and selectivity. At P2Y1,2,4,11 receptors, there is a preference for the North conformation as indicated with (N)-methanocarba analogues. The P2Y1 antagonist MRS2500 inhibited ADP-induced human platelet aggregation with an IC50 of 0.95 nM. MRS2365, an (N)-methanocarba analogue of 2-MeSADP, displayed potency (EC50) of 0.4 nM at the P2Y1 receptor, with >10 000-fold selectivity in comparison to P2Y12 and P2Y13 receptors. At P2Y6 receptors there is a dramatic preference for the South conformation. Three-dimensional structures of P2Y receptors have been deduced from structure activity relationships (SAR), mutagenesis and modelling studies. Detailed three-dimensional structures of P2X receptors have not yet been proposed. PMID:16805423

  1. Rational discovery of novel nuclear hormone receptor antagonists

    NASA Astrophysics Data System (ADS)

    Schapira, Matthieu; Raaka, Bruce M.; Samuels, Herbert H.; Abagyan, Ruben

    2000-02-01

    Nuclear hormone receptors (NRs) are potential targets for therapeutic approaches to many clinical conditions, including cancer, diabetes, and neurological diseases. The crystal structure of the ligand binding domain of agonist-bound NRs enables the design of compounds with agonist activity. However, with the exception of the human estrogen receptor-, the lack of antagonist-bound "inactive" receptor structures hinders the rational design of receptor antagonists. In this study, we present a strategy for designing such antagonists. We constructed a model of the inactive conformation of human retinoic acid receptor- by using information derived from antagonist-bound estrogen receptor-α and applied a computer-based virtual screening algorithm to identify retinoic acid receptor antagonists. Thus, the currently available crystal structures of NRs may be used for the rational design of antagonists, which could lead to the development of novel drugs for a variety of diseases.

  2. Synthesis of actively adjustable springs by antagonistic redundant actuation

    NASA Technical Reports Server (NTRS)

    Yi, Byung-Ju; Freeman, Robert A.

    1992-01-01

    A methodology for active spring generation is presented based on antagonistic redundant actuation. Antagonistic properties are characterized using an effective system stiffness. 'Antagonistic stiffness' is generated by preloading a closed-chain (parallel) linkage system. Internal load distribution is investigated along with the necessary conditions for spring synthesis. The performance and stability of a proposed active spring are shown by simulation, and applications are discussed.

  3. Sexually antagonistic selection in human male homosexuality.

    PubMed

    Camperio Ciani, Andrea; Cermelli, Paolo; Zanzotto, Giovanni

    2008-01-01

    Several lines of evidence indicate the existence of genetic factors influencing male homosexuality and bisexuality. In spite of its relatively low frequency, the stable permanence in all human populations of this apparently detrimental trait constitutes a puzzling 'Darwinian paradox'. Furthermore, several studies have pointed out relevant asymmetries in the distribution of both male homosexuality and of female fecundity in the parental lines of homosexual vs. heterosexual males. A number of hypotheses have attempted to give an evolutionary explanation for the long-standing persistence of this trait, and for its asymmetric distribution in family lines; however a satisfactory understanding of the population genetics of male homosexuality is lacking at present. We perform a systematic mathematical analysis of the propagation and equilibrium of the putative genetic factors for male homosexuality in the population, based on the selection equation for one or two diallelic loci and Bayesian statistics for pedigree investigation. We show that only the two-locus genetic model with at least one locus on the X chromosome, and in which gene expression is sexually antagonistic (increasing female fitness but decreasing male fitness), accounts for all known empirical data. Our results help clarify the basic evolutionary dynamics of male homosexuality, establishing this as a clearly ascertained sexually antagonistic human trait. PMID:18560521

  4. Sexually Antagonistic Selection in Human Male Homosexuality

    PubMed Central

    Camperio Ciani, Andrea; Cermelli, Paolo; Zanzotto, Giovanni

    2008-01-01

    Several lines of evidence indicate the existence of genetic factors influencing male homosexuality and bisexuality. In spite of its relatively low frequency, the stable permanence in all human populations of this apparently detrimental trait constitutes a puzzling ‘Darwinian paradox’. Furthermore, several studies have pointed out relevant asymmetries in the distribution of both male homosexuality and of female fecundity in the parental lines of homosexual vs. heterosexual males. A number of hypotheses have attempted to give an evolutionary explanation for the long-standing persistence of this trait, and for its asymmetric distribution in family lines; however a satisfactory understanding of the population genetics of male homosexuality is lacking at present. We perform a systematic mathematical analysis of the propagation and equilibrium of the putative genetic factors for male homosexuality in the population, based on the selection equation for one or two diallelic loci and Bayesian statistics for pedigree investigation. We show that only the two-locus genetic model with at least one locus on the X chromosome, and in which gene expression is sexually antagonistic (increasing female fitness but decreasing male fitness), accounts for all known empirical data. Our results help clarify the basic evolutionary dynamics of male homosexuality, establishing this as a clearly ascertained sexually antagonistic human trait. PMID:18560521

  5. Small molecule TSHR agonists and antagonists.

    PubMed

    Neumann, S; Gershengorn, M C

    2011-04-01

    TSH activates the TSH receptor (TSHR) thereby stimulating the function of thyroid follicular cells (thyrocytes) leading to biosynthesis and secretion of thyroid hormones. Because TSHR is involved in several thyroid pathologies, there is a strong rationale for the design of small molecule "drug-like" ligands. Recombinant human TSH (rhTSH, Thyrogen(®)) has been used in the follow-up of patients with thyroid cancer to increase the sensitivity for detection of recurrence or metastasis. rhTSH is difficult to produce and must be administered by injection. A small molecule TSHR agonist could produce the same beneficial effects as rhTSH but with greater ease of oral administration. We developed a small molecule ligand that is a full agonist at TSHR. Importantly for its clinical potential, this agonist elevated serum thyroxine and stimulated thyroidal radioiodide uptake in mice after its absorption from the gastrointestinal tract following oral administration. Graves' disease (GD) is caused by persistent, unregulated stimulation of thyrocytes by thyroid-stimulating antibodies (TSAbs) that activate TSHR. We identified the first small molecule TSHR antagonists that inhibited TSH- and TSAb-stimulated signalling in primary cultures of human thyrocytes. Our results provide proof-of-principle for effectiveness of small molecule agonists and antagonists for TSHR. We suggest that these small molecule ligands are lead compounds for the development of higher potency ligands that can be used as probes of TSHR biology with therapeutic potential. PMID:21511239

  6. Antagonistic coevolution between quantitative and Mendelian traits.

    PubMed

    Yamamichi, Masato; Ellner, Stephen P

    2016-03-30

    Coevolution is relentlessly creating and maintaining biodiversity and therefore has been a central topic in evolutionary biology. Previous theoretical studies have mostly considered coevolution between genetically symmetric traits (i.e. coevolution between two continuous quantitative traits or two discrete Mendelian traits). However, recent empirical evidence indicates that coevolution can occur between genetically asymmetric traits (e.g. between quantitative and Mendelian traits). We examine consequences of antagonistic coevolution mediated by a quantitative predator trait and a Mendelian prey trait, such that predation is more intense with decreased phenotypic distance between their traits (phenotype matching). This antagonistic coevolution produces a complex pattern of bifurcations with bistability (initial state dependence) in a two-dimensional model for trait coevolution. Furthermore, with eco-evolutionary dynamics (so that the trait evolution affects predator-prey population dynamics), we find that coevolution can cause rich dynamics including anti-phase cycles, in-phase cycles, chaotic dynamics and deterministic predator extinction. Predator extinction is more likely to occur when the prey trait exhibits complete dominance rather than semidominance and when the predator trait evolves very rapidly. Our study illustrates how recognizing the genetic architectures of interacting ecological traits can be essential for understanding the population and evolutionary dynamics of coevolving species. PMID:27009218

  7. Coordinated Regulation of Hepatic Phase I and II Drug-Metabolizing Genes and Transporters using AhR-, CAR-, PXR-, PPARα-, and Nrf2-Null Mice

    PubMed Central

    Aleksunes, Lauren M.

    2012-01-01

    The transcription factors aryl hydrocarbon receptor (AhR), constitutive androstane receptor (CAR), pregnane X receptor (PXR), peroxisome proliferator-activated receptor α (PPARα), and nuclear factor erythroid 2-related factor 2 (Nrf2) regulate genes encoding drug-metabolizing enzymes and transporters in livers of mice after chemical activation. However, the specificity of their transcriptional regulation has not been determined systematically in vivo. The purpose of this study was to identify genes encoding drug-metabolizing enzymes and transporters altered by chemical activators in a transcription factor-dependent manner using wild-type and transcription factor-null mice. Chemical activators were administered intraperitoneally to mice once daily for 4 days. Livers were collected 24 h after the final dose, and total RNA was isolated for mRNA quantification of cytochromes P450, NAD(P)H quinone oxidoreductase 1 (Nqo1), aldehyde dehydrogenases (Aldhs), glutathione transferases (Gsts), sulfotransferases (Sults), UDP-glucuronosyltransferases (Ugts), organic anion-transporting polypeptides (Oatps), and multidrug resistance-associated proteins (Mrps). Pharmacological activation of each transcription factor leads to mRNA induction of drug metabolic and transport genes in livers of male and female wild-type mice, but no change in null mice: AhR (Cyp1a2, Nqo1, Aldh7a1, Ugt1a1, Ugt1a6, Ugt1a9, Ugt2b35, Sult5a1, Gstm3, and Mrp4), CAR (Cyp2b10, Aldh1a1, Aldh1a7, Ugt1a1, Ugt2b34, Sult1e1, Sult3a1, Sult5a1, Papps2, Gstt1, Gsta1, Gsta4, Gstm1–4, and Mrp2–4), PXR (Cyp3a11, Ugt1a1, Ugt1a5, Ugt1a9, Gsta1, Gstm1–m3, Oatp1a4, and Mrp3), PPARα (Cyp4a14, Aldh1a1, mGst3, Gstm4, and Mrp4), and Nrf2 (Nqo1, Aldh1a1, Gsta1, Gsta4, Gstm1–m4, mGst3, and Mrp3–4). Taken together, these data reveal transcription factor specificity and overlap in regulating hepatic drug disposition genes by chemical activators. Coordinated regulation of phase I, phase II, and transport genes by

  8. EGCG protects endothelial cells against PCB 126-induced inflammation through inhibition of AhR and induction of Nrf2-regulated genes

    SciTech Connect

    Han, Sung Gu; Han, Seong-Su; Toborek, Michal; Hennig, Bernhard

    2012-06-01

    Tea flavonoids such as epigallocatechin gallate (EGCG) protect against vascular diseases such as atherosclerosis via their antioxidant and anti-inflammatory functions. Persistent and widespread environmental pollutants, including polychlorinated biphenyls (PCB), can induce oxidative stress and inflammation in vascular endothelial cells. Even though PCBs are no longer produced, they are still detected in human blood and tissues and thus considered a risk for vascular dysfunction. We hypothesized that EGCG can protect endothelial cells against PCB-induced cell damage via its antioxidant and anti-inflammatory properties. To test this hypothesis, primary vascular endothelial cells were pretreated with EGCG, followed by exposure to the coplanar PCB 126. Exposure to PCB 126 significantly increased cytochrome P450 1A1 (Cyp1A1) mRNA and protein expression and superoxide production, events which were significantly attenuated following pretreatment with EGCG. Similarly, EGCG also reduced DNA binding of NF-κB and downstream expression of inflammatory markers such as monocyte chemotactic protein-1 (MCP-1) and vascular cell adhesion protein-1 (VCAM-1) after PCB exposure. Furthermore, EGCG decreased endogenous or base-line levels of Cyp1A1, MCP-1 and VCAM-1 in endothelial cells. Most of all, treatment of EGCG upregulated expression of NF-E2-related factor 2 (Nrf2)-controlled antioxidant genes, including glutathione S transferase (GST) and NAD(P)H:quinone oxidoreductase 1 (NQO1), in a dose-dependent manner. In contrast, silencing of Nrf2 increased Cyp1A1, MCP-1 and VCAM-1 and decreased GST and NQO1 expression, respectively. These data suggest that EGCG can inhibit AhR regulated genes and induce Nrf2-regulated antioxidant enzymes, thus providing protection against PCB-induced inflammatory responses in endothelial cells. -- Highlights: ► PCBs cause endothelial inflammation and subsequent atherosclerosis. ► Nutrition can modulate toxicity by environmental pollutants. ► We

  9. Corticospinal control of antagonistic muscles in the cat.

    PubMed

    Ethier, Christian; Brizzi, Laurent; Giguère, Dominic; Capaday, Charles

    2007-09-01

    We recently suggested that movement-related inter-joint muscle synergies are recruited by selected excitation and selected release from inhibition of cortical points. Here we asked whether a similar cortical mechanism operates in the functional linking of antagonistic muscles. To this end experiments were done on ketamine-anesthetized cats. Intracortical microstimulation (ICMS) and intramuscular electromyographic recordings were used to find and characterize wrist, elbow and shoulder antagonistic motor cortical points. Simultaneous ICMS applied at two cortical points, each evoking activity in one of a pair of antagonistic muscles, produced co-contraction of antagonistic muscle pairs. However, we found an obvious asymmetry in the strength of reciprocal inhibition; it was always significantly stronger on physiological extensors than flexors. Following intravenous injection of a single bolus of strychnine, a cortical point at which only a physiological flexor was previously activated also elicited simultaneous activation of its antagonist. This demonstrates that antagonistic corticospinal neurons are closely grouped, or intermingled. To test whether releasing a cortical point from inhibition allows it to be functionally linked with an antagonistic cortical point, one of three GABA(A) receptor antagonists, bicuculline, gabazine or picrotoxin, was injected iontophoretically at one cortical point while stimulation was applied to an antagonistic cortical point. This coupling always resulted in co-contraction of the represented antagonistic muscles. Thus, antagonistic motor cortical points are linked by excitatory intracortical connections held in check by local GABAergic inhibition, with reciprocal inhibition occurring at the spinal level. Importantly, the asymmetry of cortically mediated reciprocal inhibition would appear significantly to bias muscle maps obtained by ICMS in favor of physiological flexors. PMID:17880397

  10. Mutually-antagonistic interactions in baseball networks

    NASA Astrophysics Data System (ADS)

    Saavedra, Serguei; Powers, Scott; McCotter, Trent; Porter, Mason A.; Mucha, Peter J.

    2010-03-01

    We formulate the head-to-head matchups between Major League Baseball pitchers and batters from 1954 to 2008 as a bipartite network of mutually-antagonistic interactions. We consider both the full network and single-season networks, which exhibit structural changes over time. We find interesting structure in the networks and examine their sensitivity to baseball’s rule changes. We then study a biased random walk on the matchup networks as a simple and transparent way to (1) compare the performance of players who competed under different conditions and (2) include information about which particular players a given player has faced. We find that a player’s position in the network does not correlate with his placement in the random walker ranking. However, network position does have a substantial effect on the robustness of ranking placement to changes in head-to-head matchups.

  11. Association of polymorphisms in AhR, CYP1A1, GSTM1, and GSTT1 genes with levels of DNA damage in peripheral blood lymphocytes among coke-oven workers

    SciTech Connect

    Yongwen Chen; Yun Bai; Jing Yuan; Weihong Chen; Jianya Sun; Hong Wang; Huashan Liang; Liang Guo; Xiaobo Yang; Hao Tan; Yougong Su; Qingyi Wei; Tangchun Wu

    2006-09-15

    Accumulating evidence has shown that both DNA damage caused by the metabolites of polycyclic aromatic hydrocarbons (PAH) and genetic polymorphisms in PAH-metabolic genes contribute to individual susceptibility to PAH-induced carcinogenesis. However, the functional relevance of genetic polymorphisms in PAH-metabolic genes in exposed individuals is still unclear. In this study of 240 coke-oven workers (the exposed group) and 123 non-coke-oven workers (the control group), we genotyped for polymorphisms in the AhR, CYP1A1, GSTM1, and GSTT1 genes by PCR methods, and determined the levels of DNA damage in peripheral blood lymphocytes using the alkaline comet assay. It was found that the ln-transformed Olive tail moment (Olive TM) values in the exposed group were significantly higher than those in the control group. Furthermore, in the exposed group, the Olive TM values in subjects with the AhR Lys{sup 554} variant genotype were higher than those with the AhR Arg{sup 554}/Arg{sup 554} genotype. Similarly, the Olive TM values in the non-coke-oven workers with the CYP1A1 MspI CC + CT genotype were lower than the values of those with the CYP1A1 MspI TT genotype. However, these differences were not evident for GSTM1 and GSTT1. These results suggested that the polymorphism of AhR might modulate the effects of PAHs in the exposed group; however, the underlying molecular mechanisms by which this polymorphism may have affected the levels of PAH-induced DNA damage warrant further investigation.

  12. Antagonistic and Bargaining Games in Optimal Marketing Decisions

    ERIC Educational Resources Information Center

    Lipovetsky, S.

    2007-01-01

    Game theory approaches to find optimal marketing decisions are considered. Antagonistic games with and without complete information, and non-antagonistic games techniques are applied to paired comparison, ranking, or rating data for a firm and its competitors in the market. Mix strategy, equilibrium in bi-matrix games, bargaining models with…

  13. Microbial antagonists of Verticillium dahliae colonize cotton root system

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Verticillium wilt remains one of the most severe diseases affecting cotton production in Uzbekistan. We are investigating microbial antagonist to control this pathogen. To this end, we have identified several antagonists of Verticillium dahliae (Bacillus sp. 234, Bacillus sp. 3, Streptomyces roseofl...

  14. Pros and cons of vitamin K antagonists and non-vitamin K antagonist oral anticoagulants.

    PubMed

    Riva, Nicoletta; Ageno, Walter

    2015-03-01

    Anticoagulant treatment can be currently instituted with two different classes of drugs: the vitamin K antagonists (VKAs) and the newer, "novel" or non-vitamin K antagonist oral anticoagulant drugs (NOACs). The NOACs have several practical advantages over VKAs, such as the rapid onset/offset of action, the lower potential for food and drug interactions, and the predictable anticoagulant response. However, the VKAs currently have a broader spectrum of indications, a standardized monitoring test, and established reversal strategies. The NOACs emerged as alternative options for the prevention and treatment of venous thromboembolism and for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. Nevertheless, there remain some populations for whom the VKAs remain the most appropriate anticoagulant drug. This article discusses the advantages and disadvantages of VKAs and NOACs. PMID:25703519

  15. Early gonadotropin-releasing hormone antagonist start improves follicular synchronization and pregnancy outcome as compared to the conventional antagonist protocol

    PubMed Central

    Park, Chan Woo; Hwang, Yu Im; Koo, Hwa Seon; Kang, Inn Soo; Yang, Kwang Moon

    2014-01-01

    Objective To assess whether an early GnRH antagonist start leads to better follicular synchronization and an improved clinical pregnancy rate (CPR). Methods A retrospective cohort study. A total of 218 infertile women who underwent IVF between January 2011 and February 2013. The initial cohort (Cohort I) that underwent IVF between January 2011 and March 2012 included a total of 68 attempted IVF cycles. Thirty-four cycles were treated with the conventional GnRH antagonist protocol, and 34 cycles with an early GnRH antagonist start protocol. The second cohort (Cohort II) that underwent IVF between June 2012 and February 2013 included a total of 150 embryo-transfer (ET) cycles. Forty-three cycles were treated with the conventional GnRH antagonist protocol, 34 cycles with the modified early GnRH antagonist start protocol using highly purified human menopause gonadotropin and an addition of GnRH agonist to the luteal phase support, and 73 cycles with the GnRH agonist long protocol. Results The analysis of Cohort I showed that the number of mature oocytes retrieved was significantly higher in the early GnRH antagonist start cycles than in the conventional antagonist cycles (11.9 vs. 8.2, p=0.04). The analysis of Cohort II revealed higher but non-significant CPR/ET in the modified early GnRH antagonist start cycles (41.2%) than in the conventional antagonist cycles (30.2%), which was comparable to that of the GnRH agonist long protocol cycles (39.7%). Conclusion The modified early antagonist start protocol may improve the mature oocyte yield, possibly via enhanced follicular synchronization, while resulting in superior CPR as compared to the conventional antagonist protocol, which needs to be studied further in prospective randomized controlled trials. PMID:25599038

  16. Pharmacokinetic interactions with calcium channel antagonists (Part I).

    PubMed

    Schlanz, K D; Myre, S A; Bottorff, M B

    1991-11-01

    Calcium channel antagonists are a diverse class of drugs widely used in combination with other therapeutic agents. The potential exists for many clinically significant pharmacokinetic interactions between these and other concurrently administered drugs. The mechanisms of calcium channel antagonist-induced changes in drug metabolism include altered hepatic blood flow and impaired hepatic enzyme metabolising activity. Increases in serum concentrations and/or reductions in clearance have been reported for several drugs used with a number of calcium channel antagonists. A number of reports and studies of calcium channel antagonist interactions have yielded contradictory results and the clinical significance of pharmacokinetic changes seen with these agents is ill-defined. The first part of this article deals with interactions between calcium antagonists and marker compounds, theophylline, midazolam, lithium, doxorubicin, oral hypoglycaemics and cardiac drugs. PMID:1773549

  17. Prostanoid receptor antagonists: development strategies and therapeutic applications

    PubMed Central

    Jones, RL; Giembycz, MA; Woodward, DF

    2009-01-01

    Identification of the primary products of cyclo-oxygenase (COX)/prostaglandin synthase(s), which occurred between 1958 and 1976, was followed by a classification system for prostanoid receptors (DP, EP1, EP2 …) based mainly on the pharmacological actions of natural and synthetic agonists and a few antagonists. The design of potent selective antagonists was rapid for certain prostanoid receptors (EP1, TP), slow for others (FP, IP) and has yet to be achieved in certain cases (EP2). While some antagonists are structurally related to the natural agonist, most recent compounds are ‘non-prostanoid’ (often acyl-sulphonamides) and have emerged from high-throughput screening of compound libraries, made possible by the development of (functional) assays involving single recombinant prostanoid receptors. Selective antagonists have been crucial to defining the roles of PGD2 (acting on DP1 and DP2 receptors) and PGE2 (on EP1 and EP4 receptors) in various inflammatory conditions; there are clear opportunities for therapeutic intervention. The vast endeavour on TP (thromboxane) antagonists is considered in relation to their limited pharmaceutical success in the cardiovascular area. Correspondingly, the clinical utility of IP (prostacyclin) antagonists is assessed in relation to the cloud hanging over the long-term safety of selective COX-2 inhibitors. Aspirin apart, COX inhibitors broadly suppress all prostanoid pathways, while high selectivity has been a major goal in receptor antagonist development; more targeted therapy may require an intermediate position with defined antagonist selectivity profiles. This review is intended to provide overviews of each antagonist class (including prostamide antagonists), covering major development strategies and current and potential clinical usage. PMID:19624532

  18. Resistance to teratogenesis by F1 and F2 embryos of PAH-adapted Fundulus heteroclitus is strongly inherited despite reduced recalcitrance of the AHR pathway.

    PubMed

    Clark, Bryan W; Bone, A J; Di Giulio, R T

    2014-12-01

    Atlantic killifish (Fundulus heteroclitus) inhabiting the Atlantic Wood Superfund site on the Elizabeth River (Portsmouth, VA, USA) are exposed to a complex mixture of polycyclic aromatic hydrocarbons (PAHs) from former creosote operations, but are resistant to the acute toxicity and cardiac teratogenesis caused by PAHs. The resistance is associated with a dramatic recalcitrance to induction of cytochrome P450 (CYP1) metabolism enzymes following exposure to aryl hydrocarbon receptor (AHR) agonists, along with an elevated antioxidant response and increased expression of several other xenobiotic metabolism and excretion enzymes. However, the heritability of the resistance in the absence of chemical stressors has been inconsistently demonstrated. Understanding the heritability of this resistance will help clarify the nature of population-level responses to chronic exposure to PAH mixtures and aid in identifying the important mechanistic components of resistance to aryl hydrocarbons. We compared the response of Atlantic Wood F1 and F2 embryos to benzo[k]fluoranthene (BkF), benzo[a]pyrene (BaP), 3,3',4,4',5-pentachlorobiphenyl (PCB-126), and a mixture of BkF and fluoranthene (Fl) to that of F1 embryos of reference site killifish. Resistance to cardiac teratogenesis and induction of CYP mRNA expression and CYP activity was determined. We found that both Atlantic Wood F1 and F2 embryos were highly resistance to cardiac teratogenesis. However, the resistance by Atlantic Wood F2 embryos to induction of CYP mRNA expression and enzyme activity was intermediate between that of Atlantic Wood F1 embryos and reference embryos. These results suggest that resistance to cardiac teratogenesis in Atlantic Wood fish is conferred by multiple factors, not all of which appear to be fully genetically heritable. PMID:24374617

  19. Resistance to teratogenesis by F1 and F2 embryos of PAH-adapted Fundulus heteroclitus is strongly inherited despite reduced recalcitrance of the AHR pathway

    PubMed Central

    Clark, B. W.; Bone, A. J.; Di Giulio, R. T.

    2014-01-01

    Atlantic killifish (Fundulus heteroclitus) inhabiting the Atlantic Wood Superfund site on the Elizabeth River (Portsmouth, VA, USA) are exposed to a complex mixture of polycyclic aromatic hydrocarbons (PAHs) from former creosote operations, but are resistant to the acute toxicity and cardiac teratogenesis caused by PAHs. The resistance is associated with a dramatic recalcitrance to induction of cytochrome P450 (CYP1) metabolism enzymes following exposure to aryl hydrocarbon receptor (AHR) agonists, along with an elevated antioxidant response and increased expression of several other xenobiotic metabolism and excretion enzymes. However, the heritability of the resistance in the absence of chemical stressors has been inconsistently demonstrated. Understanding the heritability of this resistance will help clarify the nature of population-level responses to chronic exposure to PAH mixtures and aid in identifying the important mechanistic components of resistance to aryl hydrocarbons. We compared the response of Atlantic Wood F1 and F2 embryos to benzo[k]fluoranthene (BkF), benzo[a]pyrene (BaP), 3,3’,4,4’,5-pentachlorobiphenyl (PCB-126), and a mixture of BkF and fluoranthene (Fl) to that of F1 embryos of reference site killifish. Resistance to cardiac teratogenesis and induction of CYP mRNA expression and CYP activity was determined. We found that both Atlantic Wood F1 and F2 embryos were highly resistance to cardiac teratogenesis. However, the resistance by Atlantic Wood F2 embryos to induction of CYP mRNA expression and enzyme activity was intermediate between that of Atlantic Wood F1 embryos and reference embryos. These results suggest that resistance to cardiac teratogenesis in Atlantic Wood fish is conferred by multiple factors, not all of which appear to be fully genetically heritable. PMID:24374617

  20. Cannabinoid withdrawal in mice: inverse agonist vs neutral antagonist

    PubMed Central

    Tai, Sherrica; Nikas, Spyros P.; Shukla, Vidyanand G.; Vemuri, Kiran; Makriyannis, Alexandros; Järbe, Torbjörn U.C.

    2015-01-01

    Rationale Previous reports shows rimonabant's inverse properties may be a limiting factor for treating cannabinoid dependence. To overcome this limitation neutral antagonists were developed, to address mechanisms by which an inverse agonist and neutral antagonist elicit withdrawal. Objective Introduces an animal model to study cannabinoid dependence by incorporating traditional methodologies and profiling novel cannabinoid ligands with distinct pharmacological properties/modes of action by evaluating their pharmacological effects on CB1-receptor (CB1R) related physiological/behavioral endpoints. Methods The cannabinergic AM2389 was acutely characterized in the tetrad (locomotor activity, analgesia, inverted screen/catalepsy bar test and temperature); with some comparisons made to Δ9-tetrahydrocannabinol (THC). Tolerance was measured in mice repeatedly administered AM2389. Antagonist-precipitated withdrawal was characterized in cannabinoid-adapted mice induced by either centrally acting antagonists, rimonabant and AM4113, or an antagonist with limited brain penetration, AM6545. Results In the tetrad, AM2389 was more potent and longer acting than THC, suggesting a novel approach for inducing dependence. Repeated administration of AM2389 led to tolerance by attenuating hypothermia that was induced by acute AM2389 administration. Antagonist-precipitated withdrawal signs were induced by rimonabant or AM4113, but not by AM6545. Antagonist-precipitated withdrawal was reversed by reinstating AM2389 or THC. Conclusions These findings suggest cannabinoid-precipitated withdrawal may not be ascribed to the inverse properties of rimonabant, but rather to rapid competition with the agonist at the CB1R. This withdrawal syndrome is likely centrally-mediated, since only the centrally acting CB1R antagonists elicited withdrawal, i.e., such responses were absent after the purported peripherally selective CB1R antagonist AM6545. PMID:25772338

  1. Nalmefene: radioimmunoassay for a new opioid antagonist.

    PubMed

    Dixon, R; Hsiao, J; Taaffe, W; Hahn, E; Tuttle, R

    1984-11-01

    A specific radioimmunoassay (RIA) has been developed for the quantitation of a new opioid antagonist, nalmefene, in human plasma. The method employs a rabbit antiserum to an albumin conjugate of naltrexone-6-(O-carboxymethyl)oxime and [3H]naltrexone as the radioligand. Assay specificity was achieved by extraction of nalmefene from plasma at pH 9 into ether prior to RIA. The procedure has a limit of sensitivity of 0.2 ng/mL of nalmefene using a 0.5-mL sample of plasma for analysis. The intra- and interassay coefficients of variation did not exceed 5.6 and 11%, respectively. The specificity of the RIA was established by demonstrating excellent agreement (r = 0.99) with a less sensitive and more time consuming HPLC procedure in the analysis of clinical plasma samples. The use of the RIA for the pharmacokinetic evaluation of nalmefene is illustrated with plasma concentration profiles of the drug in humans following intravenous and oral administration. PMID:6520774

  2. Endothelin receptor antagonists in pulmonary arterial hypertension.

    PubMed

    Dupuis, J; Hoeper, M M

    2008-02-01

    The endothelin (ET) system, especially ET-1 and the ET(A) and ET(B) receptors, has been implicated in the pathogenesis of pulmonary arterial hypertension (PAH). Together with prostanoids and phosphodiesterase 5 inhibitors, ET receptor antagonists have become mainstays in the current treatment of PAH. Three substances are currently available for the treatment of PAH. One of these substances, bosentan, blocks both ET(A) and ET(B) receptors, whereas the two other compounds, sitaxsentan and ambrisentan, are more selective blockers of the ET(A) receptor. There is ongoing debate as to whether selective or nonselective ET receptor blockade is advantageous in the setting of PAH, although there is no clear evidence that receptor selectivity is relevant with regard to the clinical effects of these drugs. For the time being, other features, such as safety profiles and the potential for pharmacokinetic interactions with other drugs used in the treatment of PAH, may be more important than selectivity or nonselectivity when selecting treatments for individual patients. PMID:18238950

  3. Antagonistic neural networks underlying differentiated leadership roles

    PubMed Central

    Boyatzis, Richard E.; Rochford, Kylie; Jack, Anthony I.

    2014-01-01

    The emergence of two distinct leadership roles, the task leader and the socio-emotional leader, has been documented in the leadership literature since the 1950s. Recent research in neuroscience suggests that the division between task-oriented and socio-emotional-oriented roles derives from a fundamental feature of our neurobiology: an antagonistic relationship between two large-scale cortical networks – the task-positive network (TPN) and the default mode network (DMN). Neural activity in TPN tends to inhibit activity in the DMN, and vice versa. The TPN is important for problem solving, focusing of attention, making decisions, and control of action. The DMN plays a central role in emotional self-awareness, social cognition, and ethical decision making. It is also strongly linked to creativity and openness to new ideas. Because activation of the TPN tends to suppress activity in the DMN, an over-emphasis on task-oriented leadership may prove deleterious to social and emotional aspects of leadership. Similarly, an overemphasis on the DMN would result in difficulty focusing attention, making decisions, and solving known problems. In this paper, we will review major streams of theory and research on leadership roles in the context of recent findings from neuroscience and psychology. We conclude by suggesting that emerging research challenges the assumption that role differentiation is both natural and necessary, in particular when openness to new ideas, people, emotions, and ethical concerns are important to success. PMID:24624074

  4. Indole-like Trk receptor antagonists.

    PubMed

    Tammiku-Taul, Jaana; Park, Rahel; Jaanson, Kaur; Luberg, Kristi; Dobchev, Dimitar A; Kananovich, Dzmitry; Noole, Artur; Mandel, Merle; Kaasik, Allen; Lopp, Margus; Timmusk, Tõnis; Karelson, Mati

    2016-10-01

    The virtual screening for new scaffolds for TrkA receptor antagonists resulted in potential low molecular weight drug candidates for the treatment of neuropathic pain and cancer. In particular, the compound (Z)-3-((5-methoxy-1H-indol-3-yl)methylene)-2-oxindole and its derivatives were assessed for their inhibitory activity against Trk receptors. The IC50 values were computationally predicted in combination of molecular and fragment-based QSAR. Thereafter, based on the structure-activity relationships (SAR), a series of new compounds were designed and synthesized. Among the final selection of 13 compounds, (Z)-3-((5-methoxy-1-methyl-1H-indol-3-yl)methylene)-N-methyl-2-oxindole-5-sulfonamide showed the best TrkA inhibitory activity using both biochemical and cellular assays and (Z)-3-((5-methoxy-1-methyl-1H-indol-3-yl)methylene)-2-oxindole-5-sulfonamide was the most potent inhibitor of TrkB and TrkC. PMID:27318978

  5. Antagonists for acute oral cadmium chloride intoxication

    SciTech Connect

    Basinger, M.A.; Jones, M.M.; Holscher, M.A.; Vaughn, W.K.

    1988-01-01

    An examination has been carried out on the relative efficacy of a number of chelating agents when acting as antagonists for oral cadmium chloride intoxication in mice. The compounds were administered orally after the oral administration of cadmium chloride at 1 mmol/kg. Of the compounds examined, several were useful in terms of enhancing survival, but by far the most effective in both enhancing survival and leaving minimal residual levels of cadmium in the liver and the kidney, was meso-2,3-dimercaptosuccinic acid (DMSA). Several polyaminocarboxylic acids also enhanced survival. The most effective of these in reducing liver and kidney levels of cadmium were diethylenetriaminepentaacetic acid (DTPA), trans-1,2-diaminocyclohexane-N,N,N'N'-tetraacetic acid (CDTA), and triethylenetetraminehexaacetic acid (TTHA). D-Penicillamine (DPA) was found to promote survival but also led to kidney cadmium levels higher than those found in the controls. Sodium 2,3-dimercaptopropane-1-sulfonate (DMPS) was as effective in promoting survival as DMSA but left levels of cadmium in the kidney and liver that were approximately four times greater than those found with DMSA.

  6. Antagonistic neural networks underlying differentiated leadership roles.

    PubMed

    Boyatzis, Richard E; Rochford, Kylie; Jack, Anthony I

    2014-01-01

    The emergence of two distinct leadership roles, the task leader and the socio-emotional leader, has been documented in the leadership literature since the 1950s. Recent research in neuroscience suggests that the division between task-oriented and socio-emotional-oriented roles derives from a fundamental feature of our neurobiology: an antagonistic relationship between two large-scale cortical networks - the task-positive network (TPN) and the default mode network (DMN). Neural activity in TPN tends to inhibit activity in the DMN, and vice versa. The TPN is important for problem solving, focusing of attention, making decisions, and control of action. The DMN plays a central role in emotional self-awareness, social cognition, and ethical decision making. It is also strongly linked to creativity and openness to new ideas. Because activation of the TPN tends to suppress activity in the DMN, an over-emphasis on task-oriented leadership may prove deleterious to social and emotional aspects of leadership. Similarly, an overemphasis on the DMN would result in difficulty focusing attention, making decisions, and solving known problems. In this paper, we will review major streams of theory and research on leadership roles in the context of recent findings from neuroscience and psychology. We conclude by suggesting that emerging research challenges the assumption that role differentiation is both natural and necessary, in particular when openness to new ideas, people, emotions, and ethical concerns are important to success. PMID:24624074

  7. Multiple Targeting Approaches on Histamine H3 Receptor Antagonists

    PubMed Central

    Khanfar, Mohammad A.; Affini, Anna; Lutsenko, Kiril; Nikolic, Katarina; Butini, Stefania; Stark, Holger

    2016-01-01

    With the very recent market approval of pitolisant (Wakix®), the interest in clinical applications of novel multifunctional histamine H3 receptor antagonists has clearly increased. Since histamine H3 receptor antagonists in clinical development have been tested for a variety of different indications, the combination of pharmacological properties in one molecule for improved pharmacological effects and reduced unwanted side-effects is rationally based on the increasing knowledge on the complex neurotransmitter regulations. The polypharmacological approaches on histamine H3 receptor antagonists on different G-protein coupled receptors, transporters, enzymes as well as on NO-signaling mechanism are described, supported with some lead structures. PMID:27303254

  8. Endothelin receptor antagonists in the treatment of pulmonary arterial hypertension.

    PubMed

    Langleben, David

    2007-03-01

    The recognition that endothelin-1 contributes to the pathogenesis of pulmonary arterial hypertension has led to the development of clinically useful endothelin receptor antagonists that improve symptoms and functional capacity and alter the natural history of the disease in a beneficial way. The antagonists have varying degrees of selectivity for the two classes of endothelin receptor, termed ETA and ETB, and the varying degrees may translate into clinical differences. Endothelin receptor antagonists have become an integral part of therapy for pulmonary arterial hypertension, and the indications for their use are expanding. PMID:17338931

  9. Multiple Targeting Approaches on Histamine H3 Receptor Antagonists.

    PubMed

    Khanfar, Mohammad A; Affini, Anna; Lutsenko, Kiril; Nikolic, Katarina; Butini, Stefania; Stark, Holger

    2016-01-01

    With the very recent market approval of pitolisant (Wakix®), the interest in clinical applications of novel multifunctional histamine H3 receptor antagonists has clearly increased. Since histamine H3 receptor antagonists in clinical development have been tested for a variety of different indications, the combination of pharmacological properties in one molecule for improved pharmacological effects and reduced unwanted side-effects is rationally based on the increasing knowledge on the complex neurotransmitter regulations. The polypharmacological approaches on histamine H3 receptor antagonists on different G-protein coupled receptors, transporters, enzymes as well as on NO-signaling mechanism are described, supported with some lead structures. PMID:27303254

  10. The muscarinic antagonists scopolamine and atropine are competitive antagonists at 5-HT3 receptors.

    PubMed

    Lochner, Martin; Thompson, Andrew J

    2016-09-01

    Scopolamine is a high affinity muscarinic antagonist that is used for the prevention of post-operative nausea and vomiting. 5-HT3 receptor antagonists are used for the same purpose and are structurally related to scopolamine. To examine whether 5-HT3 receptors are affected by scopolamine we examined the effects of this drug on the electrophysiological and ligand binding properties of 5-HT3A receptors expressed in Xenopus oocytes and HEK293 cells, respectively. 5-HT3 receptor-responses were reversibly inhibited by scopolamine with an IC50 of 2.09 μM. Competitive antagonism was shown by Schild plot (pA2 = 5.02) and by competition with the 5-HT3 receptor antagonists [(3)H]granisetron (Ki = 6.76 μM) and G-FL (Ki = 4.90 μM). The related molecule, atropine, similarly inhibited 5-HT evoked responses in oocytes with an IC50 of 1.74 μM, and competed with G-FL with a Ki of 7.94 μM. The reverse experiment revealed that granisetron also competitively bound to muscarinic receptors (Ki = 6.5 μM). In behavioural studies scopolamine is used to block muscarinic receptors and induce a cognitive deficit, and centrally administered concentrations can exceed the IC50 values found here. It is therefore possible that 5-HT3 receptors are also inhibited. Studies that utilise higher concentrations of scopolamine should be mindful of these potential off-target effects. PMID:27108935

  11. Single exposure of dopamine D1 antagonist prevents and D2 antagonist attenuates methylphenidate effect

    PubMed Central

    Claussen, Catherine M; Witte, Lindsey J; Dafny, Nachum

    2015-01-01

    Methylphenidate (MPD) is a readily prescribed drug for the treatment of attention deficit hyperactivity disorder (ADHD) and moreover is used illicitly by youths for its cognitive-enhancing effects and recreation. MPD exposure in rodents elicits increased locomotor activity. Repetitive MPD exposure leads to further augmentation of their locomotor activity. This behavioral response is referred to as behavioral sensitization. Behavioral sensitization is used as an experimental marker for a drug’s ability to elicit dependence. There is evidence that dopamine (DA) is a key player in the acute and chronic MPD effect; however, the role of DA in the effects elicited by MPD is still debated. The objective of this study was to investigate the role of D1 and/or D2 DA receptors in the acute and chronic effect of MPD on locomotor activity. The study lasted for 12 consecutive days. Seven groups of male Sprague Dawley® rats were used. A single D1 or D2 antagonist was given before and after acute and chronic MPD administration. Single injection of D1 DA antagonist was able to significantly attenuate the locomotor activity when given prior to the initial MPD exposure and after repetitive MPD exposure, while the D2 DA antagonist partially attenuated the locomotor activity only when given before the second MPD exposure. The results show the role, at least in part, of the D1 DA receptor in the mechanism of behavioral sensitization, whereas the D2 DA receptor only partially modulates the response to acute and chronic MPD. PMID:27186140

  12. Biomolecular recognition of antagonists by α7 nicotinic acetylcholine receptor: Antagonistic mechanism and structure-activity relationships studies.

    PubMed

    Peng, Wei; Ding, Fei

    2015-08-30

    As the key constituent of ligand-gated ion channels in the central nervous system, nicotinic acetylcholine receptors (nAChRs) and neurodegenerative diseases are strongly coupled in the human species. In recently years the developments of selective agonists by using nAChRs as the drug target have made a large progress, but the studies of selective antagonists are severely lacked. Currently these antagonists rest mainly on the extraction of partly natural products from some animals and plants; however, the production of these crude substances is quite restricted, and artificial synthesis of nAChR antagonists is still one of the completely new research fields. In the context of this manuscript, our primary objective was to comprehensively analyze the recognition patterns and the critical interaction descriptors between target α7 nAChR and a series of the novel compounds with potentially antagonistic activity by means of virtual screening, molecular docking and molecular dynamics simulation, and meanwhile these recognition reactions were also compared with the biointeraction of α7 nAChR with a commercially natural antagonist - methyllycaconitine. The results suggested clearly that there are relatively obvious differences of molecular structures between synthetic antagonists and methyllycaconitine, while the two systems have similar recognition modes on the whole. The interaction energy and the crucially noncovalent forces of the α7 nAChR-antagonists are ascertained according to the method of Molecular Mechanics/Generalized Born Surface Area. Several amino acid residues, such as B/Tyr-93, B/Lys-143, B/Trp-147, B/Tyr-188, B/Tyr-195, A/Trp-55 and A/Leu-118 played a major role in the α7 nAChR-antagonist recognition processes, in particular, residues B/Tyr-93, B/Trp-147 and B/Tyr-188 are the most important. These outcomes tally satisfactorily with the discussions of amino acid mutations. Based on the explorations of three-dimensional quantitative structure

  13. Complications of TNF-α antagonists and iron homeostasis

    EPA Science Inventory

    TNF-α is a central regulator of inflammation and its blockade downregulates other proinflammatory cytokines, chemokines, and growth factors. Subsequently, TNF-α antagonists are currently used in treatment regimens directed toward several inflammatory diseases. Despite a beneficia...

  14. Anthropomorphic finger antagonistically actuated by SMA plates.

    PubMed

    Engeberg, Erik D; Dilibal, Savas; Vatani, Morteza; Choi, Jae-Won; Lavery, John

    2015-10-01

    Most robotic applications that contain shape memory alloy (SMA) actuators use the SMA in a linear or spring shape. In contrast, a novel robotic finger was designed in this paper using SMA plates that were thermomechanically trained to take the shape of a flexed human finger when Joule heated. This flexor actuator was placed in parallel with an extensor actuator that was designed to straighten when Joule heated. Thus, alternately heating and cooling the flexor and extensor actuators caused the finger to flex and extend. Three different NiTi based SMA plates were evaluated for their ability to apply forces to a rigid and compliant object. The best of these three SMAs was able to apply a maximum fingertip force of 9.01N on average. A 3D CAD model of a human finger was used to create a solid model for the mold of the finger covering skin. Using a 3D printer, inner and outer molds were fabricated to house the actuators and a position sensor, which were assembled using a multi-stage casting process. Next, a nonlinear antagonistic controller was developed using an outer position control loop with two inner MOSFET current control loops. Sine and square wave tracking experiments demonstrated minimal errors within the operational bounds of the finger. The ability of the finger to recover from unexpected disturbances was also shown along with the frequency response up to 7 rad s(-1). The closed loop bandwidth of the system was 6.4 rad s(-1) when operated intermittently and 1.8 rad s(-1) when operated continuously. PMID:26292164

  15. Suppressing antagonistic bioengineering feedbacks doubles restoration success.

    PubMed

    Suykerbuyk, Wouter; Bouma, Tjeerd J; van der Heide, Tjisse; Faust, Cornelia; Govers, Laura L; Giesen, Wim B J T; de Jong, Dick J; van Katwijk, Marieke M

    2012-06-01

    In a seagrass restoration project, we explored the potential for enhancing the restoration process by excluding antagonistic engineering interactions (i.e., biomechanical warfare) between two ecosystem engineers: the bioturbating lugworm Arenicola marina and the sediment-stabilizing seagrass Zostera noltii Hornem. Applying a shell layer underneath half of our seagrass transplants successfully reduced adult lugworm density by over 80% and reduced lugworm-induced microtopography (a proxy for lugworm disturbance) at the wave-sheltered site. At the wave-exposed site adult lugworm densities and microtopography were already lower than at the sheltered site but were further reduced in the shell-treated units. Excluding lugworms and their bioengineering effects corresponded well with a strongly enhanced seagrass growth at the wave-sheltered site, which was absent at the exposed site. Enhanced seagrass growth in the present study was fully assigned to the removal of lugworms' negative engineering effects and not to any (indirect) evolving effects such as an altered biogeochemistry or sediment-stabilizing effects by the shell layer. The context-dependency implies that seagrass establishment at the exposed site is not constrained by negative ecosystem-engineering interactions only, but also by overriding physical stresses causing poor growth conditions. Present findings underline that, in addition to recent emphasis on considering positive (facilitating) interactions in ecological theory and practice, it is equally important to consider negative engineering interactions between ecosystem-engineering species. Removal of such negative interactions between ecosystem-engineering species can give a head start to the target species at the initial establishment phase, when positive engineering feedbacks by the target species on itself are still lacking. Though our study was carried out in a marine environment with variable levels of wave disturbance, similar principles may be

  16. Azogabazine; a photochromic antagonist of the GABAA receptor.

    PubMed

    Huckvale, Rosemary; Mortensen, Martin; Pryde, David; Smart, Trevor G; Baker, James R

    2016-07-12

    The design and synthesis of azogabazine is described, which represents a highly potent (IC50 = 23 nM) photoswitchable antagonist of the GABAA receptor. An azologization strategy is adopted, in which a benzyl phenyl ether in a high affinity gabazine analogue is replaced by an azobenzene, with resultant retention of antagonist potency. We show that cycling from blue to UV light, switching between trans and cis isomeric forms, leads to photochemically controlled antagonism of the GABA ion channel. PMID:27327397

  17. Identification of M-CSF agonists and antagonists

    DOEpatents

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

    2000-02-15

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

  18. Deficiency of interleukin-1 receptor antagonist responsive to anakinra.

    PubMed

    Schnellbacher, Charlotte; Ciocca, Giovanna; Menendez, Roxanna; Aksentijevich, Ivona; Goldbach-Mansky, Raphaela; Duarte, Ana M; Rivas-Chacon, Rafael

    2013-01-01

    We describe a 3-month-old infant who presented to our institution with interleukin (IL)-1 receptor antagonist deficiency (DIRA), which consists of neutrophilic pustular dermatosis, periostitis, aseptic multifocal osteomyelitis, and persistently high acute-phase reactants. Skin findings promptly improved upon initiation of treatment with anakinra (recombinant human IL-1 receptor antagonist), and the bony lesions and systemic inflammation resolved with continued therapy. PMID:22471702

  19. Bradykinin antagonists modified with dipeptide mimetic beta-turn inducers.

    PubMed

    Alcaro, Maria C; Vinci, Valerio; D'Ursi, Anna M; Scrima, Mario; Chelli, Mario; Giuliani, Sandro; Meini, Stefania; Di Giacomo, Marcello; Colombo, Lino; Papini, Anna Maria

    2006-05-01

    Bradykinin (BK) is involved in a wide variety of pathophysiological processes. Potent BK peptide antagonists can be developed introducing constrained unnatural amino acids, necessary to force the secondary structure of the molecule. In this paper, we report a structure-activity relationship study of two peptide analogues of the potent B2 antagonist HOE 140 by replacing the D-Tic-Oic dipeptide with conformationally constrained dipeptide mimetic beta-turn inducers. PMID:16504505

  20. CXCR3 antagonist VUF10085 binds to an intrahelical site distinct from that of the broad spectrum antagonist TAK–779

    PubMed Central

    Nedjai, Belinda; Viney, Jonathan M; Li, Hubert; Hull, Caroline; Anderson, Caroline A; Horie, Tomoki; Horuk, Richard; Vaidehi, Nagarajan; Pease, James E

    2015-01-01

    Background and Purpose The chemokine receptor CXCR3 is implicated in a variety of clinically important diseases, notably rheumatoid arthritis and atherosclerosis. Consequently, antagonists of CXCR3 are of therapeutic interest. In this study, we set out to characterize binding sites of the specific low MW CXCR3 antagonist VUF10085 and the broad spectrum antagonist TAK-779 which blocks CXCR3 along with CCR2 and CCR5. Experimental Approach Molecular modelling of CXCR3, followed by virtual ligand docking, highlighted several CXCR3 residues likely to contact either antagonist, notably a conserved aspartate in helix 2 (Asp-1122:63), which was postulated to interact with the quaternary nitrogen of TAK-779. Validation of modelling was carried out by site-directed mutagenesis of CXCR3, followed by assays of cell surface expression, ligand binding and receptor activation. Key Results Mutation of Asn-1323.33, Phe-207 and Tyr-2716.51 within CXCR3 severely impaired both ligand binding and chemotactic responses, suggesting that these residues are critical for maintenance of a functional CXCR3 conformation. Contrary to our hypothesis, mutation of Asp-1122:63 had no observable effects on TAK-779 activity, but clearly decreased the antagonist potency of VUF 10085. Likewise, mutations of Phe-1313.32, Ile-2796.59 and Tyr-3087.43 were well tolerated and were critical for the antagonist activity of VUF 10085 but not for that of TAK-779. Conclusions and Implications This more detailed definition of a binding pocket within CXCR3 for low MW antagonists should facilitate the rational design of newer CXCR3 antagonists, with obvious clinical potential. PMID:25425280

  1. The chlorinated AHR ligand 3,3′,4,4′,5-pentachlorobiphenyl (PCB126) promotes reactive oxygen species (ROS) production during embryonic development in the killifish (Fundulus heteroclitus)

    USGS Publications Warehouse

    Arzuaga, Xabier; Wassenberg, Deena; Giulio, Richard D.; Elskus, Adria

    2006-01-01

    Exposure to dioxin-like chemicals that activate the aryl hydrocarbon receptor (AHR) can result in increased cellular and tissue production of reactive oxygen species (ROS). Little is known of these effects during early fish development. We used the fish model, Fundulus heteroclitus, to determine if the AHR ligand and pro-oxidant 3,3′,4,4′,5-pentachlorobiphenyl (PCB126) can increase ROS production during killifish development, and to test a novel method for measuring ROS non-invasively in a living organism. The superoxide-sensitive fluorescent dye, dihydroethidium (DHE), was used to detect in ovo ROS production microscopically in developing killifish exposed to PCB126 or vehicle. Both in ovo CYP1A activity (ethoxyresorufin-o-deethylase, EROD) and in ovo ROS were induced by PCB126. In ovo CYP1A activity was inducible by PCB126 concentrations as low as 0.003 nM, with maximal induction occurring at 0.3 nM PCB126. These PCB126 concentrations also significantly increased in ovo ROS production in embryonic liver, ROS being detectable as early as 5 days post-fertilization. These data demonstrate that the pro-oxidant and CYP1A inducer, PCB126, increases both CYP1A activity and ROS production in developing killifish embryos. The superoxide detection assay (SoDA) described in this paper provides a semi-quantitative, easily measured, early indicator of altered ROS production that can be used in conjunction with simultaneous in ovo measurements of CYP1A activity and embryo development to explore functional relationships among biochemical, physiological and developmental responses to AHR ligands.

  2. Prenatal 3,3',4,4',5-pentachlorobiphenyl exposure modulates induction of rat hepatic CYP 1A1, 1B1, and AhR by 7,12-dimethylbenz[a]anthracene

    SciTech Connect

    Wakui, Shin . E-mail: wakui@azabu-u.ac.jp; Yokoo, Kiyofumi; Takahashi, Hiroyuki; Muto, Tomoko; Suzuki, Yoshihiko; Kanai, Yoshikatsu; Hano, Hiroshi; Furusato, Masakuni; Endou, Hitoshi

    2006-02-01

    We previously reported the finding that prenatal exposure to a relatively low dose of PCB126 increases the rate of DMBA-induced rat mammary carcinoma, while a high dose decreased it. One of the most important factors determining the sensitivity to mammary carcinogenesis is the metabolic stage at administration of the carcinogenic agent. DMBA is a procarcinogen that recruits the host metabolism to yield its ultimate carcinogenic form, and CYP1A1 and CYP1B1 (CYP1) conduct this metabolism. We investigated the hepatic expression of CYP1 and AhR following oral administration of DMBA (100 mg/kg b.w.) (i.g.) to 50-day-old female Sprague-Dawley rats whose dams had been treated (i.g.) with 2.5 ng, 250 ng, 7.5 {mu}g of PCB126/kg or the vehicle on days 13 to 19 post-conception. Real-time quantitative RT-PCR analysis revealed that the prenatal exposure to a relatively low dose of PCB126 (the 250 ng group) prolonged the higher expression of CYP1A1, CYP1B1, and AhR mRNA, while prenatal exposure to a high dose of PCB126 (the 7.5 {mu}g group) prolonged the higher expression of CYP1A1 and AhR mRNA. Western blotting and immunohistochemical analyses were consistent with mRNAs changes. Because DMBA oxidation produces a highly mutagenic metabolite and is finally catalyzed by CYP1B1, a relatively low PCB126 dose might produce the biological character to potentially increase the risk of DMBA-induced mammary carcinoma.

  3. The combined effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin and the phytoestrogen genistein on steroid hormone secretion, AhR and ERβ expression and the incidence of apoptosis in granulosa cells of medium porcine follicles.

    PubMed

    Piasecka-Srader, Joanna; Sadowska, Agnieszka; Nynca, Anna; Orlowska, Karina; Jablonska, Monika; Jablonska, Olga; Petroff, Brian K; Ciereszko, Renata E

    2016-02-20

    Low doses of endocrine disrupting chemicals (EDCs) used in combination may act in a manner different from that of individual compounds. The objective of the study was to examine in vitro effects of low doses of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; 100 pM) and genistein (500 nM) on: 1) progesterone (P4) and estradiol (E2) secretion (48 h); 2) dynamic changes in aryl hydrocarbon receptor (AhR) mRNA and protein expression (1, 3, 6, 24 and 48 h); 3) dynamic changes in estrogen receptor β (ERβ) mRNA and protein expression (1, 3, 6, 24 and 48 h); and 4) induction of apoptosis in porcine granulosa cells derived from medium follicles (3, 6 and 24 h). TCDD had no effect on P4 or E2 production, but potentiated the inhibitory effect of genistein on P4 production. In contrast to the individual treatments which did not produce any effects, TCDD and genistein administered together decreased ERβ and AhR protein expression in granulosa cells. Moreover, the inhibitory effect of TCDD on AhR mRNA expression was abolished by genistein. The treatments did not induce apoptosis in the cells. In summary, combined effects of low concentrations of TCDD and genistein on follicular function of pigs differed from that of individual compounds. The results presented in the current paper clearly indicate that effects exerted by low doses of EDCs applied in combination must be taken into consideration when studying potential risk effects of EDCs on biological processes. PMID:26568065

  4. Antagonistic versus non-antagonistic models of balancing selection: Characterizing the relative timescales and hitchhiking effects of partial selective sweeps

    PubMed Central

    Connallon, Tim; Clark, Andrew G.

    2012-01-01

    Antagonistically selected alleles -- those with opposing fitness effects between sexes, environments, or fitness components -- represent an important component of additive genetic variance in fitness-related traits, with stably balanced polymorphisms often hypothesized to contribute to observed quantitative genetic variation. Balancing selection hypotheses imply that intermediate-frequency alleles disproportionately contribute to genetic variance of life history traits and fitness. Such alleles may also associate with population genetic footprints of recent selection, including reduced genetic diversity and inflated linkage disequilibrium at linked, neutral sites. Here, we compare the evolutionary dynamics of different balancing selection models, and characterize the evolutionary timescale and hitchhiking effects of partial selective sweeps generated under antagonistic versus non-antagonistic (e.g., overdominant and frequency-dependent selection) processes. We show that that the evolutionary timescales of partial sweeps tend to be much longer, and hitchhiking effects are drastically weaker, under scenarios of antagonistic selection. These results predict an interesting mismatch between molecular population genetic and quantitative genetic patterns of variation. Balanced, antagonistically selected alleles are expected to contribute more to additive genetic variance for fitness than alleles maintained by classic, non-antagonistic mechanisms. Nevertheless, classical mechanisms of balancing selection are much more likely to generate strong population genetic signatures of recent balancing selection. PMID:23461340

  5. Early Illustrations of Geste Antagoniste in Cervical and Generalized Dystonia

    PubMed Central

    Broussolle, Emmanuel; Laurencin, Chloé; Bernard, Emilien; Thobois, Stéphane; Danaila, Teodor; Krack, Paul

    2015-01-01

    Background Geste antagoniste, or sensory trick, is a voluntary maneuver that temporarily reduces the severity of dystonic postures or movements. We present a historical review of early reports and illustrations of geste antagoniste. Results In 1894, Brissaud described this phenomenon in Paris in patients with torticollis. He noted that a violent muscular contraction could be reversed by a minor voluntary action. He considered the improvement obtained by what he called “simple mannerisms, childish behaviour or fake pathological movements” was proof of the psychogenic origin of what he named mental torticollis. This concept was supported by photographical illustrations of the patients. The term geste antagoniste was used by Brissaud’s pupils, Meige and Feindel, in their 1902 monograph on movement disorders. Other reports and illustrations of this sign were published in Europe between 1894 and 1906. Although not mentioned explicitly, geste antagoniste was also illustrated in a case report of generalized dystonia in Oppenheim’s 1911 seminal description of dystonia musculorum deformans in Berlin. Discussion Brissaud-Meige’s misinterpretation of the geste antagoniste unfortunately anchored the psychogenic origin of dystonia for decades. In New York, Herz brought dystonia back into the realm of organic neurology in 1944. Thereafter, it was given prominence by other authors, notably Fahn and Marsden in the 1970–1980s. Nowadays, neurologists routinely investigate for geste antagoniste when a dystonic syndrome is suspected, because it provides a further argument in favor of dystonia. The term alleviating maneuver was proposed in 2014 to replace sensory trick or geste antagoniste. This major sign is now part of the motor phenomenology of the 2013 Movement Disorder Society’s classification of dystonia. PMID:26417535

  6. The Genomic Location of Sexually Antagonistic Variation: Some Cautionary Comments

    PubMed Central

    Fry, James D.

    2013-01-01

    Sexually antagonistic polymorphisms are polymorphisms in which the allele that is advantageous in one sex is deleterious in the other sex. In an influential 1984 paper, W. Rice hypothesized that such polymorphisms should be relatively common on the X chromosome (or on the W in female-heterogametic species) but relatively rare on the autosomes. Here, I show that there are plausible assumptions under which the reverse is expected to be true, and point out recent studies that give evidence for sexually antagonistic variation on the autosomes. Although more work is needed to resolve the issue, it is premature to conclude that the X chromosome is a “hot spot” for the accumulation of sexually antagonistic variation. PMID:19922443

  7. Neutralization of Staphylococcal Enterotoxin B by an Aptamer Antagonist

    PubMed Central

    Wang, Kaiyu; Gan, Longjie; Jiang, Li; Zhang, Xianhui; Yang, Xiangyue; Chen, Min

    2015-01-01

    Staphylococcal enterotoxin B (SEB) is a major virulence factor for staphylococcal toxic shock syndrome (TSS). SEB activates a large subset of the T lymphocytic population, releasing proinflammatory cytokines. Blocking SEB-initiated toxicity may be an effective strategy for treating TSS. Using a process known as systematic evolution of ligands by exponential enrichment (SELEX), we identified an aptamer that can antagonize SEB with nanomolar binding affinity (Kd = 64 nM). The aptamer antagonist effectively inhibits SEB-mediated proliferation and cytokine secretion in human peripheral blood mononuclear cells. Moreover, a PEGylated aptamer antagonist significantly reduced mortality in a “double-hit” mouse model of SEB-induced TSS, established via sensitization with d-galactosamine followed by SEB challenge. Therefore, our novel aptamer antagonist may offer potential therapeutic efficacy against SEB-mediated TSS. PMID:25624325

  8. Transient receptor potential ankyrin 1 (TRPA1) antagonists.

    PubMed

    Preti, Delia; Saponaro, Giulia; Szallasi, Arpad

    2015-01-01

    The transient receptor potential ankyrin 1 (TRPA1) channel is an irritant sensor highly expressed on nociceptive neurons. The clinical use of TRPA1 antagonists is based on the concept that TRPA1 is active during disease states like neuropathic pain. Indeed, in Phase 2a proof-of-concept studies the TRPA1 antagonist GRC17536 has shown efficacy in patients with painful diabetic neuropathy. Moreover, animal studies suggest that the therapeutic value of TRPA1 antagonists extends beyond pain to pruritus, asthma and cough with limited safety concerns. This review provides a comprehensive overview of the patent literature (since 2007) on small-molecule inhibitors of the TRPA1 channel. Despite the clear progress, many unanswered questions remain. Future advancement to Phase 3 studies will assess the real translational potential of this research field. PMID:25853468

  9. Metabotropic glutamate receptor antagonists but not NMDA antagonists affect conditioned taste aversion acquisition in the parabrachial nucleus of rats.

    PubMed

    Vales, Karel; Zach, Petr; Bielavska, Edita

    2006-02-01

    The effect of glutamate receptor antagonists on conditioned taste aversion (CTA) was studied in rats. The association of the short-term memory of a gustatory conditioned stimulus (CS) with visceral malaise (unconditioned stimulus, US) in the CTA paradigm takes place in the parabrachial nuclei (PBN) of the brainstem. The first direct evidence of participation of glutamatergic neurotransmission in the PBN during CTA demonstrated that the extracellular level of glutamate rises during saccharin drinking (Bielavska et al. in Brain Res 887:413-417, 2000). Our results show an effect of microdialysis administration of selective GluR antagonists into the PBN on the formation of CTA engram. We used four glutamate receptor (GluR) antagonists of different types (D-AP5, MK-801 as antagonists of ionotropic GluR and L-AP3, MSPG as antagonists of metabotropic GluR). The disruptive effect of MK-801 on CTA formation in the PBN is concentration-dependent, with the greatest inhibition under the higher concentrations eliciting significant disruption. The application of D-AP5 (0.1, 1, 5 mM) did not elicit a statistically significant blockade of CTA acquisition. This indicates that the association of the US-CS in the PBN is not dependent on NMDA receptors. On the contrary, application of L-AP3 (0.1, 1, 5 mM) blocked the CS-US association. PMID:16273405

  10. Pharmacokinetic interactions with calcium channel antagonists (Part II).

    PubMed

    Schlanz, K D; Myre, S A; Bottorff, M B

    1991-12-01

    Since calcium channel antagonists are a diverse class of drugs frequently administered in combination with other agents, the potential for clinically significant pharmacokinetic drug interactions exists. These interactions occur most frequently via altered hepatic blood flow and impaired hepatic enzyme activity. Part I of the article, which appeared in the previous issue of the Journal, dealt with interactions between calcium antagonists and marker compounds, theophylline, midazolam, lithium, doxorubicin, oral hypoglycaemics and cardiac drugs. Part II examines interactions with cyclosporin, anaesthetics, carbamazepine and cardiovascular agents. PMID:1782739

  11. Oxytocin antagonists for the management of preterm birth: a review.

    PubMed

    Usta, Ihab M; Khalil, Ali; Nassar, Anwar H

    2011-06-01

    Preterm birth, the leading cause of neonatal morbidity and mortality, is estimated at incidence of 12.7% of all births, which has not decreased over the last four decades despite intensive antenatal care programs aimed at high-risk groups, the widespread use of tocolytics, and a series of other preventive and therapeutic interventions. Oxytocin antagonists, namely atosiban, represent an appealing choice that seems to be effective with apparently fewer side effects than the traditional tocolytics. This article reviews the available literature on the pharmacokinetics, mode of administration, and clinical utility of oxytocin antagonists for acute and maintenance tocolysis with special emphasis on its safety profile. PMID:21170825

  12. Discovery of cannabinoid-1 receptor antagonists by virtual screening.

    PubMed

    Lee, Gil Nam; Kim, Kwang Rok; Ahn, Sung-Hoon; Bae, Myung Ae; Kang, Nam Sook

    2010-09-01

    In this work, we tried to find a new scaffold for a CB1 receptor antagonist using virtual screening. We first analyzed structural features for the known cannabinoid-1 receptor antagonists and, then, we built pharmacophore models using the HipHop concept and carried out a docking study based on our homology CB1 receptor 3D structure. The most active compound, including thiazole-4-one moiety, showed an activity value of 125 nM IC(50), with a good PK profile. PMID:20667724

  13. Cholestasis of pregnancy, pruritus and 5-hydroxytryptamine 3 receptor antagonists.

    PubMed

    Schumann, Roman; Hudcova, Jana

    2004-09-01

    Pruritus, an early symptom of intrahepatic cholestasis of pregnancy, may be severe. Conventional treatment includes ursodeoxycholic acid and cholestyramine. Ondansetron, a 5-hydroxytryptamine 3 receptor antagonist antiemetic, has been shown to reduce pruritus of different etiologies including cholestasis. We now report the successful preoperative use of ondansetron in a patient with pruritus from intrahepatic cholestasis of pregnancy. While the mechanism for our patient's response is poorly understood, 5-hydroxytryptamine 3 receptor antagonists should be further evaluated and possibly considered as a treatment option for intrahepatic cholestasis of pregnancy-related pruritus. PMID:15315599

  14. Discovery of Tertiary Sulfonamides as Potent Liver X Receptor Antagonists

    SciTech Connect

    Zuercher, William J.; Buckholz†, Richard G.; Campobasso, Nino; Collins, Jon L.; Galardi, Cristin M.; Gampe, Robert T.; Hyatt, Stephen M.; Merrihew, Susan L.; Moore, John T.; Oplinger, Jeffrey A.; Reid, Paul R.; Spearing, Paul K.; Stanley, Thomas B.; Stewart, Eugene L.; Willson, Timothy M.

    2010-08-12

    Tertiary sulfonamides were identified in a HTS as dual liver X receptor (LXR, NR1H2, and NR1H3) ligands, and the binding affinity of the series was increased through iterative analogue synthesis. A ligand-bound cocrystal structure was determined which elucidated key interactions for high binding affinity. Further characterization of the tertiary sulfonamide series led to the identification of high affinity LXR antagonists. GSK2033 (17) is the first potent cell-active LXR antagonist described to date. 17 may be a useful chemical probe to explore the cell biology of this orphan nuclear receptor.

  15. Discovery of small molecule antagonists of TRPV1.

    PubMed

    Rami, Harshad K; Thompson, Mervyn; Wyman, Paul; Jerman, Jeffrey C; Egerton, Julie; Brough, Stephen; Stevens, Alexander J; Randall, Andrew D; Smart, Darren; Gunthorpe, Martin J; Davis, John B

    2004-07-16

    Small molecule antagonists of the vanilloid receptor 1 (TRPV1, also known as VR1) are disclosed. Ureas such as 5 (SB-452533) were used to explore the structure activity relationship with several potent analogues identified. Pharmacological studies using electrophysiological and FLIPR Ca(2+) based assays showed compound 5 was an antagonist versus capsaicin, noxious heat and acid mediated activation of TRPV1. Study of a quaternary salt of 5 supports a mode of action in which compounds from this series cause inhibition via an extracellularly accessible binding site on the TRPV1 receptor. PMID:15203132

  16. Histamine 2 Receptor Antagonists and Proton Pump Inhibitors.

    PubMed

    Brinkworth, Megan D; Aouthmany, Mouhammad; Sheehan, Michael

    2016-01-01

    Within the last 50 years, the pharmacologic market for gastric disease has grown exponentially. Currently, medical management with histamine 2 receptor antagonist and proton pump inhibitors are the mainstay of therapy over surgical intervention. These are generally regarded as safe medications, but there are growing numbers of cases documenting adverse effects, especially those manifesting in the skin. Here we review the pharmacology, common clinical applications, and adverse reactions of both histamine 2 receptor antagonists and proton pump inhibitors with a particular focus on the potential for allergic reactions including allergic contact dermatitis. PMID:27172303

  17. Characterization of a novel non-steroidal glucocorticoid receptor antagonist

    SciTech Connect

    Li, Qun-Yi; Zhang, Meng; Hallis, Tina M.; DeRosier, Therese A.; Yue, Jian-Min; Ye, Yang; Mais, Dale E.; Wang, Ming-Wei

    2010-01-15

    Selective antagonists of the glucocorticoid receptor (GR) are desirable for the treatment of hypercortisolemia associated with Cushing's syndrome, psychic depression, obesity, diabetes, neurodegenerative diseases, and glaucoma. NC3327, a non-steroidal small molecule with potent binding affinity to GR (K{sub i} = 13.2 nM), was identified in a high-throughput screening effort. As a full GR antagonist, NC3327 greatly inhibits the dexamethasone (Dex) induction of marker genes involved in hepatic gluconeogenesis, but has a minimal effect on matrix metalloproteinase 9 (MMP-9), a GR responsive pro-inflammatory gene. Interestingly, the compound recruits neither coactivators nor corepressors to the GR complex but competes with glucocorticoids for the interaction between GR and a coactivator peptide. Moreover, NC3327 does not trigger GR nuclear translocation, but significantly blocks Dex-induced GR transportation to the nucleus, and thus appears to be a 'competitive' GR antagonist. Therefore, the non-steroidal compound, NC3327, may represent a new class of GR antagonists as potential therapeutics for a variety of cortisol-related endocrine disorders.

  18. Antagonistic peptide technology for functional dissection of CLE peptides revisited

    PubMed Central

    Czyzewicz, Nathan; Wildhagen, Mari; Cattaneo, Pietro; Stahl, Yvonne; Pinto, Karine Gustavo; Aalen, Reidunn B.; Butenko, Melinka A.; Simon, Rüdiger; Hardtke, Christian S.; De Smet, Ive

    2015-01-01

    In the Arabidopsis thaliana genome, over 1000 putative genes encoding small, presumably secreted, signalling peptides can be recognized. However, a major obstacle in identifying the function of genes encoding small signalling peptides is the limited number of available loss-of-function mutants. To overcome this, a promising new tool, antagonistic peptide technology, was recently developed. Here, this antagonistic peptide technology was tested on selected CLE peptides and the related IDA peptide and its usefulness in the context of studies of peptide function discussed. Based on the analyses, it was concluded that the antagonistic peptide approach is not the ultimate means to overcome redundancy or lack of loss-of-function lines. However, information collected using antagonistic peptide approaches (in the broad sense) can be very useful, but these approaches do not work in all cases and require a deep insight on the interaction between the ligand and its receptor to be successful. This, as well as peptide ligand structure considerations, should be taken into account before ordering a wide range of synthetic peptide variants and/or generating transgenic plants. PMID:26136270

  19. Antagonistic peptide technology for functional dissection of CLE peptides revisited.

    PubMed

    Czyzewicz, Nathan; Wildhagen, Mari; Cattaneo, Pietro; Stahl, Yvonne; Pinto, Karine Gustavo; Aalen, Reidunn B; Butenko, Melinka A; Simon, Rüdiger; Hardtke, Christian S; De Smet, Ive

    2015-08-01

    In the Arabidopsis thaliana genome, over 1000 putative genes encoding small, presumably secreted, signalling peptides can be recognized. However, a major obstacle in identifying the function of genes encoding small signalling peptides is the limited number of available loss-of-function mutants. To overcome this, a promising new tool, antagonistic peptide technology, was recently developed. Here, this antagonistic peptide technology was tested on selected CLE peptides and the related IDA peptide and its usefulness in the context of studies of peptide function discussed. Based on the analyses, it was concluded that the antagonistic peptide approach is not the ultimate means to overcome redundancy or lack of loss-of-function lines. However, information collected using antagonistic peptide approaches (in the broad sense) can be very useful, but these approaches do not work in all cases and require a deep insight on the interaction between the ligand and its receptor to be successful. This, as well as peptide ligand structure considerations, should be taken into account before ordering a wide range of synthetic peptide variants and/or generating transgenic plants. PMID:26136270

  20. Neuroprotection by NMDA receptor antagonists in a variety of neuropathologies.

    PubMed

    Palmer, G C

    2001-09-01

    Because of adverse reactions, early efforts to introduce high affinity competitive or use-dependent NMDA receptor antagonists into patients suffering from stroke, head trauma or epilepsy met with failure. Later it was discovered that both low affinity use-dependent NMDA receptor antagonists and compounds with selective affinity for the NR2B receptor subunit met the criteria for safe administration into patients. Furthermore, these low affinity antagonists exhibit significant mechanistic differences from their higher affinity counterparts. Success of the latter is attested to the ability of the following low affinity compounds to be marketed: 1) Cough suppressant-dextromethorphan (available for decades); 2) Parkinson's disease--amantadine, memantine and budipine; 3) Dementia--memantine; and 4) Epilepsy--felbamate. Moreover, Phase III clinical trials are ongoing with remacemide for epilepsy and Huntington's disease and head trauma for HU-211. A host of compounds are or were under evaluation for the possible treatment of stroke, head trauma, hyperalgesia and various neurodegenerative disorders. Despite the fact that other drugs with associated NMDA receptor mechanisms have reached clinical status, this review focuses only on those competitive and use-dependent NMDA receptor antagonists that reached clinical trails. The ensuing discussions link the in vivo pharmacological investigations that led to the success/mistakes/ failures for eventual testing of promising compounds in the clinic. PMID:11554551

  1. Non-NMDA receptor antagonist-induced drinking in rat

    NASA Technical Reports Server (NTRS)

    Xu, Z.; Johnson, A. K.

    1998-01-01

    Glutamate has been implicated in the central control of mechanisms that maintain body fluid homeostasis. The present studies demonstrate that intracerebroventricular (i.c.v.) injections of the non-N-methyl-d-aspartate (NMDA) receptor antagonists 6, 7-dinitroquinoxaline-2,3-dione (DNQX) and 6-cyano-7-nitroquinoxaline-2,3 dione (CNQX) induce drinking in rats. The dipsogenic effect of i.c.v. DNQX was antagonized by the non-NMDA receptor agonist alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA). The water intake induced by DNQX was also blocked by pretreatment with a NMDA receptor antagonist, MK-801, but not by angiotensin type 1 (AT1) or acetylcholine muscarinic receptor antagonists (losartan and atropine). The results indicate that non-NMDA receptors may exert a tonic inhibitory effect within brain circuits that control dipsogenic activity and that functional integrity of NMDA receptors may be required for the non-NMDA receptor antagonists to induce water intake. Copyright 1998 Published by Elsevier Science B.V.

  2. The Effect of Antagonist Muscle Sensory Input on Force Regulation

    PubMed Central

    Onushko, Tanya; Schmit, Brian D.; Hyngstrom, Allison

    2015-01-01

    The purpose of this study was to understand how stretch-related sensory feedback from an antagonist muscle affects agonist muscle output at different contraction levels in healthy adults. Ten young (25.3 ± 2.4 years), healthy subjects performed constant isometric knee flexion contractions (agonist) at 6 torque levels: 5%, 10%, 15%, 20%, 30%, and 40% of their maximal voluntary contraction. For half of the trials, subjects received patellar tendon taps (antagonist sensory feedback) during the contraction. We compared error in targeted knee flexion torque and hamstring muscle activity, with and without patellar tendon tapping, across the 6 torque levels. At lower torque levels (5%, 10%, and 15%), subjects produced greater knee torque error following tendon tapping compared with the same torque levels without tendon tapping. In contrast, we did not find any difference in torque output at higher target levels (20%, 30%, and 40%) between trials with and without tendon tapping. We also observed a load-dependent increase in the magnitude of agonist muscle activity after tendon taps, with no associated load-dependent increase in agonist and antagonist co-activation, or reflex inhibition from the antagonist tapping. The findings suggest that at relatively low muscle activity there is a deficiency in the ability to correct motor output after sensory disturbances, and cortical centers (versus sub-cortical) are likely involved. PMID:26186590

  3. Odor interaction between Bourgeonal and its antagonist undecanal.

    PubMed

    Brodin, Malin; Laska, Matthias; Olsson, Mats J

    2009-09-01

    The perceived quality of a binary mixture will, as a rule of thumb, be dominated by the quality of the stronger unmixed component. On the other hand, there are mechanisms that, in theory, suggest that this will not always be true; one example being receptor antagonism. Undecanal has been indicated as an antagonist for bourgeonal-sensitive receptors in the human olfactory epithelium. Therefore, we investigated mixtures of isointense concentrations of bourgeonal and undecanal and, as a control, mixtures of isointense concentrations of bourgeonal and n-butanol. Both mixture types were investigated at 2 levels of concentration. The particular aim was to see if the bourgeonal-undecanal mixtures would exhibit asymmetric odor quality favoring the perception of the antagonist and the control mixture would not. For the control mixture, indeed odor quality tended to be dominated by the strongest component before mixing as would be suggested from previous studies. In line with the hypothesis, the bourgeonal-undecanal mixture was dominated by the antagonist's quality, but only when mixed at higher concentrations, altogether suggesting the effects of a low-affinity receptor antagonism. This is, to our knowledge, the first demonstration of how antagonistic interaction at the level of the receptor can affect the perception of odor mixtures in humans. PMID:19620388

  4. Retention and Outcome in a Narcotic Antagonist Treatment Program.

    ERIC Educational Resources Information Center

    Capone, Thomas; And Others

    1986-01-01

    Patients in an outpatient narcotic antagonist treatment program were followed through their course of treatment. Those who remained longer were found to enter treatment with more stable employment records and less recent opiate use. They also appeared more successful at termination, with better vocational stability, less extraneous drug use, and…

  5. Precycle Estradiol in Synchronization and Scheduling of Antagonist Cycles.

    PubMed

    Saple, Shilpa; Agrawal, Mukesh; Kawar, Simi

    2016-08-01

    Antagonist cycles have an inherent issue of lack of flexibility. As a result where batching of cycles is desired, it is not the preferred protocol in ART cycles. There is also the limitation of ovarian response in antagonist cycle due to the size heterogenesities of antral follicles at the start of stimulation. Among the different options available, use of estrogen in the luteal phase of the preceding cycle has definitely shown benefits with regard to better control of cycle as well as synchronization of follicles available for stimulation. The article gives a detailed analysis of the different options available for timing the egg collection in antagonist cycles, the advantages and drawbacks, and the method of use of estrogen. Whereas in the majority of the trials where estrogen pretreatment was used, the goal of scheduling of egg collection was definitely achieved, increased duration and dose of gonadotropin stimulation were required. There was definite advantage of higher oocyte yield in these cycles. The possibility of premature LH rise later during stimulation and subsequent poor implantation in these cycles has to be further evaluated. Nevertheless, batching of patient friendly antagonist cycles can be effectively possible by use of precycle estrogen treatment. PMID:27382226

  6. 2-Cycloalkyl phenoxyacetic acid CRTh2 receptor antagonists.

    PubMed

    Sandham, David A; Aldcroft, Clive; Baettig, Urs; Barker, Lucy; Beer, David; Bhalay, Gurdip; Brown, Zarin; Dubois, Gerald; Budd, David; Bidlake, Louise; Campbell, Emma; Cox, Brian; Everatt, Brian; Harrison, David; Leblanc, Catherine J; Manini, Jodie; Profit, Rachael; Stringer, Rowan; Thompson, Katy S; Turner, Katharine L; Tweed, Morris F; Walker, Christoph; Watson, Simon J; Whitebread, Steven; Willis, Jennifer; Williams, Gareth; Wilson, Caroline

    2007-08-01

    High throughput screening identified a phenoxyacetic acid scaffold as a novel CRTh2 receptor antagonist chemotype, which could be optimised to furnish a compound with functional potency for inhibition of human eosinophil shape change and oral bioavailability in the rat. PMID:17531480

  7. ALTERNATE ENZYMES FOR USE IN CHOLINESTERASE ANTAGONIST MONITORS, (CAM'S)

    EPA Science Inventory

    The Cholinesterase Antagonist Monitors ('CAM's') normally use cholinesterase as the sensor in the detection of organophosphate and carbamate pesticides. The present investigation has been concerned with a search for alternate enzymes that could be used in the CAM system and that ...

  8. Aryl biphenyl-3-ylmethylpiperazines as 5-HT7 receptor antagonists.

    PubMed

    Kim, Jeeyeon; Kim, Youngjae; Tae, Jinsung; Yeom, Miyoung; Moon, Bongjin; Huang, Xi-Ping; Roth, Bryan L; Lee, Kangho; Rhim, Hyewhon; Choo, Il Han; Chong, Youhoon; Keum, Gyochang; Nam, Ghilsoo; Choo, Hyunah

    2013-11-01

    The 5-HT7 receptor (5-HT7 R) is a promising therapeutic target for the treatment of depression and neuropathic pain. The 5-HT7 R antagonist SB-269970 exhibited antidepressant-like activity, whereas systemic administration of the 5-HT7 R agonist AS-19 significantly inhibited mechanical hypersensitivity and thermal hyperalgesia. In our efforts to discover selective 5-HT7 R antagonists or agonists, aryl biphenyl-3-ylmethylpiperazines were designed, synthesized, and biologically evaluated against the 5-HT7 R. Among the synthesized compounds, 1-([2'-methoxy-(1,1'-biphenyl)-3-yl]methyl)-4-(2-methoxyphenyl)piperazine (28) was the best binder to the 5-HT7 R (pKi =7.83), and its antagonistic property was confirmed by functional assays. The selectivity profile of compound 28 was also recorded for the 5-HT7 R over other serotonin receptor subtypes, such as 5-HT1 R, 5-HT2 R, 5-HT3 R, and 5-HT6 R. In a molecular modeling study, the 2-methoxyphenyl moiety attached to the piperazine ring of compound 28 was proposed to be essential for the antagonistic function. PMID:24039134

  9. Medium-Induced Antagonistic Behavior in Staphylococcus Aureus.

    ERIC Educational Resources Information Center

    Benathen, Isaiah A.

    1992-01-01

    Antagonism is the production of substances by microorganisms that inhibit or prevent the growth of other bacteria. This paper demonstrates the antagonistic behavior of gram-positive coccus on the B. subtilis and Enterococcus faecalis gram-positive microorganisms, showing that the process of antagonism is sometimes dependent on the nutritional…

  10. Myofascial force transmission via extramuscular pathways occurs between antagonistic muscles.

    PubMed

    Huijing, Peter A; Baan, Guus C

    2008-01-01

    Most often muscles (as organs) are viewed as independent actuators. To test if this is true for antagonistic muscles, force was measured simultaneously at: (1) the proximal and distal tendons of the extensor digitorum muscle (EDL) to quantify any proximo-distal force differences, as an indicator of myofascial force transmission, (2) at the distal tendons of the whole antagonistic peroneal muscle group (PER) to test if effects of EDL length changes are present and (3) at the proximal end of the tibia to test if myofascially transmitted force is exerted there. EDL length was manipulated either at the proximal or distal tendons. This way equal EDL lengths are attained at two different positions of the muscle with respect to the tibia and antagonistic muscles. Despite its relatively small size, lengthening of the EDL changed forces exerted on the tibia and forces exerted by its antagonistic muscle group. Apart from its extramuscular myofascial connections, EDL has no connections to either the tibia or these antagonistic muscles. Proximal EDL lengthening increased distal muscular forces (active PER DeltaF approximately +1.7%), but decreased tibial forces (passive from 0.3 to 0 N; active DeltaF approximately -5%). Therefore, it is concluded that these antagonistic muscles do not act independently, because of myofascial force transmission between them. Such a decrease in tibial force indicates release of pre-strained connections. Distal EDL lengthening had opposite effects (tripling passive force exerted on tibia; active PER force DeltaF approximately -3.6%). It is concluded that the length and relative position of the EDL is a co-determinant of passive and active force exerted at tendons of nearby antagonistic muscle groups. These results necessitate a new view of the locomotor apparatus, which needs to take into account the high interdependence of muscles and muscle fibres as force generators, as well as proximo-distal force differences and serial and parallel

  11. Plant polyphenols differentially modulate inflammatory responses of human keratinocytes by interfering with activation of transcription factors NF{kappa}B and AhR and EGFR-ERK pathway

    SciTech Connect

    Potapovich, Alla I.; Lulli, Daniela; Fidanza, Paolo; Kostyuk, Vladimir A.; De Luca, Chiara; Pastore, Saveria; Korkina, Liudmila G.

    2011-09-01

    Molecular mechanisms underlying modulation of inflammatory responses in primary human keratinocytes by plant polyphenols (PPs), namely the glycosylated phenylpropanoid verbascoside, the stilbenoid resveratrol and its glycoside polydatin, and the flavonoid quercetin and its glycoside rutin were evaluated. As non-lethal stimuli, the prototypic ligand for epidermal growth factor receptor (EGFR) transforming growth factor alpha (TGFalpha), the combination of tumor necrosis factor (TNFalpha) and interferon (IFNgamma) (T/I), UVA + UVB irradiation, and bacterial lipopolysaccharide (LPS) were used. We demonstrated differential modulation of inflammatory responses in keratinocytes at signal transduction, gene transcription, and protein synthesis levels as a function of PP chemical structure, the pro-inflammatory trigger used, and PP interaction with intracellular detoxifying systems. The PPs remarkably inhibited constitutive, LPS- and T/I-induced but not TGFalpha-induced ERK phosphorylation. They also suppressed NFkappaB activation by LPS and T/I. Verbascoside and quercetin invariably impaired EGFR phosphorylation and UV-associated aryl hydrocarbon receptor (AhR)-mediated signaling, while rutin, polydatin and resveratrol did not affect EGFR phosphorylation and further activated AhR machinery in UV-exposed keratinocytes. In general, PPs down-regulated gene expression of pro-inflammatory cytokines/enzymes, except significant up-regulation of IL-8 observed under stimulation with TGFalpha. Both spontaneous and T/I-induced release of IL-8 and IP-10 was suppressed, although 50 {mu}M resveratrol and polydatin up-regulated IL-8. At this concentration, resveratrol activated both gene expression and de novo synthesis of IL-8 and AhR-mediated mechanisms were involved. We conclude that PPs differentially modulate the inflammatory response of human keratinocytes through distinct signal transduction pathways, including AhR and EGFR. - Graphical abstract: Display Omitted Highlights

  12. Diversity, distribution, and antagonistic activities of rhizobacteria of Panax notoginseng

    PubMed Central

    Fan, Ze-Yan; Miao, Cui-Ping; Qiao, Xin-Guo; Zheng, You-Kun; Chen, Hua-Hong; Chen, You-Wei; Xu, Li-Hua; Zhao, Li-Xing; Guan, Hui-Lin

    2015-01-01

    Background Rhizobacteria play an important role in plant defense and could be promising sources of biocontrol agents. This study aimed to screen antagonistic bacteria and develop a biocontrol system for root rot complex of Panax notoginseng. Methods Pure-culture methods were used to isolate bacteria from the rhizosphere soil of notoginseng plants. The identification of isolates was based on the analysis of 16S ribosomal RNA (rRNA) sequences. Results A total of 279 bacteria were obtained from rhizosphere soils of healthy and root-rot notoginseng plants, and uncultivated soil. Among all the isolates, 88 showed antagonistic activity to at least one of three phytopathogenic fungi, Fusarium oxysporum, Fusarium solani, and Phoma herbarum mainly causing root rot disease of P. notoginseng. Based on the 16S rRNA sequencing, the antagonistic bacteria were characterized into four clusters, Firmicutes, Proteobacteria, Actinobacteria, and Bacteroidetesi. The genus Bacillus was the most frequently isolated, and Bacillus siamensis (Hs02), Bacillus atrophaeus (Hs09) showed strong antagonistic activity to the three pathogens. The distribution pattern differed in soil types, genera Achromobacter, Acidovorax, Brevibacterium, Brevundimonas, Flavimonas, and Streptomyces were only found in rhizosphere of healthy plants, while Delftia, Leclercia, Brevibacillus, Microbacterium, Pantoea, Rhizobium, and Stenotrophomonas only exist in soil of diseased plant, and Acinetobacter only exist in uncultivated soil. Conclusion The results suggest that diverse bacteria exist in the P. notoginseng rhizosphere soil, with differences in community in the same field, and antagonistic isolates may be good potential biological control agent for the notoginseng root-rot diseases caused by F. oxysporum, Fusarium solani, and Panax herbarum. PMID:27158229

  13. Accumulation of Deleterious Mutations Near Sexually Antagonistic Genes.

    PubMed

    Connallon, Tim; Jordan, Crispin Y

    2016-01-01

    Mutation generates a steady supply of genetic variation that, while occasionally useful for adaptation, is more often deleterious for fitness. Recent research has emphasized that the fitness effects of mutations often differ between the sexes, leading to important evolutionary consequences for the maintenance of genetic variation and long-term population viability. Some forms of sex-specific selection-i.e., stronger purifying selection in males than females-can help purge a population's load of female-harming mutations and promote population growth. Other scenarios-e.g., sexually antagonistic selection, in which mutations that harm females are beneficial for males-inflate genetic loads and potentially dampen population viability. Evolutionary processes of sexual antagonism and purifying selection are likely to impact the evolutionary dynamics of different loci within a genome, yet theory has mostly ignored the potential for interactions between such loci to jointly shape the evolutionary genetic basis of female and male fitness variation. Here, we show that sexually antagonistic selection at a locus tends to elevate the frequencies of deleterious alleles at tightly linked loci that evolve under purifying selection. Moreover, haplotypes that segregate for different sexually antagonistic alleles accumulate different types of deleterious mutations. Haplotypes that carry female-benefit sexually antagonistic alleles preferentially accumulate mutations that are primarily male harming, whereas male-benefit haplotypes accumulate mutations that are primarily female harming. The theory predicts that sexually antagonistic selection should shape the genomic organization of genetic variation that differentially impacts female and male fitness, and contribute to sexual dimorphism in the genetic basis of fitness variation. PMID:27226163

  14. Accumulation of Deleterious Mutations Near Sexually Antagonistic Genes

    PubMed Central

    Connallon, Tim; Jordan, Crispin Y.

    2016-01-01

    Mutation generates a steady supply of genetic variation that, while occasionally useful for adaptation, is more often deleterious for fitness. Recent research has emphasized that the fitness effects of mutations often differ between the sexes, leading to important evolutionary consequences for the maintenance of genetic variation and long-term population viability. Some forms of sex-specific selection—i.e., stronger purifying selection in males than females—can help purge a population’s load of female-harming mutations and promote population growth. Other scenarios—e.g., sexually antagonistic selection, in which mutations that harm females are beneficial for males—inflate genetic loads and potentially dampen population viability. Evolutionary processes of sexual antagonism and purifying selection are likely to impact the evolutionary dynamics of different loci within a genome, yet theory has mostly ignored the potential for interactions between such loci to jointly shape the evolutionary genetic basis of female and male fitness variation. Here, we show that sexually antagonistic selection at a locus tends to elevate the frequencies of deleterious alleles at tightly linked loci that evolve under purifying selection. Moreover, haplotypes that segregate for different sexually antagonistic alleles accumulate different types of deleterious mutations. Haplotypes that carry female-benefit sexually antagonistic alleles preferentially accumulate mutations that are primarily male harming, whereas male-benefit haplotypes accumulate mutations that are primarily female harming. The theory predicts that sexually antagonistic selection should shape the genomic organization of genetic variation that differentially impacts female and male fitness, and contribute to sexual dimorphism in the genetic basis of fitness variation. PMID:27226163

  15. Transcription alterations of microRNAs, cytochrome P4501A1 and 3A65, and AhR and PXR in the liver of zebrafish exposed to crude microcystins.

    PubMed

    Li, Xiaoyu; Ma, Junguo; Fang, Qian; Li, Yuanyuan

    2013-10-01

    MicroRNAs are small non-coding regulatory RNAs that not only control diverse cellular processes but also regulate gene expression induced by environmental chemicals. However, little is known about the role of microRNAs in liver response of fish to the exposure of cyanobacterial hepatotoxin microcystins (MCs). In the present study, the transcription levels of 4 miRNAs (dre-miR-21, dre-miR-122, dre-miR-27b, and dre-miR-148), cytochromes P450s CYP1A1 and CYP3A65, and their receptors, aryl hydrocarbon receptor (AhR, for CYP1A1) and pregnane X receptor (PXR, for CYP3A65), in the liver of zebrafish were evaluated after 24 h of 50, 200, or 800 μg/L of crude MCs exposure by using the quantitative real-time PCR method. The results showed that MCs-exposure elevated the transcription levels of dre-miR-21 and dre-miR-27b while down-regulated the expressions of dre-miR-122 and dre-miR-148. However, CYP1A1 transcription remained unchanged while mRNA levels of AhRR1 and AhR2 were significantly higher than that of control. Furthermore, the expressions of CYP3A65 and its receptor PXR were up-regulated by MCs-exposure at higher concentrations (200, or 800 μg/L of crude MCs). Therefore we suggest that CYP3A65 and PXR may be involved in the metabolization and detoxification of MCs in zebrafish, which may be regulated by dre-miR-27b. This work might be beneficial for the discovery of new potential diagnostic biomarker and drug target for hepatosis caused by MC. PMID:23851223

  16. Analgesic effectiveness of the narcotic agonist-antagonists

    PubMed Central

    Houde, Raymond W.

    1979-01-01

    1 Two fundamentally different types of narcotic-antogonists have been found to be very effective analgesics with relatively low dependence-producing potentials. 2 These two drug classes can be distinguished as being either morphine-like or nalorphine-like on the basis of their subjective and objective effects after single doses and on chronic administration, and by the character of their abstinence syndromes on abrupt withdrawal or on precipitation by other antagonists. 3 To explain differences in side effects associated with their analgesic actions, the existence of three types of receptors has been postulated: a μ receptor which is believed to be associated with euphoria and other typical morphine-like effects and a kappa (χ) and a sigma (σ) receptor which are believed to be associated with the sedative and psychotomimetic effects, respectively, of the nalorphine-like drugs. 4 The antagonist-analgesics of the morphine-type have the characteristics of being agonists of low intrinsic activity but with high affinity for the μ receptor. Representative analgesics of this type are profadol, propiram and buprenorphine. 5 The antagonist-analgesics of the nalorphine-type are drugs which are believed to have varying degrees of affinity and intrinsic activity at all three receptors, but characteristically seem to act merely as competitive antagonists with no intrinsic activity at the μ receptor. Representative analgesics of this type are pentazocine, nalbuphine and butorphanol. 6 There are considerable differences among the individual drugs of each type in terms of their analgesic and narcotic-antagonistic potencies. However, clear differences in analgesic efficacy among any of the antagonist-analgesics remain to be proved. All give evidence of being capable of relieving pain in nondependent patients in situations in which doses of morphine (or its surrogates) usually used would be effective. 7 The major advantages of the partial agonists of the morphine-type over the

  17. Calcium channel antagonists and the treatment of migraine.

    PubMed

    Greenberg, D A

    1986-01-01

    Despite ongoing dispute over the pathophysiologic basis of migraine, the vasospastic theory of pathogenesis has brought to the forefront a promising class of new antimigraine agents, the Ca2+ channel antagonists. Voltage-dependent Ca2+ channels, integral membrane proteins that permit extracellular Ca2+ to enter cells down their electrical and concentration gradients, have a universal role in stimulus-response coupling in excitable cells. Thus, they participate in translating electrical excitation into secretory and contractile events. Ca2+ channel antagonists, a structurally diverse group of organic compounds, inhibit ion flux through voltage-dependent Ca2+ channels by binding to specific, channel-associated drug receptor sites and thereby reduce the frequency of channel opening in response to membrane depolarization. Ca2+ channels in cardiac muscle, smooth muscle, and neurons all exhibit high affinity for Ca2+ channel antagonists, although neurons also contain a population of drug-resistant channels. Extensive clinical experience in the use of Ca2+ channel antagonists has accumulated from their application to nonneurologic, especially cardiovascular, disorders. Three such drugs, nifedipine, verapamil, and diltiazem, are currently available in the United States, although none are specifically approved for use in migraine. Other agents, such as nimodipine, are likely to be released in the near future. A large number of clinical studies have now addressed the efficacy of Ca2+ channel antagonists in the prophylaxis of migraine headache. Dihydropyridines (nifedipine and nimodipine), phenylalkylamines (verapamil), diphenylalkylamines (flunarizine), and benzothiazepines (diltiazem) have all been examined, and a beneficial effect has been noted in each case. The limited directly comparative data currently available and the difficulties involved in comparing the results of different studies do not presently support claims of superiority for any single agent. This is an

  18. Pharmacological characterization of antagonists of the C5a receptor

    PubMed Central

    Paczkowski, Natalii J; Finch, Angela M; Whitmore, Jacqueline B; Short, Anna J; Wong, Allan K; Monk, Peter N; Cain, Stuart A; Fairlie, David P; Taylor, Stephen M

    1999-01-01

    Potent and highly selective small molecule antagonists have recently been developed by us for C5a receptors (C5aR) on human polymorphonuclear leukocytes (PMN). In this study we compared a new cyclic antagonist, F-[OPdChaWR], with an acyclic derivative, MeFKPdChaWr, for their capacities to bind to C5aR on human PMN and human umbilical artery membranes. We also compared their inhibition of myeloperoxidase (MPO) secretion from human PMNs and their inhibition of human umbilical artery contraction induced by human recombinant C5a.In both PMNs and umbilical artery, the cyclic and acyclic C5a antagonists displayed insurmountable antagonism against C5a. There were differences in selectivities for the C5aR with F-[OPdChaWR] (pKb 8.64±0.21) being 30 times more potent than MeFKPdChaWr (pKb 7.16±0.11, P<0.05) in PMNs, but of similar potency (pKb 8.19±0.38 vs pKb 8.28±0.29, respectively) in umbilical artery. This trend was also reflected in their relative binding affinities, both antagonists having similar affinities (−logIC50 values) for C5aR in umbilical artery membranes (F-[OPdChaWR], 7.00±0.46; MeFKPdChaWr, 7.23±0.17), whereas in PMN membranes the C5aR affinity of the cycle F-[OPdChaWR] (7.05±0.06) was four times higher than that of acyclic MeFKPdChaWr (6.43±0.24, P<0.05).In summary, the results reveal that these antagonists are insurmountable in nature against C5a for C5aR on at least two human cell types, and the differences in relative receptor binding affinities and antagonistic potencies against C5a are consistent with differences in receptors within these cell types. The nature of these differences is yet to be elucidated. PMID:10602324

  19. Integrative role for serotonergic and glutamatergic receptor mechanisms in the action of NMDA antagonists: potential relationships to antipsychotic drug actions on NMDA antagonist responsiveness.

    PubMed

    Breese, George R; Knapp, Darin J; Moy, Sheryl S

    2002-06-01

    NMDA receptor antagonists worsen symptoms in schizophrenia and induce schizophrenic-like symptoms in normal individuals. In animals, NMDA antagonist-induced behavioral responses include increased activity, head weaving, deficits in paired pulse inhibition and social interaction, and increased forced swim immobility. Repeated exposure to NMDA antagonists in animals results in behavioral sensitization-a phenomenon accentuated in rats with dopaminergic neurons lesioned during development. In keeping with an involvement of serotonin and glutamate release in NMDA antagonist action, selected behaviors induced by NMDA antagonists are minimized by 5-HT(2A) receptor antagonists and mGLU2 receptor agonists. These observations provide promising new approaches for treating acute NMDA antagonist-induced psychosis. Further, acute atypical antipsychotic drugs also minimize NMDA antagonist actions to a greater degree than typical antipsychotics. However, because knowledge concerning acute versus chronic effectiveness of various antipsychotic drugs against NMDA antagonist neuropathology is limited, future studies to define more fully the basis of their differences in efficacy after chronic treatment could provide an understanding of their actions on neural mechanisms responsible for the core pathogenesis of schizophrenia. PMID:12204191

  20. Synthesis and α1-adrenoceptor antagonist activity of tamsulosin analogues.

    PubMed

    Sagratini, Gianni; Angeli, Piero; Buccioni, Michela; Gulini, Ugo; Marucci, Gabriella; Melchiorre, Carlo; Poggesi, Elena; Giardinà, Dario

    2010-12-01

    Tamsulosin (-)-1 is the most utilized α(1)-adrenoceptor antagonist in the benign prostatic hyperplasia therapy owing to its uroselective antagonism and capability in relieving both obstructive and irritative lower urinary tract symptoms. Here we report the synthesis and pharmacological study of the homochiral (-)-1 analogues (-)-2-(-)-5, bearing definite modifications in the 2-substituted phenoxyethylamino group in order to evaluate their influence on the affinity profile for α(1)-adrenoceptor subtypes. The benzyl analogue (-)-3, displaying a preferential antagonist profile for α1A-than α1D-and α1B-adrenoceptors, and a 12-fold higher potency at α1A-adrenoceptors with respect to the α1B subtype, may have improved uroselectivity compared to (-)-1. PMID:20934789

  1. Antagonist coactivation of trunk stabilizer muscles during Pilates exercises.

    PubMed

    Rossi, Denise Martineli; Morcelli, Mary Hellen; Marques, Nise Ribeiro; Hallal, Camilla Zamfolini; Gonçalves, Mauro; Laroche, Dain P; Navega, Marcelo Tavella

    2014-01-01

    The purpose of this study was to compare the antagonist coactivation of the local and global trunk muscles during mat-based exercises of Skilled Modern Pilates. Twelve women performed five exercises and concurrently, surface EMG from internal oblique (OI), multifidus (MU), rectus abdominis (RA) and iliocostalis lumborum (IL) muscles was recorded bilaterally. The percentage of antagonist coactivation between local (OI/MU) and global muscles (RA/IL) was calculated. Individuals new to the practice of these exercises showed differences in coactivation of the trunk muscles between the exercises and these results were not similar bilaterally. Thus, in clinical practice, the therapist should be aware of factors such as compensation and undesirable rotation movements of the trunk. Moreover, the coactivation of global muscles was higher bilaterally in all exercises analyzed. This suggests that the exercises of Skilled Modern Pilates only should be performed after appropriate learning and correct execution of all principles, mainly the Centering Principle. PMID:24411147

  2. Antagonistic otolith-visual units in cat vestibular nuclei

    NASA Technical Reports Server (NTRS)

    Daunton, Nancy G.; Christensen, Carol A.

    1992-01-01

    The nature of neural coding of visual (Vis) and vestibular (Vst) information on translational motion in the region of the vestibular nuclei was investigated using extracellular single-unit recordings in alert adult cats. Responses were recorded and averaged over 60 cycles of stimulation in the vertical and horizontal planes, which included the Vst (movement of the animal in the dark), Vis (movement within lighted visual surround), and combined Vis and Vst (movement of the animal within the lighted stationary visual surround). Data are reported on responses to stimulations along the axis showing maximal sensitivity. A small number of units were identified that showed an antagonistic relationship between their Vis and Vst responses (since they were maximally excited by Vis and by Vst stimulations in the same direction). Results suggest that antagonistic units may belong to an infrequently encountered, but functionally distinct, class of neurons.

  3. Antagonistic Coevolution of Marine Planktonic Viruses and Their Hosts

    NASA Astrophysics Data System (ADS)

    Martiny, Jennifer B. H.; Riemann, Lasse; Marston, Marcia F.; Middelboe, Mathias

    2014-01-01

    The potential for antagonistic coevolution between marine viruses and their (primarily bacterial) hosts is well documented, but our understanding of the consequences of this rapid evolution is in its infancy. Acquisition of resistance against co-occurring viruses and the subsequent evolution of virus host range in response have implications for bacterial mortality rates as well as for community composition and diversity. Drawing on examples from a range of environments, we consider the potential dynamics, underlying genetic mechanisms and fitness costs, and ecological impacts of virus-host coevolution in marine waters. Given that much of our knowledge is derived from laboratory experiments, we also discuss potential challenges and approaches in scaling up to diverse, complex networks of virus-host interactions. Finally, we note that a variety of novel approaches for characterizing virus-host interactions offer new hope for a mechanistic understanding of antagonistic coevolution in marine plankton.

  4. Lead Optimization Studies of Cinnamic Amide EP2 Antagonists

    PubMed Central

    2015-01-01

    Prostanoid receptor EP2 can play a proinflammatory role, exacerbating disease pathology in a variety of central nervous system and peripheral diseases. A highly selective EP2 antagonist could be useful as a drug to mitigate the inflammatory consequences of EP2 activation. We recently identified a cinnamic amide class of EP2 antagonists. The lead compound in this class (5d) displays anti-inflammatory and neuroprotective actions. However, this compound exhibited moderate selectivity to EP2 over the DP1 prostanoid receptor (∼10-fold) and low aqueous solubility. We now report compounds that display up to 180-fold selectivity against DP1 and up to 9-fold higher aqueous solubility than our previous lead. The newly developed compounds also display higher selectivity against EP4 and IP receptors and a comparable plasma pharmacokinetics. Thus, these compounds are useful for proof of concept studies in a variety of models where EP2 activation is playing a deleterious role. PMID:24773616

  5. Endothelin receptor antagonists as disease modifiers in systemic sclerosis.

    PubMed

    Shetty, Nagalakshmi; Derk, Chris T

    2011-02-01

    Systemic sclerosis (SSc) is a multisystem connective tissue disease of unknown etiology that is characterized by inflammation, vascular dysfunction and fibrosis of the skin and visceral organs. SSc is clinically diverse both in terms of the burden of skin and organ involvement and the rate of progression of the disease. Recent studies indicate that the endothelin system, especially ET-1 and the ETA and ETB receptors may play a key role in the pathogenesis of SSc. A new class of drugs, endothelin receptor antagonists has been introduced for treatment of patients with pulmonary arterial hypertension (PAH). Bosentan, a dual endothelin receptor antagonist as well as Sitaxsentan and Ambrisentan, selective blockers of the ETA receptor have proven effective in SSc-PAH. This effect may be mediated through both a vasodilatory and antifibrotic effect, thus making these agents attractive as potential disease modifying agents for SSc. PMID:21184655

  6. Rational design of high affinity tachykinin NK1 receptor antagonists.

    PubMed

    Boyle, S; Guard, S; Higginbottom, M; Horwell, D C; Howson, W; McKnight, A T; Martin, K; Pritchard, M C; O'Toole, J; Raphy, J

    1994-05-01

    The rational design of a non-peptide tachykinin NK1 receptor antagonist, [(2-benzofuran)-CH2OCO]-(R)-alpha-MeTrp-(S)-NHCH(CH3)P h (28, PD 154075) is described. Compound 28 has a Ki = 9 and 0.35 nM for the NK1 receptor binding site in guinea-pig cerebral cortex membranes and human IM9, cells respectively (using [125I] Bolton-Hunter-SP as the radioligand). It is a potent antagonist in vitro where it antagonises the contractions mediated by SPOMe in the guinea-pig ileum (KB = 0.3 nM). Compound 28 is active in vivo in the guinea-pig plasma extravasation model, where it is able to block the SPOMe-induced protein plasma extravasation (monitored by Evans Blue) in the bladder with an ID50 of 0.02 mg kg-1 iv. PMID:7922147

  7. Non-imidazole histamine NO-donor H3-antagonists.

    PubMed

    Tosco, Paolo; Bertinaria, Massimo; Di Stilo, Antonella; Cena, Clara; Fruttero, Roberta; Gasco, Alberto

    2005-01-01

    Recently a series of H3-antagonists related to Imoproxifan was realised (I); in these products the oxime substructure of the lead was constrained in NO-donor furoxan systems and in the corresponding furazan derivatives. In this paper, a new series of compounds derived from I by substituting the imidazole ring with the ethoxycarbonylpiperazino moiety present in the non-imidazole H3-ligand A-923 is described. For all the products synthesis and preliminary pharmacological characterisation, as well as their hydrophilic-lipophilic balance, are reported. The imidazole ring replacement generally results in a decreased H3-antagonist activity with respect to the analogues of series I and, in some cases, induces relaxing effects on the electrically contracted guinea-pig ileum, probably due to increased affinity for other receptor systems. PMID:15927183

  8. Lead optimization studies of cinnamic amide EP2 antagonists.

    PubMed

    Ganesh, Thota; Jiang, Jianxiong; Yang, Myung-Soon; Dingledine, Ray

    2014-05-22

    Prostanoid receptor EP2 can play a proinflammatory role, exacerbating disease pathology in a variety of central nervous system and peripheral diseases. A highly selective EP2 antagonist could be useful as a drug to mitigate the inflammatory consequences of EP2 activation. We recently identified a cinnamic amide class of EP2 antagonists. The lead compound in this class (5d) displays anti-inflammatory and neuroprotective actions. However, this compound exhibited moderate selectivity to EP2 over the DP1 prostanoid receptor (∼10-fold) and low aqueous solubility. We now report compounds that display up to 180-fold selectivity against DP1 and up to 9-fold higher aqueous solubility than our previous lead. The newly developed compounds also display higher selectivity against EP4 and IP receptors and a comparable plasma pharmacokinetics. Thus, these compounds are useful for proof of concept studies in a variety of models where EP2 activation is playing a deleterious role. PMID:24773616

  9. Novel alkoxy-oxazolyl-tetrahydropyridine muscarinic cholinergic receptor antagonists.

    PubMed

    Shannon, H E; Bymaster, F P; Hendrix, J C; Quimby, S J; Mitch, C H

    1995-01-01

    The purpose of the present studies was to compare a novel series of alkoxy-oxazolyl-tetrahydropyridines (A-OXTPs) as muscarinic receptor antagonists. The affinity of these compounds for muscarinic receptors was determined by inhibition of [3H]pirenzepine to M1 receptors in hippocampus, [3H]QNB to M2 receptors in brainstem, and [3H]oxotremorine-M to high affinity muscarinic agonist binding sites in cortex. All of the compounds had higher affinity for [3H]pirenzepine than for [3H]QNB or [3H]oxotremorine-M labeled receptors, consistent with an interpretation that they are relatively selective M1 receptor antagonists, although none were as selective as pirenzepine. In addition, dose-response curves were determined for antagonism of oxotremorine-induced salivation (mediated by M3 receptors) and tremor (mediated by non-M1 receptors) in mice. In general, the A-OXTPs were equipotent and equieffective in antagonizing both salivation and tremor, although there were modest differences for some compounds. Dose-response curves also were determined on behavior maintained under a spatial-alternation schedule of food presentation in rats as a measure of effects on working memory. The A-OXTPs produced dose-related decreases in percent correct responding at doses three- to ten-fold lower than those which decreased rates of responding. However, only one compound, MB-OXTP, produced effects on percent correct responding consistent with a selective effect on memory as opposed to non-memory variables. The present results provide evidence that these alkoxy-oxazolyl-tetrahydropyridines are a novel series of modestly M1-selective muscarinic receptor antagonists, and that one member of the series, MB-OXTP, appears to be more selective in its effects on memory than previously studies muscarinic antagonists. PMID:7753969

  10. Construction, purification, and characterization of a chimeric TH1 antagonist

    PubMed Central

    Bello-Rivero, Iraldo; Torrez-Ruiz, Yeny; Blanco-Garcés, Elizabeth; Pentón-Rol, Giselle; Fernández-Batista, Osmani; Javier-González, Luís; Gerónimo-Perez, Haydee; López-Saura, Pedro

    2006-01-01

    Background TH1 immune response antagonism is a desirable approach to mitigate some autoimmune and inflammatory reactions during the course of several diseases where IL-2 and IFN-γ are two central players. Therefore, the neutralization of both cytokines could provide beneficial effects in patients suffering from autoimmune or inflammatory illnesses. Results A chimeric antagonist that can antagonize the action of TH1 immunity mediators, IFN-γ and IL-2, was designed, engineered, expressed in E. coli, purified and evaluated for its in vitro biological activities. The TH1 antagonist molecule consists of the extracellular region for the human IFNγ receptor chain 1 fused by a four-aminoacid linker peptide to human 60 N-terminal aminoacid residues of IL-2. The corresponding gene fragments were isolated by RT-PCR and cloned in the pTPV-1 vector. E. coli (W3110 strain) was transformed with this vector. The chimeric protein was expressed at high level as inclusion bodies. The protein was partially purified by pelleting and washing. It was then solubilized with strong denaturant and finally refolded by gel filtration. In vitro biological activity of chimera was demonstrated by inhibition of IFN-γ-dependent HLA-DR expression in Colo 205 cells, inhibition of IFN-γ antiproliferative effect on HEp-2 cells, and by a bidirectional effect in assays for IL-2 T-cell dependent proliferation: agonism in the absence versus inhibition in the presence of IL-2. Conclusion TH1 antagonist is a chimeric protein that inhibits the in vitro biological activities of human IFN-γ, and is a partial agonist/antagonist of human IL-2. With these attributes, the chimera has the potential to offer a new opportunity for the treatment of autoimmune and inflammatory diseases. PMID:16716222

  11. Calmodulin antagonists promote TRA-8 therapy of resistant pancreatic cancer

    PubMed Central

    Yuan, Kaiyu; Yong, Sun; Xu, Fei; Zhou, Tong; McDonald, Jay M; Chen, Yabing

    2015-01-01

    Pancreatic cancer is highly malignant with limited therapy and a poor prognosis. TRAIL-activating therapy has been promising, however, clinical trials have shown resistance and limited responses of pancreatic cancers. We investigated the effects of calmodulin(CaM) antagonists, trifluoperazine(TFP) and tamoxifen(TMX), on TRA-8-induced apoptosis and tumorigenesis of TRA-8-resistant pancreatic cancer cells, and underlying mechanisms. TFP or TMX alone did not induce apoptosis of resistant PANC-1 cells, while they dose-dependently enhanced TRA-8-induced apoptosis. TMX treatment enhanced efficacy of TRA-8 therapy on tumorigenesis in vivo. Analysis of TRA-8-induced death-inducing-signaling-complex (DISC) identified recruitment of survival signals, CaM/Src, into DR5-associated DISC, which was inhibited by TMX/TFP. In contrast, TMX/TFP increased TRA-8-induced DISC recruitment/activation of caspase-8. Consistently, caspase-8 inhibition blocked the effects of TFP/TMX on TRA-8-induced apoptosis. Moreover, TFP/TMX induced DR5 expression. With a series of deletion/point mutants, we identified CaM antagonist-responsive region in the putative Sp1-binding domain between −295 to −300 base pairs of DR5 gene. Altogether, we have demonstrated that CaM antagonists enhance TRA-8-induced apoptosis of TRA-8-resistant pancreatic cancer cells by increasing DR5 expression and enhancing recruitment of apoptotic signal while decreasing survival signals in DR5-associated DISC. Our studies support the use of these readily available CaM antagonists combined with TRAIL-activating agents for pancreatic cancer therapy. PMID:26320171

  12. Discovery of aryloxy tetramethylcyclobutanes as novel androgen receptor antagonists.

    PubMed

    Guo, Chuangxing; Linton, Angelica; Kephart, Susan; Ornelas, Martha; Pairish, Mason; Gonzalez, Javier; Greasley, Samantha; Nagata, Asako; Burke, Benjamin J; Edwards, Martin; Hosea, Natilie; Kang, Ping; Hu, Wenyue; Engebretsen, Jon; Briere, David; Shi, Manli; Gukasyan, Hovik; Richardson, Paul; Dack, Kevin; Underwood, Toby; Johnson, Patrick; Morell, Andrew; Felstead, Robert; Kuruma, Hidetoshi; Matsimoto, Hiroaki; Zoubeidi, Amina; Gleave, Martin; Los, Gerrit; Fanjul, Andrea N

    2011-11-10

    An aryloxy tetramethylcyclobutane was identified as a novel template for androgen receptor (AR) antagonists via cell-based high-throughput screening. Follow-up to the initial "hit" established 5 as a viable lead. Further optimization to achieve full AR antagonism led to the discovery of 26 and 30, both of which demonstrated excellent in vivo tumor growth inhibition upon oral administration in a castration-resistant prostate cancer (CRPC) animal model. PMID:21936524

  13. NMDA antagonist properties of the putative antiaddictive drug, ibogaine.

    PubMed

    Popik, P; Layer, R T; Fossom, L H; Benveniste, M; Geter-Douglass, B; Witkin, J M; Skolnick, P

    1995-11-01

    Both anecdotal reports in humans and preclinical studies indicate that ibogaine interrupts addiction to a variety of abused substances including alcohol, opiates, nicotine and stimulants. Based on the similarity of these therapeutic claims to recent preclinical studies demonstrating that N-methyl-D-aspartate (NMDA) antagonists attenuate addiction-related phenomena, we examined the NMDA antagonist properties of ibogaine. Pharmacologically relevant concentrations of ibogaine produce a voltage-dependent block of NMDA receptors in hippocampal cultures (Ki, 2.3 microM at -60 mV). Consistent with this observation, ibogaine competitively inhibits [3H]1-[1-(2-thienyl)-cyclohexyl]piperidine binding to rat forebrain homogenates (Ki, 1.5 microM) and blocks glutamate-induced cell death in neuronal cultures (IC50, 4.5 microM). Moreover, at doses previously reported to interfere with drug-seeking behaviors, ibogaine substitutes as a discriminative stimulus (ED50, 64.9 mg/kg) in mice trained to discriminate the prototypic voltage-dependent NMDA antagonist, dizocilpine (0.17 mg/kg), from saline. Consistent with previous reports, ibogaine reduced naloxone-precipitated jumping in morphine-dependent mice (ED50, 72 mg/kg). Although pretreatment with glycine did not affect naloxone-precipitated jumping in morphine-dependent mice, it abolished the ability of ibogaine to block naloxone-precipitated jumping. Taken together, these findings link the NMDA antagonist actions of ibogaine to a putative "antiaddictive" property of this alkaloid, its ability to reduce the expression of morphine dependence. PMID:7473163

  14. Neurokinin-1 Receptor Antagonists in Preventing Postoperative Nausea and Vomiting

    PubMed Central

    Liu, Meng; Zhang, Hao; Du, Bo-Xiang; Xu, Feng-Ying; Zou, Zui; Sui, Bo; Shi, Xue-Yin

    2015-01-01

    Abstract Newly developed neurokinin-1 receptor (NK-1R) antagonists have been recently tried in the prevention of postoperative nausea and vomiting (PONV). This systematic review and meta-analysis was conducted to explore whether NK-1R antagonists were effective in preventing PONV. The PRISMA statement guidelines were followed. Randomized clinical trials (RCTs) that tested the preventive effects of NK-1R antagonists on PONV were identified by searching EMBASE, CINAHL, PubMed, and the Cochrane Library databases followed by screening. Data extraction was performed using a predefined form and trial quality was assessed using a modified Jadad scale. The primary outcome measure was the incidence of PONV. Meta-analysis was performed for studies using similar interventions. Network meta-analysis (NMA) was conducted to compare the anti-vomiting effects of placebo, ondansetron, and aprepitant at different doses. Fourteen RCTs were included. Meta-analysis found that 80 mg of aprepitant could reduce the incidences of nausea (3 RCTs with 224 patients, pooled risk ratio (RR) = 0.60, 95% confidence interval (CI) = 0.47 to 0.75), and vomiting (3 RCTs with 224 patients, pooled RR = 0.13, 95% CI = 0.04 to 0.37) compared with placebo. Neither 40 mg (3 RCTs with 1171 patients, RR = 0.47, 95% CI = 0.37 to 0.60) nor 125 mg (2 RCTs with 1058 patients, RR = 0.32, 95% CI = 0.13 to 0.78) of aprepitant showed superiority over 4 mg of ondansetron in preventing postoperative vomiting. NMA did not find a dose-dependent effect of aprepitant on preventing postoperative vomiting. Limited data suggested that NK-1R antagonists, especially aprepitant were effective in preventing PONV compared with placebo. More large-sampled high-quality RCTs are needed. PMID:25984662

  15. Calcium antagonists in the prevention of motion sickness.

    PubMed

    Lee, J A; Watson, L A; Boothby, G

    1986-01-01

    Flunarizine is a calcium antagonist which has proved clinically useful in controlling chronic vertigo. In a double blind crossover trial 10 subjects were used to compare the electronystagmic responses to motion in patients taking flunarizine, prochlorperazine maleate, or placebo. Flunarizine is shown to be a powerful peripherally acting labyrinthine suppressant, with application in the prevention of motion sickness. Flunarizine produces none of the central depressive side effects characteristic of antihistamines and anticholinergics, which are the conventional anti-motion sickness drugs. PMID:3510617

  16. Pulmonary vascular reactivity: effect of PAF and PAF antagonists.

    PubMed

    Chen, C R; Voelkel, N F; Chang, S W

    1992-11-01

    We investigated the effects of two different platelet-activating factor (PAF) antagonists, SRI 63-441 and WEB 2086, on PAF-, angiotensin II-, and hypoxia-induced vasoconstrictions in isolated rat lungs perfused with a physiological salt solution. Bolus injection of PAF (0.5 micrograms) increased pulmonary arterial and microvascular pressures and caused lung edema. Both SRI 63-441, a PAF-analogue antagonist, and WEB 2086, a thienotriazolodiazepine structurally unrelated to PAF, completely blocked PAF-induced vasoconstriction and lung edema at 10(-5) M. At a lower concentration (10(-6) M), WEB 2086 was more effective than SRI 63-441. WEB 2086 also blocked the pulmonary vasodilation induced by low-dose PAF (15 ng) in blood-perfused lungs preconstricted with hypoxia. SRI 63-441 and CV 3988 (another PAF analogue antagonist), but not WEB 2086, caused acute pulmonary vasoconstriction at 10(-5) M and severe lung edema at a higher concentration (10(-4) M). PAF-induced but not SRI- or CV-induced pulmonary vasoconstriction and edema were inhibited by WEB 2086. In addition, SRI 63-441 potentiated angiotensin II- and hypoxia-induced vasoconstrictions. This effect of SRI 63-441 is not due to PAF receptor blockade because 1) addition of PAF (1.6 nM) to the perfusate likewise potentiated angiotensin II-induced vasoconstriction and 2) WEB 2086 did not cause a similar response. We conclude that both SRI 63-441 and WEB 2086 are effective inhibitors of PAF actions in the rat pulmonary circulation. However, antagonists with structures analogous to PAF (SRI 63-441 and CV 3988) can have significant pulmonary vasoactive side effects. PMID:1474049

  17. The H2-receptor antagonist era in duodenal ulcer disease.

    PubMed Central

    Marks, I. N.

    1992-01-01

    This paper reviews the remarkable impact of H2-receptor antagonists on duodenal ulcer management. The development and the scientific rationale of these agents are presented, and efficacy and safety aspects in the short- and long-term treatment of duodenal ulcer disease discussed. Attention is focused on the possible role of "acid rebound" in ulcer relapse following the withdrawal of therapy and on the clinical relevance of prolonged suppression of acid secretion in patients on long-term therapy. PMID:1364125

  18. Receptor mechanisms and circuitry underlying NMDA antagonist neurotoxicity.

    PubMed

    Farber, N B; Kim, S H; Dikranian, K; Jiang, X P; Heinkel, C

    2002-01-01

    NMDA glutamate receptor antagonists are used in clinical anesthesia, and are being developed as therapeutic agents for preventing neurodegeneration in stroke, epilepsy, and brain trauma. However, the ability of these agents to produce neurotoxicity in adult rats and psychosis in adult humans compromises their clinical usefulness. In addition, an NMDA receptor hypofunction (NRHypo) state might play a role in neurodegenerative and psychotic disorders, like Alzheimer's disease and schizophrenia. Thus, understanding the mechanism underlying NRHypo-induced neurotoxicity and psychosis could have significant clinically relevant benefits. NRHypo neurotoxicity can be prevented by several classes of agents (e.g. antimuscarinics, non-NMDA glutamate antagonists, and alpha(2) adrenergic agonists) suggesting that the mechanism of neurotoxicity is complex. In the present study a series of experiments was undertaken to more definitively define the receptors and complex neural circuitry underlying NRHypo neurotoxicity. Injection of either the muscarinic antagonist scopolamine or the non-NMDA antagonist NBQX directly into the cortex prevented NRHypo neurotoxicity. Clonidine, an alpha(2) adrenergic agonist, protected against the neurotoxicity when injected into the basal forebrain. The combined injection of muscarinic and non-NMDA Glu agonists reproduced the neurotoxic reaction. Based on these and other results, we conclude that the mechanism is indirect, and involves a complex network disturbance, whereby blockade of NMDA receptors on inhibitory neurons in multiple subcortical brain regions, disinhibits glutamatergic and cholinergic projections to the cerebral cortex. Simultaneous excitotoxic stimulation of muscarinic (m(3)) and glutamate (AMPA/kainate) receptors on cerebrocortical neurons appears to be the proximal mechanism by which the neurotoxic and psychotomimetic effects of NRHypo are mediated. PMID:11803444

  19. Tumor necrosis factor-alpha antagonists and neuropathy.

    PubMed

    Stübgen, Joerg-Patrick

    2008-03-01

    Tumor necrosis factor (TNF)-alpha plays an important role in many aspects of immune system development, immune-response regulation, and T-cell-mediated tissue injury. The evidence that TNF-alpha, released by autoreactive T cells and macrophages, may contribute to the pathogenesis of immune-mediated demyelinating neuropathies is reviewed. TNF-alpha antagonists (infliximab, etanercept, adalimumab) are indicated for the treatment of advanced inflammatory rheumatic and bowel disease, but these drugs can induce a range of autoimmune diseases that also attack the central and peripheral nervous systems. Case histories and series report on the association between anti-TNF-alpha treatment and various disorders of peripheral nerve such as Guillain-Barré syndrome, Miller Fisher syndrome, chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy with conduction block, mononeuropathy multiplex, and axonal sensorimotor polyneuropathies. The proposed pathogeneses of TNF-alpha-associated neuropathies include both a T-cell and humoral immune attack against peripheral nerve myelin, vasculitis-induced nerve ischemia, and inhibition of signaling support for axons. Most neuropathies improve over a period of months by withdrawal of the TNF-alpha antagonist, with or without additional immune-modulating treatment. Preliminary observations suggest that TNF-alpha antagonists may be useful as an antigen-nonspecific treatment approach to immune-mediated neuropathies in patients with a poor response to, or intolerance of, standard therapies, but further studies are required. PMID:18041052

  20. μ Opioid receptor: novel antagonists and structural modeling

    NASA Astrophysics Data System (ADS)

    Kaserer, Teresa; Lantero, Aquilino; Schmidhammer, Helmut; Spetea, Mariana; Schuster, Daniela

    2016-02-01

    The μ opioid receptor (MOR) is a prominent member of the G protein-coupled receptor family and the molecular target of morphine and other opioid drugs. Despite the long tradition of MOR-targeting drugs, still little is known about the ligand-receptor interactions and structure-function relationships underlying the distinct biological effects upon receptor activation or inhibition. With the resolved crystal structure of the β-funaltrexamine-MOR complex, we aimed at the discovery of novel agonists and antagonists using virtual screening tools, i.e. docking, pharmacophore- and shape-based modeling. We suggest important molecular interactions, which active molecules share and distinguish agonists and antagonists. These results allowed for the generation of theoretically validated in silico workflows that were employed for prospective virtual screening. Out of 18 virtual hits evaluated in in vitro pharmacological assays, three displayed antagonist activity and the most active compound significantly inhibited morphine-induced antinociception. The new identified chemotypes hold promise for further development into neurochemical tools for studying the MOR or as potential therapeutic lead candidates.

  1. μ Opioid receptor: novel antagonists and structural modeling

    PubMed Central

    Kaserer, Teresa; Lantero, Aquilino; Schmidhammer, Helmut; Spetea, Mariana; Schuster, Daniela

    2016-01-01

    The μ opioid receptor (MOR) is a prominent member of the G protein-coupled receptor family and the molecular target of morphine and other opioid drugs. Despite the long tradition of MOR-targeting drugs, still little is known about the ligand-receptor interactions and structure-function relationships underlying the distinct biological effects upon receptor activation or inhibition. With the resolved crystal structure of the β-funaltrexamine-MOR complex, we aimed at the discovery of novel agonists and antagonists using virtual screening tools, i.e. docking, pharmacophore- and shape-based modeling. We suggest important molecular interactions, which active molecules share and distinguish agonists and antagonists. These results allowed for the generation of theoretically validated in silico workflows that were employed for prospective virtual screening. Out of 18 virtual hits evaluated in in vitro pharmacological assays, three displayed antagonist activity and the most active compound significantly inhibited morphine-induced antinociception. The new identified chemotypes hold promise for further development into neurochemical tools for studying the MOR or as potential therapeutic lead candidates. PMID:26888328

  2. Biased signaling: potential agonist and antagonist of PAR2.

    PubMed

    Kakarala, Kavita Kumari; Jamil, Kaiser

    2016-06-01

    Protease activated receptor 2 (PAR2) has emerged as one of the promising therapeutic targets to inhibit rapidly metastasizing breast cancer cells. However, its elusive molecular mechanism of activation and signaling has made it a difficult target for drug development. In this study, in silico methods were used to unfold PAR2 molecular mechanism of signaling based on the concept of GPCR receptor plasticity. Although, there are no conclusive evidences of the presence of specific endogenous ligands for PAR2, the efficacy of synthetic agonist and antagonist in PAR2 signaling has opened up the possibilities of ligand-mediated signaling. Furthermore, it has been proved that ligands specific for one GPCR can induce signaling in GPCRs belonging to other subfamilies. Therefore, the aim of this study was to identify potential agonists and antagonists from the GPCR ligand library (GLL), which may induce biased signaling in PAR2 using the concept of existence of multiple ligand-stabilized receptor conformations. The results of our in silico study suggest that PAR2 may show biased signaling mainly with agonists of serotonin type 1, β-adrenergic type 1,3 and antagonists of substance K (NK1), serotonin type 2, dopamine type 4, and thromboxane receptors. Further, this study also throws light on the putative ligand-specific conformations of PAR2. Thus, the results of this study provide structural insights to putative conformations of PAR2 and also gives initial clues to medicinal chemists for rational drug design targeting this challenging receptor. PMID:26295578

  3. Toxicological Differences Between NMDA Receptor Antagonists and Cholinesterase Inhibitors.

    PubMed

    Shi, Xiaodong; Lin, Xiaotian; Hu, Rui; Sun, Nan; Hao, Jingru; Gao, Can

    2016-08-01

    Cholinesterase inhibitors (ChEIs), represented by donepezil, rivastigmine, and galantamine, used to be the only approved class of drugs for the treatment of Alzheimer's disease. After the approval of memantine by the Food and Drug Administration (FDA), N-methyl-d-aspartic acid (NMDA) receptor antagonists have been recognized by authorities and broadly used in the treatment of Alzheimer's disease. Along with complementary mechanisms of action, NMDA antagonists and ChEIs differ not only in therapeutic effects but also in adverse reactions, which is an important consideration in clinical drug use. And the number of patients using NMDA antagonists and ChEIs concomitantly has increased, making the matter more complicated. Here we used the FDA Adverse Event Reporting System for statistical analysis , in order to compare the adverse events of memantine and ChEIs. In general, the clinical evidence confirmed the safety advantages of memantine over ChEIs, reiterating the precautions of clinical drug use and the future direction of antidementia drug development. PMID:26769920

  4. Twisted Gastrulation, a BMP Antagonist, Exacerbates Podocyte Injury

    PubMed Central

    Yamada, Sachiko; Nakamura, Jin; Asada, Misako; Takase, Masayuki; Matsusaka, Taiji; Iguchi, Taku; Yamada, Ryo; Tanaka, Mari; Higashi, Atsuko Y.; Okuda, Tomohiko; Asada, Nariaki; Fukatsu, Atsushi; Kawachi, Hiroshi; Graf, Daniel; Muso, Eri; Kita, Toru; Kimura, Takeshi; Pastan, Ira; Economides, Aris N.; Yanagita, Motoko

    2014-01-01

    Podocyte injury is the first step in the progression of glomerulosclerosis. Previous studies have demonstrated the beneficial effect of bone morphogenetic protein 7 (Bmp7) in podocyte injury and the existence of native Bmp signaling in podocytes. Local activity of Bmp7 is controlled by cell-type specific Bmp antagonists, which inhibit the binding of Bmp7 to its receptors. Here we show that the product of Twisted gastrulation (Twsg1), a Bmp antagonist, is the central negative regulator of Bmp function in podocytes and that Twsg1 null mice are resistant to podocyte injury. Twsg1 was the most abundant Bmp antagonist in murine cultured podocytes. The administration of Bmp induced podocyte differentiation through Smad signaling, whereas the simultaneous administration of Twsg1 antagonized the effect. The administration of Bmp also inhibited podocyte proliferation, whereas simultaneous administration of Twsg1 antagonized the effect. Twsg1 was expressed in the glomerular parietal cells (PECs) and distal nephron of the healthy kidney, and additionally in damaged glomerular cells in a murine model of podocyte injury. Twsg1 null mice exhibited milder hypoalbuminemia and hyperlipidemia, and milder histological changes while maintaining the expression of podocyte markers during podocyte injury model. Taken together, our results show that Twsg1 plays a critical role in the modulation of protective action of Bmp7 on podocytes, and that inhibition of Twsg1 is a promising means of development of novel treatment for podocyte injury. PMID:24586548

  5. Effects of two antagonistic ecosystem engineers on infaunal diversity

    NASA Astrophysics Data System (ADS)

    González-Ortiz, V.; Alcazar, P.; Vergara, J. J.; Pérez-Lloréns, J. L.; Brun, F. G.

    2014-02-01

    The role of ecosystem engineers has been highlighted in recent decades because of their importance for ecosystem functioning, although the interaction between different antagonistic engineer species and their effects on ecosystems have been so far poorly investigated. Coastal areas are good natural laboratories to explore such interactions, since they are often inhabited by macrophyte beds (autogenic engineers) and bioturbator species (allogenic engineers) with antagonistic effects on ecosystem properties and processes (e.g. species diversity, nutrient fluxes, etc.). The main goal of this study was to determine how coexisting antagonistic ecosystem engineers could influence benthic diversity and available resources in soft-bottom areas. To achieve this goal, a two-month experiment was carried out in situ by introducing artificial seagrass patches in a soft-bottom area inhabited by the fiddler crab Uca tangeri. Both the experimental exclusion of burrows as well as the presence of artificial seagrass-like structures (mimics) resulted in higher macrobenthic density and species richness in the benthic community. Resource availability for organisms (sediment chlorophyll a and epiphytes) was also favoured by the presence of mimics. Therefore, the higher structural complexity (above- and below-ground) associated with seagrass mimics promoted positive effects for infauna such as creation of a new habitat ready to colonize, reduction of the crab burrowing activity and the enhancement of resource availability, which resulted in increased diversity in the benthic community.

  6. Drosophila IAP antagonists form multimeric complexes to promote cell death

    PubMed Central

    Sandu, Cristinel; Ryoo, Hyung Don

    2010-01-01

    Apoptosis is a specific form of cell death that is important for normal development and tissue homeostasis. Caspases are critical executioners of apoptosis, and living cells prevent their inappropriate activation through inhibitor of apoptosis proteins (IAPs). In Drosophila, caspase activation depends on the IAP antagonists, Reaper (Rpr), Head involution defective (Hid), and Grim. These proteins share a common motif to bind Drosophila IAP1 (DIAP1) and have partially redundant functions. We now show that IAP antagonists physically interact with each other. Rpr is able to self-associate and also binds to Hid and Grim. We have defined the domain involved in self-association and demonstrate that it is critical for cell-killing activity in vivo. In addition, we show that Rpr requires Hid for recruitment to the mitochondrial membrane and for efficient induction of cell death in vivo. Both targeting of Rpr to mitochondria and forced dimerization strongly promotes apoptosis. Our results reveal the functional importance of a previously unrecognized multimeric IAP antagonist complex for the induction of apoptosis. PMID:20837774

  7. Oral mineralocorticoid antagonists for recalcitrant central serous chorioretinopathy

    PubMed Central

    Chin, Eric K; Almeida, David RP; Roybal, C Nathaniel; Niles, Philip I; Gehrs, Karen M; Sohn, Elliott H; Boldt, H Culver; Russell, Stephen R; Folk, James C

    2015-01-01

    Purpose To evaluate the effect and tolerance of oral mineralocorticoid antagonists, eplerenone and/or spironolactone, in recalcitrant central serous chorioretinopathy. Methods Retrospective consecutive observational case series. Primary outcome measures included central macular thickness (CMT, μm), macular volume (MV, mm3), Snellen visual acuity, and prior treatment failures. Secondary outcomes included duration of treatment, treatment dosage, and systemic side effects. Results A total of 120 patients with central serous chorioretinopathy were reviewed, of which 29 patients were treated with one or more mineralocorticoid antagonists. The average age of patients was 58.4 years. Sixteen patients (69.6%) were recalcitrant to other interventions prior to treatment with oral mineralocorticoid antagonists, with an average washout period of 15.3 months. The average duration of mineralocorticoid antagonist treatment was 3.9±2.3 months. Twelve patients (52.2%) showed decreased CMT and MV, six patients (26.1%) had increase in both, and five patients (21.7%) had negligible changes. The mean decrease in CMT of all patients was 42.4 μm (range, −136 to 255 μm): 100.7 μm among treatment-naïve patients, and 16.9 μm among recalcitrant patients. The mean decrease in MV of all patients was 0.20 mm3 (range, −2.33 to 2.90 mm3): 0.6 mm3 among treatment-naïve patients, and 0.0 mm3 among recalcitrant patients. Median visual acuity at the start of therapy was 20/30 (range, 20/20–20/250), and at final follow-up it was 20/40 (range, 20/20–20/125). Nine patients (39.1%) experienced systemic side effects, of which three patients (13.0%) were unable to continue therapy. Conclusion Mineralocorticoid antagonist treatment had a positive treatment effect in half of our patients. The decrease in CMT and MV was much less in the recalcitrant group compared to the treatment-naïve group. An improvement in vision was seen only in the treatment-naïve group. Systemic side effects, even at

  8. Nicotinic Receptor Antagonists as Treatments for Nicotine Abuse

    PubMed Central

    Crooks, Peter A.; Bardo, Michael T.; Dwoskin, Linda P.

    2014-01-01

    Despite the proven efficacy of current pharmacotherapies for tobacco dependence, relapse rates continue to be high, indicating that novel medications are needed. Currently, several smoking cessation agents are available, including varenicline (Chantix®), bupropion (Zyban®), and cytisine (Tabex®). Varenicline and cytisine are partial agonists at the α4β2* nicotinic acetylcholine receptor (nAChR). Bupropion is an antidepressant but is also an antagonist at α3β2* ganglionic nAChRs. The rewarding effects of nicotine are mediated, in part, by nicotine-evoked dopamine (DA) release leading to sensitization, which is associated with repeated nicotine administration and nicotine addiction. Receptor antagonists that selectivity target central nAChR subtypes mediating nicotine-evoked DA release should have efficacy as tobacco use cessation agents with the therapeutic advantage of a limited side-effect profile. While α-conotoxin MII (α-CtxMII)-insensitive nAChRs (e.g., α4β2*) contribute to nicotine-evoked DA release, these nAChRs are widely distributed in the brain, and inhibition of these receptors may lead to nonselective and untoward effects. In contrast, α-CtxMII-sensitive nAChRs mediating nicotine-evoked DA release offer an advantage as targets for smoking cessation, due to their more restricted localization primarily to dopaminergic neurons. Small drug-like molecules that are selective antagonists at α-CtxMII-sensitive nAChR subtypes that contain α6 and β2 subunits have now been identified. Early research identified a variety of quaternary ammonium analogs that were potent and selective antagonists at nAChRs mediating nicotine-evoked DA release. More recent data have shown that novel, non-quaternary bis-1,2,5,6-tetrahydropyridine analogs potently inhibit (IC50<1 nM) nicotine-evoked DA release in vitro by acting as antagonists at α-CtxMII-sensitive nAChR subtypes; these compounds also decrease NIC self-administration in rats. PMID:24484986

  9. Virtual High-Throughput Screening To Identify Novel Activin Antagonists.

    PubMed

    Zhu, Jie; Mishra, Rama K; Schiltz, Gary E; Makanji, Yogeshwar; Scheidt, Karl A; Mazar, Andrew P; Woodruff, Teresa K

    2015-07-23

    Activin belongs to the TGFβ superfamily, which is associated with several disease conditions, including cancer-related cachexia, preterm labor with delivery, and osteoporosis. Targeting activin and its related signaling pathways holds promise as a therapeutic approach to these diseases. A small-molecule ligand-binding groove was identified in the interface between the two activin βA subunits and was used for a virtual high-throughput in silico screening of the ZINC database to identify hits. Thirty-nine compounds without significant toxicity were tested in two well-established activin assays: FSHβ transcription and HepG2 cell apoptosis. This screening workflow resulted in two lead compounds: NUCC-474 and NUCC-555. These potential activin antagonists were then shown to inhibit activin A-mediated cell proliferation in ex vivo ovary cultures. In vivo testing showed that our most potent compound (NUCC-555) caused a dose-dependent decrease in FSH levels in ovariectomized mice. The Blitz competition binding assay confirmed target binding of NUCC-555 to the activin A:ActRII that disrupts the activin A:ActRII complex's binding with ALK4-ECD-Fc in a dose-dependent manner. The NUCC-555 also specifically binds to activin A compared with other TGFβ superfamily member myostatin (GDF8). These data demonstrate a new in silico-based strategy for identifying small-molecule activin antagonists. Our approach is the first to identify a first-in-class small-molecule antagonist of activin binding to ALK4, which opens a completely new approach to inhibiting the activity of TGFβ receptor superfamily members. in addition, the lead compound can serve as a starting point for lead optimization toward the goal of a compound that may be effective in activin-mediated diseases. PMID:26098096

  10. The pharmacology of fluparoxan: a selective alpha 2-adrenoceptor antagonist.

    PubMed Central

    Halliday, C. A.; Jones, B. J.; Skingle, M.; Walsh, D. M.; Wise, H.; Tyers, M. B.

    1991-01-01

    1. This paper describes the pharmacology of the novel alpha 2-adrenoceptor antagonist fluparoxan (GR 50360) which is currently being studied clinically as a potential anti-depressant. Idazoxan and yohimbine were included in many studies for comparison. 2. In the rat isolated, field-stimulated vas deferens and the guinea-pig isolated, field-stimulated ileum preparations, fluparoxan was a reversible competitive antagonist of the inhibitory responses to the alpha 2-adrenoceptor agonist UK-14304 with pKB values of 7.87 and 7.89 respectively. In the rat isolated anococcygeus muscle, fluparoxan was a much weaker competitive antagonist of the contractile response to the alpha 1-adrenoceptor agonist phenylephrine with a pKB of 4.45 giving an alpha 2: alpha 1-adrenoceptor selectivity ratio of greater than 2500. 3. In the conscious mouse, fluparoxan (0.2-3.0 mg kg-1) was effective by the oral route and of similar potency to idazoxan in preventing clonidine-induced hypothermia and antinociception. In the rat, UK-14304-induced hypothermia (ED50 = 1.4 mg kg-1, p.o. or 0.5 mg kg-1, i.v.) and rotarod impairment (ED50 = 1.1 mg kg-1 p.o. or 1.3 mg kg-1, i.v.) were antagonized by fluparoxan. Fluparoxan, 0.67-6 mg kg-1, p.o., also prevented UK-14304-induced sedation and bradycardia in the dog. 4. In specificity studies fluparoxan had low or no affinity for a wide range of neurotransmitter receptor sites at concentrations up to at least 1 x 10(-5) M. It displayed weak affinity for 5-HT1A (pIC50 = 5.9) and 5-HT1B (pKi = 5.5) binding sites in rat brain.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1677298

  11. Sexually Antagonistic “Zygotic Drive” of the Sex Chromosomes

    PubMed Central

    Rice, William R.; Gavrilets, Sergey; Friberg, Urban

    2008-01-01

    Genomic conflict is perplexing because it causes the fitness of a species to decline rather than improve. Many diverse forms of genomic conflict have been identified, but this extant tally may be incomplete. Here, we show that the unusual characteristics of the sex chromosomes can, in principle, lead to a previously unappreciated form of sexual genomic conflict. The phenomenon occurs because there is selection in the heterogametic sex for sex-linked mutations that harm the sex of offspring that does not carry them, whenever there is competition among siblings. This harmful phenotype can be expressed as an antagonistic green-beard effect that is mediated by epigenetic parental effects, parental investment, and/or interactions among siblings. We call this form of genomic conflict sexually antagonistic “zygotic drive”, because it is functionally equivalent to meiotic drive, except that it operates during the zygotic and postzygotic stages of the life cycle rather than the meiotic and gametic stages. A combination of mathematical modeling and a survey of empirical studies is used to show that sexually antagonistic zygotic drive is feasible, likely to be widespread in nature, and that it can promote a genetic “arms race” between the homo- and heteromorphic sex chromosomes. This new category of genomic conflict has the potential to strongly influence other fundamental evolutionary processes, such as speciation and the degeneration of the Y and W sex chromosomes. It also fosters a new genetic hypothesis for the evolution of enigmatic fitness-reducing traits like the high frequency of spontaneous abortion, sterility, and homosexuality observed in humans. PMID:19096519

  12. Virtual High-Throughput Screening To Identify Novel Activin Antagonists

    PubMed Central

    Zhu, Jie; Mishra, Rama K.; Schiltz, Gary E.; Makanji, Yogeshwar; Scheidt, Karl A.; Mazar, Andrew P.; Woodruff, Teresa K.

    2015-01-01

    Activin belongs to the TGFβ superfamily, which is associated with several disease conditions, including cancer-related cachexia, preterm labor with delivery, and osteoporosis. Targeting activin and its related signaling pathways holds promise as a therapeutic approach to these diseases. A small-molecule ligand-binding groove was identified in the interface between the two activin βA subunits and was used for a virtual high-throughput in silico screening of the ZINC database to identify hits. Thirty-nine compounds without significant toxicity were tested in two well-established activin assays: FSHβ transcription and HepG2 cell apoptosis. This screening workflow resulted in two lead compounds: NUCC-474 and NUCC-555. These potential activin antagonists were then shown to inhibit activin A-mediated cell proliferation in ex vivo ovary cultures. In vivo testing showed that our most potent compound (NUCC-555) caused a dose-dependent decrease in FSH levels in ovariectomized mice. The Blitz competition binding assay confirmed target binding of NUCC-555 to the activin A:ActRII that disrupts the activin A:ActRII complex’s binding with ALK4-ECD-Fc in a dose-dependent manner. The NUCC-555 also specifically binds to activin A compared with other TGFβ superfamily member myostatin (GDF8). These data demonstrate a new in silico-based strategy for identifying small-molecule activin antagonists. Our approach is the first to identify a first-in-class small-molecule antagonist of activin binding to ALK4, which opens a completely new approach to inhibiting the activity of TGFβ receptor superfamily members. in addition, the lead compound can serve as a starting point for lead optimization toward the goal of a compound that may be effective in activin-mediated diseases. PMID:26098096

  13. Central actions of a novel and selective dopamine antagonist

    SciTech Connect

    Schulz, D.W.

    1985-01-01

    Receptors for the neurotransmitter dopamine traditionally have been divided into two subgroups: the D/sub 1/ class, which is linked to the stimulation of adenylate cyclase-activity, and the D/sub 2/ class which is not. There is much evidence suggesting that it is the D/sub 2/ class which is not. There is much evidence suggesting that it is the D/sub 2/ dopamine receptor that mediates the physiological and behavioral actions of dopamine in the intact animal. However, the benzazepine SCH23390 is a dopamine antagonist which has potent behavioral actions while displaying apparent neurochemical selectivity for the D/sub 1/ class of dopamine receptors. The purpose of this dissertation was to (1) confirm and characterize this selectivity, and (2) test certain hypothesis related to possible modes of action of SCH233390. The inhibition of adenylate cyclase by SCH23390 occurred via an action at the dopamine receptor only. A radiolabeled analog of SCH23390 displayed the receptor binding properties of a specific high-affinity ligand, and regional receptor densities were highly correlated with dopamine levels. The subcellular distribution of (/sup 3/H)-SCH23390 binding did not correspond completely with that of dopamine-stimulated adenylate cyclase. The neurochemical potency of SCH23390 as a D/sub 1/ receptor antagonist was preserved following parental administration. A variety of dopamine agonists and antagonists displayed a high correlation between their abilities to compete for (/sup 3/H)-SCH23390 binding in vitro and to act at an adenylate cyclase-linked receptor. Finally, the relative affinities of dopamine and SCH23390 for both D/sub 1/ receptors and (/sup 3/H)-SCH23390 binding sites were comparable. It is concluded that the behavioral effects of SCH23390 are mediated by actions at D/sub 1/ dopamine receptors only, and that the physiological importance of this class of receptors should be reevaluated.

  14. Extra-helical binding site of a glucagon receptor antagonist.

    PubMed

    Jazayeri, Ali; Doré, Andrew S; Lamb, Daniel; Krishnamurthy, Harini; Southall, Stacey M; Baig, Asma H; Bortolato, Andrea; Koglin, Markus; Robertson, Nathan J; Errey, James C; Andrews, Stephen P; Teobald, Iryna; Brown, Alastair J H; Cooke, Robert M; Weir, Malcolm; Marshall, Fiona H

    2016-05-12

    Glucagon is a 29-amino-acid peptide released from the α-cells of the islet of Langerhans, which has a key role in glucose homeostasis. Glucagon action is transduced by the class B G-protein-coupled glucagon receptor (GCGR), which is located on liver, kidney, intestinal smooth muscle, brain, adipose tissue, heart and pancreas cells, and this receptor has been considered an important drug target in the treatment of diabetes. Administration of recently identified small-molecule GCGR antagonists in patients with type 2 diabetes results in a substantial reduction of fasting and postprandial glucose concentrations. Although an X-ray structure of the transmembrane domain of the GCGR has previously been solved, the ligand (NNC0640) was not resolved. Here we report the 2.5 Å structure of human GCGR in complex with the antagonist MK-0893 (ref. 4), which is found to bind to an allosteric site outside the seven transmembrane (7TM) helical bundle in a position between TM6 and TM7 extending into the lipid bilayer. Mutagenesis of key residues identified in the X-ray structure confirms their role in the binding of MK-0893 to the receptor. The unexpected position of the binding site for MK-0893, which is structurally similar to other GCGR antagonists, suggests that glucagon activation of the receptor is prevented by restriction of the outward helical movement of TM6 required for G-protein coupling. Structural knowledge of class B receptors is limited, with only one other ligand-binding site defined--for the corticotropin-releasing hormone receptor 1 (CRF1R)--which was located deep within the 7TM bundle. We describe a completely novel allosteric binding site for class B receptors, providing an opportunity for structure-based drug design for this receptor class and furthering our understanding of the mechanisms of activation of these receptors. PMID:27111510

  15. [Alpha1-adrenoceptor subtypes and alpha1-adrenoceptor antagonists].

    PubMed

    Muramatsu, Ikunobu; Suzuki, Fumiko; Tanaka, Takashi; Yamamoto, Hatsumi; Morishima, Shigeru

    2006-03-01

    Alpha(1)-adrenoceptors are widely distributed in the human body and play important physiologic roles. Three alpha(1)-adrenoceptor subtypes (alpha(1A), alpha(1B) and alpha(1D)) have been cloned and show different pharmacologic profiles. In addition, a putative alpha(1)-adrenoceptor (alpha(1L) subtype) has also been proposed. Recently, three drugs (tamsulosin, naftopidil, and silodosin) have been developed in Japan for the treatment of urinary obstruction in patients with benign prostatic hyperplasia. In this review, we describe recent alpha(1)-adrenoceptor subclassifications and the pharmacologic characteristics (subtype selectivity and clinical relevance) of alpha(1)-adrenoceptor antagonists. PMID:16518082

  16. Chroman and tetrahydroquinoline ureas as potent TRPV1 antagonists.

    PubMed

    Schmidt, Robert G; Bayburt, Erol K; Latshaw, Steven P; Koenig, John R; Daanen, Jerome F; McDonald, Heath A; Bianchi, Bruce R; Zhong, Chengmin; Joshi, Shailen; Honore, Prisca; Marsh, Kennan C; Lee, Chih-Hung; Faltynek, Connie R; Gomtsyan, Arthur

    2011-03-01

    Novel chroman and tetrahydroquinoline ureas were synthesized and evaluated for their activity as TRPV1 antagonists. It was found that aryl substituents on the 7- or 8-position of both bicyclic scaffolds imparted the best in vitro potency at TRPV1. The most potent chroman ureas were assessed in chronic and acute pain models, and compounds with the ability to cross the blood-brain barrier were shown to be highly efficacious. The tetrahydroquinoline ureas were found to be potent CYP3A4 inhibitors, but replacement of bulky substituents at the nitrogen atom of the tetrahydroisoquinoline moiety with small groups such as methyl can minimize the inhibition. PMID:21315587

  17. Antagonistic effect of epiphytic bacteria from marine algae, southeastern India.

    PubMed

    Chellaram, C; Raja, P; John, A Alex; Krithika, S

    2013-05-01

    Aim of this study was to evaluate the antagonistic potential of epibiotic bacteria from seaweeds, Ulva lactuca, Dictyota dichotoma and Padina tetrastromatica against some potent human pathogens. The epibiotic bacteria of Ulva lactuca shows higher level of inhibition properties than the other species. The strain UL1 shows broad spectrum inhibitory activity against 7 pathogens. The inhibitory level of epibiotic bacteria ranged from low to moderate activity. The present investigation suggests that the epibiotic bacteria are good source for the isolation of antibacterial compounds of biomedical importance. The compounds can further be purified and can used to save mankind from dreadful diseases. PMID:24498807

  18. Esthetic Prosthetic Restorations: Reliability and Effects on Antagonist Dentition

    PubMed Central

    Daou, Elie E.

    2015-01-01

    Recent advances in ceramics have greatly improved the functional and esthetic properties of restorative materials. New materials offer an esthetic and functional oral rehabilitation, however their impact on opposing teeth is not welldocumented. Peer-reviewed articles published till December 2014 were identified through Pubmed (Medline and Elsevier). Scientifically, there are several methods of measuring the wear process of natural dentition which enhances the comparison of the complicated results. This paper presents an overview of the newly used prosthetic materials and their implication on antagonist teeth or prostheses, especially emphasizing the behavior of zirconia restorations. PMID:26962376

  19. The Rotavirus Interferon Antagonist NSP1: Many Targets, Many Questions.

    PubMed

    Arnold, Michelle M

    2016-06-01

    Rotavirus is a leading cause of death due to diarrhea among young children across the globe. Despite the limited coding capacity that is characteristic of RNA viruses, rotavirus dedicates substantial resources to avoiding the host innate immune response. Among these strategies is use of the interferon antagonist protein NSP1, which targets cellular proteins required for interferon production to be degraded by the proteasome. Although numerous cellular targets have been described, there remain many questions about the mechanism of NSP1 activity and its role in promoting replication in specific host species. PMID:27009959

  20. Identification of E2F-1/Cyclin A antagonists.

    PubMed

    Sharma, S K; Ramsey, T M; Chen, Y N; Chen, W; Martin, M S; Clune, K; Sabio, M; Bair, K W

    2001-09-17

    A simple method for the synthesis of a rationally designed (S,S)-[Pro-Leu]-spirolactam scaffold is described. This was expanded to a small biased library of compounds mimicking the 'ZRXL' motif in order to identify E2F-1/Cyclin A antagonists. The synthesized compounds were evaluated in an E2F-1/Cyclin A binding assay and moderately active analogues were identified. In addition, the critical roles of Phe, Leu, Lys, and Arg residues of the identified motif were determined. PMID:11549444

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

    PubMed

    Wang, Si; Bovee, Toine F H

    2016-01-01

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

  2. Development of 1,3-diphenyladamantane derivatives as nonsteroidal progesterone receptor antagonists.

    PubMed

    Mori, Shuichi; Takeuchi, Yuki; Tanatani, Aya; Kagechika, Hiroyuki; Fujii, Shinya

    2015-02-15

    Nonsteroidal progesterone receptor (PR) full antagonists are needed as tools for elucidating the physiological functions of PR and as candidates for treatment of various diseases. We designed and synthesized 1,3-diphenyladamantane derivatives, and investigated their PR-antagonistic activity in comparison with our recently developed boron cluster-based PR antagonists. Among the synthesized adamantane derivatives, compound 9a exhibited the most potent PR-antagonistic activity (IC50: 25nM) and showed high binding affinity for the PR ligand-binding domain, comparable with that of the boron cluster-based PR antagonists. These results suggest that disubstituted adamantane, like the boron cluster m-carborane, is a promising hydrophobic pharmacophore for further structural development of nonsteroidal PR antagonists. PMID:25593098

  3. Antagonist of prostaglandin E2 receptor 4 induces metabolic alterations in liver of mice.

    PubMed

    Li, Ning; Zhang, Limin; An, Yanpeng; Zhang, Lulu; Song, Yipeng; Wang, Yulan; Tang, Huiru

    2015-03-01

    Prostaglandin E2 receptor 4 (EP4) is one of the receptors for prostaglandin E2 and plays important roles in various biological functions. EP4 antagonists have been used as anti-inflammatory drugs. To investigate the effects of an EP4 antagonist (L-161982) on the endogenous metabolism in a holistic manner, we employed a mouse model, and obtained metabolic and transcriptomic profiles of multiple biological matrixes, including serum, liver, and urine of mice with and without EP4 antagonist (L-161982) exposure. We found that this EP4 antagonist caused significant changes in fatty acid metabolism, choline metabolism, and nucleotide metabolism. EP4 antagonist exposure also induced oxidative stress to mice. Our research is the first of its kind to report information on the alteration of metabolism associated with an EP4 antagonist. This information could further our understanding of current and new biological functions of EP4. PMID:25669961

  4. Multiple GPCR conformations and signalling pathways: implications for antagonist affinity estimates

    PubMed Central

    Baker, Jillian G.; Hill, Stephen J.

    2007-01-01

    Antagonist affinity measurements have traditionally been considered important in characterizing the cell-surface receptors present in a particular cell or tissue. A central assumption has been that antagonist affinity is constant for a given receptor–antagonist interaction, regardless of the agonist used to stimulate that receptor or the downstream response that is measured. As a consequence, changes in antagonist affinity values have been taken as initial evidence for the presence of novel receptor subtypes. Emerging evidence suggests, however, that receptors can possess multiple binding sites and the same receptor can show different antagonist affinity measurements under distinct experimental conditions. Here, we discuss several mechanisms by which antagonists have different affinities for the same receptor as a consequence of allosterism, coupling to different G proteins, multiple (but non-interacting) receptor sites, and signal-pathway-dependent pharmacology (where the pharmacology observed varies depending on the signalling pathway measured). PMID:17629959

  5. Evolution of coreceptor utilization to escape CCR5 antagonist therapy.

    PubMed

    Zhang, Jie; Gao, Xiang; Martin, John; Rosa, Bruce; Chen, Zheng; Mitreva, Makedonka; Henrich, Timothy; Kuritzkes, Daniel; Ratner, Lee

    2016-07-01

    The HIV-1 envelope interacts with coreceptors CCR5 and CXCR4 in a dynamic, multi-step process, its molecular details not clearly delineated. Use of CCR5 antagonists results in tropism shift and therapeutic failure. Here we describe a novel approach using full-length patient-derived gp160 quasispecies libraries cloned into HIV-1 molecular clones, their separation based on phenotypic tropism in vitro, and deep sequencing of the resultant variants for structure-function analyses. Analysis of functionally validated envelope sequences from patients who failed CCR5 antagonist therapy revealed determinants strongly associated with coreceptor specificity, especially at the gp120-gp41 and gp41-gp41 interaction surfaces that invite future research on the roles of subunit interaction and envelope trimer stability in coreceptor usage. This study identifies important structure-function relationships in HIV-1 envelope, and demonstrates proof of concept for a new integrated analysis method that facilitates laboratory discovery of resistant mutants to aid in development of other therapeutic agents. PMID:27128349

  6. Cytoplasmic Dynein Antagonists with Improved Potency and Isoform Selectivity

    PubMed Central

    2015-01-01

    Cytoplasmic dyneins 1 and 2 are related members of the AAA+ superfamily (ATPases associated with diverse cellular activities) that function as the predominant minus-end-directed microtubule motors in eukaryotic cells. Dynein 1 controls mitotic spindle assembly, organelle movement, axonal transport, and other cytosolic, microtubule-guided processes, whereas dynein 2 mediates retrograde trafficking within motile and primary cilia. Small-molecule inhibitors are important tools for investigating motor protein-dependent mechanisms, and ciliobrevins were recently discovered as the first dynein-specific chemical antagonists. Here, we demonstrate that ciliobrevins directly target the heavy chains of both dynein isoforms and explore the structure–activity landscape of these inhibitors in vitro and in cells. In addition to identifying chemical motifs that are essential for dynein blockade, we have discovered analogs with increased potency and dynein 2 selectivity. These antagonists effectively disrupt Hedgehog signaling, intraflagellar transport, and ciliogenesis, making them useful probes of these and other cytoplasmic dynein 2-dependent cellular processes. PMID:26555042

  7. Intralocus sexual conflict for fitness: sexually antagonistic alleles for testosterone

    PubMed Central

    Mills, Suzanne C.; Koskela, Esa; Mappes, Tapio

    2012-01-01

    Intralocus sexual conflict occurs when a trait encoded by the same genetic locus in the two sexes has different optima in males and females. Such conflict is widespread across taxa, however, the shared phenotypic traits that mediate the conflict are largely unknown. We examined whether the sex hormone, testosterone (T), that controls sexual differentiation, contributes to sexually antagonistic fitness variation in the bank vole, Myodes glareolus. We compared (opposite-sex) sibling reproductive fitness in the bank vole after creating divergent selection lines for T. This study shows that selection for T was differentially associated with son versus daughter reproductive success, causing a negative correlation in fitness between full siblings. Our results demonstrate the presence of intralocus sexual conflict for fitness in this small mammal and that sexually antagonistic selection is acting on T. We also found a negative correlation in fitness between parents and their opposite-sex progeny (e.g. father–daughter), highlighting a dilemma for females, as the indirect genetic benefits of selecting reproductively successful males (high T) are lost with daughters. We discuss mechanisms that may mitigate this disparity between progeny quality. PMID:22171083

  8. Human homosexuality: a paradigmatic arena for sexually antagonistic selection?

    PubMed

    Camperio Ciani, Andrea; Battaglia, Umberto; Zanzotto, Giovanni

    2015-04-01

    Sexual conflict likely plays a crucial role in the origin and maintenance of homosexuality in our species. Although environmental factors are known to affect human homosexual (HS) preference, sibling concordances and population patterns related to HS indicate that genetic components are also influencing this trait in humans. We argue that multilocus, partially X-linked genetic factors undergoing sexually antagonistic selection that promote maternal female fecundity at the cost of occasional male offspring homosexuality are the best candidates capable of explaining the frequency, familial clustering, and pedigree asymmetries observed in HS male proband families. This establishes male HS as a paradigmatic example of sexual conflict in human biology. HS in females, on the other hand, is currently a more elusive phenomenon from both the empirical and theoretical standpoints because of its fluidity and marked environmental influence. Genetic and epigenetic mechanisms, the latter involving sexually antagonistic components, have been hypothesized for the propagation and maintenance of female HS in the population. However, further data are needed to truly clarify the evolutionary dynamics of this trait. PMID:25635045

  9. 3D pharmacophore models for thromboxane A(2) receptor antagonists.

    PubMed

    Wei, Jing; Liu, Yixi; Wang, Songqing

    2009-10-01

    Thromboxane A(2) (TXA(2)) is an endogenous arachidonic acid derivative closely correlated to thrombosis and other cardiovascular diseases. The action of TXA(2) can be effectively inhibited with TXA(2) receptor antagonists (TXRAs). Previous studies have attempted to describe the interactions between the TXA(2) receptor and its ligands, but their conclusions are still controversial. In this study, ligand-based computational drug design is used as a new and effective way to investigate the structure-activity relationship of TXRAs. Three-dimensional pharmacophore models of TXRAs were built with HypoGenRefine and HipHop modules in CATALYST software. The optimal HypoGenRefine model was developed on the basis of 25 TXRAs. It consists of two hydrophobic groups, one aromatic ring, one hydrogen-bond acceptor and four excluded volumes. The optimal HipHop model contains two hydrophobic groups and two hydrogen-bond acceptors. These models describe the key structure-activity relationship of TXRAs, can predict their activities, and can thus be used to design novel antagonists. PMID:19263096

  10. CCR9 Antagonists in the Treatment of Ulcerative Colitis

    PubMed Central

    Bekker, Pirow; Ebsworth, Karen; Walters, Matthew J.; Berahovich, Robert D.; Ertl, Linda S.; Charvat, Trevor T.; Punna, Sreenivas; Powers, Jay P.; Campbell, James J.; Sullivan, Timothy J.; Jaen, Juan C.; Schall, Thomas J.

    2015-01-01

    While it has long been established that the chemokine receptor CCR9 and its ligand CCL25 are essential for the movement of leukocytes into the small intestine and the development of small-intestinal inflammation, the role of this chemokine-receptor pair in colonic inflammation is not clear. Toward this end, we compared colonic CCL25 protein levels in healthy individuals to those in patients with ulcerative colitis. In addition, we determined the effect of CCR9 pharmacological inhibition in the mdr1a−/− mouse model of ulcerative colitis. Colon samples from patients with ulcerative colitis had significantly higher levels of CCL25 protein compared to healthy controls, a finding mirrored in the mdr1a−/− mice. In the mdr1a−/− mice, CCR9 antagonists significantly decreased the extent of wasting and colonic remodeling and reduced the levels of inflammatory cytokines in the colon. These findings indicate that the CCR9:CCL25 pair plays a causative role in ulcerative colitis and suggest that CCR9 antagonists will provide a therapeutic benefit in patients with colonic inflammation. PMID:26457007

  11. An Ultrahigh Affinity D-Peptide Antagonist Of MDM2

    PubMed Central

    Zhan, Changyou; Zhao, Le; Wei, Xiaoli; Wu, Xueji; Chen, Xishan; Yuan, Weirong; Lu, Wei-Yue; Pazgier, Marzena; Lu, Wuyuan

    2012-01-01

    The oncoprotein MDM2 negatively regulates the activity and stability of the p53 tumor suppressor, and is an important molecular target for anticancer therapy. Aided by mirror image phage display and native chemical ligation, we have previously discovered several proteolysis-resistant duodecimal D-peptide antagonists of MDM2, termed DPMI-α, β, γ. The prototypic D-peptide inhibitor DPMI-α binds (25-109)MDM2 at an affinity of 220 nM, and kills tumor cells in vitro and inhibits tumor growth in vivo by reactivating the p53 pathway. Herein, we report the design of a super-active D-peptide antagonist of MDM2, termed DPMI-δ, of which the binding affinity for (25-109)MDM2 has been improved over DPMI-α by three orders of magnitude (Kd = 220 pM). X-ray crystallographic studies validate DPMI-δ as an exceedingly potent inhibitor of the p53-MDM2 interaction, promising to be a highly attractive lead drug candidate for anticancer therapeutic development. PMID:22694121

  12. ErbB antagonists patenting: "playing chess with cancer".

    PubMed

    Aifa, Sami; Rebai, Ahmed

    2008-01-01

    ErbBs signalling is always associated with the development of the majority of solid cancers via both the MAPK pathway leading to cell cycle progression and the PI3K pathway causing cell survival. As a consequence, many ErbB antagonists have been developed and patented for cancer treatment purposes. These antagonists belong to two drug classes: monoclonal antibodies (mAbs) and small molecules competing with ATP and inhibiting the tyrosine kinase domain (TKIs). Three patented mAbs are currently approved in clinical cancer treatment: Trastuzumab (Herceptin) directed against HER2 and used to treat breast cancer, Cetuximab and Panitumumab which are anti-EGFR antibodies approved for colorectal cancer treatment. Unfortunately, these mAbs are facing cancer resistance mediated by paracrine activation of other ErbB members or compensatory ErbB signalling factors. In parallel, three TKIs have been approved to treat cancer: Gefitinib (Iressa), Erlotinib (Tarceva) inhibiting specifically EGFR and approved to treat non small cell lung cancer and Lapatinib (Tykerb) which has the dual specificity EGFR/HER2 and recently approved to treat metastatic breast cancer. These TKIs are also facing resistance mutations within the TK domain which increase its affinity to ATP. Resistance problems are leading to the adoption of a new strategy based on the combination of different therapies and this is likely to be the most promising future of cancer treatments. PMID:19075865

  13. Novel potent selective phenylglycine antagonists of metabotropic glutamate receptors.

    PubMed

    Bedingfield, J S; Jane, D E; Kemp, M C; Toms, N J; Roberts, P J

    1996-08-01

    The metabotropic glutamate (mGlu) receptor antagonist properties of novel phenylglycine analogues were investigated in adult rat cortical slices (mGlu receptors negatively coupled to adenylyl cyclase), neonatal rat cortical slices and in cultured rat cerebellar granule cells (mGlu receptors coupled to phosphoinositide hydrolysis). (RS)-alpha-methyl-4-phosphonophenylglycine (MPPG), (RS)-alpha-methyl-4-sulphonophenylglycine (MSPG), (RS)-alpha-methyl-4-tetrazolylphenylglycine (MTPG), (RS)-alpha-methyl-3-carboxymethyl-4-hydroxyphenylglycine (M3CM4HPG) and (RS)-alpha-methyl-4-hydroxy-3-phosphonomethylphenylglycine (M4H3PMPG) were demonstrated to have potent and selective effects against 10 microM L-2-amino-4-phosphonobutyrate (L-AP4)- and 0.3 microM (2S,1'S,2'S)-2-(2-carboxycyclopropyl)glycine (L-CCG-1)-mediated inhibition of forskolin-stimulated cAMP accumulation in the adult rat cortex. In contrast, these compounds demonstrated either weak or no antagonism at mGlu receptors coupled to phosphoinositide hydrolysis in either neonatal rat cortex or in cultured cerebellar granule cells. These compounds thus appear to be useful discriminatory pharmacological tools for mGlu receptors and form the basis for the further development of novel antagonists. PMID:8864696

  14. Contrasting effects of intralocus sexual conflict on sexually antagonistic coevolution.

    PubMed

    Pennell, Tanya M; de Haas, Freek J H; Morrow, Edward H; van Doorn, G Sander

    2016-02-23

    Evolutionary conflict between the sexes can induce arms races in which males evolve traits that are detrimental to the fitness of their female partners, and vice versa. This interlocus sexual conflict (IRSC) has been proposed as a cause of perpetual intersexual antagonistic coevolution with wide-ranging evolutionary consequences. However, theory suggests that the scope for perpetual coevolution is limited, if traits involved in IRSC are subject to pleiotropic constraints. Here, we consider a biologically plausible form of pleiotropy that has hitherto been ignored in treatments of IRSC and arrive at drastically different conclusions. Our analysis is based on a quantitative genetic model of sexual conflict, in which genes controlling IRSC traits have side effects in the other sex, due to incompletely sex-limited gene expression. As a result, the genes are exposed to intralocus sexual conflict (IASC), a tug-of-war between opposing male- and female-specific selection pressures. We find that the interaction between the two forms of sexual conflict has contrasting effects on antagonistic coevolution: Pleiotropic constraints stabilize the dynamics of arms races if the mating traits are close to evolutionary equilibrium but can prevent populations from ever reaching such a state. Instead, the sexes are drawn into a continuous cycle of arms races, causing the buildup of IASC, alternated by phases of IASC resolution that trigger the next arms race. These results encourage an integrative perspective on the biology of sexual conflict and generally caution against relying exclusively on equilibrium stability analysis. PMID:26755609

  15. Scaffold Optimisation of Tetravalent Antagonists of the Mannose Binding Lectin.

    PubMed

    Goti, Giulio; Palmioli, Alessandro; Stravalaci, Matteo; Sattin, Sara; De Simoni, Maria-Grazia; Gobbi, Marco; Bernardi, Anna

    2016-03-01

    Antagonists of mannose binding lectin (MBL) have shown a protective role against brain reperfusion damage after acute ischemic stroke. Here we describe the design and streamlined synthesis of glycomimetic MBL antagonists based on a new tetravalent dendron scaffold. The dendron was developed by optimisation of a known polyester structure previously demonstrated to be very efficient for ligand presentation to MBL. Replacement of a labile succinyl ester bond with a more robust amide functionality, use of a longer and more hydrophilic linker, fast modular synthesis and orthogonal functionalisation at the focal point are the main features of the new scaffold. The glycoconjugate constructs become stable to silica gel chromatography and to water solutions at physiological pH, while preserving water solubility and activity in an SPR assay against the murine MBL-C isoform. Higher-order constructs were easily assembled, as demonstrated by the synthesis of a 16-valent dendrimer, which leads to two orders of magnitude increase in activity over the tetravalent version against MBL-C. PMID:26696414

  16. Discovery of tetrahydroisoquinoline-based CXCR4 antagonists.

    PubMed

    Truax, Valarie M; Zhao, Huanyu; Katzman, Brooke M; Prosser, Anthony R; Alcaraz, Ana A; Saindane, Manohar T; Howard, Randy B; Culver, Deborah; Arrendale, Richard F; Gruddanti, Prahbakar R; Evers, Taylor J; Natchus, Michael G; Snyder, James P; Liotta, Dennis C; Wilson, Lawrence J

    2013-11-14

    A de novo hit-to-lead effort involving the redesign of benzimidazole-containing antagonists of the CXCR4 receptor resulted in the discovery of a novel series of 1,2,3,4-tetrahydroisoquinoline (TIQ) analogues. In general, this series of compounds show good potencies (3-650 nM) in assays involving CXCR4 function, including both inhibition of attachment of X4 HIV-1IIIB virus in MAGI-CCR5/CXCR4 cells and inhibition of calcium release in Chem-1 cells. Series profiling permitted the identification of TIQ-(R)-stereoisomer 15 as a potent and selective CXCR4 antagonist lead candidate with a promising in vitro profile. The drug-like properties of 15 were determined in ADME in vitro studies, revealing low metabolic liability potential. Further in vivo evaluations included pharmacokinetic experiments in rats and mice, where 15 was shown to have oral bioavailability (F = 63%) and resulted in the mobilization of white blood cells (WBCs) in a dose-dependent manner. PMID:24936240

  17. A prototypical Sigma-1 receptor antagonist protects against brain ischemia

    PubMed Central

    Schetz, John A.; Perez, Evelyn; Liu, Ran; Chen, Shiuhwei; Lee, Ivan; Simpkins, James W.

    2016-01-01

    Previous studies indicate that the Sigma-1 ligand 4-phenyl-1-(4-phenylbutyl) piperidine (PPBP) protects the brain from ischemia. Less clear is whether protection is mediated by agonism or antagonism of the Sigma-1 receptor, and whether drugs already in use for other indications and that interact with the Sigma-1 receptor might also prevent oxidative damage due to conditions such as cerebral ischemic stroke. The antipsychotic drug haloperidol is an antagonist of Sigma-1 receptors and in this study it potently protects against oxidative stress-related cell death in vitro at low concentrations. The protective potency of haloperidol and a number of other butyrophenone compounds positively correlate with their affinity for a cloned Sigma-1 receptor, and the protection is mimicked by a Sigma-1 receptor-selective antagonist (BD1063), but not an agonist (PRE-084). In vivo, an acute low dose (0.05 mg/kg s.c.) of haloperidol reduces by half the ischemic lesion volume induced by a transient middle cerebral artery occlusion. These in vitro and in vivo pre-clinical results suggest that a low dose of acutely administered haloperidol might have a novel application as a protective agent against ischemic cerebral stroke and other types of brain injury with an ischemic component. PMID:17919467

  18. Percolation on networks with antagonistic and dependent interactions

    NASA Astrophysics Data System (ADS)

    Kotnis, Bhushan; Kuri, Joy

    2015-03-01

    Drawing inspiration from real world interacting systems, we study a system consisting of two networks that exhibit antagonistic and dependent interactions. By antagonistic and dependent interactions we mean that a proportion of functional nodes in a network cause failure of nodes in the other, while failure of nodes in the other results in failure of links in the first. In contrast to interdependent networks, which can exhibit first-order phase transitions, we find that the phase transitions in such networks are continuous. Our analysis shows that, compared to an isolated network, the system is more robust against random attacks. Surprisingly, we observe a region in the parameter space where the giant connected components of both networks start oscillating. Furthermore, we find that for Erdős-Rényi and scale-free networks the system oscillates only when the dependence and antagonism between the two networks are very high. We believe that this study can further our understanding of real world interacting systems.

  19. Contrasting effects of intralocus sexual conflict on sexually antagonistic coevolution

    PubMed Central

    Pennell, Tanya M.; de Haas, Freek J. H.; Morrow, Edward H.; van Doorn, G. Sander

    2016-01-01

    Evolutionary conflict between the sexes can induce arms races in which males evolve traits that are detrimental to the fitness of their female partners, and vice versa. This interlocus sexual conflict (IRSC) has been proposed as a cause of perpetual intersexual antagonistic coevolution with wide-ranging evolutionary consequences. However, theory suggests that the scope for perpetual coevolution is limited, if traits involved in IRSC are subject to pleiotropic constraints. Here, we consider a biologically plausible form of pleiotropy that has hitherto been ignored in treatments of IRSC and arrive at drastically different conclusions. Our analysis is based on a quantitative genetic model of sexual conflict, in which genes controlling IRSC traits have side effects in the other sex, due to incompletely sex-limited gene expression. As a result, the genes are exposed to intralocus sexual conflict (IASC), a tug-of-war between opposing male- and female-specific selection pressures. We find that the interaction between the two forms of sexual conflict has contrasting effects on antagonistic coevolution: Pleiotropic constraints stabilize the dynamics of arms races if the mating traits are close to evolutionary equilibrium but can prevent populations from ever reaching such a state. Instead, the sexes are drawn into a continuous cycle of arms races, causing the buildup of IASC, alternated by phases of IASC resolution that trigger the next arms race. These results encourage an integrative perspective on the biology of sexual conflict and generally caution against relying exclusively on equilibrium stability analysis. PMID:26755609

  20. Evolution of coreceptor utilization to escape CCR5 antagonist therapy

    PubMed Central

    Zhang, Jie; Gao, Xiang; Martin, John; Rosa, Bruce; Chen, Zheng; Mitreva, Makedonka; Henrich, Timothy; Kuritzkes, Daniel; Ratner, Lee

    2016-01-01

    The HIV-1 envelope interacts with coreceptors CCR5 and CXCR4 in a dynamic, multi-step process, its molecular details not clearly delineated. Use of CCR5 antagonists results in tropism shift and therapeutic failure. Here we describe a novel approach using full-length patient-derived gp160 quasispecies libraries cloned into HIV-1 molecular clones, their separation based on phenotypic tropism in vitro, and deep sequencing of the resultant variants for structure-function analyses. Analysis of functionally validated envelope sequences from patients who failed CCR5 antagonist therapy revealed determinants strongly associated with coreceptor specificity, especially at the gp120-gp41 and gp41-gp41 interaction surfaces that invite future research on the roles of subunit interaction and envelope trimer stability in coreceptor usage. This study identifies important structure-function relationships in HIV-1 envelope, and demonstrates proof of concept for a new integrated analysis method that facilitates laboratory discovery of resistant mutants to aid in development of other therapeutic agents. PMID:27128349

  1. Inhibition of ionotropic neurotransmitter receptors by antagonists: strategy to estimate the association and the dissociation rate constant of antagonists with very strong affinity to the receptors.

    PubMed

    Aoshima, H; Inoue, Y; Hori, K

    1992-10-01

    Since binding of an agonist to an ionotropic neurotransmitter receptor causes not only channel opening, but also desensitization of the receptor, inhibition of the receptor by the antagonist sometimes becomes very complicated. The transient state kinetics of ligand association and dissociation, and desensitization of the receptor were considered on the basis of the minimal model proposed by Hess' group, and the following possibilities were proposed. 1) When an agonist is simultaneously applied to the receptor with an antagonist whose affinity to the receptor is extremely strong and different from that of the agonist, it is usually impossible to estimate the real inhibition constant exactly from the responses because desensitization of the receptor proceeds before the equilibrium of the ligand binding. Simultaneous addition of the antagonist with strong affinity to the receptor may apparently accelerate inactivation (desensitization) of the receptor. The association rate constant of the antagonist can be estimated by analyses of the rate of the inactivation in the presence and the absence of the antagonist. 2) A preincubated antagonist with a slow dissociation rate constant, i.e., a very effective inhibitor, may cause apparent noncompetitive inhibition of the receptor, since the receptor is desensitized by an agonist as soon as the antagonist dissociates from the receptor and the dissociation of the antagonist from the receptor becomes the rate-determining step. A nicotinic acetylcholine receptor (nAChR) was expressed in Xenopus oocytes by injecting mRNA prepared from Electrophorus electricus electroplax and used for the experiments on inhibition by an antagonist.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1337082

  2. Dioxin-like activity in sediments from Tai Lake, China determined by use of the H4IIE-luc bioassay and quantification of individual AhR agonists.

    PubMed

    Xia, Jie; Su, Guanyong; Zhang, Xiaowei; Shi, Wei; Giesy, John P; Yu, Hongxia

    2014-01-01

    Deterioration of the general ecosystem and specifically quality of the water in Tai Lake (Ch: Taihu), the third largest freshwater in China, is of great concern. However, knowledge on status and trends of dioxin-like compounds in Tai Lake was limited. This study investigated AhR-mediated potency and quantified potential aryl hydrocarbon receptor (AhR) agonists in sediments from four regions (Meiliang Bay, Zhushan Lake, Lake Center, Corner of Zhushan Lake, and Meiliang Bay) of Tai Lake by use of the in vitro H4IIE-luc, cell-based, transactivation, reporter gene assay, and instrumental analysis. Concentrations of 2,3,7,8-tetrachlorodibenzo-p-dioxin equivalents (Bio-TEQs) in sediments ranged from less than the limit of detection to 114.5 pg/g, dry weight, which indicated that organic extracts of sediments exhibited significant AhR-mediated potencies. Results of the potency balance analysis demonstrated that acid-labile, dioxin-like compounds represented a greater proportion of concentrations of Bio-TEQs in sediments from Tai Lake. Concentrations of 2,3,7,8-tetrachlorodibenzo-p-dioxin equivalents calculated as the sum of the product of concentrations of individual congeners and their respective relative potencies (Chem-TEQs) based on polycyclic aromatic hydrocarbons and/or polychlorinated biphenyls represented no more than 10% of the total concentrations of Bio-TEQs. PMID:23925657

  3. Angiotensin antagonists with increased specificity for the renal vasculature.

    PubMed Central

    Taub, K J; Caldicott, W J; Hollenberg, N K

    1977-01-01

    This study was designed to ascertain whether renal vascular angiotensin receptors differ from other systemic angiotensin receptors and whether, on that basis, antagonists with greater specificity for the renal vasculature can be defined. Femoral and renal blood flow and their responses to angiotensin II (AII) and its heptapeptide analogue, 1-des Asp AII (AIII), were measured with an electromagnetic flowmeter in 26 dogs. For the kidney, the threshold doses of AII and AIII were identical (2.5+/-0.27 vs. 2.3+/-0.35 pmol/100 ml renal blood flow, with similar dose-response curves. In contrast, AII had a greater pressor effect (P less than 0.001) and produced more femoral vasoconstriction (P less than 0.001) than AIII. All four antagonists studied (1-Sar, 8-Ala AII [P113]; 8-Ala AII; 1-des Asp, 8-Ala AII; 1-des Asp, 8-Ile AII) induced parallel shifts in the renal blood flow response to AII and AIII. P113 induced greater blockade than 8-Ala AII (P less than 0.001) which, in turn, was more effective than 1-des Asp, 8-Ala AII (P less than 0.001). 1-des Asp, 8-Ile AII was as effective as P113. Each analogue induced an identical inhibition of the renal vascular response to AII and AIII. In addition, AII and AIII induced cross-tachyphylaxis. All lines of evidence suggested that AII and AIII act on a single receptor in the kidney, which differs at least functionally from other systemic vascular receptors. The possibility that heptapeptide analogues represent angiotensin antagonists with greater specificity for the renal vasculature was pursued in a model in which the renin-angiotensin system is activated. Acute, partial thoracic inferior vena caval occlusion was induced in an additional 16 dogs. P113 induced progressive, dose-related hypotension and a limited increase in renal blood flow in this model. The 1-des Asp, 8-Ile AII analogue, conversely, induced a consistent, larger, dose-related renal blood flow increase, with significantly less hypotension over a wide dose range

  4. Functionalized Congeners of P2Y1 Receptor Antagonists:

    SciTech Connect

    de Castro, Sonia; Maruoka, Hiroshi; Hong, Kunlun; Kilbey, II, S Michael; Costanzi, Stefano; Hechler, Béatrice; Gachet, Christian; Harden, T. Kendall; Jacobson, Kenneth A.

    2010-01-01

    The P2Y{sub 1} receptor is a prothrombotic G protein-coupled receptor (GPCR) activated by ADP. Preference for the North (N) ring conformation of the ribose moiety of adenine nucleotide 3',5'-bisphosphate antagonists of the P2Y{sub 1} receptor was established by using a ring-constrained methanocarba (a bicyclo[3.1.0]hexane) ring as a ribose substitute. A series of covalently linkable N{sup 6}-methyl-(N)-methanocarba-2'-deoxyadenosine-3',5'-bisphosphates containing extended 2-alkynyl chains was designed, and binding affinity at the human (h) P2Y{sub 1} receptor determined. The chain of these functionalized congeners contained hydrophilic moieties, a reactive substituent, or biotin, linked via an amide. Variation of the chain length and position of an intermediate amide group revealed high affinity of carboxylic congener 8 (K{sub i} 23 nM) and extended amine congener 15 (K{sub i} 132 nM), both having a 2-(1-pentynoyl) group. A biotin conjugate 18 containing an extended {epsilon}-aminocaproyl spacer chain exhibited higher affinity than a shorter biotinylated analogue. Alternatively, click coupling of terminal alkynes of homologous 2-dialkynyl nucleotide derivatives to alkyl azido groups produced triazole derivatives that bound to the P2Y{sub 1} receptor following deprotection of the bisphosphate groups. The preservation of receptor affinity of the functionalized congeners was consistent with new P2Y{sub 1} receptor modeling and ligand docking. Attempted P2Y{sub 1} antagonist conjugation to PAMAM dendrimer carriers by amide formation or palladium-catalyzed reaction between an alkyne on the dendrimer and a 2-iodopurine-derivatized nucleotide was unsuccessful. A dialkynyl intermediate containing the chain length favored in receptor binding was conjugated to an azide-derivatized dendrimer, and the conjugate inhibited ADP-promoted human platelet aggregation. This is the first example of attaching a strategically functionalized P2Y receptor antagonist to a PAMAM dendrimer to

  5. Substituted tetrahydroisoquinolines as selective antagonists for the orexin 1 receptor.

    PubMed

    Perrey, David A; German, Nadezhda A; Gilmour, Brian P; Li, Jun-Xu; Harris, Danni L; Thomas, Brian F; Zhang, Yanan

    2013-09-12

    Increasing evidence implicates the orexin 1 (OX1) receptor in reward processes, suggesting OX1 antagonism could be therapeutic in drug addiction. In a program to develop an OX1 selective antagonist, we designed and synthesized a series of substituted tetrahydroisoquinolines and determined their potency in OX1 and OX2 calcium mobilization assays. Structure-activity relationship (SAR) studies revealed limited steric tolerance and a preference for electron deficiency at the 7-position. Pyridylmethyl groups were shown to be optimal for activity at the acetamide position. Computational studies resulted in a pharmacophore model and confirmed the SAR results. Compound 72 significantly attenuated the development of place preference for cocaine in rats. PMID:23941044

  6. Development of second generation EP2 antagonists with high selectivity

    PubMed Central

    Ganesh, Thota; Jiang, Jianxiong; Dingledine, Ray

    2014-01-01

    EP2 receptor has emerged as an important biological target for therapeutic intervention. In particular, it has been shown to exacerbate disease progression of a variety of CNS and peripheral diseases. Deletion of the EP2 receptor in mouse models recapitulates several features of the COX-2 inhibition, thus presenting a new avenue for anti-inflammatory therapy which could bypass some of the adverse side effects observed by the COX-2 inhibition therapy. We have recently reported a cinnamic amide class of EP2 antagonists with high potency, but these compounds exhibited a moderate selectivity against prostanoid receptor DP1. Moreover they possess acrylamide moiety in the structure, which may result in liver toxicity over longer period of use in a chronic disease model. Thus, we now developed a second generation compounds that devoid of the acrylamide functionality and possess high potency and improved (>1000-fold) selectivity to EP2 over other prostanoid receptors. PMID:24937185

  7. Identification of Bexarotene as a PPARγ Antagonist with HDX

    PubMed Central

    Marciano, David P.; Kuruvilla, Dana S.; Pascal, Bruce D.; Griffin, Patrick R.

    2015-01-01

    The retinoid x receptors (RXRs) are the pharmacological target of Bexarotene, an antineoplastic agent indicated for the treatment of cutaneous T cell lymphoma (CTCL). The RXRs form heterodimers with several nuclear receptors (NRs), including peroxisome proliferator-activated receptor gamma (PPARγ), to regulate target gene expression through cooperative recruitment of transcriptional machinery. Here we have applied hydrogen/deuterium exchange (HDX) mass spectrometry to characterize the effects of Bexarotene on the conformational plasticity of the intact RXRα:PPARγ heterodimer. Interestingly, addition of Bexarotene to PPARγ in the absence of RXRα induced protection from solvent exchange, suggesting direct receptor binding. This observation was confirmed using a competitive binding assay. Furthermore, Bexarotene functioned as a PPARγ antagonist able to alter rosiglitazone induced transactivation in a cell based promoter:reporter transactivation assay. Together these results highlight the complex polypharmacology of lipophilic NR targeted small molecules and the utility of HDX for identifying and characterizing these interactions. PMID:26451138

  8. Crystal Structure of Antagonist Bound Human Lysophosphatidic Acid Receptor 1

    PubMed Central

    Chrencik, Jill E.; Roth, Christopher B.; Terakado, Masahiko; Kurata, Haruto; Omi, Rie; Kihara, Yasuyuki; Warshaviak, Dora; Nakade, Shinji; Asmar-Rovira, Guillermo; Mileni, Mauro; Mizuno, Hirotaka; Griffith, Mark T.; Rodgers, Caroline; Han, Gye Won; Velasquez, Jeffrey; Chun, Jerold; Stevens, Raymond C.

    2015-01-01

    Summary Lipid biology continues to emerge as an area of significant therapeutic interest, particularly as the result of an enhanced understanding of the wealth of signaling molecules with diverse physiological properties. This growth in knowledge is epitomized by lysophosphatidic acid (LPA), which functions through interactions with six cognate G protein-coupled receptors. Herein we present three crystal structures of LPA1 in complex with antagonist tool compounds selected and designed through structural and stability analysis. Structural analysis combined with molecular dynamics identified a basis for ligand access to the LPA1 binding pocket from the extracellular space contrasting with the proposed access for the sphingosine 1-phosphate receptor. Characteristics of the LPA1 binding pocket raise the possibility of promiscuous ligand recognition of phosphorylated endocannabinoids. Cell-based assays confirmed this hypothesis, linking the distinct receptor systems through metabolically related ligands with potential functional and therapeutic implications for treatment of disease. PMID:26091040

  9. Vasopressin receptor antagonists, heart failure, and polycystic kidney disease.

    PubMed

    Torres, Vicente E

    2015-01-01

    The synthesis of nonpeptide orally bioavailable vasopressin antagonists devoid of agonistic activity (vaptans) has made possible the selective blockade of vasopressin receptor subtypes for therapeutic purposes. Vaptans acting on the vasopressin V2 receptors (aquaretics) have attracted attention as a possible therapy for heart failure and polycystic kidney disease. Despite a solid rationale and encouraging preclinical testing, aquaretics have not improved clinical outcomes in randomized clinical trials for heart failure. Additional clinical trials with select population targets, more flexible dosing schedules, and possibly a different drug type or combination (balanced V1a/V2 receptor antagonism) may be warranted. Aquaretics are promising for the treatment of autosomal dominant polycystic kidney disease and have been approved in Japan for this indication. More studies are needed to better define their long-term safety and efficacy and optimize their utilization. PMID:25493947

  10. Competitive binding of antagonistic peptides fine-tunes stomatal patterning

    PubMed Central

    Lee, Jin Suk; Hnilova, Marketa; Maes, Michal; Lin, Ya-Chen Lisa; Putarjunan, Aarthi; Han, Soon-Ki; Avila, Julian; U.Torii, Keiko

    2015-01-01

    During development, cells interpret complex, often conflicting signals to make optimal decisions. Plant stomata, the cellular interface between a plant and the atmosphere, develop according to positional cues including a family of secreted peptides, EPIDERMAL PATTERNING FACTORS (EPFs). How these signaling peptides orchestrate pattern formation at a molecular level remains unclear. Here we report that Stomagen/EPF-LIKE9 peptide, which promotes stomatal development, requires ERECTA (ER)-family receptor kinases and interferes with the inhibition of stomatal development by the EPF2-ER module. Both EPF2 and Stomagen directly bind to ER and its co-receptor TOO MANY MOUTHS. Stomagen peptide competitively replaced EPF2 binding to ER. Furthermore, application of EPF2, but not Stomagen, elicited rapid phosphorylation of downstream signaling components in vivo. Our findings demonstrate how a plant receptor agonist and antagonist define inhibitory and inductive cues to fine-tune tissue patterning on the plant epidermis. PMID:26083750

  11. Biological control of soybean damping-off by antagonistic rhizobacteria.

    PubMed

    Sharifi Tehrani, A; Zebarjad, A; Hedjaroud, Gh A; Mohammadi, M

    2002-01-01

    Experiments were carried out with 133 bacterial isolates that were collected from soybean rhizosphere. These strains were used to investigate their biocontrol traits in vitro and their ability to suppress the soybean damping-off in vivo (soil and seed treatments). Three highly effective isolates were selected from these antagonists for subsequent studies. According to the biochemical, physiological and morphological tests, these isolates (B-2, B-12 and B-80) were identified as Bacillus spp. In soil treatment, the isolate B-3 with 70.8%, B-12 with 66.7%, B-80 with 54.2% had the highest effect on reducing the soybean damping-off. In seed treatment, the isolates B-43 with 62.5%, B-12 with 58.4 and B-80 with 45.8%, had the greatest effect on reducing the disease. These isolates produced volatile metabolites that inhibited mycelial growth of Phytophthora sojae. PMID:12701446

  12. Interleukin-1 receptor antagonist gene therapy for arthritis.

    PubMed

    Krishnan, B R

    1999-08-01

    Rheumtatoid arthritis (RA) is a crippling, autoimmune disease, and is characterized by inflammation and destruction of joint tissue. Interleukin-1 (IL-1) has been identified as a key pro-inflammatory cytokine responsible for inflammation. One of the mechanisms of regulation of activity of IL-1 is IL-1 receptor antagonist (IL-1ra)-mediated: IL-1RA competes with IL-1 for binding to the IL-1 receptor. Significant progress has been made in the potential application of IL-1ra gene therapyfor the treatment of arthritis. Various vectors have been tested for the delivery of the IL-1ra gene to the intra-articular region. Recent studies in humans have provided encouraging prospects for IL-1ra-mediated arthritis gene therapy. PMID:11713759

  13. [Treatment of pulmonary arterial hypertension: endothelin-receptor antagonists].

    PubMed

    Hoeper, M M

    2006-12-01

    Endothelin-1 (ET-1) is of significance in the pathophysiology and prognosis of pulmonary hypertension (PHT). Bosentan, an endothelin-receptor antagonist, currently plays a central role in the treatment of PHT, because it improves exercise capacity, hemodynamics, clinical symptoms and right ventricular function, achieving a survival duration of 2- 3 years. Bosentan causes an increase of transaminases in about 10% of patients, but this effect is reversible on dosage reduction or discontinuing the medication. However, transaminases should be measured every 4 weeks while patients are on bosentan. Almost all current guidelines list bosentan as of equal value to sildenafil or prostacyclin analogues in the first-line treatment of patients in NYHA functional class III and also, with narrower indications, of those in class IV. PMID:17139593

  14. 1/f scaling in heart rate requires antagonistic autonomic control

    NASA Astrophysics Data System (ADS)

    Struzik, Zbigniew R.; Hayano, Junichiro; Sakata, Seiichiro; Kwak, Shin; Yamamoto, Yoshiharu

    2004-11-01

    We present systematic evidence for the origins of 1/f -type temporal scaling in human heart rate. The heart rate is regulated by the activity of two branches of the autonomic nervous system: the parasympathetic (PNS) and the sympathetic (SNS) nervous systems. We examine alterations in the scaling property when the balance between PNS and SNS activity is modified, and find that the relative PNS suppression by congestive heart failure results in a substantial increase in the Hurst exponent H towards random-walk scaling 1/f2 and a similar breakdown is observed with relative SNS suppression by primary autonomic failure. These results suggest that 1/f scaling in heart rate requires the intricate balance between the antagonistic activity of PNS and SNS.

  15. Small molecule antagonists of melanopsin-mediated phototransduction

    PubMed Central

    Jones, Kenneth A.; Hatori, Megumi; Mure, Ludovic S.; Bramley, Jayne R.; Artymyshyn, Roman; Hong, Sang-Phyo; Marzabadi, Mohammad; Zhong, Huailing; Sprouse, Jeffrey; Zhu, Quansheng; Hartwick, Andrew T.E.; Sollars, Patricia J.; Pickard, Gary E.; Panda, Satchidananda

    2013-01-01

    Melanopsin, expressed in a subset of retinal ganglion cells, mediates behavioral adaptation to ambient light and other non-image forming photic responses. This has raised the possibility that pharmacological manipulation of melanopsin can modulate several CNS responses including photophobia, sleep, circadian rhythms and neuroendocrine function. Here we describe the identification of a potent synthetic melanopsin antagonist with in vivo activity. Novel sulfonamide compounds inhibiting melanopsin (opsinamides) compete with retinal binding to melanopsin and inhibit its function without affecting rod/cone mediated responses. In vivo administration of opsinamides to mice specifically and reversibly modified melanopsin-dependent light responses including the pupillary light reflex and light aversion. The discovery of opsinamides raises the prospect of therapeutic control of the melanopsin phototransduction system to regulate light-dependent behavior and remediate pathological conditions. PMID:23974117

  16. Exploring antagonistic metabolites of established biocontrol agent of marine origin.

    PubMed

    Rane, Makarand Ramesh; Sarode, Prashant Diwakar; Chaudhari, Bhushan Liladhar; Chincholkar, Sudhir Bhaskarrao

    2008-12-01

    Biocontrol ability of Pseudomonas aeruginosa ID 4365, a biocontrol agent of groundnut phytopathogens from marine origin, was previously attributed to the production of pyoverdin type of siderophores. However, pyoverdin-rich supernatants of this organism showed better antifungal activity compared to equivalent amount of purified pyoverdin indicating presence of undetected metabolite(s) in pyoverdin rich supernatants. On the basis of observation that antagonistic activity was iron-dependent and iron-independent, an attempt was made to detect the presence of additional metabolites. In addition to pyoverdin, strain produced additional siderophores, viz. pyochelin and salicylic acid. Two broad spectrum antifungal compounds, viz. pyocyanin and phenazine-1-carboxylic acid, were detected, characterized, and activity against phytopathogens was demonstrated. Iron- and phosphate-dependent co-production of siderophores and phenazines was confirmed. Strain showed additional features like production of hydrogen cyanide, indol-3-acetic acid, and phosphate solubilization. PMID:18626581

  17. Effect of diseases on response to vitamin K antagonists.

    PubMed

    Self, Timothy H; Owens, Ryan E; Sakaan, Sami A; Wallace, Jessica L; Sands, Christopher W; Howard-Thompson, Amanda

    2016-04-01

    Introduction The purpose of this review article is to summarize the literature on diseases that are documented to have an effect on response to warfarin and other VKAs. Methods We searched the English literature from 1946 to September 2015 via PubMed, EMBASE, and Scopus for the effect of diseases on response vitamin K antagonists including warfarin, acenocoumarol, phenprocoumon, and fluindione. Discussion Among many factors modifying response to VKAs, several disease states are clinically relevant. Liver disease, hyperthyroidism, and CKD are well documented to increase response to VKAs. Decompensated heart failure, fever, and diarrhea may also elevate response to VKAs, but more study is needed. Hypothyroidism is associated with decreased effect of VKAs, and obese patients will likely require higher initial doses of VKAs. Conclusion In order to minimize risks with VKAs while ensuring efficacy, clinicians must be aware of the effect of disease states when prescribing these oral anticoagulants. PMID:26695107

  18. Mesenteric vascular reactivity to histamine receptor agonists and antagonists. [Dogs

    SciTech Connect

    Walus, K.M.; Fondacaro, J.D.; Jacobson, E.D.

    1981-05-01

    Response patterns of intestinal blood flow, oxygen extraction and consumption, blood flow distribution, and motility were assessed during intraarterial infusions of histamine, histamine after H1 or H2 blockade, dimaprit or dimaprit after H2 blockade. Histamine produced an initial peak response of blood flow with a slow decrease thereafter. Oxygen extraction was evenly depressed throughout the infusion, and oxygen consumption increased at the beginning. All initial responses were blocked by tripelennamine. Ranitidine, a new H2 antagonist, accelerated the decay of all responses. Dimaprit produced effects identical to those of histamine after tripelennamine. Distribution of blood flow was unchanged at the beginning of histamine infusion, but subsequently showed a shift to muscularis which was blocked by tripelennamine. Histamine usually stimulated intestinal contractions and this effect was abolished by tripelennamine. Thus, H1 stimulation, besides producing an initial vasodilation, increases oxygen uptake and redistributes flow to the muscularis.

  19. Oxycodone with an opioid receptor antagonist: A review.

    PubMed

    Davis, Mellar P; Goforth, Harold W

    2016-01-01

    The rationale for putting opioid antagonists with an agonist is to improve pain control, to reduce side effects, and/or to reduce abuse. The combination of prolonged release (PR) oxycodone and naloxone reduces constipation as demonstrated in multiple studies and has been designated a tamper-resistant opioid by the Food and Drug Administration. Bioequivalence of the combination product compared with PR oxycodone has not been established. Several of the pivotal studies provided suboptimal laxative support in the control arm of the randomized trials. Two noninferiority trials have demonstrated equivalent analgesia between PR oxycodone and the combination product at doses of less than 120 mg of oxycodone per day. There appears to be an analgesic ceiling above 80-120 mg of oxycodone per day. Safety monitoring during randomized trials was not been well described in published manuscripts. Benefits appear to be better for those with chronic noncancer pain compared with individuals with cancer when constipation was the primary outcome. PMID:26908305

  20. Physico-chemical pathways in radioprotective action of calmodulin antagonists

    NASA Astrophysics Data System (ADS)

    Varshney, Rajeev; Kale, R. K.

    1996-04-01

    Ghost membranes prepared from erythrocytes of Swiss albino mice were irradiated with gamma rays at a dose rate of 0.9 Gy/s. The fluidity of membrane decreased with radiation dose and in the presence of calmodulin antagonists (CA) like chlorpromazine (CPZ), promethazine (PMZ) and trimeprazine (TMZ) it increased. Radiation induced release of Ca 2+ from membranes. This release was inhibited by CA mainly by CPZ and PMZ. Being Ca 2+ dependent, the changes in the activity of acetylcholine estrase (AchE) following irradiation was also studied. Radiation decreased the activity of AchE in dose dependent manner. Presence of CPZ and PMZ diminished the radiation induced inhibition of AchE but not in the presence of TMZ at the lower concentration tested. It is suggested that apart from scavenging of free radicals, CA perhaps exert their euxoic radioprotective effect through Ca 2+ dependent processes.

  1. Activins and activin antagonists in the prostate and prostate cancer.

    PubMed

    Gold, Elspeth; Risbridger, Gail

    2012-08-15

    Activins are members of the TGF-β super-family. There are 4 mammalian activin subunits (β(A), β(B), β(C) and β(E)) that combine to form functional proteins. The role of activin A (β(A)β(A)) is well characterized and known to be a potent growth and differentiation factor. Two of the activin subunits (β(C) and β(E)) were discovered more recently and little is known about their biological functions. In this review the evidence that activin-β(C) is a significant regulator of activin A bioactivity is presented and discussed. It is concluded that activin-β(C), like other antagonists of activin A, is an important growth regulator in prostate health and disease. PMID:21787836

  2. Adenosine receptor antagonist and augmented vasodilation during hypoxic exercise.

    PubMed

    Casey, Darren P; Madery, Brandon D; Pike, Tasha L; Eisenach, John H; Dietz, Niki M; Joyner, Michael J; Wilkins, Brad W

    2009-10-01

    We tested the hypothesis that adenosine contributes to augmented skeletal muscle vasodilation during hypoxic exercise. In separate protocols, subjects performed incremental rhythmic forearm exercise (10% and 20% of maximum) during normoxia and normocapnic hypoxia (80% arterial O2 saturation). In protocol 1 (n = 8), subjects received an intra-arterial administration of saline (control) and aminophylline (adenosine receptor antagonist). In protocol 2 (n = 10), subjects received intra-arterial phentolamine (alpha-adrenoceptor antagonist) and combined phentolamine and aminophylline administration. Forearm vascular conductance (FVC; in ml x min(-1).100 mmHg(-1)) was calculated from forearm blood flow (in ml/min) and blood pressure (in mmHg). In protocol 1, the change in FVC (DeltaFVC; change from normoxic baseline) during hypoxic exercise with saline was 172 +/- 29 and 314 +/- 34 ml x min(-1) x 100 mmHg(-1) (10% and 20%, respectively). Aminophylline administration did not affect DeltaFVC during hypoxic exercise at 10% (190 +/- 29 ml x min(-1)x100 mmHg(-1), P = 0.4) or 20% (287 +/- 48 ml x min(-1) x 100 mmHg(-1), P = 0.3). In protocol 2, DeltaFVC due to hypoxic exercise with phentolamine infusion was 313 +/- 30 and 453 +/- 41 ml x min(-1) x 100 mmHg(-1) (10% and 20% respectively). DeltaFVC was similar at 10% (352 +/- 39 ml min(-1) x 100 mmHg(-1), P = 0.8) and 20% (528 +/- 45 ml x min(-1) x 100 mmHg(-1), P = 0.2) hypoxic exercise with combined phentolamine and aminophylline. In contrast, DeltaFVC to exogenous adenosine was reduced by aminophylline administration in both protocols (P < 0.05 for both). These observations suggest that adenosine receptor activation is not obligatory for the augmented hyperemia during hypoxic exercise in humans. PMID:19661449

  3. N-Benzylpiperidine Derivatives as α7 Nicotinic Receptor Antagonists.

    PubMed

    Criado, Manuel; Mulet, José; Sala, Francisco; Sala, Salvador; Colmena, Inés; Gandía, Luis; Bautista-Aguilera, Oscar M; Samadi, Abdelouahid; Chioua, Mourad; Marco-Contelles, José

    2016-08-17

    A series of multitarget directed propargylamines, as well as other differently susbstituted piperidines have been screened as potential modulators of neuronal nicotinic acetylcholine receptors (nAChRs). Most of them showed antagonist actions on α7 nAChRs. Especially, compounds 13, 26, and 38 displayed submicromolar IC50 values on homomeric α7 nAChRs, whereas they were less effective on heteromeric α3β4 and α4β2 nAChRs (up to 20-fold higher IC50 values in the case of 13). Antagonism was concentration dependent and noncompetitive, suggesting that these compounds behave as negative allosteric modulators of nAChRs. Upon the study of a series of less complex derivatives, the N-benzylpiperidine motif, common to these compounds, was found to be the main pharmacophoric group. Thus, 2-(1-benzylpiperidin-4-yl)-ethylamine (48) showed an inhibitory potency comparable to the one of the previous compounds and also a clear preference for α7 nAChRs. In a neuroblastoma cell line, representative compounds 13 and 48 also inhibited, in a concentration-dependent manner, cytosolic Ca(2+) signals mediated by nAChRs. Finally, compounds 38 and 13 inhibited 5-HT3A serotonin receptors whereas they had no effect on α1 glycine receptors. Given the multifactorial nature of many pathologies in which nAChRs are involved, these piperidine antagonists could have a therapeutic potential in cases where cholinergic activity has to be negatively modulated. PMID:27254782

  4. GABAA receptor modulating steroid antagonists (GAMSA) are functional in vivo.

    PubMed

    Johansson, Maja; Strömberg, Jessica; Ragagnin, Gianna; Doverskog, Magnus; Bäckström, Torbjörn

    2016-06-01

    GABAA receptor modulating steroid antagonists (GAMSA) selectively inhibit neurosteroid-mediated enhancement of GABA-evoked currents at the GABAA receptor. 3α-hydroxy-neurosteroids, notably allopregnanolone and tetrahydrodeoxycorticosterone (THDOC), potentiate GABAA receptor-mediated currents. On the contrary, various 3β-hydroxy-steroids antagonize this positive neurosteroid-mediated modulation. Importantly, GAMSAs are specific antagonists of the positive neurosteroid-modulation of the receptor and do not inhibit GABA-evoked currents. Allopregnanolone and THDOC have both negative and positive actions. Allopregnanolone can impair encoding/consolidation and retrieval of memories. Chronic administration of a physiological allopregnanolone concentration reduces cognition in mice models of Alzheimer's disease. In humans an allopregnanolone challenge impairs episodic memory and in hepatic encephalopathy cognitive deficits are accompanied by increased brain ammonia and allopregnanolone. Hippocampal slices react in vitro to ammonia by allopregnanolone synthesis in CA1 neurons, which blocks long-term potentiation (LTP). Thus, allopregnanolone may impair learning and memory by interfering with hippocampal LTP. Contrary, pharmacological treatment with allopregnanolone can promote neurogenesis and positively influence learning and memory of trace eye-blink conditioning in mice. In rat the GAMSA UC1011 inhibits an allopregnanolone-induced learning impairment and the GAMSA GR3027 restores learning and motor coordination in rats with hepatic encephalopathy. In addition, the GAMSA isoallopregnanolone antagonizes allopregnanolone-induced anesthesia in rats, and in humans it antagonizes allopregnanolone-induced sedation and reductions in saccadic eye velocity. 17PA is also an effective GAMSA in vivo, as it antagonizes allopregnanolone-induced anesthesia and spinal analgesia in rats. In vitro the allopregnanolone/THDOC-increased GABA-mediated GABAA receptor activity is antagonized

  5. Prostaglandins, H2-receptor antagonists and peptic ulcer disease.

    PubMed

    Bright-Asare, P; Habte, T; Yirgou, B; Benjamin, J

    1988-01-01

    Peptic ulcer develops when offensive factors overwhelm defensive processes in the gastroduodenal mucosa. Offensive factors include NSAIDs, hydrochloric acid-peptic activity, bile reflux, and some products of the lipoxygenase pathway such as leukotriene B4; whereas defensive processes are largely mediated by prostaglandins through poorly understood mechanisms uniformly termed cytoprotection. Cytoprotection, a physiological process working through the products of arachidonic acid metabolism, may result from the net effect of the protective actions of prostaglandins versus the damaging actions of leukotrienes. Some prostaglandins also have antisecretory effects. Therefore the peptic ulcer healing effects of prostaglandin analogues, all of which have significant antisecretory activity, may be more due to their antisecretory effects than primarily to their effects on mucosal defences. Certain drug-induced gastroduodenal lesions, e.g. NSAID-induced ulcers, which are often unresponsive to H2-receptor antagonists, have been healed and their recurrence prevented by the use of PGE1 and PGE2 analogues. All the prostaglandin analogues investigated to date in humans have the potential for inducing abortion, an important side effect which may limit their worldwide use. The optimal prostaglandin analogue for ulcer healing should not induce abortion and should be potently cytoprotective. The predominant damaging agent in the development of peptic ulcer disease is gastric hydrochloric acid. Thus, the worldwide established efficacy and safety of H2-receptor antagonists such as cimetidine, ranitidine, famotidine and most recently of roxatidine acetate suggest that these agents have become the standard by which other forms of anti-ulcer therapy should be judged. PMID:2905237

  6. Comparison of GnRH Agonist, GnRH Antagonist, and GnRH Antagonist Mild Protocol of Controlled Ovarian Hyperstimulation in Good Prognosis Patients

    PubMed Central

    Vrtacnik-Bokal, Eda; Pozlep, Barbara; Virant-Klun, Irma

    2015-01-01

    The reports on how to stimulate the ovaries for oocyte retrieval in good prognosis patients are contradictory and often favor one type of controlled ovarian hyperstimulation (COH). For this reason, we retrospectively analyzed data from IVF/ICSI cycles carried out at our IVF Unit in good prognosis patients (aged <38 years, first and second attempts of IVF/ICSI, more than 3 oocytes retrieved) to elucidate which type of COH is optimal at our condition. The included patients were undergoing COH using GnRH agonist, GnRH antagonist or GnRH antagonist mild protocol in combination with gonadotrophins. We found significant differences in the average number of retrieved oocytes, immature oocytes, fertilized oocytes, embryos, transferred embryos, embryos frozen per cycle, and cycles with embryo freezing between studied COH protocols. Although there were no differences in live birth rate (LBR), miscarriages, and ectopic pregnancies between compared protocols, pregnancy rate was significantly higher in GnRH antagonist mild protocol in comparison with both GnRH antagonist and GnRH agonist protocols and cumulative LBR per cycle was significantly higher in GnRH antagonist mild protocol in comparison to GnRH agonist protocol. Our data show that GnRH antagonist mild protocol of COH could be the best method of choice in good prognosis patients. PMID:25866508

  7. Discovery and pharmacological profile of new hydrophilic 5-HT(4) receptor antagonists.

    PubMed

    Brudeli, Bjarne; Navaratnarajah, Mirusha; Andressen, Kjetil Wessel; Manfra, Ornella; Moltzau, Lise Román; Nilsen, Nils Olav; Levy, Finn Olav; Klaveness, Jo

    2014-09-15

    The synthesis and pharmacological data of some new and potent hydrophilic 5-HT4 receptor antagonists are described. Propanediol derivative 25 was identified as a potent antagonist with low affinity for the hERG potassium channel and promising pharmacokinetics. PMID:25149506

  8. Control of blue mold of apple by combining controlled atmosphere, antagonist mixtures and sodium bicarbonate

    Technology Transfer Automated Retrieval System (TEKTRAN)

    'Golden Delicious' apples were wound-inoculated with Penicillium expansum, treated with various combinations of sodium bicarbonate and two antagonists, and stored in air or controlled atmosphere (1.4% O2, 3% CO2). The fruit were stored for 2 or 4 months at 1°C. The antagonists survived and their p...

  9. Agar composition affects in vitro screening of biocontrol activity of antagonistic microorganisms.

    PubMed

    Bosmans, L; De Bruijn, I; De Mot, R; Rediers, H; Lievens, B

    2016-08-01

    Agar-based screening assays are the method of choice when evaluating antagonistic potential of bacterial biocontrol-candidates against pathogens. We showed that when using the same medium, but different agar compositions, the activity of a bacterial antagonist against Agrobacterium was strongly affected. Consequently, results from in vitro screenings should be interpreted cautiously. PMID:27166668

  10. Discovery of MK-7246, a selective CRTH2 antagonist for the treatment of respiratory diseases.

    PubMed

    Gallant, Michel; Beaulieu, Christian; Berthelette, Carl; Colucci, John; Crackower, Michael A; Dalton, Chad; Denis, Danielle; Ducharme, Yves; Friesen, Richard W; Guay, Daniel; Gervais, François G; Hamel, Martine; Houle, Robert; Krawczyk, Connie M; Kosjek, Birgit; Lau, Stephen; Leblanc, Yves; Lee, Ernest E; Levesque, Jean-François; Mellon, Christophe; Molinaro, Carmela; Mullet, Wayne; O'Neill, Gary P; O'Shea, Paul; Sawyer, Nicole; Sillaots, Susan; Simard, Daniel; Slipetz, Deborah; Stocco, Rino; Sørensen, Dan; Truong, Vouy Linh; Wong, Elizabeth; Wu, Jin; Zaghdane, Helmi; Wang, Zhaoyin

    2011-01-01

    In this manuscript we wish to report the discovery of MK-7246 (4), a potent and selective CRTH2 (DP2) antagonist. SAR studies leading to MK-7246 along with two synthetic sequences enabling the preparation of this novel class of CRTH2 antagonist are reported. Finally, the pharmacokinetic and metabolic profile of MK-7246 is disclosed. PMID:21106375

  11. Hotspots of damage by antagonists shape the spatial structure of plant-pollinator interactions.

    PubMed

    Rodríguez-Rodríguez, María C; Jordano, Pedro; Valido, Alfredo

    2015-08-01

    The balance between mutualistic and antagonistic plant-animal interactions and their spatial variation results in a highly dynamic mosaic of reproductive success within plant populations. Yet, the ecological drivers of this small-scale heterogeneity of interaction patterns and their outcomes remain virtually unexplored. We analyzed spatial structure in the frequency and intensity of interactions that vertebrate pollinators (birds and lizards) and invertebrate antagonists (florivores, nectar larcenists, and seed predators) had when interacting with the insular plant Isoplexis canariensis, and their effect on plant fitness. Spatially autocorrelated variation in plant reproductive success (fruit and viable seed set) emerged from the combined action of mutualists and antagonists, rather than reflecting the spatial pattern of any specific animal group. However, the influence of antagonists on plant fitness was stronger primarily due to the florivores' action on earlier reproductive stages, consuming and damaging floral structures before the arrival of pollinators. Our results indicate that the early action of antagonists creates hotspots of increased plant damage, where the effects of later acting mutualists are not translated into increased reproductive benefits. We foresee the potential for antagonists to shape the intra-population mosaics of plant fitness in situations where antagonists outnumber mutualists, when their interactions occur before those of mutualists, and when mutualists can detect and avoid damaged plants while foraging. Severely damaged plants in antagonistic hotspots might be excluded from the mating network and render a limited production of viable seeds, reducing both the growth rate of the plant population and the effective population size. PMID:26405743

  12. Identification of potent CNS-penetrant thiazolidinones as novel CGRP receptor antagonists.

    PubMed

    Joshi, Pramod; Anderson, Corey; Binch, Hayley; Hadida, Sabine; Yoo, Sanghee; Bergeron, Danielle; Decker, Caroline; terHaar, Ernst; Moore, Jonathan; Garcia-Guzman, Miguel; Termin, Andreas

    2014-02-01

    Calcitonin gene-related peptide (CGRP) has been implicated in acute migraine pathogenesis. In an effort to identify novel CGRP receptor antagonists for the treatment of migraine, we have discovered thiazolidinone 49, a potent (Ki=30 pM, IC50=1 nM), orally bioavailable, CNS-penetrant CGRP antagonist with good pharmacokinetic properties. PMID:24405707

  13. Discovery of novel non-steroidal reverse indole mineralocorticoid receptor antagonists.

    PubMed

    Ogawa, Anthony K; Bunte, Ellen Vande; Mal, Rudrajit; Lan, Ping; Sun, Zhongxiang; Crespo, Alejandro; Wiltsie, Judyann; Clemas, Joseph; Gibson, Jack; Contino, Lisa; Lisnock, JeanMarie; Zhou, Gaochao; Garcia-Calvo, Margarita; Jochnowitz, Nina; Ma, Xiuying; Pan, Yi; Brown, Patricia; Zamlynny, Beata; Bateman, Thomas; Leung, Dennis; Xu, Ling; Tong, Xinchun; Liu, Kun; Crook, Martin; Sinclair, Peter

    2016-06-15

    Reported herein are a series of reverse indoles that represent novel non-steroidal mineralocorticoid receptor (MR) antagonists. The key structure-activity relationships (SAR) are presented below. This reverse indole series is exemplified by a compound that demonstrated efficacy in an acute natriuresis rodent model comparable to marketed MR antagonists, spironolactone and eplerenone. PMID:27161805

  14. New strategies for effective treatment of vitamin K antagonist-associated bleeding.

    PubMed

    Yates, S G; Sarode, R

    2015-06-01

    Vitamin K antagonists have been used as oral anticoagulants in the treatment and prevention of thromboembolic events for over half a century. Although vitamin K antagonists are effective in the management of thromboembolic events, the need for routine monitoring and the associated risk of bleeding has resulted in the development and licensing of direct oral anticoagulants for specific clinical indications. Despite these developments, vitamin K antagonists remain the oral anticoagulants of choice in many clinical conditions. Severe bleeding associated with oral anticoagulation requires urgent reversal. Several options for the reversal of vitamin K antagonist exist, including vitamin K, prothrombin complex concentrates and plasma. In this manuscript, we review current evidence and provide physicians with treatment strategies for more effective management of vitamin K antagonist-associated bleeding. PMID:26149021

  15. Prazosin, an alpha 1-adrenergic receptor antagonist, suppresses experimental autoimmune encephalomyelitis in the Lewis rat.

    PubMed Central

    Brosnan, C F; Goldmuntz, E A; Cammer, W; Factor, S M; Bloom, B R; Norton, W T

    1985-01-01

    Prazosin, an antagonist of alpha 1-adrenergic receptors, has been found to suppress the clinical and histological expression of experimental autoimmune encephalomyelitis (EAE) in the Lewis rat. Suppression was more significant in females than in males and was a dose-dependent phenomenon. Analysis of the effect of other adrenergic receptor antagonists supports the conclusion that the suppressive effect of prazosin is a consequence of blockade of the alpha 1-receptor since treatment with either the alpha 2-antagonist yohimbine or the beta-antagonist propranolol exacerbated the disease, whereas treatment with the long-acting mixed alpha 1/alpha 2-antagonist phenoxybenzamine had some suppressive activity. Treatment with prazosin was also able to suppress clinical and histological signs of EAE in animals sensitized by adoptive transfer with activated spleen or lymph node cells. Whether prazosin acts through altering vascular permeability or the immune response, or both, remains to be determined. Images PMID:2994053

  16. Use of the H3 receptor antagonist radioligand [3H]-A-349821 to reveal in vivo receptor occupancy of cognition enhancing H3 receptor antagonists

    PubMed Central

    Miller, TR; Milicic, I; Bauch, J; Du, J; Surber, B; Browman, KE; Marsh, K; Cowart, M; Brioni, JD; Esbenshade, TA

    2009-01-01

    Background and purpose: The histamine H3 receptor antagonist radioligand [3H]-A-349821 was characterized as a radiotracer for assessing in vivo receptor occupancy by H3 receptor antagonists that affect behaviour. This model was established as an alternative to ex vivo binding methods, for relating antagonist H3 receptor occupancy to blood levels and efficacy in preclinical models. Experimental approach: In vivo cerebral cortical H3 receptor occupancy by [3H]-A-349821 was determined in rats from differences in [3H]-A-349821 levels in the isolated cortex and cerebellum, a brain region with low levels of H3 receptors. Comparisons were made to relate antagonist H3 receptor occupancy to blood levels and efficacy in a preclinical model of cognition, the five-trial inhibitory avoidance response in rat pups. Key results: In adult rats, [3H]-A-349821, 1.5 µg·kg−1, penetrated into the brain and cleared more rapidly from cerebellum than cortex; optimally, [3H]-A-349821 levels were twofold higher in the latter. With increasing [3H]-A-349821 doses, cortical H3 receptor occupancy was saturable with a binding capacity consistent with in vitro binding in cortex membranes. In studies using tracer [3H]-A-349821 doses, ABT-239 and other H3 receptor antagonists inhibited H3 receptor occupancy by [3H]-A-349821 in a dose-dependent manner. Blood levels of the antagonists corresponding to H3 receptor occupancy were consistent with blood levels associated with efficacy in the five-trial inhibitory avoidance response. Conclusions and implications: When employed as an occupancy radiotracer, [3H]-A-349821 provided valid measurements of in vivo H3 receptor occupancy, which may be helpful in guiding and interpreting clinical studies of H3 receptor antagonists. PMID:19413577

  17. Dotarizine versus flunarizine as calcium antagonists in chromaffin cells.

    PubMed Central

    Villarroya, M; Gandía, L; Lara, B; Albillos, A; López, M G; García, A G

    1995-01-01

    1. Dotarizine is a novel piperazine derivative structurally related to flunarizine that is currently being evaluated in clinical trials for its antimigraine and antivertigo effects. This clinical profile may be related to its Ca2+ antagonist properties. Therefore, the actions of both compounds as calcium antagonists were compared in bovine chromaffin cells. 2. Dotarizine and flunarizine blocked 45Ca2+ uptake into K+ depolarized chromaffin cells (70 mM K+/0.5 mM Ca2+ for 60 s) in a concentration-dependent manner, with IC50s of 4.8 and 6.7 microM, respectively. 3. Dotarizine and flunarizine also inhibited the whole-cell Ca2+ and Ba2+ currents (ICa, IBa) in voltage-clamped chromaffin cells, induced by depolarizing test pulses to 0 mV, during 50 ms, from a holding potential of -80 mV. Blockade exhibited IC50s of 4 microM for dotarizine and 2.2 microM for flunarizine. Dotarizine increased the rate of inactivation of ICa and IBa; inhibition of whole-cell currents was use-dependent. 4. Transient increases of the cytosolic Ca2+ concentration, [Ca2+]i, produced by K+ stimulation (70 mM K+ for 5 s) of single fura-2-loaded chromaffin cells, were also inhibited by dotarizine and flunarizine with IC50s of 1.2 and 0.6 microM, respectively. Upon washout of dotarizine, the [Ca2+]i increases recovered fully after 5-10 min. In contrast, the responses remained largely inhibited 10 min after washing out flunarizine. 5. Catecholamine release induced by K+ stimulation (10-s pulses of 70 mM) was inhibited by dotarizine with an IC50 of 2.6 microM and by flunarizine with an IC50 of 1.2 microM. The blocking effects of both compounds developed slowly, and was fully established after 20-30 min of superfusion.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7881736

  18. The Role of α1-Adrenoceptor Antagonists in the Treatment of Prostate and Other Cancers.

    PubMed

    Batty, Mallory; Pugh, Rachel; Rathinam, Ilampirai; Simmonds, Joshua; Walker, Edwin; Forbes, Amanda; Anoopkumar-Dukie, Shailendra; McDermott, Catherine M; Spencer, Briohny; Christie, David; Chess-Williams, Russ

    2016-01-01

    This review evaluates the role of α-adrenoceptor antagonists as a potential treatment of prostate cancer (PCa). Cochrane, Google Scholar and Pubmed were accessed to retrieve sixty-two articles for analysis. In vitro studies demonstrate that doxazosin, prazosin and terazosin (quinazoline α-antagonists) induce apoptosis, decrease cell growth, and proliferation in PC-3, LNCaP and DU-145 cell lines. Similarly, the piperazine based naftopidil induced cell cycle arrest and death in LNCaP-E9 cell lines. In contrast, sulphonamide based tamsulosin did not exhibit these effects. In vivo data was consistent with in vitro findings as the quinazoline based α-antagonists prevented angiogenesis and decreased tumour mass in mice models of PCa. Mechanistically the cytotoxic and antitumor effects of the α-antagonists appear largely independent of α 1-blockade. The proposed targets include: VEGF, EGFR, HER2/Neu, caspase 8/3, topoisomerase 1 and other mitochondrial apoptotic inducing factors. These cytotoxic effects could not be evaluated in human studies as prospective trial data is lacking. However, retrospective studies show a decreased incidence of PCa in males exposed to α-antagonists. As human data evaluating the use of α-antagonists as treatments are lacking; well designed, prospective clinical trials are needed to conclusively demonstrate the anticancer properties of quinazoline based α-antagonists in PCa and other cancers. PMID:27537875

  19. Pharmacophore modeling of dual angiotensin II and endothelin A receptor antagonists.

    PubMed

    Xue, Wei-Zhe; Lü, Wei; Zhou, Zhi-Ming; Wang, Zhan-Li

    2009-09-01

    Three-dimensional pharmacophore models were generated for AT1 and ET(A) receptors based on highly selective AT1 and ET(A) antagonists using the program Catalyst/HipHop. Both the best pharmacophore model for selective AT1 antagonists (Hypo-AT(1)-7) and ETA antagonists (Hypo-ET(A)-1) were obtained through a careful validation process. All five features contained in Hypo-AT(1)-7 and Hypo-ET(A)-1 (hydrogen-bond acceptor (A), hydrophobic aliphatic (Z), negative ionizable (N), ring aromatic (R), and hydrophobic aromatic (Y)) seem to be essential for antagonists in terms of binding activity. Dual AT1 and ET(A) receptor antagonists (DARAs) can map to both Hypo-AT(1)-7 and Hypo-ET(A)-1, separately. Comparison of Hypo-AT(1)-7 and Hypo-ET(A)-1, not only AT1 and ET(A) antagonist pharmacophore models consist of essential features necessary for compounds to be highly active and selective toward their corresponding receptor, but also have something in common. The results in this study will act as a valuable tool for designing and researching structural relationship of novel dual AT1 and ET(A) receptor antagonists. PMID:20055175

  20. Effect of calmodulin antagonists on the growth and graviresponsiveness of primary roots of maize

    NASA Technical Reports Server (NTRS)

    Stinemetz, C. L.; Hasenstein, K. H.; Young, L. M.; Evans, M. L.

    1992-01-01

    We examined the effect of calmodulin (CaM) antagonists applied at the root tip on root growth, gravity-induced root curvature, and the movement of calcium across the root tip and auxin (IAA) across the elongation zone of gravistimulated roots. All of the CaM antagonists used in these studies delayed gravity-induced curvature at a concentration (1 micromole) that did not affect root growth. Calmodulin antagonists (> or = 1 micromole) inhibited downward transport of label from 45Ca2+ across the caps of gravistimulated roots relative to the downward transport of 45Ca2+ in gravistimulated roots which were not treated with CaM antagonists. Application of CaM antagonists at the root tip (> or = 1 micromole) also decreased the relative downward movement of label from 3H-IAA applied to the upper side of the elongation zone of gravistimulated roots. In general, tip application of antagonists inhibited neither the upward transport of 45Ca2+ in the root tip nor the upward movement of label from 3H-IAA in the elongation zone of gravistimulated roots. Thus, roots treated with CaM antagonists > or = 1 micromole become less graviresponsive and exhibit reduced or even a reversal of downward polarity of calcium transport across the root tip and IAA transport across the elongation zone. The results indicate that calmodulin-regulated events play a role in root gravitropism.

  1. [Distribution and characteristics of soil antagonistic actinomycetes on northern slope of Taibai Mountain, Qinling].

    PubMed

    Zhu, Wen-Jie; Xue, Quan-Hong; Cao, Yan-Ru; Xue, Lei; Shen, Guang-Hui; Lai, Hang-Xian

    2011-11-01

    Twelve representative soil samples were collected from different altitudes on the northern slope of Taibai Mountain to study the distribution and characteristics of soil antagonistic actinomyces by using agar block method. There existed a great deal of soil antagonistic actinomyces in the study area. Among the 141 actinomycete strains isolated, 116 strains (82.3%) showed antagonism toward 12 target bacteria or fungi. The antagonistic strains at altitudes 800-1845, 3488, 3655, and 3670 m occupied 73.7% -86.8%, 81.3%, 78.9% and 82.3% of the total, respectively. 42.1% of the strains at altitudes 1200-2300 m and > 3400 m showed strong and broad spectrum antagonistic activity, suggesting that there was a great potential for the isolation of actinomycete strains with strong anti-biotic capability at these altitudes. 24.1% of the antagonistic actinomycetes showed antagonism against Staphyloccocus aureu, and 2.4%, 6.9% and 11.2% of them showed activity toward Verticillium dahliae in cotton, Phytophthora sp. in strawberry and Neonectria radiciccla in ginseng, respectively. This study showed that the soil actinomycete antagonistic potentiality (SAAP) could be used as a quantitative indicator to evaluate the potential of antagonistic actinomycete resources in soil. PMID:22303680

  2. Impact of Plant Species and Site on Rhizosphere-Associated Fungi Antagonistic to Verticillium dahliae Kleb.

    PubMed Central

    Berg, Gabriele; Zachow, Christin; Lottmann, Jana; Götz, Monika; Costa, Rodrigo; Smalla, Kornelia

    2005-01-01

    Fungi with antagonistic activity toward plant pathogens play an essential role in plant growth and health. To analyze the effects of the plant species and the site on the abundance and composition of fungi with antagonistic activity toward Verticillium dahliae, fungi were isolated from oilseed rape and strawberry rhizosphere and bulk soil from three different locations in Germany over two growing seasons. A total of 4,320 microfungi screened for in vitro antagonism toward Verticillium resulted in 911 active isolates. This high proportion of fungi antagonistic toward the pathogen V. dahliae was found for bulk and rhizosphere soil at all sites. A plant- and site-dependent specificity of the composition of antagonistic morphotypes and their genotypic diversity was found. The strawberry rhizosphere was characterized by preferential occurrence of Penicillium and Paecilomyces isolates and low numbers of morphotypes (n = 31) and species (n = 13), while Monographella isolates were most frequently obtained from the rhizosphere of oilseed rape, for which higher numbers of morphotypes (n = 41) and species (n = 17) were found. Trichoderma strains displayed high diversity in all soils, but a high degree of plant specificity was shown by BOX-PCR fingerprints. The diversity of rhizosphere-associated antagonists was lower than that of antagonists in bulk soil, suggesting that some fungi were specifically enriched in each rhizosphere. A broad spectrum of new Verticillium antagonists was identified, and the implications of the data for biocontrol applications are discussed. PMID:16085804

  3. Impact of plant species and site on rhizosphere-associated fungi antagonistic to Verticillium dahliae kleb.

    PubMed

    Berg, Gabriele; Zachow, Christin; Lottmann, Jana; Götz, Monika; Costa, Rodrigo; Smalla, Kornelia

    2005-08-01

    Fungi with antagonistic activity toward plant pathogens play an essential role in plant growth and health. To analyze the effects of the plant species and the site on the abundance and composition of fungi with antagonistic activity toward Verticillium dahliae, fungi were isolated from oilseed rape and strawberry rhizosphere and bulk soil from three different locations in Germany over two growing seasons. A total of 4,320 microfungi screened for in vitro antagonism toward Verticillium resulted in 911 active isolates. This high proportion of fungi antagonistic toward the pathogen V. dahliae was found for bulk and rhizosphere soil at all sites. A plant- and site-dependent specificity of the composition of antagonistic morphotypes and their genotypic diversity was found. The strawberry rhizosphere was characterized by preferential occurrence of Penicillium and Paecilomyces isolates and low numbers of morphotypes (n = 31) and species (n = 13), while Monographella isolates were most frequently obtained from the rhizosphere of oilseed rape, for which higher numbers of morphotypes (n = 41) and species (n = 17) were found. Trichoderma strains displayed high diversity in all soils, but a high degree of plant specificity was shown by BOX-PCR fingerprints. The diversity of rhizosphere-associated antagonists was lower than that of antagonists in bulk soil, suggesting that some fungi were specifically enriched in each rhizosphere. A broad spectrum of new Verticillium antagonists was identified, and the implications of the data for biocontrol applications are discussed. PMID:16085804

  4. The Role of α1-Adrenoceptor Antagonists in the Treatment of Prostate and Other Cancers

    PubMed Central

    Batty, Mallory; Pugh, Rachel; Rathinam, Ilampirai; Simmonds, Joshua; Walker, Edwin; Forbes, Amanda; Anoopkumar-Dukie, Shailendra; McDermott, Catherine M.; Spencer, Briohny; Christie, David; Chess-Williams, Russ

    2016-01-01

    This review evaluates the role of α-adrenoceptor antagonists as a potential treatment of prostate cancer (PCa). Cochrane, Google Scholar and Pubmed were accessed to retrieve sixty-two articles for analysis. In vitro studies demonstrate that doxazosin, prazosin and terazosin (quinazoline α-antagonists) induce apoptosis, decrease cell growth, and proliferation in PC-3, LNCaP and DU-145 cell lines. Similarly, the piperazine based naftopidil induced cell cycle arrest and death in LNCaP-E9 cell lines. In contrast, sulphonamide based tamsulosin did not exhibit these effects. In vivo data was consistent with in vitro findings as the quinazoline based α-antagonists prevented angiogenesis and decreased tumour mass in mice models of PCa. Mechanistically the cytotoxic and antitumor effects of the α-antagonists appear largely independent of α 1-blockade. The proposed targets include: VEGF, EGFR, HER2/Neu, caspase 8/3, topoisomerase 1 and other mitochondrial apoptotic inducing factors. These cytotoxic effects could not be evaluated in human studies as prospective trial data is lacking. However, retrospective studies show a decreased incidence of PCa in males exposed to α-antagonists. As human data evaluating the use of α-antagonists as treatments are lacking; well designed, prospective clinical trials are needed to conclusively demonstrate the anticancer properties of quinazoline based α-antagonists in PCa and other cancers. PMID:27537875

  5. Lipopeptide antagonists of growth hormone-releasing hormone with improved antitumor activities.

    PubMed

    Zarandi, Marta; Varga, Jozsef L; Schally, Andrew V; Horvath, Judit E; Toller, Gabor L; Kovacs, Magdolna; Letsch, Markus; Groot, Kate; Armatis, Patricia; Halmos, Gabor

    2006-03-21

    Antagonists of growth hormone-releasing hormone (GHRH) synthesized previously inhibit proliferation of various human cancers, but derivatisation with fatty acids could enhance their clinical efficacy. We synthesized a series of antagonists of GHRH(1-29)NH(2) acylated at the N terminus with monocarboxylic or alpha,omega-dicarboxylic acids containing six to sixteen carbon atoms. These peptides are analogs of prior potent antagonists JV-1-36, JV-1-38, and JV-1-65 with phenylacetyl group at their N terminus. Several new analogs, including MZ-J-7-46 and MZ-J-7-30, more effectively inhibited GHRH-induced GH release in vitro in a superfused rat pituitary system than their parent compound JV-1-36 and had increased binding affinities to rat pituitary GHRH receptors, but they showed weaker inhibition of GH release in vivo than JV-1-36. All antagonists acylated with fatty acids containing 8-14 carbon atoms inhibited the proliferation of MiaPaCa-2 human pancreatic cancer cells in vitro better than JV-1-36 or JV-1-65. GHRH antagonist MZ-J-7-114 (5 mug/day) significantly suppressed the growth of PC-3 human androgen-independent prostate cancers xenografted into nude mice and reduced serum IGF-I levels, whereas antagonist JV-1-38 had no effect at the dose of 10 mug/day. GHRH antagonists including MZ-J-7-46 and MZ-J-7-114 acylated with octanoic acid and MZ-J-7-30 and MZ-J-7-110 acylated with 1,12-dodecanedicarboxylic acid represent relevant improvements over earlier antagonists. These and previous results suggest that this class of GHRH antagonists might be effective in the treatment of various cancers. PMID:16537407

  6. Lipopeptide antagonists of growth hormone-releasing hormone with improved antitumor activities

    PubMed Central

    Zarandi, Marta; Varga, Jozsef L.; Schally, Andrew V.; Horvath, Judit E.; Toller, Gabor L.; Kovacs, Magdolna; Letsch, Markus; Groot, Kate; Armatis, Patricia; Halmos, Gabor

    2006-01-01

    Antagonists of growth hormone-releasing hormone (GHRH) synthesized previously inhibit proliferation of various human cancers, but derivatisation with fatty acids could enhance their clinical efficacy. We synthesized a series of antagonists of GHRH(1-29)NH2 acylated at the N terminus with monocarboxylic or α,ω-dicarboxylic acids containing six to sixteen carbon atoms. These peptides are analogs of prior potent antagonists JV-1-36, JV-1-38, and JV-1-65 with phenylacetyl group at their N terminus. Several new analogs, including MZ-J-7-46 and MZ-J-7-30, more effectively inhibited GHRH-induced GH release in vitro in a superfused rat pituitary system than their parent compound JV-1-36 and had increased binding affinities to rat pituitary GHRH receptors, but they showed weaker inhibition of GH release in vivo than JV-1-36. All antagonists acylated with fatty acids containing 8–14 carbon atoms inhibited the proliferation of MiaPaCa-2 human pancreatic cancer cells in vitro better than JV-1-36 or JV-1-65. GHRH antagonist MZ-J-7-114 (5 μg/day) significantly suppressed the growth of PC-3 human androgen-independent prostate cancers xenografted into nude mice and reduced serum IGF-I levels, whereas antagonist JV-1-38 had no effect at the dose of 10 μg/day. GHRH antagonists including MZ-J-7-46 and MZ-J-7-114 acylated with octanoic acid and MZ-J-7-30 and MZ-J-7-110 acylated with 1,12-dodecanedicarboxylic acid represent relevant improvements over earlier antagonists. These and previous results suggest that this class of GHRH antagonists might be effective in the treatment of various cancers. PMID:16537407

  7. A General Population Genetic Framework for Antagonistic Selection That Accounts for Demography and Recurrent Mutation

    PubMed Central

    Connallon, Tim; Clark, Andrew G.

    2012-01-01

    Antagonistic selection—where alleles at a locus have opposing effects on male and female fitness (“sexual antagonism”) or between components of fitness (“antagonistic pleiotropy”)—might play an important role in maintaining population genetic variation and in driving phylogenetic and genomic patterns of sexual dimorphism and life-history evolution. While prior theory has thoroughly characterized the conditions necessary for antagonistic balancing selection to operate, we currently know little about the evolutionary interactions between antagonistic selection, recurrent mutation, and genetic drift, which should collectively shape empirical patterns of genetic variation. To fill this void, we developed and analyzed a series of population genetic models that simultaneously incorporate these processes. Our models identify two general properties of antagonistically selected loci. First, antagonistic selection inflates heterozygosity and fitness variance across a broad parameter range—a result that applies to alleles maintained by balancing selection and by recurrent mutation. Second, effective population size and genetic drift profoundly affect the statistical frequency distributions of antagonistically selected alleles. The “efficacy” of antagonistic selection (i.e., its tendency to dominate over genetic drift) is extremely weak relative to classical models, such as directional selection and overdominance. Alleles meeting traditional criteria for strong selection (Nes >> 1, where Ne is the effective population size, and s is a selection coefficient for a given sex or fitness component) may nevertheless evolve as if neutral. The effects of mutation and demography may generate population differences in overall levels of antagonistic fitness variation, as well as molecular population genetic signatures of balancing selection. PMID:22298707

  8. A general population genetic framework for antagonistic selection that accounts for demography and recurrent mutation.

    PubMed

    Connallon, Tim; Clark, Andrew G

    2012-04-01

    Antagonistic selection--where alleles at a locus have opposing effects on male and female fitness ("sexual antagonism") or between components of fitness ("antagonistic pleiotropy")--might play an important role in maintaining population genetic variation and in driving phylogenetic and genomic patterns of sexual dimorphism and life-history evolution. While prior theory has thoroughly characterized the conditions necessary for antagonistic balancing selection to operate, we currently know little about the evolutionary interactions between antagonistic selection, recurrent mutation, and genetic drift, which should collectively shape empirical patterns of genetic variation. To fill this void, we developed and analyzed a series of population genetic models that simultaneously incorporate these processes. Our models identify two general properties of antagonistically selected loci. First, antagonistic selection inflates heterozygosity and fitness variance across a broad parameter range--a result that applies to alleles maintained by balancing selection and by recurrent mutation. Second, effective population size and genetic drift profoundly affect the statistical frequency distributions of antagonistically selected alleles. The "efficacy" of antagonistic selection (i.e., its tendency to dominate over genetic drift) is extremely weak relative to classical models, such as directional selection and overdominance. Alleles meeting traditional criteria for strong selection (N(e)s > 1, where N(e) is the effective population size, and s is a selection coefficient for a given sex or fitness component) may nevertheless evolve as if neutral. The effects of mutation and demography may generate population differences in overall levels of antagonistic fitness variation, as well as molecular population genetic signatures of balancing selection. PMID:22298707

  9. Major Depressive Disorder and Kappa Opioid Receptor Antagonists

    PubMed Central

    Li, Wei; Sun, Huijiao; Chen, Hao; Yang, Xicheng; Xiao, Li; Liu, Renyu; Shao, Liming; Qiu, Zhuibai

    2016-01-01

    Major depressive disorder (MDD) is a common psychiatric disease worldwide. The clinical use of tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs) and selective serotonin reuptake inhibitors (SSRIs)/serotonin–norepinephrine reuptake inhibitor (SNRIs) for this condition have been widely accepted, but they were challenged by unacceptable side-effects, potential drug-drug interactions (DDIs) or slow onset/lack of efficacy. The endogenous opioid system is involved in stress and emotion regulatory processes and its role in MDD has been implicated. Although several KOR antagonists including JDTic and PF-04455242 were discontinued in early clinical trials, ALKS 5461 and CERC-501(LY-2456302) survived and entered into Phase-III and Phase-II trials, respectively. Considering the efficacy and safety of early off-label use of buprenorphine in the management of the treatment-resistant depression (TRD), it will be not surprising to predict the potential success of ALKS 5461 (a combination of buprenorphine and ALKS-33) in the near future. Moreover, CERC-501 will be expected to be available as monotherapy or adjuvant therapy with other first-line antidepressants in the treatment of TRD, if ongoing clinical trials continue to provide positive benefit-risk profiles. Emerging new researches might bring more drug candidates targeting the endogenous opioid system to clinical trials to address current challenges in MDD treatment in clinical practice. PMID:27213169

  10. Chromatographic resolution of angiotensin II receptor antagonists (sartans).

    PubMed

    Tahir, Muhammad Saqlain; Adnan, Ahmad; Syed, Quratulain

    2016-08-01

    First time a simple, sensitive and unified quantification method has been developed to analyze the complete class of angiotensin II receptor antagonists which are used in the treatment of hypertension either alone or in combination with some other drugs. The most important advantage of developed method was that the eight separate drugs can be determined on a single chromatographic system without modifications in detection wavelength and mobile phase. The drugs were separated on a Purospher Star 4.6mm×25cm, 5μm, C18 column maintained at 40°C with 1mLmin(-1) flow rate using ultra violet detection at 254nm. Good separation (Rs>2.0) was achieved in a short analysis allowing simultaneous determination of all eight sartans. The effect of variation in flow rate, detection wavelength and column oven temperature was also studied. The proposed method was statistically validated in terms of precision, accuracy, linearity, specificity and robustness. The newly developed method proved to be specific, robust and accurate for the quantification of eight sartans in commercial pharmaceutical formulations. PMID:27258943

  11. Iontophoretic studies on rat hippocampus with some novel GABA antagonists.

    PubMed

    Dalkara, T; Saederup, E; Squires, R F; Krnjevic, K

    1986-08-01

    Twelve substances which appear to be GABA antagonists, judging by their ability to reverse the inhibitory effect of GABA on 35S-TBPS binding to rat brain membranes, were tested iontophoretically on population spikes in the rat hippocampus. Eight of them, including seven which completely reversed the inhibitory action of GABA on 35S-TBPS binding, caused a marked enhancement of population spikes, with slow onset and long duration and they antagonized the inhibition of population spikes by GABA. These effects were similar to those produced by bicuculline. Electrophysiologically, the most potent of the "complete reversers" were bathophenanthroline disulfonate and brucine. In vitro, amoxapine and brucine most effectively reversed the inhibitory action of GABA on 35S-TBPS binding. Of the five substances which only partly reversed the inhibitory effect of GABA on 35S-TBPS binding, four depressed the population spikes and potentiated the inhibitory action of GABA. The fifth "partial reverser", pipazethate, potently increased the population spikes, like the "complete reversers". Although other interpretations are possible the results are consistent with the existence of several GABA-A receptor types in brain, only some of which are blocked by certain partial reversers. PMID:2874465

  12. Can paternal leakage maintain sexually antagonistic polymorphism in the cytoplasm?

    PubMed Central

    Kuijper, B; Lane, N; Pomiankowski, A

    2015-01-01

    A growing number of studies in multicellular organisms highlight low or moderate frequencies of paternal transmission of cytoplasmic organelles, including both mitochondria and chloroplasts. It is well established that strict maternal inheritance is selectively blind to cytoplasmic elements that are deleterious to males – ’mother's curse’. But it is not known how sensitive this conclusion is to slight levels of paternal cytoplasmic leakage. We assess the scope for polymorphism when individuals bear multiple cytoplasmic alleles in the presence of paternal leakage, bottlenecks and recurrent mutation. When fitness interactions among cytoplasmic elements within an individual are additive, we find that sexually antagonistic polymorphism is restricted to cases of strong selection on males. However, when fitness interactions among cytoplasmic elements are nonlinear, much more extensive polymorphism can be supported in the cytoplasm. In particular, mitochondrial mutants that have strong beneficial fitness effects in males and weak deleterious fitness effects in females when rare (i.e. ’reverse dominance’) are strongly favoured under paternal leakage. We discuss how such epistasis could arise through preferential segregation of mitochondria in sex-specific somatic tissues. Our analysis shows how paternal leakage can dampen the evolution of deleterious male effects associated with predominant maternal inheritance of cytoplasm, potentially explaining why ’mother's curse’ is less pervasive than predicted by earlier work. PMID:25653025

  13. Leukotriene receptor antagonists for chronic urticaria: a systematic review

    PubMed Central

    2014-01-01

    A significant proportion of patients with chronic urticaria respond inadequately to first line treatment with antihistamines. Leukotreine receptor antagonists (LTRA) are also used for chronic urticaria, although firm recommendations on their use are lacking. We performed a systematic review of randomised trials to determine the role of LTRA in treatment of chronic urticaria. A search of PUBMED, EMBASE, SCOPUS, LILACS, the Cochrane Central Register of Controlled Trials, and the Web of Science for relevant randomized control trials or cross over studies yielded 10 eligible studies. The heterogeneity of trials were high, preventing valid meta-analysis of data. Most trials indicated that LTRA are not superior to placebo or antihistamine therapy, while combination therapy of LTRA and antihistamines appear to be more efficacious compared to antihistamine alone. The side effect profile and tolerability of this group of drugs is acceptable. The use of LTRA as monotherapy cannot be recommended. LTRA are effective add-on therapy to anti-histamines, and their use in patients responding poorly to antihistamines is justifiable. Further well designed randomized controlled trials with clear and standardized outcome measures are needed to determine the role of LTRA in chronic urticaria. PMID:24817895

  14. The role of oxytocin antagonists in repeated implantation -failure.

    PubMed

    Decleer, W; Osmanagaoglu, K; Devroey, P

    2012-01-01

    A prospective cohort study has been performed to find out if the administration of an oxytocin antagonist (Atosiban) at the occasion of embryo transfer has an effect on the pregnancy rate in patients with repeated failure of implantation. A total of 52 women with repeated failure of implantation after IVF/ICSI were included in this study. The ongoing pregnancy rate (OPR) in the total group of patients was 12 out of 52 (23.1%). Based on embryo quality all cases were categorized in two groups. One with good embryo quality (Group A) and one with poor quality embryos (Group B). Of all patients who became pregnant, 11 belonged to the group of 26 patients with good quality embryos (OPR 42.3 %) and only one to the group of 26 patients with poor quality embryos (OPR 3.8 %). Our results indicate that when good quality embryos can be obtained, the use of Atosiban at the occasion of embryo transfer might offer a significant better implantation rate in women with repeated implantation failure after IVF/ICSI. PMID:24753913

  15. Development of peripheral opioid antagonists' new insights into opioid effects.

    PubMed

    Moss, Jonathan; Rosow, Carl E

    2008-10-01

    The recent approval by the US Food and Drug Administration of 2 medications--methylnaltrexone and alvimopan--introduces a new class of therapeutic entities to clinicians. These peripherally acting mu-opioid receptor antagonists selectively reverse opioid actions mediated by receptors outside the central nervous system, while preserving centrally mediated analgesia. Methylnaltrexone, administered subcutaneously, has been approved in the United States, Europe, and Canada. In the United States, it is indicated for the treatment of opioid-induced constipation in patients with advanced illness (eg, cancer, AIDS) who are receiving palliative care, when response to laxative therapy has not been sufficient. Alvimopan, an orally administered medication, has been approved in the United States to facilitate recovery of gastrointestinal function after bowel resection and primary anastomosis. Clinical and laboratory studies performed during the development of these drugs have indicated that peripheral receptors mediate other opioid effects, including decreased gastric emptying, nausea and vomiting, pruritus, and urinary retention. Laboratory investigations with these compounds suggest that opioids affect fundamental cellular processes through mechanisms that were previously unknown. These mechanisms include modifications of human immunodeficiency virus penetration, tumor angiogenesis, vascular permeability, and bacterial virulence. PMID:18828971

  16. Orexin receptor antagonists as therapeutic agents for insomnia

    PubMed Central

    Equihua, Ana C.; De La Herrán-Arita, Alberto K.; Drucker-Colin, Rene

    2013-01-01

    Insomnia is a common clinical condition characterized by difficulty initiating or maintaining sleep, or non-restorative sleep with impairment of daytime functioning. Currently, treatment for insomnia involves a combination of cognitive behavioral therapy (CBTi) and pharmacological therapy. Among pharmacological interventions, the most evidence exists for benzodiazepine (BZD) receptor agonist drugs (GABAA receptor), although concerns persist regarding their safety and their limited efficacy. The use of these hypnotic medications must be carefully monitored for adverse effects. Orexin (hypocretin) neuropeptides have been shown to regulate transitions between wakefulness and sleep by promoting cholinergic/monoaminergic neural pathways. This has led to the development of a new class of pharmacological agents that antagonize the physiological effects of orexin. The development of these agents may lead to novel therapies for insomnia without the side effect profile of hypnotics (e.g., impaired cognition, disturbed arousal, and motor balance difficulties). However, antagonizing a system that regulates the sleep-wake cycle may create an entirely different side effect profile. In this review, we discuss the role of orexin and its receptors on the sleep-wake cycle and that of orexin antagonists in the treatment of insomnia. PMID:24416019

  17. Agonists and Antagonists of TGF-β Family Ligands.

    PubMed

    Chang, Chenbei

    2016-01-01

    The discovery of the transforming growth factor β (TGF-β) family ligands and the realization that their bioactivities need to be tightly controlled temporally and spatially led to intensive research that has identified a multitude of extracellular modulators of TGF-β family ligands, uncovered their functions in developmental and pathophysiological processes, defined the mechanisms of their activities, and explored potential modulator-based therapeutic applications in treating human diseases. These studies revealed a diverse repertoire of extracellular and membrane-associated molecules that are capable of modulating TGF-β family signals via control of ligand availability, processing, ligand-receptor interaction, and receptor activation. These molecules include not only soluble ligand-binding proteins that were conventionally considered as agonists and antagonists of TGF-β family of growth factors, but also extracellular matrix (ECM) proteins and proteoglycans that can serve as "sink" and control storage and release of both the TGF-β family ligands and their regulators. This extensive network of soluble and ECM modulators helps to ensure dynamic and cell-specific control of TGF-β family signals. This article reviews our knowledge of extracellular modulation of TGF-β growth factors by diverse proteins and their molecular mechanisms to regulate TGF-β family signaling. PMID:27413100

  18. Vasopressin receptor antagonists and their role in clinical medicine

    PubMed Central

    Narayen, Girish; Mandal, Surya Narayan

    2012-01-01

    Hyponatremia is the most common electrolyte abnormality in hospitalized patients. Its treatment is based not only on extracellular fluid volume status of patients but also on its pathogenetic mechanisms. Conventional treatment of hyponatremia like fluid restriction, which is useful in euvolemic and hypervolemic hyponatremia, has very poor patient compliance over long term. Vasopressin receptor antagonists (Vaptans) are a new group of nonpeptide drugs which have been used in various clinical conditions with limited success. Whereas conivaptan is to be administered intravenously, the other vaptans like tolvaptan, lixivaptan, and satavaptan are effective as oral medication. They produce aquaresis by their action on vasopressin type 2 (V2R) receptors in the collecting duct and thus increase solute free water excretion. Vaptans are being used as an alternative to fluid restriction in euvolemic and hypervolemic hyponatremic patients. Efficacy of vaptans is now well accepted for management of correction of hyponatremia over a short period. However, its efficacy in improving the long-term morbidity and mortality in patients with chronic hyponatremia due to cirrhosis and heart failure is yet to be established. Vaptans have not become the mainstay treatment of hyponatremia yet. PMID:22470853

  19. Calcium antagonists. A role in the management of cyanide poisoning

    SciTech Connect

    Maduh, E.U.; Porter, D.W.; Baskin, S.I.

    1993-12-31

    The physiological role of calcium was demonstrated by Ringer (1883) when he linked the omission of calcium (Ca++) from the bathing medium to the induction of cardiac arrest in the isolated frog heart. This observation established that Ca++ controlled muscle contraction but it was not until the autumn of 1963 that the specific pharmacological significance of this contribution was realised by Fleckenstein (1964), leading to the development of Ca++ antagonism as a concept in drug action (Fleckenstein 1977). Identifying the precise role of Ca++ ions in toxic cell injury and tissue death attributable to drug and chemical intoxication has lagged behind developments in Ca++ physiology and pharmacology and to date, much remains to be learned, although studies aimed at characterising the role of Ca++ in cytotoxic cell injury are receiving intense attention (Bondy Komulainen 1988; Maduh et al. l988a, l99Oa,b; Orrenius et al. 1989; Trump et al. 1989). On the other hand, the importance of cyanide as a poison has been known from antiquity (for references to earlier literature see Baskin Fricke 1992; Solomonson 1981). In experimental cyanide poisoning, recent studies have examined alterations in cell Ca++ and the influence of Ca++ antagonists in the management of this chemical toxicological emergency. These efforts have principally focused on the cellular Ca++ homeostasis system, its interrelationship with cellular components, and its susceptibility to cyanide action.

  20. Nalmefene: intravenous safety and kinetics of a new opioid antagonist.

    PubMed

    Dixon, R; Howes, J; Gentile, J; Hsu, H B; Hsiao, J; Garg, D; Weidler, D; Meyer, M; Tuttle, R

    1986-01-01

    In a placebo-controlled, double-blind study we evaluated the safety and kinetics of a new narcotic antagonist, nalmefene, after 2, 6, 12, and 24 mg intravenous doses to healthy men. At each dose level four subjects received active drug and two received placebo. The drug was well tolerated at all dose levels with only mild and transient side effects, the most common of which was lightheadedness. The plasma concentration-time data were best fit with a triexponential equation, and the terminal elimination phase had a harmonic mean t1/2 of 8 to 9 hours. Only about 5% of the dose was excreted in the urine as intact nalmefene, with up to 60% excreted as nalmefene glucuronide. Although intersubject differences were noted, mean or dose-normalized mean kinetic parameters such as clearance, steady-state volume of distribution, terminal t1/2, and AUC showed no consistent trends related to increasing doses, indicating that nalmefene has linear pharmacokinetics. PMID:3943269

  1. Streptomycetes and micromycetes as perspective antagonists of fungal phytopathogens.

    PubMed

    Postolaky, O; Syrbu, T; Poiras, N; Baltsat, K; Maslobrod, S; Boortseva, S

    2012-01-01

    Among natural factors that permanently influence on the plants, the soil microorganisms play a special role for the growing of plants as habitants of their rhizosphere. Mainly they are the representatives of actinomycetes genus Streptomyces and fungal genus Penicillium and their metabolic products stimulate plant growth and inhibit the growth of pathogenic fungi and bacteria. The aim of our study was to determine the antagonism of actinomycetes and micromycetes isolated from soils of R. Moldova against the fungal pathogens of agricultural plants. The strains were isolated from 5 types of chernozem (black soil) from central zone of R. Moldova, with different concentration of humus. Most of micromycetes and streptomycetes were isolated from soil sample 1 (monoculture of maize) and soil sample 2 (Poltava road border) with similar humus content (2.4-2.6%). The antifungal activity of micromycetes strains was occurring mostly against Fusarium solani and Thelaviopsis basicola, at streptomycetes against Alternaria alternata and Botrytis cinerea. It was revealed the strains completely inhibit the growth of Alt. alternata (streptomycetes strains 23, 33, 37), B. cinerea (Streptomyces sp. 17), and F. solani (Penicillium sp. 104). Our results allow to consider the actinomycetes Streptomyces sp.9, Streptomyces sp. 12, Streptomyces sp. 17, Streptomyces sp. 37 Streptomyces sp. 66 and micromycetes Penicillium sp. 5, Penicillium sp. 65, Penicillium sp. 104 isolated from soils of R. Moldova, as prospective strains-antagonists against the phytopathogenic fungus, the causative agents of agricultural plants deseasis. PMID:23878981

  2. Side Effects of Leukotriene Receptor Antagonists in Asthmatic Children

    PubMed Central

    Erdem, Semiha Bahceci; Nacaroglu, Hikmet Tekin; Unsal Karkiner, Canan Sule; Gunay, Ilker; Can, Demet

    2015-01-01

    Background: Leukotriene receptor antagonists (LTRAs) are drugs which have been widely used more than ten years. As the use of LTRAs increases, our knowledge with respect to their side effects increases as well. Objectives: The objective of our study was to evaluat the observed side effects of LTRAs used in patients with astma. Patients and Methods: 1024 patients treated only with LTRAs owing to asthma or early wheezing were included in the study for a five-year period. The observed side effects of LTRAs in these patients were retrospectively investigated. The side effects were divided into two parts as psychiatric and non-psychiatric. Results: Among the 1024 cases included in the study, 67.5% of the patients out of 41 with side effects were male, 32.5% were female and the average age was 6.5 years. The rate of patients with asthma was 63.41% and 36.58% of the patients had early wheezing. It was determined that sex, age and diagnosis (early wheezing or asthma) of the patients were ineffective in the emergence of side effects. The average period for the emergence of side effects was the first month. It was observed that hyperactivity was the most frequently observed psychiatric side effect and that abdominal pain was the non-psychiatric side effect. Conclusions: The side effects of LTRAs were common in children. Therefore, patients must be informed at the beginning of the treatment and they must be evaluated at certain intervals. PMID:26495098

  3. Antagonistic Activity of Lactobacillus Isolates against Salmonella typhi In Vitro

    PubMed Central

    Abdel-Daim, Amira; Hassouna, Nadia; Hafez, Mohamed; Ashor, Mohamed Seif Aldeen; Aboulwafa, Mohammad M.

    2013-01-01

    Background. Enteric fever is a global health problem, and rapidly developing resistance to various drugs makes the situation more alarming. The potential use of Lactobacillus to control typhoid fever represents a promising approach, as it may exert protective actions through various mechanisms. Methods. In this study, the probiotic potential and antagonistic activities of 32 Lactobacillus isolates against Salmonella typhi were evaluated. The antimicrobial activity of cell free supernatants of Lactobacillus isolates, interference of Lactobacillus isolates with the Salmonella adherence and invasion, cytoprotective effect of Lactobacillus isolates, and possibility of concurrent use of tested Lactobacillus isolates and antibiotics were evaluated by testing their susceptibilities to antimicrobial agents, and their oxygen tolerance was also examined. Results. The results revealed that twelve Lactobacillus isolates could protect against Salmonella typhi infection through interference with both its growth and its virulence properties, such as adherence, invasion, and cytotoxicity. These Lactobacillus isolates exhibited MIC values for ciprofloxacin higher than those of Salmonella typhi and oxygen tolerance and were identified as Lactobacillus plantarum. Conclusion. The tested Lactobacillus plantarum isolates can be introduced as potential novel candidates that have to be subjected for in vivo and application studies for treatment and control of typhoid fever. PMID:24191248

  4. Blood flow distribution with adrenergic and histaminergic antagonists

    SciTech Connect

    Baker, C.H.; Davis, D.L.; Sutton, E.T.

    1989-03-01

    Superficial fibular nerve stimulation (SFNS) causes increased pre- and post-capillary resistances as well as increased capillary permeability in the dog hind paw. These responses indicate possible adrenergic and histaminergic interactions. The distribution of blood flow between capillaries and arteriovenous anastomoses (AVA) may depend on the relative effects of these neural inputs. Right hind paws of anesthetized heparinized dogs were vascularly and neurally isolated and perfused with controlled pressure. Blood flow distribution was calculated from the venous recovery of 85Sr-labeled microspheres (15 microns). The mean transit times of 131I-albumin and 85Sr-labeled microspheres were calculated. The effects of adrenergic and histaminergic antagonists with and without SFNS were determined. Phentolamine blocked the entire response to SFNS. Prazosin attenuated increases in total and AVA resistance. Yohimbine prevented increased total resistance, attenuated the AVA resistance increase, and revealed a decrease in capillary circuit resistance. Pyrilamine attenuated total resistance increase while SFNS increased capillary and AVA resistances. Metiamide had no effect on blood flow distribution with SFNS. The increase in AVA resistance with SFNS apparently resulted from a combination of alpha 1 and alpha 2 receptor stimulation but not histaminergic effects.

  5. Competitive binding of antagonistic peptides fine-tunes stomatal patterning.

    PubMed

    Lee, Jin Suk; Hnilova, Marketa; Maes, Michal; Lin, Ya-Chen Lisa; Putarjunan, Aarthi; Han, Soon-Ki; Avila, Julian; Torii, Keiko U

    2015-06-25

    During development, cells interpret complex and often conflicting signals to make optimal decisions. Plant stomata, the cellular interface between a plant and the atmosphere, develop according to positional cues, which include a family of secreted peptides called epidermal patterning factors (EPFs). How these signalling peptides orchestrate pattern formation at a molecular level remains unclear. Here we report in Arabidopsis that Stomagen (also called EPF-LIKE9) peptide, which promotes stomatal development, requires ERECTA (ER)-family receptor kinases and interferes with the inhibition of stomatal development by the EPIDERMAL PATTERNING FACTOR 2 (EPF2)-ER module. Both EPF2 and Stomagen directly bind to ER and its co-receptor TOO MANY MOUTHS. Stomagen peptide competitively replaced EPF2 binding to ER. Furthermore, application of EPF2, but not Stomagen, elicited rapid phosphorylation of downstream signalling components in vivo. Our findings demonstrate how a plant receptor agonist and antagonist define inhibitory and inductive cues to fine-tune tissue patterning on the plant epidermis. PMID:26083750

  6. Cysteinyl Leukotriene Receptor Antagonists Decrease Cancer Risk in Asthma Patients

    PubMed Central

    Tsai, Ming-Ju; Wu, Ping-Hsun; Sheu, Chau-Chyun; Hsu, Ya-Ling; Chang, Wei-An; Hung, Jen-Yu; Yang, Chih-Jen; Yang, Yi-Hsin; Kuo, Po-Lin; Huang, Ming-Shyan

    2016-01-01

    Previous in vitro and in vivo studies have demonstrated the potential of using cysteinyl leukotriene receptor antagonists (LTRAs) for chemoprevention, but this has not been investigated in any clinical setting. We therefore investigated the chemopreventive effect of LTRAs in a nationwide population-based study. From the Taiwan National Health Insurance Research Database, we enrolled adults with newly-diagnosed asthma between 2001 and 2011. Among these patients, each LTRA user was matched with five randomly-selected LTRA non-users by sex, age, asthma diagnostic year and modified Charlson Comorbidity Index score. We considered the development of cancer as the outcome. Totally, 4185 LTRA users and 20925 LTRA non-users were identified. LTRA users had a significantly lower cancer incidence rate than LTRA non-users did. Multivariable Cox regression analyses adjusting for baseline characteristics and comorbidities showed LTRA use was an independent protecting factor (hazard ratio = 0.31 [95% CI: 0.24–0.39]), and cancer risk decreased progressively with higher cumulative dose of LTRAs. In conclusion, this study revealed that the LTRA use decreased cancer risk in a dose-dependent manner in asthma patients. The chemopreventive effect of LTRAs deserves further study. PMID:27052782

  7. Novel dominant negative Smad antagonists to TGFbeta signaling.

    PubMed

    Ho, Joanne; Chen, Hui; Lebrun, Jean-Jacques

    2007-07-01

    We previously identified a critical serine/threonine residue within the linker domain of Smad2/3, phosphorylated by the kinase GRK2 which plays a critical role in regulating Smad signaling. To define the mechanism by which GRK2-mediated phosphorylation modifies Smad2/3 behavior at the molecular level, we generated mutant Smads where the GRK2 phosphorylation site was replaced with an aspartic acid (D) to mimic the properties of a phospho-residue or an alanine (A) as a control. Interestingly, overexpression of either the D or A mutant inhibits TGFbeta signaling, but through two distinct mechanisms. The D mutant is properly localized and released from the plasma membrane upon ligand stimulation, but fails to interact with the type I receptor kinase. The A mutant properly interacts with and is phosphorylated by the type I receptor, translocates to the nucleus and homodimerizes with wild-type R-Smads, but it fails to form a heterocomplex with Smad4. As a result, both mutants act as antagonists of endogenous TGFbeta signaling through divergent mechanisms. The D mutant acts by blocking endogenous R-Smads phosphorylation and the A mutant acts by preventing endogenous R-Smad/Smad4 heterocomplexes. Thus, mutation of the GRK2 phosphorylation site within the Smad generates dominant negative Smads that efficiently inhibit TGFbeta responses. PMID:17360157

  8. Applicability of DPI formulations for novel neurokinin receptor antagonist.

    PubMed

    Kumon, M; Yabe, Y; Kasuya, Y; Suzuki, M; Kusai, A; Yonemochi, E; Terada, K

    2008-05-22

    A novel triple neurokinin receptor antagonist (TNRA) could have pharmaceutical efficacy for asthma and/or chronic obstructive pulmonary disease. TNRA is potentially developed as inhalation medicine. The aim of this investigation was to evaluate the applicability of dry powder inhaler (DPI) formulation for TNRA. DPI formulation containing lactose was used for this feasibility study. Mechanofusion process for surface modification was applied on lactose particles to prepare four different DPI formulations. The mixture of TNRA and lactose was administered to rats intratracheally using an insufflator. The deposition pattern and blood concentration profile of TNRA were evaluated. Although there was no significant difference in deposition on deep lungs between the four formulations, DPI formulations containing mechanofusion-processed lactose showed longer T(max) and t(1/2) and higher AUC(0-infinity) and MRT compared to that containing intact lactose. On the other hand, the contact angle measurement showed that the mechanofusion process decreased the polar part of the surface energy of the lactose. Therefore, the prolongation of the wetting of the formulated powder mixture seemed to delay the dissolution of TNRA deposited in respiratory tract. It was concluded that DPI formulation containing mechanofusion-processed lactose could be suitable for inhalation of TNRA. PMID:18294787

  9. Intraguild predation provides a selection mechanism for bacterial antagonistic compounds

    PubMed Central

    Leisner, J. J.; Haaber, J.

    2012-01-01

    Bacteriocins are bacterial proteinaceous toxins with bacteriostatic or bacteriocidal activity towards other bacteria. The current theory on their biological role concerns especially colicins, with underlying social interactions described as an example of spite. This leads to a rock–paper–scissors game between colicin producers and sensitive and resistant variants. The generality of this type of selection mechanism has previously been challenged with lactic acid bacterial (LAB) bacteriocins as an example. In the natural environment of LAB, batch cultures are the norm opposed to the natural habitats of Escherichia coli where continuous cultures are prevailing. This implies that fitness for LAB, to a large degree, is related to survival rates (bottleneck situations) rather than to growth rates. We suggest that the biological role of LAB bacteriocins is to enhance survival in the stationary growth phase by securing a supply of nutrients from lysed target cells. Thus, this social interaction is an example of selfishness rather than of spite. Specifically, it fits into an ecological model known as intraguild predation (IGP), which is a combination of competition and predation where the predator (LAB bacteriocin producer) and prey (bacteriocin susceptible bacteria) share similar and often limited resources. We hypothesize that IGP may be a common phenomenon promoting microbial production of antagonistic compounds. PMID:22951735

  10. CGRP Receptor Antagonists in the Treatment of Migraine

    PubMed Central

    Durham, Paul L.; Vause, Carrie V.

    2011-01-01

    Based on preclinical and clinical studies, the neuropeptide calcitonin gene-related peptide (CGRP) is proposed to play a central role in the underlying pathology of migraine. CGRP and its receptor are widely expressed in both the peripheral and central nervous system by multiple cell types involved in the regulation of inflammatory and nociceptive responses. Peripheral release of CGRP from trigeminal nerve fibers within the dura and from the cell body of trigeminal ganglion neurons is likely to contribute to peripheral sensitization of trigeminal nociceptors. Similarly, the release of CGRP within the trigeminal nucleus caudalis can facilitate activation of nociceptive second order neurons and glial cells. Thus, CGRP is involved in the development and maintenance of persistent pain, central sensitization, and allodynia, events characteristic of migraine pathology. In contrast, CGRP release within the brain is likely to function in an anti-nociceptive capacity. This review will focus on the development and clinical data on CGRP receptor antagonists as well as discussing their potential roles in migraine therapy via modulation of multiple cell types within the peripheral and central nervous systems. PMID:20433208

  11. NMDA receptor antagonist ketamine impairs feature integration in visual perception.

    PubMed

    Meuwese, Julia D I; van Loon, Anouk M; Scholte, H Steven; Lirk, Philipp B; Vulink, Nienke C C; Hollmann, Markus W; Lamme, Victor A F

    2013-01-01

    Recurrent interactions between neurons in the visual cortex are crucial for the integration of image elements into coherent objects, such as in figure-ground segregation of textured images. Blocking N-methyl-D-aspartate (NMDA) receptors in monkeys can abolish neural signals related to figure-ground segregation and feature integration. However, it is unknown whether this also affects perceptual integration itself. Therefore, we tested whether ketamine, a non-competitive NMDA receptor antagonist, reduces feature integration in humans. We administered a subanesthetic dose of ketamine to healthy subjects who performed a texture discrimination task in a placebo-controlled double blind within-subject design. We found that ketamine significantly impaired performance on the texture discrimination task compared to the placebo condition, while performance on a control fixation task was much less impaired. This effect is not merely due to task difficulty or a difference in sedation levels. We are the first to show a behavioral effect on feature integration by manipulating the NMDA receptor in humans. PMID:24223927

  12. NMDA Receptor Antagonist Ketamine Impairs Feature Integration in Visual Perception

    PubMed Central

    Meuwese, Julia D. I.; van Loon, Anouk M.; Scholte, H. Steven; Lirk, Philipp B.; Vulink, Nienke C. C.; Hollmann, Markus W.; Lamme, Victor A. F.

    2013-01-01

    Recurrent interactions between neurons in the visual cortex are crucial for the integration of image elements into coherent objects, such as in figure-ground segregation of textured images. Blocking N-methyl-D-aspartate (NMDA) receptors in monkeys can abolish neural signals related to figure-ground segregation and feature integration. However, it is unknown whether this also affects perceptual integration itself. Therefore, we tested whether ketamine, a non-competitive NMDA receptor antagonist, reduces feature integration in humans. We administered a subanesthetic dose of ketamine to healthy subjects who performed a texture discrimination task in a placebo-controlled double blind within-subject design. We found that ketamine significantly impaired performance on the texture discrimination task compared to the placebo condition, while performance on a control fixation task was much less impaired. This effect is not merely due to task difficulty or a difference in sedation levels. We are the first to show a behavioral effect on feature integration by manipulating the NMDA receptor in humans. PMID:24223927

  13. Calcium channel antagonists decrease the ethanol withdrawal syndrome.

    PubMed

    Little, H J; Dolin, S J; Halsey, M J

    1986-12-01

    Withdrawal from chronic ethanol intake results in a syndrome of tremor and hyperexcitability, which can progress to seizures and death. Drugs used therapeutically to alleviate the syndrome have sedative actions and dependence liability of their own. The basis of the syndrome is unclear, although ethanol affects many neuronal functions, including membrane calcium conductance. Calcium channel blocking drugs have been used in cardiovascular disorders; they bind to high affinity sites in the brain but have few overt actions on the central nervous system. We have tested the effects of four calcium channel antagonists on the ethanol withdrawal syndrome in rats. Nitrendipine and nimodipine abolished all spontaneous seizures and prevented or reduced seizures following an audiogenic stimulus, and mortality. Verapamil significantly decreased seizure incidence and both it and flunarizine lowered mortality. The dihydropyridines were considerably more effective than diazepam in the withdrawal syndrome but had little effect on pentylenetetrazol seizures, against which diazepam gave good protection. The calcium channel inhibitors showed no sedative activity in normal animals. The results provide evidence that alterations in calcium conductance may be involved in the ethanol withdrawal syndrome and offer possibilities for the development of non-sedative therapeutic treatment of this syndrome. PMID:3784769

  14. Functionalized Congener Approach to Muscarinic Antagonists: Analogues of Pirenzepine

    PubMed Central

    Karton, Yishai; Bradbury, Barton J.; Baumgold, Jesse; Paek, Robert; Jacobson, Kenneth A.

    2012-01-01

    The M1-selective muscarinic receptor antagonist pirenzepine (5,11-dihydro-11-[(4-methyl-1-piperazinyl)acetyl]-6H-pyrido[2,3-b] [1,4]benzodiazepin-6-one) was derivatized to explore points of attachment of functionalized side chains for the synthesis of receptor probes and ligands for affinity chromatography. The analogues prepared were evaluated in competitive binding assays versus [3H]-N-methylscopolamine at four muscarinic receptor subtypes (m1AChR-m4AChR) in membranes from rat heart tissue and transfected A9L cells. 9-(Hydroxymethyl)pirenzepine, 8-(methylthio)pirenzepine, and a series of 8-aminosulfonyl derivatives were synthesized. Several 5-substituted analogues of pirenzepine also were prepared. An alternate series of analogues substituted on the 4-position of the piperazine ring was prepared by reaction of 4-desmethylpirenzepine with various electrophiles. An N-chloroethyl analogue of pirenzepine was shown to form a reactive aziridine species in aqueous buffer yet failed to affinity label muscarinic receptors. Within a series of aminoalkyl analogues, the affinity increased as the length of the alkyl chain increased. Shorter chain analogues were generally much less potent than pirenzepine, and longer analogues (7–10 carbons) were roughly as potent as pirenzepine at m1 receptors, but were nonselective. Depending on the methylene chain length, acylation or alkyl substitution of the terminal amine also influenced the affinity at muscarinic receptors. PMID:2066986

  15. Bioactivation pathways of the cannabinoid receptor 1 antagonist rimonabant.

    PubMed

    Bergström, Moa Andresen; Isin, Emre M; Castagnoli, Neal; Milne, Claire E

    2011-10-01

    In the present work, the characterization of the biotransformation and bioactivation pathways of the cannabinoid receptor 1 antagonist rimonabant (Acomplia) is described. Rimonabant was approved in Europe in 2006 for the treatment of obesity but was withdrawn in 2008 because of a significant drug-related risk of serious psychiatric disorders. The aim of the present work is to characterize the biotransformation and potential bioactivation pathways of rimonabant in vitro in human and rat liver microsomes. The observation of a major iminium ion metabolite led us to perform reactive metabolite trapping, covalent binding to proteins, and time-dependent inhibition of cytochrome P450 3A4 studies. The major biotransformation pathways were oxidative dehydrogenation of the piperidinyl ring to an iminium ion, hydroxylation of the 3 position of the piperidinyl ring, and cleavage of the amide linkage. In coincubations with potassium cyanide, three cyanide adducts were detected. A high level of covalent binding of rimonabant in human liver microsomes was observed (920 pmol equivalents/mg protein). In coincubations with potassium cyanide and methoxylamine, the covalent binding was reduced by approximately 40 and 30%, respectively, whereas GSH had no significant effect on covalent binding levels. Rimonabant was also found to inhibit cytochrome P450 3A4 irreversibly in a time-dependent manner. In view of these findings, it is noteworthy that, to date, no toxicity findings related to the formation of reactive metabolites from rimonabant have been reported. PMID:21733882

  16. [Management of vitamin K antagonists in the elderly].

    PubMed

    Belleville, Tiphaine; Pautas, Éric; Gaussem, Pascale; Siguret, Virginie

    2014-01-01

    Elderly patients of 80 years and above are commonly frail, due to substantial comorbid conditions and numerous medications. Managing elderly patients receiving vitamin K antagonists (VKA) is challenging because those patients are at high risk of both thrombosis and bleeding. Special considerations on the choice of the VKA drug, dosing and monitoring have to be taken into account in the elderly in order to avoid over-anticoagulation and to minimize the haemorrhagic risk which consequences may be dramatic or fatal in this age group. In these patients, INR monitoring is crucial, especially at the start of treatment. The use of dosing algorithms specifically developed for elderly patients allows to decrease over-anticoagulation during the initiation period. INR has to be monitored more frequently in case of acute illness or in case of modification of the associated drugs. Patient information and education are of great importance, even in geriatric patients and has been shown to improve the quality of anticoagulation. Even though the use of direct oral anticoagulants is currently expanding, prescribing VKA in elderly patients in whom the prevalence of severe renal insufficiency remains up to date. PMID:24736138

  17. Cysteinyl Leukotriene Receptor Antagonists Decrease Cancer Risk in Asthma Patients.

    PubMed

    Tsai, Ming-Ju; Wu, Ping-Hsun; Sheu, Chau-Chyun; Hsu, Ya-Ling; Chang, Wei-An; Hung, Jen-Yu; Yang, Chih-Jen; Yang, Yi-Hsin; Kuo, Po-Lin; Huang, Ming-Shyan

    2016-01-01

    Previous in vitro and in vivo studies have demonstrated the potential of using cysteinyl leukotriene receptor antagonists (LTRAs) for chemoprevention, but this has not been investigated in any clinical setting. We therefore investigated the chemopreventive effect of LTRAs in a nationwide population-based study. From the Taiwan National Health Insurance Research Database, we enrolled adults with newly-diagnosed asthma between 2001 and 2011. Among these patients, each LTRA user was matched with five randomly-selected LTRA non-users by sex, age, asthma diagnostic year and modified Charlson Comorbidity Index score. We considered the development of cancer as the outcome. Totally, 4185 LTRA users and 20925 LTRA non-users were identified. LTRA users had a significantly lower cancer incidence rate than LTRA non-users did. Multivariable Cox regression analyses adjusting for baseline characteristics and comorbidities showed LTRA use was an independent protecting factor (hazard ratio = 0.31 [95% CI: 0.24-0.39]), and cancer risk decreased progressively with higher cumulative dose of LTRAs. In conclusion, this study revealed that the LTRA use decreased cancer risk in a dose-dependent manner in asthma patients. The chemopreventive effect of LTRAs deserves further study. PMID:27052782

  18. Rap1 and Rap2 Antagonistically Control Endothelial Barrier Resistance

    PubMed Central

    Pannekoek, Willem-Jan; Linnemann, Jelena R.; Brouwer, Patricia M.; Bos, Johannes L.; Rehmann, Holger

    2013-01-01

    Rap1 and Rap2 are closely related proteins of the Ras family of small G-proteins. Rap1 is well known to regulate cell-cell adhesion. Here, we have analysed the effect of Rap-mediated signalling on endothelial permeability using electrical impedance measurements of HUVEC monolayers and subsequent determination of the barrier resistance, which is a measure for the ease with which ions can pass cell junctions. In line with its well-established effect on cell-cell junctions, depletion of Rap1 decreases, whereas activation of Rap1 increases barrier resistance. Despite its high sequence homology with Rap1, depletion of Rap2 has an opposite, enhancing, effect on barrier resistance. This effect can be mimicked by depletion of the Rap2 specific activator RasGEF1C and the Rap2 effector MAP4K4, establishing Rap2 signalling as an independent pathway controlling barrier resistance. As simultaneous depletion or activation of both Rap1 and Rap2 results in a barrier resistance comparable to control cells, Rap1 and Rap2 control barrier resistance in a reciprocal manner. This Rap1-antagonizing effect of Rap2 is established independent of junctional actin formation. These data establish that endothelial barrier resistance is determined by the combined antagonistic actions of Rap1 and Rap2. PMID:23469100

  19. Mineralocorticoid Receptor Antagonists for Treatment of Hypertension and Heart Failure

    PubMed Central

    Sica, Domenic A.

    2015-01-01

    Spironolactone and eplerenone are both mineralocorticoid-receptor antagonists. These compounds block both the epithelial and nonepithelial actions of aldosterone, with the latter assuming increasing clinical relevance. Spironolactone and eplerenone both affect reductions in blood pressure either as mono- or add-on therapy; moreover, they each afford survival benefits in diverse circumstances of heart failure and the probability of renal protection in proteinuric chronic kidney disease. However, as use of mineralocorticoid-blocking agents has expanded, the hazards inherent in taking such drugs have become more apparent. Whereas the endocrine side effects of spironolactone are in most cases little more than a cosmetic annoyance, the potassium-sparing effects of both spironolactone and eplerenone can prove disastrous, even fatal, if sufficient degrees of hyperkalemia emerge. For most patients, however, the risk of developing hyperkalemia in and of itself should not discourage the sensible clinician from bringing these compounds into play. Hyperkalemia should always be considered a possibility in patients receiving either of these medications; therefore, anticipatory steps should be taken to minimize the likelihood of its occurrence if long-term therapy of these agents is being considered. PMID:27057293

  20. Locomotor adaptation to a soleus EMG-controlled antagonistic exoskeleton.

    PubMed

    Gordon, Keith E; Kinnaird, Catherine R; Ferris, Daniel P

    2013-04-01

    Locomotor adaptation in humans is not well understood. To provide insight into the neural reorganization that occurs following a significant disruption to one's learned neuromuscular map relating a given motor command to its resulting muscular action, we tied the mechanical action of a robotic exoskeleton to the electromyography (EMG) profile of the soleus muscle during walking. The powered exoskeleton produced an ankle dorsiflexion torque proportional to soleus muscle recruitment thus limiting the soleus' plantar flexion torque capability. We hypothesized that neurologically intact subjects would alter muscle activation patterns in response to the antagonistic exoskeleton by decreasing soleus recruitment. Subjects practiced walking with the exoskeleton for two 30-min sessions. The initial response to the perturbation was to "fight" the resistive exoskeleton by increasing soleus activation. By the end of training, subjects had significantly reduced soleus recruitment resulting in a gait pattern with almost no ankle push-off. In addition, there was a trend for subjects to reduce gastrocnemius recruitment in proportion to the soleus even though only the soleus EMG was used to control the exoskeleton. The results from this study demonstrate the ability of the nervous system to recalibrate locomotor output in response to substantial changes in the mechanical output of the soleus muscle and associated sensory feedback. This study provides further evidence that the human locomotor system of intact individuals is highly flexible and able to adapt to achieve effective locomotion in response to a broad range of neuromuscular perturbations. PMID:23307949

  1. Vasopressin and vasopressin antagonists in heart failure and hyponatremia.

    PubMed

    Farmakis, Dimitrios; Filippatos, Gerasimos; Kremastinos, Dimitrios T; Gheorghiade, Mihai

    2008-06-01

    Increased synthesis of arginine vasopressin (AVP) plays a critical role in fluid retention and hyponatremia in patients with heart failure. The AVP receptor antagonists constitute a new class of agents that are promising in the management of hyponatremia and congestion. Three of these agents--conivaptan, tolvaptan, and lixivaptan--have been studied in clinical settings. All are effective in inducing aquaresis (ie, electrolyte-free water excretion) and normalizing serum sodium concentration. They are well tolerated without causing electrolyte disorders, hypotension, or renal impairment. Conivaptan has been approved by the US Food and Drug Administration for short-term intravenous treatment of euvolemic hyponatremia of variable etiology but has not been adequately studied in heart failure. The addition of tolvaptan to standard therapy in hospitalized patients with heart failure has led to symptomatic improvement and decreased body weight, but there is no long-term clinical benefit. Early data on lixivaptan in heart failure suggest a dose-dependent aquaresis effect, and larger studies are under way. PMID:18765079

  2. The effect of epistasis on sexually antagonistic genetic variation

    PubMed Central

    Arnqvist, Göran; Vellnow, Nikolas; Rowe, Locke

    2014-01-01

    There is increasing evidence of segregating sexually antagonistic (SA) genetic variation for fitness in laboratory and wild populations, yet the conditions for the maintenance of such variation can be restrictive. Epistatic interactions between genes can contribute to the maintenance of genetic variance in fitness and we suggest that epistasis between SA genes should be pervasive. Here, we explore its effect on SA genetic variation in fitness using a two locus model with negative epistasis. Our results demonstrate that epistasis often increases the parameter space showing polymorphism for SA loci. This is because selection in one locus is affected by allele frequencies at the other, which can act to balance net selection in males and females. Increased linkage between SA loci had more marginal effects. We also show that under some conditions, large portions of the parameter space evolve to a state where male benefit alleles are fixed at one locus and female benefit alleles at the other. This novel effect of epistasis on SA loci, which we term the ‘equity effect’, may have important effects on population differentiation and may contribute to speciation. More generally, these results support the suggestion that epistasis contributes to population divergence. PMID:24870040

  3. Development of specific dopamine D-1 agonists and antagonists

    SciTech Connect

    Sakolchai, S.

    1987-01-01

    To develop potentially selective dopamine D-1 agonists and to investigate on the structural requirement for D-1 activity, the derivatives of dibenzocycloheptadiene are synthesized and pharmacologically evaluated. The target compounds are 5-aminomethyl-10,11-dihydro-1,2-dihydroxy-5H-dibenzo(a,d)cycloheptene hydrobromide 10 and 9,10-dihydroxy-1,2,3,7,8,12b-hexahydrobenzo(1,2)cyclohepta(3,4,5d,e)isoquinoline hydrobromide 11. In a dopamine-sensitive rat retinal adenylate cyclase assay, a model for D-1 activity, compound 10 is essentially inert for both agonist and antagonist activity. In contrast, compound 11 is approximately equipotent to dopamine in activation of the D-1 receptor. Based on radioligand and binding data, IC{sub 50} of compound 11 for displacement of {sup 3}H-SCH 23390, a D-1 ligand, is about 7 fold less than that for displacement of {sup 3}H-spiperone, a D-2 ligand. These data indicate that compound 11 is a potent selective dopamine D-1 agonist. This study provides a new structural class of dopamine D-1 acting agent: dihydroxy-benzocycloheptadiene analog which can serve as a lead compound for further drug development and as a probe for investigation on the nature of dopamine D-1 receptor.

  4. [Near-patient testing devices to monitor vitamin K antagonists].

    PubMed

    Brionne-Francois, Marie; Le Querrec, Agnès; Lasne, Dominique

    2013-11-01

    Monitoring of the anticoagulant effect with the International normalized ratio (INR) is essential for patients receiving vitamin K antagonists (VKAs). The majority of point of care (POC) devices for INR monitoring has shown a good precision and accuracy with results similar to those obtained in a laboratory. In many countries, INR POC devices are widely used at home by the patients for self-testing. Their use in the hospital by the clinical staff (doctor or nurses) for bedside measurement is also growing. The INR POC testing is performed using fully automated devices. Capillary blood samples are easy to obtain. In the emergency room, POC INR devices are commonly used. This improves the quality of care for patient with suspicion of VKAs overdosage. INR measurement using bedside monitors is also of great interest in care units for specific populations of patients like paediatrics or geriatrics. Moreover, bedside INR monitoring may be useful in anticoagulant clinics or when the care unit is far from a laboratory. Although the bedside INR monitors are easy to use, their implementation requires adequate training and intermittent re-evaluation of any person performing the tests to ensure reliability of results. Such equipment must comply with EN ISO 22870 standard for POC testing accreditation, under the supervision of a biologist. In order to achieve these targets, connect the instrument to the laboratory's data management system is essential. PMID:24235329

  5. Sexually antagonistic epigenetic marks that canalize sexually dimorphic development.

    PubMed

    Rice, William R; Friberg, Urban; Gavrilets, Sergey

    2016-04-01

    The sexes share the same autosomal genomes, yet sexual dimorphism is common due to sex-specific gene expression. When present, XX and XY karyotypes trigger alternate regulatory cascades that determine sex-specific gene expression profiles. In mammals, secretion of testosterone (T) by the testes during foetal development is the master switch influencing the gene expression pathways (male vs. female) that will be followed, but many genes have sex-specific expression prior to T secretion. Environmental factors, like endocrine disruptors and mimics, can interfere with sexual development. However, sex-specific ontogeny can be canalized by the production of epigenetic marks (epimarks) generated during early ontogeny that increase sensitivity of XY embryos to T and decrease sensitivity of XX embryos. Here, we integrate and synthesize the evidence indicating that canalizing epimarks are produced during early ontogeny. We will also describe the evidence that such epimarks sometimes carry over across generations and produce mosaicism in which some traits are discordant with the gonad. Such carryover epimarks are sexually antagonistic because they benefit the individual in which they were formed (via canalization) but harm opposite-sex offspring when they fail to erase across generations and produce gonad-trait discordances. SA-epimarks have the potential to: i) magnify phenotypic variation for many sexually selected traits, ii) generate overlap along many dimensions of the masculinity/femininity spectrum, and iii) influence medically important gonad-trait discordances like cryptorchidism, hypospadias and idiopathic hirsutism. PMID:26600375

  6. Non-vitamin K antagonist oral anticoagulants (NOACs): a view from the laboratory.

    PubMed

    Blann, A D

    2014-01-01

    Disadvantages with traditional anticoagulants (vitamin K antagonists and heparinoids) have led to the development on non-vitamin K antagonist oral anticoagulants (NOACs). These agents are set to replace the traditional anticoagulants in situations such as following orthopaedic surgery, in atrial fibrillation, and in the prevention and treatment of venous thromboembolism. Although superior to vitamin K antagonists and heparinoids in several aspects, NOACs retain the ability to cause haemorrhage and, despite claims to the contrary, may need monitoring. This review aims to summarise key aspects of the NOACs of relevance to the laboratory. PMID:25562993

  7. [Antagonistic properties of Lactobacillus plantarum strains, isolated from traditional fermented products of Ukraine].

    PubMed

    Vasyliuk, O M; Kovalenko, N K; Harmasheva, I L

    2014-01-01

    The antagonistic activity of 109 lactobacillus strains, isolated from traditional fermented products of Ukraine, has been investigated and it has been shown that the significant part of strains show different levels of inhibition of opportunistic and phytopathogenic microorganisms. It has been shown that the antagonistic effect of Lactobacillus plantarum strains on the opportunistic and phytopathogenic microorganisms was dependent on the sources of Lactobacillus strains isolation. L. plantarum strains show a higher level of inhibition against phytopathogenic microorganisms than opportunistic test-strains. Eleven strains of L. plantarum demonstrated antagonistic activity for all used test-strains. PMID:25007440

  8. Small molecular weight protein-protein interaction antagonists: an insurmountable challenge?

    PubMed

    Dömling, Alexander

    2008-06-01

    Several years ago small molecular weight protein-protein interaction (PPI) antagonists were considered as the Mount Everest in drug discovery and generally regarded as too difficult to be targeted. However, recent industrial and academic research has produced a great number of new antagonists of diverse PPIs. This review structurally analyses small molecular weight PPI antagonists and their particular targets as well as tools to discover such compounds. Besides general discussions there will be a focus on the PPI p53/mdm2. PMID:18501203

  9. AZD-4818, a chemokine CCR1 antagonist: WO2008103126 and WO2009011653.

    PubMed

    Norman, Peter

    2009-11-01

    The applications WO2008103126 and WO2009011653, respectively, claim: i) Combinations of a spirocyclic piperidine chemokine CCR1 antagonist with a corticosteroid, and their use for the treatment of asthma and chronic obstructive pulmonary disease. ii) Processes for the preparation of a spirocyclic piperidine derivative, a chemokine CCR1 antagonist. These applications point to the preferred compound being a development compound. The evidence for this compound being AZD-4818, a chemokine CCR1 antagonist that was in Phase II development for the treatment of chronic obstructive pulmonary disease, is reviewed in the light of these and earlier patents relating to it. PMID:19586423

  10. The metabotropic glutamate receptor subtype 5 antagonist fenobam is analgesic and has improved in vivo selectivity compared with the prototypical antagonist 2-methyl-6-(phenylethynyl)-pyridine.

    PubMed

    Montana, Michael C; Cavallone, Laura F; Stubbert, Kristi K; Stefanescu, Andrei D; Kharasch, Evan D; Gereau, Robert W

    2009-09-01

    Metabotropic glutamate receptor subtype 5 (mGlu5) has been demonstrated to play a role in the modulation of numerous nociceptive modalities. When administered via peripheral, intrathecal, or systemic routes, mGlu5 antagonists have analgesic properties in a variety of preclinical pain models. Despite a wealth of data supporting the use of mGlu5 antagonists to treat pain, studies have been limited to preclinical animal models due to a lack of mGlu5 antagonists that are approved for use in humans. It has been demonstrated previously that fenobam [N-(3-chlorophenyl)-N'-(4,5-dihydro-1-methyl-4-oxo-1H-imidazole-2-yl)urea], an anxiolytic shown to be safe and effective in human trials, is a selective and potent noncompetitive antagonist of mGlu5 (J Pharmacol Exp Ther 315:711-721, 2005). Here, we report a series of studies aimed at testing whether fenobam, similar to the prototypical mGlu5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP), has analgesic properties in mice. We show that fenobam reduces formalin-induced pain behaviors and relieves established inflammation-induced thermal hypersensitivity in mice. Similar results were seen with MPEP. Administration of fenobam resulted in an increase in locomotor activity in the open-field task but did not impair performance on the accelerating Rotarod. Analysis of brain and plasma fenobam levels indicated that fenobam is rapidly concentrated in brain after intraperitoneal administration in mice but is essentially cleared from circulation within 1 h after injection. Fenobam had no analgesic effect in mGlu5 knockout mice, whereas the prototypical antagonist MPEP retained significant analgesic efficacy in mGlu5 knockouts. These results demonstrate that fenobam is analgesic in mice and has an improved in vivo selectivity for mGlu5 over MPEP. PMID:19515968

  11. Development of interleukin-1 receptor antagonist mutants with enhanced antagonistic activity in vitro and improved therapeutic efficacy in collagen-induced arthritis.

    PubMed

    Dahlén, Eva; Barchan, Karin; Herrlander, Daniel; Höjman, Patrik; Karlsson, Marie; Ljung, Lill; Andersson, Mats; Bäckman, Eva; Hager, Ann-Christin Malmborg; Walse, Björn; Joosten, Leo; van den Berg, Wim

    2008-04-01

    Interleukin-1 receptor antagonist (IL-1Ra) is a naturally occurring inhibitor of the pro-inflammatory interleukin-1-mediated activation of the interleukin-1 receptor (IL-1R). Although wild-type IL-1Ra is used for treatment of inflammatory diseases, its effect is moderate and/or short-lived. The objective of this study was to generate IL-1Ra mutants with enhanced antagonistic activity for potential therapeutic use. Using a directed evolution approach in which libraries of IL-1Ra gene mutants were generated and screened in functional assays, mutants with desired properties were identified. Initially, diversity was introduced into the IL-1Ra using random mutagenesis. Mutations resulting in enhanced antagonistic activity were identified by screening in a reporter cell assay. To further enhance the antagonistic activity, selected mutations were recombined using the DNA recombination technology Fragment-INduced Diversity (FIND). Following three rounds of FIND recombination, several mutants with up to nine times enhanced antagonistic activity (mean IC50 +/- SEM value: 0.78 +/- 0.050 vs. 6.8 +/- 1.1 ng/ml for mutant and wild-type, respectively) were identified. Sequence analysis identified the mutations D47N, E52R and E90Y as being most important for this effect, however, the mutations P38Y, H54R, Q129L and M136N further enhanced the antagonistic function. Analysis of identified mutations in protein models based on the crystal structure of the IL-1Ra/IL-1R complex suggested that mutations found to enhance the antagonistic activity had a stabilizing effect on the IL-1Ra mutants or increased the affinity for the IL-1R. Finally, the therapeutic effect of one mutant was compared to that of wild-type IL-1Ra in collagen-induced arthritis in mice. Indeed, the enhanced antagonistic effect of the mutants observed in vitro was also seen in vivo. In conclusion, these results demonstrate that directed evolution of IL-1Ra is an effective means of generating highly potent therapeutic

  12. Screening of Peptide Ligands for Pyrroloquinoline Quinone Glucose Dehydrogenase Using Antagonistic Template-Based Biopanning

    PubMed Central

    Abe, Koichi; Yoshida, Wataru; Terada, Kotaro; Yagi-Ishii, Yukiko; Ferri, Stefano; Ikebukuro, Kazunori; Sode, Koji

    2013-01-01

    We have developed a novel method, antagonistic template-based biopanning, for screening peptide ligands specifically recognizing local tertiary protein structures. We chose water-soluble pyrroloquinoline quinone (PQQ) glucose dehydrogenase (GDH-B) as a model enzyme for this screening. Two GDH-B mutants were constructed as antagonistic templates; these have some point mutations to induce disruption of local tertiary structures within the loop regions that are located at near glucose-binding pocket. Using phage display, we selected 12-mer peptides that specifically bound to wild-type GDH-B but not to the antagonistic templates. Consequently, a peptide ligand showing inhibitory activity against GDH-B was obtained. These results demonstrate that the antagonistic template-based biopanning is useful for screening peptide ligands recognizing the specific local tertiary structure of proteins. PMID:24287902

  13. Kynurenic acid amides as novel NR2B selective NMDA receptor antagonists.

    PubMed

    Borza, István; Kolok, Sándor; Galgóczy, Kornél; Gere, Anikó; Horváth, Csilla; Farkas, Sándor; Greiner, István; Domány, György

    2007-01-15

    A novel series of kynurenic acid amides, ring-enlarged derivatives of indole-2-carboxamides, was prepared and identified as in vivo active NR2B subtype selective NMDA receptor antagonists. The synthesis and SAR studies are discussed. PMID:17074483

  14. Identification of Trisubstituted-pyrazol Carboxamide Analogs as Novel and Potent Antagonists of Farnesoid X Receptor

    PubMed Central

    Yu, Donna D.; Lin, Wenwei; Forman, Barry M.; Chen, Taosheng

    2014-01-01

    Farnesoid X receptor (FXR, NRIH4) plays a major role in the control of cholesterol metabolism. This suggests that antagonizing the transcriptional activity of FXR is a potential means to treat cholestasis and related metabolic disorders. Here we describe the synthesis, biological evaluation, and structure-activity relationship (SAR) studies of trisubstituted-pyrazol carboxamides as novel and potent FXR antagonists. One of these novel FXR antagonists, 4j has an IC50 of 7.5 nM in an FXR binding assay and 468.5 nM in a cell-based FXR antagonistic assay. Compound 4j has no detectable FXR agonistic activity or cytotoxicity. Notably, 4j is the most potent FXR antagonist identified to date; it has a promising in vitro profile and could serve as an excellent chemical tool to elucidate the biological function of FXR. PMID:24775917

  15. H3 receptor ligands: new imidazole H3-antagonists endowed with NO-donor properties.

    PubMed

    Bertinaria, Massimo

    2003-03-01

    Synthesis and pharmacological properties of a group of compounds obtained by coupling the H(3)-antagonist SKF 91486 with the NO-donor 3-phenylfuroxan-4-yloxy and 3-benzenesulfonylfuroxan-4-yloxy moieties, as well as with the corresponding furazan analogues, devoid of NO-donating properties, are reported. All the products were tested for their H(3)-antagonistic and H(2)-agonistic properties on electrically-simulated guinea-pig ileum segments and guinea-pig papillary muscle, respectively. All the synthesised compounds displayed good H(3)-antagonistic properties (pA(2) range 7.02-8.49) while behaving only as weak partial H(2)-agonists. Derivative 28, the best NO-donor of the series, was able to trigger a dual NO-dependent muscle relaxation and H(3)-antagonistic effect on guinea-pig illeum. PMID:12620423

  16. Antagonism of Paf-induced oedema formation in rabbit skin: a comparison of different antagonists.

    PubMed Central

    Hellewell, P. G.; Williams, T. J.

    1989-01-01

    1. Eight platelet activating factor (Paf) antagonists were evaluated as inhibitors of oedema formation in rabbit skin induced by intradermal injection of Paf plus prostaglandin E2 (PGE2). Antagonists were tested by both intradermal (i.d.) and intravenous (i.v.) routes. 2. Intradermal injection of two antagonists structurally-related to Paf (SRI 63-675 and CV-3988) resulted in a partial inhibition of Paf-induced oedema formation but at high doses of antagonist, marked agonist activities were detected. CV-3988 administered i.v. inhibited Paf-induced plasma leakage by 73-80%; however, oedema responses to a range of other inflammatory mediators were also reduced, albeit to a lesser extent (40-60%). SRI 63-675 administered i.v. did not significantly inhibit Paf-induced oedema. 3. The antagonist 48740 RP administered either i.d. or i.v. showed partial, but selective, inhibition of Paf-induced oedema formation, although the doses required were high when compared with other antagonists. 4. BN 52021 was a weak Paf antagonist when injected i.d., but following i.v. administration the responses to Paf were inhibited by 63-71%. Responses to all other mediators tested were unaffected. 5. Kadsurenone and its synthetic derivatives, L-652,731 and L-659,989 all blocked responses to Paf in the skin. L-659,989 was the most potent, achieving almost total inhibition when injected i.d. and i.v.; moreover, it was selective for Paf. L-652,731 was more potent than kadsurenone. 6. WEB 2086 given i.d. and i.v. showed similar activity to L-659,989 and it was also selective for Paf-induced oedema formation. 7. These results illustrate that in rabbit skin not all Paf antagonists are selective for Paf, some showing agonist-like activity which can mask antagonist properties. It is suggested that before ascribing a role for endogenous Paf in an inflammatory reaction based on results with antagonists, the activity of the antagonists in the model under investigation should be rigorously established

  17. Pentobarbital anesthesia alters pulmonary vascular response to neural antagonists.

    PubMed

    Nyhan, D P; Goll, H M; Chen, B B; Fehr, D M; Clougherty, P W; Murray, P A

    1989-05-01

    We investigated the effects of pentobarbital sodium anesthesia on vasoregulation of the pulmonary circulation. Our specific objectives were to 1) assess the net effect of pentobarbital on the base-line pulmonary vascular pressure-to-cardiac index (P/Q) relationship compared with that measured in conscious dogs, and 2) determine whether autonomic nervous system (ANS) regulation of the intact P/Q relationship is altered during pentobarbital. P/Q plots were constructed by graded constriction of the thoracic inferior vena cava, which produced stepwise decreases in Q. Pentobarbital (30 mg/kg iv) had no net effect on the base-line P/Q relationship. In contrast, changes in the conscious intact P/Q relationship in response to ANS antagonists were markedly altered during pentobarbital. Sympathetic alpha-adrenergic receptor block with prazosin caused active pulmonary vasodilation (P less than 0.01) in conscious dogs but caused vasoconstriction (P less than 0.01) during pentobarbital. Sympathetic beta-adrenergic receptor block with propranolol caused active pulmonary vasoconstriction (P less than 0.01) in both groups, but the magnitude of the vasoconstriction was attenuated (P less than 0.05) during pentobarbital at most levels of Q. Finally, cholinergic receptor block with atropine resulted in active pulmonary vasodilation (P less than 0.01) in conscious dogs, whereas vasoconstriction (P less than 0.01) was observed during pentobarbital. Thus, although pentobarbital had no net effect on the base-line P/Q relationship measured in conscious dogs, ANS regulation of the intact pulmonary vascular P/Q relationship was altered during pentobarbital anesthesia. PMID:2566280

  18. Antagonistic effects of tetrodotoxin on aconitine-induced cardiac toxicity.

    PubMed

    Ono, Takiyoshi; Hayashida, Makiko; Tezuka, Akito; Hayakawa, Hideyuki; Ohno, Youkichi

    2013-01-01

    Aconitine, well-known for its high cardiotoxicity, causes severe arrhythmias, such as ventricular tachycardia and ventricular fibrillation, by opening membrane sodium channels. Tetrodotoxin, a membrane sodium-channel blocker, is thought to antagonize aconitine activity. Tetrodotoxin is a potent blocker of the skeletal muscle sodium-channel isoform Na(v)1.4 (IC50 10 nM), but micromolar concentrations of tetrodotoxin are required to inhibit the primary cardiac isoform Na(v)1.5. This suggests that substantial concentrations of tetrodotoxin are required to alleviate the cardiac toxicity caused by aconitine. To elucidate the interaction between aconitine and tetrodotoxin in the cardiovascular and respiratory systems, mixtures of aconitine and tetrodotoxin were simultaneously administered to mice, and the effects on electrocardiograms, breathing rates, and arterial oxygen saturation were examined. Compared with mice treated with aconitine alone, some mice treated with aconitine-tetrodotoxin mixtures showed lower mortality rates and delayed appearance of arrhythmia. The decreased breathing rates and arterial oxygen saturation observed in mice receiving aconitine alone were alleviated in mice that survived after receiving the aconitine-tetrodotoxin mixture; this result suggests that tetrodotoxin is antagonistic to aconitine. When the tetrodotoxin dose is greater than the dose that can block tetrodotoxin-sensitive sodium channels, which are excessively activated by aconitine, tetrodotoxin toxicity becomes prominent, and the mortality rate increases because of the respiratory effects of tetrodotoxin. In terms of cardiotoxicity, mice receiving the aconitine-tetrodotoxin mixture showed minor and shorter periods of change on electrocardiography. This finding can be explained by the recent discovery of tetrodotoxin-sensitive sodium-channel cardiac isoforms (Na(v)1.1, 1.2, 1.3, 1.4 and 1.6). PMID:24189353

  19. Reversal Strategies for Vitamin K Antagonists in Acute Intracerebral Hemorrhage

    PubMed Central

    Parry-Jones, Adrian R; Di Napoli, Mario; Goldstein, Joshua N; Schreuder, Floris H B M; Tetri, Sami; Tatlisumak, Turgut; Yan, Bernard; van Nieuwenhuizen, Koen M; Dequatre-Ponchelle, Nelly; Lee-Archer, Matthew; Horstmann, Solveig; Wilson, Duncan; Pomero, Fulvio; Masotti, Luca; Lerpiniere, Christine; Godoy, Daniel Agustin; Cohen, Abigail S; Houben, Rik; Al-Shahi Salman, Rustam; Pennati, Paolo; Fenoglio, Luigi; Werring, David; Veltkamp, Roland; Wood, Edith; Dewey, Helen M; Cordonnier, Charlotte; Klijn, Catharina J M; Meligeni, Fabrizio; Davis, Stephen M; Huhtakangas, Juha; Staals, Julie; Rosand, Jonathan; Meretoja, Atte

    2015-01-01

    Objective There is little evidence to guide treatment strategies for intracerebral hemorrhage on vitamin K antagonists (VKA-ICH). Treatments utilized in clinical practice include fresh frozen plasma (FFP) and prothrombin complex concentrate (PCC). Our aim was to compare case fatality with different reversal strategies. Methods We pooled individual ICH patient data from 16 stroke registries in 9 countries (n = 10 282), of whom 1,797 (17%) were on VKA. After excluding 250 patients with international normalized ratio < 1.3 and/or missing data required for analysis, we compared all-cause 30-day case fatality using Cox regression. Results We included 1,547 patients treated with FFP (n = 377, 24%), PCC (n = 585, 38%), both (n = 131, 9%), or neither (n = 454, 29%). The crude case fatality and adjusted hazard ratio (HR) were highest with no reversal (61.7%, HR = 2.540, 95% confidence interval [CI] = 1.784–3.616, p < 0.001), followed by FFP alone (45.6%, HR = 1.344, 95% CI = 0.934–1.934, p = 0.112), then PCC alone (37.3%, HR = 1.445, 95% CI = 1.014–2.058, p = 0.041), compared to reversal with both FFP and PCC (27.8%, reference). Outcomes with PCC versus FFP were similar (HR = 1.075, 95% CI = 0.874–1.323, p = 0.492); 4-factor PCC (n = 441) was associated with higher case fatality compared to 3-factor PCC (n = 144, HR = 1.441, 95% CI = 1.041–1.995, p = 0.027). Interpretation The combination of FFP and PCC might be associated with the lowest case fatality in reversal of VKA-ICH, and FFP may be equivalent to PCC. Randomized controlled trials with functional outcomes are needed to establish the most effective treatment. PMID:25857223

  20. Cardiac electrophysiologic effects of a new calcium antagonist, lacidipine.

    PubMed

    Cerbai, E; DeBonfioli Cavalcabó, P; Masini, I; Visentin, S; Giotti, A; Mugelli, A

    1990-04-01

    Lacidipine is a new 1,4-dihydropyridine derivative with potent and long-lasting antihypertensive activity. We used intracellular microelectrodes to characterize the electrophysiologic properties of lacidipine on different cardiac preparations. Lacidipine (10(-8) -10(-6) M) dose-dependently decreased contractility of driven sheep Purkinje fibers. For concentrations less than or equal to 10(-7) M, this effect was associated with a selective decrease of the plateau height. Higher concentrations (3 X 10(-7) and 10(-6) M), however, affected action potential amplitude, overshoot, and maximum rate of depolarization. In the same range of concentrations, lacidipine did not affect normal automaticity of guinea-pig sinus node and sheep Purkinje fibers. Lacidipine (10(-6) M) consistently blocked barium-induced abnormal automaticity in Purkinje fibers and reduced the amplitude and Vmax of the slow action potentials induced by histamine (10(-5) M) in guinea pig papillary muscle depolarized by potassium (22 mM). The effect of lacidipine on the slow inward current (Isi) was studied in shortened Purkinje fibers under voltage-clamp conditions. Lacidipine (10(-7)-10(-6) M) reduced the Isi without affecting the I-V relationship. None of the effects of lacidipine was reversed by 2-h washout. The results indicate that lacidipine has calcium-antagonistic properties in cardiac tissues. Its cardiac effects occur at concentrations 100 times higher than those active in the vascular smooth muscle. The lack of recovery of the lacidipine effects suggests that its interaction with the calcium channel may occur at an inner site of the cell membrane. PMID:1691391

  1. Selective β2-adrenergic Antagonist Butoxamine Reduces Orthodontic Tooth Movement

    PubMed Central

    Sato, T.; Miyazawa, K.; Suzuki, Y.; Mizutani, Y.; Uchibori, S.; Asaoka, R.; Arai, M.; Togari, A.; Goto, S.

    2014-01-01

    Recently, involvement of the sympathetic nervous system in bone metabolism has attracted attention. β2-Adrenergic receptor (β2-AR) is presented on osteoblastic and osteoclastic cells. We previously demonstrated that β-AR blockers at low dose improve osteoporosis with hyperactivity of the sympathetic nervous system via β2-AR blocking, while they may have a somewhat inhibitory effect on osteoblastic activity at high doses. In this study, the effects of butoxamine (BUT), a specific β2-AR antagonist, on tooth movement were examined in spontaneously hypertensive rats (SHR) showing osteoporosis with hyperactivity of the sympathetic nervous system. We administered BUT (1 mg/kg) orally, and closed-coil springs were inserted into the upper-left first molar. After sacrifice, we calculated the amount of tooth movement and analyzed the trabecular microarchitecture and histomorphometry. The distance in the SHR control was greater than that in the Wistar-Kyoto rat group, but no significant difference was found in the SHR treated with BUT compared with the Wistar-Kyoto rat control. Analysis of bone volume per tissue volume, trabecular number, and osteoclast surface per bone surface in the alveolar bone showed clear bone loss by an increase of bone resorption in SHR. In addition, BUT treatment resulted in a recovery of alveolar bone loss. Furthermore, TH-immunoreactive nerves in the periodontal ligament were increased by tooth movement, and BUT administration decreased TH-immunoreactive nerves. These results suggest that BUT prevents alveolar bone loss and orthodontic tooth movement via β2-AR blocking. PMID:24868013

  2. Calcium antagonist properties of the bisbenzylisoquinoline alkaloid cycleanine.

    PubMed

    Martínez, J A; Bello, A; Rubio, L L; Rodríguez, C; Galán, L; Caudales, E; Alvarez, J L

    1998-01-01

    The alkaloid cycleanine ([12aR-(12aR,24aR)]-2,3,12a,13,14,15,24,24a-octa hydro-5,6,17,18- tetramethoxy-1,13-dimethyl-8, 11:20,23-dietheno-1H,12H [1,10]dioxacyclooctadecino[2,3,4-ij:11,12,13-i'j']diisoquinolin e) was extracted from the bulbs of Stephania glabra (Roxb) Miers and its effects on cardiac and smooth muscle preparations were studied and compared to those of nifedipine (1,4-dihydro-2, 6-dimethyl-4-(2-nitrophenyl)-3,5-pyridine dicarboxylic acid dimethylesther). Cycleanine inhibited the KCl-induced contraction of rabbit aortic rings with higher potency than nifedipine. IC50s for cycleanine and nifedipine were 0.8 and 7.10(-9) M respectively. Cycleanine had minor effects on the norepinephrine-induced contraction of rabbit aortic rings. Cycleanine and nifedipine also depressed the contraction of rat ventricular preparations but with lower potency (IC50 = 3 and 0.03.10(-6) M respectively). Action potential duration of rat right ventricular strips was decreased by both compounds. L-type Ca-current (ICaL) of single rat ventricular cardiomyocytes was inhibited by cycleanine in a voltage- and frequency-dependent manner. With a higher potency nifedipine inhibited ICaL in a tonic and almost frequency-independent manner. The results suggest that cycleanine can act as a potent vascular selective Ca-antagonist. PMID:9565772

  3. Antagonistic interaction between Trichoderma asperellum and Phytophthora capsici in vitro*

    PubMed Central

    Jiang, Heng; Zhang, Liang; Zhang, Jing-ze; Ojaghian, Mohammad Reza; Hyde, Kevin D.

    2016-01-01

    Phytophthora capsici is a phytopathogen that causes a destructive pepper blight that is extremely difficult to control. Using a fungicide application against the disease is costly and relatively ineffective and there is also a huge environmental concern about the use of such chemicals. The genus Trichoderma has been known to have a potential biocontrol issue. In this paper we investigate the mechanism for causing the infection of T. asperellum against P. capsici. Trichoderma sp. (isolate CGMCC 6422) was developed to have a strong antagonistic action against hyphae of P. capsici through screening tests. The strain was identified as T. asperellum through using a combination of morphological characteristics and molecular data. T. asperellum was able to collapse the mycelium of the colonies of the pathogen through dual culture tests by breaking down the pathogenic hyphae into fragments. The scanning electron microscope showed that the hyphae of T. asperellum surrounded and penetrated the pathogens hyphae, resulting in hyphal collapse. The results show that seven days after inoculation, the hyphae of the pathogen were completely degraded in a dual culture. T. asperellum was also able to enter the P. capsici oospores through using oogonia and then developed hyphae and produced conidia, leading to the disintegration of the oogonia and oospores. Seven days after inoculation, an average 10.8% of the oospores were infected, but at this stage, the structures of oospores were still intact. Subsequently, the number of infected oospores increased and the oospores started to collapse. Forty-two days after inoculation, almost all the oospores were infected, with 9.3% of the structures of the oospores being intact and 90.7% of the oospores having collapsed.

  4. Antagonists of retinoic acid receptors (RARs) are potent growth inhibitors of prostate carcinoma cells

    PubMed Central

    Hammond, L A; Krinks, C H Van; Durham, J; Tomkins, S E; Burnett, R D; Jones, E L; Chandraratna, R A S; Brown, G

    2001-01-01

    Novel synthetic antagonists of retinoic acid receptors (RARs) have been developed. To avoid interference by serum retinoids when testing these compounds, we established serum-free grown sub-lines (>3 years) of the prostate carcinoma lines LNCaP, PC3 and DU145. A high affinity pan-RAR antagonist (AGN194310, Kd for binding to RARs = 2–5 nM) inhibited colony formation (by 50%) by all three lines at 16–34 nM, and led to a transient accumulation of flask-cultured cells in G1 followed by apoptosis. AGN194310 is 12–22 fold more potent than all-trans retinoic acid (ATRA) against cell lines and also more potent in inhibiting the growth of primary prostate carcinoma cells. PC3 and DU145 cells do not express RARβ, and an antagonist with predominant activity at RARβ and RARγ (AGN194431) inhibited colony formation at concentrations (∼100 nM) commensurate with a Kd value of 70 nM at RARγ. An RARα antagonist (AGN194301) was less potent (IC50 ∼200 nM), but was more active than specific agonists of RARα and of βγ. A component(s) of serum and of LNCaP-conditioned medium diminishes the activity of antagonists: this factor is not the most likely candidates IGF-1 and EGF. In vitro studies of RAR antagonists together with data from RAR-null mice lead to the hypothesis that RARγ-regulated gene transcription is necessary for the survival and maintenance of prostate epithelium. The increased potencies of RAR antagonists, as compared with agonists, suggest that antagonists may be useful in the treatment of prostate carcinoma. © 2001 Cancer Research Campaign http://www.bjcancer.com PMID:11487280

  5. Rigidified 2-aminopyrimidines as histamine H4 receptor antagonists: effects of substitution about the rigidifying ring.

    PubMed

    Koenig, John R; Liu, Huaqing; Drizin, Irene; Witte, David G; Carr, Tracy L; Manelli, Arlene M; Milicic, Ivan; Strakhova, Marina I; Miller, Thomas R; Esbenshade, Timothy A; Brioni, Jorge D; Cowart, Marlon

    2010-03-15

    Three novel series of histamine H(4) receptor (H(4)R) antagonists containing the 2-aminopyrimidine motif are reported. The best of these compounds display good in vitro potency in both functional and binding assays. In addition, representative compounds are able to completely block itch responses when dosed ip in a mouse model of H(4)-agonist induced scratching, thus demonstrating their activities as H(4)R antagonists. PMID:20171098

  6. Synthesis of oxazolo[4,5-c]quinoline TRPV1 antagonists.

    PubMed

    Voight, Eric A; Daanen, Jerome F; Kort, Michael E

    2010-12-17

    An efficient synthesis of 2-amino-oxazolo[4,5-c]quinoline TRPV1 antagonists is described via a thiourea formation/carbodiimide cyclization sequence. Synthetic route optimization eliminates intermediate isolations and facilitates the rapid preparation of a series of novel pentacyclic TRPV1 antagonists. From this series, compound (S)-4 was identified as a potent and selective ligand for the TRPV1 ion channel. PMID:21090730

  7. Effect of H2 antagonists on outcome of simple closure for perforated duodenal ulcer.

    PubMed

    Koh, K B; Chang, K W

    1992-10-01

    The treatment of perforated duodenal ulcer is controversial. Since the advent of H2 antagonists, the number of ulcer operations has declined tremendously. We wanted to find out if the addition of a H2 antagonist after simple closure of a perforated duodenal ulcer would change the outcome and therefore reviewed 46 patients treated in this fashion. Our results show that this is a safe and effective way of treating patients with perforated duodenal ulcer. PMID:1360708

  8. Three years in vivo wear: core-ceramic, veneers, and enamel antagonists

    PubMed Central

    Esquivel-Upshaw, Josephine F.; Rose, William F.; Barrett, Allyson A.; Oliveira, Erica R.; Yang, Mark C.K.; Clark, Arthur E.; Anusavice, Kenneth J.

    2012-01-01

    Objectives Test the hypotheses that there are equivalent wear rates for enamel-versus-enamel and ceramic-versus-enamel, analyzing the in vivo wear of crown ceramics, their natural enamel antagonists, and the corresponding two contralateral teeth; and, that bite force does not correlate with the wear. Methods A controlled, clinical trial was conducted involving patients needing full coverage crowns opposing enamel antagonists. Bite forces were measured using a bilateral gnathodynamometer. Single-unit restorations of metal/ceramic (Argedent 62, Argen Corp/IPS d.SIGN veneer); or, core-ceramic/veneer from either, Empress2/Eris, or e.maxPress core/e.maxCeram glaze (ceramics: Ivoclar Vivadent, USA) were randomly assigned, fabricated and cemented. Impressions were made of the ceramic crowns, as well as each maxillary and mandibular quadrant at one week (baseline) and one, two and three years. Resulting models were scanned (3D laser scanner). Maximum wear was calculated by superimposing baseline with annual images. Results There were a total of thirty-six crowns required for thirty-one patients. Each restoration had three associated enamel teeth; 1) crown, 2) antagonist, 3) contralateral, and 4) contralateral-antagonist. SAS PROC MIXED (α=0.05) indicated no statistical significance for mean maximum wear among crown ceramics, enamel antagonists and contralaterals. However, enamel wear was statistically significant in relation to intraoral location (p=0.04) and among years (p<0.02). Analyzed alone, the enamel contralateral-antagonist exhibited significantly greater wear (p<0.001). Considering all wear sites, there was no correlation with bite force (p=0.15). Significance The ceramics and their antagonists exhibited in vivo wear rates within the range of normal enamel. Future studies should examine the wear implications of the contralateral-antagonist enamel. PMID:22410113

  9. Histamine H3 receptor antagonist decreases cue-induced alcohol reinstatement in mice.

    PubMed

    Nuutinen, Saara; Mäki, Tiia; Rozov, Stanislav; Bäckström, Pia; Hyytiä, Petri; Piepponen, Petteri; Panula, Pertti

    2016-07-01

    We have earlier found that the histamine H3 receptor (H3R) antagonism diminishes motivational aspects of alcohol reinforcement in mice. Here we studied the role of H3Rs in cue-induced reinstatement of alcohol seeking in C57BL/6J mice using two different H3R antagonists. Systemic administration of H3R antagonists attenuated cue-induced alcohol seeking suggesting that H3R antagonists may reduce alcohol craving. To understand how alcohol affects dopamine and histamine release, a microdialysis study was performed on C57BL/6J mice and the levels of histamine, dopamine and dopamine metabolites were measured in the nucleus accumbens. Alcohol administration was combined with an H3R antagonist pretreatment to reveal whether modulation of H3R affects the effects of alcohol on neurotransmitter release. Alcohol significantly increased the release of dopamine in the nucleus accumbens but did not affect histamine release. Pretreatment with H3R antagonist ciproxifan did not modify the effect of alcohol on dopamine release. However, histamine release was markedly increased with ciproxifan. In conclusion, our findings demonstrate that H3R antagonism attenuates cue-induced reinstatement of alcohol seeking in mice. Alcohol alone does not affect histamine release in the nucleus accumbens but H3R antagonist instead increases histamine release significantly suggesting that the mechanism by which H3R antagonist inhibits alcohol seeking found in the present study and the decreased alcohol reinforcement, reward and consumption found earlier might include alterations in the histaminergic neurotransmission in the nucleus accumbens. These findings imply that selective antagonists of H3Rs could be a therapeutic strategy to prevent relapse and possibly diminish craving to alcohol use. This article is part of the Special Issue entitled 'Histamine Receptors'. PMID:26107118

  10. Characterization and bioactivity of novel calcium antagonists - N-methoxy-benzyl haloperidol quaternary ammonium salt

    PubMed Central

    Chen, Yi-Cun; Zhu, Wei; Zhong, Shu-Ping; Zheng, Fu-Chun; Gao, Fen-Fei; Zhang, Yan-Mei; Xu, Han; Zheng, Yan-Shan; Shi, Gang-Gang

    2015-01-01

    BACKGROUND AND PURPOSE Calcium antagonists play an important role in clinical practice. However, most of them have serious side effects. We have synthesized a series of novel calcium antagonists, quaternary ammonium salt derivatives of haloperidol with N-p-methoxybenzyl (X1), N-m-methoxybenzyl (X2) and N-o-methoxybenzyl (X3) groups. The objective of this study was to investigate the bioactivity of these novel calcium antagonists, especially the vasodilation activity and cardiac side-effects. The possible working mechanisms of these haloperidol derivatives were also explored. EXPERIMENTAL APPROACH Novel calcium antagonists were synthesized by amination. Compounds were screened for their activity of vasodilation on isolated thoracic aortic ring of rats. Their cardiac side effects were explored. The patch-clamp, confocal laser microscopy and the computer-fitting molecular docking experiments were employed to investigate the possible working mechanisms of these calcium antagonists. RESULTS The novel calcium antagonists, X1, X2 and X3 showed stronger vasodilation effect and less cardiac side effect than that of classical calcium antagonists. They blocked L-type calcium channels with an potent effect order of X1 > X2 > X3. Consistently, X1, X2 and X3 interacted with different regions of Ca2+-CaM-CaV1.2 with an affinity order of X1 > X2 > X3. CONCLUSIONS The new halopedidol derivatives X1, X2 and X3 are novel calcium antagonists with stronger vasodilation effect and less cardiac side effect. They could have wide clinical application. PMID:26544729

  11. Design and evaluation of xanthine based adenosine receptor antagonists: Potential hypoxia targeted immunotherapies

    PubMed Central

    Thomas, Rhiannon; Lee, Joslynn; Chevalier, Vincent; Sadler, Sara; Selesniemi, Kaisa; Hatfield, Stephen; Sitkovsky, Michail; Ondrechen, Mary Jo; Jones, Graham B.

    2015-01-01

    Molecular modeling techniques were applied to the design, synthesis and optimization of a new series of xanthine based adenosine A2A receptor antagonists. The optimized lead compound was converted to a PEG derivative and a functional in vitro bioassay used to confirm efficacy. Additionally, the PEGylated version showed enhanced aqueous solubility and was inert to photoisomerization, a known limitation of existing antagonists of this class. PMID:24126093

  12. Serotonin 2C receptor antagonists induce fast-onset antidepressant effects.

    PubMed

    Opal, M D; Klenotich, S C; Morais, M; Bessa, J; Winkle, J; Doukas, D; Kay, L J; Sousa, N; Dulawa, S M

    2014-10-01

    Current antidepressants must be administered for several weeks to produce therapeutic effects. We show that selective serotonin 2C (5-HT2C) antagonists exert antidepressant actions with a faster-onset (5 days) than that of current antidepressants (14 days) in mice. Subchronic (5 days) treatment with 5-HT2C antagonists induced antidepressant behavioral effects in the chronic forced swim test (cFST), chronic mild stress (CMS) paradigm and olfactory bulbectomy paradigm. This treatment regimen also induced classical markers of antidepressant action: activation of cAMP response element-binding protein (CREB) and induction of brain-derived neurotrophic factor (BDNF) in the medial prefrontal cortex (mPFC). None of these effects were induced by subchronic treatment with citalopram, a prototypical selective serotonin reuptake inhibitor (SSRI). Local infusion of 5-HT2C antagonists into the ventral tegmental area was sufficient to induce BDNF in the mPFC, and dopamine D1 receptor antagonist treatment blocked the antidepressant behavioral effects of 5-HT2C antagonists. 5-HT2C antagonists also activated mammalian target of rapamycin (mTOR) and eukaryotic elongation factor 2 (eEF2) in the mPFC, effects recently linked to rapid antidepressant action. Furthermore, 5-HT2C antagonists reversed CMS-induced atrophy of mPFC pyramidal neurons. Subchronic SSRI treatment, which does not induce antidepressant behavioral effects, also activated mTOR and eEF2 and reversed CMS-induced neuronal atrophy, indicating that these effects are not sufficient for antidepressant onset. Our findings reveal that 5-HT2C antagonists are putative fast-onset antidepressants, which act through enhancement of mesocortical dopaminergic signaling. PMID:24166413

  13. Modulation of bitter taste perception by a small molecule hTAS2R antagonist

    PubMed Central

    Slack, Jay P.; Brockhoff, Anne; Batram, Claudia; Menzel, Susann; Sonnabend, Caroline; Born, Stephan; Galindo, Maria Mercedes; Kohl, Susann; Thalmann, Sophie; Ostopovici-Halip, Liliana; Simons, Christopher T.; Ungureanu, Ioana; Duineveld, Kees; Bologa, Cristian G.; Behrens, Maik; Furrer, Stefan; Oprea, Tudor I.; Meyerhof, Wolfgang

    2010-01-01

    Summary Human bitter taste is mediated by the hTAS2R family of G protein-coupled receptors [1-4]. The discovery of the hTAS2Rs enables the potential to develop specific bitter receptor antagonists that could be beneficial as chemical probes to examine the role of bitter receptor function in gustatory and non-gustatory tissues. In addition, they could have widespread utility in food and beverages fortified with vitamins, antioxidants and other nutraceuticals since many of these have unwanted bitter aftertastes. We employed a high-throughput screening approach to discover a novel bitter receptor antagonist (GIV3727) that inhibits activation of hTAS2R31 by saccharin and acesulfame K, two common artificial sweeteners. Pharmacological analyses revealed that GIV3727 likely acts as an orthosteric, insurmountable antagonist of hTAS2R31. Surprisingly, we also found that this compound could inhibit five additional hTAS2Rs, including the closely related receptor hTAS2R43. Molecular modeling and site-directed mutagenesis studies suggest that two residues in helix seven are important for antagonist activity in hTAS2R43/31. In human sensory trials, GIV3727 significantly reduced the bitterness associated with the two sulphonamide sweeteners, indicating that TAS2R antagonists are active in vivo. Our results demonstrate that small molecule bitter receptor antagonists can effectively reduce the bitter taste qualities of foods, beverages, and pharmaceuticals. PMID:20537538

  14. Slow wave sleep-inducing effects of first generation H1-antagonists.

    PubMed

    Saitou, K; Kaneko, Y; Sugimoto, Y; Chen, Z; Kamei, C

    1999-10-01

    The present study was performed to see if first-generation histamine H1-antagonists are useful sedative-hypnotic drugs. Increases in electroencephalogram (EEG) power spectra of the delta band (0-4 Hz) at the frontal cortex and theta band (4-8 Hz) at the hippocampus in rats were used as an indexes of sleep. The H1-antagonists used in this study resulted in a decrease in sleep latency and an increase in sleep duration (slow wave sleep). The rate of REM (rapid eye movement) sleep during slow wave sleep was decreased by H1-antagonists and brotizolam. The order of potency of H1-antagonists for the reduction in sleep latency (from greatest to least) was promethazine>chlorpheniramine>diphenhydramine and pyrilamine, and that for the increase in sleep duration was chlorpheniramine>promethazine>diphenhydramine and pyrilamine. Brotizolam was more potent than these H1-antagonists, with 14-18-fold and 4-14-fold greater effects on sleep latency and duration, respectively. These results clearly show that H1-antagonists are effective in mild to moderate insomnia as sedative-hypnotic drugs. PMID:10549859

  15. QT interval prolongation and torsade de pointes: Synergistic effect of flecainide and H1 receptor antagonists

    PubMed Central

    Acosta-Materán, Carlos; Díaz-Oliva, Eloy; Fernández-Rodríguez, Diego; Hernández-Afonso, Julio

    2016-01-01

    A high percentage of patients having atrial fibrillation (AF) presents with paroxysmal AF. Flecainide, the prototypic class Ic anti-arrhythmic drug is the most effective drug to maintain sinus rhythm in this subgroup of patients, though the drug has potential pro-arrhythmic effects. Furthermore, the H1 receptor antagonists are the most commonly prescribed drugs for the symptomatic treatment of pruritus. Despite having low number of adverse effects, the H1 receptor antagonists have cardiotoxic effects. Flecainide and H1 receptor antagonists present arrhythmic complications including QT interval prolongation and torsade de pointes (TdP). The case presented here is a 65-year-old female who was diagnosed of atrial fibrillation and presented with rashes in lower extremities. The patient was treated using flecainide and H1 receptor antagonists (loratadine and hydroxyzine) that prolonged QT interval and induced TdP. The concomitant administration of flecainide and H1 receptor antagonists seems to have a synergistic effect in QT interval prolongation and subsequent TdP. The concurrent administration of H1 receptor antagonists to patients receiving class Ic anti-arrhythmic drugs should be avoided in order to reduce arrhythmic risk in this population. PMID:27440957

  16. Analyzing the antagonistic potential of the lichen microbiome against pathogens by bridging metagenomic with culture studies

    PubMed Central

    Cernava, Tomislav; Müller, Henry; Aschenbrenner, Ines A.; Grube, Martin; Berg, Gabriele

    2015-01-01

    Naturally occurring antagonists toward pathogens play an important role to avoid pathogen outbreaks in ecosystems, and they can be applied as biocontrol agents for crops. Lichens present long-living symbiotic systems continuously exposed to pathogens. To analyze the antagonistic potential in lichens, we studied the bacterial community active against model bacteria and fungi by an integrative approach combining isolate screening, omics techniques, and high resolution mass spectrometry. The highly diverse microbiome of the lung lichen [Lobaria pulmonaria (L.) Hoffm.] included an abundant antagonistic community dominated by Stenotrophomonas, Pseudomonas, and Burkholderia. While antagonists represent 24.5% of the isolates, they were identified with only 7% in the metagenome; which means that they were overrepresented in the culturable fraction. Isolates of the dominant antagonistic genus Stenotrophomonas produced spermidine as main bioactive component. Moreover, spermidine-related genes, especially for the transport, were identified in the metagenome. The majority of hits identified belonged to Alphaproteobacteria, while Stenotrophomonas-specific spermidine synthases were not present in the dataset. Evidence for plant growth promoting effects was found for lichen-associated strains of Stenotrophomonas. Linking of metagenomic and culture data was possible but showed partly contradictory results, which required a comparative assessment. However, we have shown that lichens are important reservoirs for antagonistic bacteria, which open broad possibilities for biotechnological applications. PMID:26157431

  17. Analyzing the antagonistic potential of the lichen microbiome against pathogens by bridging metagenomic with culture studies.

    PubMed

    Cernava, Tomislav; Müller, Henry; Aschenbrenner, Ines A; Grube, Martin; Berg, Gabriele

    2015-01-01

    Naturally occurring antagonists toward pathogens play an important role to avoid pathogen outbreaks in ecosystems, and they can be applied as biocontrol agents for crops. Lichens present long-living symbiotic systems continuously exposed to pathogens. To analyze the antagonistic potential in lichens, we studied the bacterial community active against model bacteria and fungi by an integrative approach combining isolate screening, omics techniques, and high resolution mass spectrometry. The highly diverse microbiome of the lung lichen [Lobaria pulmonaria (L.) Hoffm.] included an abundant antagonistic community dominated by Stenotrophomonas, Pseudomonas, and Burkholderia. While antagonists represent 24.5% of the isolates, they were identified with only 7% in the metagenome; which means that they were overrepresented in the culturable fraction. Isolates of the dominant antagonistic genus Stenotrophomonas produced spermidine as main bioactive component. Moreover, spermidine-related genes, especially for the transport, were identified in the metagenome. The majority of hits identified belonged to Alphaproteobacteria, while Stenotrophomonas-specific spermidine synthases were not present in the dataset. Evidence for plant growth promoting effects was found for lichen-associated strains of Stenotrophomonas. Linking of metagenomic and culture data was possible but showed partly contradictory results, which required a comparative assessment. However, we have shown that lichens are important reservoirs for antagonistic bacteria, which open broad possibilities for biotechnological applications. PMID:26157431

  18. Molecular Gymnastics: Mechanisms of HIV-1 Resistance to CCR5 Antagonists and Impact on Virus Phenotypes.

    PubMed

    Roche, Michael; Borm, Katharina; Flynn, Jacqueline K; Lewin, Sharon R; Churchill, Melissa J; Gorry, Paul R

    2016-01-01

    Human immunodeficiency virus type 1 (HIV-1) enters host cells through the binding of its envelope glycoproteins (Env) to the host cell receptor CD4 and then subsequent binding to a chemokine coreceptor, either CCR5 or CXCR4. CCR5 antagonists are a relatively recent class addition to the armamentarium of anti-HIV-1 drugs. These compounds act by binding to a hydrophobic pocket formed by the transmembrane helices of CCR5 and altering the conformation of the extracellular domains, such that they are no longer recognized by Env. Maraviroc is the first drug within this class to be licenced for use in HIV-1 therapy regimens. HIV resistance to CCR5 antagonists occurs either through outgrowth of pre-existing CXCR4-using viruses, or through acquisition of the ability of CCR5-using HIV-1 to use the antagonist bound form of CCR5. In the latter scenario, the mechanism underlying resistance is through complex alterations in the way that resistant Envs engage CCR5. These significant changes are unlikely to occur without consequence to the viral entry phenotype and may also open up new avenues to target CCR5 antagonist resistant viruses. This review discusses the mechanism of action of CCR5 antagonists, how HIV resistance to CCR5 antagonists occurs, and the subsequent effects on Env function. PMID:26324043

  19. Effects of certain muscarinic antagonists on the actions of anticholinesterases on cat skeletal muscle.

    PubMed

    Brimblecombe, R W; French, M C; Webb, S N

    1979-04-01

    1. The effects of some muscarinic antagonists, namely, N-ethyl-2-pyrrolidylmethyl-cyclopentylphenyl glycollate (PMCG), N-methyl-4-piperidyl-phenylcyclohexyl glycollate (PPCG, racemate and R and S enantiomers) and 4'-N-methyl-piperidyl-1-phenyl-cyclopentane carboxylate (G3063) on organophosphate (sarin, soman)- and carbamate (neostigmine)-induced twitch augmentation have been studied in cat soleus muscle. 2. The results of a preliminary study comparing the potency of sarin and soman in inhibiting the acetylcholinesterase activity of muscle in relation to the effect on the maximal twitch response indicated that there is not a simple relationship between degree of enzyme inhibition by these drugs and alteration of muscle function. 3. The muscarinic antagonists studied were capable of preventing or reversing sarin-, soman- or neostigmine-induced twitch augmentation. Doses sufficient to give complete protection from the effects of the anticholinesterase agents had little or no effect on the twitch response of normal muscle. 4. The protective action of these muscarinic antagonists is dose-dependent but independent of known antagonist actions at muscarinic receptors. 5. The effects of some local anaesthetics (lignocaine, prilocaine, cinchocaine, procaine) and other membrane stabilizers (quinine, ketamine, chlorpromazine, triflupromazine) were compared with those of the muscarinic antagonists in an attempt to elucidate the mode of action of these acetylcholine antagonists. The evidence is insufficient to exclude the involvement of a membrane stabilizing action. PMID:435681

  20. Repeated dosing of ABT-102, a potent and selective TRPV1 antagonist, enhances TRPV1-mediated analgesic activity in rodents, but attenuates antagonist-induced hyperthermia.

    PubMed

    Honore, Prisca; Chandran, Prasant; Hernandez, Gricelda; Gauvin, Donna M; Mikusa, Joseph P; Zhong, Chengmin; Joshi, Shailen K; Ghilardi, Joseph R; Sevcik, Molly A; Fryer, Ryan M; Segreti, Jason A; Banfor, Patricia N; Marsh, Kennan; Neelands, Torben; Bayburt, Erol; Daanen, Jerome F; Gomtsyan, Arthur; Lee, Chih-Hung; Kort, Michael E; Reilly, Regina M; Surowy, Carol S; Kym, Philip R; Mantyh, Patrick W; Sullivan, James P; Jarvis, Michael F; Faltynek, Connie R

    2009-03-01

    Transient receptor potential vanilloid type 1 (TRPV1) is a ligand-gated ion channel that functions as an integrator of multiple pain stimuli including heat, acid, capsaicin and a variety of putative endogenous lipid ligands. TRPV1 antagonists have been shown to decrease inflammatory pain in animal models and to produce limited hyperthermia at analgesic doses. Here, we report that ABT-102, which is a potent and selective TRPV1 antagonist, is effective in blocking nociception in rodent models of inflammatory, post-operative, osteoarthritic, and bone cancer pain. ABT-102 decreased both spontaneous pain behaviors and those evoked by thermal and mechanical stimuli in these models. Moreover, we have found that repeated administration of ABT-102 for 5-12 days increased its analgesic activity in models of post-operative, osteoarthritic, and bone cancer pain without an associated accumulation of ABT-102 concentration in plasma or brain. Similar effects were also observed with a structurally distinct TRPV1 antagonist, A-993610. Although a single dose of ABT-102 produced a self-limiting increase in core body temperature that remained in the normal range, the hyperthermic effects of ABT-102 effectively tolerated following twice-daily dosing for 2 days. Therefore, the present data demonstrate that, following repeated administration, the analgesic activity of TRPV1 receptor antagonists is enhanced, while the associated hyperthermic effects are attenuated. The analgesic efficacy of ABT-102 supports its advancement into clinical studies. PMID:19135797

  1. USDA-ARS, OHIO STATE UNIVERSITY COOPERATIVE RESEARCH ON BIOLOGICALLY CONTROLLING FUSARIUM HEAD BLIGHT: 2. 2002 FIELD TESTS OF ANTAGONIST AND ANTAGONIST/FUNGICIDE MIXTURES

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Research on optimizing methods for selectively isolating, mass producing, and utilizing microbial antagonists effective against Fusarium head blight (FHB) on wheat was initiated in 1997 at NCAUR in Peoria, IL, in conjunction with the Ohio State University. Biological control agents discovered in th...

  2. Antagonist Models for Relapse Prevention and Reducing HIV Risk.

    PubMed

    Woody, George E; Krupitsky, Evgeny; Zvartau, Edwin

    2016-09-01

    Naltrexone is an antagonist that binds tightly to μ-opioid receptors and blocks the subjective and analgesic effects of opioids. It does not produce physiologic dependence and precipitates withdrawal if administered to an opioid dependent person, thus starting it must begin with detoxification. It was first available in the mid-1970s as a 50 mg tablet that blocked opioids for 24-36 h if taken daily, or every 2-3 days at higher doses - for example: 100 mg Monday and Wednesday, 150 mg on Friday. From a pharmacological perspective it worked very well and was hoped to be an effective treatment but results were disappointing due to low patient interest and high dropout followed by relapse. Interest in it waned but rose again in the late 1990's when injecting opioid use and the rapid spread of HIV in the Russian Federation converged with an international interest in reducing the spread of HIV. One result was a series of meetings sponsored by the U.S. National Institute on Drug Abuse (NIDA) and Pavlov State Medical University in St. Petersburg, Russian Federation, on ways to reduce the spread of HIV in that country. Addiction treatment was a clear priority and discussions showed that naltrexone could have a role since agonist treatment is against Russian law but naltrexone is approved and the government funds over 25,000 beds for detoxification, which is the first step in starting naltrexone treatment. These meetings were followed by NIDA studies that showed better compliance to oral naltrexone than in prior U.S. studies with the expected reductions in HIV injecting risk for those that stayed in treatment. These events and findings provided a background and identified an infrastructure for the study that led to FDA approval of extended release injectable naltrexone for preventing relapse to opioid dependence. This paper will briefly review findings from these studies and end with comments on the potential role of extended release naltrexone as a meaningful addition

  3. Roles of Amino Acids and Subunits in Determining the Inhibition of Nicotinic Acetylcholine Receptors by Competitive Antagonists

    PubMed Central

    Dilger, James P.; Vidal, Ana Maria; Liu, Man; Mettewie, Claire; Suzuki, Takahiro; Pham, Anh; Demazumder, Deeptankar

    2008-01-01

    Background Binding sites for agonists and competitive antagonists (nondepolarizing neuromuscular blocking agents) are located at the α–δ and α–ε subunit interfaces of adult nicotinic acetylcholine receptors. Most information about the amino acids that participate in antagonist binding comes from binding studies with (+)-tubocurarine and metocurine. These bind selectively to the α–ε interface but are differentially sensitive to mutations. To test the generality of this observation, the authors measured current inhibition by five competitive antagonists on wild-type and mutant acetylcholine receptors. Methods HEK293 cells were transfected with wild-type or mutant (αY198F, εD59A, εD59N, εD173A, εD173N, δD180K) mouse muscle acetylcholine receptor complementary DNA. Outside-out patches were excised and perfused with acetylcho-line in the absence and presence of antagonist. Concentration–response curves were constructed to determine antagonist IC50. An antagonist-removal protocol was used to determine dissociation and association rates. Results Effects of mutations were antagonist specific. αY198F decreased the IC50 of (+)-tubocurarine 10-fold, increased the IC50 of vecuronium 5-fold, and had smaller effects on other antagonists. (+)-Tubocurarine was the most sensitive antagonist to εD173 mutations. εD59 mutations had large effects on metocurine and cisatracurium. δD180K decreased inhibition by pancuronium, vecuronium, and cisatracurium. Inhibition by these antagonists was increased for receptors containing two δ subunits but no ε subunit. Differences in IC50 arose from differences in both dissociation and association rates. Conclusion Competitive antagonists exhibited different patterns of sensitivity to mutations. Except for pancuronium, the antagonists were sensitive to mutations at the α–ε interface. Pancuronium, vecuronium, and cisatracurium were selective for the α–δ interface. This suggests the possibility of synergistic

  4. Both glutamate receptor antagonists and prefrontal cortex lesions prevent induction of cocaine sensitization and associated neuroadaptations.

    PubMed

    Li, Y; Hu, X T; Berney, T G; Vartanian, A J; Stine, C D; Wolf, M E; White, F J

    1999-12-01

    Behavioral sensitization to psychomotor stimulants is accompanied by a number of alterations in the mesoaccumbens dopamine (DA) system, including DA autoreceptor subsensitivity in the ventral tegmental area (VTA) and DA D1 receptor supersensitivity in the nucleus accumbens (NAc). We investigated the role of excitatory amino acid (EAA) transmission in the induction of cocaine sensitization and these accompanying DA receptor alterations. To do so, we used three glutamate receptor antagonists, the noncompetitive NMDA receptor antagonist MK-801 (0.1 mg/kg), the competitive NMDA receptor antagonist CGS 19755 (10.0 mg/kg), and the AMPA receptor antagonist NBQX (12.5 mg/kg). Rats received daily double injections of either one of these antagonists or saline with either cocaine (15.0 mg/kg) or saline for 5 days. Cocaine sensitization was defined as an increase in horizontal locomotor activity in response to cocaine challenge (7.5 mg/kg) on the third day of withdrawal. All three antagonists prevented the induction of cocaine sensitization. Extracellular single cell recordings revealed that these antagonists also prevented the induction of DA autoreceptor subsensitivity in the VTA and DA D1 receptor supersensitivity in the NAc. To determine whether the relevant glutamate receptors were under regulation by medial prefrontal cortex (mPFC) EAA efferents, we next lesioned the mPFC bilaterally with ibotenic acid at least 7 days before repeated cocaine treatment began. These lesions also prevented the induction of cocaine sensitization and the associated neuroadaptations. Our findings indicate that glutamate transmission from mPFC to the mesoaccumbens DA system is critical for the induction of cocaine sensitization and its cellular correlates. PMID:10523754

  5. The intricate relationship between sexually antagonistic selection and the evolution of sex chromosome fusions.

    PubMed

    Matsumoto, Tomotaka; Kitano, Jun

    2016-09-01

    Sex chromosomes are among the most evolutionarily labile features in some groups of animals. One of the mechanisms causing structural changes of sex chromosomes is fusion with an autosome. A recent study showed that the establishment rates of Y chromosome-autosome fusions are much higher than those of other fusions (i.e., X-autosome, W-autosome, and Z-autosome fusions) in fishes and reptiles. Although sexually antagonistic selection may be one of the most important driving forces of sex chromosome-autosome fusions, a previous theoretical analysis showed that sexually antagonistic selection alone cannot explain the excess of Y-autosome fusions in these taxa. This previous analysis, however, is based on the assumption that sexually antagonistic selection is symmetric, sexually antagonistic alleles are maintained only by selection-drift balance (i.e., no supply of mutation), and only one type of fusion arises within a population. Here, we removed these assumptions and made an individual-based model to simulate the establishment of sex chromosome-autosome fusions. Our simulations showed that the highest establishment rate of Y-autosome fusion can be achieved when the fusion captures a rare male-beneficial allele, if the recurrent mutation rates are high enough to maintain the polymorphism of alleles with asymmetric, sexually antagonistic effects. Our results demonstrate that sexually antagonistic selection can influence the dynamics of sex chromosome structural changes, but the type of fusion that becomes the most common depends on fusion rates, recurrent mutation rates, and selection regimes. Because the evolutionary fate of sex chromosome-autosome fusions is highly parameter-sensitive, further attempts to empirically measure these parameters in natural populations are essential for a better understanding of the roles of sexually antagonistic selection in sex chromosome evolution. PMID:27259387

  6. Plant-Dependent Genotypic and Phenotypic Diversity of Antagonistic Rhizobacteria Isolated from Different Verticillium Host Plants

    PubMed Central

    Berg, Gabriele; Roskot, Nicolle; Steidle, Anette; Eberl, Leo; Zock, Angela; Smalla, Kornelia

    2002-01-01

    To study the effect of plant species on the abundance and diversity of bacterial antagonists, the abundance, the phenotypic diversity, and the genotypic diversity of rhizobacteria isolated from potato, oilseed rape, and strawberry and from bulk soil which showed antagonistic activity towards the soilborne pathogen Verticillium dahliae Kleb. were analyzed. Rhizosphere and soil samples were taken five times over two growing seasons in 1998 and 1999 from a randomized field trial. Bacterial isolates were obtained after plating on R2A (Difco, Detroit, Mich.) or enrichment in microtiter plates containing high-molecular-weight substrates followed by plating on R2A. A total of 5,854 bacteria isolated from the rhizosphere of strawberry, potato, or oilseed rape or bulk soil from fallow were screened by dual testing for in vitro antagonism towards Verticillium. The proportion of isolates with antagonistic activity was highest for strawberry rhizosphere (9.5%), followed by oilseed rape (6.3%), potato (3.7%), and soil (3.3%). The 331 Verticillium antagonists were identified by their fatty acid methyl ester profiles. They were characterized by testing their in vitro antagonism against other pathogenic fungi; their glucanolytic, chitinolytic, and proteolytic activities; and their BOX-PCR fingerprints. The abundance and composition of Verticillium antagonists was plant species dependent. A rather high proportion of antagonists from the strawberry rhizosphere was identified as Pseudomonas putida B (69%), while antagonists belonging to the Enterobacteriaceae (Serratia spp., Pantoea agglomerans) were mainly isolated from the rhizosphere of oilseed rape. For P. putida A and B plant-specific genotypes were observed, suggesting that these bacteria were specifically enriched in each rhizosphere. PMID:12089011

  7. Plant-dependent genotypic and phenotypic diversity of antagonistic rhizobacteria isolated from different Verticillium host plants.

    PubMed

    Berg, Gabriele; Roskot, Nicolle; Steidle, Anette; Eberl, Leo; Zock, Angela; Smalla, Kornelia

    2002-07-01

    To study the effect of plant species on the abundance and diversity of bacterial antagonists, the abundance, the phenotypic diversity, and the genotypic diversity of rhizobacteria isolated from potato, oilseed rape, and strawberry and from bulk soil which showed antagonistic activity towards the soilborne pathogen Verticillium dahliae Kleb. were analyzed. Rhizosphere and soil samples were taken five times over two growing seasons in 1998 and 1999 from a randomized field trial. Bacterial isolates were obtained after plating on R2A (Difco, Detroit, Mich.) or enrichment in microtiter plates containing high-molecular-weight substrates followed by plating on R2A. A total of 5,854 bacteria isolated from the rhizosphere of strawberry, potato, or oilseed rape or bulk soil from fallow were screened by dual testing for in vitro antagonism towards VERTICILLIUM: The proportion of isolates with antagonistic activity was highest for strawberry rhizosphere (9.5%), followed by oilseed rape (6.3%), potato (3.7%), and soil (3.3%). The 331 Verticillium antagonists were identified by their fatty acid methyl ester profiles. They were characterized by testing their in vitro antagonism against other pathogenic fungi; their glucanolytic, chitinolytic, and proteolytic activities; and their BOX-PCR fingerprints. The abundance and composition of Verticillium antagonists was plant species dependent. A rather high proportion of antagonists from the strawberry rhizosphere was identified as Pseudomonas putida B (69%), while antagonists belonging to the Enterobacteriaceae (Serratia spp., Pantoea agglomerans) were mainly isolated from the rhizosphere of oilseed rape. For P. putida A and B plant-specific genotypes were observed, suggesting that these bacteria were specifically enriched in each rhizosphere. PMID:12089011

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

    PubMed Central

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

    2012-01-01

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

  9. APORPHINOID ANTAGONISTS OF 5-HT2A RECEPTORS: FURTHER EVALUATION OF RING A SUBSTITUENTS AND THE SIZE OF RING C

    PubMed Central

    Ponnala, Shashikanth; Kapadia, Nirav; Navarro, Hernán A.; Harding, Wayne W.

    2014-01-01

    A series of ring A modified analogs of nantenine as well as structural variants in ring C were synthesized and evaluated for antagonist activity at 5-HT2A and α1A receptors. Halogenation improves 5-HT2A antagonist potency in molecules containing a C1 methoxyl/C2 methoxyl or C1 methoxyl/C2 hydroxyl moiety. Bromination or iodination (but not chlorination) with the latter moiety also significantly increased α1A antagonist potency. Homologation or contraction of ring C adversely affected antagonist activity at both receptors, implying that a six-membered ring C motif is beneficial for high antagonist potency at both receptors. Molecular docking studies suggest that the improved antagonist activity (by virtue of improved affinity) of C3 halogenated aporphines in this study, is attributable to favorable interactions with the C3 halogen and F339 and/or F340. PMID:24766771

  10. 5-HT2B Receptor Antagonists Inhibit Fibrosis and Protect from RV Heart Failure

    PubMed Central

    Janssen, Wiebke; Schymura, Yves; Novoyatleva, Tatyana; Luitel, Himal; Tretyn, Aleksandra; Pullamsetti, Soni Savai; Weissmann, Norbert; Seeger, Werner; Ghofrani, Hossein Ardeschir; Schermuly, Ralph Theo

    2015-01-01

    Objective. The serotonin (5-HT) pathway was shown to play a role in pulmonary hypertension (PH), but its functions in right ventricular failure (RVF) remain poorly understood. The aim of the current study was to investigate the effects of Terguride (5-HT2A and 2B receptor antagonist) or SB204741 (5-HT2B receptor antagonist) on right heart function and structure upon pulmonary artery banding (PAB) in mice. Methods. Seven days after PAB, mice were treated for 14 days with Terguride (0.2 mg/kg bid) or SB204741 (5 mg/kg day). Right heart function and remodeling were assessed by right heart catheterization, magnetic resonance imaging (MRI), and histomorphometric methods. Total secreted collagen content was determined in mouse cardiac fibroblasts isolated from RV tissues. Results. Chronic treatment with Terguride or SB204741 reduced right ventricular fibrosis and showed improved heart function in mice after PAB. Moreover, 5-HT2B receptor antagonists diminished TGF-beta1 induced collagen synthesis of RV cardiac fibroblasts in vitro. Conclusion. 5-HT2B receptor antagonists reduce collagen deposition, thereby inhibiting right ventricular fibrosis. Chronic treatment prevented the development and progression of pressure overload-induced RVF in mice. Thus, 5-HT2B receptor antagonists represent a valuable novel therapeutic approach for RVF. PMID:25667920

  11. Large-scale preparation and characterization of non-pegylated and pegylated superactive ovine leptin antagonist.

    PubMed

    Niv-Spector, Leonora; Shpilman, Michal; Boisclair, Yves; Gertler, Arieh

    2012-02-01

    Superactive ovine leptin antagonist (SOLA) was prepared by rational mutagenesis of the ovine leptin antagonist L39A/D40A/F41A mutant prepared previously in our lab by mutating wild type leptin to D23L/L39A/D40A/F41A. SOLA was expressed in Escherichia coli as insoluble inclusion bodies, refolded and purified to homogeneity (as evidenced by SDS-PAGE and analytical gel filtration) by ion-exchange chromatography. The purified protein was mono-pegylated at its N terminus by 20-kDa linear pegylation reagent. The D23L mutation resulted in ca. 5- to 6-fold increased affinity toward soluble human leptin binding domain and 6- to 8-fold increased inhibitory activity in two different in vitro bioassays. This increase was similar, though not identical, to our previous results with superactive mouse and human leptin antagonists. Pegylation decreased overall activity by 5- to 8-fold, but as shown previously for superactive mouse leptin antagonist, the prolonged half life in the circulation will likely result in higher activity in vivo. As amino acids 6-31 (VQDDTKTLIKTIVTRINDISHTQSVS), making up a main part of the first α-helix, are identical in human, mouse, rat, ovine, bovine and pig leptins, we anticipate that D23L mutations of the respective leptins will result in similar increases in affinity and consequent activity of other leptin antagonists. PMID:22040607

  12. New insights into the stereochemical requirements of the bradykinin B1 receptor antagonists binding.

    PubMed

    Lupala, Cecylia S; Gomez-Gutierrez, Patricia; Perez, Juan J

    2016-07-01

    Bradykinin (BK) is a nonapeptide involved in several pathophysiological conditions including among others, septic and haemorrhagic shock, anaphylaxis, arthritis, rhinitis, asthma, inflammatory bowel disease. Accordingly, BK antagonists have long been sought after for therapeutic intervention. Action of BK is mediated through two different G-protein coupled receptors known as B1 and B2. Although there are several B1 antagonists reported in literature, their pharmacological profile is not yet optimal so that new molecules need to be discovered. In the present work we have constructed an atomistic model of the B1 receptor and docked diverse available non-peptide antagonists in order to get a deeper insight into the structure-activity relationships involving binding to this receptor. The model was constructed by homology modeling using the chemokine CXC4 and bovine rhodopsin receptors as template. The model was further refined using molecular dynamics for 600ns with the protein embedded in a POPC bilayer. From the refinement process we obtained an average structure that was used for docking studies using the Glide software. Antagonists selected for the docking studies include Compound 11, Compound 12, Chroman28, SSR240612, NPV-SAA164 and PS020990. The results of the docking study underline the role of specific receptor residues in ligand binding. The results of this study permitted to define a pharmacophore that describes the stereochemical requirements of antagonist binding, and can be used for the discovery of new compounds. PMID:27469392

  13. Antagonistic interactions between endophytic cultivable bacterial communities isolated from the medicinal plant Echinacea purpurea.

    PubMed

    Maida, Isabel; Chiellini, Carolina; Mengoni, Alessio; Bosi, Emanuele; Firenzuoli, Fabio; Fondi, Marco; Fani, Renato

    2016-09-01

    In this work we have studied the antagonistic interactions existing among cultivable bacteria isolated from three ecological niches (rhizospheric soil, roots and stem/leaves) of the traditional natural medicinal plant Echinacea purpurea. The three compartments harboured different taxonomic assemblages of strains, which were previously reported to display different antibiotic resistance patterns, suggesting the presence of differential selective pressure due to antagonistic molecules in the three compartments. Antagonistic interactions were assayed by the cross-streak method and interpreted using a network-based analysis. In particular 'within-niche inhibition' and 'cross-niche inhibition' were evaluated among isolates associated with each compartment as well as between isolates retrieved from the three different compartments respectively. Data obtained indicated that bacteria isolated from the stem/leaves compartment were much more sensitive to the antagonistic activity than bacteria from roots and rhizospheric soil. Moreover, both the taxonomical position and the ecological niche might influence the antagonistic ability/sensitivity of different strains. Antagonism could play a significant role in contributing to the differentiation and structuring of plant-associated bacterial communities. PMID:26013664

  14. Genetic Diversity and Phylogeny of Antagonistic Bacteria against Phytophthora nicotianae Isolated from Tobacco Rhizosphere

    PubMed Central

    Jin, Fengli; Ding, Yanqin; Ding, Wei; Reddy, M.S.; Fernando, W.G. Dilantha; Du, Binghai

    2011-01-01

    The genetic diversity of antagonistic bacteria from the tobacco rhizosphere was examined by BOXAIR-PCR, 16S-RFLP, 16S rRNA sequence homology and phylogenetic analysis methods. These studies revealed that 4.01% of the 6652 tested had some inhibitory activity against Phytophthora nicotianae. BOXAIR-PCR analysis revealed 35 distinct amplimers aligning at a 91% similarity level, reflecting a high degree of genotypic diversity among the antagonistic bacteria. A total of 25 16S-RFLP patterns were identified representing over 33 species from 17 different genera. Our results also found a significant amount of bacterial diversity among the antagonistic bacteria compared to other published reports. For the first time; Delftia tsuruhatensis, Stenotrophomonas maltophilia, Advenella incenata, Bacillus altitudinis, Kocuria palustris, Bacillus licheniformis, Agrobacterium tumefaciens and Myroides odoratimimus are reported to display antagonistic activity towards Phytophthora nicotianae. Furthermore, the majority (75%) of the isolates assayed for antagonistic activity were Gram-positives compared to only 25% that were Gram-negative bacteria. PMID:21686169

  15. Bazedoxifene-scaffold-based mimetics of solomonsterols A and B as novel pregnane X receptor antagonists.

    PubMed

    Hodnik, Žiga; Peterlin Mašič, Lucija; Tomašić, Tihomir; Smodiš, Domen; D'Amore, Claudio; Fiorucci, Stefano; Kikelj, Danijel

    2014-06-12

    Pregnane X receptor (PXR), a member of the NR1I nuclear receptor family, acts as a xenobiotic sensor and a paramount transcriptional regulator of drug-metabolizing enzymes and transporters. The overexpression of PXR in various cancer cells indicates the importance of PXR as a drug target for countering multidrug resistance in anticancer treatments. We describe the discovery of novel bazedoxifene-scaffold-based PXR antagonists inspired by the marine sulfated steroids solomonsterol A and B as natural leads. A luciferase reporter assay on a PXR-transfected HepG2 cell line identified compounds 19-24 as promising PXR antagonists. Further structure-activity relationship studies of the most active PXR antagonist from the series (compound 20, IC50 = 11 μM) revealed the importance of hydroxyl groups as hydrogen-bond donors for PXR antagonistic activity. PXR antagonists 20 and 24 (IC50 = 14 μM), in addition to the downregulation of PXR expression, exhibited inhibition of PXR-induced CYP3A4 expression, which illustrates their potential to suppress PXR-regulated phase-I drug metabolism. PMID:24828006

  16. Temperature and Pomaceous Flower Age Related to Colonization by Erwinia amylovora and Antagonists.

    PubMed

    Pusey, P L; Curry, E A

    2004-08-01

    ABSTRACT Fire blight of apple and pear is initiated by epiphytic populations of Erwinia amylovora on flower stigmas. Predicting this disease and managing it with microbial antagonists depends on an understanding of bacterial colonization on stigmas. Detached 'Manchurian' crab apple flowers were inoculated with E. amylovora and subjected to a range of constant temperatures or various fluctuating temperature regimes. Results may have application to disease risk assessment systems such as the Cougarblight model, which now are based on in vitro growth of the pathogen. In other experiments, detached crab apple flowers and attached 'Gala' apple flowers were maintained at different temperatures for various periods before inoculation with E. amylovora or antagonists (Pseudomonas fluorescens strain A506 and Pantoea agglomerans strains C9-1 and E325). Maximum stigma age supporting bacterial multiplication decreased as temperature increased, and was reduced by pollination. Stigmas were receptive to bacteria at ages older than previously reported, probably due to less interference from indigenous organisms. The study revealed antagonist limitations that possibly affect field performance (e.g., the inability of strain A506 to grow on relatively old stigmas conducive to the pathogen). Such deficiencies could be overcome by selecting other antagonists or using antagonist mixtures in the orchard. PMID:18943112

  17. Sphingosine-1-Phosphate Receptor-2 Antagonists: Therapeutic Potential and Potential Risks

    PubMed Central

    Blankenbach, Kira V.; Schwalm, Stephanie; Pfeilschifter, Josef; Meyer zu Heringdorf, Dagmar

    2016-01-01

    The sphingosine-1-phosphate (S1P) signaling system with its specific G-protein-coupled S1P receptors, the enzymes of S1P metabolism and the S1P transporters, offers a multitude of promising targets for drug development. Until today, drug development in this area has nearly exclusively focused on (functional) antagonists at the S1P1 receptor, which cause a unique phenotype of immunomodulation. Accordingly, the first-in class S1P1 receptor modulator, fingolimod, has been approved for the treatment of relapsing-remitting multiple sclerosis, and novel S1P1 receptor (functional) antagonists are being developed for autoimmune and inflammatory diseases such as psoriasis, inflammatory bowel disease, lupus erythematodes, or polymyositis. Besides the S1P1 receptor, also S1P2 and S1P3 are widely expressed and regulate many diverse functions throughout the body. The S1P2 receptor, in particular, often exerts cellular functions which are opposed to the functions of the S1P1 receptor. As a consequence, antagonists at the S1P2 receptor have the potential to be useful in a contrasting context and different areas of indication compared to S1P1 antagonists. The present review will focus on the therapeutic potential of S1P2 receptor antagonists and discuss their opportunities as well as their potential risks. Open questions and areas which require further investigations will be emphasized in particular. PMID:27445808

  18. Opposite effects of GABAA and NMDA receptor antagonists on ethanol-induced behavioral sleep in rats.

    PubMed

    Beleslin, D B; Djokanović, N; Jovanović Mićić, D; Samardzić, R

    1997-01-01

    The effects of the GABAA receptor antagonists, pentylenetetrazol, bicuculline, and picrotoxin, the glycine antagonist, strychnine, and the NMDA receptor antagonist, memantine, on ethanol-induced behavioral sleep and body temperature were investigated. Pentylenetetrazol, bicuculline, and picrotoxin given prior and following ethanol reduced the behavioral sleep and potentiated the hypothermia caused by ethanol. However, convulsions appeared when bicuculline, but not pentylenetetrazol and picrotoxin, were given following ethanol. After the reversal of unconsciousness in rats without convulsions the animals remained awake throughout the experiments without motor incoordination, hyperexcitability, and sedation, but they were in hypothermia within 12 h. The glycine antagonist, strychnine, given prior or after ethanol had virtually no effect on ethanol-induced behavioral sleep and hypothermia. Ethanol given prior or following strychnine failed to antagonize strychnine-induced convulsions. The NMDA receptor antagonist, memantine, given following ethanol potentiated the behavioral sleep and had virtually no effect on hypothermia induced by ethanol. It is suggested that the ethanol-induced behavioral sleep may be attributed to its ability to enhance the GABAergic mechanisms and to inhibit NMDA-mediated excitatory responses. However, the ethanol-induced hypothermia may be ascribed solely to the facilitation of GABAergic transmission. Further, it is postulated that a bidirectional inhibitory system subserves the regulation of behavioral sleep and convulsions. However, one-way inhibitory system underlies the ethanol-induced hypothermia. PMID:9085718

  19. Abscisic Acid Analogues That Act as Universal or Selective Antagonists of Phytohormone Receptors.

    PubMed

    Rajagopalan, Nandhakishore; Nelson, Ken M; Douglas, Amy F; Jheengut, Vishal; Alarcon, Idralyn Q; McKenna, Sean A; Surpin, Marci; Loewen, Michele C; Abrams, Suzanne R

    2016-09-13

    The plant hormone abscisic acid (ABA) plays many important roles in controlling plant development and physiology, from flowering to senescence. ABA is now known to exert its effects through a family of soluble ABA receptors, which in Arabidopsis thaliana has 13 members divided into three clades. Homologues of these receptors are present in other plants, also in relatively large numbers. Investigation of the roles of each homologue in mediating the diverse physiological roles of ABA is hampered by this genetic redundancy. We report herein the in vitro screening of a targeted ABA-like analogue library and identification of novel antagonist hits, including the analogue PBI686 that had been developed previously as a probe for identifying ABA-binding proteins. Further in vitro characterization of PBI686 and development of second-generation leads yielded both receptor-selective and universal antagonist hits. In planta assays in different species have demonstrated that these antagonist leads can overcome various ABA-induced physiological changes. While the general antagonists open up a hitherto unexplored avenue for controlling plant growth through inhibition of ABA-regulated physiological processes, the receptor-selective antagonist can be developed into chemical probes to explore the physiological roles of individual receptors. PMID:27523384